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Fluorine in Organic

Chemistry

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page i

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

Fluorine in OrganicChemistry

Richard D. Chambers FRSEmeritus Professor of Chemistry

University of Durham, UK

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page iii

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Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page iv

Tomy wife Anne and our grandchildren,

Daniel, Benjamin, Alexandra, and Jack,who give us so much pleasure

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page v

Contents

Foreword xv

by Professor George A. Olah

Preface xvii

1 GENERAL DISCUSSION OF ORGANIC FLUORINE CHEMISTRY 1

I General introduction 1

A Properties 1

B Historical development 2

II Industrial applications 3

A Introduction 3

B Compounds and materials of high thermal and chemical stability 3

1 Inert fluids 4

2 Polymers 5

C Biological applications 5

1 Volatile anaesthetics 6

2 Pharmaceuticals 7

3 Imaging techniques 7

4 Plant protection agents 9

D Biotransformations of fluorinated compounds 9

E Applications of unique properties 12

1 Surfactants 12

2 Textile treatments 12

3 Dyes 12

III Electronic effects in fluorocarbon systems 13

A Saturated systems 14

B Unsaturated systems 14

C Positively charged species 15

D Negatively charged species 15

E Free radicals 16

IV Nomenclature 16

A Systems of nomenclature 17

B Haloalkanes 18

References 19

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vii

2 PREPARATION OF HIGHLY FLUORINATED COMPOUNDS 23

I Introduction 23

A Source of fluorine 23

II Fluorination with metal fluorides 23

A Swarts reaction and related processes (halogen exchange using HF) 24

1 Haloalkanes 25

2 Influence of substituent groups 26

B Alkali metal fluorides 27

1 Source of fluoride ion 28

2 Displacements at saturated carbon 29

3 Displacements involving unsaturated carbon 30

Alkene derivatives 30

Aromatic compounds 31

C High-valency metal fluorides 31

1 Cobalt trifluoride and metal tetrafluorocobaltates 32

III Electrochemical fluorination (ECF) 33

IV Fluorination with elemental fluorine 35

A Fluorine generation 35

B Reactions 35

C Control of fluorination 36

1 Dilution with inert gases 36

D Fluorinated carbon 39

E Fluorination of compounds containing functional groups 39

V Halogen fluorides 40

References 41

3 PARTIAL OR SELECTIVE FLUORINATION 47

I Introduction 47

II Displacement of halogen by fluoride ion 47

A Silver fluoride 47

B Alkali metal fluorides 47

C Other sources of fluoride ion 49

D Miscellaneous reagents 50

III Replacement of hydrogen by fluorine 51

A Elemental fluorine 51

1 Elemental fluorine as an electrophile 52

B Electrophilic fluorinating agents containing O–F bonds 56

C Electrophilic fluorinating agents containing N–F bonds 58

D Xenon difluoride 60

E Miscellaneous 60

IV Fluorination of oxygen-containing functional groups 62

A Replacement of hydroxyl groups by fluorine 62

1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent 62

2 Diethylaminosulphur trifluoride (DAST) and related reagents 63

3 Fluoroalkylamine reagents (FARs) 65

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viii Contents

B Replacement of ester and related groups by fluorine 66

C Fluorination of carbonyl and related compounds 66

1 Sulphur tetrafluoride and derivatives 66

D Cleavage of ethers and epoxides 69

V Fluorination of sulphur-containing functional groups 71

VI Fluorination of nitrogen-containing functional groups 73

A Fluorodediazotisation 73

B Ring opening of azirines and aziridines 74

C Miscellaneous 75

VII Addition to alkenes and alkynes 76

A Addition of hydrogen fluoride 76

B Direct addition of fluorine 77

C Indirect addition of fluorine 79

D Halofluorination 80

E Addition of fluorine and oxygen groups 82

F Other additions 82

References 83

4 THE INFLUENCE OF FLUORINE OR FLUOROCARBON

GROUPS ON SOME REACTION CENTRES 91

I Introduction 91

II Steric effects 91

III Electronic effects of polyfluoroalkyl groups 92

A Saturated systems 92

1 Strengths of Acids 92

2 Bases 93

B Unsaturated systems 94

1 Apparent resonance effects 94

2 Inductive and field effects 97

IV The perfluoroalkyl effect 97

V Strengths of unsaturated fluoro-acids and -bases 98

VI Fluorocarbocations 99

A Effect of fluorine as a substituent in the ring on electrophilic

aromatic substitution 99

B Electrophilic additions to fluoroalkenes 101

C Relatively stable fluorinated carbocations 102

1 Fluoromethyl cations 104

D Effect of fluorine atoms not directly conjugated with the

carbocation centre 105

VII Fluorocarbanions 107

A Fluorine atoms attached to the carbanion centre 108

B Fluorine atoms and fluoroalkyl substituents adjacent to the

carbanion centre 111

C Stable perfluorinated carbanions 112

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Contents ix

D Acidities of fluorobenzenes and derivatives 113

E Acidities of fluoroalkenes 115

VIII Fluoro radicals 115

A Fluorine atoms and fluoroalkyl groups attached to the

radical centre 115

B Stable perfluorinated radicals 117

C Polarity of radicals 117

References 118

5 NUCLEOPHILIC DISPLACEMENT OF HALOGEN FROM

FLUOROCARBON SYSTEMS 122

I Substituent effects of fluorine or fluorocarbon groups

on the SN2 process 122

A Electrophilic perfluoroalkylation 126

II Fluoride ion as a leaving group 128

A Displacement of fluorine from saturated carbon – SN2 processes 128

1 Acid catalysis 129

2 Influence of heteroatoms on fluorine displacement 131

B Displacement of fluorine and halogen from unsaturated carbon –

addition–elimination mechanism 131

1 Substitution in fluoroalkenes 132

2 Substitution in aromatic compounds 133

References 135

6 ELIMINATION REACTIONS 137

I b-Elimination of hydrogen halides 137

A Effect of the leaving halogen 137

B Substituent effects 138

C Regiochemistry 139

D Conformational effects 140

E Elimination from polyfluorinated cyclic systems 142

II b-Elimination of metal fluorides 144

III a-Eliminations: generation and reactivity of fluorocarbenes and

polyfluoroalkylcarbenes 147

A Fluorocarbenes 147

1 From haloforms 147

2 From halo-ketones and –acids 149

3 From organometallic compounds 149

4 From organophosphorous compounds 151

5 Pyrolysis and fragmentation reactions 151

B Polyfluoroalkylcarbenes 154

C Structure and reactivity of fluorocarbenes and

polyfluoroalkylcarbenes 156

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x Contents

1 Fluorocarbenes 156

2 Polyfluoroalkylcarbenes 158

References 159

7 POLYFLUOROALKANES, POLYFLUOROALKENES,

POLYFLUOROALKYNES AND DERIVATIVES 162

I Perfluoroalkanes and perfluorocycloalkanes 162

A Structure and bonding 162

1 Carbon–fluorine bonds 162

2 Carbon–carbon bonds 162

B Physical properties 163

C Reactions 163

1 Hydrolysis 163

2 Defluorination and functionalisation 164

3 Fragmentation 166

D Fluorous biphase techniques 166

II Perfluoroalkenes 167

A Stability, structure and bonding 167

B Synthesis 169

C Nucleophilic attack 171

1 Orientation of addition and relative reactivities 172

2 Reactivity and regiochemistry of nucleophilic attack 172

3 Products formed 176

4 Substitution with rearrangement – SN20 processes 176

5 Cycloalkenes 183

6 Fluoride-ion-induced reactions 185

7 Addition reactions 186

8 Fluoride-ion-catalysed rearrangements of fluoroalkenes 187

9 Fluoride-ion-induced oligomerisation reactions 188

10 Perfluorocycloalkenes 190

D Electrophilic attack 191

E Free-radical additions 196

1 Orientation of addition and rates of reaction 197

2 Telomerisation 202

3 Polymerisation 203

F Cycloadditions 205

1 Formation of four-membered rings 205

2 Formation of six-membered rings – Diels–Alder reactions 209

3 Formation of five-membered rings – 1,3-dipolar cycloaddition

reactions 212

4 Cycloadditions involving heteroatoms 214

G Polyfluorinated conjugated dienes 214

1 Synthesis 214

2 Reactions 216

3 Perfluoroallenes 218

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Contents xi

III Fluoroalkynes and (fluoroalkyl)alkynes 218

A Introduction and synthesis 218

B Reactions 222

1 Perfluoro-2-butyne 222

Formation of polymers and oligomers 222

Reactions with nucleophiles 223

Fluoride-ion-induced reactions 223

Cycloadditions 224

Free-radical additions 226

References 227

8 FUNCTIONAL COMPOUNDS CONTAINING OXYGEN,

SULPHUR OR NITROGEN AND THEIR DERIVATIVES 236

I Oxygen derivatives 236

A Carboxylic acids 236

1 Synthesis 236

2 Properties and derivatives 238

3 Trifluoroacetic acid 240

4 Perfluoroacetic anhydride 241

5 Peroxytrifluoroacetic acid 242

B Aldehydes and ketones 243

1 Synthesis 243

2 Reactions 243

Addition to C5O 246

Reactions with fluoride ion 251

C Perfluoro-alcohols 254

1 Monohydric alcohols 254

2 Dihydric alcohols 255

3 Alkoxides 257

D Fluoroxy compounds 258

E Perfluoro-oxiranes (epoxides) 259

F Peroxides 264

II Sulphur derivatives 265

A Perfluoroalkanesulphonic acids 265

B Sulphides and polysulphides 270

C Sulphur(IV) and sulphur(VI) derivatives 272

D Thiocarbonyl compounds 272

III Nitrogen derivatives 275

A Amines 275

B N–O compounds 277

1 Nitrosoalkanes 277

2 Bistrifluoromethyl nitroxide 278

C Aza-alkenes 278

D Azo compounds 284

E Diazo compounds and diazirines 284

References 287

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xii Contents

9 POLYFLUOROAROMATIC COMPOUNDS 296

I Synthesis 296

A General considerations 296

B Saturation/re-aromatisation 297

C Substitution processes 298

1 Replacement of H by F 298

2 Replacement of 2Nþ2 by F: the Balz–Schiemann reaction 300

3 Replacement of 2OH or 2SH by F 300

4 Replacement of Cl by F 300

II Properties and reactions 306

A General 306

B Nucleophilic aromatic substitution 307

1 Benzenoid compounds 307

Orientation and reactivity 310

Mechanism 311

2 Heterocyclic compounds 315

Pyridines and related nitrogen heterocyclic(azabenzenoid) compounds 315

Polysubstitution 320

Acid-induced processes 321

3 Fluoride-ion-induced reactions 325

Polyfluoroalkylation 325

Other systems 332

4 Cyclisation reactions 332

C Reactions with electrophilic reagents 336

D Free-radical attack 338

1 Carbene and nitrene additions 338

E Reactive intermediates 341

1 Organometallics 341

Lithium and magnesium derivatives 342

Copper compounds 346

2 Arynes 346

3 Free radicals 349

4 Valence isomers 351

Nitrogen derivatives 353

References 358

10 ORGANOMETALLIC COMPOUNDS 365

I General methods and synthesis 365

A From iodides, bromides and hydro compounds 365

1 Perfluoroalkyl derivatives 365

2 Derivatives of unsaturated systems 366

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Contents xiii

B From unsaturated fluorocarbons 367

1 Fluoride-ion-initiated reactions 367

II Lithium and magnesium 368

A From saturated compounds 368

B From alkenes 369

C From trifluoropropyne 370

D From polyfluoro-aromatic compounds 371

III Zinc and mercury 371

A Zinc 371

B Mercury 373


2 Unsaturated derivatives 374

3 Cleavage by electrophiles 375

IV Boron and aluminium 376

A Boron 376


2 Unsaturated derivatives 377

B Aluminium 380

V Silicon and tin 381

A Silicon 381

B Tin 385

VI Transition metals 387

A Copper 388

B Other metals 388

References 395

Index 399

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xiv

xiv Contents

Foreword

by Professor George A. OlahNobel Laureate

Chambers’ book Fluorine in Organic Chemistry was published 30 years ago and became a

classic of the field. A revised and updated edition is a significant and authoritative

contribution by one of the leaders of organic fluorine chemistry. Organic fluorine

chemistry has grown enormously in significance and scope in the intervening three

decades, not in small measure by the contribution of the author and his colleagues.

The new edition will be of great value and help not only to those interested in fluorine

chemistry, but also to the wider chemical community. When considering a new edition of

a ‘classic’ of chemical literature, it is most appropriate to maintain broadly the layout

and aims of the original book, concentrating on methodology, mechanism and the unique

chemistry of highly fluorinated compounds. Understandably, therefore, it is outside

the scope to discuss medicinal and biochemical aspects. Readers interested in these topics

are advised to use the extensive reviews that are available elsewhere.

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:06pm page xv

xv

Preface

This book is a revision and update of one that was first published in 1973, followed by

two small reprintings. The original was prompted by Professor George Olah, during a year

that I spent as a Visiting Lecturer in Cleveland. My aim for the original edition was to

present an overview of organofluorine chemistry, in a way that corresponded with modern

organic chemistry. Of course this involved including a mechanistic basis of the subject,

which was still evolving at the time; to my knowledge, this was the first broad attempt to

do so. The original book appears to have served a useful purpose because, for a number of

years now, friends in the field have encouraged me to write an update.

In the intervening years since the first edition the subject has grown enormously, and

any idea of a single-author comprehensive volume would now be a preposterous under-

taking. Consequently, I have concentrated attention on illustrating the principles of the

subject, and especially those concerning highly fluorinated compounds, where the chem-

istry is quite unusual. Inevitably, important areas are omitted: for example the impact of

fluorine as a label in biochemistry, which is outside my expertise. However, I hope that

there are enough key references to important areas that I have neglected.

Inevitably, my choice of illustrative examples is subjective and I apologise in advance

for all the beautiful examples that have not been included.

The considerable task of producing the manuscript would not have been completed

without the continued help of a long-term friend and collaborator, Dr. John Hutchinson, to

whom I am deeply indebted. Also, my sincere thanks to the Leverhulme Trust for an

Emeritus Fellowship, during the tenure of which the book was written. Thanks also to my

colleague, Dr Graham Sandford, for invaluable help and discussions, and to Dr Darren

Holling, Rachel Slater and Chris Hargreaves for reading the manuscript. Last, but not

least, thanks to my wife Anne for her continued forbearance.

Dick Chambers

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:06pm page xvii

xvii

Chapter 1

General Discussion of OrganicFluorine Chemistry

I GENERAL INTRODUCTION

One of the major activities of chemists in industry and academia is the search for ‘special-

effect’ chemicals, i.e. systems with new chemistry and with novel properties that can be

exploited by industry. There are, of course, many ways of creating novel systems but the

introduction of carbon–fluorine bonds into organic compounds has led to spectacular

industrial developments, together with an exciting field of organic chemistry and bio-

chemistry.

Fluorine is unique in that it is possible to replace hydrogen by fluorine in organic

compounds without gross distortion of the geometry of the system but, surprisingly,

compounds containing carbon–fluorine bonds are rare in nature [1, 2]. In principle,

therefore, we could introduce carbon–fluorine bonds singly, or multiply, so that there is

the potential for a vast extension to organic chemistry, providing that the appropriate

methodology can be developed. Consequently, the study of systems containing carbon–

fluorine bonds has become a very important area of research and the subject already

constitutes a major branch of organic chemistry, while imposing a strenuous test on our

fundamental theories and mechanisms. Moreover, as we shall see later in this chapter, the

applications of fluorine-containing organic compounds span virtually the whole range of

the chemical and life-science industries and it is quite clear that wherever organic

chemistry, biochemistry and chemical industry progress, fluorine-containing compounds

will have an important role to play.

Surprisingly, this situation is still not reflected in current general textbooks; the

reasons can be traced partly to the very rapid growth of the subject, as well as the

difficulty that all workers experience in reaching a wider audience. Therefore, it is

hoped that this book will help by presenting an outline of fluorine chemistry on a broadly

mechanistic basis. This volume stems from an earlier book [3] on the subject; its aim

remains to provide an overview through highlighting a variety of topics but with no

attempt to provide comprehensive coverage of the literature. Where appropriate, books

and reviews will be cited and the author therefore acknowledges the many sources,

referred to either here or in the following text, to which this book is intended to be

complementary [4–39].

A Properties

Fluorocarbon systems, in general, present no peculiar handling difficulties and the

familiar and powerful techniques of isolation, purification and identification in organic

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 1

1Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

chemistry are applicable in every way. In fact, fluorocarbons themselves are characterised

by high thermal stability and, indeed, elemental fluorine is so very reactive because it

forms such strong bonds with other elements, including carbon. Volatilities of hydrocar-

bons and corresponding fluorocarbons are surprisingly similar, despite the increased

molecular weight of the latter, and indicate a general feature that intermolecular bonding

forces are reduced in the perfluorocarbon systems. A final, and by no means least

important, similarity between hydrocarbon and fluorocarbon chemistry is that, like

hydrogen-1, fluorine-19 has a nuclear spin quantum number of 1/2 and so nuclear

magnetic resonance spectroscopy plays a powerful role in characterisation [40]. Indeed,

the only tool that is not easily available for fluorine is the observation of fluorine isotope

effects, because the longest-lived isotope is F-18, with a half-life of only 109 minutes [41]

although, even with this limitation, applications as a mechanistic probe have been

reported [42].

B Historical development

It could be argued that fluorocarbon chemistry began with Moissan in 1890 when he

claimed to have isolated tetrafluoromethane from the reaction of fluorine with carbon,

but these results were in error [43, 44]. Swarts, a Belgian chemist, began his studies on the

preparation of fluorocarbon compounds [45] by exchange reactions around 1890 and

for about 25 years from 1900 he was virtually the only worker publishing in the field.

He continued until about 1938, and during that time he contributed a great deal in

outlining methods of preparation for a large number of partly fluorinated compounds. It

was on the foundation of Swarts’s work that Midgley and Henne [46] in 1930 were able

to apply fluoromethanes and ethanes as refrigerants, and this development gave the

subject some financial impetus for progress. Tetrafluoromethane was the first perfluor-

ocarbon to be isolated pure; it was reported in 1926 by Lebeau and Damiens [47] but

not properly characterised by them until 1930 [48] and, in the same year, by Ruff and

Keim [49]. Swarts made trifluoroacetic acid [50] as early as 1922 and in 1931 reported

that the electrolysis of an aqueous solution of the latter gave pure perfluoroethane [51].

Nevertheless, the first liquid perfluorocarbons were not characterised until 1937, when

Simons and Block found that mercury promotes reaction between carbon and fluorine

[52]; they were able to isolate CF4, C2F6, C3F8, C4F10 (two isomers), cyclo-C6F12 and

C6F14.

It was established that these compounds are very thermally and chemically stable and

this led to suggestions by Simons that these materials might be resistant to UF6, which

was found to be the case. There then ensued a period of very rapid development in the

synthesis of fluorocarbon materials, the goal being stable lubricants and gaskets for use in

the gaseous diffusion plant for concentrating the 235U isotope, using UF6. These wartime

developments have been published in various collected forms [53–55]. Tetrafluoroethene

was obtained by Ruff and Bretschneider in 1933, who decomposed tetrafluoromethane in

an electric arc [56] while Locke et al. [57] developed a synthesis in 1934, which involved

zinc dehalogenation of CF2Cl2CF2Cl. Then the formation of polytetrafluoroethene [58]

was discovered in 1938 and in the same period chlorotrifluoroethene was found to

polymerise to give a very stable inert transparent polymer. The wartime efforts involved

development of these and other new materials. Nevertheless, even at the end of the


2 Chapter 1

wartime work the subject was not well developed as an area of organic chemistry.

However, its potential was recognised by a number of workers and, since then, progress

has been extremely rapid. In the 1950s much progress was made on the chemistry

of functional derivatives and a whole new fluorocarbon organometallic chemistry began

to emerge. A major and greatly under-appreciated development of the period was the

introduction of fluorinated anaesthetics which, being non-flammable, revolutionised

anaesthesia. Also during this period was the development of fluorinated elastomers

which, together with other fluorinated materials, were critical in the development

of supersonic and space flight. It is clear, therefore, that this infant subject made

crucial contributions to some of the most exciting scientific developments of the 20th

century.

The period from 1960 onwards saw perfluoroaromatic chemistry rapidly unfold,

selective methods for fluorination develop, and fluorinated compounds play an increas-

ingly important role in the pharmaceutical and plant-protection industries. Indeed, there

have been so many interesting developments in the subject since the original edition

[3] that it will be impossible to do justice to this era in one small volume. Remarkably,

it has been reported that organofluorine compounds constitute 6–7% of all new com-

pounds recorded in Chemical Abstracts up to 1990 and 7–8% of all chemical patents up to

1997 contain fluorinated compounds. This in itself is an outstanding output for the

relatively limited number of workers in the field worldwide and is a tribute to their

dedication [59].

II INDUSTRIAL APPLICATIONS

A Introduction

Even in 1992, it was estimated that business involving the sale of compounds containing

carbon–fluorine bonds was worth around US$50 billion per annum [60] and it has

certainly increased since then. In this chapter, only a short survey of the major industrial

applications of fluorinated molecules is possible and the reader is directed to a number of

books and reviews [17, 20, 29, 61–65] for further details.

B Compounds and materials of high thermal and chemicalstability [29]

The greater strength of the carbon–fluorine over the carbon–hydrogen bond leads to

considerably enhanced thermal stability for perfluorocarbon systems over their hydrocar-

bon analogues, and stability towards oxidation is dramatic. Moreover, the large number of

non-bonding p-electrons, which virtually shield the carbon backbone from attack in a

perfluorocarbon, must contribute significantly to these properties and, at the same time,

produce novel surface effects. Furthermore, perfluorinated systems are quite inert to

microbiological attack and so, combining these observations, it is reasonable to conclude

that perfluorocarbon surfaces provide the ultimate in organic materials for protection

against chemical and atmospheric corrosion. A further unique property of perfluorocar-

bons is that they are both water- and hydrocarbon-repellent and the implications for fabric

treatment are obvious.


General Discussion of Organic Fluorine Chemistry 3

1 Inert fluids

The chlorofluorocarbons (CFCs) were introduced over 60 years ago as refrigerants [46] to

replace gases such as ammonia and sulphur dioxide. In 1974, at the peak of production,

900 000 tonnes of CFCs, principally CF2Cl2 (CFC-12), CFCl3 (CFC-11) and CHFCl2(CFC-22), were manufactured mainly for use as refrigerants, aerosols and foam blowing

agents. However, it was eventually recognised that the inertness of volatile CFCs is itself

a problem because they survive unchanged up to the stratosphere, where they dissociate

under short-wavelength solar ultraviolet radiation, releasing chlorine atoms which then

catalyse the decomposition of ozone to oxygen [66, 67]. Consequently, the Montreal

Protocol, which was introduced in 1987 and revised in 1990 and 1992, caused the

complete phase-out of production and use of the CFC range of compounds. This legisla-

tion forced refrigerant manufacturers to identify alternative ranges of non-toxic, stable

chemicals which, additionally, possess low ozone depletion potentials (ODPs) and low

global warming potentials (GWPs) to meet customer needs and regulatory requirements.

Hydrofluorocarbons (HFCs), being free of chorine atoms, have ODPs of zero, making

these products ideal systems for replacing CFCs. One of the major unsung achievements

of the chemical industry has been the rapid development to large-scale production of these

substitutes for CFCs; for example, CF3CFH2 (HFC-134a) is an acceptable substitute for

CF2Cl2 (CFC-12) in refrigeration applications.

Bromofluorocarbons possess outstanding fire-extinguishing ability: CF3Br has been

used for automatic systems where the use of water is as potentially damaging as a fire, for

instance in art galleries and in libraries, or in aircraft where highly efficient non-toxic

agents are required. However, on an atom-to-atom basis bromine atoms are estimated to

be 40 times more effective at destroying ozone than chlorine atoms, and therefore the

Montreal Protocol required the complete phase-out of bromofluorocarbon use in 1994.

Alternative ‘in-kind’ replacements [68] of these halon fire extinguishers are being de-

veloped and currently CHF3 (DuPont) and CF3CFHCF3 (Great Lakes), amongst others,

are on the market [69], but at the time of writing the problem of finding replacements for

bromofluorocarbons for application as fire-fighting agents in aircraft is largely unsolved.

Perfluorocarbon fluids, such as the Flutect range (F2 Chemicals Ltd), find many uses

in the electronics industry. For instance, the complete immersion of electronic compon-

ents in a bath of perfluorocarbon fluid can efficiently cool overheated circuits and, by a

similar process, the airtight packaging around highly valuable and sensitive equipment

can be tested in complete safety for leaks.

Since perfluorocarbons are inert to microbiological attack, many potential medical uses

of these fluids have been investigated. The report by Clark in 1966 that perfluorocarbons

can dissolve significant amounts of oxygen [70] prompted the exciting suggestion that such

fluids could be used as ‘artificial blood’ [71] and the now-classic photograph of a rat

breathing under liquid perfluorocarbon has been reproduced countless times. Perfluorocar-

bons are immiscible with blood and do not dissolve the essential mineral nutrients required.

Consequently, emulsions of perfluorocarbons with an aqueous buffer solution containing

various surfactants have been formulated as potential blood substitutes. Although products

have been approved and marketed, there is no commercially successful emulsion.

The need to extend the liquid range of perfluorinated systems to very high molecular

weights was satisfied by the important introduction of perfluoropolyethers (PFPEs) [72]


4 Chapter 1

as high-boiling inert fluids, such as Krytoxt (DuPont), Fomblint (Ausimont) and

Demnumt (Daikin), for use in demanding environments and for long-term reliability

(Figure 1.1). These fluids have the longest liquid range known [73], remaining in fluid

form from �1008C to 3508C and, consequently, are used for the lubrication of many

diverse precision instruments, from the mechanisms of luxury watches to the moving

parts of geostationary satellites and even for computer discs.

2 Polymers [73a]

Since the first synthesis of polychlorotrifluoroethene and the discovery of polytetrafluor-

oethene (PTFE) in the late 1930s, the global production of fluoropolymers has grown to

over 60 000 tonnes per annum. Fluoropolymers possess a unique combination of proper-

ties [74–76] which ensure a wide range and continually growing number of applications

for these materials. The fabled ‘non-stick’ properties of PTFE may be attributed to the

abundance of non-bonding electron pairs and the coefficient of friction has been related to

that of wet ice on wet ice. Some examples of commercial fluoropolymers are listed in

Table 1.1 along with just some of the many applications.

The remarkable feature of this area is that materials such as Vitont (DuPont) and

related elastomers, which were once regarded as esoteric and appropriate in cost only for

‘space flight’ and related applications, have now entered widely into the automobile

industry. Lumiflont (Asahi Glass Co., Japan), a high-performance paint which is fam-

ously used on the Hikari ‘bullet trains’ in Japan, and various coatings for protection of

concrete and stone building materials have also emerged. The gradual public realisation

that the higher cost of high-performance products makes longer-term economic sense is

the driving force behind the continued growth of this industry. Perfluorinated ionomer

membranes [77], such as Nafiont (DuPont) and Flemiont (Daikin), are increasingly

being used as cell-dividing membranes for chlor-alkali cells, replacing the mercury

cells that have, understandably, led to so much public concern.

C Biological applications [29, 61, 62]

The physiological properties of many biologically significant molecules can be modu-

lated if fluorine or fluorinated groups are incorporated into their structure [24, 78]; factors

affecting the change in biological activity of a substrate upon fluorination are complex

[79].

F

F

O

F

CF3

OCF2CF2CF2 OCF2 OCF2CF2

n

Lubricants, coatings

Fomblin® (Ausimont)Krytox® (DuPont)

n m

Demnum® (Daikin)

Lubricants, vacuum pump oils

n

Figure 1.1



1 Volatile anaesthetics

Prior to 1956, the most common anaesthetics included diethyl ether and chloroethane,

with the associated risks. Fluothanet (ICI) was the first widely used fluorine-containing

volatile anaesthetic [80], and such was its success that it has been estimated that 70–80%

of all anaesthesias carried out in 1980 were performed using this substance. However,

Isofluranet, Sevofluranet and Desfluranet are now commercially available alternatives

in the general quest for less readily metabolised systems and faster recovery times of the

patients (Figure 1.2).

Table 1.1 Applications of fluoropolymers

Polymer Monomer(s) Applications

PTFE CF2=CF2 Cookware coatings; Goretext

(W.R. Gore Co.) waterproof

clothing; electrical insulators;

medical uses such as artificial

blood vessels.

FEP CF2=CF2 + CF3CF=CF2 Fabrication by conventional melt

processing; wire and cable

insulators; heat-sealable film,

tubing.

PFA CF2=CF2 + RFOCF=CF2 Injection-moulded parts for use in

aggressive environments.

Teflon AFt (DuPont)O O

F F

CF3 CF3

CF2=CF2+Optically clear, used in corrosive

environments where glass is

unsuitable, e.g. in computer chip

manufacture.

Cytopt (Asahi) CF2=CFO(CF2)nCF=CF2 Optically clear, used in corrosive

environments, e.g. computer

chip manufacture.

PCTFE CF2=CFCl Gaskets, seals, oils, coatings,

transparent inert covers.

PVDF CF2=CH2 Weather-resistant coatings; cable

insulation; piezo-electric devices.

PVF CH2=CHF

CF2=CH2 + CF3CF=CF2

Coatings, flexible films.

VitonAt (DuPont) Elastomers used for sealants, O-

rings, fuel-resistant seals for

aircraft and automobiles.

Nafiont (DuPont)CF2�CF2 + F2C�C

(OCF2CF)nO

F

CF2CF2X

CF3

�

2

Membranes in chlor-alkali cells.

Flemiont (Daikin)

Nafion, X ¼ CO2H

Flemion, X ¼ SO2H

(CF3)2CHOCH2F CF3CHFOCHF2

Sevoflurane® Desflurane®

CF3CHClBr CF3CHClOCHF2

Fluothane® Isoflurane®

Figure 1.2


6 Chapter 1

2 Pharmaceuticals

Fluorinated corticosteroids were the first successful commercial products where useful

modification of biological activity was achieved by introduction of a carbon–fluorine

bond. Subsequently, the interest of the pharmaceutical industry in this approach has

grown substantially and many new fluorine-containing products are available or are in

advanced screening stages.

Simplistically, an orally administered drug must: (a) be absorbed through the gut into

the bloodstream, (b) then pass through a series of phospholipid membranes (transport)

before reaching the correct site of action, and (c) bind and produce the desired effect at

the appropriate enzyme site. Following this stage, the drug should be metabolised neither

too quickly, nor into toxic by-products. The incorporation of fluorine into a biologically

active molecule may modulate all of these functions as well as the more obvious effects

of enhancing the acidity or reducing the base strength of appropriate proximate functional

groups. Size is not the dominant factor, although steric requirements in biology are not so

easy to establish, and a range of factors arising from fluorine substitution are at work [81–

83] and will continue to be evaluated for some considerable time. Fluorine

or trifluoromethyl substituents generally enhance the lipophilicity of an aromatic sub-

strate and so increase the rate of transport of the drug to the active site. A contributing

factor could be, for example, the change in acidity of the drug upon fluorination,

thus enhancing the solubility. Whatever the relative importance of the contributing

factors, introduction of a fluorine atom at the C-6 site in the antibacterial fluoroquinolone

drugs, e.g. Ciproflaxint (Bayer), increases the rate of cell penetration by up to 70 times.

Fluorine substitution in drugs may affect binding in two ways [61]. First, it is often

possible to vary the dipole moment (e.g. using two fluorine substituents that are ortho,

meta or para in a phenyl group); secondly, it is possible that fluorine may be displaced

from the bound drug, leading to covalent binding, in a process referred to as ‘suicide

inhibition’. The anti-metabolite 5-fluorouracil (5-FU) is almost certainly effective in part

through this process. A further significant effect of introducing fluorine is the resulting

enhanced resistance to metabolic oxidation and therefore to potentially toxic by-products,

thus increasing both the effective lifetime and the safety of a drug.

Some examples of fluorinated pharmaceuticals currently on the healthcare market are

given in Figure 1.3. Both Ciprofloxacint (Bayer), a member of the 6-fluoroquinolone

antibacterial agent range, and the controversial ‘sunshine drug’ Prozact (Eli Lilley), the

leading member of a new family of selective serotonin re-uptake inhibitor (SSRI)

antidepressants, are in the world top 20 best-selling pharmaceuticals and achieve annual

sales in the region of US$1 billion each.

3 Imaging techniques

The isotope fluorine-18 has a half-life of 109 minutes and decays by positron emission;

therefore molecules containing this isotope can be monitored by positron emission

tomography (PET), which is a technique that is especially useful for non-invasive in

vivo study of metabolic processes [41]. For example, 2-fluorodeoxyglucose is transported

into cells in the same manner as glucose but, after rapid phosphorylation, further metab-

olism is inhibited because of the fluorine, thus effectively trapping the radiolabelled



molecule in a cell. Uptake of fluorine-18 gives a direct measure of the rate of glucose

metabolism in the part of the body under study. Similarly, 18F-DOPA acts as a tracer for

DOPA, which is a neurotransmitter in the brain, and the PET study of the complex

metabolism and biodistribution of DOPA is hoped to provide a quantitative measure of

the dopaminergic neurons in the brain [84] (Figure 1.4).

Non-invasive monitoring of therapeutic agents can also be performed by 19F magnetic

resonance imaging (MRI); the negligible natural fluorine background and the high

sensitivity of 19F NMR spectroscopy has made possible the study of the in vivo action

and metabolic pathways of fluorine-containing drugs. For instance, 19F MRI has demon-

strated that 5-fluorouracil is metabolised to NH2CH2CHFCOOH.

N

N

H

H

F

ON

NH CF3

HO

OH

N

OHN

N

F

F

N

CO2H

N

F

NH

O NCH3

H

5-Fluorouracil(anti-cancer)

Trifluridine®(anti-viral)

Fluconazole®(anti-fungal)

Ciprofloxacin®(antibacterial)

Prozac®(anti-depressant)

N

NN O

O

O

O

O

F3C

CH2OH

CH3

HO

F

OH

O

O

Betamethasone®(anti-inflammatory)

Figure 1.3 Examples of drugs containing fluorine


8 Chapter 1

Perfluorooctyl bromide is being used very successfully to enhance the contrast between

healthy and diseased tissue in 1H MRI procedures and as a general imaging agent for

X-ray and other forms of examination of soft tissue.

4 Plant protection agents [62]

Environmental concerns have imposed massive constraints on plant protection products,

and the impressive progress towards lower dose levels for effective control is another of

the unrecognised success stories of the chemical industry. Fluorinated molecules have

played an important role in these developments, leading to a range of successful herbi-

cides, insecticides and fungicides [85]. Trifluralin (Dow), a herbicide used principally for

the control of grassy weeds in a wide range of crops, has been in use for over 25 years and

peak sales in the mid 1980s reached US$400 million per annum. Fusiladet is another

widely successful herbicide used for the control of weeds in broad-leaf crops at low

dosage rates. The pyrethroid derivative Cyhalothrint is a successful insecticide and the

fungicide sector contains five significant products with fluorine incorporated in the

substrate. Flutriafolt is used for protecting cereal crops and Flutolanilt is used mainly

in the Far East for controlling crop diseases (Figure 1.5).

D Biotransformations of fluorinated compounds

As the occurrence of fluoride ion is so widespread, it is particularly surprising that

compounds containing carbon–fluorine bonds are rarely found in nature [1, 2]. Potassium

monofluoroacetate occurs in several tropical and sub-tropical plants located in the

southern hemisphere, such as Dichapetalum cymosum (South Africa, very toxic to

animals) and Oxylobium parviform (Australia). Some plants, such as soya bean (Glycine

max), are able to synthesise fluoroacetate when grown in fluoride-rich soil. A shrub

occurring in Sierra Leone, Dichapetalum toxicarium (ratsbane), is also poisonous, par-

ticularly the seeds, and this has been attributed to the occurrence of v-fluoro-oleic acid,

CH2FðCH2Þ7CH5CHðCH2Þ7COOH [86]. Nucleocidin, an adenine-containing antibiotic,

has been isolated from the fermentation broths of a micro-organism Streptomyces calvus [1].

The fact that only 12 compounds containing C–F bonds have been found in nature so

far [87] leads to the questions of (a) whether this is a consequence of the difficulty of

forming C–F bonds in the first place, and (b) whether subsequent enzymic transform-

ations in plants and animals are inhibited by the presence of C–F bonds. Fluorine, as

fluoride ion, although extremely abundant, is present in largely insoluble salts. Moreover,

fluoride ion is extensively hydrated because of the strength of hydrogen bonding, and in

O

FHO

HO

HO

OH

F

OH

HONH2

CO2H

18F-2-Fluorodeoxyglucose(PET Scanning Agent)

18F-6-Fluoro-DOPA(NMR Scanning Agent)

Figure 1.4



the hydrated state it is relatively unreactive as a nucleophile. It seems likely, therefore,

that the dearth of C–F bonds in nature is essentially due to a combination of these effects,

which inhibit C–F bond formation.

However, an exception to this situation is the formation of the toxin fluoroacetate,

which inhibits the Krebs cycle. Moreover, O’Hagan and co-workers have successfully

identified the first fluorinase enzyme, in the bacterium Streptomyces cattleya, which

catalyses the formation of a C–F bond [88] (Figure 1.6).

These results then raise the issue of how the fluoride becomes an active nucleophile in

this system: at this stage, the most likely scenario is that fluoride ion is drawn into

lipophilic sites on the enzyme and effectively de-solvated, to make it more reactive.

Exciting prospects for the future are indicated by the identification of this fluorinase

system [88].

In contrast, there are now many examples in the literature to indicate that, when

presented with organic compounds already labelled with fluorine, enzymes may be

tolerant to the presence of fluorine, depending on the number of C–F bonds and their

location [89, 90]. For example, baker’s yeast may lead to significant asymmetric reduc-

tion of carbonyl (Figure 1.7).

Likewise, various kinetic resolutions of fluorinated compounds have been achieved,

e.g. the acetate of 1,1,1-trifluoro-2-octanol has been transformed into (R)-1,1,1-trifluoro-

2-octanol (Figure 1.8).

NnPr2

NO2O2N

CF3N

F3C

O

OOnBu

Me

F3C

Cl

OO

Flutriafol® Flutolanil®

N

OH

N N

F

Trifluralin®

F

Fusilade®

N

H

CF3

OiPr

Cyhalothrin®

O

O CN

O

Figure 1.5 Examples of plant-protecting agents containing fluorine


10 Chapter 1

The use of CHF [91] and CF2 [92] groups as oxygen mimics has been explored and

fluoromethylenephosphonates, as phosphate mimics [93], have been employed as binding

agents for a promising approach to catalytic antibodies [94] although inevitably these sites

must be more sterically demanding than oxygen. Of course a fluorine atom itself is

isoelectronic with an oxygen anion and, not surprisingly, fluorinated carbohydrates

have been widely explored [22, 95], as have fluorinated amino-acids and peptides [31,

96]. Indeed, fluorine is advocated as a tool for exploring the conformations of amides and

peptides [97]. The presence of fluorine, with the opportunity of observation by 19F NMR,

free from the often complex 1H signals, can be an extremely useful probe.

N

NN

N

NH2

N

NN

N

NH2

F−

OS+Me

O

OH3N

+−

HO OH

O

HO OH

F

NAD+

F

O

OH

F

O

H

Fluorinase

5'-FDAS-adenosylmethionine

FluoroacetaldehydeFluoroacetate

½88�

Figure 1.6

CH2FCOPh

FH2C Ph

58%

R (90% ee)

OH ½89�

Figure 1.7

OCOMe

F3C CH2CO2Et

Lipase MYOH

F3C CH2CO2Et

OCOMe

F3C CH2CO2Et

(R) 96% ee

½89�

Figure 1.8



It should be clear from this cursory discussion, and the publications referred to, that the

roles of fluorine in drug design and in applications to biochemistry are very large and

burgeoning topics that are hugely important.

E Applications of unique properties

1 Surfactants [29]

The low surface energy possessed by highly fluorinated compounds has allowed the

development of fluorine-containing surfactants that are especially effective in very low

concentrations [98–100]. Surfactants based on straight fluorocarbon chains are the most

efficient known, and a terminal trifluoromethyl group is essential to this efficiency.

Fluorinated surfactants are used in fire-fighting foams, as emulsifiers for polymerisations

and as additives to paints. Cationic, anionic and non-ionic surfactants containing per-

fluorinated groups have been marketed; examples of each are given in Figure 1.9.

2 Textile treatments [29]

Polyacrylates bearing pendant perfluoroalkyl groups are extremely difficult to wet, due to

the very low surface energy of the partially fluorinated polymer. When surfaces of

materials are coated with such polymers, their oil and water repellencies are greatly

enhanced and this has been used to great effect in the textile-finishing area. Products such

as Zepelt (DuPont) are used for coating fabrics, as furniture sprays, and as carpet and

leather finishing agents. However, the highly successful Scotchgardt (3M) was removed

from the marketplace following concerns about the appearance of perfluoro-octyl

sulphonic acid in various blood samples, albeit in extremely low concentrations. How-

ever, the extreme stability of the acid could lead to a build-up in biological systems.

Techniques for plasma polymerisation have been progressed significantly in recent

years [101] and direct formation of fluorocarbon coatings on surfaces, including textiles,

holds much promise.

3 Dyes [29]

Fibre-reactive dyes are water-soluble dyes containing a chromophore that is attached to a

reactive group which then may be attacked by fibres containing nucleophiles to form a

F3C CF3

O

C2F5

C2F5

F3C

SO3

Anionic

Na

I

Cationic

C8F17SO2NH(CH2)3NMe3

C8F17CH2CH2O(CH2CH2O)nH

Non-ionic

Figure 1.9 Fluorinated surfactants


12 Chapter 1

dye–fibre bond. Fluorinated heterocycles, such as pyrimidines or triazines, are the most

widely used ‘carrier systems’ for dye chromophores since the fluorine on the heterocyclic

ring may be attacked by hydroxyl groups on the cellulose or cotton fibre surface, as

outlined below (Figure 1.10) (see Chapter 9 for a discussion of nucleophilic aromatic

substitution of fluorine). The incorporation of trifluoromethyl groups into a chromophore

can give the dye increased light fastness and improved clarity.

A similar approach to conferring oil-repellency on cellulose surfaces has been de-

scribed using perfluoro(isopropyl-s-triazine)s [102].

For various reasons, the superior properties of most liquid-crystalline materials con-

tained in LCD displays depend critically on the presence of fluorinated substructures

[103]. In particular, perfluorinated groups have displaced cyano groups for their role in

inducing polarity.

III ELECTRONIC EFFECTS IN FLUOROCARBON SYSTEMS

The electronic properties and size of fluorine relative to hydrogen and chlorine are set out

in Table 1.2; at this point it is worthwhile to examine some of the possible consequences

of these differences for the chemistry of fluorocarbon systems. In this way it can be

emphasised, at the outset, how far-reaching these effects will be and, at the same time, it

sets the scene for a rational approach to the chemistry.

First, the large ionisation energy of fluorine implies that species involving electron-

deficient fluorine might be less common than those involving hydrogen or chlorine. The

ionisation energy of chlorine is, in fact, less than that of hydrogen and chloronium ions

N

NCl

N

NCl

NH-Dye

N

NCl

NH-Dye

OCotton

FDye-NH2

FCotton-OH

F

Figure 1.10

Table 1.2 Electronic properties

H F Cl Ref.

Electronic configuration 1s1 . . . 2s22p5 . . . 3s23p53d0 –

Electronegativity (Pauling) 2.20 3.98 3.16 [104]

Ionisation energy kJmol�1� �a

1312 1681 1251 [104]

Electron affinity kJmol�1� �

b 74.0 332.6 348.5 [104]

Bond energies of C2X in

CX4 kJmol�1� � 446.4 546.0 305.0 [19]

Bond energies of X2X

kJmol�1� � 434 157 242 [105]

Bond lengths of C2Xc (A) 1.091 1.319 1.767 [19]

van der Waals radius (A) 1.20 1.47 1.75 [104]

Preference as a leaving group Hþ F� Cl� –

a Xþ þ e� ! Xb Xþ e� ! X�c Covalent radii in CX4



2Clþ2 (as well as 2Brþ2 or 2Iþ2) are now well established [106], whereas the

analogous fluoronium species 2Fþ2 have not been observed. It is particularly interesting

that the electron affinity of fluorine is actually less than that of chlorine because, here, we

have the first indication of repulsion between unshared electron pairs raising the energy of

the system, and it is likely that this factor accounts for the lower bond strength of F2F

than Cl2Cl bonds; it will become apparent that electron-pair repulsions are very import-

ant in fluorocarbon chemistry. Overall we can expect profound differences between

hydrocarbon and fluorocarbon systems arising from, in particular: (a) electronegativity

differences, (b) the existence of unshared electron pairs associated with fluorine, (c) the

tendency for displacement of fluorine as F� from unsaturated fluorocarbons, (d) the higher

bond strength of C2F than C2H and, to a lesser extent, (e) the larger size of fluorine than

hydrogen [107]. Differences between fluorocarbon and chlorocarbon systems are likely to

be influenced by (a) the larger steric requirements of chlorine, (b) the lower bond strength

of C2Cl than C2F, and (c) the greater availability of 3d orbitals of chlorine.

We can now outline, in a collective fashion, some electronic effects of fluorine that act,

or have been suggested to act, in a fluorocarbon system but no attempt is made to discuss

the detail of these effects at this point.

A Saturated systems

(1) Inductive (through s-bonds) and field (through space) effects arise from a highly

polar bond (�Is), resulting in electron withdrawal to fluorine (Figure 1.11).

(2) ‘Double bond–no bond resonance’ (and equivalent molecular orbital descriptions)

has been suggested to be involved (�R) (Figure 1.12).

This may be described in molecular orbital terms as interaction of s-electrons in C2F

with low-lying s�-orbitals in the other C2F bonds.

B Unsaturated systems

(1) Inductive (�Is) effects act as in saturated systems.

(2) Inductive and field effects result in the polarisation of p-electrons (�Ip)

(Figure 1.13).

C F

dd +

Figure 1.11

CF F F C F

Figure 1.12

C C

Fd - d +

Figure 1.13


14 Chapter 1

(3) Coulombic or Pauli repulsion occurs between electron pairs on fluorine and

p-electrons (þIp) (Figure 1.14).

Thus, there is a dichotomy in behaviour of fluorine because effects 1 and 2 lead to

electron withdrawal whereas 3 leads to return of electron density from fluorine.

(4) ‘No-bond resonance’ (�R) is illustrated in Figure 1.15.

C Positively charged species

(1) Inductive electron withdrawal (�Is) would tend to destabilise a carbocation (Figure

1.16).

(2) Mesomeric interaction (þM) of an unshared pair with the empty orbital on carbon, if

operating, would lead to stabilisation (Figure 1.17).

Later discussion will show that fluorine directly attached to a carbocation centre, as in

1.16A and 1.17A, overall is clearly a stabilising influence, but the effect of fluorine more

remote from the centre, as in 1.16B, is strongly destabilising.

D Negatively charged species

(1) Inductive electron withdrawal (�Is) would lead to stabilisation (Figure 1.18).

δ+ δ−C C

F

Figure 1.14

C C F CC

F

F

CF3C

� �

Figure 1.15

C CCF F

1.16A 1.16B

Figure 1.16

C+

F

1.17A

C F+

Figure 1.17

C C CF F

1.18A 1.18B

Figure 1.18



(2) Repulsion between adjacent electron pairs (þIp) would be destabilising (Figure

1.19).

It will become apparent that fluorine not directly attached to the carbanionic carbon

1.18B is strongly stabilising but, when directly attached as in 1.18A and 1.19A, it has

either a moderate stabilising effect compared with hydrogen, or it definitely destabilises,

depending on the stereochemistry of the carbanion.

(3) A ‘negative hyperconjugation’ has been proposed (Figure 1.20).

Again, in MO terms, this would be described as interaction of the filled p-orbital on

carbon with s�-orbitals associated with C2F bonds.

E Free radicals

(1) Inductive electron withdrawal (�Is) will affect the polar characteristics, and hence

reactivity, of a radical (Figure 1.21).

(2) All substituents replacing hydrogen should lower the potential energy of a free

radical; this may be represented as a resonance stabilisation (Figure 1.22).

Even from the foregoing crude but useful generalisations, it will be appreciated how

unusual the chemistry of fluorocarbon compounds is.

IV NOMENCLATURE [108, 109]

The nomenclature of fluorocarbon derivatives is based on regarding them as derivatives

of the corresponding hydrocarbon compounds.

C F

1.19A

Figure 1.19

C C

F

F

F CCF

FF�

Figure 1.20

C F

d -d +

Figure 1.21

C F C F

Figure 1.22


16 Chapter 1

A Systems of nomenclature

The number of fluorine atoms is indicated in the name and the positions are indicated by

numerals or Greek letters according to normal conventions, for example as in Figure 1.23.

To avoid cumbersome use of numbers, when the number of hydrogen atoms in a

molecule is four or less and the ratio of hydrogen to halogen atoms is not more than

1:3, then the position of the hydrogen atoms is designated, for example, as in Figure 1.24.

Another system frequently used involves adding a prefix ‘perfluoro’ before the name of

the corresponding hydrocarbon analogue. This indicates that all hydrogen atoms that are

not part of a recognised functional group are replaced by fluorine, for example as in

Figure 1.25.

For cyclic systems, a capital F in the centre of the ring is used frequently to denote that

all unmarked bonds are to fluorine, for example as in Figure 1.26.

There are ambiguities and limitations to the use of the ‘perfluoro’ prefix; it should not

be used for some substituted derivatives, for example see Figure 1.27.

OCF3

CF3

F F

F F

Hexafluoroacetone 1,1,4,4-Tetrafluorocyclohexane

Figure 1.23

CF3CFHCF3 2H-heptafluoropropane

CHClFCF2CF3 1H-1-chlorohexafluoropropane

Figure 1.24

N

CF3

FF

Perfluorocyclobutane

(CF3)3C-OH

Perfluoro-t-butanol Perfluoro(4-methylpyridine)

Figure 1.25

F Perfluorocyclohexane

Figure 1.26

Cl

Cl

F 1,2-dichlorohexafluorocyclobutane

Figure 1.27



A simple method for indicating the geometry of stereoisomers is indicated in Figure

1.28.

For highly fluorinated systems the ‘perfluoro’ system is often much less cumbersome

and immediately more meaningful than the numerical system and, for this reason, it will

often be used in this book. Both systems can be used, together with parentheses, to refer to

individual groups (Figure 1.29).

In many cases, the abbreviations RF and ArF are used to represent perfluoroalkyl and

perfluoroaryl groups respectively.

A further system of nomenclature has been authorised by the ACS, whereby a capital F

preceding the name of a substrate indicates perfluorination, for example as in Figure 1.30.

B Haloalkanes [109]

A perverse system of nomenclature exists for the CFC, HCFC and HFC groups of

compounds and, whatever objections to it may be made, it seems to be here to stay.

Therefore, to avoid much frustration it is advisable to become acquainted with the rules.

A series of three numbers are used (or two if the first is zero) that indicate, in order, the

following:

Number of carbon atoms minus one (C� 1)

Number of hydrogen atoms plus one (H þ 1)

Number of fluorine atoms (F)

Chlorine atoms are not included and, for bromine derivatives, B is added, followed by the

number of bromine atoms. Also, a cyclic system has the numbers prefixed by C, for

example:

Tetrachlorodifluoroethane C2Cl4F2 112

Trichlorofluoromethane CCl3F 11

Perfluorocyclobutane C4F8 C318

Dibromodifluoromethane CBr2F2 12B2

H

H

F

H

H

F

1H, 2H / - perfluorocyclohexane 1H, / 2H - perfluorocyclohexane

Figure 1.28

C6H5CF2CF2CF2CF2CF3 (Perfluoro-n-pentyl)benzene

C6H5CF2CF2CFHCF2CF3 (3H-decafluoro-n-pentyl)benzene

Figure 1.29

CF3CF2COOH F-propanoic acid F F-benzene

Figure 1.30


18 Chapter 1

For positional isomers, the deviation from symmetrical fluorine substitution is denoted by

a letter, for example:

CF2H2CF2H 134

CF32CFH2 134a

REFERENCES

1 D.B. Harper and D. O’Hagan, Nat. Prod. Rep., 1994, 11, 123.

2 D.B. Harper and D. O’Hagan, J. Fluorine Chem., 2000, 100, 127.

3 R.D. Chambers, Fluorine in Organic Chemistry, John Wiley and Sons, New York, 1973.

4 M. Stacey, J.C. Tatlow, A.G. Sharpe, et al. (eds), Advances in Fluorine Chemistry, Vols 1–7,

Butterworth, London, 1960–1973.

5 P. Tarrant (ed.), Fluorine Chemistry Reviews, Vols 1–8, Dekker, New York, 1967–1977.

6 M. Howe-Grant (ed.), Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol.11, Organic Fluorine Compounds, John Wiley and Sons, New York, 1994.

7 M. Howe-Grant (ed.), Fluorine Chemistry: A Comprehensive Treatment, John Wiley and Sons,

New York, 1995.

8 A.E. Pavlath and A.L. Leffler, Aromatic Fluorine Compounds, Reinhold, New York, 1962.

9 A.J. Rudge, The Manufacture and Use of Fluorine and its Compounds, Oxford University

Press, London, 1962.

10 W.A. Sheppard and C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969.

11 S. Patai (ed.), The Chemistry of the Carbon–Halogen Bond, John Wiley and Sons, London,

1973.

12 L.A. Wall, Fluoropolymers, Wiley-Interscience, New York, 1973.

13 R. Filler, Biochemistry Involving Carbon–Fluorine Bonds, American Chemical Society,

Washington DC, 1976.

14 J.W. Root, Fluorine-containing Free Radicals, American Chemical Society, Washington DC,

1978.

15 R.D. Chambers and S.R. James in Halo Compounds, ed. J.F. Stoddart, Pergamon, Oxford,

1979, p. 493.

16 R. Filler and Y. Kobayashi (eds), Biomedical Aspects of Fluorine Chemistry, Elsevier Bio-

medical Press, Amsterdam, 1982.

17 R. E. Banks (ed.), Preparation, Properties and Industrial Applications of OrganofluorineCompounds, Ellis Horwood, Chichester, 1982.

18 I.L. Knunyants and G.G. Yakobson, Synthesis of Fluoro-organic Compounds, Springer-Verlag,

Berlin, 1985.

19 B.E. Smart in Fluorinated Organic Molecules, ed. J.F. Liebman and A. Greenberg, VCH

Publishers, Deerfield Beach, 1986, p. 141.

20 R.E. Banks, D.W.A. Sharp and J.C. Tatlow (eds), Fluorine: The First One Hundred Years,

Elsevier Sequoia, New York, 1986.

21 J.F. Liebman, A. Greenberg and W.R. Dolbier (eds), Fluorine Containing Molecules, Struc-ture, Reactivity, Synthesis and Applications, VCH Publishers, New York, 1988.

22 N.F. Taylor (ed.), Fluorinated Carbohydrates: Chemical and Biochemical Aspects, American

Chemical Society, Washington DC, 1988.

23 L. German and S. Zemskov (eds), New Fluorinating Agents in Organic Synthesis, Springer-

Verlag, Berlin, 1989.

24 J.T. Welch and S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, John Wiley and Sons,

New York, 1991.

25 J.T. Welch (ed.), Selective Fluorination in Organic and Bioorganic Chemistry, American

Chemical Society, Washington, DC, 1991.

26 K.L. Kirk, Biochemistry of Halogenated Organic Compounds, Plenum, New York, 1991.



27 G.A. Olah, R.D. Chambers and G.K.S. Prakash (eds), Synthetic Fluorine Chemistry,

Wiley-Interscience, New York, 1992.

28 M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd revised edition, Ellis Horwood,

Chichester, 1992.

29 R.E. Banks, B.E. Smart and J.C. Tatlow (eds), Organofluorine Chemistry. Principles andCommercial Applications, Plenum, New York, 1994.

30 T. Hayashi and V.A. Soloshonok, Tetrahedron: Asymm., 1994, 5, 955.

31 V.P. Kukhar and V.A. Soloshonok, Fluorine-containing Amino Acids, John Wiley and Sons,

New York, 1995.

32 M. Hudlicky and A.E. Pavlath (eds), Chemistry of Organic Fluorine Compounds II, American

Chemical Society, Washington DC, 1995.

33 T.L. Gilchrist (ed.), Comprehensive Organic Functional Group Transformations, Vol. 6,

Elsevier Science, Oxford, 1995.

34 B.E. Smart, Chem. Rev., 1996, 96, 1555.

35 G. Resnati and V.A. Soloshonok, Tetrahedron, 1996, 52, 1.

36 B. Baasner, H. Hegemann and J.C. Tatlow (eds), Houben-Weyl: Methods of Organic Chemis-try, Vols E10a–E10c, Organo-fluorine Compounds, Georg Thieme, Stuttgart, 1999.

37 J.H. Clark, D. Wails, and T.W. Bastock, Aromatic Fluorination, CRC Press, Boca Raton,

1996.

38 R.D. Chambers (ed.), Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermedi-ates, Springer-Verlag, Berlin, 1997.

39 R.D. Chambers (ed.), Organofluorine Chemistry: Techniques and Synthons, Springer-Verlag,

Berlin, 1997.

40 W.S. Brey and M.L. Brey in Fluorine-19 NMR, ed. D.M. Grant and R.K. Harris, John Wiley

and Sons, New York, 1996, p. 2063.

41 M.R. Kilbourn, Fluorine-18 Labeling of Radiopharmaceuticals, National Academy Press,

Washington DC, 1990.

42 O. Matsson, S. Axelsson, A. Hussenius and P. Ryberg, Acta. Chem. Scand., 1999, 53, 670.

43 H. Moissan, Compt. Rend., 1890, 110, 276.

44 H. Moissan, Le Fluor et ses Composes, Steinheil, Paris, 1900.

45 F. Swarts, Bull. Acad. Roy. Belg., 1892, 24, 474.

46 T. Midgley and A.L. Henne, Ind. Eng. Chem., 1930, 22, 542.

47 P. Lebeau and A. Damiens, Compt. Rend., 1926, 182, 1340.

48 P. Lebeau and A. Damiens, Compt. Rend., 1930, 191, 939.

49 O. Ruff and R. Keim, Z. Anorg. Allg. Chem., 1930, 192, 249.



52 J.H. Simons and L.P. Block, J. Am. Chem. Soc., 1937, 59, 1407.

53 J.H. Simons (ed.), Fluorine Chemistry, Vol. 1, Academic Press, New York, 1950.

54 J.H. Simons (ed.), Fluorine Chemistry, Vol. 2, Academic Press, New York, 1954.

55 C. Slesser and S.R. Schram (eds), Preparation, Properties and Technology of Fluorine andOrganic Fluoro Compounds, McGraw-Hill, New York, 1951.

56 O. Ruff and O. Bretschneider, Z. Anorg. Allg. Chem., 1933, 210, 173.

57 E.G. Locke, W.R. Brode and A.L. Henne, J. Am. Chem. Soc., 1934, 56, 1726.

58 R.J. Plunkett, US Pat. 2 230 654 (1941); Chem. Abstr., 1941, 35, 3365.

59 H. Schofield, J. Fluorine Chem., 1999, 100, 7.

60 S. Rozen in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash,

John Wiley, New York, 1992, p. 143.

61 R.E. Banks and K.C. Lowe, Fluorine in Medicine in the 21st Century, UMIST Chemserve,

Manchester, 1994.

62 R.E. Banks, Fluorine in Agriculture, Fluorine Technology Ltd, Manchester, 1994.

63 R.E. Banks, Fluorocarbons and their Derivatives, MacDonald, London, 1970.


20 Chapter 1

64 R.L. Powell in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner,

H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 59.

65 M. Silvester, Speciality Chemicals, 1991, 392.

66 M.J. Molina, Angew. Chem., Int. Ed. Engl., 1996, 35, 1778.

67 F.S. Rowland, Angew. Chem., Int. Ed. Engl., 1996, 35, 1786.

68 C.S. Todd, The Use of Halons in the United Kingdom and the Scope for Substitution, HMSO,

London, 1991.

69 R.E. Banks, J. Fluorine Chem., 1994, 67, 193.

70 L.C. Clark and F. Gollan, Science, 1966, 152, 1755.

71 J.G. Riess, Chem. Rev., 2001, 101, 2797.

72 R.M. Flynn in Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11, ed. M. Howe-

Grant, John Wiley and Sons, New York, 1994, p. 525.

73 R.J. Lagow, T.R. Bierschenk, T.J. Juhlke and H. Kawa in Synthetic Fluorine Chemistry, ed.

G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 97.

73a G. Hougham (ed.) Fluoropolymers, Academic/Plenum Publishers, New York, 1999.

74 D.P. Carlson and W. Schmeigel in Ullmanns Encyclopedia of Industrial Chemistry, Vol. A11,

VCH Publishers, Weinheim, 1988, p. 393.

75 R.F. Brady, Chem. Britain, 1990, 26, 427.

76 C.A. Sperati in Properties of Fluoropolymers, ed. J. Brandrup and E.H. Immergut, Wiley, New

York, 1975.

77 A. Eisenberg and H.L. Yeager, Perfluorinated Ionomer Membranes, American Chemical

Society, Washington DC, 1982.

78 V.A. Soloshonok (ed.), Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets,

John Wiley and Sons, New York, 1999.

79 M. Schlosser in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed.

V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 613.

80 D.F. Halpern in Anaesthetics Review, ed. R.E. Banks and K.C. Lowe, UMIST Chemserve,

Manchester, 1994, Paper 15.

81 B.E. Smart, J. Fluorine Chem., 2001, 109, 3.

82 D. O’Hagan and H.S. Rzepa, J. Chem. Soc., Chem. Commun., 1997, 645.

83 D. Seebach, Angew. Chem., Int. Ed. Engl., 1990, 29, 1320.

84 M.R. Kilbourn in Fluorine-18 in Nuclear Medicine, ed. R.E. Banks, UMIST Chemserve,

Manchester, 1994.

85 S.B. Walker, Fluorine Compounds as Agrochemicals, Fluorochem Ltd, Glossop, 1989.

86 S.R.A. Peters and R.J. Hall, J. Biochem. Pharmacol., 1959, 2, 25.

87 D. O’Hagan and D.B. Harper, Nat. Prod. Rep., 1994, 11, 123.

88 D. O’Hagan, C. Schaffrath, S.L. Cobb, J.T.G. Hamilton and C.D. Murphy, Nature, 2002,

416, 279.

89 T. Kitazume and T. Yamazaki in Organofluorine Chemistry. Techniques and Synthons, ed.

R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 91.

90 T. Fujisawa and M. Shimizu in Enantiocontrolled Synthesis of Fluoro-organic BiomedicalTargets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 307.

91 T.F. Herpin, W.B. Motherwell and M.J. Tozer, Tetrahedron: Asymm., 1994, 5, 2265.

92 D.M. LeGrand and S.M. Roberts, J. Chem. Soc., Chem. Commun., 1993, 1284.

93 D.B. Berkowitz and M. Bose, J. Fluorine Chem., 2001, 112, 13.

94 S. Cesaro-Tadic, D. Lagos, A. Honegger, J.H. Rickard, L.J. Partridge, G.M. Blackburn and

A. Pluecktun, Nat. Biotechnol., 2003, 21, 679.

95 B. Novo and G. Resnati in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets,

ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 349.

96 K. Uneyama in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed.


97 C.R.S. Briggs, D. O’Hagan, J.A.K. Howard and D. Yufit, J. Fluorine Chem., 2003, 119, 9.



98 K. Shinoda, M. Hato and T. Hayaski, J. Phys. Chem., 1972, 76, 909.

99 H. Kuneida and K. Shinoda, J. Phys. Chem., 1976, 80, 2468.

100 W. Guo, T.A. Brown and B.M. Fung, J. Phys. Chem., 1991, 95, 1829.

101 J.P. Badyal, Chem. Britain, 2001, 37, 45.

102 R.D. Chambers, C. Magron, G. Sandford, J.A.K. Howard and D.S. Yufit, J. Fluorine Chem.,

1999, 97, 69.

103 P. Kirsch and M. Bremer, Angew. Chem., Int. Ed. Engl., 2000, 39, 4216.

104 B.E. Smart in Organofluorine Chemistry. Principles and Commercial Applications, ed.

R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 57.

105 N.N. Greenwood and A. Earnshaw, Chemistry of the Elements, Pergamon, Oxford, 1989.

106 G.A. Olah, Halonium Ions, Wiley-Interscience, New York, 1975.

107 C.G. Beguin in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed.


108 R.E. Banks and J.C. Tatlow in Organofluorine Chemistry. Principles and CommercialApplications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 1.

109 R.E. Banks in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner,



22 Chapter 1

Chapter 2

Preparation of Highly FluorinatedCompounds

I INTRODUCTION

Two different approaches have been adopted here in describing fluorination reactions: the

production of highly fluorinated systems is discussed in this chapter on the basis of a

comparison of methods, whereas selective fluorinations are described in Chapter 3 in

terms of the conversion of functional groups. If we wish to produce highly fluorinated

systems, then the starting materials are usually hydrocarbons, polychloro compounds or,

of course, highly fluorinated ‘building-blocks’ for conversion to other compounds.

A Source of fluorine

Fluorine is widely distributed in nature [1] and it is estimated that, among the elements,

fluorine is about thirteenth in abundance. Phosphate rock, which is processed on a

multimillion-ton scale as raw material for the fertiliser industry, contains as much as

3.8% of fluorine and is a very rich source of the element. However, the fluorine recovered

from this process as fluorosilicic acid is still not a commercially competitive source of

fluorine compared with fluorspar (CaF2), although reserves of the latter are said to be

limited and it is expected that use of fluoride in phosphate rocks will eventually be

increased.

For industry, the source of fluorine is essentially anhydrous hydrogen fluoride [2],

which is made commercially by distillation (b.p. 19.58C) from a mixture of fluorspar and

concentrated sulphuric acid. The liquid fumes in air and great care must be taken to avoid

its contact with the skin, otherwise unpleasant burns are obtained which are difficult to

heal and often require a subcutaneous injection of calcium gluconate [3, 4]. Synthesis of

highly fluorinated compounds, starting from hydrogen fluoride, is therefore achieved by a

variety of techniques: directly by reaction of an organic compound with hydrogen fluoride

or by electrolysing solutions of certain compounds in HF, or indirectly by reactions with

elemental fluorine or with metallic fluorides (Figure 2.1).

II FLUORINATION WITH METAL FLUORIDES [5]

There is a considerable literature [6–8] on this group of reactions, embracing an extremely

wide variety of experimental conditions, and the patent literature abounds with reports of

different ‘catalyst’ systems. It is possible to group some of these reactions partly on a

basis of mechanism if some rather broad generalisations are made about the mechanistic

pathways. The aim here is to assist in the choice of the type of reagent but it is not



CaF2 anhydrous HF

Metal Fluorides Transition MetalFluorides

F2KF.2HF

m.p. ca. 100� C

H2SO4

Figure 2.1

intended to imply that detailed mechanisms are understood, nor should the classifications

be regarded as rigid. There are three main groups, as described below.

A Swarts reaction and related processes (halogen exchangeusing HF)

These reactions are based on hydrogen fluoride and involve, essentially, a nucleophilic

displacement of halogen (for convenience, in the sense intended throughout this book, this

term usually excludes fluorine). However, only the most reactive halides such as allylic

and benzylic ones can be fluorinated by anhydrous HF alone [9] (Figure 2.2).

PhCCl3 PhCF3

N

CCl3

Cl

HF, 40 � C70%

N

CF3

Cl

Ph3CCl Ph3CFHF, rt

HF, catalyst

300−500 � C80%

62%

½9�

Figure 2.2

Hydrogen fluoride acts both as a Friedel–Crafts catalyst and a fluorinating agent in a

one-step preparation of trifluoromethylated aromatics [10] (Figure 2.3).

CF3

+ CCl4 + HF5hr, 100 � C

92%

½10�

Figure 2.3

Halogen exchange at less activated sites requires a Lewis acid catalyst and an important

part of the function of the catalyst, usually a metal fluoride or a chromium species, is to

assist the removal of halogen as halide ion. Therefore, these reactions could be considered

to involve carbocationic intermediates (Figure 2.4).

C Cl + MFx C MFxCl C FF

Figure 2.4


24 Chapter 2

It is more likely, however, that four-centre reactions occur since the metal fluorides can

be used either alone or in catalytic amounts in the presence of anhydrous hydrogen

fluoride. This latter process was developed by Swarts and it now usually bears his

name (Figure 2.5).

C Cl + MFx CF

C F

Cl

F

MFx-1

δ + δ −

Figure 2.5

Generally, reactions performed in the liquid phase utilise hydrogen fluoride in combin-

ation with antimony fluoride catalysts and their efficiency stems from the greater strength

of the bond from antimony to chlorine than to fluorine. Pentavalent antimony catalysts,

such as SbF5 and SbF3Cl2, are more efficient than trivalent species because they are

extremely strong Lewis acids. Carbocations are formed in the presence of antimony

pentahalides and, indeed, one of the now-classic techniques developed by Olah and

his co-workers for the generation of relatively stable carbocations involves the reaction

of an organic halide with antimony pentafluoride, in solvents such as sulphur dioxide, at

low temperature [11]. On the industrial scale, reactions are performed in the vapour

phase and chromium(III)-based catalysts are extensively used in the production of

hydrofluorocarbons (HFCs).

In general, in this group of fluorination reactions, reactivities of the substrates and the

nature of the products obtained can be accounted for in terms of the corresponding

carbocation intermediates.

1 Haloalkanes

For many years chlorofluorocarbons (CFCs) were manufactured in huge quantities by

Swarts-type processes but, after the introduction of the Montreal Protocol legislation,

these compounds were superseded by non-ozone depleting HFCs (see Chapter 1).

Fortunately, much of the chemistry developed for the manufacture of the CFCs can be

adapted for the production of HFCs [7, 12–15].

Generally, conversion of 2CCl3 groups to 2CFCl2 can be easily accomplished,

reflecting both the stabilisation of the intermediate carbocations by chlorine and the relief

in steric strain associated with replacement of chlorine by fluorine. Further fluorination of

the 2CFCl2 group is possible but becomes progressively more difficult [3] due to the

decrease in the donating ability of the chlorine. Fluorination of 2CFCl2 groups can also

be achieved but RFCH2Cl moieties (where RF ¼ perfluoroalkyl) are generally very

difficult to fluorinate due to the lower stability of the derived carbocation intermediates.

These effects can all be seen in the two most important industrial routes to HFC-134a,

now a leading refrigerant, in which chromium(III) catalysts are used in conjunction with

HF for the halogen exchange steps [15] (Figure 2.6).


Preparation of Highly Fluorinated Compounds 25

HF HF

Cr(III) Cr(III)

HF AlCl3CF2ClCFCl2

CF3CH2F

CCl3-CCl3

Cr(III)

CF3CCl3

CF3CH2F

CF3CH2Cl

CF3CFCl2

HF

HF

CCl2=CHCl CF2ClCClH2

HFC 134a

H2 / Pd

HFC 134a

Cr(III)

½15�

Figure 2.6

2 Influence of substituent groups

Groups such as alkyl [16] and aryl [17], double bonds [18], oxygen [19] and sulphur [20]

(that are known to stabilise carbocations), when attached to the carbon centres that are

undergoing halogen exchange, activate the process (Figure 2.7).

i, SbF3 / SbCl5, 150� C60% 6%

+

CCl2�CClCCl3 CF3CCl�CCl2 CF2ClCCl�CCl2

43% 28%

i+

i+

85% 10%

iCCl3CF2OCH3 84%

CCl3�S�CH3 CF3−S−CH3 73%

PhCCl2CCl3 PhCF2CCl3 PhCFClCCl3

CH3CCl2CH3 CH3CF2CH3 CH3CFClCH3

CCl3CCl2OCH3

i

i, SbF3, 150� C

i, SbF3 / SbCl5, rt

i, SbF3 / SbCl5, 90� C

i

i, SbF3, reflux

½17�

½18�

½16�

½19�

½20�

Figure 2.7


26 Chapter 2

In reactions with hexachlorobutadiene, 1,4-addition of chlorine precedes fluorination

and the product arises from exchange at the two reactive allylic trihalomethyl groups [21].

Perchlorocyclopentene [22] and hexachlorobenzene [23] are also extensively fluorinated

by this procedure (Figure 2.8).

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl2C�CClCCl=CCl2 CCl3CCl�CClCCl3

CF3CCl�CClCF3 + CF3CCl�CFCF3

Cl F 72%SbF3, SbF3Cl2

ClSbF5, 160 � C

F

30%

F +

20%

SbF3Cl2½21�

½22�

½23�

Figure 2.8

The fluorination of hexachloroacetone by HF over chromia catalysts at high tempera-

ture is an efficient process for the synthesis of hexafluoroacetone [20] (Figure 2.9).

O

Cl3C CCl3

O

F3C CF3Chromia cat.

HF, 350 � C ½20�

Figure 2.9

In addition to the antimony fluorides, silver, mercury, thallium, aluminium, zinc,

zirconium, chromium and other fluorides [7] such as mercury(II) fluoride, vanadium

pentafluoride [24] and various transition metal oxide fluorides [25] have been used in

exchange processes, although much less widely.

B Alkali metal fluorides (see also Chapter 3, Section IIB) [26]

This second group of reactions is related to the first in that nucleophilic displace-

ment of a halide ion is involved, but here Lewis acid assistance by the metal fluoride

is not a prime factor. Therefore, ionic fluorides are applicable where an unassisted

nucleophilic displacement process is feasible, even if forcing conditions are necessary

(Figure 2.10).



F C C C C C CClF

ClF + Cl

Figure 2.10

1 Source of fluoride ion

Fluoride ion is much smaller than chloride (ionic radii 1.47 and 1.75 A, respectively [27])

and the heat of hydration of fluoride is about 134 kJmol�1 greater than chloride. The order

of nucleophilic strength of halide ions in aqueous solution is I� � Br� > Cl� > F�,

which is the opposite of the order of strengths of the bonds of the halogens to carbon.

Therefore, the order of reactivity is a consequence of the greater difficulty in disturbing

the hydration sphere of the smaller ions. The same order seems to be observed in most

hydrogen-bonding solvents but, in dipolar aprotic solvents, the order follows that of

increasing halogen bond strength to carbon, that is F� > Cl� > Br� � I� [28]. Conse-

quently, in order to reduce hydrogen bonding between the fluoride ion source and the

solvent, and hence to increase the nucleophilic strength of fluoride, reactions are generally

carried out using polar, aprotic media [29, 30] such as acetonitrile, sulpholane,

N-methylpyrollidinone or glymes. These solvents dissolve sufficient metal fluoride, due

to coordination of the oxygen or nitrogen donor groups present with the metal cation, and

presumably the fluoride ion remains relatively unsolvated. These fluorinations are not

simply solution-phase processes, because some reaction undoubtedly occurs on the

surface; indeed, the surface area of the metal fluoride is extremely important to reactivity

and in some cases it has been demonstrated that the amount of solid metal fluoride is

important [31]. Also, in some circumstances the alkali metal fluorides can be used most

effectively without a solvent [32, 33], and in these cases it is likely that an MF/MCl melt

is produced as the reaction proceeds.

Fluoride ion is a relatively strong base which has been used to effect a large number of

base-catalysed reactions in general organic synthesis [34, 35] and so, if forcing conditions

are required for a particular halogen exchange reaction, the limiting feature can be proton

abstraction by fluoride ion from the solvent or the substrate. Because of the low solubility

of metal fluorides in even very polar aprotic solvents, high temperatures are generally

required; this restricts the use of alkali metal fluorides to relatively simple substrates.

Consequently, development of more reactive forms of fluoride ion, which may be useful

for introduction of fluorine into more complex molecules, is an area of continuing interest

[36, 37]. Methods of activating metal fluorides (usually potassium fluoride) fall into two

broad classes: (a) increasing the surface area of the metal fluoride by spray drying [38,

39], freeze drying [40], recrystallising from methanol [41] or absorbing onto a solid inert

support such as calcium fluoride [42], alumina [43], graphite [44] or a polymer [45]; or,

(b) increasing the solubility of the metal fluoride in aprotic solvents by the addition of co-

ordinating crown ethers [46, 47] such as 18-crown-6 or a phase-transfer catalyst such as

tetraphenylphosphonium bromide [48, 49] or a tetra-alkylammonium salt [50]. A search

for other more soluble sources of nucleophilic fluoride continues and reagents such as

tetra-alkylammonium fluorides [51, 52], various amine hydrofluorides [53, 54], diethyl-

aminosulphur trifluoride [55] (DAST), tetrabutylammonium (triphenylsilyl)difluorosili-


28 Chapter 2

cate [56] and tris(dimethylamino)sulphonium difluorotrimethylsiliconate [57] (TAS-F)

have been used for the selective introduction of fluorine into organic substrates with

varying degrees of success. However, in soluble reagents such as Me4NF and other so-

called ‘naked fluoride’ systems, the fluoride ion is so exceptionally reactive that compet-

ing proton abstraction from the solvent, such as acetonitrile, or halogen exchange with a

chlorinated solvent takes place [51, 58]. Consequently, in the development of new

fluoride-ion reagents, a balance must be achieved between having sufficiently high

fluoride nucleophilicity to effect halogen exchange and, at the same time, sufficiently

low fluoride-ion basicity to prevent unwanted side reactions. Indeed, it has been reported

that hydrated tetrabutylammonium fluoride is beneficial in reducing elimination products

in reactions with 1-bromo-octane [52] (Figure 2.11).

Bu4NF + 10H2O + C8H17Br80 � C

C8H17F + CH2�CH-C6H13

91% 9%CH3CN

½52�

Figure 2.11

Under most aprotic conditions a general order of reactivity of the alkali-metal

fluorides is CsF > KF > NaF, LiF; that is, the fluoride with the lowest lattice energy is

the most efficient fluorinating agent. This highlights the over-simplification of ignoring

the role of the counter-ion in nucleophilic displacement of halide by fluoride ion. In

reactions that do not involve a solvent, the lattice energy itself will be an especially

important factor in the process, as for example in Figure 2.12. When the metal M is large,

the lattice energy difference between the halides is most favourable for the exchange

reaction [59].

C Cl C FMF + MCl +

Figure 2.12

A general process that involves direct and efficient reaction of fluorspar with organic

halides would be very desirable but, so far, this has not been realised, except through

generation in situ of hydrogen fluoride [60].

2 Displacements at saturated carbon

Displacement of halide by fluoride ion from alkyl halides usually occurs by an SN2

process with inversion of configuration [37], and since it is well known that nucleophilic

displacement of chloride from polychloroalkanes becomes progressively more difficult

with increasing chlorine content, it is hardly surprising that highly fluorinated alkanes are

not generally synthesised by this method. However, in favourable cases more than one

fluorine atom can be introduced; some examples illustrating different conditions used in

‘Halex’ processes are given in Table 2.1. Other selective nucleophilic fluorinations are

discussed later (Chapter 3, Section II).



3 Displacements involving unsaturated carbon

Alkene derivatives: There are three processes that can lead to nucleophilic displacement

of halide by fluoride ion in unsaturated systems (Figure 2.13).

X

X

F F

XF

F + + X

F+ X

1. Addition / Elimination

2. Allylic or Benzylic Substitution

3. Nucleophilic Substitution with Rearrangement, SN2'

X

F+ XF

Figure 2.13 Displacement of halide by fluoride

Only perfluorocyclopentene has been synthesised directly by this route; it can be seen that,

here, allylic rearrangements can occur to make all positions potentially vinylic and therefore

reactive [64]. An analogous situation applies to hexachlorobutadiene. These reactions may

also be carried out with potassium fluoride that has been exposed to Sulpholan or 18-crown-

6, but then suspended in a fluorocarbon. Under these conditions, a significant proportion of

hexafluoro-2-butyne is formed, presumably because the latter is extracted into the fluoro-

carbon, pre-empting further reaction with fluoride [65] (Figure 2.14).

Table 2.1 Fluorinations with alkali-metal fluorides

Compound Conditions Products Yield (%) Ref.

C6H13Cl KF; (CH2OH)2;(HOCH2CH2)2O; 175–1858C C6H13F 54 [61]

CH2Cl2 KF, HF, 3008C CH2F2 82 [62]

CHCl2COOCH3 KF, 220–2308C CHF2COOCH3 18 [63]

CH3(CH2)7Br KF, 18-crown-6, MeCN CH3(CH2)7F 92 [46]

CCl3CCl2CCl3 KF, 1908C CF3CCl2CF3 � 60 [64]

N

Cl

N-Methyl-2-pyrrolidone

KF, 4808C, autoclave, no solvent

N

F

N

F

Cl

[32]


30 Chapter 2

25% 75%

Cl

Cl

F

NMP = N-methyl-2-Pyrrolidone

Cl

F

KF, NMP, 200 � CCl

ClCl

F

F

Fetc.

CCl2=CClCCl=CCl2

KF / NMP

KF/Sulpholan,Perfluorocarbon

CFCl2−CHClCCl=CCl2 CF3CH=CFCF3

CF3CH=CFCF3 CF3C CF3

½65�

Figure 2.14

Aromatic compounds: Nucleophilic displacement of halide ion from haloaromatic com-

pounds containing other electronegative substituents is well known; this process has been

widely exploited for the synthesis of fluorinated aromatic compounds (Table 2.1) and is

discussed later (see Chapter 9, Section II).

C High-valency metal fluorides

This group of reactions [66, 67] is distinguished from those discussed earlier on the basis

that the previous examples involve overall nucleophilic displacement reactions of groups

(mainly other halogen) by fluoride, frequently with some degree of assistance for the

leaving group by the metal. However, with the present group, the process involves change

of a higher-valency metal fluoride to a lower-valency state, and therefore the metal acts

somewhat like a fluorine carrier, although it is emphasised that these reactions do not

involve the formation and reaction of elemental fluorine (Figure 2.15).

The high-valency metal fluorides, mainly cobalt trifluoride, bring about extensive

fluorination: hydrogen is replaced by fluorine and saturation of double bonds and aro-

matic systems usually takes place, while chlorine is frequently retained. There is much

less fragmentation during this process than during direct fluorination by elemental

fluorine, because the heat of reaction with cobalt trifluoride is approximately half that

of the corresponding direct fluorination process [68] (Figure 2.16).



C H C F

C C C

F

C

F

+ 2MFn + HF + 2MFn-1

+ 2MFn + 2MFn-1

Figure 2.15

2 CoF2 + F2

H

2 CoF3 , ∆H (250�C) = −234kJmol−1

+ F2 CoF3 + HF + 2 CoF2C C

½68�

Figure 2.16 DH is ca� 209 to �230 compared with ca �426 to �435 kJmol-1 for direct fluorination

The most important member of this group is cobalt trifluoride; the present discussion

will be essentially limited to the use of this fluorinating agent, although use of a variety of

other fluorides has been reported, with varying degrees of success [66, 67]. Other related

high-valency metal salts such as the tetrafluorocobaltates of potassium [69, 70] and

caesium [71], KAgF4 [72] and K2NiF6 [73] (compare also NiF3, Section III) are milder

fluorinating agents for aromatic systems. It is also worthwhile to re-emphasise that the

classifications presented here must not be regarded as rigid because, for example, antim-

ony pentafluoride has characteristics that really span both groups.

It is now reasonably well established that cobalt trifluoride fluorinations proceed via a

one-electron transfer oxidative process [74, 75] as outlined in Figure 2.17.

CoF3

CoF2 + F

R�H−H +

RCoF3

R-H

rearrange

R�F+

R' R R�FR'�FF

CoF3

½74; 75�

Figure 2.17

The presence of carbocationic intermediates was inferred from the isolation of other

perfluorinated isomers formed via rearrangement upon fluorination of n-hexane [75].

Similar arguments have been suggested for fluorinations of aromatics [74, 76, 77], ethers

[78] and amines [79].

1 Cobalt trifluoride and metal tetrafluorocobaltates

Laboratory-scale fluorinations with cobalt trifluoride most commonly utilise the tech-

nique pioneered by Fowler and his co-workers [80] whereby cobalt trifluoride is formed,


32 Chapter 2

and subsequently regenerated, by passing fluorine over the difluoride under agitation. The

substrate is then added in the vapour phase, in a stream of nitrogen usually at high

temperatures (300–4008C). Industrial processes [81], such as that used by F2 Chemicals

Ltd for the production of a range of perfluorocarbon fluids (Flutect), are operated on a

continuous process in which both fluorine and the hydrocarbon are fed simultaneously

into the reactor, enabling fluorination and regeneration of the trifluoride to occur. This

method is probably the best available for general synthesis of saturated fluorocarbons and

both open-chain and cyclic fluorocarbons have been produced readily from appropriate

aliphatic or aromatic hydrocarbons, yields usually being quite high (Table 2.2).

Formation of perfluorinated ethers by cobalt trifluoride is generally a low-yielding

process, because of fragmentation and partial fluorination. However, incorporation into

the substrate of electron-withdrawing polyfluoroalkyl groups moderates the fluorination

and allows high yields to be obtained [78].

III ELECTROCHEMICAL FLUORINATION (ECF) [87]

Simons and his co-workers discovered a remarkable fluorination process [88–90] which is

still being studied [87, 91–95]. Many organic compounds dissolve readily in anhydrous

Table 2.2 Fluorinations using cobalt trifluoride

Starting material Conditions (8C) Product Yield (%) Ref.

n-C5H12 275–325 n-C5F12 67% [80]

C2H5

350

C2F5

F

85% [82]

350 F F [83]

N

350

NF F

[84]

Cl 350 C6F12�nCln [85]

O CF2CFHCF3

440

O CF2CF2CF3

F 70% [78]

O N CH3 100 O N CF3F [86]



hydrogen fluoride to give conducting solutions and it was found that when a direct electric

current was passed through a solution of this type, or through a suspension of a compound

in anhydrous hydrogen fluoride to which some electrolyte had been added to give a

conducting medium, hydrogen was evolved at the cathode and the organic material was

fluorinated. Low voltages are used (usually 5–6 V) so that generation of elemental

fluorine is not involved. However, the process is not well understood and suggestions

concerning the mechanism broadly fall into two classes [94]. High-valency nickel fluor-

ides formed at the surface of the anode are the most likely fluorinating agents [96],

although formation of radical cation intermediates has been suggested [97] (Figure 2.18).

R H R H R R−e −e

R�F−H F ½97�

Figure 2.18

The method is similar to the use of high-valency metal fluorides because it is usual for

all the hydrogen in an organic compound to be replaced by fluorine; unsaturated centres,

multiple bonds or aromatic systems are saturated but some functional groups are retained,

and it is this last feature that makes this method attractive. Unfortunately, however,

although many examples are quoted, especially in the patent literature, the yields are

frequently difficult to deduce or are very low. This is particularly the case with hydrocar-

bons and, in general, as the length of the hydrocarbon chain in functional compounds

increases, so the yields decrease. Under its present state of development the method is

only preparatively useful in limited cases, for example for carboxylic or sulphonic acids,

amines and some ethers (see Table 2.3) where the yields are particularly high, or in cases

where alternative methods are even more inefficient. The process is in commercial use for

the production of a range of perfluorocarbons and perfluoro acids.

Table 2.3 Electrochemical fluorinations

Starting material Product Yield (%) Ref.

n-C8H18 n-C8F18 15 þ tar [89]

(C2H5)3N (C2F5)3N 27 [98]

N F N

F

F 37 [99]

(CH3)2S CF3SF5 þ (CF3)2SF4 20þ 2 [100]

CH3COF CF3COF 85 [101]

C7H15COCl C7F15COF 20 [102]

CH3SO2F CF3SO2F 96 [103]

C8H17SO2Cl C8F17SO2F 25 [103]

O CF2CFHCF3 O CF2CF2CF3

F50 [104]


34 Chapter 2

Work with pre-formed high-valency nickel fluorides, i.e. NiF3 and NiF4, has demon-

strated the very high level of reactivity of such compounds [105–107]. These are the only

reagents described so far that will bring about complete fluorination at room temperature

or below (Figure 2.19), and therefore mirror ECF procedures.

O RFHRFH O C3F7C3F7

i, NiF3, anhyd.HF, −28� C to rt, 24hr

F

RFH = -CF2CFH-CF3

i

Figure 2.19

Clearly these results support the idea of forming higher nickel fluorides at the anode

surface during ECF but there is also the possibility that these high-valency systems could

be simply regarded as fluorine atom carriers, which would account for the high level of

reactivity. For any oxidation process proceeding by the ECBECN mechanism described in

Figure 2.18, it would be expected that fluorination should become progressively more

difficult to achieve. However, presentation of a surface of, essentially, fluorine atoms to a

substrate would circumvent this difficulty of interpretation. It is worth noting that the

nickel fluoride K2NiF6 [108] decomposes on heating to give elemental fluorine.

IV FLUORINATION WITH ELEMENTAL FLUORINE [109]

A Fluorine generation

Since anhydrous hydrogen fluoride is not sufficiently conducting, fluorine is generated at

the anode by electrolysis of KF�2HF, which melts conveniently around 1008C and the

cell can therefore be run at a reasonable temperature. Considerable research has been

carried out on the design of fluorine cells and this is fully discussed elsewhere [2, 110].

B Reactions

Reactions between hydrocarbons and elemental fluorine are extremely exothermic be-

cause of the high heats of formation of bonds from fluorine to carbon and hydrogen

(approximately 456 and 560 kJmol�1, respectively) [27, 111]. The value of DH for the

dissociation of fluorine is very low (ca. 157 kJmol�1), so it is frequently assumed that

the preferred fluorination process proceeds by a radical chain mechanism (Figure 2.20),

although this may not always be the case.

F2 2F

RH + F R + HF

R + F2 RF + F

K = 10−20

Figure 2.20

Fluorinations will proceed in the dark, and the initiation process poses a question. It has

been pointed out [112] that, although fluorine is not appreciably dissociated at room



temperature (F2 ¼ 2F � , K ¼ 10�20), the low activation energy of the hydrogen abstrac-

tion reaction would mean that even this low degree of dissociation would be sufficient to

start the chain process. Nevertheless, Miller and co-workers suggested the possibility of

an initiation process [113–115] in which molecular fluorine reacts with a hydrocarbon

molecule to yield an alkyl radical, hydrogen fluoride and a fluorine atom (Figure 2.21).

R + HF + F ∆H = +16.3 kJmol−1RH + F2 ½113�115�

Figure 2.21

This is an attractive idea and there is ample precedent for this process with other

halogens [116]. In reactions of fluorine with alkenes, the thermodynamics are more

convincing [112] and there appears to be some supporting experimental evidence

(Figure 2.22).

C C F C C+ F2 + F ∆H = −156.9 kJmol−1 ½112�

Figure 2.22

It was shown that a mixture of tetrachloroethene and chlorine did not react until a trace

of fluorine was introduced, whereupon chlorination took place [114] (Figure 2.23).

CCl2=CCl2 + Cl2 CCl3-CCl3F2 (trace)

85% ½114�

Figure 2.23

Also, it has been suggested that dimerisation of haloalkenes observed during the

interaction with fluorine at low temperatures (< �508C) arises by a free-radical chain

mechanism initiated in this way [115].

C Control of fluorination

A consideration of the thermodynamics of fluorination reactions shows that the overall

energy released upon substituting a hydrogen by fluorine [111] (430 kJmol�1) is sufficient

to cause carbon–carbon bond cleavage (ca. 355 kJmol�1) leading to substrate degradation.

Consequently, after many early attempts to effect direct fluorination had resulted in

violent reactions, it was not until effective methods were developed for dissipating the

considerable heat generated that any real progress was made [117, 118].

1 Dilution with inert gases

It is possible to control direct fluorination reactions in their initial stages by using fluorine

extensively diluted in an inert gas, such as nitrogen or helium, long reaction times, and by

cooling the reactor to low temperatures. After partial fluorination of a substrate has been

achieved, further fluorination generally requires more forcing conditions, since the sub-

strate is now less activated towards radical substitution. Therefore, the concentration of

fluorine and the temperature of the reaction may be raised to effect perfluorination. The

‘LaMar’ process has been developed by Lagow and Margrave with their co-workers [111,


36 Chapter 2

117, 119, 120] to prepare many perfluoroalkanes [111, 121] and perfluoroadamantane

derivatives as well as functional perfluoro compounds (Table 2.4 in Section E, below).

In a related ‘aerosol fluorination’ technique [122–124], a substrate is absorbed onto fine

particles of sodium fluoride which are then sprayed into a stream of dilute fluorine; many

perfluorinated highly branched and cyclic alkanes have been prepared by this method.

Other techniques for perfluorination with elemental fluorine make use of fluorocarbon

solvents which act both as a heat sink in the early stages of fluorination and as a solvent to

dissolve high concentrations of fluorine, which is helpful towards ensuring complete

fluorination in the later ‘finishing’ stages [125, 126]. Perfluorination may be further

aided by photolysis under UV irradiation [127] or by the addition of a highly reactive

substrate, such as benzene [126], that also acts as a fluorine-atom generator (see above).

Maintaining a high fluorine atom flux is at the heart of perfluorination techniques.

Moderation of the early stages of direct fluorination may be achieved by further fluorin-

ation of partially fluorinated systems, where the first fluorine may be introduced by

methodology that does not involve the use of elemental fluorine [128] (Figure 2.24).

CH3(-OCH2CH2-)nCH3 + CF2=CFCF3

RFCF2(-OCFCF2-)nCF2RF

RF

RFH RFRF

F 91%

RF = CF2CF2CF3RFH = CF2CFHCF3

i, ii

i, 50% v:v F2 in N2; ii, Room temperature, then 280� C

RFH O O

RFH

RFH = CF2CFHCF3

RF = CF2CF2CF3

F2

RFHCH2(-OCHCH2-)nCH2RFH

½128�

½129, 130�

Figure 2.24

Using these approaches, the successful further fluorination of partly fluorinated esters

has been cleverly developed into a process for the synthesis of the important copolymer

component perfluoro(propyl vinyl ether), PPVE [131] (Figure 2.25).

A quite different, but realistic, approach to temperature control and efficient mixing

involves the use of microreactors [129, 130, 132, 133]; a simple design is shown in Figure

2.26 [129]. These techniques are under active development but microreactor designs are

now available that could be used on an industrial scale for the efficient and safe use of

fluorine.

Polyethylene vessels may be treated with fluorine in a blow moulding process (Airopakt,

Air Products) so as to provide a fluorocarbon coating [134], but it seems highly unlikely that

this treatment can be regarded as simply providing a polytetrafluoroethene (PTFE)



HOCH2CH(CH3)OC3F7 FC(O)CF(CF3)OC3F7

C3F7OCF(CF3)C(O)�OCH2CH(CH3)OC3H7

C3F7OCF(CF3)C(O)�OCF2CF(CF3)OC3F7

2 FC(O)CF(CF3)OC3F7

CF2=CFOC3F7 PPVE

F2

+

i) NaOHii)Heat

∆

½131�

Figure 2.25

Figure 2.26 Reprinted with the permission of the Royal Society of Chemistry

surface [135, 136]. Such containers [137] possess excellent resistance to hydrocarbon

solvent penetration [135, 138], probably because of enhanced cross-linking in the surface,

and have been used successfully as fuel tanks by the automobile industry for many years.

Other techniques of surface fluorination and oxyfluorination have been used to modify

polymer surfaces.


38 Chapter 2

D Fluorinated carbon [139]

Fluorination of graphite at high temperature (300–5008C) gives a white powder which

approximates to the composition (CF)n. X-ray studies indicate that the fluorine atoms are

strongly bonded to carbon but are contained between the graphite layers [140]. Graphite

fluorides have similar properties to PTFE and have been exploited commercially as

speciality lubricants and in high-performance lithium batteries [141].

Direct fluorination of Buckminsterfullerene, C60, has been studied by several groups

[142]. It is claimed that C60F48 can be isolated as an intact sphere [143] and, moreover, as

a single isomer after fluorination at 2508C. Photoelectron spectroscopy studies suggest

that as the level of fluorination is raised above C60F48, carbon–carbon bond cleavage

occurs, thus cracking the sphere [144, 145]. A fluoroxyfullerene, C60F17OF, has been

characterised [146].

Mesophase pitch, derived from coal tar, reacts smoothly with fluorine to give pitch

fluoride [147, 148] with a composition between CF1:3 and CF1:6, as a yellowish white

solid which differs from graphite fluoride in that it is soluble in some fluorocarbon

solvents. Consequently, thin films of pitch fluoride may be deposited on materials

and the resulting surfaces have been claimed to have even lower surface energies than

PTFE.

E Fluorination of compounds containing functional groups

When functional groups are present, the products can be quite complex. Primary and

secondary amines give NF2 and NF compounds respectively and fluorination of sulphur

compounds gives products in which the sulphur has been oxidised to its maximum

valency state of six [149] (Table 2.4). Hydroxy compounds can give fluoroalkyl hypo-

fluorites (fluoroxy compounds) (see also Chapter 3, Section IIIB), the corresponding alkyl

derivatives not being stable [150, 151]; bisfluoroxy derivatives have also been isolated

[152–154] (Figure 2.27).

CH3OH

i, F2, Cu/Ag, 160−180 � C

CO2

i, F2, CsF, −196 � C to rt

CF2(OF)2

CF3OFi

i

½150�

½153�

Figure 2.27

Perfluorinations of many ethers [155], cryptands [156], polyethers [119, 157], includ-

ing the largest perfluoro-macrocycle [158], perfluoro [60]-crown-20 [123, 159], and the

first perfluorinated sugar [160], orthocarbonates [161, 162], ketones [163, 164], esters

[124, 165], phosphanes [166] and alkyl halides [167, 168] have been successfully

accomplished by the LaMar or aerosol processes (Table 2.4).



V HALOGEN FLUORIDES

The reactions of halogen fluorides with organic compounds have been reviewed [174,

175] but their usefulness for the preparation of highly fluorinated substrates is limited to

reactions with the corresponding perhalo-organic compounds [176] (Figure 2.28).

Table 2.4 Fluorination using dilute fluorine

Starting material Product Yield (%) Ref.

Conditions: F2 in He or N2, �788C to rt

(CH3)3CCH2CH2C(CH3)3 (CF3)3CCF2CF2C(CF3)3 89 [169]

C

4

C

4

F 96 [170]

F

F

H3C

H3C F3C

F3C

F 26 [171]

CH2CH2O

(CH3)3C�CH2�SH

n CF2CF2O n

(CF3)3C�CF2�SF5

–

91

[172]

[149]

Conditions: 268C and lower

CH2CH2O20

CF2CF2O20

[159]

Conditions: �908C to rt

O

O

O

O

O

O

O

OF3C

F3C

F3C

O

OCF3

F2

F

F[160]

Conditions: Aerosol fluorination

Cl Cl

F60 [173]

O

O

F3CCF2 O

O CF3

CF3

F 65 [124]


40 Chapter 2

CBr4 CF3Br 94%

CI4 CF3I 95%

BrF3

IF5

½176�

Figure 2.28

Liquid-phase halogenation of hexachlorobenzene with chlorine trifluoride appears to

proceed by a series of additions and vinylic and allylic substitutions until all of the

hexachlorobenzene is converted into chlorofluorocyclohexenes, C6Fn(Cl10�n) (n ¼mainly 4, 5 and 6), and conversion to cyclohexane derivatives occurs only upon the

passage of quite a large excess of chlorine trifluoride [177] (Figure 2.29). The cyclohex-

ene derivatives produced mainly retain the structure 2CCl5CCl2.

A mixture of iodine with iodine pentafluoride, or bromine with bromine trifluoride, will

add iodine monofluoride or bromine monofluoride respectively to fluorinated alkenes;

this constitutes a very convenient route to the corresponding monohalopolyfluoroalkanes

[178, 179], which is of considerable importance to the surfactant business (Figure 2.30).

C6Cl6ClF3, 240�C

C6F7Cl3 (2%) + C6F6Cl4 (10%) + C6F4Cl4 (4%)

+ C6F5Cl5 (30%) + C6F4Cl6 (35%)

½177�

Figure 2.29

2I2 + IF5 + 5CF3CF=CF2150� C

5(CF3)2CFI 99%

2I2 + IF5 + 5CF2=CF2 5CF3CF2I 86% ½178, 179�

Figure 2.30

REFERENCES

1 G.C. Finger in Advances in Fluorine Chemistry, Vol. 2, ed. M. Stacey, J.C. Tatlow and

A.G. Sharpe, Butterworth, London, 1961, p. 35.

2 A.J. Rudge, The Manufacture and Use of Fluorine and its Compounds, Oxford University

Press, London, 1962.


Chichester, 1992.

4 R. Miethen and D. Peters in Houben-Weyl: Methods of Organic Chemistry. Vol. E10a, ed.

B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 95.

5 B. Baasner, H. Hegemann and J.C. Tatlow (eds), Houben-Weyl: Methods of Organic Chemis-try. Vol. E10a, Organo-fluorine Compounds, Georg Thieme, Stuttgart, 1999.

6 R. Stephens and J.C. Tatlow, Quart. Rev., 1962, 16, 44.

7 A.K. Barbour, L.J. Belf and M.W. Buxton, Adv. Fluorine Chem., 1963, 3, 181.

8 G.G. Furin and V.V. Bardin in New Fluorinating Agents in Organic Synthesis, ed. L. German

and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 117.

9 M.A. McClinton and D.A. McClinton, Tetrahedron, 1992, 48, 6555.

10 A. Marhold and E. Klauke, J. Fluorine Chem., 1981, 18, 281.

11 G.A. Olah, G.K.S. Prakash, and J. Sommer, Superacids, Wiley, New York, 1985.



12 J.M. Hamilton, Adv. Fluorine Chem., 1963, 3, 117.

13 B.E. Smart and R.E. Fernandez in Kirk-Othmer Encyclopedia of Chemical Technology, 4th

edition, Vol. 11, ed. M. Howe-Grant, John Wiley and Sons, New York, 1994, p. 499.

14 A.J. Elliot in Organofluorine Chemistry. Principles and Commercial Applications, ed.


15 V.N.M. Rao in Organofluorine Chemistry. Principles and Commercial Applications, ed.


16 A.L. Henne, M.W. Renoll and H.M. Leicester, J. Am. Chem. Soc., 1939, 61, 938.

17 L.V. Johnson, F. Smith, M. Stacey and J.C. Tatlow, J. Chem. Soc., 1952, 4710.

18 A.L. Henne, A.M. Whaley and J.K. Stevenson, J. Am. Chem. Soc., 1941, 63, 3478.

19 C.B. Miller and C. Woolf, US Pat. 2 803 665 (1957); Chem. Abstr., 1958, 52, 2047d.

20 W.E. Truce, G.H. Birum and E.T. McBee, J. Am. Chem. Soc., 1952, 74, 3594.

21 A.L. Henne and P. Trott, J. Am. Chem. Soc., 1947, 69, 1820.

22 A. Latif, J. Ind. Chem. Soc., 1953, 30, 524.

23 A.J. Leffler, J. Org. Chem., 1959, 24, 1132.

24 V.V. Bardin, A.A. Avramenko, G.G. Furin, V.A. Krasilnikov, A.I. Karelin, P.P. Tushin and

V.A. Petrov, J. Fluorine Chem., 1990, 49, 385.

25 J.H. Holloway, E.G. Hope, P.J. Townson and R.L. Powell, J. Fluorine Chem., 1996, 76, 105.

26 L.R. Subramanian and G. Siegemund in Houben-Weyl: Methods of Organic Chemistry, Vol.E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 548.



28 I.N. Rozhkov and I.L. Knunyants, Dokl. Akad. Nauk. SSSR (Eng. Transl.), 1971, 199, 622.

29 A.J. Parker in Use of Dipolar Aprotic Solvents in Organic Chemistry, ed. R.A. Raphael,

E.C. Taylor and H. Wynberg, Wiley-Interscience, New York, 1965, p. 1.

30 J.C. Clark and D. MacQuarrie, J. Fluorine Chem., 1987, 35, 591.

31 R.D. Chambers, J.A. Jackson, W.K.R. Musgrave and R.A. Storey, J. Chem. Soc., 1968, 2221.

32 R.D. Chambers, J. Hutchinson and W.K.R. Musgrave, J. Chem. Soc., 1964, 3573.

33 R.E. Banks, R.N. Haszeldine, J.V. Latham and I.M. Young, J. Chem. Soc., 1965, 594.

34 J.H. Clark, Chem. Rev., 1980, 80, 429.

35 G.G. Yakobson and N.E. Akhmetova, Synthesis, 1983, 169.

36 J.A. Wilkinson, Chem. Rev., 1992, 92, 505.

37 G. Resnati, Tetrahedron, 1993, 49, 9385.

38 N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida and T. Tatsuio, Chem. Lett., 1981, 761.

39 R.E. Banks, K.N. Mothersdale, A.E. Tipping, E. Tsiliopoulos, H.J. Cozens, D.E.M. Wotton and

J.C. Tatlow, J. Fluorine Chem., 1990, 46, 529.

40 Y. Kimura and H. Suzuki, Tetrahedron Lett., 1989, 30, 1271.

41 T.P. Smyth, A. Carey and B.K. Hodnett, Tetrahedron, 1995, 51, 6363.

42 J.H. Clark, A.J. Hyde and D.K. Smith, J. Chem. Soc., Chem. Commun., 1986, 791.

43 T. Ando, S.J. Brown, J.H. Clark, D.G. Cork, T. Hanafusa, J. Ichichara, J.M. Miller and

M.S. Robertson, J. Chem. Soc., Perkin Trans. 2, 1986, 791.

44 V.V. Aksenov, V.M. Vlasov, V.I. Danilkin, P.P. Rodionov and G.N. Shnitko, J. FluorineChem., 1990, 46, 57.

45 H. Liu, P. Wang and P. Sun, J. Fluorine Chem., 1989, 43, 429.

46 C.L. Liotta and H.P. Harris, J. Am. Chem. Soc., 1974, 96, 2250.

47 V.V. Aksenov, V.M. Vlasov, I.M. Moryakina, P.P. Rodionov, V.P. Fadeeva, V.S. Chertok and

G.G. Yakobson, J. Fluorine Chem., 1985, 28, 73.

48 J.H. Clark and D.J. MacQuarrie, Tetrahedron Lett., 1987, 28, 111.

49 Y. Yoshida, Y. Kimura and M. Tomoi, Chem. Lett., 1990, 769.

50 S. Dermiek and Y. Sason, J. Org. Chem., 1985, 50, 879.

51 K.O. Christe, W.W. Wilson, R.D. Wilson, R. Bau and J.A. Feng, J. Am. Chem. Soc., 1990, 112,

7619.


42 Chapter 2

52 D. Albanese, D. Landini and M. Penso, J. Org Chem., 1998, 63, 9589.

53 N. Yoneda, Tetrahedron, 1991, 47, 5329.

54 R.D. Chambers, S.R. Korn and G. Sandford, J. Fluorine Chem., 1994, 69, 103.

55 M. Hudlicky, Org. Reactions, 1988, 35, 513.

56 A.S. Pilcher, H.L. Ammon and P. DeShong, J. Am. Chem. Soc., 1995, 117, 5166.

57 W.B. Farnham and R.L. Harlow, J. Am. Chem. Soc., 1981, 103, 4608.

58 K.O. Christe and W.W. Wilson, J. Fluorine Chem., 1990, 47, 117.

59 A.G. Sharpe, Quart. Rev., 1957, 11, 49.

60 G. Rotenberg, M. Royz, O. Arrad and Y. Sasson, J. Chem. Soc., Perkin Trans. 1, 1999, 1491.

61 F.W. Hoffmann, J. Am. Chem. Soc., 1948, 70, 2596.

62 W. Verbeck and W. Sundermeyer, Angew. Chem., Int. Ed. Engl., 1966, 5, 314.

63 E. Gryszkiewicz-Trochimowski, A. Sporzynski and J. Wnuk, Rec. Trav. Chim., 1947, 66, 413.

64 J.T. Maynard, J. Org. Chem., 1963, 28, 112.

65 R.D. Chambers and A.R. Edwards, J. Chem. Soc., Perkin Trans 1, 1997, 3623.

66 M. Stacey and J.C. Tatlow, Adv. Fluorine Chem., 1960, 1, 166.

67 J. Burdon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner,


68 R.S. Jessup, F.G. Brickwedde and M.T. Wechsler, J. Res. Nat. Bur. Stand., 1950, 44, 457.

69 P.L. Coe, R.G. Plevey and J.C. Tatlow, J. Chem. Soc. C, 1969, 1060.

70 J. Bailey, R.G. Plevey and J.C. Tatlow, J. Fluorine Chem., 1988, 39, 23.

71 J. Bailey, R.G. Plevey and J.C. Tatlow, J. Fluorine Chem., 1987, 37, 1.

72 R.G. Plevey, M.P. Steward and J.C. Tatlow, J. Fluorine Chem., 1973, 3, 259.

73 R.G. Plevey, R.W. Rendell and M.P. Steward, J. Fluorine Chem., 1973, 3, 267.

74 R.D. Chambers, D.T. Clark, T.F. Holmes, W.K.R. Musgrave and I. Ritchie, J. Chem. Soc.,Perkin Trans 1, 1974, 114.

75 J. Burdon, J.C. Creasey, L.D. Proctor, R.G. Plevey and J.R.N. Yeoman, J. Chem. Soc., PerkinTrans 2, 1991, 445.

76 J. Burdon and I.W. Parsons, Tetrahedron, 1975, 31, 2401.


78 R.D. Chambers, B. Grievson, F.G. Drakesmith and R.L. Powell, J. Fluorine Chem., 1985,

29, 323.

79 R.W. Rendell and B. Wright, Tetrahedron, 1979, 35, 2405.

80 R.D. Fowler, W.B. Burford, J.M. Hamilton, R.G. Sweet, C.E. Weber, J.S. Kasper and I. Litant

in Preparation, Properties and Technology of Fluorine and Organic Fluoro-campounds, ed.

C. Slesser and S.R. Schram, McGraw-Hill, New York, 1951, p. 349.

81 B.D. Joyner, J. Fluorine Chem., 1986, 33, 337.

82 R.N. Haszeldine and F. Smith, J. Chem. Soc., 1950, 3617.

83 A.K. Barbour, G.B. Barlow and J.C. Tatlow, J. Appl. Chem., 1952, 2, 127.

84 R.G. Plevey, R.W. Rendell and J.C. Tatlow, J. Fluorine Chem., 1982, 21, 413.

85 P. Johncock, R.H. Mobbs and W.K.R. Musgrave, Ind. Eng. Chem., Proc. Res. Dev., 1962,

1, 267.

86 R.W. Rendell and B. Wright, Tetrahedron, 1978, 34, 197.

87 F.G. Drakesmith in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers,

Springer-Verlag, Berlin, 1997, p. 197.

88 J.H. Simons in Fluorine Chemistry, Vol. 1, ed. J.H. Simons, Academic Press, New York, 1950,

p. 401.

89 J. Burdon and J.C. Tatlow, Adv. Fluorine Chem., 1960, 1, 129.

90 S. Nagase, Fluorine Chem. Rev., 1967, 1, 77.

91 N. Watanabe, J. Fluorine Chem., 1983, 22, 205.

92 P. Sartori, Bull. Electrochem., 1990, 6, 471.

93 T. Abe and S. Nagase in Organofluorine Chemistry. Preparation, Properties and IndustrialApplications, ed. R.E. Banks, Ellis Horwood, Chichester, 1982, p. 19.



94 Y.W. Alsmeyer, W.V. Childs, R.M. Flynn, G.G.I. Moore and J.C. Smeltzer in OrganofluorineChemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and

J.C. Tatlow, Plenum, New York, 1994, p. 121.

95 K. Pohmer and A. Bulan in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed.

B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 305.

96 A. Dimitrov, S. Rudiger, N.V. Ignatyev and S. Datchenkov, J. Fluorine Chem., 1990, 50, 197.


98 E.A. Kauck and J.H. Simons, G.B. Pat. 666 733 (1952); Chem. Abtsr., 1952, 46, 6015c.

99 R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1962, 3407.

100 A.F. Clifford, H.K. El-Shamy, H.J. Emeleus and R.N. Haszeldine, J. Chem. Soc., 1953, 2372.

101 H.M. Scholberg and H.G. Bryce, US Pat. 2 717 871 (1955); Chem. Abstr., 1955, 49, 15572 h.

102 H.W. Prokop, H.J. Zhou, S.Q. Xu, C.H. Wu, S.R. Chuey and C.C. Liu, J. Fluorine Chem.,

1989, 43, 257.

103 T. Gramstad and R.N. Haszeldine, J. Chem. Soc., 1956, 173.

104 R.D. Chambers, R.W. Fuss, M. Jones, P. Sartori, A.P. Swales and R. Herkelmann, J. FluorineChem., 1990, 49, 409.

105 N. Bartlett, R.D. Chambers, A.J. Roche, R.C.H. Spink, L. Chacon and J.M. Whalen, J. Chem.Soc., Chem. Commun., 1996, 1049.

106 J.M. Whalen, L. Chacon and N. Bartlett, Proc. Electrochem. Soc., 1997, 97-15, 1.

107 J.M. Whalen, L.C. Chacon and N. Bartlett in The Oxidation of Oxygen and Related Chemistry– Selected Papers of Neil Bartlett, ed. N. Bartlett, World Scientific, Singapore, 2001, p. 395.

108 K.O. Christe, Inorg. Chem., 1986, 25, 3721.

109 K.O. Christe, N. Watanabe, T. Tojo, S. Rozen, R.J. Lagow, J. Adcock, D.T. Meshri and

D.B. Hage in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner,


110 J.F. Ellis and G.F. May, J. Fluorine Chem., 1986, 33, 133.

111 R.J. Lagow and J.L. Margrave, Prog. Inorg. Chem., 1979, 26, 161.

112 J.M. Tedder, Adv. Fluorine Chem., 1961, 2, 104.

113 W.T. Miller and A.L. Dittman, J. Am. Chem. Soc., 1956, 78, 2793.

114 W.T. Miller, S.D. Koch and F.W. McLafferty, J. Am. Chem. Soc., 1956, 78, 4992.

115 W.T. Miller and S.D. Koch, J. Am. Chem. Soc., 1957, 79, 3084.

116 W.A. Pryor, Free Radicals, McGraw-Hill, New York, 1966.

117 R.R. Lagow in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner,


118 S. Rozen in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner,


119 R.J. Lagow, T.R. Bierschenk, T.J. Juhlke and H. Kawa in Synthetic Fluorine Chemistry, ed.

G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 97.

120 R.J. Lagow in Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol. 11, ed.

M. Howe-Grant, John Wiley and Sons, New York, 1994, p. 482.

121 W.H. Lin and R.J. Lagow, J. Fluorine Chem., 1990, 50, 345.

122 J.L. Adcock, K. Horita and E.B. Renk, J. Am. Chem. Soc., 1981, 103, 6937.

123 J. Adcock in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner,


124 J.L. Adcock in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and

G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 127.

125 T.R. Bierschenk, T. Juhlke and R.J. Lagow, WO Pat. 87/02 992 (1987); Chem. Abstr., 1987,

107, 176772v.

126 T.R. Bierschenk, T. Juhlke, H. Kawa and R.J. Lagow, WO Pat. 90/03 353 A1 (1990); Chem.Abstr., 1991, 114, 231007 w.

127 T. Ono, K. Yamanouchi and K.V. Scherer, J. Fluorine Chem., 1995, 73, 267.

128 R.D. Chambers, A.K. Joel and A.J. Rees, J. Fluorine Chem., 2000, 101, 97.


44 Chapter 2

129 R.D. Chambers and R.C.H. Spink, J. Chem Soc., Chem. Commun., 1999, 883.

130 R.D. Chambers, D. Holling, R.C.H. Spink and G. Sandford, Lab on a Chip, 2001, 1, 132.

131 T. Okazoe, K. Watanabe, M. Itoh, D. Shirakawa, H. Morofushi, H. Okamoto and

S. Tatematsu, Adv. Sci. Synth., 2001, 343, 215.

132 K. Jahnisch, M. Baerns, V. Hessel, W. Erhfeld, V. Haverkamp, H. Lowe, C. Wille

and A. Gruber, J. Fluorine Chem., 2000, 105, 117.

133 N. deMas, A. Gunther, M.A. Schmit and K.F. Jensen, Ind. Eng. Chem. Res., 2003, 42, 698.

134 M. Anand, J.P. Hobbs and I.J. Brass in Organofluorine Chemistry. Principles and Commer-cial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994,

p. 469.

135 F.J. du Toit and R.D. Sanderson, J. Fluorine Chem., 1999, 98, 107.

136 A.P. Kharitonov, Pop. Plastics Packaging, 1997, 75.

137 Various authors, Ind. Res. Dev., 1978, 12, 102.

138 J.P. Hobbs, P.B. Henderson and M.R. Pascolini, J. Fluorine Chem., 2000, 104, 87.

139 D.T. Meshri and D.B. Hage in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a,

ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 209.

140 N. Watanabe, T. Nakajima and H. Touhara, Graphite Fluorides, Elsevier, New York,

1988.

141 G.A. Shia and G. Mani in Organofluorine Chemistry. Principles and Commercial Applica-tions., ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 483.

142 K. Kniaz, J.E. Fischer, H. Selig, G.B.M. Vaughan, W.J. Romanow, D.M. Cox, S.K. Chowdh-

ury, J.P. McCauley, R.M. Strongin and A.B. Smith, J. Am. Chem. Soc., 1993, 115, 6060.

143 A.A. Gakh, A.A. Tuinman, J.L. Adcock, R.A. Sachleben and R.N. Compton, J. Am. Chem.Soc., 1994, 116, 819.

144 A.A. Tuinman, A.A. Gakh, J.L. Adcock and R.N. Compton, J. Am. Chem. Soc., 1993, 115,

5885.

145 D.M. Cox, S.D. Cameron, A. Tuinman, A. Gakh, J.L. Adcock, R.N. Compton, E.W. Hagaman,

K. Kniaz, J.E. Fischer, R.M. Strongin, M.A. Cichy and A.B. Smith, J. Am. Chem. Soc., 1994,

116, 1115.

146 A.D. Darwish, A.K. Abdul-Sada, A.G. Avent, S.M. Street and R. Taylor, J. Fluorine Chem.,

2003, 121, 185.

147 H. Fujimoto, M. Yoshikawa, A. Mabuchi and T. Maeda, J. Fluorine Chem., 1992, 57, 65.

148 H. Fujimoto, A. Mabuchi, T. Maeda, Y. Matsumara, N. Watanabe and H. Touhara, Carbon,

1992, 30, 851.

149 H.N. Huang, H. Roesky and R.J. Lagow, Inorg. Chem., 1991, 30, 789.

150 K.B. Kellog and G.H. Cady, J. Am. Chem. Soc., 1948, 70, 3986.

151 J.H. Prager, J. Org. Chem., 1966, 31, 392.

152 P.G. Thompson, J. Am. Chem. Soc., 1967, 89, 1811.

153 R.L. Cauble and G. Cady, J. Am. Chem. Soc., 1967, 89, 1962.

154 F.A. Hohorst and J.M. Shreeve, J. Am. Chem. Soc., 1967, 89, 1809.

155 D.F. Persico, H.N. Huang, R.J. Lagow and L.C. Clark, J. Org. Chem., 1985, 50, 5156.

156 W.D. Clark, T-Y. Lin, S.D. Maleknia and R.J. Lagow, J. Org. Chem., 1990, 55, 5933.

157 K.S. Sung and R.J. Lagow, J. Am. Chem. Soc., 1995, 117, 4276.

158 M. Biollaz and J. Kalvoda, Helv. Chim. Acta, 1977, 60, 2703.

159 H-C. Wei and R.J. Lagow, J. Chem. Soc., Chem. Commun., 2000, 2139.

160 T.-Y. Lin, H-C. Chang and R.J. Lagow, J. Org. Chem., 1999, 64, 8127.

161 W-H. Lin, W.D. Clark and R.J. Lagow, J. Org. Chem., 1989, 54, 1990.

162 J.L. Adcock, M.L. Robin and S. Zuberi, J. Fluorine Chem., 1987, 37, 327.

163 J.L. Adcock and M.L. Robin, J. Org. Chem., 1983, 48, 2437.

164 J.L. Adcock and H. Luo, J. Org. Chem., 1992, 57, 4297.

165 J.L. Adcock and R.J. Lagow, J. Am. Chem. Soc., 1974, 96, 7588.

166 J.J. Kampa, J.W. Nail and R.J. Lagow, Angew. Chem., Int. Ed. Engl., 1995, 34, 1241.



167 J.L. Adcock, W.D. Evans and L. Heller-Grossman, J. Org. Chem., 1983, 48, 4953.

168 J.L. Adcock and W.D. Evans, J. Org. Chem., 1984, 49, 2719.

169 E.K.S. Liu and R.J. Lagow, J. Fluorine Chem., 1979, 14, 71.

170 R.E. Aikman and R.J. Lagow, J. Org. Chem., 1982, 47, 2789.

171 G. Robertson, E.K.S. Liu and R.J. Lagow, J. Org. Chem., 1978, 43, 4981.

172 G.E. Gerhardt and R.J. Lagow, J. Org. Chem., 1978, 43, 4505.

173 J.L. Adcock, H. Luo and S.S. Zuberi, J. Org. Chem., 1992, 57, 4749.

174 W.K.R. Musgrave, Adv. Fluorine Chem., 1960, 1, 1.

175 L.S. Boguslavskaya and N.N. Chuvatkin in New Fluorinating Agents in Organic Synthesis,

ed. L. German and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 140.

176 A.A. Banks, H.J. Emeleus, R.N. Haszeldine and V. Kerrigan, J. Chem. Soc., 1948, 2188.

177 R.D. Chambers, J. Heyes and W.K.R. Musgrave, Tetrahedron, 1963, 19, 891.

178 R.D. Chambers, W.K.R. Musgrave and J. Savory, J. Chem. Soc., 1961, 3779.

179 M. Hauptschein and M. Braid, J. Am. Chem. Soc., 1961, 83, 2383.


46 Chapter 2

Chapter 3

Partial or Selective Fluorination

I INTRODUCTION

Whereas the previous chapter dealt largely with the synthesis of highly fluorinated

systems, here we will be concerned with methods available for introducing mainly one,

or two, fluorine atoms at specific points in a molecule, although many of these processes

can, of course, be applied to already partly fluorinated systems in order to introduce more

fluorine.

The merits and importance of introducing a single fluorine atom into biologically

significant compounds was discussed in Chapter 1, and many reviews are available

concerning the synthesis of selectively fluorinated compounds [1–20]; the reader

is directed to these for comprehensive literature coverage. The following discussion is

intended to illustrate the types of reagents required to effect replacement of a wide range

of functional groups.

II DISPLACEMENT OF HALOGEN BY FLUORIDE ION

A Silver fluoride

Much early work [21] involved the use of silver(I) fluoride, conveniently prepared from

the oxide or carbonate with 40% hydrogen fluoride, for the exchange of single halogen

atoms in alkyl halides [22] and other systems [23]. The use of calcium fluoride as a solid,

inert support may increase the reactivity of silver fluoride [24] (Figure 3.1).

CH3(CH2)15 CO2Me

Br

CH3(CH2)15 CO2Me

F

i AgF, CH3CN, H2O, 80 � C, 2hr

84%

C8H17I

i AgF, CaF2, 75 � C, 10min

C8H17F 80%

i

i

½24�

Figure 3.1

B Alkali metal fluorides (see also Chapter 2, Section IIB)

Potassium fluoride is used most frequently as a balance between reactivity and economy,

because efficiency decreases in the series CsF > KF > NaF. Different forms of KF are

available and a number of ‘catalysts’ have been used to enhance the reactivity of KF in



aprotic solvents (see Chapter 2, Section IIB). Acid fluorides, alkyl fluorides and fluoro-

aromatics are obtained from the corresponding chlorides by reaction with potassium

fluoride (Figure 3.2). Surprisingly, although it is usually stressed (as we have done in

Chapter 2) that a metal fluoride should be dry, because fluoride ion is deactivated by its

co-ordination sphere in aqueous solution, the addition of small amounts of water is

necessary to obtain halogen exchange [25]. Alternatively, phase-transfer agents or

crown polyethers may achieve the same result. It is the author’s view that these additions

are necessary to remove other metal halide impurities from the surface of the fluoride,

CH3COCl CH3COF

i, KF, CH3COOH, 100 � C

76%

C6H5CH�CHSO2Cl C6H5CH�CHSO2F

i, KF, xylene, reflux

51%

i

i

MF + n-C8H17Bri or ii

n-C8H17F + MBr

i, MF = KF plus small amounts water, 85� C 60%ii, MF = Bu4NF.3H2O, 60 � C 71%

MF + BrCH2COOEti

FCH2COOEt + MBr 70%

i, MF = CsF + 10% Bu4NF, 40 � C

BrCH2CH2OHi

FCH2CH2OH 72%

CH3CH2CHBrCOOEti

CH3CH2CHFCOOEt 78%

i, KF, Hexadecyltributylphosphonium bromide, heat

O(CH2)3OMs

i

O(CH2)3F

92%

N NBuMe

BF4 , H2O (5 equiv), 100 � Ci, KF,

½29�

½30�

½25�

½25�

½27�

½28�

Figure 3.2


48 Chapter 3

because electron spectroscopy for chemical analysis (ESCA) results have demonstrated

[26] that the other metal halide impurities are concentrated on the surface of the fluoride,

even in samples that are ‘pure’ by bulk analysis. More remarkable is the fact that, using

an ionic liquid as solvent, addition of five equivalents of water gave high reactivity

and no elimination product [27]. A semi-molten mixture of potassium fluoride in hexa-

decyltributylphosphonium bromide (m.p. 56–588C) is surprisingly effective [28]

(Figure 3.2).

C Other sources of fluoride ion

The low solubility, highly hygroscopic nature and low reactivity of alkali metal fluorides,

and the sometimes harsh reaction conditions required for these fluorides to effect halogen

exchange, have prompted a search for a source of fluoride ion that is easily handled,

highly reactive, selective and soluble in organic solvents; several reagents possessing

organic, lipophilic counter-ions have been developed for this task with varying degrees of

success [18].

Maximum fluoride ion nucleophilicity is achieved if the reagents are free from mois-

ture; tetrabutylammonium fluoride (TBAF), obtained commercially as the trihydrate, can

be partially dried either by heating at 408C under high vacuum [31] or, chemically, by

reaction with hexamethyldisilazane [32], but prolonged heating of TBAF causes

decomposition to occur via a Hofmann elimination pathway [33]. However, tetramethyl-

ammonium fluoride [34] and adamantyltrimethylammonium fluoride [35] are more

stable and they can be obtained in an anhydrous state by heating under vacuum after

recrystallisation from propanol. Fluoride ion sources have been described that contain

more elaborate counter-ions including tris(dimethylamino)sulphonium difluorotrimethyl-

siliconate (TAS-F) [12], a phosphazenium fluoride [36], cobaltocenium fluoride [37] and

‘Proton Sponge’ (PS) [38] (Table 3.1).

Table 3.1 Halogen exchange by various sources of fluoride ion

Substrate Reagent/Conditions Product Yield (%) Ref.

CH2¼CHCH2Br Bu4NF, 258C CH2¼CHCH2F 85 [33]

Cl

O

Ph

THF=HMPTa, 958C, Bu4NþHF�2

F

O

Ph

[39]

RX 2Bu4NF�nH2O RF [40]

(R ¼ alkyl, X ¼ Cl, Br) CH3CN

PhCH2Br Ph4PHF2 PhCH2F 100 [41]

CH3CN, 508C

PhCH2Cl Cp2CoFb PhCH2F 95 [37]

THF, rt

C2H5I TAS-Fc C2H5F 85 [12]

CH3CN, rt

Contd


Partial or Selective Fluorination 49

Hydrogen fluoride under vigorous conditions may be used in favourable circumstances,

for example to make fluoromethyl ethers [44] (Figure 3.3a).

OH

Cl

+ CCl4

OCCl3

Cl

OCF3

Cl

70%

i

i, HF, 150 � C

½44�

Figure 3.3a

Aromatic systems need to be activated towards nucleophilic attack to enable halogen

exchange to occur (see Chapter 9) and the sulphonyl group has been employed as a

disposable activating group [45] (Figure 3.3b). Addition of triphenyltin fluoride is

claimed to be beneficial [46].

D Miscellaneous reagents

Alkyl bromides are effectively transformed into alkyl fluorides by both chlorine mono-

fluoride [47] (Figure 3.4) and the less reactive bromine trifluoride [48–50]. Since tertiary

Table 3.1 Contd


CH3ðCH2Þ7Br Bu4NþPh3SiF�2 CH3ðCH2Þ7F 85 [42]

CH3CN, 808C

Cl

O

Ph

PS=HFd

CH3CN, rtF

O

Ph76 [38]

Ph Cl

OPyridine�9HF

08CPh F

O[43]

a HMPT, hexamethylphosphoric triamide.

b Cp2CoF

Co F

c TAS-F

[(Me2N)3S]+ [(CH3)3SiF2]− Me2N NMe2

. HF

d PS / HF


50 Chapter 3

Cl

R Cl

SO2Cli

Cl

R F

SO2F

Cl

R Fii, iii

R = H, Mei, KF, Ph4PBrii, NaOHiii, H2SO4, heat

½45�

Figure 3.3b

CH3CH2CH2Br + ClF CH3CH2CH2F + CH3CHFCH3

30% 70%

CH2Cl�CH2Br + BrF3

rtCH2Cl�CH2F 80%

0 � C½47�

½48, 49�

Figure 3.4

bromides react the most readily, and rearrangement occurs on reaction with primary

alkyl bromides, a carbocationic mechanism has been proposed.

The use of p-iodotoluene difluoride for replacement of iodine by fluorine has beeen

described as a nucleophilic displacement of IF2, as a good leaving group, in a pre-formed

iodoalkane difluoride [51]. Note that iodine is displaced in preference to p-TsO in this

system (Figure 3.5a).

RCH2Ii RCH2 IF2

F

RCH2F

i, p-MeC6H4IF2, Et3N.4HF, CH2Cl2

74%R = p-TsO

½51�

Figure 3.5a

However, a Pummerer-type process is involved in the introduction of two fluorine

atoms into phenylsulphanated lactams [52] (Figure 3.5b, p. 52).

The reaction of fluorine or xenon difluoride with iodoalkanes gives fluoroalkanes by

similar processes [53, 54].

III REPLACEMENT OF HYDROGEN BY FLUORINE [55, 56]

A Elemental fluorine

From the previous discussion on extensive fluorination (Chapter 2, Section IV) it might be

assumed that, in general, it will be very difficult to effect the selective replacement of

hydrogen by fluorine in preparatively useful reactions. This has been the perceived

wisdom in the past but the situation is changing rapidly [56].



NPhS

O

ArIF2 NPhS

O

ArIF2 NPhS

O

F

F

I F

Ar

NPhS

O

F

N

O

F

PhS

F

½52�

Figure 3.5b

The first indication that fluorine could be used as a selective fluorinating agent was

reported by Bockemuller in 1933 concerning reactions with butyric acid [57]. Fluorin-

ation only occurs at the b- and g- positions, demonstrating that the regioselectivity of the

process can be heavily influenced by the presence of an electron-withdrawing group in

the substrate. This demonstrates the electrophilic nature of fluorine, although low-

temperature fluorination of hydrocarbons is still much less selective than the correspond-

ing chlorinations [58]. However, hydrogen atoms attached to tetrahedral carbon, through

orbitals with a high p contribution, can be selectively replaced by fluorine when the

reaction is carried out using a polar solvent such as chloroform or nitromethane [11,

59–61]. Even tertiary hydrogens in steroids may be selectively replaced using fluorine

[62, 63] (Figure 3.6). It has been demonstrated that acetonitrile can be an effective solvent

for these reactions, crucially allowing reactions to be carried out at higher temperatures

[64, 65] (Figure 3.7).

1 Elemental fluorine as an electrophile

The question arises as to whether these reactions involve molecular fluorine as an

electrophile or electrophilic fluorine atoms. In principle, nucleophilic attack on fluorine

could be promoted in a number of ways. Interaction of the leaving group, which in this

case is fluoride, with a protonic or Lewis acid has been demonstrated [66] (Figure 3.8) and

we will see that reagents containing bonds from fluorine to oxygen or, especially, to

nitrogen (which provide excellent leaving groups) are particularly effective.

For some reactions with saturated hydrocarbons, an electrophilic process involving a

non-classical three-centre, two-electron transition state similar to other electrophilic

substitutions at s-bonds [67] has been suggested [11, 65] (Figure 3.9). The facts that

the stereochemistry is retained [11, 65] and products of elimination or rearrangement are

not observed, as well as the result of ab initio calculations relating to the fluorination of

methane [68], provide support for this argument. Moreover, there is a very close parallel

between the products arising from reactions of elemental fluorine and of Selectfluort (see

Section IIIC) with alkanes and cycloalkanes [64, 65]. There is an even stronger case for


52 Chapter 3

OR ORF

OR

F

F

AcO

OAc

H

AcO

OAc

F

i, F2, N2, −70 � C, CHCl3, CFCl3 (1:1)

+

60% 10%

R = −CO-C6H4NO2

50%

i

i, F2 in N2(10% v/v), C6H5-NO2, −78 � C, CFCl3, CHCl3

i

½62, 63�

Figure 3.6

H

H

H

F

i, F2 in N2 (10% v/v), CH3CN, 0 � C

i54%, 68% conversion ½11, 64, 65�

Figure 3.7

F H H + HF

COOH

F

COOH

F

Nu: + F

F

Nuc

i, F2/N2, 98% H2SO4, room temp.

i

½66�

Figure 3.8



H FH

F F HCCl3

OCOC6H4NO2

Me

OCOC6H4NO2

Me F

i, F2, N2, −70 � C, CHCl3, CFCl3 (1:1)

60%i

½11, 65�

Figure 3.9

N–F reagents acting as electrophiles, because radical clock experiments with these

systems do not support a radical process [69, 70].

Consequently, in a given situation, the question as to whether a fluorination involves

fluorine atoms (which themselves are very electrophilic, and such processes will therefore

have polar characteristics) or nucleophilic attack on a molecule of elemental fluorine is

difficult to assess. Both processes almost certainly occur, depending on the system and

conditions.

The changing perspective on the viability of fluorine as a reagent is illustrated by the

fact that many selective fluorinations of substrates [8] containing carbon centres of high

electron density have now been described, including a variety of enolate derivatives [71,

72], stabilised carbanions [73, 74], steroids [75] and 1,3-dicarbonyl derivatives [76]

(Table 3.2) as well as some aromatic compounds [77]. Fluorinated aminoacids have

been obtained by direct fluorination [78] (Figure 3.10).

Table 3.2 Selective fluorinations with elemental fluorine

Substrate Conditions Product Yield (%) Ref.

OSiMe3 F2, N2

�788C, CFCl3

OF

78 [71]

OEt

OSiMe3 F2, N2

�788C, CFCl3 OEt

O

F

57 [79]

NO2

HO2N

OHi) OH�

ii) F2, N2, 58C, H2O

NO2

FO2N

OH84 [74]

Contd


54 Chapter 3

COOMe

NHCOPh

F2COOMe

NHCOPh

R = Alkyl or aryl

H

RRCHF F

COOH

NH2

RCHF F

COOH

NHCOPhRCHF F ½78�

Figure 3.10

It has been established that elemental fluorine can be used to functionalise saturated

sites in a two-step process using BF3 and this is one of the more direct methodologies, for

this purpose, that has been described so far [65] (Figure 3.11).

H

H

i

StereochemistryRetained

F

H

ii

H

N

H

HMe

O

iiii, F2, CH3CN, 0 � Cii, BF3.Et2Oiii, CH3CN, H2O

½65�

Figure 3.11

Table 3.2 Contd

Substrate Conditions Product Yield (%) Ref.

O

OEt

O

F2, N2

108C, HCOOH

O

OEt

O

F

90 [76]

O

O

OHO

O

F2, N2

�408C, CH3CNO

OOHC

O

O

F 71 [80]



B Electrophilic fluorinating agents containing O–F bonds [81, 82]

Several organic hypofluorites, including trifluoromethyl (CF3OF) [83–85], perfluoroethyl

(C2F5OF) [86], trifluoroacetyl (CF3COOF) [87] and acetyl hypofluorite (CH3COOF)

[88, 89], are now known which have found applications as fluorinating agents [90–94]

(Figure 3.12).

OCF3 FNu: + F Nu + OCF3

R

R'

H

COOR''i, ii R'

R

OSiMe3

OR''

iiiR

R'

F

COOR''

i, LDAii, Me3SiCliii, MeCOOF

R = R' = n-Pr, R'' = Me, 90%R = Ph, R' = Et, R'' = Me, 80%

½89�

Figure 3.12

The ability of fluorine to act as an electrophile in these systems is achieved not so much

by the withdrawal of electronic charge from fluorine but by the creation of excellent

leaving groups attached to fluorine. If a good leaving group is not incorporated in this

way, the hypofluorites can act as sources of positively charged alkoxonium ions, as in the

cases of methyl and tert-butyl hypofluorite [95, 96] (Figure 3.13), rather than as electro-

philic fluorinating reagents.

R1 R2 R1 R2

F OMe

i, MeOF, CH3CN, −40 � C Room Temp

C6H5-CH=CH2

i, t-BuOF, CH3CN

CHC6H5-C

Fδ +

δ −δ +

δ −

60-70%i

i

C6H5-CHFCH2Ot-Bu

Ot-Bu

½95�

½96�

Figure 3.13


56 Chapter 3

However, single-electron transfers promoted by photolysis, are the most likely pro-

cesses when CF3OF is used as the fluorinating reagent [93]. Examples of the use of

hypofluorites for conversion of C2H to C2F bonds are given in Table 3.3.

Caesium fluoroxysulphate (CsSO4F) [94] is a solid electrophilic fluorinating agent that

is very easily prepared [100] (Figure 3.14) but, unfortunately, is very prone to rapid

uncontrolled decomposition. However, it has been used for the fluorination of hydrocar-

bons [101] and aromatics [102–104] (Figure 3.15).

Cs2SO4 + F2 CsSO3OFH2O ½100�

Figure 3.14

p-XC6H4SnMe3

i, CsSO3OF, CH3CN, −4 to 0 � C

p-XC6H4F

X = H, 69%; = Cl, 87%; = Me 86%

i, CsSO3OF, BF3, CH3CN

FC6H4RC6H5Ri

i

½102�104�

Figure 3.15

Table 3.3 Fluorinations using O–F reagents


NO2 i) MeONa, MeOH

ii) AcOF, CFCl3, 08C

F NO2

85 [97]

O

i) LDA, THF

ii) AcOF, �788C

OF

86 [98]

OEt

O OAcOF,

CFCl3, CHCl3, � 758C OEt

O O

F

72 [99]



C Electrophilic fluorinating agents containing N–F bonds[105–107]

There is now available a range of stable, easily handled, solid electrophilic fluorinating

agents of the N–F type. These remarkable reagents are generally prepared by reaction of a

neutral base [108] or a salt [109] with fluorine (Figure 3.16).

N

N

CH2Cl

(CF3SO2)2NH +

N

N

(CF3SO2)2NFF2

CH2Cl

F

HF+

2BF4BF4

i, F2, N2, NaBF4, CH3CN, −35 � C

i

Selectfluor®

½108�

½109�

Figure 3.16

Reported reagents of this class include N-fluorobis(trifluoromethanesulphonyl)imide

[110, 111], N-fluoro-N-alkyl-sulphonamides [112], dihydro-N-fluoro-2-pyridone [113],

N-fluoropyridinium salts [114–116], N-fluoroquinuclidinium [117] and related salts [118,

119], N-fluoroperfluoroalkyl sulphonamides [120, 121] and N-fluorosultams [122], some

of which are commercially available (e.g. Selectfluort, Air Products). Many fluorinations

of resonance-stabilised carbanions [119], phosphonates [123], 1,3-dicarbonyls [124, 125],

enol acetates [115], enol silyl ethers [119], enamines [119], aromatics (Chapter 9), double

bonds and compounds containing carbon–sulphur bonds [126] have been performed under

mild conditions (Table 3.4) and even enantioselective fluorinations of enolates are

possible when appropriate homochiral N-fluorosultams are used [127, 128], or other

homochiral substrates [129]. Considerable encouragement is given by reports of relatively

high enantioselectivity in some processes where N–F compounds have been used in the

presence of various chiral catalysts [130, 131], although the latter are currently used in

significant proportions.

Table 3.4 Fluorinations using electrophilic N–F fluorinating reagents

Substrate Reagent/Conditions Product Ref.

PhOMe

CH3

O

S

N

Me Me

F

O O

PhOMe

CH3

O

F

[122]

n-Pr P

O

OEtOEt

LDA, THF, �788C to rt

PhSO2Þ2NF�

LDA, THF

n-Pr P

O

OEtOEt

F F

[123]

Contd


58 Chapter 3

It is frequently overlooked that, following fluorination, some of these systems, e.g.

Selectfluort, are extremely acidic and may, consequently, ionise the carbon–fluorine

bond just formed, leading to a carbocation and subsequent reaction with the solvent

(see Section IIIA) [65].

These fluorinations are generally considered to proceed by nucleophilic attack on

fluorine, rather than via an electron-transfer mechanism [115], as determined from radical

Table 3.4 Contd

Substrate Reagent/Conditions Product Ref.

O OCF3SO2Þ2NF�

CH2Cl2, rt

O O

F

[124]

Ph NMe2

O O

N

N

CH2Cl

F

2BF4−

Ph NMe2

O O

F

[125]

CH3CN, rt

OSiMe3

N

F

OTf−

O

F

[115]

CH2Cl2, reflux

OAcO U

S-ArAcO

N

N

CH2Cl

F

2BF4−

OAcO U

S-ArAcO

F [126]

Et3N, CH3CN, rt

O

CO2Et

N

SF

O

O

O

F

CO2Et [127]

NaH, Et2O, rt



clock experiments [69, 70]. Consistent with this view, ionic liquids have been used as

solvents for fluorinations of aromatic systems with Selectfluort [132, 133] and supercrit-

ical carbon dioxide has been used with 2,2’-bipyridinium fluorides [134].

D Xenon difluoride [135–137]

This reagent acts as a source of electrophilic fluorine but the nature of the products can

depend on the acidity of the glass surface of the vessel used. Otherwise a single electron

transfer process may intervene [138] (Figure 3.17).

+ +

i ii

i) Aprotic conditionsii) Protic conditions

OSiMe3

O

F

O

F

O

OO

X X

F

X = O, CH2

i, XeF2, BF3.OEt2

i

XeF2XeF2

½139�

½138�

Figure 3.17

Xenon difluoride has also been used for the fluorination of enol derivatives [5] and

1,3-dicarbonyl compounds [140], and fluorination of activated aromatic substrates is

possible in the presence of a Lewis acid [141].

E Miscellaneous

Fluorinations using perchloryl fluoride (FClO3) have been reported [17, 142] but, since

the perchloric acid that is formed as a side-product gives an explosive mixture with

organic compounds, this approach to selective fluorinations is not recommended.

Fluorination of hydrocarbons, such as adamantane, is possible using a mixture of

nitrosonium tetrafluoroborate and pyridine�HF [143] (Figure 3.18).

Oxidative fluorination of phenols in amine�HF solution gives difluorodienones [144]

(Figure 3.19).

Fluorination of aromatic substrates has been reported [145].


60 Chapter 3

H

NO

R3C�H R3C

R3C

R3C�NO

R3C�F

i, NO+BF−4, Py.HF

i ½143�

Figure 3.18

OH O

F F

30%

i, PbO2, Py.HF

i½144�

Figure 3.19

Oxidative fluorination of toluene derivatives to the corresponding fluoromethylben-

zenes is possible using appropriate lead or nickel complexes in liquid hydrogen fluoride,

but fluorination becomes more difficult as the reaction progresses because fluorine

substituents increase the oxidation potential of the substrate [146] (Figure 3.20). Conse-

quently, it seems unlikely that the ECF process (Chapter 2, Section III) could proceed to

perfluorination by an analogous mechanism.

HF, −e

−e

etc

−H+Pb(OAc)4Ar�CH3 (Ar�CH3) Ar�CH2

Ar�CH2Ar�CH2FAr�CF2H

Ar = p-C6H4NO2

½146�

Figure 3.20

a-Fluoro sulphides may be prepared by reaction of the parent sulphides with

either XeF2 [147], an N–F-type reagent [148], or anodic fluorination in Et3N�3HF as

the electrolytic medium [149, 150]. A Pummerer-type mechanism has been proposed

(Figure 3.21a).

RS

CH3 RS

CH3

F

S CR

F

RS

CH2F

H

H

−H

Figure 3.21a

Similarly, a-fluoro sulphoxides are prepared by fluorination using DAST [151].



Remarkably, iodine pentafluoride in Et3N�3HF acts, in some cases, like an

electrophilic fluorinating agent, replacing C2H in preference to oxygen functions [152]

(Figure 3.21b).

F F

COCH2SEt

i, ii

F F

COCF2SEt

82%

CH3COCH2COOEt + IF5

i, iiiCH3COCHFCOOEt

71%i, Et3N.3HFii, heptane 74� Ciii, heptane 40� C

+ IF5

½152�

Figure 3.21b

IV FLUORINATION OF OXYGEN-CONTAINING FUNCTIONALGROUPS

A Replacement of hydroxyl groups by fluorine

1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent

The low boiling point and the health hazard associated with anhydrous hydrogen fluoride

makes it very difficult to handle in the laboratory, even though it is used extensively by

industry. Various amine/hydrogen fluoride complexes, which are markedly less volatile

and less acidic than hydrogen fluoride, have been prepared and used as fluorinating agents

[15, 153]. The most commonly used base/HF systems are triethylamine tris(hydrogen-

fluoride) and pyridinium poly(hydrogenfluoride) (PPHF, Olah’s reagent). Secondary

and tertiary alcohols can be converted to the corresponding fluorides by reaction

with pyridine�ðHFÞn [43] (Figure 3.22). Preferential fluorination of tertiary alcohols over

OH F

OH F

i, Pyridine.(HF)n, 20 � C, 2 hr

99%

95%

i

i, Pyridine.(HF)n, 20 � C, 1 hr

i

½43�

Figure 3.22


62 Chapter 3

secondary hydroxyl groups is possible, due to the much higher reactivity of tertiary

hydroxyl groups towards pyridine�ðHFÞn [154] (Figure 3.23).

O

HO

OH O

HO

F

i, Pyridine.(HF)n, −35� C, CH2H2

i ½154�

Figure 3.23

Proton Sponge�HF (Figure 3.24) is a particularly useful system which is an effective

fluoride-ion donor for appropriate fluorinations [38, 155]; it is likely that the proton in this

system is much less involved in H-bonding to fluoride than is the proton in hydrogen

fluoride.

Me2N NMe2

H

FProton Sponge. HF (PS.HF)

PS.HF + CF2�CFCF3

i(CF3)2CF

C3F6F3C

F3C

C2F3

F

72%i, CH3CN, rt

N

NH

Cli

N

NH

F + PS.HCl

i, PS.HF, CH3CN, rt79%

½38�

Figure 3.24

A combination of IF5 with Et3N�3HF appears to be effective in replacing hydroxyl

[152] (Figure 3.25).

2 Diethylaminosulphur trifluoride (DAST) and related reagents [156–158]

DAST was first used as an alternative fluorinating agent to sulphur tetrafluoride, by

Middleton [159]. Although DAST, prepared by the reaction of SF4 with diethylamino-

trimethylsilane [160] (Figure 3.26), can be used in normal laboratory glassware at



p-CH3-C6H4-CH2OH p-CH3-C6H4-CH2Fi, ii

83%i, Et3N.3HFii, CH2Cl2

+ IF5 ½152�

Figure 3.25

Et2N�SF3 + Me3SiFSF4 + Et2N�SiMe3

DAST

½159�

Figure 3.26

atmospheric pressure, care must be exercised since it may decompose violently above

508C [161]. Consequently, more stable analogues such as the morpholino [162] and

piperidino derivatives have been used and a methoxyethyl derivative has become com-

mercially available, MeOCH2CH2Þ2NSF3

�(Deoxo-Fluort, Air Products Company)

[163].

Primary, secondary, tertiary and allylic hydroxyl groups are replaced by fluorine in

excellent yields [12, 164] via a process involving an intermediate alkoxysulphur difluor-

ide, the presence of which is supported by both spectroscopic [165] and chemical

evidence [166] (Figure 3.27).

R�O�SF2NEt2R�OH + Et2N�SF3 R�F + FSONEt2F ½165, 166�

Figure 3.27

For most substrates SN2 replacement of hydroxyl by fluorine occurs with complete

inversion of configuration [12] although retention of stereochemistry is observed when

neighbouring groups containing either C5C double bonds, oxygen or nitrogen become

involved in the reaction centre [17]. Allylic alcohols may be converted to mixtures of

isomeric allyl fluorides by either an SNi or SN20 process [12] (Figure 3.28).

R

OSF

F NEt2

R

OSF

F NEt2

F

SN2'

RF

SNi

½12�

Figure 3.28


64 Chapter 3

Such is the versatility of DAST and related reagents that many fluorinated derivatives

of natural products, including steroids, carbohydrates, nucleosides, prostaglandins and

vitamin D analogues, amongst others, have been successfully synthesised [10, 16, 17]

(Table 3.5).

Generally, sulphur tetrafluoride can only be used for fluorodehydroxylations of acidic

alcohols, otherwise extensive decomposition to side-products predominates. However,

b-fluoroamino acids can be prepared by such a process [7].

3 Fluoroalkylamine reagents (FARs) [170]

Fluoroalkylamine reagents (FARs) such as the Yarovenko reagent [171], Et2N�CF2CFClH,

and Ishikawa’s reagent [172], Et2N�CF2CFHCF3, have been used to fluorinate alcohols,

carboxylic acids and hydroxyamino acids [173–175] (Figure 3.29), most probably by a

process outlined in Figure 3.30. More recently, the adduct to tetrafluoroethene,

Me2N�CF2CF2H, has been shown to be a viable alternative reagent [176].

Enantio-controlled processes have been developed [177]; polymer-supported [178]

FARs and other related systems such as PhCF22NMe2 have also been studied [179],

and reactions in supercritical carbon dioxide have been reported [180].

2,2-Difluoro-1,3-dimethylimidazoline (DFI) has recently been prepared and is

very useful for replacing OH in alcohols by F. Carbonyl is converted to CF2 with

accompanying elimination in some cases, whereas carboxyl is not converted to CF3

[181] (Figure 3.31).

Table 3.5 Replacement of hydroxyl groups by fluorine

Substrate Reagents/Conditions Product Yield (%) Ref.

n-C8H17OH DAST n-C8H17-F 90 [159]

CH2Cl2, �708C to rt

PhCH2CH2OH Deoxo-Fluort PhCH2CH2F 85 [163]

CH2Cl2, rt, 16 h

O

OMeHO

F

HO

HO

DAST

CH2Cl2, �408C to rt O

OMeHO

F

F

HO71 [167]

Et2OÞ2POCHðOHÞPh�

DAST Et2OÞ2POCHFPh�

53 [168]

CH2Cl2, rt

OH3C

O

O

SPh

OH

DAST

CH2Cl2, 08C

OH3C

O

O

F

SPh

[169]



HO

O

F

O

HO OMe

O

F OMe

O

45%

57%

i, Et2NCF2CFClH, CH2Cl2

i, Et2NCF2CFHCF3, CH2Cl2, 18 hr

i

i½173�175�

Figure 3.29

N CEt

EtCFHCF3

F

F

N CEt

EtCFHCF3

F

RO

H

N CEt

EtCFHCF3

F

O

N CEt

EtCFHCF3

F

O

N CEt

EtCFHCF3

O

R H

RR

N CEt

EtCFHCF3

O

R F

−F

+ F

−F

−H

Figure 3.30

B Replacement of ester and related groups by fluorine

Fluoride-ion substitution of an acetyl group has, generally, been limited to the preparation

of glycosyl fluorides [182] (Figure 3.32).

However, displacement of sulphur ester groups such as tosylate [183], mesylate [184]

and triflate [185] groups are of much greater synthetic importance. These excellent

leaving groups are readily displaced by an active source of fluoride ion; this process

represents an efficient method for the overall transformation of hydroxyl groups to

fluorinated derivatives (Figure 3.33).

C Fluorination of carbonyl and related compounds

1 Sulphur tetrafluoride and derivatives

Sulphur tetrafluoride, a colourless gas (b.p. �388C) with toxicity of the same order as

phosgene, has been commercially available since a practical method for its synthesis was


66 Chapter 3

NNMe Me

O

COCl2NN

Me MeCl

Cl

KFNN

Me MeF F

DFI

n-C8H17OH

i, iii

n-C8H17F 87%

p-HOC6H4-NO2

i, ii

p-FC6H4-NO2 62%

O

i, iv

F F F

21% 72%i, DFIii, CH3CN, 25 � Ciii, CH3CN, 85 � Civ, Glyme, 85� C

½181�

Figure 3.31

O

OO

O

O

OCOCH3

i, HF, CH3NO2, Ac2O, 0 � C, 3 hr

O

OO

AcO

AcO

F

i½182�

Figure 3.32

developed [186, 187] (Figure 3.34), although it is difficult to purify [188]. Its most general

function is to exchange C5O for CF2 and it is usefully applied to the conversion of

aldehydes and ketones to the corresponding difluorides, and of carboxylic acids (via the

acid fluoride) to trifluoromethyl derivatives. Many examples have been documented and

reviewed [2, 7, 156, 189] (Figure 3.35).

The observation that anhydrides are not as reactive as carboxylic acids led to the use of

acid catalysts with sulphur tetrafluoride; reactions are frequently carried out in the

presence of anhydrous hydrogen fluoride, while BF3, AsF3, PF5 and TiF4 are also potent

catalysts [190]. Conversions can be achieved in the presence of a wide range of other

functional groups, for example bromo, chloro and unsaturated functions, although under

some circumstances halogen exchange occurs [191]. Exchange of C5O for CF2 occurs in

many classes of carbonyl compounds [2, 7, 156, 189], such as amides, esters,

1,2-dicarbonyls, hydroxy ketones, lactones, acid halides, carboxylic acids, some quinones



n-C8H17OSO2C6H4CH3 n-C8H17F

OCH3

O

OSO2CH3

OCH3

O

F

O

ClOSO2CF3

O

Cl

F

i, KF, PEG 400, 27hr, 50� C

59%

i, KF, HCONH2, 60 � C, 20 torr

83%: 96% e.e.

i, Bu4NF, THF, 4 hr

65%

i

i

i

½183�

½184�

½185�

Figure 3.33

3 SCl2 + 4 NaF SF4 + S2Cl2 + 4 NaCl 90%CH3CN, 70 � C

3SCl2 + 4Py.(HF)n SF4 + S2Cl2

½186�

½187�

Figure 3.34

C6H5�CHOSF4, 150 � C

81%C6H5�CHF2

80%SF4, 170 � C

CF3C CCF3HOOCC CCOOH

Figure 3.35

and fluoroformates (Table 3.6). Quite reasonably, the mechanism has been formulated as

in Figure 3.36 [190]. Conversion of benzene-1,3,5-tricarboxylic acid to the corresponding

tris (trifluoromethyl) compound provided a new source of bulky ligands for the organo-

metallic chemist [192] (Figure 3.37).

The intervention of a radical process has been suggested to account for the anomalous

reaction with anthrone, leading to exchange of hydrogen for fluorine rather than attack at

the carbonyl group [193] (Figure 3.38).

Aminosulphur trifluorides, which are easier to handle than SF4, can also be used for the

conversion of most aldehydes and ketones to difluoromethylene derivatives; numerous

examples have been documented [12] (Table 3.6). A similar reaction mechanism to that

for SF4 may be assumed.

Molybdenum hexafluoride [201], chlorine monofluoride [49] and phenylsulphur tri-

fluoride [202] have all been used to perform similar transformations in a limited number

of cases.


68 Chapter 3

C OXFn

C O XFn

SF4C O XFn

F SF3

C

F

O SF3 + XFnC

F

O SF2

F

F XFn−1

C F

F

+ SOF2 + XFnXFn = Lewis Acid

δ δ δδ½190�

Figure 3.36

HOOC

COOH

COOH F3C

CF3

CF3 F3C

CF3

CF3

Lietc ½192�

Figure 3.37

F F

82%

i, SF4, HF, CH2Cl2

O O

i ½193�

Figure 3.38

D Cleavage of ethers and epoxides [157]

The reaction between epoxides and HF gives fluorohydrins and, generally, other

products resulting from extensive polymerisation. However, the acidity and reactivity

of HF may be decreased by the addition of a base, either an amine or KF, or by

complexation with a Lewis acid, such as borontrifluoride etherate [174]. Consequently,

pyridine�HF, Et3N�3HF [203] and i-Pr2NH�3HF [204] efficiently cleave epoxides to

give excellent yields of fluorohydrins (Figure 3.39).

O FH

H

OHi-Pr2NH.HF ½204�

Figure 3.39

The regioselectivity of the reaction is dependent on the hydrofluorinating reagent used.

Pyridine�ðHFÞn is highly acidic and the reaction proceeds by protonation of the ring

oxygen, followed by fluoride ion attack on the carbon atom upon which the developing



positive charge is most readily stabilised. Conversely, i-Pr2NH�3HF is not sufficiently

acidic to protonate the ring oxygen significantly and so ring opening occurs by fluoride-

ion attack at the least hindered carbon atom in an SN2 process [205] (Figure 3.40). Larger

oxygen-containing rings can also be cleaved [206] (Figure 3.41).

Recently, silicon tetrafluoride [207] and tetrabutylphosphonium fluoride [208] have

been used to prepare fluorohydrins from epoxides. Generation of a superacid is required

for the ring opening of a perfluorinated oxirane [209] (Figure 3.42).

Silyl ethers may be cleaved by either Bu4NF=CH3SO2F [210] or ArPF4 [211] to give

alkyl fluorides. Fluoroformates decarboxylate, on heating in the presence of an acid

catalyst, to give the corresponding fluoride [212, 213] (Figure 3.43).

Table 3.6 Fluorination of carbonyl and related groups

Substrate Reagent, conditions Product Yield (%) Ref.

C6H5CHO SF4, 1508C, 6 h C6H5CF2H 81 [194]

C6H5CHO Deoxo-Fluort, rt C6H5CF2H 95 [163]

O

O O

O

SF4, 1308C

O

O F

F

F

F [195]

N

CO2H

SF4, 1008C

N

CF3

25 [196]

CO2H

CO2H

CO2H

CO2H

SF4, HF, 2008C

CF3

CF3

O

F F

F F

76 [197]

HO2C CO2H

HO2C CO2H

SF4, HF, 1408C

F3C CF3

F3C CF3

18 [198]

OOMe

O O

O

H

DAST, CH2Cl2, rt

OOMe

O O

HF2C

45 [199]

C6H5COCH2F DAST, benzene, 508C C6H5CF2CH2F 82 [200]


70 Chapter 3

O

OBu OBu

F

OH

OBu

OH

F

+

Reagent : i-Pr2N.3HF Ratio : 6 1 Yield, 81% Pyridine.HF 1 4 68%

½205�

Figure 3.40

O

F F

F F

CF3

COF

HF, 95 � C½206�

Figure 3.41

O CF3F

F CF3

(CF3)3COH 56%

i, HF, SbF5, 100 � C

i ½209�

Figure 3.42

OCOF F

i, AlF3, HF, 200−300 � C

i

Me MeOCOF

i

Me MeF

i, HF, 130 � C 69-75%

½212, 213�

½214�

Figure 3.43

V FLUORINATION OF SULPHUR-CONTAINING FUNCTIONALGROUPS

Several methods concerning the formation of CF, CF2 and CF3 groups by fluorodesul-

phurisation [215, 216] processes have been reported (Table 3.7). Generally, these fluor-

inations are achieved by first activating the C2S or C5S bonds by complexation of the

sulphur atom with a thiophilic reagent, such as an iodonium-ion source, followed by

nucleophilic attack at the carbon atom, now a site of developing positive charge, by

fluoride ion (Figure 3.44).



Table 3.7 Fluorodesulphurisation reactions


O

BnO

BnOBnO

BnOS-Ar

p-MeC6H4-IF2

CH2Cl2, � 788C to rt

O

BnO

BnOBnO

BnO

F

[217]

n-Pr

CF3

S S Pyridine�ðHFÞn, NBSa

�78�C to rtn-Pr

CF2CF3

[218]

Ph

S S

Br

F2, I2, CH3CN, rt

CF2Ph

Br[219]

S S

C6H11 H

BrF3

CF2H

70 [220]

OMe

S

DASTb, CH2Cl2, rtO

F

S

[221]

S

C(SEt)3Pyridine�ðHFÞn, NBS

�788C to rt S

CF3 [222]

S

SEtBr

BrF3, 08C

Br CF3

[223]

MeO

N

S

SMe

PhCH2

Bu4Nþ H2F�3

NBS, rt

MeO

NCF3

PhCH2

[224]

a NBS, N-bromosuccinimide.b DAST, diethylaminosulphur trifluoride.


72 Chapter 3

C S R C S R

I

C F

F

I

Figure 3.44

More recently, dithionylium salts (3.45A) have been explored for reactions with diols,

amines and even azide [225], in the presence of fluoride sources, and an electrophilic

brominating agent 5,5-dimethylhydantoin (DBH) to effect desulphurisation. High yields

are obtained under very mild conditions (Figure 3.45).

S

S

R CF3SO3

3.45A

RCF2N3

89%

i-iv

i, Me3SiN3, CH2Cl2, 0�Cii, Bu4NF, THF, 0�Ciii, Et3N.3HFiv, DBH

½225�

Figure 3.45

VI FLUORINATION OF NITROGEN-CONTAININGFUNCTIONAL GROUPS

A Fluorodediazotisation [226]

In the classic Balz–Schiemann reaction [227, 228], arylamines are converted to fluoro-

aromatics via the corresponding diazonium tetrafluoroborate salts. The leaving group,

molecular nitrogen, is lost on pyrolysis and the mechanism appears to involve formation

of an aryl cation, which then abstracts fluoride ion from the tetrafluoroborate counter-ion

(Figure 3.46). Variations of this procedure include the use of nitrite esters [229] as

alternative nitrosating agents and the decomposition of hexafluorophosphate [230] and

hexafluoroantimonate [231] diazonium salts. Photolysis [232], rather than pyrolysis, has

been successfully used for the decomposition stage. When anhydrous HF, or the less

volatile pyridine�ðHFÞn, is used as the reaction medium, isolation of the intermediate is

unnecessary because decomposition of the diazonium salt occurs in situ. Many fluorinated

aromatics can be prepared (Table 3.8) and, indeed, fluorobenzene is manufactured on a

multi-ton scale using this methodology. Benefits arising from the use of ionic liquids have

been claimed [233].

Ar�NH2

i, HCl, NaNO2ii, HBF4

Ar�N2 BF4heat

Ar�Fi, ii ½227, 228�

Figure 3.46



R COOH

H2N H

R

N2 H

HO

O

R

HO H

O

R COOH

F H

(HF)nF

½234�

Figure 3.47

By a similar process, amino acids have been converted to a-fluorocarboxylic acids by

fluorodediazotisation processes [234] and, generally, retention of configuration is ob-

served due to neighbouring group participation of the adjacent carboxyl group (Figure

3.47 and Table 3.8).

B Ring opening of azirines and aziridines

Aziridines may be ring-opened regioselectively by either HF or amine�HF mixtures to

give b-fluoroamine derivatives [239, 240]. The mechanism, either SN1 or SN2, and

consequently the stereochemical outcome of the reaction are greatly influenced by the

precise nature of both the aziridine and the fluorinating agent used. For example, phenyl-

substituted aziridines can be considered to react via the most stable carbocation in an SN1

process, which accounts for the mixture of stereoisomers obtained [239] (Figure 3.48).

1-Azirines also may be ring-opened in a similar manner [241].

Table 3.8 Fluorodediazotisation


Me

NH2

Me

i, NaNO2, HCl

ii, HBF4

iii, Heat

Me

F

Me

[235]

N NH

H2N CO2Eti, NaNO2, HBF4

ii, hn, HBF4, � 508CN NH

F CO2Et39 [236]

N

NH2

NaNO2, pyridine�HF

N

F

93 [237]

H3C COOH

H2N H

NaNO2, pyridine�HFR COOH

F H

76 [238]


74 Chapter 3

HN

Ph Me

HH

Ph Me

HNH2

H2N

Ph Me

HH

H Me

PhNH2

Ph Me

HNH2F F

69% 8%

+

H

F

½239�

Figure 3.48

C Miscellaneous

Nucleophilic substitution of nitro [242, 243] and trimethylammonium groups [244] by

fluoride ion has been employed for the preparation of a number of fluoroaliphatic and

fluoroaromatic substrates (Figure 3.49).

NO2

NO2

NO2

F

N(CH3)3

NO2

18F

NO2

KF, sulpholan(NO2)2CF2 59%(NO2)3CF

70%

ClO4

i, Me4NF, DMSO, 100� C, 4 hr

i, Cs18F, DMSO, 120� C

91%

i

i

½242, 243�

½242, 243�

½244�

Figure 3.49

Hydrazones can be converted into gem-difluorides upon reaction with either fluorine

[245], bromine monofluoride (generated in situ) [246] or ‘iodine monofluoride’ [247],

and the reaction of diazoketones with fluorine results in similar transformations [248]

(Figure 3.50).



CH3

NNH2

CF2CH3

EtO OEt

O O

N2

EtO OEt

O O

i, Pyridine.(HF)n, NBS, CH2Cl2

F F

60%

70%

i, F2, CFCl3, −70 � C

CH3

NNH2

‘IF’

CF2CH3

80%

i

i

½248�

½246�

½247�

Figure 3.50

VII ADDITIONS TO ALKENES AND ALKYNES [249]

A Addition of hydrogen fluoride

Addition of hydrogen fluoride to alkenes proceeds, as might be expected, via transaddition in a typical Markovnikov process, with the complicating effect of cationic

polymerisation of the alkenes [250] (see also Chapter 7). However, side-products

resulting from polymerisation of the alkene may be reduced by performing the reaction

in a lower-acidity amine�HF mixture [43] (Figure 3.51).

F

CH3�CH�CH2

HF, −45 � CCH3CHFCH3 62%

i, Pyridine.(HF)n, THF, 0 � C

65%i

½250�

½43�

Figure 3.51

Reactions with less nucleophilic, halogenated alkenes require more vigorous conditions

and a Lewis acid catalyst is generally added to prepare commercially significant fluoro-

haloalkanes [251, 252] (Figure 3.52).

Addition to acetylenes occurs under a variety of conditions; the reaction of acetylene

with hydrogen fluoride is important for the manufacture of vinyl fluoride, although the


76 Chapter 3

CF2�CHCl

CH2Cl�CCl2F 89%

BF3, 25�C

HF

CHCl�CCl2HF, TaF5

CF3CH2Cl 90%

½251, 252�

Figure 3.52

addition proceeds further to give some difluoroethane [253]. With pyridine�HF the

reaction goes via the expected intermediate fluoroalkene to give difluoroalkanes only

[43] (Figure 3.53).

70%

i, Pyridine.(HF)n, THF, 0�C

C4H9CF2CH3C4H9C CHi ½43�

Figure 3.53

The addition of hydrogen fluoride to electron-deficient alkenes and alkynes can be

achieved in certain cases via an indirect process in which reaction of the alkene or alkyne

with fluoride ion leads to a carbanion that abstracts a proton from the solvent. This

method, however, is limited to cases where other reactions of the carbanion are hindered

or less favourable [254, 255] (Figure 3.54).

C6H5

FF

OR

O C6H5

OR

O

CF3

CO2Me

H

F

MeO2C

i, Bu4NF, THF, 0�C, MeC6H4SO3H

R = methyl

71%

90%

MeOOCC CCOOMe

i

i, Bu4NH2F3, CH2Cl CH2Cl, 60�C

i

½254�

½255�

Figure 3.54

Hydrofluorination of corresponding C5N bonds of isocyanates and diazoketones gives

carbamyl fluorides and a-fluoroketones repectively [43].

B Direct addition of fluorine

It was first shown that the addition of fluorine to haloalkenes can be controlled if the

temperature is lowered, competition between fluorine addition and dimer formation being

dependent on the conditions [256] (Figure 3.55).

Russian workers subsequently reported controlled addition to vinyl acetate [257]

and fumaric acid [258], to give difluoroethyl acetate and monofluoroacetaldehyde, re-

spectively. Selective fluorination of many alkanes [8, 259], such as acenaphthene [260],



CF3CF=CFCF3

F2, −75 � CCF3CF2CF2CF3 + [CF3CF2CF(CF3)]2

CFCl3

½256�

Figure 3.55

1,1-diphenylethene [261] and many steroids [236], is now possible in sometimes surpris-

ingly high yield by passing fluorine diluted with an inert gas through a solution of the

unsaturated compound (Table 3.9).

Unlike other halogenation reactions, direct fluorinations of alkenes give products

resulting predominantly from syn addition, and a mechanism suggesting a four-centred

intermediate formed by a concerted pathway was first proposed to account for this [238].

Further experimental [259] and theoretical work [235] provide evidence for an electro-

philic mechanism involving a tight ion-pair (3.56A) as an intermediate. Collapse of this

ion-pair 3.56A gives the syn-1,2-difluoride, whilst loss of a proton forms a fluoroalkene

which may then undergo further fluorination to yield a trifluoride (Figure 3.56). Three

products are observed in the fluorination of 1,1-diphenylethene [238] (Figure 3.57).

A carbocationic intermediate is further supported by observed rearrangements [236]

(Figure 3.58).

Table 3.9 Direct fluorination of alkenes

Substrate Reagent, conditions Product Yield (%) Ref.

OF2, N2

CFCl3, CHCl3, EtOH

�758C

O

F F

35 [259]

O OF

F

65 [237]

N

Boc

OF2, N2

CFCl3, CHCl3, EtOH

�788CN

Boc

OF

F 41 [262]

OAcO

OAc

AcO

F2, Ar

CFCl3, �788C

OAcO

OAc

AcO

F

F

40 [263]


78 Chapter 3

H

F

F

H

FF

F FF

HH

FF FF

δδ

−H

F

F2

3.56A

½235, 259�

Figure 3.56

Ph2C�CH2 Ph2CFCH2F + Ph2C�CHF + Ph2CFCF2H14% 78% 8%

F2, N2 ½238�

Figure 3.57

O

Cl

AcOCl

F2, N2

O

F

O

F

F

F

FO

½236�

Figure 3.58

C Indirect addition of fluorine

Reaction of alkenes with an electrophilic fluorinating agent such as caesium fluoroxy-

sulphate, in the presence of fluoride ion, can result in addition of fluorine to the double

bond [264] (Figure 3.59).

Carbocationic species are also considered to be intermediates in reactions between

iodobenzene difluoride and alkenes [265, 266]. Tetrafluorination of alkynes is possible

using nitrosonium tetrafluoroborate and pyridine�ðHFÞn [267] (Figure 3.60).



Ph

Ph

PhH

FH

F

Ph

i, CsSO3OF, HF, CH2Cl2, 20 � C

syn:anti65 : 35

i ½264�

Figure 3.59

i, NO BF4, Pyridine.(HF)n

75%iPhCF2CF2PhPhC CPh

½267�

Figure 3.60

Of course, most reactive metal fluorides, such as cobalt trifluoride [268] and vanadium

pentafluoride, will react with alkenes but the reactions can be very difficult to control,

except for haloalkenes [269]. Much easier control is possible with xenon fluorides [137],

the reactivity decreasing in the series XeF6 > XeF4 > XeF2. Since the first report of the

use of xenon difluoride for the addition of fluorine to double bonds, many studies have

been published and reviewed [54, 135] (Figure 3.61).

++ XeF2

1387

HF, CH2Cl2

PhCH�CHPh + XeF2

HF, CH2Cl2PhCHFCHFPh 90%

cistrans

erythreo:threo = 53 : 47

62 : 38

F

F FF

½270�

Figure 3.61

The reaction is non-stereoselective, contrary to direct fluorination, and it is found that

only slight changes in either the reaction conditions or the structure of the substrate can

give rise to differing amounts of syn or anti addition. The addition of a Lewis acid, usually

HF [270] or BF3 �Et2O [271], to the reaction mixture gives much higher yields of the

desired difluoroalkanes, and both ionic and single-electron transfer pathways have been

suggested [272, 273].

The very reactive species PbðOCOCH3Þ2F2, formed in situ by the reaction of lead tetra-

acetate with hydrogen fluoride [274], has been used very effectively for adding fluorine to

alkenes, especially in the synthesis of the biologically important 6a-fluoro steroidal

hormones [275].

D Halofluorination

The combination of a source of electrophilic halogen together with a fluoride ion reagent

permits efficient halofluorination of nucleophilic carbon–carbon double bonds; products

resulting from addition in a trans stereochemistry are usually obtained (Figure 3.62).


80 Chapter 3

HalHal Hal

F

F

Figure 3.62

A wide variety of reagent systems have been developed to carry out this synthetically

useful reaction (Table 3.10).

The intermediate halonium ion may undergo well-established carbocationic rearrange-

ments, for instance in the halofluorination of norbornadiene [276] (Figure 3.63).

The reaction has been used extensively for the introduction of fluorine into steroids

[277], where a curious anomaly arises between BrF and IF addition. As indicated,

stereospecific anti addition occurs in most reactions but syn addition of BrF or IF to

carbohydrates has been observed [278]. Halofluorination of alkynes proceeds as expected,

although further reaction of the resulting alkene derivative can occur.

Table 3.10 Halofluorination of alkenes and alkynes


NIS ,a

pyridine�HF

I

F65 [43]

C4H9DBH ,b KF�2H2O

H2SO4, CH2Cl2

C4H9Br

F

C4H9F

Br

+

87 (9:1) [279]

Me

N I BF4−

2

Me

I

F 60 [280]

CH2Cl2, 08C

Br2, AgNO3

pyridine�HF

F

Br

85 [43]

a NIS, N-iodosuccinimide.b DBH, 1,3-dibromo-5,5-dimethylhydantoin.



Br F

F

Br

Br

Br

i, NBS, Et3N.3HF, CH2Cl2, 0 � C

53%

38%

5%

i ½276�

Figure 3.63

E Addition of fluorine and oxygen groups

Evidence has been presented that hypofluorites (see Section IIIB) can act as sources of

electrophilic fluorine for reactions with electron-rich double bonds [11, 93]. Syn addition

usually occurs and a tight ion-pair intermediate similar to that postulated to occur in the

direct fluorination of alkenes can be envisaged. However, electron-transfer processes

have been invoked [93] to explain some anomalous results and cannot be discounted

[281] (Figure 3.64).

O

AcO

H3C

AcO

O

AcO

H3C

AcO

O

AcO

H3C

AcOX

Y +

X

Y

X=F, Y=OCF3, 31%X=Y=F, 22%

X=F, Y=OCF3, 11%X=Y=F, 12%

i, CF3OF, CFCl3, −70 � C

i½281�

Figure 3.64

Additions of hypofluorites to unsaturated sites have been performed [17] on a wide

variety of substrates [282, 283] (Figure 3.65).

CsSO3OF reacts with alkenes to give fluoroalkyl sulphates [284].

F Other additions

In a similar process to halofluorination, sulphur- [285], selenium- [286] and nitrogen-

containing [43] groups and fluorine may be added to hydrocarbon double bonds by

reaction of an alkene with an electrophilic reagent of the heteroatom species in conjunc-

tion with a fluoride-ion source (Figure 3.66). As expected, Markovnikov addition in trans

stereochemistry occurs mainly.


82 Chapter 3

OMeF

OAc

AcO

OAc

AcOOCF3F

59%

40%

i, CH3OF, CH3OH, CH3CN, −40 � C

i

i, CF3OF, CFCl3, −75 � C

i

½282�

½283�

Figure 3.65

CH3

Ph SCH3

FH

PhH

CH3

MeO MeOF

SePh

i, (CH3)2SSCH3 BF4−, Et3N.3HF, CH2Cl2, rt

90%

i, PhSeCl, AgF, CH3CN

NO2

F

53%

65%

i, NO2BF4, Pyridine.HF, 0� C

i

i

i ½285�

½286�

½43�

Figure 3.66

REFERENCES

1 W.A. Sheppard, Org. Reactions, 1974, 21, 125.

2 G.A. Boswell, W.C. Ripka, R.M. Scribner and C.W. Tullock, Org. Reactions, 1974, 21, 1.

3 M. Schlosser, Tetrahedron, 1978, 34, 3.

4 M.R.C. Gerstenberger and A. Haas, Angew. Chem., Int. Ed. Engl., 1981, 20, 647.

5 S. Rozen and R. Filler, Tetrahedron, 1985, 41, 1111.

6 A. Haas and M. Lieb, Chimia, 1985, 39, 134.

7 C.J. Wang, Org. Reactions, 1985, 34, 319.

8 S.T. Purrington, B.S. Kagen and T.B. Patrick, Chem. Rev., 1986, 86, 997.



9 J.T. Welch, Tetrahedron, 1987, 43, 3123.

10 J. Mann, Chem. Soc. Rev., 1987, 16, 381.

11 S. Rozen, Acc. Chem. Res., 1988, 21, 307.

12 M. Hudlicky, Org. Reactions, 1988, 35, 513.

13 L. German and S. Zemskov, New Fluorinating Agents in Organic Synthesis, Springer-Verlag,

Berlin, 1989.

14 P. Bravo and G. Resnati, Tetrahedron: Asymm., 1990, 1, 661.

15 N. Yoneda, Tetrahedron, 1991, 47, 5329.

16 J.A. Wilkinson, Chem. Rev., 1992, 92, 505.

17 G. Resnati, Tetrahedron, 1993, 49, 9385.

18 O.A. Mascaretti, Aldrichimica Acta, 1993, 26, 47.

19 R.E. Banks and J.C. Tatlow in Synthesis of Organofluorine Compounds, ed. R.E. Banks,

B.E. Smart and J.C. Tatlow, Plenum, New York, 1994.

20 Houben-Weyl: Methods of Organic Chemistry, Vols E10a and E10b, Organo-fluorine Com-pounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999.

21 A.K. Barbour, L.J. Belf and M.W. Buxton, Adv. Fluorine Chem., 1963, 3, 181.


23 F.L.M. Pattison and B.C. Saunders, J. Chem. Soc., 1949, 2745.

24 T. Ando, D.G. Cork, M. Fujita and T. Kimura, Chem. Lett., 1988, 1877.

25 G. Bram, A. Loupy and P. Pigeon, Synthetic Commun., 1988, 18, 1661.

26 R.D. Chambers and D.T. Clark, unpublished observations.

27 D.W. Kim, C.E. Song and D.Y. Chi, J. Am. Chem. Soc., 2002, 124, 10278.

28 P.S. Bhadury, K.S. Raza, and D.K. Jaiswal, J. Fluorine Chem., 1999, 99, 115.

29 A.N. Nesmejanow and E.J. Kahn, Berichte, 1934, 67, 370.

30 W.T. Bruce and F.D. Hoerger, J. Am. Chem. Soc., 1954, 76, 3230.

31 R.K. Sharma and J.L. Fry, J. Org. Chem., 1983, 48, 2112.

32 H. Vorbruggen and K. Krolikiewicz, Tetrahedron Lett., 1984, 25, 1259.

33 D.P. Cox, J. Terpinski and W. Lawrynowicz, J. Org. Chem., 1984, 49, 3216.

34 K.O. Christe, W.W. Wilson, R.D. Wilson, R. Bau, and J. A. Feng, J. Am. Chem. Soc., 1990,

112, 7619.

35 K.M. Harmon, B.A. Southworth, K.E. Wilson and P.K. Keefer, J. Org. Chem., 1993, 58, 7294.

36 R. Schwesinger, R. Link, G. Thiele, H. Rotter, D. Houert, H. Limbach and F. Mannle, Angew.Chem., Int. Ed. Engl., 1991, 30, 1372.

37 B.K. Bennett, R.G. Harrison and T.G. Richmond, J. Am. Chem. Soc., 1994, 116, 11165.

38 R.D. Chambers, S.R. Korn and G. Sandford, J. Fluorine Chem., 1994, 69, 103.

39 P. Bosch, F. Camps, E. Chamorro, V. Gasol and A. Guerrero, Tetrahedron Lett., 1987, 28,

4733.

40 D. Albanese, D. Landini and M. Penso, J. Org Chem., 1998, 63, 9589.

41 S.J. Brown and J.H. Clark, J. Fluorine Chem., 1985, 30, 251.

42 A.S. Pilcher, H.L. Ammon, and P. DeShong, J. Am. Chem. Soc., 1995, 117, 5166.

43 G.A. Olah, J.T. Welch, Y.D. Vankar, M. Nojima, I. Kerekes and J.A. Olah, J. Org. Chem.,1979, 44, 3872.

44 A. Feiring, J. Org. Chem., 1979, 44, 2907.

45 H. Kageyama, H. Suzuki and Y. Kimura, J. Fluorine Chem., 2000, 101, 85.

46 R. Bujok and M. Markosza, Synlett, 2002, 1285.

47 L.S. Boguslavskaya, N.N. Chuvatkin, I.Y. Panteleeva and L.A. Ternovskoi, Zh. Org. Khim.,1982, 18, 938.

48 N.N. Chuvatkin, A.V. Kartashova, T.V. Morozova and L.S. Boguslavskaya, Zh. Org. Khim.,1987, 23, 269.

49 L.S. Boguslavskaya and N.N. Chuvatkin in New Fluorinating Agents in Organic Synthesis, ed.

L. German and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 140.

50 S. Rozen, D. Rechavai and A. Hagooly, J. Fluorine Chem., 2001, 111, 161.


84 Chapter 3

51 M. Sawaguchi, S. Hara, Y. Nakamura, S. Ayuba, T. Fukuhara and N. Yoneda, Tetrahedron,

2001, 57, 3315.

52 M.F. Greaney, W.B. Motherwell and D.A. Tocher, Tetrahedron Lett., 2001, 42, 8523.

53 S. Rozen and M. Brand, J. Org. Chem., 1981, 46, 733.

54 M.A. Tius, Tetrahedron, 1995, 51, 6605.

55 Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorine Compounds,

ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999.

56 J. Hutchinson and G. Sandford in Organofluorine Chemistry. Techniques and Synthons, ed.

R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 1.

57 W. Bockemuller, Annalen, 1933, 506, 20.

58 J.M. Tedder, Adv. Fluorine Chem., 1961, 2, 104.

59 S. Rozen, C. Gal and Y. Faust, J. Am. Chem. Soc., 1980, 102, 6860.

60 S. Rozen and C. Gal, J. Org. Chem., 1987, 52, 2769.

61 S. Rozen in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash,

John Wiley and Sons, New York, 1992, p. 143.

62 D. Alker, D.H.R. Barton, R.H. Hesse, J. Lister-James, R.E. Markwell, M.M. Pechet, S. Rozen,

T. Takeshita, and H.T. Toh, Nouv. J. Chem., 1980, 4, 239.

63 D.H.R. Barton, R.H. Hesse, R.E. Markwell, M.M. Pechet and S. Rozen, J. Am. Chem. Soc.,1976, 98, 3036.

64 R.D. Chambers, M. Parsons, G. Sandford and R. Bowden, J. Chem. Soc., Chem. Commun.,2000, 959.

65 R.D. Chambers, A.M. Kenwright, M. Parsons, G. Sandford and J.S. Moilliet, J. Chem. Soc.,Perkin Trans. 1, 2002, 2091.

66 R.D. Chambers, C.J. Skinner, J. Hutchinson and J. Thomson, J. Chem. Soc., Perkin Trans.1, 1996, 605.

67 G.A. Olah, G.K.S. Prakash, R.E. Williams, L.D. Field and K. Wade, Hypercarbon Chemistry,

John Wiley and Sons, New York, 1987.

68 C. Kaneko, A. Toyota, J. Chiba, A. Shigihara and H. Ichikawa, Chem. Pharm. Bull., 1994, 42,

745.

69 E. Differding and G.M. Ruegg, Tetrahedron Lett., 1991, 32, 3815.

70 S.P. Vincent, M.D. Burkhart, C. Tsai, Z. Zhang and C. Wong, J. Org. Chem., 1999, 64, 5264.

71 S.T. Purrington, N.V. Lazaridis and C.L. Bumgardner, Tetrahedron Lett., 1986, 27, 2715.

72 S.T. Purrington, C.L. Bumgardner, N.V. Lazaridis and P. Singh, J. Org. Chem., 1987, 52, 4307.

73 V. Grakauskas and K. Baum, J. Org. Chem., 1968, 33, 3080.

74 V. Grakauskas, J. Org. Chem., 1969, 34, 965.

75 S. Rozen and G. Ben-Shushan, J. Org. Chem., 1986, 51, 3522.

76 R.D. Chambers, M.P. Greenhall and J. Hutchinson, J. Chem. Soc., Chem. Commun., 1995, 21.

77 R.D. Chambers, C.J. Skinner, J. Thomson and J. Hutchinson, J. Chem. Soc., Chem. Commun.,1995, 17.

78 C. Kaneko, J. Chiba, A. Toyota and M. Sato, Chem. Pharm. Bull., 1995, 43, 760.

79 S.T. Purrington and D.L. Woodard, J. Org. Chem., 1990, 55, 3423.

80 H. Kamaya, M. Satao and C. Kaneko, Tetrahedron Lett., 1997, 38, 587.

81 S. Rozen, Chem. Rev., 1996, 96, 1717.

82 M. Zupan in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 270.

83 D.H.R. Barton, Pure Appl. Chem., 1970, 21, 285.


85 R.H. Hesse, Isr. J. Chem., 1978, 17, 60.

86 O. Lerman and S. Rozen, J. Org. Chem., 1980, 45, 4122.

87 S. Rozen and O. Lerman, J. Org. Chem., 1980, 45, 672.

88 S. Rozen, O. Lerman and M. Kol, J. Chem. Soc., Chem. Commun., 1981, 443.



89 S. Rozen, A. Hagooly and R. Harduf, J. Org. Chem., 2001, 66, 7464.

90 J.M. Shreeve, Adv. Inorg. Chem. Radiochem., 1983, 26, 119.

91 M. Lustig and J.M. Shreeve, Adv. Fluorine Chem., 1973, 7, 175.

92 J. Kollonitsch, Isr. J. Chem., 1978, 17, 53.

93 F.M. Mukhametshin in New Fluorinating Agents in Organic Synthesis, ed. L. German


94 G.G. Furin in New Fluorinating Reagents in Organic Synthesis, ed. L. German and

S. Zemskov, Springer-Verlag, Berlin, 1989, p. 35.

95 T.J. McCarthy, T.A. Bonasera, M.J. Welch and S. Rozen, J. Chem. Soc., Chem. Commun.,1993, 561.

96 E.H. Appelman, D. French, E. Mishani and S. Rozen, J. Am. Chem. Soc., 1993, 115, 1379.

97 S. Rozen, A. Bar-Haim and E. Mishani, J. Org. Chem., 1994, 59, 6800.

98 S. Rozen and M. Brand, Synthesis, 1985, 665.

99 O. Lerman and S. Rozen, J. Org. Chem., 1983, 48, 724.

100 E.H. Appelman, L.J. Basile and R.C. Thompson, J. Am. Chem. Soc., 1979, 101, 3384.

101 M. Zupan and S. Stavber, Tetrahedron, 1989, 45, 2737.

102 S. Stavber and M. Zupan, J. Fluorine Chem., 1981, 17, 597.

103 M.R. Bryce, R.D. Chambers, S.T. Mullins and A. Parkin, J. Chem Soc., Chem. Commun.,1986, 1623.

104 M.R. Bryce, R.D. Chambers, S.T. Mullins and A. Parkin, Bull. Soc. Chim. Fr., 1986, 930.

105 G.S. Lal, G.P. Pez and R.G. Syvret, Chem. Rev., 1996, 96, 1737.

106 R.E. Banks, J. Fluorine Chem., 1998, 87, 1.

107 G.G. Furin in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 434.

108 S. Singh, D.D. DesMarteau, S.S. Zuberi, M. Witz and H.-N. Huang, J. Am. Chem. Soc., 1987,

109, 7194.

109 R.E. Banks, I. Sharif and R.G. Prichard, Acta. Crystallogr., Sect. C, 1993, 49, 492.

110 D.D. Desmarteau and M. Witz, J. Fluorine Chem., 1991, 52, 7.

111 R.E. Banks, V. Murtagh, H.M. Marsden and R.G. Syvret, J. Fluorine Chem., 2001, 112, 271.

112 W.E. Barnette, J. Am. Chem. Soc., 1984, 106, 452.

113 S.T. Purrington and W.A. James, J. Org. Chem., 1983, 48, 761.

114 T. Umemoto, K. Harasawa, G. Tomizawa, K. Kawada and K. Tomita, Bull. Chem. Soc. Jpn.,1991, 64, 1081.

115 T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada and K. Tomita, J. Am.Chem. Soc., 1990, 112, 8563.

116 L. Strekowski and A.S. Kiselyov, Adv. Heterocycl. Chem., 1995, 62, 1.

117 R.E. Banks, R.A. Duboisson and E. Tsiliopoulos, J. Fluorine Chem., 1986, 32, 461.

118 R.E. Banks, S.N. Mohialdin-Khaffaf, G.S. Lal, I. Sharif and R.G. Syvret, J. Chem. Soc.,Chem. Commun., 1992, 595.

119 G.S. Lal, J. Org. Chem., 1993, 58, 2791.

120 S. Singh, D.D. Desmarteau, S.S. Zuberi, M. Witz and H.-N. Huang, J. Am. Chem. Soc., 1987,

109, 7194.

121 G. Resnati and D.D. Desmarteau, J. Org. Chem., 1991, 56, 4925.

122 E. Differding and R.W. Lang, Helv. Chim. Acta, 1989, 72, 1248.

123 E. Differding, R.O. Duthaler, A. Krieger, G.M. Ruegg and C. Schmit, Synlett, 1991, 395.

124 X. Ze-Qi, D.D. Desmarteau and Y. Gotoh, J. Fluorine Chem., 1992, 58, 71.

125 R.E. Banks, N.J. Lawrence and A.L. Popplewell, J. Chem. Soc., Chem. Commun., 1994, 343.

126 G.S. Lal, Synth. Commun., 1995, 25, 725.

127 E. Differding and R.W. Lang, Tetrahedron Lett., 1988, 29, 6087.

128 Y. Takeuchi, T. Suzuki, A. Satoh, T. Shiragami and N. Shibata, J. Org. Chem., 1999, 64,

5708.


86 Chapter 3

129 D.W. Komas and J.K. Coward, J. Org. Chem., 2001, 66, 8831.

130 R. Frantz, L. Hintermann, M. Perseghini, D. Broggini and A. Togni, Org. Lett., 2003, 5, 1709.

131 Y. Hamashima, K. Yagi, H. Takano, L. Tamas and M. Sodeoka, J. Am. Chem. Soc., 2002,

124, 14530.

132 J. Baudoux, A.-F. Salit, D. Cahard and J.-C. Plaquevent, Tetrahredron Lett., 2002, 43, 6573.

133 K.K. Laali and G.I. Borodkin, J. Chem. Soc., Perkin Trans. 2, 2002, 953.

134 K. Adachi, Y. Ohira, G. Tomizawa, S. Ishihara and S. Oishi, J. Fluorine Chem., 2003, 120,

173.

135 V.V. Bardin and Y.L. Yagupolskii in New Fluorinating Agents in Organic Synthesis, ed.


136 M. Zupan and S. Stavber, Trends in Organic Chemistry, 1995, 5, 11.

137 L.M. Yagupolskii in Houben-Weyl: Methods of Organic Chemistry. Vol. E10a, ed. B. Baasner,


138 C.A. Ramsden and R.G. Smith, J. Am. Chem. Soc., 1998, 120, 6842.

139 M. Zupan, J. Iskra and S. Stavber, J. Org. Chem., 1998, 63, 878.

140 S. Rozen, E. Mishani and M. Kol, J. Am. Chem. Soc., 1992, 114, 7643.

141 S.P. Anand, L.A. Quarterman, P.A. Christian, H. Hyman and R. Filler, J. Org. Chem., 1975,

40, 3796.

142 M. Zupan in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 265.

143 G.A. Olah, J.G. Shih, B.P. Singh and B.G.B. Gupta, J. Org. Chem., 1983, 48, 3356.

144 R. Miethchen and D. Peters in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a,

Organo-fluorine Compounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme,

Stuttgart, 1999, p. 95.

145 J. Burdon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 655.

146 A.E. Feiring, J. Fluorine Chem., 1977, 10, 375.

147 X. Huang, B.J. Blackburn and A.F. Janzen, J. Fluorine Chem., 1990, 47, 145.

148 T. Umemoto and G. Tomizawa, Bull. Chem. Soc. Jpn., 1986, 59, 3625.

149 T. Brigaud and E. Laurent, Tetrahedron Lett., 1990, 31, 2287.

150 T. Fuchigami, M. Shimojo and A. Konno, J. Org. Chem., 1995, 60, 3459.

151 J.P. McCarthy, N.P. Peet, M.E.L. Tourneau and I. Muthiah, J. Am. Chem. Soc., 1985, 107,

735.

152 N. Yoneda and T. Fukuhara, Chem. Lett., 2001, 222.

153 G.A. Olah and X.Y. Li in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and


154 E.J. Parish and G.J. Schroepfer, J. Org. Chem., 1980, 45, 4034.

155 M. Darabantu, T. Lequeux, J.-C. Pommelet, N. Ple and A. Turck, Tetrahedron, 2001, 57, 739.

156 W. Dmowski in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 321.

157 M.H. Rock in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 406.

158 R.P. Singh and J.M. Shreeve, Synthesis, 2002, 2561.

159 W.J. Middleton, J. Org. Chem., 1975, 54, 574.

160 W.J. Middleton and E.M. Bingham, Org. Synth., 1979, 57, 50.

161 W.J. Middleton, Chem. Eng. News, 1979, 57, 43.

162 W.J. Middleton and K.C. Mange, J. Fluorine Chem., 1989, 43, 405.

163 G.S. Lal, G.P. Pez, R.J. Pesaresi, F.M. Prozonic and H. Chung, J. Org. Chem., 1999, 64, 7048.



164 L.N. Markovskii and V.E. Pashinnik in New Fluorinating Reagents in Organic Synthesis, ed.


165 P.L. Coe, L.D. Procter, J.A. Martin and W.A. Thomas, J. Fluorine Chem., 1992, 58, 87.

166 M. Biollaz and J. Kalvoda, Helv. Chim. Acta, 1977, 60, 2703.

167 P.J. Card and J.S. Reddy, J. Org. Chem., 1983, 48, 4734.

168 H.-J. Tsai, K.-W. Lin, T.-H. Ting and D.J. Burton, Helv. Chim. Acta, 1999, 82, 3321.

169 K.C. Nicolaou, T. Ladduwaketty, J.L. Randall and A. Chucholowski, J. Am. Chem. Soc.,1986, 108, 2466.

170 S. Bohm in Houben-Weyl: Methods of Organic Chemistry, Vol. E10b/Part 1, Organo-fluorineCompounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 99.

171 N.N. Yarovenko and M.A. Raksha, J. Gen. Chem. USSR (Engl. Trans.), 1959, 29, 2125.

172 A. Takaoka, J. Hiroshi and N. Ishikawa, Bull. Chem. Soc. Jpn., 1979, 52, 3377.

173 F. Liska, Chem. Listy, 1972, 66, 189.

174 C.M. Sharts and W.A. Sheppard, Org. Reactions, 1972, 21, 125.

175 S. Watanabe, T. Fujita and M. Sakamoto, J. Fluorine Chem., 1988, 38, 243.

176 V.A. Petrov, S. Swearingen, W. Hong and W.C. Peterson, J. Fluorine Chem., 2001, 109, 25.

177 R.L. Gree and J.P. Lellouche in Enantio-controlled Synthesis of Fluoro-organic Compounds,

ed. V.A. Soloshonok, John Wiley, Chichester, 1999, p. 63.

178 R.E. Banks, A.K. Barrage and E.J. Khoshdel, J. Fluorine Chem., 1980, 17, 93.

179 W. Dmowski and M. Kamienski, J. Fluorine Chem., 1983, 23, 219.

180 J.M. Desimone, H.-C. Wei and T.J. Romak, WO Pat. 00/68 170 (2000); Chem. Abstr., 2000,

133, 349845p.

181 H. Hayashi, H. Sonoda, K. Fukumura and T. Nagata, J. Chem. Soc., Chem. Commun., 2002,

1618.

182 R. Meithchen and T. Gabriel, J. Fluorine Chem., 1994, 67, 11.

183 D. Badone, G. Jommi, R. Pagliarin and P. Tavecchia, Synthesis, 1987, 920.

184 E. Fritz-Langhals and G. Schutz, Tetrahedron Lett., 1993, 34, 293.

185 P. Pechy, F. Gasparini and P. Vogel, Synlett, 1992, 676.

186 F.S. Fawcett and C.W. Tullock, Inorg. Synth., 1963, 7, 119.

187 G.A. Olah, M.R. Bruce and J. Welch, J. Inorg. Chem., 1977, 16, 2617.

188 W. Dmowski and R. Wieckowski, J. Fluorine Chem., 2002, 114, 103.

189 A.I. Burmakov, B.V. Kunshenko, L.A. Alekseeva and L.M. Yagupolskii in New FluorinatingAgents in Organic Synthesis, ed. L. German and S. Zemskov, Springer-Verlag, Berlin, 1989,

p. 197.

190 W.C. Smith, Angew. Chem., Int. Ed. Engl., 1962, 1, 467.

191 C.W. Tullock, R.A. Carboni, R.J. Harder, W.C. Smith and D.D. Coffman, J. Am. Chem. Soc.,1960, 82, 5107.

192 G.E. Carr, R.D. Chambers, T.F. Holmes and D.G. Parker, J. Organometal. Chem., 1987,

325, 13.

193 D.E. Applequist and R. Searle, J. Org. Chem., 1964, 29, 987.

194 W.R. Hasek, W.C. Smith and V.A. Engelhardt, J. Am. Chem. Soc., 1960, 82, 543.

195 N.N. Muratov, A.I. Burmakov, B.V. Kunshenko, L.A. Alekseeva, and L.M. Yagupolskii,

J. Org. Chem. USSR (Engl. Trans.), 1982, 18.

196 M.A. Raasch, J. Org. Chem., 1962, 27, 1406.

197 A.I. Burmakov, L.A. Alekseeva and L.M. Yagupolskii, Zh. Org. Khim., 1970, 6, 144.

198 C.R. Davis, D.C. Swenson and D.J. Burton, J. Org. Chem., 1993, 58, 6843.

199 R.A. Sharma, I. Kavai, Y.L. Fu and M. Bobek, Tetrahedron Lett., 1977, 18, 3433.

200 J. Leroy, J. Org. Chem., 1981, 40, 206.

201 F. Mathey and J. Bensoam, Tetrahedron, 1971, 27, 3965.

202 W.A. Sheppard, J. Am. Chem. Soc., 1962, 84, 3058.

203 G. Alvernhe, A. Laurent and G. Haufe, J. Fluorine Chem., 1986, 34, 147.


88 Chapter 3

204 H. Suga, T. Hamatani and M. Schlosser, Tetrahedron, 1990, 46, 4247.

205 M. Muehlbacher and C.D. Poulter, J. Org. Chem., 1988, 53, 1026.

206 W. Dmowski and R.A. Kolinski, Pol. J. Chem., 1974, 48, 1697.

207 M. Shimizu and H. Yoshioka, Tetrahedron Lett., 1989, 30, 967.

208 H. Seto, Z.H. Qian, H. Yoshioka, Y. Uchibori and M. Umeno, Chem. Lett., 1991, 1185.

209 F.J. Pavlic and P.E. Toren, J. Org. Chem., 1970, 35, 2054.

210 M. Shimizu, Y. Nakahara and H. Yoshioka, Tetrahedron Lett., 1985, 26, 4207.

211 D.U. Robert, G.N. Flatau, A. Cambon and J.G. Reiss, Tetrahedron, 1973, 29, 1877.

212 G.A. Olah and S.J. Kuhn, J. Org. Chem., 1956, 21, 1319.

213 H. Garcia, M.C. Perrod, L. Gilbert, S. Ratton and C. Rochin, J. Fluorine Chem., 1991, 54,

117.

214 N. Lui, A. Marhold and D. Bielefeldt, Germ. Pat. 422 576 (1994); Chem. Abstr., 1994, 120,

216933a.

215 J. Kollonitsch, S. Marburg and L.M. Perkins, J. Org. Chem., 1976, 41, 3107.

216 M. Kuroboshi and T. Hiyama, J. Synth. Org. Chem. Jpn., 1993, 51, 1124.

217 S. Caddick, W.B. Motherwell and J.A. Wilkinson, J. Chem. Soc., Chem. Commun., 1991, 674.

218 M. Kuroboshi and T. Hiyama, J. Fluorine Chem., 1994, 69, 127.

219 R.D. Chambers, G. Sandford and M. Atherton, J. Chem. Soc., Chem. Commun., 1995, 177.

220 R. Sasson, A. Hagooly and S. Rozen, Org. Lett., 2003, 5, 769.

221 W.H. Bunnelle, B.R. McKinnis and B.A. Narayanan, J. Org. Chem., 1990, 55, 768.

222 D.P. Matthews, J.P. Whitten and J.R. McCarthy, Tetrahedron Lett., 1986, 27, 4861.

223 S. Rozen and E. Mishani, J. Chem. Soc., Chem. Commun., 1994, 2081.

224 M. Kuroboshi and T. Hiyama, Tetrahedron Lett., 1992, 33, 4177.

225 P. Kirsch and A. Taugerbeck, Eur. J. Org. Chem., 2002, 3923.

226 B. Langlois in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 686.

227 A. Roe, Org. Reactions, 1949, 5, 193.

228 H. Suschitsky, Adv. Fluorine Chem., 1965, 4, 1.

229 H. Diehl, H. Pelster and H. Habetz, Germ. Pat. 3 141 659 A1 (1983); Chem. Abstr., 1983, 99,

70360k.

230 K.G. Rutherford, W. Redmond and J. Rigamonti, J. Org. Chem., 1961, 26, 5149.

231 C. Sellers and H. Suschitzky, J. Chem. Soc. (C), 1968, 2317.

232 K. Takahashi, K.L. Kirk and L.A. Cohen, J. Org. Chem., 1984, 49, 1951.

233 K.K. Laali and V.J. Gettwert, J. Fluorine Chem., 2001, 107, 31.

234 G.A. Olah, G.K.S. Prakash, and Y.L. Chao, Helv. Chim. Acta, 1981, 64, 2528.

235 T. Iwaoka, C. Kaneko, A. Shigihara and H. Ichikawa, J. Phys. Org. Chem., 1993, 6, 195.

236 D.H.R. Barton, J.L. James, R.H. Hesse, M.M. Pechet and S. Rozen, J. Chem. Soc., PerkinTrans. 1, 1982, 1105.

237 R.F. Merritt and T.E. Stevens, J. Am. Chem. Soc., 1966, 88, 1822.

238 R.F. Merritt, J. Org. Chem., 1966, 31, 3871.

239 T.N. Wade, J. Org. Chem., 1980, 45, 5328.

240 G.M. Alvernhe, C.M. Ennakoua, S.M. Lacombe and A.J. Laurent, J. Org. Chem., 1981, 46,

4938.

241 T.N. Wade and R. Kheribet, J. Org. Chem., 1980, 45, 5333.

242 M. Kamlet and H.G. Adolph, J. Org. Chem., 1968, 33, 3073.

243 M. Boechat and J.H. Clark, J. Chem. Soc., Chem. Commun., 1993, 921.

244 G. Angelini, M. Speranza, A.P. Wolf and C.-Y. Shiue, J. Fluorine Chem., 1985, 27, 177.

245 T.B. Patrick and P.A. Flory, J. Fluorine Chem., 1984, 25, 157.

246 G.K.S. Prakash, V.P. Reddy, X.Y. Li and G.A. Olah, Synlett, 1990, 594.

247 S. Rozen and D. Zamir, J. Org. Chem., 1991, 56, 4695.

248 T.B. Patrick, J.J. Schiebel and G.L. Cantrell, J. Org. Chem., 1981, 46, 3917.



249 P. Wolfram in Houben-Weyl: Methods of Organic Chemistry, Vol. E10b/Part 1, Organo-fluorine Compounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart,

1999, p. 308.

250 A.V. Grosse and C.B. Linn, J. Org. Chem., 1938, 3, 26.

251 A.L. Henne and R.C. Arnold, J. Am. Chem. Soc., 1948, 70, 758.


253 F.W. Swarmer, US Pat. 2 830 100 (1958); Chem. Abstr., 1958, 52, 19943a.

254 T. Kitazume and T. Onogi, Synthesis, 1988, 614.

255 J. Cousseau and P. Albert, Bull. Chim. Soc. Fr., 1986, 910.

256 W.T. Miller, J.O. Stoffer, G. Fuller and A.C. Currie, J. Am. Chem. Soc., 1964, 86, 51.

257 A.Y. Yakubovich, S.M. Rozenshtein and V.A. Ginberg, USSR Pat. 162 825 (1965); Chem.Abstr., 1965, 62, 451g.

258 A.Y. Yakubovich, V.A. Ginsberg, S.M. Rozenshtein and S.M. Smirnov, USSR Pat. 165 162

(1965); Chem. Abstr., 1965, 62, 9018g.

259 S. Rozen and M. Brand, J. Org. Chem., 1986, 51, 3607.

260 R.F. Merritt and F.A. Johnson, J. Org. Chem., 1966, 31, 1859.

261 R.F. Merritt, J. Org. Chem., 1966, 31, 3871.

262 A. Toyota, M. Aizawa, C. Habutani, M. Katagiri and C. Kaneko, Tetrahedron, 1995, 51,

8783.

263 T. Ido, C.N. Wan, J.S. Fowler and A.P. Wolf, J. Org. Chem., 1977, 42, 2341.

264 S. Stavber and M. Zupan, J. Org. Chem., 1987, 52, 919.

265 W. Carpenter, J. Org. Chem., 1966, 31, 2688.

266 T.B. Patrick, J.J. Scheibel, W.E. Hall and Y.H. Lee, J. Org. Chem., 1980, 45, 4492.

267 C. York, G.K.S. Prakash and G.A. Olah, J. Org. Chem., 1994, 59, 6493.

268 A. Bergami and J. Burdon, J. Chem. Soc., Perkin Trans. 1, 1975, 2237.

269 G.G. Furin and V.V. Bardin in New Fluorinating Agents in Organic Synthesis, ed. L. German


270 M. Zupan and A. Pollak, Tetrahedron Lett., 1974, 1015.

271 S.A. Shackelford, R.R. McGuire and J.L. Pflug, Tetrahedron Lett., 1977, 363.

272 M. Zupan, M. Metelko and S. Stavber, J. Chem. Soc., Perkin Trans. 1, 1993, 2851.

273 S. Stavber, T. Sotler, M. Zupan and A. Popovic, J. Org. Chem., 1994, 59, 5891.

274 J. Bornstein, M.R. Borden, F. Nunes and H.I. Tarlin, J. Am. Chem. Soc., 1963, 85, 1609.

275 A. Bowers, P.G. Holton, E. Denot, M.C. Loza and R. Urquiza, J. Am. Chem. Soc., 1962, 85,

1050.

276 G. Alvernhe, D. Anker, A. Laurent, G. Haufe and C. Beguin, Tetrahedron, 1988, 44, 3551.

277 A. Bowers, E. Denot and R. Becerra, J. Am. Chem. Soc., 1960, 82, 4007.

278 K.R. Wood, P.W. Kent and D. Fisher, J. Chem. Soc., 1966, 912.

279 D.Y. Chi, D.O. Kiesewetter, J.A. Katzenellenbogen, M.R. Kilbourn and M.J. Welch,

J. Fluorine Chem., 1986, 31, 99.

280 R.D. Evans and J.H. Schauble, Synthesis, 1987, 551.

281 G.C. Butchard and P.W. Kent, Tetrahedron, 1979, 35, 2439.

282 S. Rozen, O. Lerman, M. Kol and D. Hebel, J. Org. Chem., 1985, 50, 4753.

283 D.H.R. Barton, L.J. Danks, A.K. Ganguly, R.H. Hesse, G. Tarzia and M.M. Pechet, J. Chem.Soc., Perkin Trans. 1, 1976, 101.

284 N.S. Zefirov, V.V. Zhdankin, A.S. Kozmin, A.A. Fainzilberg, A.A. Gakh, B.I. Ugrak and

S.V. Romaniko, Tetrahedron, 1988, 44, 6505.

285 G. Haufe, G. Alvernhe, D. Anker, A. Laurent and C. Saluzzo, Tetrahedron Lett., 1988, 29,

2311.

286 J.R. McCarthy, D.P. Matthews and C.L. Barney, Tetrahedron Lett., 1990, 31, 973.


90 Chapter 3

Chapter 4

The Influence of Fluorineor Fluorocarbon Groups on someReaction Centres

I INTRODUCTION

Part of the interest in fluorocarbon systems lies in a comparison of the chemistry, and

particularly reaction mechanisms, of fluorocarbon derivatives with those of the corres-

ponding hydrocarbon compounds. Indeed, such comparisons pose quite a strenuous test

on our theories of organic chemistry. As will be seen, our understanding of the influence

of carbon–fluorine bonds on reaction mechanisms has made considerable progress.

Nevertheless, it must be emphasised that fluorocarbon derivatives present much more

complicated systems than their corresponding hydrocarbon compounds because, in add-

ition to effects arising from different electronegativities, the effect of the lone pairs of

electrons of fluorine that are not involved in s-bonds must be taken into consideration.

Furthermore, the relative importance of these effects seems to be very dependent on the

centre to which the fluorine is attached.

In this chapter we assess the effect of fluorine on some charged and neutral

systems largely at a qualitative level, where this effect can be relatively well defined.

Indeed, it could be argued that models of reactivity that are to be useful over a variety

of related reagents, in various concentrations and solvents, are by necessity only

qualitative.

II STERIC EFFECTS

Replacing hydrogen in an organic molecule by fluorine does not significantly alter the

geometry of many systems, but this does not necessarily mean that fluorine and hydrogen

are isosteric. A comparison of the van der Waals radii, rvðHÞ 1.20 A, rvðFÞ 1.47 A and

rv(O) 1.52 A [1], suggests that fluorine is isosteric with oxygen, and this fact has long

been recognised for the development of bioisosteric compounds in medicinal chemistry

[2]. The C–F bond length (1.38 A) is slightly longer than C–H (1.09 A); in very crowded

systems this can be significant. For example, phenyl ring rotation of the cyclophane

system (Figure 4.1) is slower when X ¼ F than when X ¼ H, because of the larger steric

requirement of fluorine over hydrogen [3].

Substituent steric effects are generally regarded in terms of Taft Es or Charlton n

parameters [4], and a number of these values for fluorinated groups, along with those for

some hydrocarbon groups, are listed in Table 4.1. These data suggest, for instance, that

CF3 groups are much more sterically demanding than methyl substituents and that they



X½3�

Figure 4.1

are more demanding than isopropyl groups. Indeed, van der Waals volumes,

CH3 ¼ 16:8 A3

compared to CF3 ¼ 42:6 A3, further illustrate this point [5] (Figure 4.2).

FF

FHH

H

42.6A316.8A3

½5�

Figure 4.2

III ELECTRONIC EFFECTS OF POLYFLUOROALKYLGROUPS [6]

In this section we will deal with the effects of a polyfluoroalkyl group as a whole attached

to a saturated, and therefore not formally charged, carbon atom. The effect of fluorine and

fluorinated groups directly bonded to reaction centres such as intermediate carbocation

and carbanion sites will be treated in separate sections.

A Saturated systems

1 Strengths of acids

As fluorine is the most electronegative element, it could be expected that the introduction

of a fluorine atom or polyfluoroalkyl group into the carbon chain of an organic acid, such

Table 4.1 Steric parameters [4]

Substituent Taft Es Charton n

H þ1.24 0

F þ0.78 —

OH þ0.69 —

CH3 0 0.52

CH2CH3 �0.07 0.56

CHðCH3Þ2 �0.47 0.76

CðCH3Þ3 �1.54 1.24

CH2F �0.24 0.62

CHF2 �0.67 0.68

CF3 �1.16 0.91


92 Chapter 4

as an alcohol or carboxylic acid, would increase the acidity of the system and, indeed, this

is the case. The pKa values [7] of a number of fluorine-containing acids, along with

related systems for comparison, are collated in Table 4.2; these data suggest that the effect

of introducing one fluorine atom is very close to that of a single chlorine atom (compare

CH2FCOOH and CH2ClCOOH).

A single fluorine substituent increases the acidity of acetic acid by ca. 100 times while

trifluoroacetic acid is ca. 1000 times stronger. As expected, the inductive effect of

trifluoromethyl falls off rapidly with distance, although the presence of a double bond

helps to relay the effect. Various workers have drawn attention to the fact that, in aqueous

solution, it is the entropy rather than the enthalpy that is more significant in determining

the differences between the strengths of acids. This is a consequence of ordering of

solvent which is greater as the acids become stronger. However, this is equally a

consequence of inductive/field effects of groups. It is not surprising that, in the gas

phase, acidities are determined by differences in enthalpies [8, 9]. It is still worth noting,

however, that perfluoroalkanecarboxylic acids are much weaker than the strong inorganic

acids: for example, the Hammett acidity function Ho for CF3COOH is �3:03 while Ho for

sulphuric acids is �11:1.

The strong inductive effect of fluoroalkyl groups has a corresponding additive

acidifying effect on alcohols (Table 4.2). For instance, perfluoro-t-butanol is of the

same order of acidity as acetic acid. The hydrates of fluoroketones are also remarkably

acidic [10].

Perfluoroalkyl groups attached to phosphorus and sulphur [11] lead to a considerable

increase in the strength of derived acids, as compared with the corresponding alkyl

derivatives. Bis(trifluoromethyl)phosphinic acid, CF3Þ2PO�OH�

, is as strong as per-

chloric acid and is the strongest phosphorus acid known [12], while trifluoromethanesul-

phonic (triflic) acid, CF3SO3H, is the strongest readily available monobasic organic acid

(H0 � 13:8) (compare conc. H2SO4, H0�11:1).

2 Bases

Fluoroalkyl groups correspondingly lower the strengths of bases. Table 4.3 shows the

dissociation constants of some amines, together with hydrocarbon derivatives for com-

parison.

Table 4.2 pKa values of some organic acids and alcohols [7]

Carboxylic acid pKa Alcohol pKa

CH3COOH 4.76 CH3CH2OH 15.9

CH2FCOOH 2.59 CF3CH2OH 12.4

CH2ClCOOH 2.86 CCl3CH2OH 12.2

CHF2COOH 1.34 ðCF3Þ2CHOH 9.3

CHCl2COOH 1.35 ðCH3Þ3COH 19.2

CF3COOH 0.52 ðCF3Þ3COH 5.1

CCl3COOH 0.56 ðCHF2Þ2CðOHÞ2 8.9

CF3CH2CH2COOH 4.15 ðCF3Þ2CðOHÞ2 6.5

CF3CH5CHCOOH 3.48 ðCF3Þ2CðOHÞCF2NO2 3.9


The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 93

The observations that secondary amines, RFÞ2NH�

, do not react with boron trifluoride,

hydrogen chloride or trifluoroacetic acid [13] also serve to indicate a lack of basic

properties. Similarly, tertiary perfluoroalkylamines are quite without basic properties.

Moreover, the oxygen atoms in perfluoroalkyl ethers and ketones are poor donors; this is

exemplified by the fact that hexafluoroacetone cannot be protonated by superacids in

solution. Such findings parallel similar observations with unsaturated derivatives where

the base strength is considerably reduced in, for example, perfluoropyridine or perfluoro-

quinoline [14] in comparison with the parent compounds.

The data, so far, clearly illustrate a very strong inductive effect (�I) by polyfluoroalkyl

groups in saturated systems, and the reduced donor properties of the hetero atom in

nitrogen or oxygen derivatives probably partly arise from some rehybridisation (greater s

character of orbitals containing the electrons not involved in s-bonds) when strongly

electronegative substituents are attached [15].

B Unsaturated systems

The deactivating effect and meta-orientating influence of trifluoromethyl in electrophilic

aromatic substitution, together with a corresponding activating influence on nucleophilic

aromatic substitution [16], are well known. Of course, these are just the results we would

expect upon introducing a strongly electron-withdrawing group, but a more precise

description of the mechanism of electron withdrawal by polyfluoroalkyl groups in these

systems has been a source of debate.

It has become normal to discuss the effects of substituents on benzene systems in terms

of the Hammett equation, log k=k0 ¼ sr, where s measures the effect of a substituent on

the reaction centre. Also, this simple concept has been elaborated, leading to correspond-

ingly modified constants (s0, sþ, s�) catering for the electronic nature of different

reactions; some of the data relating to polyfluoroalkyl groups are contained in the

following discussion (Table 4.4).

1 Apparent resonance effects (see also Section VIIB)

The overall effect of substituents may be separated into inductive (sI) and resonance (sR)

contributions, where s ¼ sI þ sR. Some of the data derived on this basis are given in

Table 4.4: they indicate an apparent resonance contribution by various polyfluoroalkyl

groups.

The problem of describing such a resonance contribution then arises, and it is immedi-

ately tempting to draw an analogy with hydrocarbon systems and invoke ‘fluorine

Table 4.3 pKb values of some amines

Amine pKb

CH3CH2NH2 10.6

CF3CH2NH2 5.7

CCl3CH2NH2 5.4

C6H5NH2 4.6

C6F5NH2 �0:36


94 Chapter 4

hyperconjugation’ or ‘carbon–fluorine double-bond no-bond resonance’. These are two

terms which have been used to refer to an effect that was originally suggested [17] to

account for the dipole moments of p-amino- and p-dimethylaminobenzotrifluoride, which

are larger than the sums of the composite bond moments. The type of interaction that was

envisaged is shown in Figure 4.3.

C C

FF

F

etc.

FF

F

Figure 4.3

The concept of fluorine negative hyperconjugation (FNHC), which in its simplest form

can be written as indicated in Figure 4.4, has had a controversial history although there

can be little doubt about the firm theoretical requirement for such an effect [18–20].

Problems have arisen because there are few rate-constant measurements that require

FNHC, in addition to inductive field effects, to account for the observations [21], although

structural evidence for 4.5A and 4.5B (Figure 4.5) now illustrates the effect well [22, 23].

C CF

C C

F

Figure 4.4

CF3O−

TAS+

4.5A 4.5B

TAS+

TAS+ = (Me2N)3S

+

F3C

F

CF3

−½23�

Figure 4.5

Table 4.4 Substituent constants for some fluorinated groups

Substituent sm sp sI sR

CH2F 0.12 0.11 0.12 �0.02

CHF2 0.29 0.32 0.32 0.06

CF3 0.43 0.54 0.42 0.10

CF2CF3 0.47 0.52 0.41 0.11

CF2Þ2CF3

�0.47 0.52 0.39 0.11

�CF CF3ð Þ2 0.37 0.53 0.48 0.04

SF5 0.63 0.86 0.56 0.27

N CF3ð Þ2 0.47 0.53 0.44 0.06

OCF3 0.47 0.27 0.50 �0.23

½22�



In molecular orbital terms, the unshared p-electrons at the carbanion site are donated

into the s� orbital of the adjacent C–F bond when the orbitals are in an anti-periplanar

configuration which ensures maximum orbital overlap [19, 20].

Trends in the C–F bond lengths and strengths in the fluoromethane series, in which the

C–F bonds strengthen and shorten with increasing fluorination, have been explained in

terms of resonance effects, but theoretical work suggests that Coulombic interactions and

hybridisation changes could also explain these observations [24]. However, the unusually

long C–F bond and short C–O bond measured for the trifluoromethoxide ion [22]

(Figure 4.6) suggests that the C–O bond possesses some double-bond character and,

similarly, the high barrier to rotation of a-fluoroamines indicates some C–N double-

bond character [25].

FF F

F

FC O C O

− −

F

½22�

Figure 4.6

Stabilities of perfluorinated carbanions have also been described using FNHC; a re-

examination [26, 27] of the acidity of CF3Þ3CH�

compared with the bicyclic compound

(Figure 4.7), in which FNHC in the carbanion would result in the formation of an internal

alkene contrary to Bredt’s rule, found that the unconstrained CF3Þ3CH�

undergoes H/D

exchange much more rapidly. If FNHC is the dominant process involved, then we would

expect sR for CF3 to be greater than for CF22CF3 but this is not the case (Table 4.4).

Calculations suggest [28] that perfluoroalkyl negative hyperconjugation can also occur, as

indicated in Figure 4.8, although this seems unlikely given the destabilising effect of

fluorine directly attached to carbanion centres (Section VI).

F F

−H

−H+

Figure 4.7

C CF3

CF3C C C

−−

Figure 4.8

Another probe technique that has been used is to compare the effects of trifluoromethyl,

at the meta and para positions, in both phenol and benzoic acid [29]. Only in the case

where the substituent is in the para position in phenol is it directly conjugated with the

ionising centre and therefore allowing a resonance effect to be important. Values of pKa

for the phenols led to the following substituent parameters: sð p-CF3Þ ¼ þ0:54 and

sðm-CF3Þ ¼ þ0:43, the ratio sð p-CF3Þ=sðm-CF3Þ being 1.25, and this is essentially


96 Chapter 4

the same as the ratio for the corresponding trifluoromethylbenzoic acids. This suggests

that the electronic effects of CF3 operating in the phenol system are the same as those

operating in the benzoic acid system and not, therefore, in accord with a resonance effect.

Also, other fluorinated groups have apparent resonance effects (Table 4.4) that would be

difficult to defend on the basis of any negative hyperconjugation scheme. For many

processes it is not really necessary to invoke the concept of fluorine hyperconjugation to

account for the observations and the most easily appreciated description of many, but by

no means all, of the results available involves polarisation of the p-electron system.

2 Inductive and field effects

It is generally recognised that the inductive effect should be subdivided into a polarisation

effect on the s-bond framework and also on the p-electrons, and it has been indicated that

a major effect of strongly electron-withdrawing groups like perfluoroalkyl is by a

through-space polarisation of the aromatic p-electrons (direct field effect).

The Ip effect of trifluoromethyl would result in polarisation of the p-system and

perhaps approach a situation similar to that which exists in pyridine (Figure 4.9a).

CF3 CF3

Nδ+

δδ+δδ+ δ+δ+

δ+

δ+

δ+

δ+

Figure 4.9a

This kind of description allows for a similar effect to be produced by other perfluor-

oalkyl groups (see Table 4.4), as well as the other fluorinated groups listed. Similar

conclusions to those drawn here are described in a much more detailed review and

analysis [30] of results available.

Electrostatic interactions have been revealed as important in influencing the ‘gaucheeffect’, whereby, in 1,2-disubstituted ethanes (4.9bA), the gauche conformer (4.9bB) is

populated to a larger extent than the anti conformer (4.9bC) [31, 31a] (Figure 4.9b).

X

Y

X

Y

H H

HH

X

H

H H

YH

4.9bA 4.9bB 4.9bC

Figure 4.9b

IV THE PERFLUOROALKYL EFFECT

Saturated, strained, small ring systems are uniquely stabilised by the introduction of

perfluoroalkyl groups, as compared with the corresponding hydrocarbon derivatives,

and this has allowed the study, for instance, of many long-lived valence-bond isomers



of aromatic and heterocyclic systems [32] (see Chapter 9). This stabilising influence,

denoted the ‘perfluoroalkyl effect’ [33], is considered to be kinetic rather than thermo-

dynamic in nature [34].

The introduction of electron-withdrawing perfluoroalkyl groups into unsaturated

systems lowers frontier orbital energies [35], as deduced by theory [36] and photoelectron

spectroscopy [37] for a series of fluorinated alkenes, and manifestations of this effect are

seen in much of the chemistry of such systems.

V STRENGTHS OF UNSATURATED FLUORO-ACIDSAND -BASES

Since fluoroalkyl groups are uniformly acid-strengthening and the order of magnitude of

the effect, relative to other haloalkyl groups, is consistent with electronegativities F > Cl,

etc., it may be expected that the same situation occurs when fluorine is attached to

unsaturated carbon. Inspection of the data in Table 4.5 quickly indicates a more compli-

cated situation because, while fluorine substitution increases the acidity relative to the

hydrocarbon analogue, the acidities are lower than the corresponding chlorocarbon

compounds in the cases of the acrylic acids and phenols.

The fluorine atoms in these locations are not only inductively electron-withdrawing but

interactions of the p-electron lone pairs of fluorine with the electron-rich double bond or

aromatic ring can lead to a net electron donation; this effect has been studied by

photoelectron spectroscopy [38, 39] (Figure 4.10). This Ip effect is discussed more fully

in relation to fluorocarbanions (Section VII).

O

F

O

F

F4 ½38, 39�

Figure 4.10

Table 4.5 Strengths of unsaturated

carboxylic acids and phenols [1, 7]

Compound pKa

CH25CHCOOH 4.25

CF25CFCOOH 1.8

CCl25CClCOOH 1.21

C6H5OH 10.0

C6F5OH 5.5

C6Cl5OH 5.26

C6H5COOH 4.21

C6F5COOH 1.75


98 Chapter 4

It has been concluded from pKa measurements and fluorine NMR data on pentafluoro-

biphenyl derivatives, for example C6F5C6H4CO2H, C6F5C6H4F etc., that the penta-

fluorophenyl group inductively withdraws electrons more strongly than phenyl but

much less strongly than trifluoromethyl, whilst pentafluorophenyl and pentachlorophenyl

have a similar capacity for electron withdrawal [40].

VI FLUOROCARBOCATIONS

In this section we will be mainly concerned with situations where fluorine atoms are

bonded to carbon, which has some formal charge F2Cþ2, either directly or by conjuga-

tion, but we will also make reference to the effect of a fluorine atom in the situation

F2C2Cþ2. As a guide we can consider boron compounds as a useful qualitative model

for carbocations, because of the isoelectronic relationship of a carbocation to boron, and

we note immediately that comparative chemistry of boron halides is most commonly

discussed in terms of 2p–p overlap being more effective with fluorine than with the other

halogens [41]. For the 2B2C2C2F situation, we note that fluoroalkyl derivatives of

tricovalent boron are extremely unstable with respect to migration of fluorine from a- or

b-carbon atoms to boron. Thus the fluorine atoms in these positions are enhancing the

electrophilic nature of boron and we might reasonably predict the same situation for a

carbocation.

This is indeed the case and, at the outset, two major effects of fluorine towards

positively charged carbon centres can be envisaged; fluorine directly bonded to a posi-

tively charged carbon atom is stabilising, via p–p interactions, whilst fluorine that is b- to

a positively charged carbon atom is inductively strongly destabilising (Figure 4.11).

C F

Stabilising

C F C C

F

Destabilising

Figure 4.11

A Effect of fluorine as a substituent in the ring on electrophilicaromatic substitution

The course of electrophilic aromatic substitution can be represented as shown in

Figure 4.12; on the basis of inductive effects of the halogens alone, we would expect

the order of reactivity to be X5H > Br > Cl > F.

X

E H

X

E

E

X

+ H

Figure 4.12



Generally, however, the reverse is the case (F > Cl > Br) (Table 4.6) and, as fluorine can

in some cases increase the reactivity of an aromatic system relative to hydrogen, these

data give a clear indication of resonance interaction between fluorine and the charged

transition state (Figure 4.13) which is reflected in the negative (i.e. electron-donating)

sþp value (Table 4.7).

E EH H

F F+

+

Figure 4.13

Whether fluorine can activate or deactivate an aromatic ring relative to hydrogen

depends on the nature of the attacking electrophile. When the reagent is less reactive

(late transition state) such as in molecular chlorinations and brominations [42, 43] (Table

4.6), resonance stabilisation of the Wheland-like transition state becomes far more

important and so fluorine activates the system. On the other hand, nitration of fluoro-

benzene is slower than the corresponding reaction with benzene.

Some s values [44] for the halogens are listed in Table 4.7 and the following general

principles may be drawn from the data [43]. The sm and sþm values indicate that fluorine

influences the reaction centre mainly by the �I effect, but as the values follow the inverse

order of electronegativity it can be concluded that the þM effect may also be in operation

Table 4.6 Relative rates of para-chlorination and bromination of halobenzenes and halodurenes [42]

Substituent (X) H F Cl Br

Partial rate factor, fp, for para-chlorination of C6H5X 1 6.3 0.4 0.25

Relative rates of bromination of

X

MeMe

Me Me

1a 4.62 0.145 0.062

a After statistical correction.

Table 4.7 s Values for halogen substituents on an aromatic ring [43, 44]

so sm sþm sp sþp

F 0.93 0.335 0.35 0.06 �0:075

Cl 1.28 0.375 0.40 0.225 0.115

Br 1.35 0.39 0.405 0.23 0.15


100 Chapter 4

at the meta position. Ortho halogens also activate in the order F > Cl > Br although the

so values are potentially influenced by steric effects

B Electrophilic additions to fluoroalkenes [45]

The orientations and rates of addition of electrophiles to partially fluorinated alkenes

follow the arguments developed in the preceding sections. For example, the rates of

addition of trifluoroacetic acid to 2-halopropenes (Table 4.8) are in the order F > Cl > Br

and provide evidence of the enhanced stabilisation of a carbon atom bearing a positive

charge by 2p–2p interaction with fluorine [46] (Figure 4.14).

H+ H2C CFCH3 H3C H3C

H3C OCOCF3

CH3 CH3

CH3

CF3COO−

C

F

+C

F

C

F

+

+ ½46�

Figure 4.14

The orientation of electrophilic addition to trifluoropropene was originally thought to

be a reflection of the relative stabilities of the intermediate carbocations 4.15A and 4.15B

(Figure 4.15), but it was subsequently found that trifluoropropene is dimerised, rather than

protonated in highly acidic media [47, 48]. Deuterium labelling studies indicated that the

reaction proceeds via initial fluoride ion abstraction to yield an intermediate allyl cation

[49] (Figure 4.16).

CF3CHCH3

4.15A 4.15B

+CF3CH2CH2

+

Figure 4.15

Table 4.8 First-order rate constants for reaction of trifluoroacetic

acid with CH25CX�CH3 at 258C [46]

X 105kðs�1Þ kX=kH

H 4.81 1

F 340 71

Cl 1.70 0.35

Br 0.395 0.082



F3C�CH�CH2

FSO3HFSO3

− HF+

+

FSO3− HF

(H− shift)

H

H

H

F

F

H

H

H

HCF3

CF3CH=CH2

CF3CH3

CH3

F3C

F

F

½49�

Figure 4.16

A similar mechanism has been advanced for the dimerisation of hexafluoropropene

[50] (Figure 4.17) and other fluorinated propenes [45, 51] to analogous dimers.

CF3CF�CF2

SbF5

F3C

F

F

CF(CF3)2

½50�

Figure 4.17

C Relatively stable fluorinated carbocations

The now-classic technique pioneered by Nobel Laureate George Olah and co-workers

[52, 53] for preparing relatively stable long-lived carbocations, and their direct observa-

tion in solution by NMR, has been applied to the study of a number of classes of

fluorinated carbocationic species [52–55], including alkyl, aryl, allyl and tropylium

cations (Table 4.9).

In general, a halogenated precursor is dissolved in either neat SbF5 or an SbF5=SO2

mixture, at or below room temperature [56] (Figure 4.18).

H3C CH3C

F

H3C CH3C

F

F

SbF6

i, SbF5, −60 � C, SO2

i

½56�

Figure 4.18

The 19F NMR spectrum of the dimethylfluorocarbocation [56] shows that the fluorine

is de-shielded by a massive 260 ppm from the covalent starting material and this observa-

tion argues quite commandingly for p(p–p) resonance stabilisation of the carbocation by

fluorine (Figure 4.19).

F F

Figure 4.19


102 Chapter 4

The difluorobenzyl cation (Figure 4.20) is stable under conditions in which the benzyl

cation undergoes rapid polymerisation [57] and 13C and 19F NMR studies [58] have shown

that, as the electron demand of the aromatic ring increases (i.e. R is electron-withdrawing),

the p( p–p) donation of fluorine to the carbocation centre also increases, leaving the

electron density at Cþ relatively constant for a variety of aromatic substituents.

CF2Cl CF2

R R

C

R

F

F

SbF5Cli, SbF5, −75�C, SO2

i½57�

Figure 4.20

Table 4.9 Stable fluorinated carbocations observed in solution by NMR spectroscopy

Carbocation Ref. Carbocation Ref.

CH3 CF2 [61]

F F

F F

F

[62]

H3C CH3C

F

[56]

Ar F

F F

F

[50]

CF2 [57](CF3)2CFCH2CF CH CFCH2CF3

[63]

CCH3

F

[64]

F7

[59]

F

CAr Ar

[57]

Ph F

FPh

2+ [65]

ðC6F5Þ3Cþ [66]

C6F5

[67]



Other Lewis acids, such as BF3 �Et2O, have been used to induce ionisation [59, 60]

whilst protonation of suitably fluorinated unsaturated substrates may also lead to carbo-

cationic species (Figure 4.21).

F F

F F

H H

−78� C

FSO3H, SbF5

F BF3.Et2O

CH3CN F7

½59�

½60�

Figure 4.21

The protonation of fluorobenzene outlined above suggests that fluorine para to the

methylene group stabilises the arenium ion more effectively than if fluorine is at the ortho

position, whilst at positions meta to the methylene group fluorine is probably destabilising

relative to hydrogen. Consequently, the trifluorobenzenium ion 4.22A is particularly

stable whilst the corresponding tetrafluorobenzenium ion 4.22B is of reduced stability

[52] (Figure 4.22).

F F

F

H HF F

F

H H

F4.22A 4.22B

½52�

Figure 4.22

Of the several fluorine-containing dications that have been reported, the contiguous

diallylic dication shown in Figure 4.23 (4.23A), as determined by NMR experiments,

is unique. Furthermore, it seems to be the case that if fluorine atoms are sited at the

centres of highest charge density, then very long conjugated systems are possible [68]

(4.23B)

1 Fluoromethyl cations

Gas-phase hydride affinity measurements suggest that the order of stability for the

fluoromethyl cations is CHþ3 < CFþ3 < CH2Fþ < CHFþ2 , indicating that the introduction

of fluorine increases the stability of the cations relative to hydrogen [54]. The trifluoro-

methyl cation CFþ3 has been generated and observed by IR spectroscopy upon photolysis

of CF3I in an argon matrix at very low temperatures [69]. However, attempts to observe

CFþ3 in solution by ionisation of trifluorohalomethanes [32] only resulted in the


104 Chapter 4

(CF3)2CFCH2

F

H

F

F

H

F

CH2CF(CF3)2

(CF3)2CFCH2

F

H

F

CH2CF3

n

4.23A

4.23B

n = 1−3

½68�

Figure 4.23

production of CF4, even though CFþ3 is observed as a fragment ion in the mass spectra of

many organofluorine compounds.

D Effect of fluorine atoms not directly conjugated with thecarbocation centre

Even though fluoroalkyl substituents are inductively electron-withdrawing, several cat-

ionic species have been studied in which a trifluoromethyl group is attached directly to the

positively charged carbon centre [55]. The destabilising influence of a trifluoromethyl

group is manifested in a comparison of the reaction rates for the solvolysis [70], via SN1

processes, of the tosylates 4.24A and 4.24B in which the replacement of hydrogen by CF3

leads to a rate retardation of ca. 103 (Figure 4.24). Surprisingly, the introduction of a

second trifluoromethyl, as in 4.24C, leads to only a slight reduction in the rate of

solvolysis and this has been attributed to the fact that the positive charge in intermediate

4.24B is largely delocalised into the aromatic ring and so the introduction of a second

electron-withdrawing substituent, as in 4.24C, has little effect on the stability of the

resulting carbocation.

When such delocalisation is not possible, however, the effect of attaching CF3 groups

adjacent to the carbocation site on the rate of solvolysis is additive; for instance, compare

the rates of solvolysis [71] for 4.25A, 4.25B and 4.25C in Figure 4.25.

Resonance-stabilised long-lived carbocations such as 4.26A and 4.26B have

been generated from precursor alcohols in superacidic solution [72] but, if conjugative

stabilisation is absent as in 4.26C, then only protonated alcohols are observed. Similarly,

ketones with up to three a-fluorine atoms can be protonated giving, for example, 4.26D,

whilst hexafluoroacetone is not protonated in a superacidic medium [73] (Figure 4.26).

Direct observation of a number of bridged halonium ions (X ¼ Br, Cl, I) is possible

[74] when, for example, 2,3-dihalo-2,3-dimethylbutanes are ionised in SbF5=SO2 mix-

tures; however, as yet, no analogous fluoronium ions have been observed in solution

(Figure 4.27).

Indeed, 13C NMR studies suggest that ionisation of 2,3-difluoro-2,3-dimethylbutane

gives a rapidly equilibrating mixture in which methyl 1,2-shifts, rather than fluorine

shifts, occur [75] (Figure 4.28).



H H

OTos

OMe

H CF3

OTos

OMe

F3C CF3

OTos

OMe

H CF3

OMe

Relative ratesof Solvolysis 4000 5.2 - 2.4 1

H CF3

OMe

4.24A 4.24B 4.24C

4.24B

½70�

Figure 4.24

AnO2SO

R1

R2

R1

R2

F3CH2CO

R1

R2

4.25A R1 = R2 = H 1012

4.25B R1 = CF3, R2 = H 106

4.25C R1 = R2 = CF3 1

Relative Rate

CF3CH2OH½71�

Figure 4.25

CCH3

CF3

C

CF3

C

O

F3C CH3H

HHO

F3C CH3

H

4.26A 4.26C 4.26D4.26B

½73�

Figure 4.26


106 Chapter 4

H3C

X

CH3

Y

i, SbF5, SO2, −60� C

H3C CH3

H3C CH3 H3C CH3X

X = Cl, Y = F, ClX = Br, Y = F, BrX = I, Y = F

i ½74�

Figure 4.27

H3CH3C

F

CH3

CH3

F

H3CH3C

CH3

CH3

F

H3CH3C

H3C

CH3

F

i, SbF5, SO2, −90� C

i

½75�

Figure 4.28

However, mass-spectral breakdown patterns of PhOCH2CH2F suggest that a cyclic

fluoronium ion can be observed as an ion-neutral complex in the gas phase [76], whilst

calculations indicate that the fluoronium ion is more stable than the isomeric þCH2CH2F

ion [54]. Participation by fluorine remote from the reaction centre has been postulated to

account for the product obtained from the reaction between 5-fluoro-1-pentyne and

trifluoroacetic acid [46] (Figure 4.29).

F FOCOCF3

F

OCOCF3

FH3C

F3COCO

H CF3COO

CF3COOH

½46�

Figure 4.29

Of course a bridged system must be involved, at least in the transition state, between

boron and carbon in the decomposition of diazonium salts (Figure 4.30) and, indeed,

transfer from trifluoromethyl has been observed [77] (Figure 4.30).

VII FLUOROCARBANIONS

The term ‘carbanion’ is used in the present context as a general description of systems

with negative charge on carbon, although this may be only fractional. It should also be

remembered that the nature of the species will be dependent on the counter-ion and on the

solvent [78]. Much of our information concerning substituent effects on fluorocarbanions

comes from studies of the rates of base-catalysed hydrogen, deuterium and tritium



Ar-N2 BF4− −N2 Ar----F----BF3

δ δArF + BF3

N2 CF3

40 �C

CF3

CF2F

CF2FCOOEtF

Et2O

HCO3

½77�

Figure 4.30

exchange reactions and, consequently, the substituent effects refer strictly to the transition

state 4.31B (Figure 4.31), although the effects are usually considered to apply also to the

intermediate carbanion 4.31C.

C H C H Base C + H-Base

Product 4.31D

4.31C

δ −

4.31A 4.31B

δ +

Figure 4.31

If a substituent lowers the activation energy for production of 4.31B, then we assume

that the energy of 4.31C is also lowered. However, it must be remembered that 4.31C may

still have a very short lifetime, i.e. it is kinetically unstable with respect to initial state

4.31A or some product 4.31D, even though we may refer to the effect of a substituent as

being strongly stabilising. The effect of ‘internal return’, i.e. return from 4.31B to 4.31A,

or from 4.31C to 4.31B, is also a complicating factor which affects the interpretation of

kinetic acidities. Sometimes equilibrium data are available and, obviously, this reflects

substituent effects on the energy of 4.31A and 4.31C directly.

A Fluorine atoms attached to the carbanion centre

Superficially, we would expect the high electronegativity of fluorine to stabilise a

carbanion centre, but measurements of acid strengths and exchange rates for a variety


108 Chapter 4

of halogenated compounds, discussed below, suggest that the inductive effect (Is)

of fluorine is not the dominant factor in determining the stability of the carbanions

formed [79].

Base-catalysed H/D exchange experiments for a series of haloforms [80] (Table 4.10)

demonstrate that carbanion formation is stabilised by halogen in the order I> Br>Cl> F.

When these results are combined with acidity measurements which show that

CF3H ðpKa 31Þ is little more acidic than methane (pKa 40) [81], we can conclude that,

in these systems, fluorine attached to a carbanion centre is stabilising with respect to

hydrogen but destabilising compared with the effects of other halogens. Similar conclu-

sions can be drawn from pKa measurements of a number of halobis(trifluoromethyl)

methanes [82].

On the other hand, the pKa values of a series of substituted nitromethanes [83]

(Table 4.11) suggest that, whilst chlorine bonded directly to the carbanion centre in-

creases acidity relative to hydrogen, fluorine decreases acidity and, therefore, decreases

the stability of the corresponding carbanion.

To rationalise these two contradictory results we must consider not only the stabilising

inductive effect of fluorine (Is), but also destabilising interactions between the electron

pairs on fluorine and the non-bonding electron pair at the negatively charged carbon atom

(Ip) which, for the halogens, follows the order F > Cl > Br > I [84] (Figure 4.32).

StabilisingIσ H2C F Destabilising−Iπ H2C F½84�

Figure 4.32

Table 4.10 Base-catalysed deuterium exchange in haloforms [80]

Haloform Rate of exchangea (105k) (l:mol�1s�1)

CHF3 Too slow to measure in this medium

CHCl3 820

CHBr3 101 000

CHI3 105 000

CHCl2F 16

CHBr2F 3600

CHI2F 8800

a 08C in water.

Table 4.11 Apparent ionisation constants of substituted nitromethanes

(in water, at 258C) [83]

XYCHNO2 pKa XYCHNO2 pKa

Y ¼ COOC2H5 Y ¼ NO2

X ¼ Cl 4.16 X ¼ Cl 3.80

X ¼ H 5.75 X ¼ H 3.57

X ¼ F 6.28 X ¼ F 7.70

Y ¼ Cl

X ¼ Cl 5.99

X ¼ H 7.20

X ¼ F 10.14



The net stabilising or destabilising influence of fluorine attached to a carbanion centre

is, therefore, a result of these two effects. A consideration of the geometry of carbanions

formed at both planar and tetrahedral carbon, as depicted in Figure 4.33, illustrates that

�Ip repulsion is greater at a planar carbon since, in this situation, the repelling non-

bonding electron pairs on carbon are closer in space to electron pairs on fluorine [79]

(Figure 4.33).

Tetrahedral (sp3) C Planar (sp2) C

C F C F109 �

109 � 109 �

90 �½79�

Figure 4.33

Consequently, for the haloform case (Table 4.10), since Ip repulsion for chlorine is less

than that for fluorine, chlorine as a substituent facilitates carbanion formation much more

than fluorine. The enhanced acidities of bromoform and iodoform have been attributed to

the release of steric strain on deprotonation, while the increased availability of d-orbitals

and the easier polarisation of these larger atoms [85] are effects that are at a minimum for

fluorine (Figure 4.34).

C Br C Br ½85�

Figure 4.34

The carbanion centres in nitro derivatives described in Table 4.11 are more planar

in character due to conjugative stabilisation of the negative charge by the nitro group,

and the fact that here fluorine destabilises the carbanions relative to hydrogen as a

consequence of Ip repulsion dominating over Is stabilisation. Also, the nature of other

groups attached to the central carbon affects the level of conjugation of the negative

charge with the nitro group and, consequently, the stereochemistry of the carbanion

site.

A propensity of fluorocarbanions to adopt pyramidal structures in which �Ip repul-

sions are minimised is supported by calculations [86] from which it was deduced that for

the �CH2F carbanion a pyramidal structure is 55 kJmol�1 more stable than the planar

form. Furthermore, calculations concerning a-fluorocyclopropyl anions [87] suggest that

a non-planar conformation is adopted and that the barrier to inversion is significantly

higher for a monofluorinated ring (175 kJmol�1) than for the cyclopropyl anion

(73 kJmol�1).


110 Chapter 4

B Fluorine atoms and fluoroalkyl substituents adjacent to thecarbanion centre

When a fluorine atom is located b- to a carbanion centre, F2C2C�, we would expect the

high electronegativity of fluorine to give rise to a very dominant stabilising effect (Is),

since, in this situation, there is no opportunity for Ip repulsion. Indeed, b-fluorine

substituents are very strongly stabilising but the basis of the effect has been a subject of

varied interpretation.

Attempts to determine the effect on carbanion formation of halogen atoms attached to

the adjacent carbon are generally complicated by a competing b-elimination process [88]

(Figure 4.35). However, Andreades [89] found that, for a series of monohydrofluorocar-

bons, the exchange process proceeds much more rapidly than elimination; the forward (kH)

and reverse (kD) reactions were studied (Figure 4.36; Table 4.12). These observed relative

reactivities and derived acidities indicate that the stabilities of perfluorocarbanions are in

the order tertiary > secondary > primary and, therefore, that b-fluorine (F2C2C�) is

much more effective at carbanion stabilisation than a-fluorine (F2C�) [79]. A further

demonstration of these effects is observed for ðCF3Þ3CH, which is 50 orders of magnitude

more acidic than methane. Furthermore, pentafluorocyclopentadiene [90] is only slightly

more acidic than cyclopentadiene (pKa 15) whereas pentakis(trifluoromethyl)cyclopenta-

diene ðpKa < �2Þ is even more acidic than conc. nitric acid [32, 32a]!

D CC Hal C C Hal C C−HalD2O ½88�

Figure 4.35

RF�H + CH3OD RF�D + CH3OHkH

kD

(NaOCH3)

½89�

Figure 4.36

The enhanced stability of b-fluoro carbanions (Figure 4.37) has been attributed to

fluorine negative hyperconjugation (FNHC; see Section IIIB). For instance, negative

hyperconjugation (see Section III) has been invoked to explain the enhanced reactivity

(100-fold) [27] and the higher gas-phase acidity (by 5.4 pKa units) [91] of 4.38A over the

Table 4.12 Deuterium exchange and acidities of monohydroperfluoroalkanes [89]

Compound CF3H CF3ðCF2Þ5CF2H ðCF3Þ2CFH ðCF3Þ3CH

Derived ion �CF3 CF3ðCF2Þ5CF�2 ðCF3Þ2CF� ðCF3Þ3C�

Relative reactivity 1 6 2� 105 109

Approx. pKa 31 30 20 11



C CFF

FC C F

F

F

Figure 4.37

bridgehead compound 4.38B in which negative hyperconjugation in the derived

carbanion is unfavourable. Elongated b-C2F bonds and shortened Ca2Cb bonds in

4.38C, as measured by X-ray crystallography, provides direct experimental evidence

[23] (Figure 4.38).

(CF3)3C H

HCF3

F

CF3

F (Me2N)3S+

4.38A 4.38B 4.38C

½27�

Figure 4.38

The stereochemical course of hydrogen–deuterium exchange in homochiral

PhEtHC�CF3 has been studied [15] and, like systems containing other carbanion-

stabilising groups, the extent of racemisation of the product varies with solvent.

C Stable perfluorinated carbanions [92–94]

Inevitably, the successful generation of long-lived carbocations by the protonation of

alkenes in superacid solution prompted attempts to generate observable perfluorocarba-

nions by the reaction of fluoride ion with perfluoroalkenes (‘Mirror-image chemistry’).

Although fluoroalkenes can oligomerise in the presence of fluoride ion, there are now

reported examples [79, 95] of fluorocarbanions that can be observed directly by NMR

and, in some cases, obtained as crystalline solids [96]. Their generation is achieved by

reaction of either a fluoroalkene [97] or an allene [98] with a fluoride-ion source, usually

CsF or TAS-F [99], in a suitable solvent at room temperature. Various tertiary perfluoro-

carbanions have been directly observed but carbanions with a-fluoro substituents are

usually too unstable, due to Ip repulsion (Figure 4.39). The anion 4.39A shown in Figure

4.39 is an exception [100].

Fluoride-ion-promoted carbon–carbon bond cleavage enabled the preparation of the

cyclic carbanion shown in Figure 4.40 [23].

Sigma-complexes, observed by NMR, are analagous to the well-known Wheland inter-

mediates in hydrocarbon chemistry, is possible upon the addition of CsF to perfluoro-s-

triazine derivatives [101] (Figure 4.41) but direct observation of similar s-complexes

derived from less-activated perfluoroaromatic systems has not yet been reported.

Deprotonation of hydroperfluorocarbons provides an alternative route to perfluorocar-

banions and, for example, several perfluoropentadienide [90, 102–104] (Figure 4.42) and

benzylic [105] carbanions have been prepared by this method.

A cyclopentadienide ion can also be prepared by reaction of a diene with Bu4NI via a

single-electron transfer pathway [104] (Figure 4.43).


112 Chapter 4

C CF2

F3C

F3CC CF3

F3C

F3C

F

CF3

•

CF3 CF3

CF3

CF3

F

F3C

Cs+

F F FF +i

F F Cs+

(Me2N)3S+

F F

F

i, CsF, tetraglyme

i

i, CsF, tetraglyme

i, (Me2N)3S+Me3SiF2

− (TAS-F), THF

i

4.39A

Cs+

F3C

F3C

½97�

½95�

½98�

½100�

Figure 4.39

F

F

F3C

CF3

F

FTAS-F

THF

F

F

F3C

CF3

F

F(Me2N)3S

+

½23�

Figure 4.40

N

N

N N

N

N

F

F F

F

F Cs+½101�

Figure 4.41

D Acidities of fluorobenzenes and derivatives

Inductive effects of ortho substituents are important in governing the acidity of a C–H

bond in substituted benzenes [106], and a variety of data indicate that the acidifying

influence of fluorine falls off in the order ortho � meta > para; this is illustrated by

Table 4.13 [107].



CF3

CF3 CF3

CF3

CF3 HCF3

CF3 CF3

CF3

CF3

H2O H3O½103, 104�

Figure 4.42

CF3

CF3 CF3

CF3

CF3 CF3

Bu4NICF3

CF3 CF3

CF3

CF3

Bu4N CF3I½104�

Figure 4.43

Also, the order of acidity of the dihalobenzenes, m-C6H4F2 > m-C6H4ClF >

m-C6H4Cl2, obtained from exchange data on the monodeutero derivatives [88], indicates

the greater acidifying influence of ortho-fluorine than of ortho-chlorine and is a further

illustration of the significance of inductive effects. Polyfluorobenzenes are very acidic, as

evidenced by the fact that pentafluorobenzene and 1,2,4,5-tetrafluorobenzene, for

example, are metallated with butyl lithium rather than undergoing nucleophilic substitu-

tion [108]; see Chapter 9, Section IIE. This is illustrated by the data in Table 4.14, which

contains a comparison of rates of exchange of tritium and of nucleophilic substitution.

Table 4.13 Relative rates of base-catalysed deuterium exchange [107]

Rate, relative to

Compound Benzene Toluene

[2-D] Fluorobenzene 6:3� 105 —

[3-D] Fluorobenzene 107 —

[4-D] Fluorobenzene 11.2 —

[3-D] Benzotrifluoridea 580 —

2,5-Difluoro[Me-D1]toluene — 350

a Trifluoromethyl [3-D] benzene.

Table 4.14 Rates of tritium exchange and of nucleophilic substitution by sodium

methoxide [109]

104k l:mol�1s�1ð Þ

Polyfluorobenzene Exchange at 408C

Displacement at

508C

Pentafluorobenzene 1360 1.05

1,2,3,4-Tetrafluorobenzene 0.0053 0.018

1,2,4,5-Tetrafluorobenzene 58 < 10�4

1,2,3,5-Tetrafluorobenzene 5.6 0.049

1,3-Difluorobenzene 0.0061


114 Chapter 4

Also relating to these data is the observation that substitution accompanies metallation in

the reaction of 1,2,3,4-tetrafluorobenzene with butyl lithium [108].

Fluorine substituents in the ring also enhance the acidity of hydrogen at benzylic

positions [82]; for example, the acidity of 2,5-difluorotoluene relative to toluene is

shown in Table 4.13. Indeed, a comparison of the equilibrium acidities of C6F5Þ2CH2

�

and C6F5ð Þ3CH with the values for diphenylmethane and triphenylmethane indicates that

substitution of each phenyl group by pentafluorophenyl results in an enhancement of

acidity by 5–6 pK units; this effect has also been attributed, principally, to a strong

inductive influence by polyfluoroaryl groups [110].

E Acidities of fluoroalkenes

Studies on the influence of halogen on the acidity of hydrogen in 1-chloro-2-fluoroethene

showed that the kinetic acidity of the hydrogen a- to chlorine is greater than that for

hydrogen a- to fluorine, in accordance with lower Ip repulsions for chlorine a- to the

carbanion centre [79].

Similarly, the pKa values for a range of halogenated ethenes [26] (Table 4.15) demon-

strate that a-halogen substituents facilitate vinyl carbanion formation in the same order as

in the haloform series, i.e. Br > Cl > F.

Calculations suggest that negative hyperconjugation is also a factor in vinylic systems

although the vinyl anions are thermodynamically unstable relative to the formation of

ethyne and fluoride ion [111].

VIII FLUORO RADICALS [112, 113]

A Fluorine atoms and fluoroalkyl groups attached to the radicalcentre

The organic chemist is interested in the separate effects of fluorine substituents on (a) the

rate constants for formation of radicals and (b) the effect on the subsequent reactivity of

these radicals; but it is not always easy to disentangle this information from experimental

observations.

Do fluorine substituents have an effect on thermodynamic stabilisation, or not? We

might expect fluorine to have a similar stabilising influence to that of oxygen on the

formation of radicals (Figure 4.44). However, we have already noted the schizophrenic

nature of fluorine in carbanions, where inductive electron withdrawal wrestles with Ip

electron repulsion, and it is a similar situation with radicals.

Table 4.15 Acidities of halogenated

alkenes [26]

Carbon acid pKa

CCl25CHBr 24.6

CCl25CHCl 25.0

CF25CHCl 25.3

CCl25CHF 26.3

CF25CHF 27.2



O CH2 O CH2

Figure 4.44

Stabilities of methyl and fluoromethyl radicals have been calculated [114] to be in the

order CFl

3 < CHl

3 < CF2Hl

< CFHl

2 and the relative rates of formation of such radicals,

measured in b-scission reactions of a series of t-butoxy radical derivatives, as shown in

Figure 4.45, lend support to this conclusion [115].

R C

CH3

CH3

O CO2 R C

CH3

CH3

O

O

R CH3

O

H3C CH3

+ CH3

∆

2 k2

+ R

k1

½115�

Figure 4.45

Methyl radicals are essentially planar but ESR measurements [116], supported by

theoretical calculations [114], show that fluoromethyl radicals deviate from planarity to

increasingly pyramidal structures upon further fluorination, with CF3l measured to be

49.18 from planarity. The barriers to inversion of fluoromethyl radicals increase in the

order CFHl

2 < CF2Hl

< CFl

3 while fluorocyclopropyl radicals (Figure 4.46) adopt a fixed

pyramidal conformation at the radical centre [117], as determined by ESR at �1088C.

The tendency for fluorine to induce pyrimidalisation of radical centres has also been used

to account for the stereochemistry of products [118].

F

H3C CH3

½117�

Figure 4.46

Electronegative groups lower orbital energies and therefore, in principle, the high

electronegativity of fluorine should lower the orbital energy of an attached carbon radical

centre. Additionally, conjugative interactions between the singly occupied orbital of the

carbon and the lone pairs on fluorine would be a stabilising interaction, which would

simultaneously render the carbon atom more nucleophilic (Figure 4.47). The fact that

further stabilisation by fluorine substitution is negligible, after the first substituent,

suggests that Ip repulsion becomes more important as we increase the charge on carbon

and this also accounts for the tetrahedral nature of the trifluoromethyl radical. This is

exactly analogous to the effect of fluorine substituents on carbanions, where electron-pair

repulsions are minimised in a pyramidal conformation (Figure 4.48).


116 Chapter 4

C FH

HC F

H

H

Figure 4.47

C FH

FC F

H

F

Figure 4.48

B Stable perfluorinated radicals

The effect of fluorine substituents that are not directly attached to the radical centre is

more difficult to define, although calculations [114, 119] suggest an order of stability

CH3CHl

2 > FCH2CHl

2 > F2CHCHl

> CHl

3 > CF3CHl

2 which is, intuitively, the opposite

of the order which might be anticipated. Obviously, polyfluoroalkyl substituents will be

strongly electron-withdrawing, making the radical more electrophilic in character and in

some cases steric crowding is so severe at multi-substituted radical centres that the radicals

are kinetically very stable. An example is the ‘Scherer radical’ [120] (Figure 4.49), which

is stable at room temperature, even in the presence of oxygen.

CF3

CF3

F3CF

CF3

F3CF

F

CF3

F3CF

CF3

F3CF

C2F5

F2½120�

Figure 4.49

Likewise, the radical shown in Figure 4.50 is a stable perfluorovinyl system [121].

F2

(CF3)3CF

C C

CF(CF3)3

F

(CF3)3CFC CCF(CF3)3 ½121�

Figure 4.50

C Polarity of radicals

It is increasingly apparent that polar characteristics of radicals are important in organic

synthesis [122] and the effect of fluorine on the polarity of radicals is very significant.

Reactions of perfluoroalkyl radicals with a series of substituted p-styrenes [123]

(Figure 4.51) shows that the rate constant for radical addition to alkenes increases as

the alkene becomes more electron-rich (Table 4.16) and, in similar additions, perfluoro-

alkyl radicals reacted 40 000 times faster with 1-hexene than the corresponding alkyl

radicals.



R R

C8F17

+ C8F17½123�

Figure 4.51

Likewise, perfluorinated radicals react more rapidly with electron-rich alkenes (X¼H)

than with electrophilic alkenes (X¼F) in some intramolecular processes [124] (Figure

4.52). Similarly, rates of hydrogen abstraction by perfluoroalkyl radicals from a series of

aromatic thiols were greatest from the most nucleophilic thiol [125]; clearly, taken

together, these data show that perfluoroalkyl radicals are highly electrophilic in character,

in comparison with alkyl radicals, which are of course more nucleophilic.

F2CCF2

CF2

CF2

X

X X X CX2H

F

X XH

X F+

X = F, kA 4.9 x 105 s−1, Only 3-4% 4.52A formed

X = H, kA 1.06 x 107 s−1, kB 3.5 x 106 s−1

4.52A 4.52B½124�

Figure 4.52

REFERENCES



2 C.W. Thornber, Chem. Soc. Rev., 1979, 8, 563.

3 S.A. Sherrod, R.L.d. Costa, R.A. Barnes and V. Boekelheide, J. Am. Chem. Soc., 1974, 96, 1565.

4 R. Gallo, Prog. Phys. Org. Chem., 1983, 14, 115.

5 D. Seebach, Angew. Chem., Int. Ed. Engl., 1990, 29, 1320.

6 M. Schlosser, Angew. Chem., Int. Ed. Engl., 1998, 110, 1497.

7 R. Stewart, The Proton: Applications to Organic Chemistry, Academic Press, London, 1985.

8 G.V. Calder and T.J. Barton, J. Chem. Educ., 1971, 48, 338.

Table 4.16 Relative rates of addition of

perfluoro-octyl radicals to para-substituted

styrenes [123]

R kreladd

OCH3 1.41

CH3 1.33

H 1.0

Cl 0.77

CF3 0.53


118 Chapter 4

9 M. Katawta, S. Ten-no, S. Kato and F. Hirata, J. Phys. Chem., 1966, 100, 1111.

10 W.J. Middleton and R.V. Lindsey, J. Am. Chem. Soc., 1964, 86, 4948.

11 R.N. Haszeldine and J.M. Kidd, J. Chem. Soc., 1954, 4228.

12 H.J. Emeleus, R.N. Haszeldine and R.C. Paul, J. Chem. Soc., 1954, 4228.

13 J.A. Young, S.N. Tsoukalas and R.D. Dresdner, J. Am. Chem. Soc., 1958, 80, 3604.

14 R.D. Chambers, M. Hole, B. Iddon, W.K.R. Musgrave and R.A. Storey, J. Chem. Soc. (C),1966, 2328.

15 D.J. Cram, Fundamentals of Carbanion Chemistry, Academic Press, New York, 1965.

16 R.J. DePasquale and C. Tamborski, J. Org. Chem., 1967, 32, 3163.

17 J.D. Roberts, R.L. Webb and E.A. McElhill, J. Am. Chem. Soc., 1950, 72, 408.

18 A.E. Reed and P.v.R. Schleyer, J. Am. Chem. Soc., 1990, 112, 1434.

19 D.A. Dixon, T. Fukunaga and B.E. Smart, J. Am. Chem. Soc., 1986, 108, 4027.

20 D.S. Friedman, M.M. Framel and L.C. Allen, Tetrahedron, 1985, 41, 499.

21 R.D. Chambers, J.S. Waterhouse and D.L.H. Williams, Tetrahedron Lett., 1974, 743.

22 W.B. Farnham, B.E. Smart, W.J. Middleton and J.C. Calabrese, J. Am. Chem. Soc., 1985, 107,

4565.

23 W.B. Farnham, D.A. Dixon and J.C. Calabrese, J. Am. Chem. Soc., 1988, 110, 2607.

24 K.B. Wilberg and P.R. Rablen, J. Am. Chem. Soc., 1993, 115, 614.

25 M.M. Rahman, D.M. Lemal and W.P. Dailey, J. Am. Chem. Soc., 1988, 110, 1964.

26 A. Streitwieser, D. Holtz, G.R. Ziegler, J.O. Stoffer, M.L. Brokow and F. Guibe, J. Am. Chem.Soc., 1976, 98, 5229.

27 J.H. Sleigh, R. Stephens and J.C. Tatlow, J. Chem. Soc., Chem. Commun., 1979, 921.

28 Y. Apeloig, Chem. Commun., 1981, 396.

29 C.J. Liotta and D.F. Smith, J. Chem. Soc., Chem. Commun., 1968, 416.

30 D. Holtz, Prog. Phys. Org. Chem., 1971, 8, 1.

31 P.R. Rablan, R.W. Hoffmann, D.A. Hrovat and W.T. Borden, J. Chem. Soc., Perkin II, 1999,

1719.

31a D. O’Hagan and H.S. Rzepa, J.C.S. Chem. Commun., 1997, 645.

32 B.E. Smart in The Chemistry of Functional Groups. Supplement D: Fluorocarbons, ed. S. Patai

and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 603.

32a E.D. Lagamis and D.M. Lemal, J. Amer. Chem. Soc., 1980, 102, 6633.

33 D.M. Lemal and L.H. Dunlap, J. Am. Chem. Soc., 1972, 94, 6562.

34 A. Greenberg, J.F. Liebman and D.V. Vechten, Tetrahedron, 1980, 36, 1161.

35 M.R. Bryce, R.D. Chambers and G. Taylor, J. Chem. Soc., Perkin 1, 1984, 509.

36 I.N. Rozhkov and Y.A. Borisov, Bull. Acad. Sci. USSR, 1992, 41, 1041.

37 L.N. Domelsmith, K.N. Houk, C. Piedrahita and W.J. Dolbier, J. Am. Chem. Soc., 1978, 100,

6908.

38 D.H. White, P.B. Condit and R.G. Bergman, J. Am. Chem. Soc., 1972, 94, 1348.

39 J. Bastide and E. Heilbronner, J. Electron Spec. Relat. Phenom., 1979, 16, 205.


41 F.A. Cotton and G. Wilkinson, Advanced Inorganic Chemistry, John Wiley and Sons, New

York, 1988.

42 P.B.d.l. Mare and J.H. Ridd, Aromatic Substitution, Butterworths, London, 1959.

43 R. Taylor, Electrophilic Aromatic Substitution, John Wiley and Sons, New York, 1990.

44 M. Charlton, Prog. Phys. Org. Chem., 1971, 8, 235.

45 V.A. Petrov and V.V. Bardin in Organofluorine Chemistry. Fluorinated Alkenes and ReactiveIntermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 64.

46 P.E. Peterson, Acc. Chem. Res., 1971, 4, 407.

47 P.C. Myhre and G.D. Andrews, J. Am. Chem. Soc., 1970, 92, 7595.

48 K.M. Koshy, D. Roy and T.T. Tidwell, J. Am. Chem. Soc., 1979, 101, 357.


50 R.D. Chambers, A. Parkin and R.S. Matthews, J. Chem. Soc., Perkin 1, 1976, 2107.



51 G.G. Belen’ki, J. Fluorine Chem., 1996, 77, 107.

52 G.A. Olah and Y.K. Mo, Adv. Fluorine Chem., 1973, 7, 69.

53 G.A. Olah and Y.K. Mo in Carbonium Ions, Vol. 5, ed. G.A. Olah and P.v.R. Schleyer, Wiley-

Interscience, New York, 1976, p. 2135.

54 A.D. Allen and T.T. Tidwell, Adv. Carbocation Chem., 1989, 1, 1.

55 X. Creary, Chem. Rev., 1991, 91, 1625.

56 G.A. Olah, R.D. Chambers and M.B. Comisarow, J. Am. Chem. Soc., 1967, 89, 1268.

57 G.A. Olah, C.A. Cupas and M.B. Comisarow, J. Am. Chem. Soc., 1966, 88, 362.

58 G.K.S. Prakash, L. Heiliger and G.A. Olah, J. Fluorine Chem., 1990, 49, 33.

59 W.P. Dailey and D.M. Lemal, J. Am. Chem. Soc., 1984, 106, 1169.

60 G.A. Olah and T.E. Kiovsky, J. Am. Chem. Soc., 1967, 89, 5692.

61 G.A. Olah, M. Stephenson, J.G. Shih, V.V. Krishnamurthy and G.K.S. Prakash, J. FluorineChem., 1988, 40, 319.

62 M.V. Galakhov, V.A. Petrov, V.I. Bakhmutov, G.G. Belen’kii, B.A. Kvasov, L.S. German and

E.I. Fedin, Bull. Acad. Sci. USSR, 1985, 34, 279.

63 R.D. Chambers, M. Salisbury, G. Absey and G. Moggi, J. Chem. Soc., Chem. Commun.,

1988, 680.

64 G.A. Olah and M.B. Comisarow, J. Am. Chem. Soc., 1969, 89, 2955.

65 G.A. Olah and J.S. Staral, J. Am. Chem. Soc., 1976, 98, 6290.

66 G.A. Olah and M.B. Comisarow, J. Am. Chem. Soc., 1966, 89, 1028.

67 G.A. Olah, G.K.S. Prakash and G. Liang, J. Am. Chem. Soc., 1977, 99, 5683.

68 R.D. Chambers, G.C. Apsey, P. Odello, G. Moggi and W. Navarrini, Macromol. Symp., 1994,

82, 33.

69 F.T. Prochaska and L. Andrews, J. Am. Chem. Soc., 1978, 100, 2102.

70 A.D. Allen, V.M. Kanagasabapathy and T.T. Tidwell, J. Am. Chem. Soc., 1986, 108, 3470.

71 P.G. Gassman and J.B. Hall, J. Am. Chem. Soc., 1984, 106, 4267.

72 G.A. Olah and C.U. Pittman, J. Am. Chem. Soc., 1966, 88, 3310.

73 G.A. Olah, A. Burrichter, G. Rasul, A.K. Yudin and G.K.S. Prakash, J. Org. Chem., 1996,

61, 1934.

74 G.A. Olah, Halonium Ions, Wiley-Interscience, New York, 1975.

75 G.A. Olah, G.K.S. Prakash and V.V. Krishnamurthy, J. Org. Chem., 1983, 48, 5116.

76 V. Nguyen, X. Cheng and T.H. Morton, J. Am. Chem. Soc., 1992, 114, 7127.

77 D. Ferraris, C. Cox, R. Anand and T. Lectka, J. Am. Chem. Soc., 1997, 119, 4319.

78 H. Koch and J. Koch in Fluorine Containing Molecules. Structure and Reactivity, ed.

A. Greenberg, J.F. Liebman and W.R. Dolbier, VCH, New York, 1988, p. 99.

79 R.D. Chambers and M.R. Bryce in Fluoro-carbanions, ed. E. Buncel and T. Durst, Elsevier,

New York, 1987, p. 271.

80 J. Hine, N.W. Burske, M. Hine and P.B. Langford, J. Am. Chem. Soc., 1957, 79, 1406.

81 R.G. Pearson and R.L. Dillon, J. Am. Chem. Soc., 1953, 75, 2439.

82 K.J. Klabunde and D.J. Burton, J. Am. Chem. Soc., 1972, 94, 5895.

83 H.G. Adolph and M.J. Kamlet, J. Am. Chem. Soc., 1966, 88, 4761.

84 D.T. Clark, N.J. Murrell and J.M. Tedder, J. Chem. Soc., 1963, 1250.

85 J. Hine, Physical Organic Chemistry, McGraw-Hill, New York, 1962.

86 J. Burdon, D.W. Davies and G.d. Cande, J. Chem. Soc., Perkin 1, 1979, 1205.

87 J. Tyrrell, V.M. Kolb and C.Y. Meyers, J. Am. Chem. Soc., 1979, 101, 3497.

88 J. Hine and P.B. Langford, J. Org. Chem., 1962, 27, 4149.

89 S. Andreades, J. Am. Chem. Soc., 1964, 86, 2003.

90 G. Paprott and K. Seppelt, J. Am. Chem. Soc., 1984, 106, 4060.

91 I.A. Koppel, J. Am. Chem. Soc., 1994, 116, 8654.

92 D.J. Burton, Z.-Y. Yang and W. Qiu, Chem. Rev., 1996, 96, 1641.

93 W.B. Farnham, Chem. Rev., 1996, 96, 1633.


120 Chapter 4

94 R.D. Chambers and J.F.S. Vaughan in Organofluorine Chemistry. Fluorinated Alkenes andReactive Intermediates, ed. R.D. Chambers, Springer Verlag, Berlin, 1997, p. 1.

95 R.D. Chambers, R.S. Matthews, G. Taylor and R.L. Powell, J. Chem. Soc., Perkin 1, 1980,

435.

96 W.B. Farnham, D.A. Dixon and J.C. Calabrese, J. Am. Chem. Soc., 1988, 110, 2607.

97 A.E. Bayliff and R.D. Chambers, J. Chem. Soc., Perkin 1, 1988, 201.

98 W.B. Farnham, W.J. Middleton, W.C. Fultz and B. E. Smart, J. Am. Chem. Soc., 1986, 108,

3125.

99 B.E. Smart, W.J. Middleton and W.B. Farnham, J. Am. Chem. Soc., 1986, 108, 4905.

100 R.D. Chambers and T. Nakamura, J. Chem. Soc., Perkin Trans. 1, 2001, 398.

101 R.D. Chambers, P.D. Philpot and P.L. Russell, J. Chem. Soc., Perkin 1, 1977, 1605.

102 R.D. Chambers and M.P. Greenhall, J. Chem. Soc., Chem. Commun., 1990, 1128.

103 E.D. Laganis and D.M. Lemal, J. Am. Chem. Soc., 1980, 102, 6633.

104 R.D. Chambers, S.J. Mullins, A.J. Roche and J.F.S. Vaughan, J. Chem. Soc., Chem. Commun.,

1995, 841.

105 R.D. Chambers, M.P. Greenhall and M.J. Seabury, J. Chem. Soc., Perkin 1, 1991, 2061.

106 A. Streitwieser and J.H. Hammons, Prog. Phys. Org. Chem., 1965, 3, 41.

107 A. Streitwieser and F. Mares, J. Am. Chem. Soc., 1968, 90, 644.

108 R.J. Harper, E.J. Soloski and C. Tamborski, J. Org. Chem., 1964, 29, 2385.

109 A. Streitwieser, J.A. Hudson and F. Mares, J. Am. Chem. Soc., 1968, 90, 648.

110 R. Filler and C.-S. Wang, J. Chem. Soc., Chem. Commun., 1968, 287.

111 P.v.R. Schleyer and A.J. Kos, Tetrahedron, 1983, 39, 1141.

112 W.R. Dolbier, Chem. Rev., 1996, 96, 1557.

113 W.R. Dolbier in Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermediates,

ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 97.

114 D.J. Pasto, R. Krasnansky and C. Zercher, J. Org. Chem., 1987, 52, 3062.

115 X.K. Xiang, X.Y. Li and K.Y. Wang, J. Org. Chem., 1989, 54, 5648.

116 R.W. Fessenden and R.H. Schuler, J. Chem. Phys., 1965, 43, 2704.

117 T. Kawamura, M. Tsumara, Y. Yokomichi and T. Yonezawa, J. Am. Chem. Soc., 1977, 99,

8251.

118 S.F. Wnuk, D.R. Companioni, V. Neschadimenko and M.J. Robins, J. Org. Chem., 2002, 67,

8794.

119 A. Pross and L. Radom, Tetrahedron, 1980, 36, 1999.

120 K.V. Scherer, T. Ono, K. Yamanouchi, R. Fernandez, P. Henderson and H. Goldwhite, J. Am.Chem. Soc., 1985, 107, 718.

121 B.L. Turmanskii, V.F. Chestkov, N.I. Delyagina, S.R. Sterlin, N.N. Bubnov and L.S. German,

Russ. Chem. Bull., 1995, 44, 962.

122 W.B. Motherwell and D. Crich, Free Radical Chain Reactions in Organic Synthesis,

Academic Press, London, 1992.

123 D.V. Avila, K.U. Ingold, J. Lusztyk, W.R. Dolbier, H.Q. Pan and M. Muir, J. Am. Chem. Soc.,

1994, 116, 99.

124 X.X. Rong, H.Q. Pan and W.R. Dolbier, J. Am. Chem. Soc., 1994, 116, 4521.

125 W.R. Dolbier and X.X. Rong, Tetrahedron Lett., 1994, 35, 6225.



Chapter 5

Nucleophilic Displacement ofHalogen from FluorocarbonSystems

It is the aim of this chapter to develop a model for the very broad spectrum of reactivity of

fluorine-containing systems towards nucleophiles. Substituent effects of fluorine and

fluorocarbon groups on the SN1 process were considered earlier, in a more general

discussion of carbocations (see Chapter 4, Section VI); effects on the SN2 process will

now be examined. Then the broader principles of displacement of fluorine, as fluoride ion,

from carbon in different environments will be discussed to emphasise why, for example,

nucleophilic displacement of fluoride ion from perfluoroalkenes occurs extremely rapidly

while, in contrast, perfluoroalkanes are characterised by extreme inertness.

I SUBSTITUENT EFFECTS OF FLUORINE ORFLUOROCARBON GROUPS ON THE SN2 PROCESS

In general, substituent effects on the SN2 process are not easy to predict [1] because, in

principle, electron-withdrawing or -donating groups can either accelerate or retard the

process, depending on whether bond making, between carbon and nucleophile, or bond

breaking, between carbon and the leaving group, is emphasised. The situation is further

complicated by substituent effects either resulting in mechanistic change or creating very

significant steric effects. Nevertheless, halogen substituents not directly attached to the

reaction centre usually reduce SN2 reactivity in alkyl halides [2], as illustrated by the data

in Table 5.1. Clearly, the effects are not large and are not very different for the individual

halogens.

Similarly, nucleophilic displacements from centres substituted with CF3 groups are

retarded [3–5] in comparison with corresponding alkyl derivatives, due to steric hindrance

and fluorine lone-pair repulsion of the incoming nucleophile, but preparatively useful

Table 5.1 Reactivities of RBr towards NaOPh (in MeOH

at 208C) [2]

R k (l:mol�1s�1 � 104)

CH3CH2 39.1

CH3CH2CH2 25.6

FCH2CH2 4.95

ClCH2CH2 5.61

BrCH2CH2 4.99


122 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

reactions are possible when a sufficiently good leaving group, such as tosyl, is employed

[6] (Figure 5.1). The effect of introducing fluorine a-, b- or g- to the reaction centre in

solvolysis reactions can be very substantial, especially inhibiting SN1 processes [7, 8].

CF3CH2X + I− CF3CH2I + X− ½6�

Figure 5.1

A single-electron transfer process may be a competing mechanism in reactions between

sterically demanding nucleophiles and CF3CH2I, since side products arising from radical

coupling reactions are observed [9].

In contrast, fluorine or fluorocarbon groups directly attached to the reaction centre have

a much more pronounced effect [4]; for example, the hydrolytic displacement of chloride

from PhCHFCl appears to be activated with respect to benzyl chloride [10], although the

situation is complicated by concomitant SN1 and SN2 processes.

Nucleophilic substitution of halogen in RFCF2Hal systems is very difficult, due to

a combination of steric effects and shielding of the carbon skeleton by surrounding

non-bonding pairs on fluorine, and there are no examples of halogen substitution by an

SN2 process involving these substrates. For example, RCF2Br compounds are quite

inert to halide exchange under conditions where CH3CH2Br is reactive [4]. However, in

principle there are other ways in which RFHal systems could react with nucleophiles,

namely:

(1) Nucleophilic attack on halogen (Figure 5.2). However, this process is often very

difficult to distinguish from the single-electron process, (2), shown below. Burton

and co-workers have demonstrated that phosphorous nucleophiles react with CF2Br2

to give synthetically useful ylids and they suggested carbene intermediates to

explain their findings [11] (Figure 5.3). Halophilic attack on polyfluorinated

systems, followed by b-elimination to give intermediate polyfluorinated alkenes

that are susceptible to nucleophilic attack, has also been suggested [12] (Figure 5.4).

Nuc + Nuc�I + CF3Solvent

HCF3HI�CF3

Figure 5.2

R3P + CF2Br2 R3PBr + CF2Br

CF2Br CF2 + Br

R3P + CF2 R3P-CF2

R3P�CF2 R3PBr+ (R3PCF2Br) Br R3PBr

½11�

Figure 5.3


Nucleophilic Displacement of Halogen from Fluorocarbon Systems 123

CF2�CF2

+ PhSBr + CF2CF2Br

PhSBrPhSCF2CF2PhSCF2CF2Br

PhS

PhS

CF2CF2BrBr

½12�

Figure 5.4

(2) Single-electron transfer (SET) [13, 14] (Figure 5.5).

e.g.

NR2 +NR2

I

RF

NR2

RF

I

i

NR2

RF

−H+

H3OO

RF

i , RFI (RF = C8F17 ), Pentane, uv

Nuc RF�I Nuc

RF I etc

RF�I

RF�I

+ HI

½13, 14�

Figure 5.5

(3) A radical chain process (SRN1) (Figure 5.6).

Nuc + Nuc +

+ Nuc Nuc-RF + etcNuc-RF

RF-I

RF

RFI

RF-I

RF-I

RF+ I

Figure 5.6

An essential feature of this process is the reaction of a nucleophile with a fluoro-

carbon radical. It is important to emphasise that radicals, being electron-deficient,

are electrophilic and therefore that fluorocarbon radicals are even more electro-

philic. These processes are, of course, aided by ultraviolet irradiation and inhibited

by radical traps, or the radicals may be intercepted, e.g. by norbornene as in the

example shown in Figure 5.7a [15]. Further examples are given in Table 5.2.


124 Chapter 5

(CF3)2CFI (CF3)2CF

PhS

Norbornene

(CF3)2CFSPh

CF(CF3)2

CF(CF3)2

(CF3)2CFI

(CF3)2CFI

½15�

Figure 5.7a

Table 5.2 Substitution of halogen in RCF2Hal systems

Substrate Nucleophile, conditions Product Yield (%) Ref.

C5F11CF2I NO2ðCH3Þ2C�

Liþ

DMF, 3 h

C6F13 C

CH3

CH3

NO2 53 [16]

ClCF2CF2I OEt−

O O

Na+ CO2Et

H

ClCF2

CO2Et

50 [17]

C5F11CF2I

N

N−

O2N

Bu4N+

Electrochemistry, CH3CN

N

N

O2N

H

C6F13

94 [18]

CF2BrCF2Br PhO� Kþ PhOCF2CF2Br [19]

HMPA ,a rt

C6F13Br PhS� Kþ

DMF, rt

C6F13SPh 62 [20]

C6F13I PhS� Bu4Nþ

Benzene, H2O, rt

C6F13SPh 76 [15]

CF2Br2 Ph3P ðPh3PCF2BrÞþ Br� 100 [11]

Diglyme, rt

a HMPA, hexamethylphosphoric triamide.



Formally, an aromatic system acts as the nucleophile in SET processes involving

haloperfluoroalkanes, although the orientation pattern indicates an aromatic sustitution

by a fluorocarbon radical [21, 22] (Figure 5.7b).

H(CF2)4Cl + C6H5OCH3i

OMe

(CF2)4H

i, Na2S2O4, NaHCO3, DMSOortho : meta : para = 50 : 35 : 15

½21, 22�

Figure 5.7b

The processes described above invoke breakdown of intermediate radical-anions to

give perfluoroalkyl radicals and halide ion; this is supported by theory [23] and ESR

studies [24]. However, t-perfluoroalkyl iodides do not react with nucleophiles in this

manner because it is thermodynamically more favourable for these particular intermediate

radical-anions to break down into relatively stable perfluorocarbanions and iodine atoms

[23] (Figure 5.8). The reaction of tertiary perfluoroalkyl iodides and hexene to give

perfluoroalkenes supports this conclusion [25].

C3F7C(CF3)2I

i, Zn, CH2�CHR, AcOEt, 80� C

[C3F7C(CF3)2I]−I

C3F7C(CF3)2

−F

CF3CF2CF�C(CF3)2 CF3CF2CF2C(CF3)�CF2

1 590%

i½23�

Figure 5.8

Remarkably, electron transfer from phenylthiolate anions to perfluorodecalin occurs, to

give naphthalene derivatives [26]. It is not clear why this has not proved to be a general

process but it may be considered to involve a series of electron transfer steps (Figure 5.9).

A Electrophilic perfluoroalkylation

The 2CF2I group may be activated towards nucleophilic attack by enhancing the leaving

group ability of iodine through expansion of its valence shell to an iodonium species, and

this has culminated in the development of a range of electrophilic perfluoroalkylphenyl-

iodonium triflate (FITS) reagents [27] (Figure 5.10).

These remarkable electrophilic reagents have been used to carry out perfluoroalkyla-

tion of various nucleophilic systems, including carbanions, activated aromatics and

enolate derivatives; examples are shown in Figure 5.11.


126 Chapter 5

F F F F F

SPh SPh

SPh

SPh

SPhSPh

PhS

PhS

FFF FF F

F

F F

i, PhS Na, DMEU, 70�C, 10 days

+1e −F

+1e

−F

i

PhS

+1e etc.

½26�

Figure 5.9

RF I

Ph

RFIi

RFI(OCOCF3)2 O-Tfii

i, 80% H2O2, (CF3CO)2O

ii, Benzene, CF3SO2OH (TfOH)

½27�

Figure 5.10

OTMS

C8F17 I

Ph

O

C8F17+

MeCN, 45� C

76%

O�Tf

PhCH2MgCl C3F7IPh O�Tf−110� C

PhCH2C3F7 82%

Figure 5.11

A range of related trifluoromethylating agents in which the perfluoroalkyl group

is attached to a sulphonium leaving group have also been developed, as indicated in

Figure 5.12.



N

HS

CF3

N

H

CF3

90%

+O-Tf

DMF, 80�C

Figure 5.12

II FLUORIDE ION AS A LEAVING GROUP

The wide range of reactivity of the carbon–fluorine bond, referred to at the beginning of

this chapter, must obviously be attributable to variations in the mechanism of the

substitution process and, in particular, to the amount of bond breaking in the transition

state [28].

A Displacement of fluorine from saturated carbon – SN2processes

In addition to the two overall nucleophilic displacement processes, SN1 and SN2, we can

envisage a spectrum of transition states for the SN2 process. Various stages can be

represented by 5.13A, in which there is little or no carbon–fluorine bond breaking;

5.13B, which is concerted; and 5.13C, where carbon–fluorine bond breaking is in advance

of the new bond being formed (Figure 5.13).

C FNuc

δ +Nuc C F

δ − δ −Nuc C F

δ −δ +δ +

5.13B5.13A 5.131C

Figure 5.13

Of course, the extreme of 5.13A would be complete bond formation with the nucleo-

phile in an addition–elimination process, such as can occur when fluorine is bound to

unsaturated carbon. Since a fluorine atom attached to carbon leads to a very polar, yet

very strong, Cdþ � Fd� bond, we have two conflicting effects: (a) the attached carbon is

electron-deficient and therefore susceptible to nucleophilic attack; (b) if the transition

state involves much carbon–fluorine bond breaking, it may be of relatively high energy

depending on the degree of solvation of the developing fluoride ion. Also, fluorine is not a

polarisable atom and this contributes to the high energy of the process. Consequently,

because carbon–chlorine bonds are weaker and more polarisable, the ratio kF=kCl, for

displacement from the corresponding fluorides and chlorides, is regarded as a useful

probe for indicating the amount of carbon–halogen bond breaking in the transition state.

Factor (b) is the more important with alkyl fluorides since they are, for example, much

less readily hydrolysed than other alkyl halides (Table 5.3), but it is also evident that the

reactivity ratios are influenced considerably by the reagent.

Fluoride ions (or incipient fluoride ions) form very strong hydrogen bonds, much

stronger than corresponding bonds to chloride, and so a change to a more hydrogen-


128 Chapter 5

bonding solvent increases the reactivity of a carbon–fluorine bond relative to the other

carbon–halogen bonds [28, 30]. Table 5.4 shows the fluoride:chloride rate ratios for some

arylmethyl halides, albeit under different conditions in some cases, but the differences in

ratios are sufficiently large to suggest the trend towards an increasing ratio as the process

changes from SN1 to SN2.

1 Acid catalysis

Catalysis by protonic acids accounts for the hydrolysis of fluorides, such as trityl fluoride

[31], or elimination of hydrogen fluoride from various systems (Chapter 6), frequently

being autocatalytic. The hydrolysis of benzyl fluoride is roughly proportional to the

Hammett acidity function Ho [32], which is consistent with the scheme indicated in

Figure 5.14 [1, 33]. Indeed, the decomposition of benzyl fluoride, on storage, may be

violent [34].

PhCH2F + H+ PhCH2 F H PhCH2+ + HF ½1, 33�

Figure 5.14

Solvolysis of allylic fluorides may be acid-catalysed [35] and the influence of

fluorine substituents at different positions is interesting. Solvolysis of 5.15A occurs

where fluorine at the 1-position is able to stabilise an attached carbocation; but in the

isomer 5.15B fluorine at the 2-position deactivates and solvolysis of 5.15B does not

occur under conditions where 5.15A reacts (Figure 5.15). Similar hydrolysis of 1,2-

diethoxytetrafluorocyclobutene leads to the well-known, very stable, ‘squarate anion’

[36] (Figure 5.16a).

Hydrogen iodide is very effective in replacing fluorine by iodine in fluoroalkanes [33]

(Figure 5.16b).

Cleavage of a carbon–fluorine bond can be induced by reaction with a Lewis acid (see

Chapter 4, Section VIC). In Friedel–Crafts alkylations, alkyl fluorides are more reactive

than the chlorides [37] with, for example, aluminium halides or boron halides as catalysts

(Figure 5.17).

Table 5.3 Relative reactivities of isoamyl halides ðCH3Þ2CHðCH2Þ2X with

piperidine and sodium methoxide at 188C [29]

Reagent X ¼ F X ¼ Cl X ¼ Br X ¼ I

C5H11N 1 68.5 17 800 50 500

CH3ONa=CH3OH 1 71 3500 4500

Table 5.4 Fluorine : chlorine rate ratios for reactions of alkyl halides [28]

Halide Reagent Solvent Temp. (8C) kF=kCl

Ph3CX H2O 85% aq. Me2CO 25 1:0� 10�6

Ph2CHX H2O/EtOH 80% aq. EtOH 25 1:6� 10�4

PhCH2X H2O 10% aq. Me2CO 50 3:2� 10�3

CH3X H2O H2O 100 2:9� 10�2



RCHF�CH�CFH R

H

H

FH

R

F

H

HH

R�CH�CH�CHO

aq. HCOOH

−F

+F

R�CH�CH�CHF2

R�CHF�CF�CH2

5.15A

5.15B

H2O ½35�

Figure 5.15

OEt

F

OEt

OH

OH

O

O

O O

O O

2+

2

H2SO4 ½36�

Figure 5.16a

RF + HIi

RI + HF

i, R = 1-heptyl, 105� C, 10hr. (85%) R = cyclohexyl, 105� C, 1hr. (90%)

½33�

Figure 5.16b

BBr3

BenzeneFCH2CH2Cl C6H5CH2CH2Cl ½37�

Figure 5.17

Of course, this arises from a compensating greater strength of aluminium–fluorine or

boron–fluorine bonds than the corresponding bonds to chlorine [D(A1–F)¼ 615 kJmol�1;

D(A1–Cl) ¼ 494 kJmol�1]. This difference also seems to be the driving force in the often

very easy replacement of fluorine by chlorine, especially at allylic or benzylic positions,

using aluminium chloride [38] (Figure 5.18).

+ AlCl30� CF Cl ½38�

Figure 5.18


130 Chapter 5

2 Influence of heteroatoms on fluorine displacement

Oxygen or, particularly, nitrogen adjacent to a carbon–fluorine bond greatly increases

reactivity towards nucleophiles. Hydrolysis of a, a–difluoro ethers occurs under acid

conditions [39] (Figure 5.19). Orthoesters are produced by reaction with alkoxides;

such reactions may, however, occur via initial elimination of hydrogen fluoride, rather

than by direct nucleophilic displacement of fluoride [40] (Figure 5.20).

H2SO4CHF2CF2OC2H5 CHF2COOC2H5

½39�

Figure 5.19

KOHCHClFCF2OC2H5 CHClFC(OC2H5)3

EtOH ½40�

Figure 5.20

The exceptional ease of nucleophilic displacement of fluorine from ðC2H5Þ2-

NCF2CFClH and similar systems has been utilised as a general method for replacement

of hydroxyl by fluorine (see Chapter 3, Section IVA, Subsection 3), and probably

involves an SN1 process with internal assistance to ionisation coming from the adjacent

nitrogen [41] (Figure 5.21).

N CMe

MeCF2H

F

F

N CMe

MeCF2H

F

RCH2

OH

−F−etc

½41�

Figure 5.21

The presence of C2H bonds in a perfluorinated system can, of course, have a

profound effect, but the subsequent increase in reactivity usually stems from an

elimination–addition rather than direct nucleophilic displacement of fluoride ion

(see below).

B Displacement of fluorine and halogen from unsaturated carbon– addition–elimination mechanism

When fluorine is attached to an unsaturated carbon atom, then a two-step displacement

process can occur where the addition step may be rate-limiting (Figure 5.22) and it is

probable that the importance of influence of the C–Hal dipole, in attracting the approach-

ing nucleophile, has been under-appreciated.

If the addition stage is rate-limiting, which is usually the case, polarity of the bond to

carbon is probably the most important factor governing the activation energy required,

since fluorine is sometimes displaced more easily than chlorine or the other halogens. For

example, benzoyl fluoride reacts more readily with hydroxide than the corresponding



chloride [42, 43] (Table 5.5). However, the order of halogen mobility depends very much

on the system and the order illustrated in Table 5.5 is Br > Cl > F.

X

FNuc X

F

Nuc X

F

X

Nuc

Nuc Addition

Elimination+ F

δδ

Figure 5.22

It is reasonable to assume, therefore, that situations occur where the activation energy

associated with the elimination step is comparable with that required for the addition

stage. In these situations, overall reactivity is then also influenced by the strength of the

carbon–halogen bond and, consequently, the stronger carbon–fluorine bond has a greater

retarding effect than bonds between carbon and the other halogens.

1 Substitution in fluoroalkenes

The usually greater reactivity of vinylic fluorine than vinylic chlorine is demonstrated in

methanolyses of halonitrostyrenes [44] (Table 5.6), providing support for the two-step

process with a rate-limiting addition stage outlined above.

Table 5.5 Isopropanolysis of acid halides at 258C [43]

Compound k2 Halogen mobility ratio Cl ¼ 1

C3H7CO2X

X ¼ F 8:4� 10�10 1:6� 10�4

X ¼ Cl 5:1� 10�6 1

X ¼ Br 2:7� 10�3 5200

C4F9CO2X

X ¼ F 1:6� 10�3 4:6� 10�2

X ¼ Cl 3:5� 10�2 1

Table 5.6 Nucleophilic substitution of p-nitrohalostyrenes using

NaOMe at 258C [44]

H

X

p-NO2�C6H4

H 104kðl:mol�1s�1Þ

X ¼ F 7.21

X ¼ Cl 0.025

X ¼ Br 0.016


132 Chapter 5

However, if both fluorine and chlorine are attached to the same vinylic carbon, the

elimination stage of the mechanism becomes more important and, consequently, chlorine

is selectively displaced, reflecting the greater leaving-group ability of chlorine compared

with fluorine [45, 46] (Figure 5.23).

Cl

F

C6H5

F3C

O-Me

F

C6H5

F3C

96%

F

O-Me

C6H5

F3C

4%

+MeONa

½45, 46�

Figure 5.23

Displacement of vinylic chlorine is predominantly stereoselective whereas, in some

cases, substitution of fluorine can give a mixture of isomeric products. It has been argued

that the fluorine-containing carbanionic intermediates are more stable and longer-lived

than the corresponding chlorinated derivatives, thus allowing rotation to occur in the

carbanionic intermediate before elimination of the halide, and enabling the formation of

geometric isomers [47, 48]. The importance of the addition step, leading to a developing

carbanion in the transition state, is made evident by the very wide range of reactivity in

the series CF25CF2, CF2¼CFCF3 � CF25CðCF3Þ2, the last of these being extremely

susceptible to nucleophilic attack (Figure 5.24).

Nuc CF2�C(CF3)2 Nuc�CF2CF(CF3)2−F

Nuc�CF�CF(CF3)2

Figure 5.24

Reactions of polyfluoroalkenes are discussed in Chapter 7.

2 Substitution in aromatic compounds

Nucleophilic substitution in highly fluorinated aromatic compounds will be dealt with in

detail in Chapter 9, but it is worth noting here that, in common with most other

nucleophilic aromatic substitutions [49], the processes are likely to involve two steps,

with very little bond breaking in the rate-limiting transition state. In the classic work on

2,4-dinitrohalobenzenes with many nucleophiles, the ease of replacement of aromatic

halogen is in the order F� Cl > Br > I [49, 50], arising from a slow first step ðk1Þ and a

fast second step ðk2Þ, consistent with the scheme outlined in Figure 5.25. Of course, the

nitro groups are extremely important in lowering the energy of the developing carbanionic

transition state, leading to the intermediate complex 5.25A.

Both oxygen and nitrogen nucleophiles react more rapidly with fluoroaromatics than

corresponding sulphur and carbon nucleophiles, in accordance with Hard–Soft Acid–Base

principles [51]. It should be remembered, however, that the situation can become more

complex with, for example, base catalysis, where the rate of the second stage becomes

important; under these rather unusual conditions, an order of replacement Br > Cl > F has

been observed [52].

The second step may be rate-limiting in reactions of fluoroaryl systems with neutral

amines [53]. Loss of halide ion from the intermediate complex is catalysed by base and is



much faster when fluorine is the leaving group compared with the other halogens, due

to stronger hydrogen bonding between developing fluoride and the base [54]

(Figure 5.26).

For ortho-halonitrobenzenes, displacement of fluorine is more rapid than that of

chlorine, due to lower steric requirements [55].

X

NO2

NO2

NO2

NO2

Nuc

NO2

NO2

Nuc X

k1

X = F, Cl, Br, I

Nuc

δ

δk2

k−1

5.25A

_

½49, 50�

Figure 5.25

X

NO2

NO2

NO2

NO2

NHR

NO2

NO2

H2RN X

Base

X = F, Cl, Br, I

RNH2

½54�

Figure 5.26

Fluoroaromatics with electron-releasing substituents may be activated towards nucleo-

philic attack by complexation with chromium species [56] (Figure 5.27).

H3C F

Cr(CO)3

H3C

Cr(CO)3

CNCF3SO3H

LiCMe2CN

½56�

Figure 5.27

An oxidatively initiated nucleophilic substitution mechanism has been suggested to

account for reactions with electron-rich aromatic substrates such as 4-fluoroanisole [57]

(Figure 5.28).

The foregoing discussion has outlined principles that can account for very wide

differences in reactivities of the C2F bond. For example, while saturated perfluorocar-

bons like polytetrafluoroethene are relatively inert to nucleophiles, at the other extreme

are perfluoroisobutene, which reacts with neutral methanol, and perfluoro-1,3,5-triazine,

which is hydrolysed in moist air. As a note of caution, great care should be taken with

the systems that are very reactive to nucleophiles and correspondingly potentially

very toxic, although there is no good correlation between toxicity levels and reactivity

towards nucleophiles. More will be said about some of these systems in later chapters.


134 Chapter 5

ArF ArF−e

+ Nuc [Nuc�Ar�F]

[Nuc�Ar�F] Ar�Nuc + F

Ar�Nuc + Ar�FAr�Nuc + Ar�F

ArF

½57�

Figure 5.28

REFERENCES

1 C.A. Bunton, Nucleophilic Substitution at a Saturated Carbon Atom, Elsevier, Amsterdam,

1963.

2 J. Hine and W.H. Brader, J. Am. Chem. Soc., 1953, 75, 3964.

3 J. Hine and R.G. Ghirardelli, J. Org. Chem., 1958, 23, 1550.

4 F.G. Bordwell and W. Brannen, J. Am. Chem. Soc., 1964, 84, 4645.

5 T. Nakai, K. Tanaka and N. Ishikawa, J. Fluorine Chem., 1977, 9, 89.

6 G.V.D. Tiers, J. Am. Chem. Soc., 1953, 75, 5978.

7 X. Creary, Chem. Rev., 1991, 91, 1625.

8 A.D. Allen and T.T. Tidwell in Advances in Carbocation Chemistry, ed. X. Creary, JAI Press,

Greenwich, CT, 1989.

9 F.G. Bordwell and C.A. Wilson, J. Am. Chem. Soc., 1987, 109, 5470.

10 G. Kohnstam, D. Routledge and D.L.H. Williams, J. Chem. Soc., Chem. Commun., 1966, 113.

11 D.J. Burton, J. Fluorine Chem., 1983, 23, 339.

12 X.Y. Li, X. Jiang, H.Q. Pan, J.S. Hu and W.M. Fu, Pure Appl. Chem., 1987, 59, 1015.

13 C. Wakselman, J. Fluorine Chem., 1992, 59, 367.

14 V.I. Popov, V.N. Boiko and L.M. Yagupolskii, J. Fluorine Chem., 1982, 21, 365.


16 A.E. Feiring, J. Org. Chem., 1983, 48, 347.

17 Q.Y. Chen and Z.M. Qiu, J. Fluorine Chem., 1987, 35, 343.

18 M. Medebielle, J. Pinson and J.M. Saveant, J. Am. Chem. Soc., 1991, 113, 6872.

19 X.Y. Li, H. Pan and X. Jiang, Tetrahedron Lett., 1984, 25, 4937.

20 C. Wakselman and M. Tordeux, J. Org. Chem., 1985, 50, 4047.

21 C.-M. Hu and W.M. Huang in Fluorine Chemistry at The Millenium, ed. R.E. Banks, Elsevier,

Amsterdam, 2000, p. 261.

22 X.-T. Huang, Z.-Y. Long, and Q.-Y. Chen, J. Fluorine Chem., 2001, 111, 107.

23 S.M. Igumnov, I.N. Rozhkov, S.I. Pletnev, Y.A. Borisov and G.D. Rempel, Bull. Acad. Sci.USSR, 1989, 38, 2122.

24 A. Hasegawa, M. Shiotani and F. Williams, J. Chem. Soc., Faraday Discuss., 1978, 157.

25 S.I. Pletnev, S.M. Igumnov, I.N. Rozhkov, G.D. Rempel, V.I. Ponomarev, L.E. Deev and

V.S. Shaidurov, Bull. Acad. Sci. USSR, 1989, 38, 1892.

26 D.D. MacNicol and C.D. Robertson, Nature, 1988, 332, 59.

27 A.T. Umemoto, Chem. Rev., 1996, 96, 1757.

28 R.E. Parker, Adv. Fluorine Chem., 1963, 3, 63.

29 B.V. Tronov and E.A. Kruger, J. Russ. Phys. Chem. Soc., 1926, 58, 1270.

30 J.A. Revetllat, A. Oliva, and J. Bertran, J. Chem. Soc., Perkin Trans. II, 1984, 815.

31 A.K. Coverdale and G. Kohnstam, J. Chem. Soc., 1960, 3806.



32 C.G. Swain and E.T. Spalding, J. Am. Chem. Soc., 1960, 82, 6104.

33 M. Namavari, N. Satayamurthy, M.E. Phelps and J.R. Barrio, Tetrahedron Lett., 1990, 31,

4973.

34 S.S. Szucs, Chem. Eng. News, 1990, 68, 4.

35 T.J. Dougherty, J. Am. Chem. Soc., 1964, 86, 2236.

36 J.D. Park, S. Cohen and J.R. Lacher, J. Am. Chem. Soc., 1962, 84, 2919.

37 G.A. Olah, Friedel–Crafts and Related Reactions, Wiley-Interscience, New York, 1964.

38 R.F. Merritt, J. Am. Chem. Soc., 1967, 89, 609.

39 J.A. Young and P. Tarrant, J. Am. Chem. Soc., 1950, 72, 1860.

40 P. Tarrant and H.C. Brown, J. Am. Chem. Soc., 1951, 73, 1781.

41 V.A. Petrov, S. Swearingen, W. Hong and W.C. Petersen, J. Fluorine Chem., 2001, 109, 25.

42 C.G. Swain and C.B. Scott, J. Am. Chem. Soc., 1953, 75, 246.

43 J. Miller and Q.L. Ying, J. Chem. Soc., Perkin Trans. II, 1985, 323.

44 G. Marchese, F. Naso and G. Modena, J. Chem. Soc. (B), 1969, 290.

45 D.J. Burton and H.C. Krutzsch, J. Org. Chem., 1971, 36, 2351.

46 H.F. Koch and J.G. Koch in Fluorine-containing Molecules. Structure, Reactivity, Synthesisand Applications, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH Publishers, New

York, 1988, p. 99.

47 Y. Apeloig and Z. Rappoport, J. Am. Chem. Soc., 1979, 101, 5095.

48 B.E. Smart in The Chemistry of Functional Goups, Supplement D, ed. S. Patai and

Z. Rappoport, John Wiley and Sons, New York, 1983, p. 603.

49 J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Amsterdam, 1968.

50 V.M. Vlasov, J. Fluorine Chem., 1993, 61, 193.

51 F.G. Bordwell and D.L. Hughes, J. Am. Chem. Soc., 1986, 108, 5991.

52 T.J. Broxton, D.M. Muir and A.J. Parker, J. Org. Chem., 1975, 40, 3230.

53 N.S. Nudelman, J. Phys. Org. Chem., 1989, 2, 1.

54 E.T. Akinyela, I. Onyido and J. Hirst, J. Chem. Soc., Perkin Trans. II, 1988, 1859.

55 T.O. Bamkole, J. Hirst and E.J. Udoessien, J. Chem. Soc., Perkin Trans. II, 1973, 110.

56 F. Rose-Munch, L. Mignon and J.P. Sanchez, Tetrahedron Lett., 1991, 32, 6323.

57 L. Eberson, L. Jonsson and L.G. Wistrand, Tetrahedron, 1982, 38, 1087.


136 Chapter 5

Chapter 6

Elimination Reactions

Since eliminations cover a very wide spectrum of chemical reactions, this chapter is a

selective discussion of the subject. The mechanistic basis of b-eliminations is discussed,

largely with reference to dehydrohalogenation, and a variety of a-eliminations are

included here. Other eliminations, such as dehalogenation, are described throughout

later chapters with reference to specific syntheses.

I b-ELIMINATION OF HYDROGEN HALIDES

A Effect of the leaving halogen

Effects arising from the halogen atom that is eliminated during b-elimination of hydrogen

halide may be summed up (Figure 6.1) as: (a) b-halogen has an acidifying influence on

the adjacent hydrogen; and (b) ease of elimination will vary with the strength of the

carbon–halogen bond and the ability of halogen to accommodate a negative charge. The

combination of these effects is likely to be in the order F < Cl < Br. Of course, elimin-

ation will also be solvent-dependent. Clearly, b-elimination of hydrogen fluoride should

proceed via a transition state that will be very carbanionic in character, and at a rate

slower than corresponding hydrogen halide eliminations since carbon–halogen bond

breaking is involved in the rate-determining step. These effects are well illustrated in

eliminations from 2-phenylethyl derivatives [1, 2] (Table 6.1).

C C

H X

C C + BH+ + X

X = HalogenB

αβ

Figure 6.1

Eliminations from fluorides are often autocatalytic [3], due to assistance in ionisation

by hydrogen bonding between the leaving fluoride ion and hydrogen fluoride produced in

the reaction (Figure 6.2). As a consequence, fluorides can sometimes be more stable

in even slightly alkaline solution than in the pure state [3].

Table 6.1 Relative rates of elimination of HX from PhCH2CH2X [1, 2]

Substrate Reaction conditions X ¼ F X ¼ Cl X ¼ Br

PhCH2CH22X EtONa, EtOH, 308C 1 68 4100

PhCHBrCF22X EtONa, EtOH, 258C 1 4� 105 3� 107



C C CF H Fδ −

+ HF2−δ+

C

H

½3�

Figure 6.2

Elimination of HBr in preference to HF from the cyclohexane derivative 6.3A

further demonstrates the greater leaving-group ability of other halogens over fluorine

[4] (Figure 6.3).

F

Br

F F

(9:1)

+

6.3A

½4�

Figure 6.3

However, in some cases, HF is eliminated in preference to dehydrobromination, e.g. in

the succinic acid series [5, 6] (Figure 6.4). In these less common processes, the transition

state has significant carbanion (E1cB-like) character, and the products are probably

governed by the relative stabilities of the possible carbanionic transition states, 6.5A

and 6.5B (Figure 6.5), where a fluorine atom situated b to a developing carbanion centre,

as in 6.5B, is more stabilising than when directly attached, as in 6.5A. This effect is also

seen in eliminations from dihaloacenaphthenes [7].

Br

HO2C

F

CO2H

Br

HO2C CO2H½5, 6�

Figure 6.4

Br

HO2C CO2H

F

H

HO2C

F

CO2HBr

δ+

δ−

δ+H

δ−

B B

6.5A 6.5B more stable

Figure 6.5

B Substituent effects

A spectrum of transition states is possible for eliminations [8], varying from transition

states with considerable double-bond character, 6.6A, through those with increasing

amounts of charge developed on the b-carbon atom, 6.6B, until an E1cB mechanism is

observed [9] when the b-hydrogen has been made sufficiently acidic to be removed,

leaving a carbanion (Figure 6.6).

Base-catalysed hydrogen/deuterium exchange is still probably the only definitive probe

for the ElcB process in which H/D exchange occurs in the starting material at a rate faster


138 Chapter 6

than the second elimination stage (Figure 6.7), although internal return can be significant,

which then leads to an under-estimation of kinetic acidity [9]. Indeed, it has been

suggested that a hydrogen-bonded carbanion may be an intermediate, rather than a

transition state [10].

C C C C XX

HHδ+

δ−

6.6AConcerted

6.6BE1cB - like

½9�

Figure 6.6

C C X

H

C C X C C X

D

C C X CC

Base (−H+)

Solvent (+H+)

+ X−

Solvent (+D+)

Internal Return

½9�

Figure 6.7

Highly halogenated alkanes often undergo base-catalysed H/D exchange at rates faster

than elimination [11]; for example, H/D exchange for PhCHClCF2Cl has been measured

to be 1:65� 102 l:mol�1s�1 [9]. However, in a related system, PhCHClCF3, no H/D

exchange is observed but isotope effects suggest that the mechanism is also a two-step

E1cB process in which elimination of chloride ion from the intermediate carbanion is

much faster than deuteration [12].

C Regiochemistry

In concerted E2 eliminations from monofluorides the orientation of elimination is con-

trolled by the relative acidities of b-hydrogen in a process that is consistent with a poor

leaving group and a transition state with high carbanionic character of the b-carbon atom

[13] (Figure 6.8).

C3H7CH2 C

H

F

CH3

C4H9

H

H

H

C3H7

H

H

CH3

C3H7

H

CH3

H

MeOH

NaOMe+

+

69% 21%

9%

½13�

Figure 6.8


Elimination Reactions 139

The orientation of elimination of hydrogen halides from more highly fluorinated

systems is also governed by the relative acidities of hydrogen atoms within the molecule,

and therefore the relative stabilities of the intermediate carbanions, as well as the mobility

of the leaving halogen, which is generally in the order I > Br > Cl > F. The examples in

Figure 6.9 illustrate these points, in which the most acidic proton and the best halogen

leaving group are eliminated preferentially [14–16].

CF3CH2CHBrCH3 CF3CH�CHCH3

CHCl2CCl2CHF2 CCl2�CClCHF2

CCl3CH2CF2Cl CCl2�CHCF2Cl

KOH

EtOH

Aq. KOH

½14�

½15�

½16�

Figure 6.9

In addition to C2H acidity, elimination may also be controlled by the mobility of

fluorine from carbon, which generally decreases in the series 2CF > 2CF2 > 2CF3, as

can be seen in the examples in Figures 6.10 and 6.11. Where there is a choice, the most

stable fluoroalkene, in which the number of vinylic fluorines is at a minimum (see

Chapter 7), is the predominant product.

CF3CHFCHF2 CF3CF�CHF CF3CH�CF2+

70% 30%½17�

Figure 6.10

RFH

RFH

RF

RF

KOtert-Bu

−10�C

RFH = CF2CFHCF3 RF = CF�CFCF3

½18�

Figure 6.11

D Conformational effects

In many cases, elimination of hydrogen halide via an anti-coplanar transition state is

observed [19] (Figure 6.12) in what is commonly regarded as the most favourable process

[20, 21].

However, overall syn elimination is more common than was once thought; a variety of

factors may be responsible. The ratio of products arising from syn/anti elimination can

depend on the reaction medium, e.g. syn elimination appears to be enhanced by a less

polar medium, and this has led to the suggestion that a concerted cyclic process involving

the base may be involved [19] (Figure 6.13).


140 Chapter 6

F

FC5H11

H

C5H11 H C5H11 H

C5H11 F

F

C5H11F

H

C5H11 H C5H11 H

F C5H11

THF(only alkene formed)

(only alkene formed)THF

t-BuOK

t-BuOK

½19�

Figure 6.12

HYX

FY

X

B

M B

M

X

Y

X

Y

+ BH + MF

B = Base

M = Metal

½19�

Figure 6.13

It has been suggested that favourable hydrogen-bonding interactions between R and

trifluoromethyl in an E1cB-like transition state, 6.14B, could account for the formation of

the least thermodynamically stable isomer, 6.14C, from 6.14A; 6.14C is converted to

6.14D on heating with caesium fluoride [18] (Figure 6.14).

RCF2CFHCF3

6.14B

F3C F

F F

R

F

CF3

R

F

F

CF3

i

i, KOtert-BuOH, tert-BuOH, 0� C

ii, CsF, Tetraglyme, 200� C

ii

6.14A

6.14C

6.14D

R = Adamantyl

R

F

½18�

Figure 6.14

The preferential syn elimination of hydrogen fluoride, in preference to elimination of

hydrogen bromide, from 6.15A is particularly surprising [22] (Figure 6.15).

It is not clear how much the true preference for a gauche relationship between

a fluorine substituent and an adjacent electron-withdrawing centre [23] will have on

the ease of elimination of hydrogen fluoride, but it is clearly an area of interest.



F

CO2EtBr

H

H CO2Et

Br

H CO2Et

F

EtO2C

H

H CO2Et

EtO2C Br

anti

syn

i

i, NaOH, H2O

6.15A

½22�

Figure 6.15

E Elimination from polyfluorinated cyclic systems

Tatlow and his co-workers conducted an extremely comprehensive programme of

syntheses and structure derivations of a series of fluorinated cycloalkanes [24], and

concluded that the reactivity of the system, as well as the orientation of the cycloalkene

produced, are similarly influenced by electronic factors which have been outlined in

the preceding sections of this chapter. Anti elimination is generally the more favourable

process but conformational effects may make the syn/anti rates nearly comparable.

Elimination from the cyclohexanes 6.16A and 6.16B illustrates the balance between

electronic and conformational effects [25]. Anti elimination is possible from 6.16A,

involving removal of fluoride from >CHF rather than >CF2 since in this case electronic

(the carbon–fluorine bond in CFH is weaker than in CF2) and conformational effects

(H and F are anti-periplanar) are in concert (Figure 6.16). In contrast, anti elimination

from 6.16B can only occur with elimination of fluoride from the more stable >CF2

position and therefore anti and syn eliminations occur together.

F

F

F

F

H

F

F

F

FF

F

H

aq. KOHH

F

F

F

F

F

F

H

H

F

F

FF

F

F

aq. KOHH

F

F + F

6.16B

6.16A½25�

Figure 6.16

Electronic factors dominate reactivity in the series shown in Figure 6.17; in this

series, qualitatively, the order of reactivity indicated has been established [26]. There

is probably a relationship between reactivity and the number of acidifying b-fluorine


142 Chapter 6

atoms, which decreases as shown, and this is supported by the product from the

fluorocycohexane (Figure 6.18), where exclusive removal of the more acidic hydrogen

occurs [26].

H H

H

H

H

H

H

HH

H

F F F F> >> ½26�

Figure 6.17

F

HH

H

H

H

Faq. KOH

F ½26�

Figure 6.18

In the cyclopentane series, electronic factors remain unchanged but differences in

conformation effects may be significant. A coplanar arrangement of atoms in the transi-

tion state is energetically favourable; this can, of course, be accommodated in anti

elimination from cyclohexane systems, but only in syn elimination from highly fluorin-

ated cyclopentanes (Figure 6.19). However, anti elimination is still a favourable process

[27] for these systems and electronic factors often outweigh conformational effects in

determining the orientation of elimination.

F

H

Base

F

H

F FBase

Cyclohexane Cyclopentane

Repulsion

Figure 6.19

The reactions of cyclopentanes 6.20A and 6.20B with aqueous alkali both give the same

cylopentene by anti and syn elimination respectively, with only traces of by-products

arising from syn elimination from 6.20A or anti elimination from 6.20B (Figure 6.20).

Inward syn elimination occurs from 6.20B, giving the cyclopentene in 86% yield, and this

is a further indication that removal of fluoride from >CHF is easier than from >CF2

(Figure 6.20)

In the cyclobutane series [28] (Figure 6.21) syn and anti eliminations from 6.21A and

6.21B proceed again at much more nearly comparable rates than from corresponding

cyclohexane systems.



H

H

H

H

H H

H

F FF

6.20A 6.20B

H

−HF −HF

Figure 6.20

H

F

F

H

H

F

H

Faq. KOH+

6.21A cis6.21B trans

F F F ½28�

Figure 6.21

II b-ELIMINATION OF METAL FLUORIDES

b-Elimination of two halogen atoms is a frequently used process in the synthesis of

alkenes and alkynes, using a variety of conditions, and examples will be given later

(see Chapter 7). Normally, fluorine is not easily removed by this process, although there

are a number of cases where defluorination has been achieved, for instance in the

preparation of fluoroaromatic compounds (Chapter 9).

However, a feature of the chemistry of fluorocarbon organometallic compounds is that

decomposition by a- or b-elimination of a metal fluoride is very common. The ease with

which such decompositions occur is very variable and factors such as the strength of the

metal–fluorine bond being formed, the type of carbon–fluorine bond being broken, the

mechanism of the process and whether the metal has an available empty orbital to aid

migration of fluorine are all important in affecting the elimination. Fluorocarbon organo-

metallic reagents will be discussed separately in Chapter 10, where these points will be

illustrated; only examples of some eliminations from organolithium derivatives of poly-

fluoroalkanes and polyfluorocycloalkanes will be referred to here.

Perfluoroalkyl-lithium derivatives are thermally unstable and their use in organic syn-

thesis has been limited by competing b-elimination processes [29]. Pentafluoroethyl-

lithium has a half-life of around 8 h at �788C [30]. In complete contrast, perfluorinated

bridgehead lithio derivatives are much more stable since, in these cases, elimination of LiF

would contravene Bredt’s rule and would, therefore, be a higher-energy process. Conse-

quently, perfluoroadamantyl-lithium is stable at 08C for several days [31] (Figure 6.22).

H Li

F F½31�

Figure 6.22


144 Chapter 6

Nevertheless, evidence that bridgehead alkenes or diradical species are generated by

decomposition of 6.23A was obtained by trapping with furan [24, 32, 33] (Figure 6.23).

H LiO

F FF furan

25−30�C

6.23A

CH3Li

½24, 32, 33�

Figure 6.23

Surprisingly, the bicyclo[2.2.2]octane derivative (Figure 6.24) is much more stable [33]

than the analogous norbornyl system 6.23A, and this has been attributed to the additional

stabilising influence of the extra CF2 group, since there is no obvious stereochemical

reason for the considerable difference in the rates of decomposition. This is a quite

dramatic illustration of how electronic effects of groups which are apparently remote

from the reaction centre can have a considerable effect on reactivity; this effect, while

being well documented for other areas of organic chemistry, is not much in evidence in

reactions of organic fluorine compounds.

Li

F

Figure 6.24

A related b-elimination occurs when alkali-metal salts of perfluoroalkanecarboxylic

acids are pyrolysed [34] (Figure 6.25). The most likely process involves decarboxylation

with elimination of fluoride ion from the resultant carbanion. Indeed, the method can be

very useful for the synthesis of perfluoroalkenes (Chapter 7), the most important example

of which is shown in Figure 6.26 and is used in the production of fluorinated membranes

[35].

CF3CF2CF2CO2−

C

F

CF2F3C

F

Na+

CF3CF�CF2 + NaF

∆, −CO2

½34�

Figure 6.25

Novel chemistry that was initiated by Nakai and co-workers [36, 37] involves elimin-

ation of hydrogen fluoride from the tosylate of trifluoroethanol, followed by reaction of

the intermediate with appropriate electrophiles (Figure 6.27). A wide range of approaches

to the synthesis of difluoromethylene derivatives has ensued.



F C CF(CF3)OCF2CF(CF3)OCF2CF2SO2F

CF2�CFOCF2CF(CF3)OCF2CF2SO2F

Heat, Na2CO3

O

½35�

Figure 6.26

CF3CH2OTs CF3CHOTs CF2�CHOTs

CF2�CLiOTs

Electrophiles

Electrophiles

Various products.

i

i, LDA, THF, −78� C

CF2�C

R

BR2

CF2�C

OTs

B R

RR

ii, n-BuLi, R3Bii

−

½36, 37�

Figure 6.27

A simple alternative approach to the synthesis of difluoromethylene compounds in-

volves electron transfer from metals to carbon–oxygen or carbon–nitrogen double bonds

[38, 39] (Figure 6.28).

F3C R

−F−

( +1e)

−

−O

F3C R

R = Alkyl or Aryl

i, Mg (2 equiv.), TMS-Cl (4 equiv.), 0� C, 30 min.ii, R1R2CO

Productii

F2CR

OTMS

O

F2CR

Oi

( +1e)½38, 39�

Figure 6.28

Reactions of lithium derivatives and Grignard reagents from polyfluoroalkenes or

polyfluoroaromatic compounds are often complicated by eliminations but are generally

much more useful in synthesis than polyfluoroalkane derivatives. Generation of arynes is

discussed later (see Chapter 9).


146 Chapter 6

III a-ELIMINATIONS: GENERATION AND REACTIVITYOF FLUOROCARBENES ANDPOLYFLUOROALKYLCARBENES

Fluoromethylene and polyfluoroalkylmethylene units can be introduced into various

molecules by a variety of processes that, overall, involve a-elimination from the original

fluorocarbon system. The processes themselves are carbenoid but may not necessarily

involve carbene intermediates. There are many carbenoid procedures available for the

insertion of fluorine-containing units and they can be roughly divided into the following

four types [40, 41].

(1) Decomposition of carbanions (Figure 6.29).

X C C X−

Figure 6.29

(2) Elimination of metal and non-metal fluorides (Figure 6.30).

C M

F

C + M�F

Figure 6.30

(3) Fragmentation reactions (Figure 6.31).

C

C

CX Y X CC Y + C

Figure 6.31

(4) Decomposition of diazo compounds (Figure 6.32).

C N2 or N2 + CN

N

C

Figure 6.32

Examples of each of these types follow.

A Fluorocarbenes

1 From haloforms

The classic work of Hine and co-workers [42, 43] established that carbenes could be

generated by base hydrolysis of haloforms and that the process could be divided into two

steps (Figure 6.33).



X C Y

CHXYZ + OH−

+ Z−

CXYZ

CXYZ + H2O½42, 43�

Figure 6.33

The deprotonation step was deduced from H/D exchange studies and the second stage

from a steady-state treatment of the overall rates of hydrolysis. Stabilisation of the

intermediate carbanions by halogen follows the order I > Br > Cl > F (Chapter 4,

Section VII) and loss of halide ion in stage 2 is in the order of leaving group ability,

I > Br > Cl > F. Therefore, it was possible to conclude that the effect of fluorine on the

stability of carbenes is in the order F > Cl > Br > I [42].

Fluorine is relatively poor at stabilising directly attached carbanions; however, it

appears to be the best of the halogens at stabilising carbenes, and consequently elimin-

ation of HZ (Figure 6.33) may become concerted if X is a sufficiently good leaving group.

In eliminations of HBr from CHBrF2 no H/D exchange is observed [44], which could

indicate a concerted process, but elimination of bromide ion may, in this case, be much

faster than deuteration (cf. b-eliminations, Section I) and so a two-step process cannot be

ruled out.

A number of different bases, usually KOH or NaOH [45] with a phase-transfer catalyst

[46] or crown ether [47], have been used for generating carbenes which can be trapped by

nucleophilic species such as alkoxides, thiolates and, more usually, alkenes. This ap-

proach to carbene generation is still popular due to the low cost and the ease of handling

the reagents used; some examples are given in Figure 6.34 [45, 46, 48].

CH3

CH3

F F

H3C

H3C CH3

CH3

H3C

H3C

H3C

H3C CH3

CH3

F Cl

H3C

H3C CH3

CH3

CH2Br2 + CF2Br2 +

+ 2KBr + CBr4 + 2H2O

+ CHFCl2

i, NaOH, tetraglyme, 95� C43%

i, Bu4N+HSO

−4, 60% KOH

Br F

+ CFHBr2

i, 50% NaOH, CH2Cl2, Et3N+CH2Ph Cl

−90%

i

i

i

½48�

½45�

½46�

Figure 6.34


148 Chapter 6

2 From halo-ketones and �acids

The formation of dihalocarbenes by decomposition of trihaloacetate anions is well known

and is usually formulated as involving two steps (Figure 6.35) but, of course, the process

could be concerted.

Cl�CF2�CO

O

F�C�F

Cl�CF2 + CO2

Cl�CF2 + Cl

� �Figure 6.35

It is found that decarboxylation of dichlorofluoroacetate [49] gives about 70% of

CCl2FH via competitive abstraction of a proton from solvent by the intermediate�CCl2F anion, whereas chlorodifluoroacetate [50] gives very little CClF2H, suggesting

either that chloride ion loss in this case is faster than protonation, or that the process is

concerted. Decarboxylation procedures have been widely used, mainly for the preparation

of fluorocyclopropyl derivatives as illustrated in Figure 6.36 [51, 52].

Ph

H

H

OAc

CH3

Ph

H

F F

OAc

CH3

i, ClF2C�COO− Na+, diglyme, reflux

88%

C8H17

OAc

C8H17

H

F F

OAc

i

i, ClF2C�COO− Na+, diglyme, reflux

i

½51�

½52�

Figure 6.36

In similar processes, base-induced cleavage of halogenated ketones has been used to

prepare cyclopropane derivatives [53] (Figure 6.37).

3 From organometallic compounds

Trifluoromethyl-lithium, prepared by metal/halogen exchange, is unstable; its de-

composition probably involves generation of difluorocarbene, which dimerises [54]

(Figure 6.38).

Elimination of bromine from dibromodifluoromethane is readily achieved, and various

trapping experiments have been carried out with difluorocarbene from this source [55]

(Figure 6.39).



H3C CFCl2

OO

C

H

CFCl2H3C

i, NaH, MeOH

CFCl2

F

Cl

60%

−Cl

i

CFCl

½53�

Figure 6.37

F2C CF2CF3I CF3Li−LiF

CF2

i, CH3Li, −45� C

i

½54�

Figure 6.38

F

FCF2Br2 CF2BrLi CF2

−LiBrn-BuLi ½55�

Figure 6.39

Perfluoroalkyl anions, which form carbenes upon subsequent elimination of a-

fluorine, may be generated by cleavage of the carbon–tin and carbon–mercury bonds

in, for example, (trifluoromethyl)trimethyltin [56] and phenyl(trifluoromethyl)mercury

[57] (Figure 6.40) under very mild conditions. Carbenes may be generated from

F

F

Me3Sn CF3

89%

I−

CF3−

+ Me3Sn-I−F

−

F

F+ PhHgCF3

i, NaI, Bu4N+ I

−, 18-crown-6, 80� C 56%

CF2

i

½56�

½57�

Figure 6.40


150 Chapter 6

perfluoroalkyl anions which, in turn, may be displaced from, for example, tin, mercury or

silicon by halide ions. Here the driving force is the strength of the new bond to halogen

being formed.

A combination of zinc and CF2Br2 can be used to add difluorocarbene to relatively

reactive alkenes [58] (Figure 6.41a).

Ph

H3C

i, CF2Br2, Zn, I2 (cat), rt

Ph

H3C

F F

71%i

½58�

Figure 6.41a

Remarkably, ðCF3Þ3Bi generates difluorocarbene at low temperatures in the presence

of aluminium trichloride [59] (Figure 6.41b).

(CF3)3Bi [CF2]F

F

i ii

i, AlCl3, −30� Cii, Cyclohexene

½59�

Figure 6.41b

4 From organophosphorous compounds

Difluorocarbene can be conveniently generated at room temperature by the addition of

fluoride ion to bromodifluorophosphonium bromide and, provided that the solvents are

scrupulously dry, can be trapped by alkenes [60], dienes [61] and cycloalkenes [62]

(Figure 6.42). The phosphonium salt may be generated in situ, allowing cyclopropanation

to be carried out in a one-pot process [60] (Figure 6.43). Addition of 18-crown-6 to the

reaction medium enhances the solubility of the metal fluoride and allows cyclopropana-

tion of less nucleophilic alkenes and alkynes to be performed [63] (Figure 6.44).

5 Pyrolysis and fragmentation reactions

Pyrolytic a-elimination of HCl from CHClF2 is the basis for the manufacture of tetra-

fluoroethene on an industrial scale [64] (Figure 6.45).

A carbene intermediate has been proposed for the formation of hexafluorobenzene by

pyrolysis of CHFCl2 and CHFBr2 [65], whilst difluoroacetylene is the suggested inter-

mediate in the corresponding pyrolysis of CFBr3 [66] (Figure 6.46).

Hexafluoropropene oxide (HFPO) [67] fragments exclusively by a reversible process

at high temperature to give trifluoroacetyl fluoride and difluorocarbene only [68]

(Figure 6.47).

Cyclopropanation of electron-deficient alkenes is also possible, as shown in

Figure 6.48, but molecular rearrangements at the high temperature required for HFPO

decomposition may reduce the yield of the desired product [69–72].



H3C

H3C

CH3

CH3

F F

H3C

H3C

CH3

CH3

F F F F

Br−

+ CsF +

79%

+ Br−

22%38%

+

+ Br− F

F

92%

i, diglyme, rt

i

i, KF, triglyme, rt

i

i, CsF, triglyme, rt

i

[Ph3PCF2Br]+

[Ph3PCF2Br]+

[Ph3PCF2Br]+

½60�

½61�

½62�

Figure 6.42

H3C

H3C

F F

H3C

H3C

+ Ph3P + CsF + CF2Br2

66%i, diglyme, rt

i

½60�

Figure 6.43

Ph H

F F

+ Br−

i, KF, 18-crown-6, glyme, rt79%

iPhC CH [Ph3PCF2Br]

+

½63�

Figure 6.44

CHClF2> 650� C

0.5 atm.F2C CF2CF2 ½64�

Figure 6.45


152 Chapter 6

CHFCl2

i, Pt, 700−750� C

C6F6 + CFCl3 + CFCl�CFCl + CFCl2�CFCl2

CFBr3

i, Pt, 640� C

C6F6 35%

i

i

½65�

½66�

Figure 6.46

O F

F

F

F3C F3C F

O165−185� C

+ CF2½68�

Figure 6.47

F

H

F

FF

F

H

F F

F

F

F

FF

HH

FF

HH

FF

FF

Cl

Cl

Cl

ClCl

Cl

F

•F

F

F

CF3F3C

FF

65%

i, HFPO, 185� C, 6 h

63%

F F F

50%, 1:1

52%

+

i

i, HFPO, 175� C

i

i

i, HFPO, 175� C

i, HFPO, CaCO3, 185� C

i

CF3

CF3

½69�

½70�

½71�

½72�

Figure 6.48



Pyrolysis of various phosphorane, e.g. ðCF3Þ2PF2 [73], and fluoroalkylated tin com-

pounds [74] has been used to generate difluorocarbene. Diazirines decompose to give

carbenes by either photolysis or pyrolysis [75] (Figure 6.49).

N

N

F

F

F

+135� C

85%

F

½75�

Figure 6.49

Remarkably, tetrafluoroethene [76] and even PTFE [77] (Figure 6.50) may be used as

sources of difluorocarbene, if sufficiently high temperatures are used.

F F

i, CF2�CF2, 640� C

F F

CF2

+ F F

CF3

N

F

i, (CF2)n, 550� C

N N

F F

F3C CF3

CF3+

isomers

Cl Cl

i

i

½76�

½77�

Figure 6.50

Reactions of arc-generated carbon with fluorocarbons lead to CF, which reacts in ways

resembling carbenes to give a variety of products [78, 79] (Figure 6.51).

C + CF4 F C CF3 CF2 CF2

N

+ CF

N

F

N

F

+

F

½78�

½79�

Figure 6.51

However, there are still no general methods for the preparation of fluorocarbene,

CFH [41].

B Polyfluoroalkylcarbenes

A useful source of perfluoroalkylcarbenes is the corresponding diazoalkane, or diazirine

[80, 81], which have been obtained by a variety of routes (Chapter 8). Confirmation that

bis(trifluoromethyl)carbene is produced in the pyrolysis of these species comes from the

observation that, at low pressures, hexafluoropropene is obtained; it results from an

internal 1,2-fluoride shift in the intermediate carbene [80] (Figure 6.52).


154 Chapter 6

N2

F3C

F3CCF3CF=CF2

250� C (CF3)2C=C(CF3)2+Low pressure

½80�

Figure 6.52

Insertion reactions [81], alkene additions [82] and even additions to benzene and

hexafluorobenzene [83] have been observed using these sources of carbenes, as shown

in Figure 6.53.

F3C

F

CH3

CH3

H3C

H3C

H3C

H3C

CH3

CH3

F3C F

+170� C

30%

N2

F3C

F3C

CF3

CF3

+ F150� C F 20%

N2

F3C

H+N2

CF3CH2 76%hν ½81�

½82�

½83�

Figure 6.53

However, many reactions of bistrifluoromethyldiazoalkanes may involve formation

of an intermediate pyrazoline followed by loss of nitrogen, rather than a carbene

intermediate: a cyclic adduct has been isolated from reaction of bis(trifluoromethyl)dia-

zomethane with but-2-yne, which then loses nitrogen on pyrolysis [80] (Figure 6.54).

N2

F3C

F3C+

NN

CH3H3C

CF3

CF3

400�C

F3C CF3

H3C CH3

−N2

CH3C CCH3

½80�

Figure 6.54

Organo-metallic or -metalloid reagents provide efficient routes to fluoroalkylated

carbenes; difluoromethylfluorocarbene (6.55A) is readily generated by a general route

which involves the pyrolysis of fluoroalkylsilicon compounds [84] (Figure 6.55).



HSiCl3 + C2F4

hνCHF2CF2SiCl3 CHF2CF2SiF3

150� C

F2HC C F + SiF4(CH)3CCHFCHF2

61% 6.55A

SbF3

(CH3)3CH

½84�

Figure 6.55

The mercurial C6H5HgCFBrCF3 serves as a useful transfer agent for CF3CF [85]

(Figure 6.56).

+ C6H5HgCFBrCF3160� C

C6H6

F

CF3

87% ½85�

Figure 6.56

C Structure and reactivity of fluorocarbenesand polyfluoroalkylcarbenes

1 Fluorocarbenes

The existence of two possible and opposing effects arising from fluorine attached to the

carbon of a carbene produces a dichotomy analogous to that which occurs in fluorocar-

bocations (Chapter 4, Section VI). The inductive effect of fluorine should make the

carbon atom, which is already electron-deficient, even more electrophilic (6.57A in

Figure 6.57), but the possibility of p-bonding (6.57B) between fluorine and a vacant

orbital on carbon could also occur.

F C F F C FC FF

6.57A 6.57B

δ + δ −

Figure 6.57

On the basis of spectroscopic and thermodynamic data, it has been concluded that

p-bonding is significant in difluorocarbene [86] and to a degree which accounts for the

fact that it is surprisingly stable and relatively unreactive compared with CH2 and other

carbenes [86]. That the balance between the two effects is clearly dominated by p-bonding

is illustrated by the relative reactivities of various carbenes with different alkenes; it is

concluded that electrophilicity decreases in the series CH2 > CBr2 > CCl2 > CFCl >

CF2 and CH2 > CHF > CF2. Indeed, CF2 is considered to be amphiphilic [87].

Of course, carbenes can exist as either a singlet or triplet in the ground state, and the

calculated energy differences between these two states (DES�T ¼ ET � ES) for several

different carbenes are given in Table 6.2. Electron-withdrawing substituents lower orbital

energies and we have noted the stabilising effect of perfluoroalkyl groups on radicals


156 Chapter 6

(Chapter 4) and their strongly destabilising effect on carbocations. In parallel with these

observations, a trifluoromethyl group clearly enhances the stability of the triplet state

(Table 6.2). Conversely, fluorine directly attached to the carbene centre strongly favours

the singlet state, which, of course, contains a vacant orbital that is able to interact strongly

with the non-bonding electron pairs on fluorine. However, CFCl and CFBr are also found

to have singlet ground states [88].

The stereochemistry of reactions between carbenes and alkenes is determined by the

states of the carbenes (when generated), whereby singlet carbenes react in a stereospecific

one-step concerted process whilst triplet carbenes lead to a mixture of products via a

diradical intermediate (Figure 6.58). Consequently, since fluorocarbenes are singlets in

the ground state (Table 6.2), cyclopropanation of alkenes is often stereospecific [91]

(Figure 6.59) (for more examples, see Sections A and B).

R1

R3

R2

R4 R3 R4

R1R2

F F

R1

R3

R2R4

CF2 R3 R4

R1R2

F F

R3 R2

R1R4

F F

singlet CF2

triplet CF2

+Spin

Inversion

Figure 6.58

C2H5

C2H5H C2H5

C2H5H

F FMe3Sn-CF3

NaI74% ½91�

Figure 6.59

The selectivity of carbenes has been qualitatively estimated by a series of competition

reactions between various carbenes and mixtures of different alkenes; it is found that

electrophilic carbenes react preferentially with the most electron-rich alkene present [87,

92]. Fluorocarbenes, being less reactive, give rise to fewer products from C2H insertion

reactions than CCl2 [91] (Figure 6.60). However, selectivity may be temperature-

dependent [93, 94].

Table 6.2 Calculated energy difference between singlet

and triplet states of carbenes, DES�T [89, 90]

Carbene DES�T ðkJmol�1Þ

CH2 �246

CHF 142

CF2 808

CðCF3Þ2 �313



OO

O CCl2H

Cl Cl

CCl2

O

+

F F

CF2

(1 : 1)

½91�

Figure 6.60

2 Polyfluoroalkylcarbenes

Electronic effects in bispolyfluoroalkylcarbenes (6.61A) are clearly defined, in that the

already electron-deficient carbon is made even more electrophilic by the strong electron

withdrawal by polyfluoroalkyl groups (Figure 6.61). Polyfluoroalkylfluorocarbenes

(6.61B) are, however, an intermediate situation with the possibility of compensating

p-bonding, as described earlier.

C RFRF FCRF

δ + δ − δ +δ −

6.61A 6.61B

Figure 6.61

The extremely electrophilic nature of bis(trifluoromethyl)carbene has already been

illustrated by the formation of addition products, even with hexafluorobenzene [83]

(Section IIIB), and the high reactivity results in more side-reactions, such as insertion

into C2H bonds, than with difluorocarbene (Figure 6.62).

C(CF3)2H C(CF3)2HCF3

CF3

i, (CF3)2C�N2, hν

47% 9%44%

++i ½80�

Figure 6.62

Trifluoromethylcarbene [95] also yields high proportions of insertion products in

reactions with alkenes, whilst difluoromethylfluorocarbene is intermediate in reactivity

because, although it undergoes a range of C2H insertion reactions, it is more selective

than trifluoromethylcarbene [96].


158 Chapter 6

Polyfluoroalkylcarbenes have triplet ground states [89] and so reactions with alkenes

give isomeric mixtures of cyclopropanes, as well as other side-products, in contrast to

reactions involving difluorocarbene [80] (Figure 6.63).

H3C CH3

F3C

F3C

CH3

CH3 H3C

HH

F3C CF3

CH3

+

cis39%

trans8%49%

i, (CF3)2C�N2, hν

i

½80�

Figure 6.63

REFERENCES

1 C.H. DePuy and C.A. Bishop, J. Am. Chem. Soc., 1960, 82, 2535.

2 H.F. Koch, D.B. Dahlberg, M.F. McEnfee and C.J. Klecha, J. Am. Chem. Soc., 1976, 98, 1060.

3 N.B. Chapman and J.L. Levy, J. Chem. Soc., 1952, 1677.

4 M. Hudlicky, J. Fluorine Chem., 1986, 32, 441.

5 M. Hudlicky and T.E. Glass, J. Fluorine Chem., 1983, 23, 15.


7 E. Baciocchi, R. Ruzziconi and G.V. Sebastiani, J. Org. Chem., 1982, 47, 3237.

8 S. Alunni, V. Laureti, L. Ottavi and R. Ruzziconi, J. Org. Chem., 2003, 68, 718.

9 H.F. Koch, D.J. McLennan, J.G. Koch, W. Tumas, B. Dobson and N.H. Koch, J. Am. Chem.Soc., 1983, 105, 1930.

10 H.F. Koch in Comprehensive Carbanion Chemistry, ed. E. Buncel and T. Durst, Elsevier,

Amsterdam, 1987.

11 J. Hine, R. Wiesboeck and O.B. Ramsay, J. Am. Chem. Soc., 1961, 83, 1222.

12 H.F. Koch and J.G. Koch in Carbanion Intermediates, ed. J.F. Liebman, A. Greenberg and

W.R. Dolbier, VCH, New York, 1988.

13 R.A. Bartsch and J.F. Bunnett, J. Am. Chem. Soc., 1968, 90, 408.

14 P. Tarrant, A.M. Lovelace and M.R. Lilyquist, J. Am. Chem. Soc., 1955, 77, 2783.

15 H.W. Davis and A.M. Whaley, J. Am. Chem. Soc., 1950, 72, 4637.

16 R.P. Ruh, US Pat. 2 628 988 (1953); Chem. Abstr., 1954, 48, 1407b.

17 P. Tarrant, R.W. Whitfield and R.H. Summerville, J. Fluorine Chem., 1971, 1, 31.

18 R.D. Chambers, R.W. Fuss, R.C.H. Spink, M.P. Greenhall, A.M. Kenwright, A.S. Batsanov

and J.A.K. Howard, J. Chem. Soc., Perkin Trans. 1, 2000, 1623.

19 H. Matsuda, T. Hamatani, S. Matsubara and M. Schlosser, Tetrahedron, 1988, 44, 2865.

20 W.H. Saunders and A.F. Cockerill, Mechanisms of Elimination Reactions, John Wiley and

Sons, New York, 1973.

21 D.J. McLennan, Tetrahedron, 1975, 31, 299.

22 M. Hudlicky, Coll. Czech. Chem. Commun., 1991, 56, 1680.

23 C.R.S. Briggs, D. O’Hagan, J.A.K. Howard and D.S. Yufit, J. Fluorine Chem., 2003, 119, 9.

24 J.C. Tatlow, J. Fluorine Chem., 1995, 75, 7.

25 R.P. Smith and J.C. Tatlow, J. Chem. Soc., 1957, 2505.

26 D.E.M. Evans, W.J. Feast, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1963, 4828.

27 J. Burdon, T.M. Hodgins, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1965, 2382.

28 G. Fuller and J.C. Tatlow, J. Chem. Soc., 1961, 3198.

29 D.J. Burton and Z.Y. Yang, Tetrahedron, 1992, 48, 189.

30 P.G. Gassman and N.J. O’Reilly, J. Org. Chem., 1987, 52, 2481.



31 J.L. Adcock and H. Luo, J. Org. Chem., 1993, 58, 1999.

32 S.F. Campbell, R. Stephens and J.C. Tatlow, Tetrahedron, 1965, 21, 2997.

33 W.B. Hollyhead, R. Stephens, J.C. Tatlow and W.T. Westwood, Tetrahedron, 1969, 25, 1777.

34 R. N. Haszeldine, Fluorocarbon Derivatives, Royal Institute of Chemistry, London, 1956.

35 M. Yamabe and H. Miyake in Organofluorine Chemistry: Principles and Applications, ed.

R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum Press, New York, 1994, p. 403.

36 N.T. Nakai, K. Tanaka and N. Ishikawa, Tetrahedron Lett., 1976, 17, 1263.

37 J.M. Percy in Organofluorine Chemistry: Techniques and Synthons, ed. R.D. Chambers,

Springer, Berlin, 1997, p. 131.

38 H. Hata, T. Kobayashi, A. Amii, K. Uneyama and J.T. Welch, Tetrahedron Lett., 2002, 43,

6099.

39 K. Uneyama and H. Amii, J. Fluorine Chem., 2002, 114, 127.

40 D.J. Burton and J.L. Hahnfeld, Fluorine Chem. Rev., 1977, 8, 119.

41 B.E. Smart in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath,

ACS, Washington DC, 1995, p. 767.

42 J. Hine, Divalent Carbon, Ronald, New York, 1964.

43 W.E. Parham and E.E. Schweizer, Org. Reactions, 1963, 13, 55.

44 J. Hine and P.B. Langford, J. Am. Chem. Soc., 1957, 79, 5497.

45 G.C. Robinson, Tetrahedron Lett., 1965, 1749.

46 L. Anke, D. Reinhard and P. Weyerstahl, Liebigs Ann. Chem., 1981, 591.

47 Y. Bessiere, D.N.H. Savary and M. Schlosser, Helv. Chem. Acta, 1977, 60, 1739.

48 P. Balcerzak, M. Fedorynski and A. Jonczyk, J. Chem. Soc., Chem. Commun., 1991, 826.

49 J. Hine and D.C. Duffey, J. Am. Chem. Soc., 1959, 81, 1129.

50 J. Hine and D.C. Duffey, J. Am. Chem. Soc., 1959, 81, 1131.

51 Y. Kobayashi, T. Taguchi, T. Morikawa, T. Takase and H. Takanishi J. Org. Chem., 1982,

47, 3232.

52 T. Taguchi, T. Takigawa, Y. Tawara, T. Morikawa and Y. Kobayashi, Tetrahedron Lett., 1984,

25, 5689.

53 T. Ando, H. Tamanaka, S. Terabe, A. Horike and W. Funasaka, Tetrahedron Lett., 1967, 1123.

54 O.R. Pierce, E.T. McBee and G.F. Judd, J. Am. Chem. Soc., 1954, 76, 474.

55 V. Franzen, Chem. Ber., 1962, 95, 1964.

56 D.J. Seyferth, J. Organometal. Chem., 1973, 62, 33.

57 S.F. Sellers, W.R. Dolbier, H. Koroniak and D.M. Al-Fekri, J. Org. Chem., 1984, 49, 1033.

58 W.R. Dolbier, H. Wojtowicz and C.R. Burkholder, J. Org. Chem., 1990, 55, 5420.

59 N.V. Kirii, S.V. Pazenok, Y.L. Yagupolskii, D. Naumann and W. Turra, Russ. J. Org. Chem.,

2001, 37, 207.

60 D.J. Burton and D.G. Naae, J. Org. Chem., 1973, 95, 8467.

61 W.R. Dolbier and S.F. Sellers, J. Org. Chem., 1982, 47, 1.

62 A. Greenberg and N. Yang, J. Org. Chem., 1990, 55, 372.

63 Y. Bessard and M. Schlosser, Tetrahedron, 1991, 47, 7323.

64 A.E. Feiring in Organofluorine Chemistry. Principles and Commercial Applications, ed.

R.E. Banke, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 339.

65 R.E. Banks, J.M. Birchall, R.N. Haszeldine, J.M. Simm, H. Sutcliffe and J.H. Umfreville, Proc.Chem. Soc., 1962, 281.

66 J.M. Birchall and R.N. Haszeldine, J. Chem. Soc., 1959, 3653.

67 H. Millauer, W. Schwertfeger and G. Siegemund, Angew. Chem. Int. Ed. Engl., 1985, 24, 161.

68 W. Mahler and P.R. Resnick, J. Fluorine Chem., 1973, 3, 451.

69 P.B. Sargent and C.G. Krespan, J. Am. Chem. Soc., 1969, 91, 415.

70 W.R. Dolbier, S.F. Sellers, B.H. Al-Sader, T. H. Fielder, S. Elsheimer and B.E. Smart, Isr.J. Chem., 1981, 21, 176.

71 P.W.L. Bosbury, R. Fields, R.N. Haszeldine and G.R. Lomax, J. Chem. Soc., Perkin Trans.1, 1982, 2203.


160 Chapter 6

72 W.P. Dailey, P. Ralli, D. Wasserman and D.M. Lemal, J. Org. Chem., 1989, 54, 5516.

73 R.G. Cavell, R.C. Dobbie and W.J.R. Tyerman, Canad. J. Chem., 1967, 45, 2849.

74 J.M. Birchall, R.N. Haszeldine and D.W. Roberts, J. Chem. Soc., Chem. Commun., 1967, 287.

75 R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 758.

76 V.M. Karpov, V.E. Platonov, I.P. Chuikov and G.G. Yakobson, J. Fluorine Chem., 1983, 22,

459.

77 R.D. Chambers, R.P. Corbally, T.F. Holmes, and W.K.R. Musgrave, J. Chem. Soc., PerkinTrans. 1, 1974, 108.

78 M. Rahman, M.L. McKee and P.P. Shevlin in Fluorine-Containing Molecules, ed. J.F. Liebman,

A. Greenberg and W.R. Dolbier, VCH, New York, 1988.

79 R. Sztyrbicka, M. Rhaman and M.E. D’Aunoy, J. Am. Chem. Soc., 1990, 112, 6712.

80 D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617.

81 J.H. Atherton and R. Fields, J. Chem. Soc. C, 1968, 2276.

82 W.P. Dailey, Tetrahedron Lett., 1987, 28, 5801.

83 D.M. Gale, J. Org. Chem., 1968, 33, 2536.

84 R.N. Haszeldine and J.G. Speight, J. Chem. Soc., Chem. Commun., 1967, 995.

85 D. Seyferth and G. J. Murphy, J. Organometal. Chem., 1973, 52, C1.

86 J.P. Simons, J. Chem. Soc., 1965, 5406.

87 R.A. Moss, Acc. Chem. Res., 1980, 13, 58.

88 R.A. Seburg and R.J. McMahon, J. Org. Chem., 1993, 58, 979.

89 D.A. Dixon, J. Phys. Chem., 1986, 90, 54.

90 K.K. Irikura, W.A. Goddard and J.L. Beauchamp, J. Am. Chem. Soc., 1992, 114, 48.

91 D. Seyferth and S.P. Hopper, J. Org. Chem., 1971, 26, 620.

92 N.G. Rondan, K.N. Houk and R.A. Moss, J. Am. Chem. Soc., 1980, 102, 1770.

93 B. Giese, W.B. Lee and J. Meister, Ann. Chem., 1980, 725.

94 K.N. Houk, N.G. Rondan and J. Mareda, J. Am. Chem. Soc., 1984, 106, 4291.

95 J.H. Atherton and R. Fields, J. Chem. Soc. C, 1967, 1450.

96 R.N. Haszeldine, R. Rowland, J.G. Speight and A.E. Tipping, J. Chem. Soc., Perkin Trans. 1,

1980, 314.



Chapter 7

Polyfluoroalkanes,Polyfluoroalkenes,Polyfluoroalkynes and Derivatives

I PERFLUOROALKANESAND PERFLUOROCYCLOALKANES [1]

A Structure and bonding [2, 3]

1 Carbon–fluorine bonds

Carbon–fluorine bonds in the fluoromethane series shorten progressively upon increasing

fluorination (Table 7.1), a feature that is not observed for other carbon–halogen bonds in

halomethanes [2, 3]. Clearly, the carbon–fluorine bond shortening is accompanied by an

increase in the bond energy of the carbon–fluorine bond, whilst the variation in bond

lengths for the carbon–hydrogen bond is much smaller. In the chloromethanes the carbon–

chlorine bond weakens slightly with increasing chlorine content.

Bond-shortening in fluoromethanes has been discussed by a number of authors. Pauling

originally [5] introduced the concept of double-bond no-bond resonance (negative hyper-

conjugation, Chapter 4, Section IIIB) involving, in MO terms, interaction of non-bonding

electron pairs of fluorine with a s� orbital of a carbon–fluorine bond, to account for the

effect, and this is now well established [6] (Figure 7.1).

2 Carbon–carbon bonds

The weakest bonds in perfluoroalkanes are the carbon–carbon bonds, so it is of interest as

to whether the strengths of these bonds are affected by the introduction of fluorine. It is

Table 7.1 Bond lengths r and bond strengths B of various halomethanes [3, 4]

X ¼ F X ¼ Cl

r(C2F) (A) B(C2F) (kJmol�1) r(C2Cl) (A) B(C2Cl) (kJmol�1)

CXH3 1.385 459.8 1.781 354.0

CX2H2 1.357 500.0 1.772 335.1

CX3H 1.332 533.5 1.758 324.7

CX4 1.319 546.0 1.767 305.8



F C

F

F

F F C

F

F

F F C F

F

F

etc. ½6�

Figure 7.1

found that carbon–carbon bond strengths in a series of fluoroethanes increase upon

a-fluorination (Table 7.2).

Paradoxically, the carbon–carbon bond in hexafluoroethane is stronger than in ethane,

even though it is longer; as yet, such observations remain unaccounted for.

B Physical properties

Since the molecular weight of a fluorocarbon is considerably higher than that of the

corresponding hydrocarbon, we might expect boiling points to be increased.

It can be seen from Figure 7.2 [7] that this is not so, and that there is a remarkable similarity

between the boiling points of fluorocarbons and the corresponding hydrocarbons [8], the

increase in molecular weight being offset by a decrease in intermolecular bonding forces in

the fluorocarbon [9]. Perfluorocarbons have the potentially valuable property of dissolving

useful amounts of certain gases, including oxygen, carbon dioxide and even fluorine, and the

inertness of fluorocarbons to oxidation has led to a long-term study of fluorocarbon

emulsions in water for use as ‘artificial’ blood and other transport applications [10].

Although working systems have been demonstrated, drawbacks associated with reactions

of the immune system have, so far, limited their successful commercial development.

Fluorinated fullerenes have been studied intensively [11].

C Reactions

1 Hydrolysis

Perfluorocarbons are essentially inert to hydrolysis unless heated to very high tempera-

tures, although it has been calculated that the free energy of hydrolysis of carbon

tetrafluoride is exothermic by 304 kJmol�1 [12], and the inertness therefore stems from

a high activation barrier. The carbon backbone in a perfluorocarbon is shielded towards

attack by nucleophiles by the non-bonding electron pairs associated with the many

adjacent fluorine atoms, and this is undoubtedly a major factor contributing to the relative

inertness of fluorocarbons.

Table 7.2 Carbon–carbon bond strengths and lengths in

fluoroethanes [3]

Ethane r(C2F) (A) BDE(C2C) (kJmol�1)

CH32CH3 1.532 378.2

CH32CH2F 1.502 381.6

CH32CHF2 1.498 400.0

CH32CF3 1.494 423.4

CF32CH2F 1.501 395.8

CF32CF3 1.545 413.0


Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 163

150

100

50

02

Boi

ling

poin

t (�

C)

4 6

Number of carbon atoms

Fluorocarbons

Hydrocarbons

8

−50

−100

−150

−200

Figure 7.2 Boiling points of alkanes

2 Defluorination and functionalisation [1]

Either fusion with alkali metals or reaction with alkali-metal complexes with aromatic

hydrocarbons will break down most fluorocarbon systems, due to the high electron

affinities of these systems. Such reactions form the basis of some methods of elemental

analysis [13], the fluorine being estimated as hydrogen fluoride after ion exchange. Surface

defluorination of PTFE occurs with alkali metals and using other techniques [14]. Per-

fluorocycloalkanes give aromatic compounds by passage over hot iron and this provides a

potential route to a variety of perfluoroaromatic systems (Chapter 9, Section IB).

Electron transfer from other, less vigorous, reducing agents (Table 7.3) can result in

selective defluorination, which arises from a single-electron transfer process, under very

mild conditions (Figure 7.3).

+e−

+e−

+e−

−F−

−F−

CF2CF2 CF2CF2n

etc.

nCF2CF2 n-1

CF2CF

CF2CF2 n-1CF2CFCF2CF2 n-1

CF=CF

Figure 7.3


164 Chapter 7

When the reducing agent can also act as a nucleophile, such as thiolate anion [18]

(Figure 7.4) or ammonia sensitised by mercury [19] (Figure 7.5), functionalisation of the

unsaturated, fluorinated intermediate can occur.

F F

i, PhS−Na

+, DMEU, 70�C, 10 days

SPh

SPh SPh

SPh

SPh

SPh

PhS

PhS

i½18�

Figure 7.4

F3CCF

F3C

CF2

CF2CF3

NC

NC

NH2

CF2CF3

i, Hg/hν, NH3

CF3

Fi

HN

CN

NH2

F

i ½19�

½19�

Figure 7.5

Table 7.3 Defluorination of perfluorocarbons

Substrate Reagents/Conditions Product

Yield

(%) Ref.

F F Cp2TiF2

Al, HgCl2, THF, rtF F 40 [15]

F F Cp2Co

LiðO3SCF3Þ, Et2O, rtF F 53 [16]

F F Ph2C5O, Na

THF, rtF F 62 [17]



3 Fragmentation

Although perfluorocarbons are extremely thermally stable compounds, pyrolysis at

elevated temperatures can lead to useful preparations of some simple alkenes [20]

(Figure 7.6).

F725�C

CF2 C(CF3)2 CF2 CFCF3+

70% 20%

½20�

Figure 7.6

Vacuum pyrolysis of polytetrafluoroethene gives tetrafluoroethene as virtually the only

product [21]; this unzipping reaction is almost unique amongst depolymerisation pro-

cesses. At higher pressures the pyrolysis product contains other perfluorinated alkenes

and perfluorocyclobutane, the proportions depending on the exact reaction conditions

[22].

D Fluorous biphase techniques [1, 23, 24]

The technique of using mixtures of perfluorocarbon and hydrocarbon solvents to

aid separation and recovery of products, catalysts etc. was initiated by Horvath and

Rabai [25]. These mixtures of solvents may be largely immiscible at room temperature

but will become miscible on heating, whereupon reaction will take place. On cooling,

separation occurs and products may be recovered. If a component has an attached

perfluoroalkyl group that is sufficiently long to render that component soluble in the

perfluorocarbon (e.g. a catalyst), then recovery from the perfluorocarbon becomes easy

[25] (Figure 7.7). In this example, the product aldehyde separates from the perfluorocar-

bon solvent [26]. However, because of the high cost of perfluorocarbons and their global

warming potential, it seems unlikely that these approaches will be used in large-scale

syntheses.

1-octene n-nonanal 81%

CO/H2

25�C, C7F14

[Rh]

P(4-C6H4C6F13)3

CO/H2CO/H2

1-octene

70�C, C7F14

[Rh]

P(4-C6H4C6F13)3

25�C, C7F14

[Rh]

P(4-C6H4C6F13)3

Heat ½26�

Figure 7.7

Curran and co-workers have introduced a promising approach to separation and

purification procedures by using fluorocarbon-coated solid phases for liquid-phase chro-

matography. This approach depends on attaching a variety of perfluorocarbon tags to

functional compounds which render the eventual substrate mixture separable over the

perfluorinated stationary phase [27, 28] (Figure 7.8).


166 Chapter 7

A1 RF1

A6 RF6

A1 RF1

A6 RF6

B1 RF1

B6 RF6

MixtureSeparateComponents

Mixture

Chromatography

B1 RF1

B6 RF6

SeparateComponents

Recovery of B1-B6

and RF tags

RF1 etc. = Fluorinated tag

i

i, various chemical transformations

½27, 28�

Figure 7.8

II PERFLUOROALKENES

A Stability, structure and bonding

Substitution of hydrogen, in an alkene, by fluorine leads to increased reactivity for a

number of processes; for example, with tetrafluoroethene, heats of addition of chlorine,

hydrogenation and polymerisation are 58.5, 66.9 and 71:1 kJmol�1 greater, respectively,

than for the analogous reactions with ethene [3, 29]. These observations could be

attributed either to an increase in the carbon–fluorine bond strength upon changing the

hybridisation of the carbon atoms bonded to fluorine [30] or to p-bond destabilisation by

fluorine [31].

Here it is reasonable to note the effect of fluorine and of perfluoroalkyl groups on

orbital energies; in this regard, photoelectron spectroscopy is quite valuable. It is useful

to emphasise, again, that electron-withdrawing groups lower orbital energies, and photo-

electron spectroscopy confirms that perfluoroalkyl groups have this effect on attached

p-bonds. The same technique [32, 33] also points to the ambiguous nature of a fluorine

atom attached to a double bond (Chapter I, Section IIIB) where inductive electron

withdrawal is offset by interaction of non-bonding electron pairs on fluorine with the

p-system. Consequently, the effect of fluorine attached to a double bond on the energies

of the p-orbitals is little different from that of hydrogen, whereas perfluoroalkyl is

strongly stabilising. In contrast, a fluorine atom attached to a saturated site can only be

a stabilising influence, so we can appreciate that there is a driving force towards

decreasing the number of sites where a fluorine atom is attached to an unsaturated carbon

centre.

A consideration of the cyclobutene ring-opening reactions [34, 35] (Table 7.4) reveals

that the changes in hybridisation of carbon bonded to fluorine are the same for both

compounds T7.4A and T7.4B, and so any changes in carbon–fluorine bond energies must

also be the same. Consequently, as DH for T.7.4A is more endothermic than for T7.4B,



this difference must be due to destabilisation of the p-system by fluorine, an effect which

must increase with the number of fluorine atoms attached to the double bond.

These conclusions are supported by the measurement of the p-bond dissociation energy

[36] of CF25CF2, which is 29 kJmol�1 less than that for ethene. However, the situation is

less clear for partly fluorinated systems such as CF25CH2, in which the p-bond is

12:5 kJmol�1 more stable than in ethene [37].

cis-1,2-Difluoroethene is more thermodynamically stable by about 4�8 kJmol�1 than

the trans isomer [38]. This observation, which has been termed the cis effect, appears to

be a similar phenomenon to the conformational preference of 1,2-difluoroethane for the

gauche form [39]. A number of explanations and theoretical calculations have been

advanced [3, 39], with non-bonded attraction and conjugative destabilisation being the

most widely discussed. Of course, it could be that fluorine atoms in the trans isomer of

1,2-difluoroethene have the more destabilising influence on the p-bond.

All available data appear to point to the same underlying feature, that fluorine

prefers not to be attached to unsaturated carbon; this most probably stems from repulsion

between electron pairs on fluorine and those of the p-systems. Earlier discussions

showed that similar repulsions are important in determining the stability of fluorocarb-

anions (see Chapter 4, Section VIIA), and that these repulsive forces appear to be

critically interdependent with stereochemistry. Similar effects on fluoroalkenes are repre-

sented in Figure 7.9. The formation of a double bond involving sp2-hybridised

carbon, 7.9A, would lead to greater electron-pair repulsion than when formed from sp3-

hybridised carbon (cf. 7.9A and 7.9B); the latter would lead to ‘bent bond’ formulation

7.9B.

Extension of this approach leads to the conclusion that fluorine attached to a carbon–

carbon triple bond would be considerably destabilising, since electron-pair repulsions

with fluorine would then be at a maximum (Figure 7.10). This could partly account for the

instability of fluoroalkynes, described later (Section IIIA, below). Of course, it must not

Table 7.4 Ring opening of cyclobutenes [34]

Substrate Product DHðkJmol�1Þ EaðkJmol�1Þ Keq at 3158C

�33.5 136.0 9000

F

T7.4A F

FF2C

F2C

48.9 197.0 5:6� 10�3

F

T7.4B

CF3

CF3

F2C

F2C

CF3

CF3

1.7 192.5 8.4


168 Chapter 7

be forgotten that the electronegativity of carbon increases in the series sp3, sp2, sp and the

carbon–fluorine bond strength decreases correspondingly.

F

7.9A, C sp2

7.9B, C sp3

F C

90�109�

F

109�

C

109�

Figure 7.9

F C C

Figure 7.10

B Synthesis

There are four main general methods [40–42] for the preparation of perfluorinated

alkenes, namely dehydrohalogenation, dehalogenation, pyrolysis and halogen exchange

reactions of appropriate fluorinated precursors. The overall features of the mechanisms of

each of these processes have already been discussed (Chapters 6 and 7, Sections I and II).

Representative examples of each of these types of synthesis are collated in Table 7.5;

clearly the method of choice for the synthesis of a particular fluoroalkene will depend

Table 7.5 Synthesis of perfluoroalkenes

Reaction Ref.

Dehydrohalogenation

F

H

FReflux/30 min.

KOH/H2O [43, 44]

Contd



Table 7.5 Contd

Reaction Ref.

NaOH

CF2CFHCF3

85�C

CF CFCF3

[45]

F

F

H

Cl

F

F

F

F

KOH [46]

Dehalogenation

Cl

Cl

F F 100%CF2 CFCl200�C Zn, EtOH

[47]

Pyrolysis

iCF2 CF2 CF2 CFCF3

i, 750-800�C, Atmos Press.[48]

+

+32% 9%

53%

i(CF2 CF2)n CF2 CFCF3 CF2 CFC2F5

CF2 C(CF3)2

i, 700�C, Atmos Press.

[49]

∆CF3CF2CF2CO2

−Na+

−CO2

CF2 CFCF3 [50]

Halogen exchange

F

H59%

iCCl2 CClCCl CCl2

F3C

CF3i, KF, 200�C, NMP

[51, 52]

Cl F 72%i

i, KF, NMP, 200�C

[51]

i, KF, 18-Crown-6, Perfluorocarbon

iCCl2 CCl CCl CCl2 CF3C CCF3

[53]


170 Chapter 7

upon the availability of suitable precursors. In this section we will confine ourselves to

syntheses of per- and poly-fluoroalkenes, whilst other approaches to the preparation of

selectively fluorinated alkenes will be discussed in other chapters.

It is important to note that most of the simple highly fluorinated, commercially

significant fluoroalkenes are synthesised from materials obtained by the Swarts reaction

(Chapter 2, Section IIA) involving catalysed reactions of anhydrous hydrogen fluoride

with chloroalkanes [54] (Figure 7.11) or bromoalkanes.

CHCl3 catalystCHClF2

700�CCF2 CF2

860�CVacuum

CF2 CFCF3

CH3 CCl3catalyst

CH3 CClF2 CH2 CF2∆

HF

Pt

HF

− HCl

½54�

Figure 7.11

Decarboxylation of fluoro-acids which, in turn, are prepared by electrochemical

fluorination (ECF) on the industrial scale, is a useful route to longer-chain terminal

fluoroalkenes [50] (Figure 7.12).

n-C3H7COFE.C.F.

n-C3F7COF n-C3F7COOH

n-C3F7COO− Na

+ ∆

−CO2

C3F7 CF2=CFCF3 + NaF− F

−

H2O ½50�

Figure 7.12

Perfluorocyclopentene is exceptional in being obtained from non-fluorinated materials

by a simple one-step procedure, i.e. displacement of chlorine in perchlorocyclopentene by

fluoride ion [51], although some polyfluorochloro- and polyfluorohydro-alkenes can be

made by analogous processes [51, 52]. If a perfluorocarbon is used as the reaction

medium with potassium fluoride/18-crown-6 complex, then a variety of products may

be obtained, including hexafluoro-2-butyne [53].

Many useful, higher-molecular-weight fluoroalkenes can be conveniently prepared

by fluoride-ion-induced oligomerisation reactions of smaller fluoroalkenes such as

tetrafluoroethene and hexafluoropropene, and these methods are discussed in Section C.

C Nucleophilic attack [55–57]

Fluoroalkenes are generally much more susceptible to attack by nucleophiles than

by electrophiles and, in this respect, the chemistry of polyfluoroalkenes and their



corresponding alkenes may be said to be complementary [56]. Consequently, the term

‘mirror-image chemistry’ is appropriate to describe much of what follows (Figure 7.13).

C CF

F

F

FNuc

−+ Nuc C

F

F

CF

F

Nuc C C

F

F

H

F

F

E+

+ E C

H

H

CH

H

E C C

H

H

Nuc

H

H

Nuc−

C CH

H

H

H

H+

Figure 7.13

Nucleophilic attack on a double bond proceeds via carbanionic intermediates;

a consideration of the relative stabilities of such species as models for the corresponding

transition states accounts for most, but not all, of the observations concerning nucleophilic

addition to fluoroalkenes. The formation and direct observation by NMR of perfluoro-

alkyl anions in solution e.g. 7.14A, via addition of fluoride ion to perfluorinated

alkenes [58] is analogous to the observation of carbocations by protonation of alkenes.

The carbanions generated can be readily trapped by electrophiles [58]: in a classical

experiment Wiley [59] showed that carbanions are intermediates in nucleophilic addition

to tetrafluoroethene, by trapping the intermediate with dimethylcarbonate. Later develop-

ments showed that various nucleophiles may be used, and that fluoro-esters may be

employed as the trapping agent [60, 61] (Figure 7.14).

1 Orientation of addition and relative reactivities

Problems of orientation of attack and reactivities of fluorinated alkenes arise in a way

that is analogous but entirely complementary to the classical problems of electrophilic

attack on alkenes. For example, typical of the results that we must be able to account for is

the reaction of methoxide in methanol which occurs specifically at the CF25 site in

perfluoropropene (Figure 7.15). Also, there is a very wide range of reactivity with

perfluoroalkenes: for example, reactions of tetrafluoroethene usually require base cataly-

sis, whereas perfluoroisobutene reacts with neutral methanol.

(Caution: Like all alkylating agents, fluorinated alkenes should be treated as being

potentially toxic [62, 63]. For example, perfluoroisobutene is an extreme case and should

be avoided.)

2 Reactivity and regiochemistry of nucleophilic attack

A great deal of chemistry involving nucleophilic attack on fluorinated alkenes may

be rationalised on the basis of some simple ground rules and assumptions:

(1) There is a significant ion–dipole interaction [64] that contributes to the much greater

reactivity of alkenes bearing fluorine rather than chlorine at comparable sites [65],

and a terminal difluoromethylene is especially reactive [66] (Figure 7.16).


172 Chapter 7

F3C

F3C

CF2CF3

F+ CsF

tetraglyme

rtCF2CF2CF3

F3C

F3CCs

+

I

CF2CF2CF3

CF3

CF3

7.14A, Observable by NMR

CH3O−

+ CF2 CF2 CH3OCF2CF2−

(CH3O)2C=O

CH3OCF2CF2CO2CH3 74%

Nuc CF2 CF2 NucCF2CF2 C

O

RF

OR

NucCF2CF2

eg Nuc− = N3

−, PhO,

− CH3O,

− CH3S.

−

i

i, RFCOOR

½58�

½59�

½60, 61�

Figure 7.14

CH3O−

CF2 CFCF3

CH3OCF2CFHCF3 CH3O−

CH3OCF2CFCF3

CH3OH

CH3OCF(CF3)CF2

Figure 7.15

(2) Fluorine attached to carbon, which is itself adjacent to the carbanionic site (7.16A),

is carbanion-stabilising and therefore strongly activating, for example when X or Y

in 7.16A is CF3.

(3) When fluorine is directly attached to the carbanionic site, e.g. X or Y ¼ F in 7.16A,

the result is usually activating, but much less so than in (2). Thus, we have an

increase in reactivity in the series 7.17A–7.17C [67–69], and we can see that this

corresponds to an increase in stabilities of the derived intermediate carbanions

7.17D–7.17F (Figure 7.17).



C Fδδ

>> Clδδ

Nuc C CXY Nuc CF2 CXY etc.F

F

7.16A

δδ

C

Figure 7.16

CF2 CF2 < CF2 CFCF3 CF2 C(CF3)2

7.17A 7.17B 7.17C

NucCF2CF2−

7.17D 7.17E 7.17F

<

< <NucCF2CFCF3 NucCF2C(CF3)2

Figure 7.17

Furthermore, the rates of nucleophilic addition of diethylamine have been found to

increase in the series CF25CF2 < CF25CFCl < CF25CFBr [70] (Figure 7.18), again in

the order of increasing stability of the supposed intermediate carbanion.

(C2H5)2NH CF2 CFBr (C2H5)2NCF2CFBrH(C2H5)2NCF2CFBr−H

++H

+−

Figure 7.18

The order of reactivity CF25CðRFÞ2 > CFRF5CðRFÞ2 > ðRFÞ2C5CðRFÞ2 (where RF ¼perfluoroalkyl) has been clearly established from the isomeric system, 7.19A–7.19C, in

competition for reactions with methanol [68] (Figure 7.19).

CF2 C(RF)CF2CF3 CF3CF2(CF3)C C(CF3)CF2CF3

CF3CF C(CF3)RF

RF = CF3CFCF2CF3

7.19A 7.19B

7.19C

F−

F−

½68�

Figure 7.19

Intermediate carbanions formed by the addition of nucleophiles to fluorinated alkenes

may also be intercepted via halophilic processes [71] (Figure 7.20), as well as trapping by

electrophiles (see Figure 7.14).


174 Chapter 7

CH3O−

CF2 CFBr CH3OCF2CFBr

CF2 CFBr

CH3OCF2CFBr2 CF2 CF

Other products

½71�

Figure 7.20

However, the type of argument outlined above is insufficient to account for the

reactivity of perfluoropropene being greater than that of perfluoro-2-butene (7.21A)

(Figure 7.21), because the corresponding intermediate (7.21B) could only have margin-

ally different stability from the intermediate derived from perfluoropropene (7.17E).

There is also the greater reactivity of 7.22A than 7.22B to account for, where any

difference in stability of intermediate carbanions 7.22C and 7.22D would also be mar-

ginal (Figure 7.22).

Nuc−

CF3CF CFCF3 NucCF(CF3)CF(CF3) Products

7.21A 7.21B

Figure 7.21

RFCF C(RF)2 > (RF)2C C(RF)2

7.22A 7.22B RF = Perfluoroalkyl

NucCF(RF)C(RF)2 NucC(RF)2C(RF)2

7.22C 7.22D

Figure 7.22

Consequently, a frontier-orbital approach has also been used to account for reactivity

and orientation of attack [72]. This approach recognises that HOMO–LUMO interaction,

between nucleophile and fluorinated alkene respectively, will be important, and that

replacing a fluorine atom that is directly attached to unsaturated carbon in a fluorinated

alkene by trifluoromethyl reduces LUMO energy. This increased HOMO–LUMO inter-

action correspondingly increases reactivity, providing that the trifluoromethyl groups are

on the same carbon atom of the double bond, i.e. as in 7.17A–7.17C. However, coeffi-

cients also appear to be important, and introduction of trifluoromethyl increases the

coefficient in the LUMO at the adjacent carbon, i.e. as shown for 7.23A (Figure 7.23).

When two trifluoromethyl groups are attached to adjacent carbon atoms (7.23B), then it is

reasonable to assume that their effect on coefficients, and hence on reactivity, is opposing;

consequently the reactivity order CF25CF2 < CF25CFCF3 > CF3CF5CFCF3 is

observed.



F3C

F3CC C C C

F3C CF3

7.23A 7.23B

Figure 7.23

Strain is a very important factor affecting reactivity. This is probably best illustrated by

the relative reactivities of the dienes 7.24A–7.24C (Figure 7.24) [73] towards methanol,

giving the methoxy derivatives indicated. Diene 7.24A reacts vigorously with neutral

methanol, diene 7.24B reacts only over several days, while base is required to induce

reaction with diene 7.24C. Electronic effects in the dienes 7.24A–7.24C are essentially

equivalent and, therefore, these considerable differences in reactivity may be taken,

generally, as illustrative of the contributions that angle strain may introduce.

X

F3C

CF3

CF3

F3C Y

F F

X

Y

X

Y

FF

X, Y = F (7.24C)X = F, Y = OMeX = Y = OMe

X, Y = F (7.24B)X = F, Y = OMeX = Y = OMe

X, Y = F (7.24A)X = F, Y = OMe

Figure 7.24

3 Products formed

The nature of the products formed in these processes may be regarded as being dependent

upon the fate of an intermediate carbanion (7.25A in Figure 7.25): this can lead to proton

abstraction from the solvent to give 7.25B; elimination of fluoride to give 7.25C; or, if the

opportunity is available, an SN20 process, e.g. by elimination of fluoride ion accompanied

by allylic rearrangement to give 7.25D. The ratio of elimination to addition increases with

the reactivity of the alkene, because the stability of the carbanion 7.25A increases and, at

the same time, 7.25A becomes correspondingly less basic. Of course, the amount of

alkene 7.25C also depends on whether the reaction is simply a base-catalysed process or

whether a molecular equivalent of base is present. These processes are illustrated in

Figure 7.26 [74, 75]. All three types of product are seen in many reactions between

fluoroalkenes and nucleophiles [55, 76] (Figure 7.27). With very strong nucleophiles,

polysubstitution may occur [77] (Figure 7.28). With ammonia and other nitrogen bases, a

variety of unsaturated compounds may be obtained, such as nitriles and triazines [78–80]

(Figure 7.29).

4 Substitution with rearrangement – SN20 processes

Examples of substitutions that are accompanied by migration of the double bond are very

common with fluoroalkenes; although in most cases it is not established whether these


176 Chapter 7

Nuc C

F

C

R

Nuc-HNuc C

F

C

R

H

Nuc

R

SN2'

R = −CFR'2

R'

R'F

Nuc

−F−

(Base catalysedaddition)

7.25A 7.25B

7.25D 7.25C

+ Nuc−

Figure 7.25

n-C4H9OH + CF2 CF2 n-C4H9OCF2CF2HC4H9O

− Na+

0-40�C81%

CH3OH CF2 C(CF3)2Room

Temp.

CH3OCF C(CF3)2

CH3OCF2CH(CF3)2 65%

8%

½74�

½75�

Figure 7.26

CF2 CFCF2C4F9 CH3OCF2CFHCF2C4F9

CH3OCF CFCF2C4F9

CH3OCF2CF CFC4F9

i, CH3O− Na+, CH3OH, 50�C

(45%, addition)

+

+ (15%, substitution)

(40%, SN2')

i ½76�

Figure 7.27

4C6H5Li + CF2 CF2Room

(C6H5)2C C(C6H5)2Temp

½77�

Figure 7.28

reactions are concerted, they will be referred to as SN20 processes here [81] (Figure 7.30).

That substitution occurs by attack at the CF25 group, rather than direct displacement of

chloride from 2CF2Cl, has been deduced from the fact that, under equivalent conditions,

C6H5CClF2, CClF5CF2CClF2 and CCl25CCl2CClF2 are unreactive [82].

In non-aqueous media the relative order of reactivity of the attacking halide ions, as

nucleophiles in these processes, is F� > Cl� � I� [83]. This in itself indicates that the



NH3 CF2 CFXC

NC

N

CNXHFC CFHX

CFHX

NH3CF3CF CF2Vap.

PhaseCF3CHFCN

(CF3)2C CF2 NH3Et2O

−60�C(CF3)2CHFCN 21%

(CF3)2CHCONH2 13%

½78�

½79�

½80�

Figure 7.29

CH3O− CF2 CFCF2Cl CH3OCF2CF CF2 Cl− ½81�

Figure 7.30

CF2

C6H5

R+ C2H5O

−k1

CCF2OC2H5

C6H5

Rproducts

R k1 x 103s−1 (77�C)

CF3

CF2Cl

CF2CF3

1.9

1.8

0.67

½84�

Figure 7.31

bond-making process is most important and that the reactions involve a two-step add-

ition–elimination, rather than a concerted displacement in which the most polarisable

anion would be the most reactive. The same conclusion was drawn from a comparison of

the rates of reaction of various alkenes with ethoxide in ethanol under pseudo first-order

conditions [84] (Figure 7.31). Rearrangement products were only obtained when R was

CF2Cl, where elimination of chloride was easier, but the rate constants for the other two

examples are comparable, which indicates a rate-controlling addition step (k1).

In general it is very difficult to make any distinction between a concerted process and

the involvement of a short-lived carbanion. For clarity a number of alkene rearrangements

in the following text are written as two-step processes, but it should be emphasised that

they could involve concerted mechanisms. Products arising from substitution with re-

arrangement are frequently encountered in reactions of cyclic fluoroalkenes and in

fluoride-ion-induced rearrangements (Subsection 6, below).


178 Chapter 7

The literature concerning reactions between nucleophiles and fluoroalkenes is now

extensive and is included in various reviews [41, 55, 57, 85–92] and books devoted to

organofluorine chemistry (see the relevant chapters in the general textbooks listed in

Chapter 1, Section I). Some examples of reactions between fluoroalkenes and an illustra-

tive selection of nucleophiles are recorded in Table 7.6. The many unusual products and

the wide scope of these reactions will be apparent even from such a brief overview of the

subject. Examples of reactions involving bifunctional nucleophiles are also included,

whereas reactions involving initial attack by fluoride ion as the nucleophile are discussed

in Subsection 6, below.

Table 7.6 Reactions of fluoroalkenes with nucleophiles

Reaction Ref.

Carbon nucleophiles

+ F F 95%C8F17SiMe3

C8F17

[93]

iNCCF2CF2CO2CH3 72%CF2 CF2

i, NaCN, CO2, (CH3O)2SO2

[60]

Ph2CCN

i, Phase Transfer Conditions

Ph2C(CN)CF2CXY

Ph2C(CN)CF2CHXY Ph2C(CN)CF=CXY

iXYC�CF2

[94]

iPh-CF CFCF3 Ph2C CFCF3 PhCF C(CF3)Ph

i, PhLi, Et2OPh2C C(CF3)Ph (1 : 3.3 : 2.1)

[95]

+ F F

FF

73%

NMe2

CH3CN, rt

NMe2

[96]

CH3MgX CF2 CCl2 CH3CF2CCl2H

CH3CF CCl2

[97]

Contd



Table 7.6 Contd

Reaction Ref.

Nitrogen nucleophiles

Nrt

NN

F

CH3

F

H

F

78%

F CF CF2 + CH3NH2 [98]

F

F

F

94%

CF3

C2F5

C2F5

F3C C2F5

NH3, Et2O

0�C

C2F5

F3C

C2F5

CH2CN [99]

Oxygen nucleophiles

H

O O

+

62% 28%

iF3C

C2F5

CF3

C2F5

F3C CF3

C2F5 C2F5

F3C CF3

C2F5

i, NaOCl, H2O, CH3CN

[100]

xylene F

OMe

62%

F3C

F3C

CF2 + Bu3SnOMe0�C

F3C

F3C

[101]

F

H

F

Ph

OH

O

H

F

Ph

H

78%i

i, Montmorillonite (cat), KIO3, Hexane, Reflux

[102]

i

O

O

68%(CH2OH)2 CF2 C(CF3)2C(CF3)2

i, CH3CN, −5 to 0�C

[103]

Phosphorous nucleophiles

(100%, Z)

C3F7CF CF2 + Bu3P C3F7CF CFP(F) Bu3 [104]

Contd


180 Chapter 7

Table 7.6 Contd

Reaction Ref.

F

F

I F

i

ii

Bu3P CF2 CFCF3 Bu3P CF CFCF3

i, Et2O, −70�C to rt

BF3.Et2O

CF3Bu3P CF CFCF3 BF4

−

ii, I2, DMF, NaCO3

[105]

FF

+ Ph3P

PPh3

[106]

Sulphur nucleophiles

F

F S

S62%

F3C

F3C

K2S, DMF F3C

F3C

CF3

CF3

[107]

29%

63%

iCF2 CFCF3 CF3CFHCF2SC( S)NMe2

+ CF3CF CFSC( S)NMe2

i, Me2N CS2− Na+, DMA, 20�C

[108]

Halide ions

F F

INaI, DMF [109]

Transition metal nucleophiles

F +F

Re(CO)5−

Re(CO)5

[110]

Reduction

F

Ph H9%

iPhCF CFCF3

CF3

i, LiAlH4, glyme, 70�C

[111]

Contd



Table 7.6 Contd

Reaction Ref.

Bifunctional nucleophiles

HO

OH+

O

58%

iC2F5

C2F5

CF3

F3C

CF3

CF3

O

F3C

C2F5

i, Na2CO3, tetraglyme

[112]

NI

N

N

77%iCF3CF CFCF3 +

NH2

CF3

CF3i, K2CO3, CH2Cl2, rt

[113]

OH

+ F

N

O

F

59%

i, ii

NH2i, K2CO3, CH3CNii, NEt3

[114]

LiLi CF CF

n = 10−20n

i

i, CF2 CF2, Et2O, −110 �C

[115]

SH

i

S

NNH2

CF2 CFCF3 CH(CF3)2

i, THF, i-Pr2NEt

[116]

Fi

F Fi, CsF, Glyme, Stepwise

Me3SiOCH2(CF2)3CH2OSiMe3

OCH2(CF2)3CH2O

OCH2(CF2)3CH2O[117]

Contd


182 Chapter 7

5 Cycloalkenes

The various reactions of cyclic polyfluoroalkenes [85] (Figure 7.32) can largely be

explained on a similar basis to that described above, although the opportunity for some

rather more subtle orientation effects arises. Vinylic fluorine is generally replaced in

preference to other vinylic halogens, either in the same molecule or in comparable

systems, e.g. in the reaction of 7.32A with a deficiency of alkoxide ion. In these cases,

vinylic substitution is usually preferred over SN20 processes.

F

Cl

F

OC2H5

Cl

FC2H5O

−

7.32A

½85�

Figure 7.32

With equivalent halogen atoms at the vinylic positions, the remaining substituents have

a significant effect on the orientation of nucleophilic attack [85] (Figure 7.33). Attack on

7.33A occurs to give predominantly 7.33C and 7.33D; this has been interpreted as

indicating that CCl2 adjacent to the intermediate carbanion is more stabilising than

CF2, and similar deductions concerning CF2 and CH2 could be made from the exclusive

formation of 7.34B from 7.34A (Figure 7.34).

It has been suggested that an additional factor to be considered in determining

the products from polyfluorocyclohexenes is the stereochemistry of the elimination step

[119] (Figure 7.35). Elimination of fluoride ion may occur from the carbanion 7.35B,

produced by reaction of 7.35A with methoxide ion, by an outward (displacement with

rearrangement) or inward (vinylic displacement) process. In order to account for

the results shown, it was suggested that anti addition of methoxide occurs and that the

carbanion 7.35B partially retains its configuration [119]. Then competition occurs be-

tween an electronically favoured syn inward elimination of fluoride from 2CFOCH3, and

the stereochemically favoured anti outward elimination of fluorine from 2CF2 [120]

(Figure 7.36).

Table 7.6 Contd

Reaction Ref.

N

N

iD.B.U. + CF3CH CFCF3

i, Hexane, rt

F3C CF2H

[118]

D. B. U., 1, 5-diazabicyclo [3.4.D] nonene-5



7.33A

Cl

Cl

FF

Cl

Cl

C2H5OH

KOH

Cl

F

F

Cl

OEt

Cl

Cl

F

F

Cl

Cl

OEt

Cl

F

F

Cl

Cl

Cl

OEt

Cl

OEt

Cl

F

F

Cl

Cl

Cl

OEt

F

F

Cl

Cl

+

7.33C, 61% 7.33D, 23%

7.33B, 10%

Figure 7.33

F

F

FF C2H5O

−FF

F

F

OEt

FFF

OEt

7.34A 7.34B

Figure 7.34

R

F

F

R

FF

OMe

F

OMe

R

OMe

R

F

F F+

R

H

CH3

OCH3

% %

49 51

54

38

46

62

7.35A 7.35B 7.35C 7.35D

MeO− ½119�

Figure 7.35


184 Chapter 7

F

F

F

F

F

R

F

F

MeOF

F

FR

MeO

F

F

F

F

F

F F

F

7.35B

Figure 7.36

6 Fluoride-ion-induced reactions [56, 57, 121]

In the preceding sections we outlined reactions of fluoroalkenes with many types of

nucleophilic species, but reactions involving initial attack on fluoroalkenes by fluoride

ion have been reserved for a separate discussion here.

Pioneering work by Miller and co-workers [55, 83] established that carbanions can be

generated by reaction of fluoride ion with fluoroalkenes and an important analogy was

drawn between the role of fluoride ion in reactions with unsaturated fluorocarbons, and

the proton in reactions with unsaturated hydrocarbons [83]. In spite of the obvious

misgivings in trying to draw an analogy between carbanion and carbocation processes,

the model has been taken a surprisingly long way [56] (Figure 7.37).

F−

+ C CF

F

F3C C E+

F3C C E

H+

+ C CH

HH3C C

Nuc−

F3C C Nuc

Addition

Compare

Substitution with Rearrangement

H+ + H

+

F− + F

−

Compare

F

F F

F

F F

F

F

H

H

HH

HH

Figure 7.37



7 Addition reactions

Addition of an alkali-metal fluoride, frequently KF, CsF, ðMe2NÞ3SþMe3SiF�2 (soluble

in organic solvents) or a tetraalkylammonium salt, to a fluoroalkene in an aprotic dipolar

solvent is usually the method used to generate perfluorocarbanions. Some of

these intermediates have been directly observed by NMR [58, 121]. The intermediate

carbanions may be trapped by a variety of electrophiles, and some examples are given in

Table 7.7.

Table 7.7 Fluoride-ion-induced addition reactions to fluoroalkenes

Reaction Ref.

F DMFC 79%

F3C

F3C

CF2-CF3

+ CH3ICsF C3F7

CF3

CF3

CH3 [122]

KF, DMFPh

O

F66%CF2 CFCF3 + PhCOCl

CF3

CF3 [123]

KF75%

i, iiCF2 CF2 CH3CN

CF3CF2−

CF3CF2CO2H

i, CO2, 150�C, ii, H2SO4

[124]

F

41%

CF2 CFCF3 + C6H5N2+ Cl

− CsF

CH3CN

F3C

F3CN N C6H5

[125]

glyme82%CF2 C(CF3)2 + C6H5SCl

CsFF3C C

CF3

CF3

SC6H5 [126]

S70%CF2 CFCF3 + S

KF, 120�C F3C

F3C CF3

S CF3[127]

F F F F

Br

CsF, Br2 [128]

CF2 CFCF3 + IF5 + I2150�C 99%(CF3)2CFI [129]

Contd


186 Chapter 7

The related reactions of polyfluorinated carbanions with fluoroarenes (Figure 7.38) will

be discussed fully in Chapter 9, Section IIB.

F−

CF2 CFCF3 (CF3)2CF+N

N

F

FCF(CF3)2

½134�

Figure 7.38

8 Fluoride-ion-catalysed rearrangements of fluoroalkenes

In the absence of electrophiles, loss of fluoride ion from intermediate carbanions may

occur in a manner such as to yield the most thermodynamically stable fluoroalkene, often

resulting in isomerisation of the original reactant. Fluoroalkenes with the fewest fluorine

atoms attached to the double bond are generally the most thermodynamically stable

(see Section IIA above). Consequently, ‘internal’ isomers are usually to be expected as

the result of fluoride-ion-induced processes such as those indicated in Figure 7.39 [135,

136].

A number of remarkable fluoride-ion-induced rearrangements have been documented;

one example is given in Figure 7.40.

The possibility that many of these rearrangements are addition–elimination reactions

rather than concerted SN20 processes is supported by the isolation, in some cases, of

Table 7.7 Contd

Reaction Ref.

F

79%F3C

F3C

CF3

+ KF I2+ + IF5200�C

CF3CF2

CF3

CF3

C I [130]

i2CF2 CFCF3 + HgCl2 Hg(CF(CF3)2)2

i, KF, (CH2OMe)2, 50�C

[131]

iCF2 CFCF3 + SO2F2

(CF3)2CFSO2F

i, KF, CH3CN, 150�C, Autoclave

[132]

Fi

F E

FE

i, CsF, tetraglyme

E C C E +

E = CO2CH3

[133]



C3F7CF2CF CF2

CsF

diglymeC3F7CF CFCF3

95%

F

CF3

CF3

CF CFCF3

KF, MeCN

18-crown-6

F3C

F3C

CF2CF3

F96%

½135�

½136�

Figure 7.39

F− F

−

FF

F

F2C

F2CF

F

CF2

F

F2C

F2C CF2

F

F

CF2

F

F

F

F2C

F2C CF2

F

F

CF2

F

F

Fi, ii

i, −F− ; ii, Rearrangement

½137�

Figure 7.40

cyclised products, resulting from internal nucleophilic attack by an intermediate carba-

nion [138] (Figure 7.41).

In many thermally induced rearrangements, it is often difficult or impossible to distin-

guish between a thermally induced fluorine-atom shift and the type of fluoride-induced

rearrangement that we have just exemplified. However, evidence for photochemically

induced 1,3-shifts of fluorine in the equilibrium between 7.42A and 7.42B is very

convincing [139] (Figure 7.42).

9 Fluoride-ion-induced oligomerisation reactions

Since fluoroalkenes are so susceptible to nucleophilic attack, we might have expected

anionic polymerisation, initiated by fluoride ion, to occur readily. As we have noted,

fluorocarbanions are readily generated by fluoride-ion attack on fluoroalkenes; these


188 Chapter 7

F− CF2 CFCF2CF CF2+

F2C CF

CF2

CFCF3

F3CF3C

F F

½138�

Figure 7.41

F Fhν

F F

CF2

F F

F F

7.42A

7.42B

95%hν (Photoequilibrium)

½139�

Figure 7.42

carbanions do indeed react further with the original fluoroalkenes but this results in only

short-chain oligomers [56, 57, 92] rather than polymers. This occurs because the

extending carbanion loses fluoride ion (Route A, Figure 7.43), rather than continuing

the propagation step (Route B, Figure 7.43).

F−

+ F etc.

n + 1

B, PropagationA, Elimination of F

−

Fluoroalkenesn + 2

F

n

F ½56, 57, 92�

Figure 7.43

By contrast, anionic polymerisation of hexafluoro-2-butyne (see Section IIB) proceeds

rapidly because elimination of fluoride ion from the propagating anion is difficult, in that

it would require the formation of allenes.

The oligomerisation of tetrafluoroethene [91, 92, 140–142] demonstrates how pro-

cesses like this can be used to build up useful, synthetically more sophisticated systems

from readily available fluoroalkene precursors (Figure 7.44). The product distribution



CF2 CF2 CF3CF2CF2CF2

CF3CF2CF CF2

+F−

SN2'

CF2 CF2F−

C C

CF3

F

CF3

C2F5

CF3CF CFCF3

CF3CF2

C−

CF3

CF2CF3

Tetramer

Pentamer

CF3C2F5

CF3CF3 CF3

F

CF3

C2F5

C2F5

C2F5

CF3CF2

A−F

−

F−

F−

A

B

AB F,

− Dimerisation

½91, 92, 140�42�

Figure 7.44

depends upon the reaction conditions, with higher pressures generally leading to greater

proportions of higher-molecular-weight products [140, 143].

Similar fluoride-ion-induced oligomerisations of hexafluoropropene [143, 144] (in

which only dimers and trimers are formed, due to increased steric hindrance in the propaga-

tion step) and chlorotrifluoroethene [145] have been described. In each of these cases, highly

branched fluoroalkene systems are formed, due to the tendency of the intermediate carba-

nion to lose fluoride ion, giving the most thermodynamically stable fluoroalkene.

‘Mixed’ oligomers can also be produced by fluoride-ion-initiated reaction between two

different fluoroalkenes [146] (Figure 7.45), in which initial fluoride-ion attack occurs on

the most reactive fluoroalkene (section IIC, Subsection 2).

Oligomerisation of fluoroalkenes can also be initiated by tertiary amines, such as

pyridine [147], trimethylamine [148] and tetrakis(dimethylamino)ethylene [149], via

processes that involve either initial ylid formation or the generation in situ of an active

source of fluoride ion.

10 Perfluorocycloalkenes

Perfluorocyclobutene is much more reactive than perfluoro-cyclopentene or -cyclohexene

and this enhanced reactivity is obviously attributable to relief of angle strain on carbanion

formation. Perfluorocyclobutene [147, 150] gives a trimer and an equimolar mixture of


190 Chapter 7

(CF3)3C− CF2 CF2

60%

(CF3)3CCF2C−F2

(CF3)3CCF2CF2CF2C(CF3)2(CF3)3CCF2CF2CF C(CF3)2

+F−

−F−

(CF3)2C CF2

(CF3)2C CF2

−

½146�

Figure 7.45

dimers (see the preceding section) whilst perfluorocyclo-pentene and -hexene give dimers

only [151] (Figure 7.46).

F FF

−F F

−F−

F F F F F FF− F

−

FF

F

A

A

A½151�

Figure 7.46

For the resultant fluorocycloalkene dimers [56, 147], the number of fluorine atoms at

the double bond is not the controlling factor in determining the position of equilibrium. In

Figure 7.47, only 7.47A1 is observed from perfluorocyclohexene, preserving one strain-

free ring, whereas 7.47B2 is formed exclusively from perfluorocyclopentene, thereby

minimising eclipsing interactions. In contrast, equivalent proportions of 7.47C1 and

7.47C2 are formed from perfluorocyclobutene as a result of the reduced angle strain in

7.47C1 over 7.47C2, which compensates for eclipsing interactions.

D Electrophilic attack [152]

In general terms, highly fluorinated alkenes are relatively resistant to attack by the types

of reactant that are normally considered to be electrophilic in character [55, 153–155].

When one or more perfluoroalkyl groups are attached to the double bond, then the system



F−

F F F F

F F

F−

FF F

F F F F

(Not observed)

(Formed exclusively)

(Equimolar mixture)

7.47A1 7.47A2

7.47B1 7.47B2

7.47C1 7.47C2

½56, 147�

Figure 7.47

becomes particularly resistant to electrophilic attack, although hydrofluoroalkenes and

chlorofluoroalkenes will react with quite a range of electrophilic reagents. These effects

correspond to the expected influence of these groups on carbocation stability. Many

reactions are known [55, 154, 155] that involve addition of, for example, halogens,

interhalogen compounds, hydrogen halides and haloalkanes, sometimes in the presence

of Lewis acids, to fluoroalkenes; it is quite probable that many of these involve electro-

philic attack, although other possibilities often arise.

A number of reactions using anhydrous hydrogen fluoride as solvent have been

formulated as involving electrophilic addition of XþF�. Hexafluoropropene is unreactive

towards anhydrous hydrogen fluoride, even at 2008C, but silver fluoride in anhydrous

hydrogen fluoride reacts at 1258C and it has been suggested, therefore, that an initial

electrophilic addition of silver fluoride occurs [156] (Figure 7.48).

AgF CF2 CFCF3 AgCF(CF3)2HF

125�C

HF

HCF(CF3)2 AgF

½156�

Figure 7.48

Mercuric fluoride under similar conditions gives a stable mercurial and it was sug-

gested that strong solvation of fluoride ion, to give HnF�nþ1, inhibits nucleophilic attack by

this fluoride ion but promotes dissociation of metal fluorides, therefore leading to attack

by metal cations [156] (Figure 7.49).


192 Chapter 7

HgF2 nHF+HgF HnF

−n+1 etc

HgF2 2CF2 CFCF3HF85�C

Hg[CF(CF3)2]2 60%

½156�

Figure 7.49

A variety of interesting electrophilic addition processes have been developed, where

additions (where the electrophile is, for example, Cl, Br, I, NO2, 2OCH22,

CH2NH2, CH2OH etc.) to fluoroalkenes are achieved by reaction with a series of

reagents (Table 7.8).

Table 7.8 Electrophilic additions to fluoroalkenes

Reaction Ref.

CF2 CCl2 + HFBF3 CF3CHCl2 + polymer [157]

C

H

C10H21CH CF2 + C2H5COClAlCl3 C10H21 CO.C2H5

CF2Cl

[158]

F FBr C C Br

FF

86%

anti : syn 1:1

C6H5 CF3

+ Br2

C6H5 CF3

[159]

+ HICF2 CH2−20�C

CH3-F2I + polymer [160]

93%i

CF2 CF2 HNO3 CF3CF2NO2

i, HF, 20� C[161]

i76%CF2 CFCF3 HNO3 (CF3)2CFNO2

i, HF, 60� C[154]

63%i

FClC CFCl HNO3 NO2CFClCOOH

i, H2SO4, rt[162]

70%i

H2C CHF + CH3COCl CH3COCH2CHFCl

i, FeCl3, CH2Cl2, 0� C[163]

Contd



The orientations of addition (Table 7.8) are consistent with an electrophilic process

(Figure 7.50), bearing in mind that fluorine attached to positively charged carbon, Cþ2F,

is stabilising whereas fluorine that is b- to the carbocation centre is destabilising (Chapter

4, Section VI).

E+

E-CCl2CF2

E-CF2CCl2

F

F

Cl

Cl

Stabilising

Destabilising

Figure 7.50

Systems with perfluoroalkyl groups directly attached to the double bond are particu-

larly unreactive towards electrophiles but reaction of hexafluoropropene (HFP) with SbF5

leads to a perfluoroallyl cation, which then reacts with another molecule of HFP to give a

dimer, probably by an electrophilic process [168] (Figure 7.51) that is analogous to that

described earlier for 1,1,1-trifluoropropene [169], (Chapter 4, Section VIB). Similar

addition and isomerisation reactions, which proceed via carbocationic intermediates, are

given in Figure 7.52 [170–172].

Addition of sulphur trioxide is an important step in the process for the production of

Nafiont membrane (see Chapter 8, Section IIA) [173]; reaction with chlorotrifluoro-

ethene (CTFE) is not regioselective [174] (Figure 7.53).

Table 7.8 Contd

Reaction Ref.

99%CF2 CFCF3 + IF5/I2 (CF3)2CFI [129]

CF2 CF2 + IF5/I2 86%CF3CF2I [129]

CF2 CXCF3 + BF3/ICl/HF

X = H, F

(CF3)2CXI 60-80%[164]

CF2 CFCl + (CF3)2CO

i, AlClXFY, 100�C

O

F3C

F3C

FCl

FF

98%i

[165, 166]

CF2 CFCF3 + CH2F2

iFCH2CF(CF3)2 90%

i, SbF5, 35−50�C[167]


194 Chapter 7

CF2 CFCF3

SbF5

F

F

F

F

F

CF3-CF CFCF(CF3)2

F

F

FF

F

CF3

F

CF2+

C3F6

F−

shift

F

F

F

CF(CF3)2

F

F−

½168�

Figure 7.51

CF2 CFCF3 CF2 CF2

i, AlCl3, 25� C

F(CF2)2CF CF3 47 %

+ CF2 CF2SbF5F F

CF2CF3

HCF2CF2CF CF2 FCH CFCF2CF3

SbF5

i½170�

½171�

½172�

Figure 7.52

CF2 CF2 SO3O SO2

FF

FF

CF2 CFCl SO3O SO2

FF

FCl

O SO2

FCl

FF

i

i, CTFE bubbled through liq. SO3

½173�

½174�

Figure 7.53

However, sulphur trioxide is also a very strong Lewis acid and reaction with hexa-

fluoropropene proceeds first by fluoride elimination from the allylic position, presumably

via the perfluoroallyl cation [152] (Figure 7.54).

Tetrafluoroallene is interesting in that, in addition to its susceptibility towards nucleo-

philic attack discussed earlier, the compound also reacts readily with anhydrous hydrogen



CF2 CFCF3 SO3 CF2 CFCF2OSO2Fi or ii

i, BF3, 50�C, 6hr, (60%);

ii, B(OMe)3, 35�C, 6hr, (52%)

F2C

FC

CF2 ½152�

Figure 7.54

fluoride and other hydrogen halides, and it has been reasonably concluded that these

reactions probably involve electrophilic attack [175, 176] (Figure 7.55).

CF2 C CF2

i, anhyd. HF, −72 to 20 �C

CF3CH CF2 99%i

½175, 176�

Figure 7.55

E Free-radical additions [177–181]

A generalised free-radical addition process can be described as in Figure 7.56, using the

normal terminology for the various steps.

A BInitiator

A• + B In Initiation

A• +

A

Addition

+ Propagation

A B+ Chain Transfer

A

A

A A B A

Figure 7.56

If the A–B bond is weak and A2B is in sufficiently high proportion with respect to the

alkene, then chain transfer will compete effectively with propagation, allowing overall

free-radical addition of A2B to the double bond to occur preferentially (Figure 7.57).

A B + A BIn

Figure 7.57

Conversely, when the rate of propagation is faster than chain transfer, products arising

from telomerisation and polymerisation are formed in greater concentration. In this

section, free-radical addition to fluoroalkenes will be dealt with first, in order to establish


196 Chapter 7

some ground rules concerning the free-radical addition process, and will be followed by

telomerisation and polymerisation.

1 Orientation of addition and rates of reaction

In contrast to ionic reactions, radical additions to unsymmetrical fluoroalkenes are

frequently bi-directional; factors that affect the rate and orientation of addition depend

on, for example, polar effects, steric effects, radical stabilisation and the character of the

attacking radical [182–185].

Free-radical addition to a double bond is a strongly exothermic process, because a

p-bond is broken and a s-bond is formed and so, according to the Hammond postulate,

early transition states are involved where there is limited bond breaking or making.

Consequently, the influence of polar and steric effects becomes significant, in competition

with the stability of the developing intermediate radical formed, in determining the

orientation and relative rates of addition.

Radicals with ‘nucleophilic’ character add to electrophilic alkenes more rapidly than

to nucleophilic alkenes whilst, conversely, the rate of addition of electrophilic radicals to

electron-rich alkenes is greater than addition to electron-deficient alkenes. To be more

sophisticated, we should refer to a high-SOMO (singly occupied molecular orbital;

nucleophilic) radical interacting favourably with a low-LUMO (lowest unoccupied

molecular orbital; electrophilic) alkene but, for simplicity and brevity, we will continue

to use these ‘short-hand’ terms [177]. For instance, compare rates of addition of perfluor-

oalkyl radicals to ethene and various fluorinated derivatives with their rates of H-atom

abstraction from heptane (Table 7.9) [186]. Broadly, reactivity of the alkene decreases

with fluorine content, with trifluoromethyl having a large effect.

Addition of radicals to unsymmetrical perfluoroakenes could lead to two possible

products (Figure 7.58).

Earlier in this chapter we noted that nucleophiles attack the CF25 site in a fluorinated

alkene exclusively and, in parallel with these observations, nucleophilic radicals, such as

CH3Sl and carbon-centred radicals, give products arising predominantly from attack at

this site (Path 1). Electrophilic radicals such as trifluoromethyl, on the other hand, are less

selective and give a mixture of products (Paths 1 and 2) (Figure 7.58). Examples of the

regiochemistry of addition of trifluoromethyl to a variety of fluorinated alkenes are given

in Table 7.10.

Table 7.9 Relative rates of addition of perfluoroalkyl radicals

to alkenes versus their rates of hydrogen-atom abstraction from

heptane at 508C [186]

Alkene CF:3 C2F:5 C3F:7CH25CH2 132 340 290

CH25CHF 30 108 40

CH25CF2 9 13 —

CHF5CF2 6 9 —

CF25CF2 8 7 <0.3

CF25CFCF3 0.33



2

1 ACF2CFBCF3

BCF2CFACF3CF2CFACF3

ACF2CFCF3

A CF2 CFCF3

AB

AB

A

A

Figure 7.58

A decreasing order of reactivity (towards free-radical addition of methanol) has been

observed [188] in the order CF25CCl2 > CF25CFCl > CFCl5CFCl > CF25CHCl,

and this is largely consistent with expected effects on the relative stabilities of intermedi-

ate radicals after attack at the CF2 sites, where there is a choice. Steric inhibition to attack

accounts for the order CF25CCl2 > CFCl5CFCl.

Frontier orbital theory can also be used to explain the observed rate and orientation

patterns [185]. As we have seen (Section IIC, Subsection 2), vinylic fluorine substituents

do not affect alkene orbital energies that much in relation to hydrogen, whereas perfluoro-

alkyl groups lower LUMO energies considerably. Energies of the SOMO (singly

occupied molecular orbital) of radicals are increased in radicals containing electron-

donating substitutents and so the SOMO (of the attacking radical)–LUMO (of the

alkene) interaction is at a maximum with alkenes containing perfluoroalkyl groups in

reactions with nucleophilic radicals. The coefficients of the LUMO of the alkene can be

used, just as in nucleophilic substitution, to explain the orientation of radical addition. As

we have seen, perfluoroalkyl groups polarise the LUMO in such a way as to increase the

coefficient at the b-carbon (i.e. the CF2 sites in Table 7.11) and so SOMO–LUMO

overlap is greatest at this position.

Many examples of free-radical addition to fluoroalkenes have been recorded; some

examples are listed in Table 7.11.

Table 7.10 Regiochemistry of trifluoromethyl

radical additions to fluoroalkenes: ratio of attack at

A:B (Figure 7.58) [182, 184, 187]

Alkene Ratio

A B A:B

CH25CHF 1:0.09

CH25CF2 1:0.05

CHF5CHF 1:0.05

CH25CHCH3 1:0.1

CH25CðCH3Þ2 1:0.08

CH25CHCH5CH2 1:0.01

CH25CHCF3 1:0.01

CHF5CHCF3 1:0.33

CF25CHCH3 1:50

CF25CHCF3 1:1.5

CF25CFCF3 1:0.25


198 Chapter 7

Table 7.11 Free-radical additions to fluoroalkenes

Reaction Ref.

CF2 CFHg rays

CF2CFH2 CFHCF2H

60% 40%

[189]

i, g rays, or peroxide

CF2CFHCF3

+ CF2 CFCF3

i[45]

(CH3)2CH2 + CF2 CFCF3 (CH3)2CHCF2CFHCF3

CH3CH2CH2CF2CFHCF3

75%

3%i, (t-BuO)2, 140� C

i

[45]

+ CF2 CFCF3

RFH = CF2CFHCF3

36% 59%

RFH

RFH

RFH

RFH

RFH

RFH

RFHi, (t-BuO)2, 140� C

i

[45]

CH3OH + CF2 CFCF3 93%CF3CFHCF2CH2OH

i, (t-BuO)2, 140� C

i[190, 191]

OH

+ CF2 CFCF3

CF2CFHCF3

OH87%

i, (t-BuO)2, 180� C

i

[191]

OH

OH

+ CF2 CFCF3i

HO CF2CFHCF3

CF2CFHCF3OHi, (t-BuO)2, 140� C

[192]

Contd



Table 7.11 Contd

Reaction Ref.

O O CF2CFHCF3

70%+ CF2 CFCF3

i

i, γ rays, or hν

[193–195]

CH3(OCH2CH2)nOCH3 + CF2 CFCF3

RFHCH2[OCH(RFH)CH2]nOCHRFH

RFH = CF2CFHCF3

i, (t-BuO)2, 140 �C

i

[196, 197]

(CH3CH2)2O + [(CF3)2C CHCF2]2

O

RF

RF

F F

CH3

H3C

FF

i

i, γ-rays, rtRF = CH(CF3)2

[198]

O

Fγ ray O

H

F

83%[194]

C H

O

C

O

70%

C3H7 C3H7 CF2CFHCF3+ CF2 CFCF3

i, (C6H5CO2)2, 80� C, 16 h.

i

[190]

Ph C H

O

+ CF2 CFCF3 Ph

O

FCF3

FF

O

+i, (t-BuO)2, 140� C

iCF2CFHCF3

[199]

CHCl3 + CF2 CFCF3

i, 280� C, 116 h

CCl3CF2CFHCF3 [200]

Contd


200 Chapter 7

An interesting process, reminiscent of the Barton reaction, occurs during the radical

addition of 7.59A to HFP [205] (Figure 7.59).

Me

OH

7.59A

Me

OH

CF2CFHCF3

OH

CF2CFHCF3

CH2CF2CFHCF3

F

CF3OH

H

HF

F

F

CF3OH

H

HF

F

Hi

i, CF2 CFCF3

i

H ½205�

Figure 7.59

Table 7.11 Contd

Reaction Ref.

SiH4 + CF2 CFCF3

Hg/hνCF3CHFCF2–SiH3 51%

34%+ F2HC SiH3

F

CF3

[201]

F + HSiCl3

H SiCl3

F 80%hν [201]

F + HSn(CH3)320� C

H Sn(CH3)3

F 94%[202]

+ CF2 CF2 33%(C2H5)2P(O)H (C2H5)2P(O)CF2CF2H

i, (t-BuO)2, 140�C

i

[203]

CF2 CHCl + SF5Br 73%F5SCF2CHClBri

i, 100� C[204]



2 Telomerisation [178, 206]

Telomerisations [207, 208] are regarded as reactions in which a telogen (A2B) and

several molecules of a monomer ðR2C5CR2Þ react to give short-chain products with,

correspondingly, low molecular weights. In these reactions, the propagation step (Figure

7.56) competes with chain transfer, and a number of factors can influence the relative

effectiveness of these two processes.

In all telomerisations, the distribution of molecular weights increases, i.e. n increases

with (a) an increasing rate of free-radical addition to the alkene, (b) a decreasing rate of

the atom-transfer step, i.e. the A2B bond is stronger, (c) a higher concentration of alkene

relative to the telogen and (d) temperature.

As explained earlier in this chapter (Section IIA), the propagation step for the homo-

polymerisation of tetrafluoroethene is approximately 71 kJmol�1 more exothermic than

for ethene [2], in spite of adverse polar effects of fluorine substitution on the addition step.

It is therefore easy to obtain telomers with tetrafluoroethene and this is also the case with,

for example, trifluoroethene, chlorotrifluoroethene and 1,1-difluoroethene.

Many telogens (A2B in Figure 7.56) have been used in these processes, including

perfluoroalkyl iodides [209], a, v-di-iodoperfluoro- [210] and chlorofluoroalkanes

[211], iodine [211], iodine monochloride [212] and perfluoroalkyl bromides [213]. All

of the readily available fluorine-containing ethenes have been used as monomers in

telomerisation reactions for the production of many telomers, some of which have

important commercial applications, e.g. in the synthesis of high-efficiency surfactants

and for fire-fighting foams [214]. With CF3I and CF25CF2, a broad range of telomers is

produced unless a considerable excess of the iodide is employed [215]; but with

ðCF3Þ2CFI as telogen, where the C2I bond is more easily broken [216] (Figure 7.60),

the chain length is more easily controlled.

(CF3)2CFI + CF2=CF2175�C (CF3)2CF(CF2CF2)nI

(4.6 : 1) n = 1 (69%); n = 2 (18%)n = 3 (10%); n = 4 (3%)

½216�

Figure 7.60

The effect of the fluoroalkyl iodide on the telomer distribution is illustrated for

CH25CF2 in Table 7.12, as well as the effect of molar ratio of telogen to alkene and of

the reaction temperature.

Telomers may be used for further transformations and they are often useful ‘model

compounds’ for related polymers, for exploring cross-linking and other processes [217]

(Figure 7.61).

Telomerisation of hexafluoropropene may be achieved using fluoroalkyl iodides as

telogens [218, 219]; this is rather surprising, considering that it is very difficult to achieve

homopolymerisation of hexafluoropropene (Figure 7.62). It has been suggested [218] that

these reactions may not be radical-chain processes but could involve successive four-

centre additions of fluorocarbon iodides to the olefin (Figure 7.63).


202 Chapter 7

(CF3)2CFI CH2 CF2180� C (CF3)2CF(CH2CF2)nI

(CF3)2CF(CH2CF2)nF(CF3)2C CHCF2(CH2CF2)n-1F

SbF5 / 0�C

CsF

130� C

½217�

Figure 7.61

CF2=CFCF3 CF3I CF3 CF2CFCF3 In

n = 1 (47%); n = 2 (23%)n = 3 (19%); n = 4 (8%)n = 5 (4%).

194� C

½218, 219�

Figure 7.62

CF2 I

CF2 CFCF3

RF

Figure 7.63

3 Polymerisation [219a]

Many fluorinated polymers have been prepared using free-radical processes and the

intensity of interest in this field stems from the number of unique properties that are

bestowed on the polymer by the presence of the carbon–fluorine bonds in a system. For

example, excellent resistance to chemically aggressive environments, high thermal sta-

bility, low dielectric constant, low flammability and very low surface energies are just

some of the properties of fluorinated materials that have been exploited. Uses range from

Table 7.12 Telomerisation reactions of 1,1-difluoroethene [216]

Fluoroalkyl

iodide

RFI

Molar ratio

RFI: CH2CF2

Temp.

(8C)

Time

(h)

Conversion

of iodide (%)

Composition of RFðCH2CF2ÞnI

(mol%)

n51 2 3 4 5 6

CF3I 1 : 1 200–210 41 35 46 33 14 5 1 —

C2F5I 1 : 1 190 45 55 92 6 2 — — —

n-C3F7I 1 : 1 200 36 88 70 25 5 — — —

i-C3F7I 1 : 1 185 36 88 90 10 Trace — — —

1 : 1 220 36 90 87 13 Trace — — —

1 : 4 220 36 100 2 21 29 26 18 4



the relatively mundane but important everyday items, like coatings for pans, to crucial

materials for the development of supersonic flight and space travel, but the nature of this

book dictates that only a sample of the materials available can be illustrated here.

The fluorinated ethenes CF25CF2, CF25CFH, CF25CH2, CF25CFCl and CF25CFBr

each form homopolymers in conventional free-radical initiation procedures [220] and it is

notable that the heat of polymerisation for tetrafluoroethene is much greater than for

ethene [2]. Indeed, tetrafluoroethene and trifluoropropene are relatively dangerous mono-

mers to handle because of the risk of explosive polymerisation. In marked contrast, quite

drastic conditions are required in order to form a homopolymer from hexafluoropropene

(HFP) [221], although commercially successful copolymers of CF25CFCF3 with

CF25CF2 (i.e. FEP) and with CF25CH2 (Vitont rubber) have been developed.

Polytetrafluoroethene (PTFE), 2ðCF2CF2Þn2

PTFE is polymerised using conventional initiators [220] to give linear polymers whose

non-stick properties and chemical inertness are now familiar to all. A disadvantage of

PTFE is that it has a very high melt viscosity and cannot be used for melt-processing.

Consequently, copolymers of CF25CF2 and CF25CFCF3 (FEP polymers) are used for

this purpose (Figure 7.64). Also, introduction of a perfluoropropoxy group is a more

expensive solution to the problem, giving perfluoroalkoxy (PFA) resins.

(CF2CF2)x (CF2CF)

CF3

(CF2CF2)x (CF2CF)

OC3F7

FEP PFA

Figure 7.64

Recently, amorphous fluoropolymers have been developed in order to obtain high-

performance materials with optical clarity for microelectronic etching processes. It is

interesting that the monomer perfluoro(2,2-dimethyl-1,3-dioxole) (PDD) (Figure 7.65) is

sufficiently reactive to copolymerise with CF25CF2 to give copolymers with a high

proportion of PDD. This suggests that ether groups, which are isoelectronic with fluorine,

have a similar effect to fluorine on reactivity of alkenes towards radicals (Figure 7.65).

CF CF

O O

CF3F3C

CF2 CF2In

CF CF

O O

CF3F3C

xCF2 CF2

y

Teflon AF®PDD

Figure 7.65

Cytopt (Asahi Glass Co.) is a similar product and is produced by a novel cyclopoly-

merisation process [222] (Figure 7.66). Calculations suggest that the transition states

for forming five-membered rings (Route B) are significantly lower-energy than those for

forming six-membered rings (Route A) and therefore it is likely that polymerisation

occurs by Route A.


204 Chapter 7

CF2 CF O(CF2)2CF CF2

R

Route A O

RCF2 F

R Route B

O

F2CR

CF2

Fetc.

etc.

Polymer

Monomer

Monomer

½222�

Figure 7.66

Polychlorotrifluoroethene (PCTFE), 2ðCF22CFClÞn2

This material melts at 2138C and is therefore melt-processable giving clear films.

Polyvinyl fluoride (PVF), 2ðCH22CHFÞn2

PVF films can be made that adhere to various surfaces and are particularly important as

protective coatings for both indoor and outdoor applications.

Polyvinylidene fluoride (PVDF), 2ðCH2CF2Þn2

This material has excellent mechanical properties and is used extensively as weather

resistant coating for aluminium and various outdoor applications. The piezoelectrical

properties of the material have been exploited in a range of electronic applications [220].

Vinylidene fluoride/HFP copolymersVitont was the first of these important systems to be developed as an elastomer suitable

for use in aggressive environments. Consequently, this and related materials have made a

particularly important contribution to the development of supersonic and space flight. The

raw copolymer itself is quite unstable to the loss of hydrogen fluoride and the final

product is a result of cross-linking and curing processes. These techniques have been the

basis of much study over many years [223].

F Cycloadditions [2, 224, 225]

1 Formation of four-membered rings

One of the most unusual aspects of organofluorine chemistry is the propensity for

fluoroalkenes to form four-membered rings upon dimerisation. For example, tetrafluoro-

ethene dimerises to perfluorocyclobutane, a reaction that is not observed for ethene [226]

(Figure 7.67).

2 CF2 = CF2200�C

FAutoclave

½226�

Figure 7.67



Codimerisation occurs not only between different fluoroalkenes but also between

fluoroalkenes and other unsaturated hydrocarbons. Moreover, some of these codimerisa-

tions proceed more readily than the reactions involving only fluorinated alkenes.

Examples of addition reactions of fluoroalkenes are shown in Table 7.13. Rate constants

have been measured for ½2pþ 2p� and ½2pþ 4p� cycloadditions involving fluorinated

alkenes, employing gas-phase NMR techniques [227].

Table 7.13 Cycloaddition reactions of fluoroalkenes

Reaction Ref.

CF2 CFCl F

Cl

Cl130−250�C (E/Z = 1:1) [228]

CF3CF CF2

CF3

CF3

F3C

F

CF3

(E + Z)

(E + Z)

F

[229]

CF2 C CF2 F

CF2

CF2

[175]

CF2 CF2 CH2 CH2

FF

FF

H

HH

H

40%150�C [230]

CF2 CF2 (CH2 CH )2

FF

FF

H

HH

CH CH2

[230]

CF2 CF2

FF

FF

H

H

35%225�CHC CH [231]

Contd


206 Chapter 7

A particular driving force appears to be the presence of CF25 in the alkene; 1,2-

difluoroalkenes, 2CF5CF2, are much less reactive in this context but examples have

been recorded [235].

Dimerisation of tetrafluoroethene to perfluorocyclobutane takes place at 2008C whilst

the reverse reaction occurs at about 5008C [226]. Activation energies, measured for the

forward and back reactions, indicate that the dimerisation is exothermic by 209 kJmol�1

[236], as compared with approximately 67 kJmol�1 for the hypothetical dimerisation of

ethene, and point to factors which destabilise the fluoroalkene. Similarly, when the DH

values for cyclobutene ring opening for hydrocarbon and fluorocarbon systems were

compared earlier in this chapter (Table 7.4), it was concluded that fluorine attached to a

vinylic carbon atom raises the energy of the system, relative to that for the corresponding

hydrocarbon, leading to a lower bond strength in CF25CF2 than in ethene [36, 237]. In

forming a cyclobutane ring, not only are these repulsive forces removed but, if a CF25

was originally present, then stronger carbon–fluorine bonds are formed in 2CF22.

Therefore, the factors that probably lead to the driving force for fluoroalkenes to dimerise

as in Figure 7.68 are:

2

F

F

F

F

F

F

Figure 7.68

Table 7.13 Contd

Reaction Ref.

CF2 CFCl CH2 CHC6H5

FF

FCl

H

HH

C6H5

100�C [232]

(CF3)2CFC CF <0�C

(CF3)2CF

F

72%

(CF3)2CF

F

18%

[233]

CF2 + 110�C, 7 days

F

F47% [234]



(1) Ip repulsion is relieved.

(2) F atoms are mutually bond strengthening in the product.

(3) Substituents that stabilise di-radical intermediates will activate (see later).

With few exceptions, products are formed which result from a combination of alkenes

in a head-to-head manner, or a correspondingly regiospecific manner in codimerisations

(see Table 7.13). Furthermore, the reactions are not stereospecific.

In considering the mechanism of these reactions it is important to stress that they are

[2pþ 2p] additions, which are formally forbidden as thermally induced [2psþ 2ps]

processes according to the well-established Woodward–Hoffman rules for pericyclic

reactions. Consequently, it is much more likely that these reactions proceed via a pathway

that involves radical intermediates, although concerted processes have been claimed [238].

A process involving di-radical intermediates provides an explanation for the products

obtained in the dimerisation of 1,1-dichlorodifluoroethene (Figure 7.69). The reaction

pathway is governed by the stability of the intermediate di-radical species and, because

chlorine stabilises a radical centre more effectively than fluorine, i.e. compound 7.69B is

more stable than 7.69A, then Pathway B, leading to the head-to-head product, is preferred.

2 CF2 CCl2

CCl2 CF2

CF2 CCl2

7.69A

CF2—CCl2

CF2—CCl2

7.69B

F2

F2

Cl2

Cl2

Pathway A

Pathway B

Figure 7.69

The orientations of other cyclodimerisations may be accounted for in a similar manner

(Table 7.13). However, as the difference in the ability of the substituents at each carbon of

the alkene to stabilise a radical diminishes, then the selectivity of the process is also

reduced. For example, trifluoroethene gives a mixture of products since, in this case, the

stabilities of the two intermediate radicals 7.70C and 7.70D are similar (Figure 7.70).

2 CF2 CFH

CF2—CFH

CF2—CFH

7.70C

CF2—CFH

CFH—CF2

7.70D

H

H

F

H

F

H

(E + Z isomers)

(E + Z isomers)

Figure 7.70


208 Chapter 7

The latter reaction also illustrates that these processes are not stereospecific (see also

Table 7.13). Studies on the formation of four-membered rings by reaction between

tetrafluoroethene and di-deuterioethene led to analogous conclusions and this is further

evidence for the formation of di-radical intermediates [239, 240]. Moreover, reactions

involving alkenes with geminal capto-dative substituents (e.g. 7.71A and 7.71B which

are, of course, especially stabilising for radical intermediates) are both efficient and

regiospecific [241] (Figure 7.71).

CF2 CClSPh CH2 C(CN)t-Bu

SPh

Cl

t-Bu

CN

>

>

<

<

SPh

ClCN

t-Bu

88%

i

i, 120� C, 10hr.

7.71A 7.71B

F2

F2

½241�

Figure 7.71

The energy of the double bond may be raised by other means, e.g. by strain or by

antiaromaticity [224]. Miller, a pioneer in the field of organofluorine chemistry, generated

tetrakis(trifluoromethyl)cyclobutadiene and showed that it reacts to form a tricyclic dimer

[242] which can be converted to the corresponding cubane and cuneane derivatives by

ultraviolet radiation [243] (Figure 7.72).

When the system is appropriately substituted, cycloaddition may even proceed via

zwitterion formation [244] (Figure 7.73).

2 Formation of six-membered rings – Diels–Alder Reactions [245, 246]

In this section we will consider [4 þ 2] cycloaddition reactions in which the fluoroalkene

acts as the dienophile. For related reactions involving fluorinated dienes, see Section

IIG.

Since Diels–Alder reactions are governed by HOMO–LUMO interaction of the diene

and dienophile, we should remind ourselves that vinylic fluorine does not much alter the

orbital energies compared with hydrogen, whilst perfluoroalkyl groups significantly lower

these orbital energies [33]. Consequently, we might expect that vinylic fluorine should

have little effect on reactivity, whereas the introduction of allylic fluorine, especially via

trifluoromethyl groups, should have a significant effect in comparison with the corres-

ponding hydrocarbon analogues.

We have seen (Table 7.13) that in reactions between fluoroalkenes and dienes, [2 þ 2]

cycloaddition as opposed to [4 þ 2] cycloaddition is the dominant reaction [246, 247],

and systematic studies performed on reactions of this type, such as that between

1,1-dichlorodifluoroethene and isoprene, provide a strong case for the intermediacy of



F3C

F3C

CF3

BrF

CF3

F3C

F3C

CF3

CF3

F3C

F3C

CF3 CF3

CF3 CF3

CF3

CF3

F3C

F3C

CF3 CF3

CF3 CF3

CF3

CF2

F

Li, −20� C

hνhν

(CF3)8

300� C 300� C

(CF3)8(CF3)8

300� C

½243�

Figure 7.72

(CF3)2C C(CN)2 CH2 CHOC2H5

(CF3)2C C(CN)2

H2C CH.OC2H5

F3C

F3C

H

H

CN

CNH

OC2H5

95%

½244�

Figure 7.73

di-radicals [248] (Figure 7.74). A methyl group would be expected to make a greater

contribution to the stability of the allyl system in 7.74B than in 7.74A; this is consistent

with the product ratio observed.

Nevertheless, some Diels–Alder reactions between fluoroalkenes and dienes have been

recorded with significant amounts of product derived from Diels–Alder addition when the

diene is in the cis conformation [246, 249] (Figure 7.75).


210 Chapter 7

F2

CF2 — CCl2

Cl2

7.74 A

F2

Cl2

F2

CF2 — CCl2

Cl2

7.74 B

CF2�CCl280� C

+ +

1.6%

15% 83%

+ ½248�

Figure 7.74

+ CF2 CF2475�C F2

F2

+

F2

F2

2 : 1

½246, 249�

Figure 7.75

The thermal addition of trifluoroethene to cyclopentadiene at and below 1228C yields a

1,4-cycloadduct, with less than 0.1% of 1,2-cycloadduct, whereas a photosensitised

reaction between these two reactants (a di-radical process) leads to a product consisting

of 87% of the 1,2-cycloadduct and 13% of the 1,4-cycloadduct [250]. These contrasting

results led to the conclusion that the thermally induced Diels–Alder product arises from a

normal concerted process and it is probable that, in general, whilst the 1,2-cycloadditions

and 1,4-Diels–Alder additions are competing processes, they are mechanistically unre-

lated.

Fluoroalkenes possessing perfluoroalkyl substituents, which reduce the energy of the

frontier orbitals, undergo Diels–Alder reactions, as shown in Figure 7.76 [251, 252].

O

+ CF2 CFCF3

i, 120� C, 16 h., Et2O

O

F F

CF2

F 35%

+ CF3CF CFCF3260� C30 h

CF3F

F

CF342%

i ½251�

½252�

Figure 7.76



Fluoroalkenes that have significant ring strain in the ground state undergo Diels–Alder

reactions much more readily, due to the enhanced relief of this strain upon [4 þ 2]

cycloaddition as opposed to [2 þ 2] addition (Table 7.14)

3 Formation of five-membered rings – 1,3-dipolar cycloaddition reactions

A number of 1,3-dipolar cycloadditions to fluoroalkenes have been reported [245]; some

examples are listed in Table 7.15.

Addition of diazomethane to fluoroalkenes [72] follows the order of reactivity

ðRFÞ2C5CðRFÞ2 > ðRFÞ2C5CFRF > ðRFÞ2C5CF2, RFCF5CFRFðRF ¼ perfluoroalkyl).

In reactions involving unsymmetrical fluoroalkenes the additions are highly regiospecific,

with the carbon atom of the dipole becoming attached to the site most susceptible

Table 7.14 Diels–Alder additions to fluorinated alkenes

Reaction Ref.

80� CF

F

F

72%F [253]

F FO

O F

F OO

F10

H2H2

100%F2

[254]

Cl

F

FMe

Me

170� C, 48 h

Cl

F

F2

F2

89%

Me

Me

[255]

CF2 +

F

F

100�CF

F[256]

100�C+

F

F

F

F

30%F [257]


212 Chapter 7

to nucleophilic attack. These concerted reactions probably proceed with some character of

nucleophilic attack and the orientation of attack can be accounted for in terms of the

frontier orbital approach discussed in Section IIC, Subsection 2 [72] (Figure 7.77).

(RF)2C CF(RF)

NN

CH2

Figure 7.77

Table 7.15 1,3-Dipolar cycloaddition reactions involving fluoroalkenes

Reaction Ref.

CF3

CF3

C2F5

F

+ CH2—N NN

N HH

C2F5FCF3

CF3

94%

i, Et2O, rt

i[72, 258]

CF3

CF3C2F5

C2F5+ CH2—N N

NN HH

CF3C2F5

93%

CF3

i, Et2O, rt

i

C2F5

CF3

CF3

CF3

H

+ CH2—N Ni

NN H

HCF3

CF3 CF3

NN HH

HCF3

CF3 CF3

H

i, Et2O, rt

[198]

CF3

CF3

CF2

N NN CH2Ph

CF3CF3

FFi, 190� C, 16 h

87%+ PhCH2N3

i

[259]

F + CH2—N N N

N

F

F

55%

i, Et2O, rt, 14 days

i[72]



4 Cycloadditions involving heteroatoms

In the light of the foregoing discussion it may be expected that fluoroalkenes participate in

cycloaddition reactions with unsaturated systems containing heteroatoms [260], e.g.

nitroso compounds [261], sulphur trioxide [262], sulphur dioxide [263], nitriles [264]

and so on (Figure 7.78).

CF3NOCF2 CF2

20� C

−45� to 20� C

N O

F3C

F

F

F

F

62%

N

CF3

O CF2 CF2n

64%

RCF CF2 + SO30� C S

C C

O

FR

F F

O O

44%

CF2 CF2 SO2

S O

F

F F

F

O

FCOCF2SOF

80%

i

i, CF2Cl2, N2, hν, −32 to 90� C

CF3CNN

F FCF3

N

F

CF3

40%

R = CH2ClCHClCH2-

½261�

½262�

½263�

½264�

Figure 7.78

G Polyfluorinated conjugated dienes

1 Synthesis

Many of the synthetic approaches that are used for the preparation of fluoroalkenes can be

adopted for the synthesis of polyfluorodienes. Examples of other processes such as

reductive coupling methods and syntheses based on organometallic precursors [265] or

phosphorous ylids are also included in Table 7.16.


214 Chapter 7

Table 7.16 Synthesis of fluorodienes and polymers

Reaction Ref.

Dehydrohalogenation

HCF3

CF3

CF3

CF3CF3

CF3

HCF2

CF2

i, t-BuOK/t-BuOH

i [266]

(CF3)2CFCH2CF2 2i

(CF3)2C CHCF2 2

i, CsF, 150� C, Sealed Tube

70%[267]

Dehalogenation

CF2 CFCF CF2 78%ZnBrCF2CClFCClFCF2Br [268]

CF3

CF3

F

CF2ClCl

F

CF3

CF3

FF

FF

40%

i, Zn, 120� C, diglyme

i[269]

CF3

CF3

CF3CF3

CF3CF3

C2F5

C2F5

FF 90%

Me2NMe2N

NMe2

NMe2

, CH2Cl2, rt

i

i,

[270]

F

F

F

F

i, Na, Hg (0.5% w/w), water cooling

F

F79%i

[270]

O

Cl i

O

(FCl)6

ii

O

F

i, F2, CF2ClCFCl2 ii, Cu Bronze

[271]

Contd



2 Reactions

Fluorinated dienes, like fluoroalkenes, are very susceptible to nucleophilic attack [90, 91];

some examples of nucleophilic substitution processes are given in Table 7.17. Examples

of rearrangements and other reactions are also listed. An early demonstration that

Table 7.16 Contd

Reaction Ref.

Decarboxylation

iCF2 CFCF CF2 25−37%

i, 450� C, 0.01 mm

+

CF2 CF(CF2)2CO2Na

NaO2C(CF2)4CO2Na

[272]

Reductive coupling

I

Cl

F

i, Cu powder, DMF, 135� C

Cl

Cl

F F 75%i

[273]

I

I

F F

F

F

+

FF

F

F

50% 34%i, Cu powder, DMF, 135� C

i[273]

Fhν

F F F

Anti : Syn = 20 : 1

[274]

CF3 CF3CF3

F

F

Cu Ph

F

I

+F

F

F CF3

Ph[265, 275]

CF3CF3

CF3

F

i, PPh3, CH3CN, 25 �C

FF75%

i

[276]


216 Chapter 7

Table 7.17 Reactions of polyfluorinated dienes

Reaction Ref.

Nucleophilic attack

FF58%FF

PhO

OPh

+ PhOH

i, KF, CH3CN, rt

i[73]

F

F

CF3

CF3

CF3

CF3

+ K2SDMFrt

S

72%

(CF3)4

[73]

CF3

CF3

FF

FF

MeOHrt

F

F

CF3

CF3

H

CF2OMe

[269, 279]

F

FMeOH

rt

F

FMeO

MeO

[73]

CF3 CF3

CF2CF2+

OEt

O O

Na+

CF2

F O Me

CO2Et

FCF3

F

i

i, Tetraglyme, rt, 17 h

[280]

FF

CF3

CF3 CF3

CF3

+ t-BuOOH O

F

OCF3

CF3

CF3

CF3

F70%

i, BuLi, THF, −78� C to rt

i

[281]

Rearrangements

F

F

CF3

CF3

F

CF3

CF3

F

F F

F SbF5

0 to 5�CF

[269]

Contd



1,4-cycloadditions of fluorinated dienes may occur involved perfluorocyclo-1,3-hexa-

diene, as shown in Figure 7.79.

F + CH2 CHCO.CH3

HeatF

CO.CH3

HH

½277�

Figure 7.79

The acceptor properties of some cyclic dienes are sufficient for stable charge-transfer

salts to be isolated (Figure 7.80).

F F + [C5Me5]2Fe F F [C5Me5]2Fe+ ½278�

Figure 7.80

3 Perfluoroallenes

Perfluoroallenes are also attacked by nucleophiles and undergo cycloaddition reactions,

as shown in Table 7.18.

III FLUOROALKYNES AND (FLUOROALKYL)ALKYNES

A Introduction and synthesis

Fluorine directly attached to a carbon–carbon triple bond raises the energy of the system

due to repulsion between the p-electrons and the non-bonding electron pairs on fluorine,

as we have discussed earlier (Figure 7.10).

Table 7.17 Contd

Reaction Ref.

CF2

F FCF2

CF2

FF

hν85� C, 5 h

F

F

36%

+ F F

64%

[282]

Cycloadditions

CF2

F2C

F

FF

Ph

H

F

Ph

F CF2

H

Dioxane

60� C

4%

+

38%

HC CCPhF

[283]


218 Chapter 7

Indeed, monofluoroethyne, obtained by the pyrolysis of monofluoromaleic anhydride,

is dangerously explosive whilst difluoroethyne has not been isolated, although claims to

its preparation have been reported [287] (Figure 7.81).

O

O

O

F

650� C1-2mm

+ CO + CO2

F

F

F

HC CF ½287�

Figure 7.81

However, perfluoroalkyl substituents lower the energy of the system; for example,

perfluoropropyne is considerably more stable than the fluoroalkynes referred to above

[288] (Figure 7.82).

Perfluorodialkylalkynes, in which fluorine lone-pair–p-electron repulsions are absent,

are quite stable, and the chemistry of these substrates has been well developed [41, 289–

291]. Perfluoro-2-butyne is the most important member of this class of compounds that

can be obtained by a reasonably direct route [292] (Figure 7.83).

Hexafluoro-2-butyne has also been obtained by routes involving fluoride-ion processes,

such as by using a fluorocarbon ‘solvent’ [53] or by passing perfluorocyclobutene over a

bed of caesium fluoride or potassium fluoride [293] (Figure 7.84).

Table 7.18 Reactions of perfluoroallenes

Reaction Ref.

CF3

C�C�CF2

(CF3)2CF

CsF F

CF3

F

F

CF3

CF3

F3C

F3C

F3C F

F

F

72% 18%

[284]

CF2=C=CF2 + PhCHN2N N

CF2

F

F

Ph

78%i, benzene, rt

i [285]

CF2=C=CF2 +N

N O

H

Ph

63%i, xylene, 120� C

O+ NF

CF3

i N Ph[286]



CF2Br2 + CH2=CF2

i, Bz2O2, 110� C; ii, C, 300C; iii, hν, Br2

ii CF2BrCH=CF2

86%

Zndioxane

CF3CBr=CFBrAlBr3

CF2BrCH2CF2Br

CF2BrCHBrCF2BrCF3C C F

i

iii

½288�

Figure 7.82

CCl2=CClCCl=CCl2

i, SbF3, SbF3Cl2, 115� C

CF3CCl=CClCF3

85%

ii, Zn, (CH3CO)2O, reflux

63%

i

ii

CF3C CCF3

½292�

Figure 7.83

CCl2=CClCCl=CCl2 CF3CH=CFCF3

i ii

i, Fluorocarbon, sulpholan (25% v:v), KFii, Molecular Sieve

56%

F

F CF2

CF2F F

i

i, CsF or KF, 510−590� C, Flow system in N2

80%−90%

CF3C CCF3

CF3C CCF3

½53�

½293�

Figure 7.84

A recent direct route from CF3CH2CF2H (hydrofluorocarbon 245fa) to the lithium salt

now makes the trifluoropropyne ‘building block’ very accessible for many potential

developments [294] (Figure 7.85).

Other syntheses of a variety of fluoroalkynes are given in Table 7.19 where, in many

cases, the synthetic approaches to these compounds can be seen to be adaptations of

methods for the preparation of fluoroalkenes.


220 Chapter 7

CF3CH2CF2H CF3CH=CHF

PhCHO

Ph3SnCl

i

i, ii i, ii

60%

84%

i, n−BuLi ii, −LiF

CF3C CSnPh3

CF3C CCH(OH)Ph CF3C CLi

CF3C CH

½294�

Figure 7.85

Table 7.19 Synthesis of fluoroalkynes

Reaction Ref.

CF2=CH2 90%

i, s-BuLi, −110� C to −80� C

FC CHi

[295]

CF3CH=CICH3 45%CF3C CCH3

i, KF, crown ether, dioxane

i

[296]

C3F7CCl2CCl3HCl

77%

C3F7C CZnCl CF3C CH

i, Zn, DMF, 90−100� C

i

[297]

NN

N

RF

RF RF

hνrt

+

RF = CF(CF3)2

RFC CRF RFC N[298]

+ C6F13I70� C6 h

55%

CH3(CH2)5C CSnMe3 C6H13C CC6H13 [299]

C3F7I +220� C

C3F7CH=CHI

i, C3F7I, 220� C

KOH C3F7CI=CHC3F7

KOHC3H7C CH

C3F7C CC3F7

HC CH

i[300]

Contd



B Reactions

Formation of the lithium derivative of trifluoropropyne was described in the preceding

section [294] and the various acetylides, RFC;CM, had been prepared previously (e.g.

M ¼ Cu, Ag, Hg; RF ¼ CF3, C2F5, CF3CH2) [289]. However, most studies concerning

the reactions of perfluoroalkynes [291] have centred on the use of perfluoro-2-butyne, as

this is commercially available.

1 Perfluoro-2-butyne [289, 291]

Formation of polymers and oligomers: When perfluoro-2-butyne is heated, either

alone or with halogen compounds or a metal carbonyl, hexakis(trifluoromethyl)benzene

is obtained [303–306] (Figure 7.86). This is a very interesting compound that gives

stable valence isomers on irradiation with ultraviolet light (see Chapter 9, Section IIE,

Subsection 4).

F3C

F3C

CF3

CF3

CF3

CF3

hνStable valence isomers

375� CCF3C CCF3 ½303�306�

Figure 7.86

A high-molecular-weight, insoluble polymer is obtained when perfluoro-2-butyne is

subjected to various initiators for free-radical polymerisation (Figure 7.87). The off-white

colour of this material is remarkable for a polyacetylene! [307, 308]. Indeed, it is largely

ignored in discussions on polyacetylenes because, of course, the fact that it is not coloured

also means that the system is not conjugated: the trifluoromethyl groups keep the

p-systems out of plane relative to each other.

Table 7.19 Contd

Reaction Ref.

HO CF3

Cl

Cl

i, Ac2O, Et3N, Zn, DMF; ii, NaNH2, t-BuOH, benzene, rt

CF3

Cl

H

81%

i iip-ClC6H4

p-ClC6H4

p-C6H4C CCF3 [301]

66%

PhC CLi PhC CC8F17

i, THF, −78� C

i+ C8F17IPhOTf

[302]


222 Chapter 7

hνCF3C CCF3 -C(CF3)=C(CF3)-

n½307, 308�

Figure 7.87

Reactions with nucleophiles: The most striking feature about this alkyne is that it is

extremely electrophilic in nature, and electrophilic additions are suppressed whilst

nucleophilic additions proceed with ease in reactions with a wide range of nucleophilic

species (cf. fluoroalkenes) [309, 310] (Figure 7.88).

n–C4H9OH +20� C

89%NaOBu F3C

n-BuO

H

CF3

+ OHNaOH

50� C

OF3C

F3C

F3C

O

CF3

CF3C CCF3

CF3C CCF3

½309�

½310�

Figure 7.88

Fluoride-ion-induced reactions: A similar polymer to that in Figure 7.87 is obtained

upon anionic polymerisation of hexafluoro-2-butyne initiated by fluoride ion in a solvent

[311–313] (Figure 7.89). This is a clear example of an anionic polymerisation of an

unsaturated fluorocarbon, although the growing anion can be trapped by a sufficiently

reactive system [291, 314], such as pentafluoropyridine [315] (Figure 7.90). There is little

difference between the ultraviolet spectra of 7.90A and 7.90B, confirming that conjuga-

tion in the polyene system is inhibited by steric effects.

CF3C CCF3 CF3CF�CCF3

CF3CF�C(CF3)C(CF3)�CCF3

F

C4F6

CF3C�C(CF3)

i

i, CsF, Sulpholan

C4F6 etc.

n

½311�313�

Figure 7.89



FCF3F=CCF3

i

N

Fi =

N

F

F3C

F

CF3

7.90A

N

F

C(CF3)=C(CF3)nF

7.90B

CF3C CCF3

½315�

Figure 7.90

An equivalent polymer is also obtained from perfluorobutadiene in the presence of

fluoride ion; this is a further demonstration of the propensity of systems to rearrange to

reduce the number of fluorine atoms attached to vinyl sites [315, 316] (Figure 7.91).

F CF2=CF2

C(CF3)=C(CF3)n

i, CsF, Sulpholan, 100� C

iiCF3C CCF3 ½315, 316�

Figure 7.91

Cycloadditions [40]: Perfluoro-2-butyne is a highly reactive dienophile and many [4þ 2]

cycloaddition and 1,3-dipolar addition reactions involving this alkyne have been reported

(Table 7.20). Moreover, [2þ 2] additions with hydrocarbon alkenes are possible (Table

7.20).

Table 7.20 Cycloaddition reactions with perfluoro-2-butyne

Reaction Ref.

N

COCH3

+

i, THF, 100� C

N

CF3

CF3

100%

COPh

CF3C CCF3

i[317]

CF3CF3

+ PhN350� C N N

N Ph

80%CF3C CCF3 [318]

Contd


224 Chapter 7

Heptafluoro-2-butene, which is readily available in a laboratory synthesis from hexa-

chlorobutadiene, may be used as a synthon for perfluoro-2-butyne in cycloaddition

reactions where in situ elimination occurs [322] (Figure 7.92).

Reaction with difluorocarbene leads to the formation of novel cyclopropene and

bicyclobutane systems [323] (Figure 7.93), and similar reactions are observed using

polyfluoroalkyne derivatives of some metals [324].

Reactions with sulphur atoms alone give a variety of cyclic products, depending on the

conditions [325], but when iodine is also present the potentially aromatic compound

Table 7.20 Contd

Reaction Ref.

CF3

200� C

10 h

H3C

F3CCH3

CH3H3C

CF3C CCF3 [319]

O

CH3

100� C

6 h

OH

CF3

CF3

CH3 O

CH3

F3C

F3C

CH2=CH2

i ii

i, BF3.Et2O

ii, H2, Pt/C, 400� C

O

H3C

CF3

CF3

CF3C CCF3

[320]

∆

CF3

F3C

Polyacetylene

CF3C CCF3

[321]



CF3CH=CFCF3

CF3

−HF

CF3

CF3

F3C

91%

½322�

Figure 7.92

[CF2]F3C

F3CCF3

CF3

F F

100� C

[CF2]

100� C

F F

F F

25%

CF3C CCF3 ½323�

Figure 7.93

7.94B is produced which is a rare, and probably unique, example of the dithiete system

[326] (Figure 7.94).

CF3

CF3

CF3

S

S I2

S S

F3C

F3C

F3CS

S

S

S

7.94A 11% 7.94B 26%

7.94C 29%

CF3C CCF3

(CF3)4 ½326�

Figure 7.94

Free-radical additions: Free-radical addition reactions involving perfluoro-2-butyne are

also possible, as indicated in Figure 7.95 [327, 328].


226 Chapter 7

H

CF3

CF3

CF3

O30%

γ

220� C7 days

CF3CI�C(CF3)C3F7 68%

Z : E 3 : 4

+CH3CHO

+C3F7I

CF3C CCF3

CF3C CCF3

½327�

½328�

Figure 7.95

REFERENCES

1 G. Sandford, Tetrahedron, 2003, 59, 437.

2 B.E. Smart in The Chemistry of Functional Groups. Supplement D: Fluorocarbons, ed. S. Patai

and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 603.

3 B.E. Smart in Fluorinated Organic Molecules, ed. J.F. Liebman and A. Greenberg, VCH,

Deerfield Beach, 1986, p. 141.

4 D.F. McMillen and D.M. Golden, Ann. Rev. Phys. Chem., 1982, 33, 493.

5 L. Pauling, The Nature of the Chemical Bond, Cornell Univ. Press, Ithaca, NY, 1960.

6 N.C. Baird, Can. J. Chem., 1983, 61, 1567.

7 E.T. McBee, Ind. Eng. Chem., 1947, 19, 237.

8 M. Hudlicky, Chemistry of Organic Fluorine Compounds, Pergamon, Oxford, 1961.

9 T.J. Brice in Fluorine Chemistry, ed. J.H. Simons, Academic Press, New York, 1950, p. 436.

10 J.G. Riess, Chem. Rev., 2001, 101, 2797.

11 R. Taylor, Chemistry – A European Journal, 2001, 7, 4074.

12 W.A. Sheppard and C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969.

13 A.M.G. MacDonald in Comprehensive Analytical Chemistry, Vol. 1B, ed. C.L. Wilson and

D.W. Wilson, Elsevier, London, 1960, p. 547.

14 S. Tasker, R.D. Chambers and J.P.S. Badyal, J. Phys. Chem., 1994, 98, 124421.

15 J.L. Kiplinger and T.G. Richmond, J. Am. Chem. Soc., 1996, 118, 1805.

16 B.K. Bennett, R.G. Harrison and T.G. Richmond, J. Am. Chem. Soc., 1994, 116, 11165.

17 J.A. Marsella, A.G. Gilicinski, A.M. Coughlin and G.P. Pez, J. Org. Chem., 1992, 57, 2856.

18 D.D. MacNicol and C.D. Robertson, Nature, 1988, 332, 59.

19 J. Burdeniuc, W. Chupka and R.H. Crabtree, J. Am. Chem. Soc., 1995, 117, 10119.

20 W.H. Pearlson and L.J. Hals, US Pat. 2 617 836 (1952); Chem. Abstr., 1952, 47, 8770.

21 E.E. Lewis and M.A. Naylor, J. Am. Chem. Soc., 1947, 69, 1968.

22 M. Hudlicky, Chemistry of Organic Fluorine Compounds 2nd (revised) edition, Ellis

Horwood, Chichester, 1992.

23 J. Rabai, S. Zoltan and I.T. Horvath in Handbook of Green Chemistry, ed. J. Clark and

D. Macquarrie, Blackwell Science, Oxford, 2002, p. 502.

24 D.P. Curran, S. Hadida, A. Studer, M. He, S.-Y. Kim, Z. Luo, M. Larhed, A. Hallberg and

B. Linclau, Comb. Chem., 2000, 327.

25 I.T. Horvath, Acc. Chem. Res., 1998, 31, 641.

26 D.F. Foster, D. Gudmunsen, D.J. Adams, A.M. Stuart, E.G. Hope, D.J. Cole-Hamilton,

G.P. Schwarz and P. Pogorzelec, Tetrahedron, 2002, 58, 3901.



27 D.P. Curran, Pharmaceutical News, 2002, 9, 179.

28 D.P. Curran, Actualite Chimique, 2003, 4–5, 67.

29 C.R. Patrick, Adv. Fluorine Chem., 1961, 2, 1.

30 D. Peters, J. Chem. Phys., 1963, 38, 561.

31 P.D. Bartlett and R.C. Wheland, J. Am. Chem. Soc., 1972, 94, 2145.

32 E. Heilbronner in Proceedings of the Institute of Petroleum Conference: Molecular Spectros-copy, 1977, ed. R.S. West.

33 L.N. Domelsmith, K.N. Houk, C. Piedrahita and W.J. Dolbier, J. Am. Chem. Soc., 1978, 100,

6908.

34 J.P. Cheswick, J. Am. Chem. Soc., 1966, 88, 4800.

35 W.R. Dolbier and H. Koroniak in Fluorine-containing Molecules, ed. J.F. Liebman,

A. Greenberg and W.R. Dolbier, VCH, Weinheim, 1988, p. 65.

36 E.C. Wu and A.S. Rodgers, J. Am. Chem. Soc., 1976, 98, 6112.

37 J.M. Pickard and A.S. Rodgers, J. Am. Chem. Soc., 1972, 99, 695.

38 N.C. Craig, L.D. Piper and V.L. Wheeler, J. Phys. Chem., 1971, 75, 1453.

39 D. O’Hagan and H. Rzepa, J. Chem. Soc., 1997, 645.

40 M. Hudlicky, Chemistry of Organic Fluorine Compounds, Ellis Horwood, Chichester, 1992.

41 M.J. Silvester, Aldrichim. Acta, 1995, 28, 45.

42 M.H. Rock in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 56.

43 P.L. Coe, A.W. Mott and J.C. Tatlow, J. Fluorine Chem., 1982, 20, 167.

44 J.C. Tatlow, J. Fluorine Chem., 1995, 75, 7.

45 R.D. Chambers, R.W. Fuss, R.C.H. Spink, M.P. Greehall, A.W. Kenwright, A.S. Batsanov and

J.A.K. Howard, J. Chem. Soc., Perkin Trans. 1, 2000, 1623.

46 S.F. Campbell, F. Lancashire, R. Stephens and J.C. Tatlow, Tetrahedron, 1967, 23, 4435.

47 A.L. Henne and R.P. Ruh, J. Am. Chem. Soc., 1947, 69, 279.

48 D.A. Nelson, US Pat. 2 758 138 (1957); Chem. Abstr., 1957, 51, 3654a.

49 A.T. Morse, P.B. Ayscough and L.C. Leitch, Can. J. Chem., 1955, 33, 453.

50 J.D. LaZerte, L.J. Hals, T.S. Reid and G.H. Smith, J. Am. Chem. Soc., 1953, 75, 4525.


52 R.D. Chambers and A.J. Palmer, Tetrahedron, 1969, 25, 4217.

53 R.D. Chambers and A.R. Edwards, J. Chem. Soc., Perkin Trans. 1, 1997, 3623.

54 S.V. Gangal in Kirk-Othmer Encyclopedia of Chemical Technology, John Wiley, New York,

1994, p. 621.

55 R.D. Chambers and R.H. Mobbs, Adv. Fluorine Chem., 1965, 4, 50.

56 M.R. Bryce and R.D. Chambers in Comprehensive Carbanion Chemistry, Vol. 6, ed. E. Buncel

and T. Durst, Elsevier, Amsterdam, 1987, p. 271.

57 R.D. Chambers and J.F.S. Vaughan in Organofluorine Chemistry: Fluorinated Alkenes andReactive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 1.

58 A.E. Bayliff and R.D. Chambers, J. Chem. Soc., Perkin Trans. 1, 1988, 201.

59 D.W. Wiley, US Pat. 2 988 537 (1961); Chem. Abstr., 1962, 56, 330g.

60 C.G. Krespan, F.A. Van-Catledge and B.E. Smart, J. Am. Chem. Soc., 1984, 106, 5544.

61 C.G. Krespan and B.E. Smart, J. Org. Chem., 1986, 51, 320.

62 K. Ulm in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Baasner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 33.

63 C.M. Timperley in Fluorine Chemistry at the Millennium. Fascinated by Fluorine, ed.

R.E. Banks, Elsevier, Amsterdam, 2000, p. 499.

64 I.N. Rozhkov and Y.A. Borisov, Izv. Acad. Nauk. SSSR, Ser. Khim., 1989, 1801; Chem. Abstr.

1990, 112, 545182z.


228 Chapter 7

65 H.F. Koch in Comprehensive Carbanion Chemistry, ed. E. Buncel and T. Durst, Elsevier,

Amsterdam, 1987, p. 321.

66 H.F. Koch, J.G. Koch, B.D. Donovan, A.G. Toczko and A.J. Kielbania, J. Am. Chem. Soc.,1981, 103, 5417.

67 I.N. Rozhkov, A.A. Stepanov and Y.A. Borisov, Fourth Regular meeting of Soviet–JapaneseFluorine Chemists. Electronic Stucture and Polarographic Reduction Potentials of Olefines,Kiev, 1985, p. 125.

68 R.D. Chambers, A.A. Lindley and H.C. Fielding, J. Fluorine Chem., 1978, 12, 85.

69 I.N. Rozhkov and Y.A. Borisov, Fifth Regular meeting of Soviet–Japanese Fluorine Chemists.

Relative Reactivities of F-Alkenes in Regard to the Hard–Soft Nucleophiles, Tokyo, 1988, p. 75.

70 R.N. Sterlin, V.E. Bogachev, R.D. Yatsenko and I.L. Knunyants, Izv. Akad. Nauk SSSR, Otdel.Khim. Nauk., 1959, 2151; Chem. Abstr., 1960, 54, 108448h.

71 J. Xi-Kui, J.T. Guo-Zhen and Y.-Q. Shi, J. Fluorine Chem., 1987, 37, 405.

72 M.R. Bryce, R.D. Chambers and G. Taylor, J. Chem. Soc., Perkin Trans. 1, 1984, 509.

73 M.W. Briscoe, R.D. Chambers, S.J. Mullins, T. Nakamura and J.F.S. Vaughan, J. Chem. Soc.,Perkin Trans. 1, 1994, 3119.

74 J.D. Park, M.L. Sharrer, W.H. Breen and J.R. Lacher, J. Am. Chem. Soc., 1951, 73, 1329.

75 I.L. Knunyants, L.S. German and B.L. Dyatkin, Izv. Akad. Nauk. SSSR, Otdel. Khim. Nauk,

1956, 1353; Chem. Abstr., 1957, 51, 8037.

76 U. Gross and W. Storek, J. Fluorine Chem., 1984, 26, 457.

77 S. Dixon, J. Org. Chem., 1956, 21, 400.

78 D.D. Coffman, M.S. Raasch, G.W. Rigby, P.L. Barrick and W.E. Hanford, J. Org. Chem.,1949, 14, 747.

79 J.D. LaZerte, US Pat. 2 704 769 (1955); Chem. Abstr., 1956, 50, 2654.

80 I.L. Knunyants, L.S. German and B.L. Dyatkin, Izv. Nauk SSSR, Otdel. Khim. Nauk, 1956,

1353; Chem. Abstr., 1957, 51, 8037.

81 B.L. Dyatkin, L.S. German and I.L. Knunyants, Dokl. Akad. Nauk SSSR, 1957, 114, 320;

Chem. Abstr., 1958, 52, 251.

82 W.T. Miller and A.H. Fainberg, J. Am. Chem. Soc., 1957, 79, 4164.

83 W.T. Miller, J.H. Fried and H. Goldwhite, J. Am. Chem. Soc., 1960, 82, 3091.

84 H.F. Koch and A.J. Kielbania, J. Am. Chem. Soc., 1970, 92, 729.

85 J.D. Park, R.J. McMurtry and J.H. Adams, Fluorine Chem. Rev., 1968, 2, 55.

86 W. Dmowski, J. Fluorine Chem., 1980, 15, 299.

87 Y.V. Zeifman, E.G. Ter-Gabrielyan, N.P. Gambaryan and I.L. Knunyants, Russ. Chem. Rev.,1984, 53, 256.

88 H. Koch in Comprehensive Carbanion Chemistry, Part 5C, ed. E. Buncel and T. Durst,

Elsevier, Amsterdam, 1987, p. 321.

89 R.D. Chambers and M.R. Bryce in Comprehensive Carbanion Chemistry, Part 5C, ed.

E. Buncel and T. Durst, Elsevier, Amsterdam, 1987, p. 271.

90 R.D. Chambers, S.L. Jones, S.J. Mullins, A. Swales, P. Telford and M.L.H. West in SelectiveFluorination in Organic and Bioorganic Chemistry, ed. J.T. Welch, ACS. Symposium Series

456, Washington DC, 1991.

91 R.D. Chambers in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and

G.K.S. Prakash, John Wiley, New York, 1992, p. 359.

92 L.-F. Chen, J. Fluorine Chem., 1994, 67, 95.

93 W.B. Farnham in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and


94 M. Makosza and H. Plenkiewicz, J. Fluorine Chem., 1984, 24, 387.

95 W. Dmowszki, J. Fluorine Chem., 1984, 26, 223.

96 R.D. Chambers, S.R. Korn and G. Sandford, J. Chem. Soc., Perkin Trans. 1, 1994, 71.

97 K. Okuhara, J. Am. Chem. Soc., 1980, 102, 244.



98 A. Vij, R.L. Kirchmeier, J.M. Shreeve, T. Abe, H. Fukaya, E. Hayashi, Y. Hayakawa and

T. Ono, Inorg. Chem., 1993, 32, 5011.

99 P.L. Coe, A. Sellars and J.C. Tatlow, J. Chem. Soc., Perkin Trans. 1, 1985, 2185.

100 M.R. Bryce, R.D. Chambers and J.R. Kirk, J. Chem. Soc., Perkin Trans. 1, 1984, 1391.

101 D.I. Rossman and A.J. Muller, J. Fluorine Chem., 1993, 60, 61.

102 K. Funabiki, E. Murata, Y. Fukushima, M. Matsui and K. Shibata, Tetrahedron, 1999, 55,

4637.

103 V.A. Doroginskii, A.F. Kolmiets and G.A. Sokolskii, Zh. Org. Khim., 1983, 19, 1762; Chem.Abstr., 1983, 99, 212435q.

104 D.J. Burton, S. Shinya and R.D. Howells, J. Am. Chem. Soc., 1979, 101, 3689.

105 D.J. Burton and F.J. Mettille, J. Fluorine Chem., 1982, 20, 157.

106 M.A. Howells, R.D. Howells, N.C. Baenziger and D.J. Burton, J. Am. Chem. Soc., 1973, 95,

5366.

107 C.G. Krespan and D.C. England, J. Org. Chem., 1968, 33, 1850.

108 T. Kitazume, S. Sasaki and N. Ishikawa, J. Fluorine Chem., 1978, 12, 193.

109 G. Camaggi and F. Gozzo, J. Chem. Soc. (C), 1971, 2382.

110 P.W. Jolly, M.I. Bruce and F.G.A. Stone, J. Chem. Soc., 1965, 5830.

111 W. Dmowski, J. Fluorine Chem., 1985, 29, 273.

112 R.D. Chambers, A.A. Lindley, P.D. Philpot, H.C. Fielding, J. Hutchinson and G. Whittaker,

J. Chem. Soc., Perkin Trans. 1, 1979, 214.

113 R.E. Banks and S.M. Hitchen, J. Chem. Soc., Perkin Trans. 1, 1982, 1593.

114 A.E. Bayliff, M.R. Bryce and R.D. Chambers, J. Chem. Soc., Perkin Trans. 1, 1987, 763.

115 J.P. Droske, P.M. Johnson and P.T. Engen, Macromolecules, 1987, 20, 461.

116 C.M. Timperley, J. Fluorine Chem., 1999, 94, 37.

117 W.B. Farnham and M.J. Nappa, US Pat. 5 243 025 (1995); Chem. Abstr., 1994, 120,

324439c.

118 R.D. Chambers and A.J. Roche, J. Fluorine Chem., 1996, 79, 121.

119 A.B. Clayton, J. Roylance, D.R. Sayers, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1965,

7358.

120 R.E. Banks, A. Braithwaite, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc. (C), 1969, 996.

121 W.B. Farnham, Chem. Rev., 1996, 96, 1633.

122 W. Dmowski and R. Wozniacki, J. Fluorine Chem., 1987, 36, 385.

123 N. Ishikawa and S. Shinya, Bull. Chem. Soc. Jpn., 1975, 48, 1339.

124 D.P. Graham and W.B. McCormack, J. Org. Chem., 1966, 31, 958.

125 B.L. Dyatkin, L.G. Zhuravkova, B.I. Martynov, S.R. Sterlin and I.L. Knunyants, Chem.Commun., 1972, 618.

126 Y.V. Ziefman, L.T. Lankseva and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.),1978, 27, 2362.

127 B.L. Dyatkin, S.R. Sterlin, L.G. Zhuravkova, B.L. Martynov, E.I. Mysov and I.L. Knunyants,

Tetrahedron, 1973, 29, 2759.

128 S.I. Pletnev, S.M. Igumnov, E.V. Zakharova and K.N. Makarov, Bull. Acad. Sci. USSR (Div.Chem. Sci.), 1990, 39, 557.


130 A. Probst, K. Raab, K. Ulm and K.V. Werner, J. Fluorine Chem., 1987, 37, 223.

131 B.L. Dyatkin, S.R. Sterlin, B.I. Martynov, E.I. Mysov and I.L. Knunyants, Tetrahedron, 1971,

27, 2843.

132 GB Pat 1 189 562 (1970).

133 R.D. Chambers and M.P. Greenhall, J. Fluorine Chem., 2001, 107, 171.

134 R.D. Chambers, J.A. Jackson, W.K.R. Musgrave and R.A. Storey, J. Chem. Soc. (C), 1968,

2221.

135 T.I. Filyavkova, M.I. Kodess, N.V. Peschanskii, A.Y. Zapevalov and I.P. Kolenko, Zh. Org.Khim., 1987, 23, 1858.


230 Chapter 7

136 M. Ozawa, T. Komatsu and K. Matsuoka, Ger. Pat. 2 706 603 (1977); Chem. Abstr., 1977, 87,

183969m.

137 R.D. Chambers, J.R. Kirk, G. Taylor and R.L. Powell, J. Chem. Soc., Perkin Trans. 1, 1982,

673.

138 R.D. Dresdner, F.N. Tiumac and J.A. Young, J. Org. Chem., 1965, 30, 3524.

139 M.R. Bryce, R.D. Chambers and G. Taylor, J. Chem. Soc., Chem. Commun., 1983, 1457.

140 H.C. Fielding and A.J. Rudge, UK Pat. 1 082 127 (1967); Chem. Abstr., 1967, 66, 55009c.

141 D.P. Graham, J. Org. Chem., 1966, 31, 955.

142 R.D. Chambers, J.A. Jackson, S. Partington, P.D. Philpot and A.C. Young, J. Fluorine Chem.,1975, 6, 5.

143 J.A. Young, Fluorine Chem. Rev., 1967, 1, 359.

144 W. Dmowski, W.T. Flowers and R.N. Haszeldine, J. Fluorine Chem., 1977, 9, 94.

145 R.D. Chambers, A.A. Lindley, P.D. Philpot, H.C. Fielding and J. Hutchinson, Isr. J. Chem.,1978, 17, 150.

146 S.A. Postovoi, E.I. Mysov, Y.V. Ziefman and I.L. Knunyants, Bull. Acad. Sci. USSR (Div.Chem. Sci.), 1982, 31, 1409.

147 R.D. Chambers, G. Taylor and R.L. Powell, J. Chem. Soc., Perkin Trans. 1, 1980, 429.

148 W. Brunskill, W.T. Flowers, R. Gregory and R.N. Haszeldine, J. Chem. Soc., Chem.Commun., 1970, 1444.

149 R.D. Chambers, W.K. Gray and S.R. Korn, Tetrahedron, 1995, 51, 13167.

150 R.D. Chambers, G. Taylor and R.L. Powell, J. Chem. Soc., Perkin Trans. 1, 1980, 426.

151 R.D. Chambers, M.Y. Gribble and E. Marper, J. Chem. Soc., Perkin Trans. 1, 1973, 1710.

152 V.A. Petrov and V.V. Bardin in Organofluorine Chemistry: Fluorinated Alkenes and ReactiveIntermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 39.

153 B.L. Dyatkin, E.P. Mochalina and I.L. Knunyants, Fluorine Chem. Rev., 1969, 3, 45.

154 L.S. German and I.L. Knunyants, Angew. Chem. Int. Ed. Engl., 1969, 8, 349.

155 G.A. Olah and Y.K. Mo, J. Org. Chem., 1972, 37, 1028.

156 W.T. Miller, M.B. Freedman, J.H. Fried and H.F. Kock, J. Am. Chem. Soc., 1961, 83, 4105.

157 A.L. Henne and R.C. Arnold, J. Am. Chem. Soc., 1948, 70, 758.

158 M. Suda, Tetrahedron Lett., 1980, 21, 255.

159 D. Naae, J. Org. Chem., 1980, 45, 1394.

160 C.S. Rondestvedt, J. Org. Chem., 1977, 42, 1985.

161 I.L. Knunyants, L.S. German and I.N. Rozhkov, Bull. Acad. Sci. USSR (Div. Chem. Sci.),1963, 12, 1794.

162 I.V. Martynov, V.I. Uvarov, V.K. Brel, V.I. Anufriev and A.V. Yarkov, Bull. Acad. Sci. USSR(Div. Chem. Sci.), 1989, 2500.

163 N. Ishikawa, H. Iwakiri, K. Edamura and S. Kubota, Bull. Chem. Soc. Japan, 1981, 54, 832.

164 V.A. Petrov and C.G. Krespan, J. Org. Chem., 1996, 61, 9605.

165 V.A. Petrov, J. Org. Chem., 1995, 60, 3419.

166 C.G. Krespan and V.A. Petrov, Chem. Rev., 1996, 96, 3269.

167 G.G. Belen’kii, V.A. Petrov and P.R. Resnick, J. Fluorine Chem., 2001, 108, 15.

168 R.D. Chambers, A. Parkin and R.S. Matthews, J. Chem. Soc., Perkin Trans 1, 1976, 2107.


170 C.G. Krespan and D. Dixon, J. Fluorine Chem., 1996, 77, 117.

171 G.G. Belen’kii, E.P. Lure and L.S. German, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1976,

25, 2208.

172 T.I. Filyakova, G.G. Belenkii, E.P. Lure, A.Y. Zapevalova, I.P. Kalenko and L.S. German,

Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1979, 28, 635.

173 M. Yamabe and H. Miyake in Organofluorine Chemistry. Principles and CommercialApplications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994,

p. 403.

174 E. Gille, D. Hass, H. Holfter and M. Schonherr, J. Fluorine Chem., 1994, 69, 145.



175 R.E. Banks, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc., 1965, 978.

176 R.E. Banks, A. Braithwaite, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc. (C), 1969, 454.

177 W.R. Dolbier in Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates,


178 B. Ameduri and B. Boutevin in Organofluorine Chemistry: Fluorinated Alkenes and ReactiveIntermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 165.

179 N.O. Brace, J. Fluorine Chem., 1999, 93, 1.



182 J.M. Tedder and J.C. Walton, Tetrahedron, 1980, 36, 701.

183 J.M. Tedder, Tetrahedron, 1982, 38, 313.

184 J.M. Tedder, Angew. Chem., Int. Ed. Engl., 1982, 21, 401.

185 B. Giese, Angew. Chem., Int. Ed. Engl., 1983, 22, 753.

186 S.I. Serov, M.V. Zhuravlev, V.P. Sass and S.V. Sokolov, J. Org. Chem. USSR, 1981, 17, 48.

187 J.M. Tedder and J.C. Walton, Acc. Chem. Res., 1976, 9, 183.

188 J. Guiot, B. Amaduri, B. Boutevin and A. Fruchier, New J. Chem., 2002, 26, 1768.

189 R.D. Chambers, A.H.S. Giliani, A.F. Gibert, J. Hutchinson and R.L. Powell, J. FluorineChem., 2000, 106, 53.

190 J.D. LaZerte and R.J. Koshar, J. Am. Chem. Soc., 1955, 77, 910.

191 R.N. Haszeldine, R. Rowland, R.P. Sheppard and A.E. Tipping, J. Fluorine Chem., 1984, 28,

291.

192 R.D. Chambers, P. Diter, S.N. Dunn, C. Farren, G. Sandford, A.S. Batsanov and J.A.K.

Howard, J. Chem. Soc., Perkin Trans. 1, 2000, 1639.

193 R.D. Chambers, B. Grievson and N.M. Kelly, J. Chem. Soc., Perkin Trans. 1, 1985, 2209.

194 R.D. Chambers and B. Grievson, J. Chem. Soc., Perkin Trans. 1, 1985, 2215.

195 O. Paleta, V. Cirkva and J. Kvicala, Czech. Rep. Pat. 282 756 (1997); Chem. Abstr., 1999,

131, 44830y.

196 R.D. Chambers, A.K. Joel and A.J. Rees, J. Fluorine Chem., 2000, 101, 97.

197 R.D. Chambers, J. Hutchinson, N.M. Kelly, A.K. Joel, A.J. Rees and P.T. Telford, Isr.J. Chem., 1999, 39, 133.

198 R.D. Chambers and M. Salisbury, J. Fluorine Chem., 2000, 104, 239.

199 H. Kimoto, H. Muramatsu and K. Inukai, Bull. Chem. Soc. Jpn., 1976, 49, 1642.

200 R.N. Haszeldine, R. Rowland, A.E. Tipping and G. Tyrell, J. Fluorine Chem., 1982, 21, 253.

201 C.J. Attridge, M.G. Barlow, W.I. Bevan, D. Cooper, G.W. Cross, R.N. Haszeldine,

J. Middleton, M.J. Newlands and A.E. Tipping, J. Chem. Soc., Dalton Trans., 1976, 694.

202 W.R. Cullen and G.E. Styan, J. Organometal. Chem., 1966, 6, 633.

203 R.N. Haszeldine, D.L. Hobson and D.R. Taylor, J. Fluorine Chem., 1976, 8, 115.

204 Q.C. Mir, R. Debuhr, C. Hang, H.F. White and G.L. Gard, J. Fluorine Chem., 1980, 16, 373.

205 R.D. Chambers, C. Farren, G. Sandford, D. Yufit and J.A.K. Howard, Z. Anorg. Allg. Chem.,2002, 628, 1857.

206 B. Ameduri, B. Butevin, F. Guida-Pietrasanta and A. Rousseau, J. Fluorine Chem., 2001, 107,

397.

207 C.M. Starks, Free Radical Telomerisation, Academic Press, New York, 1974.

208 B. Boutevin and Y. Pietrasanta in Comprehensive Polymer Science, Vol. 3, ed. G. Allen and

J.C. Bevington, Pergamon, Oxford, 1989, Chapter 14.

209 J. Balague, B. Ameduri, B. Boutevin and G. Caporiccio, J. Fluorine Chem., 1995, 70, 215.

210 A. Manseri, B. Ameduri, B. Boutevin, R.D. Chambers, G. Caporiccio and A.P. Wright,


211 R.D. Chambers, M.P. Greenhall, A.P. Wright and G. Caporiccio, J. Fluorine Chem., 1995, 73,

87.

212 B. Ameduri, B. Boutevin, G.K. Kostov and P. Petrova, J. Fluorine Chem., 1995, 74, 261.

213 R.D. Chambers, L.D. Procter and G. Caporiccio, J. Fluorine Chem., 1995, 70, 241.


232 Chapter 7

214 N.S. Rao and B.E. Baker in Organofluorine Chemistry. Principles and Commercial Applica-tions, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 321.

215 R.N. Haszeldine, J. Fluorine Chem., 1953, 3761.

216 R.D. Chambers, J. Hutchinson, R.H. Mobbs and W.K.R. Musgrave, Tetrahedron, 1964, 20,

497.

217 R.D. Chambers, G.C. Apsey, P. Odello, G. Moggi and W. Navarrini, IUPAC MacromolecularSymposia 82, Fluorinated Polymers, Prague, 1994, ed. J. Kahovec.

218 H. Hauptschein, M. Braid and F.E. Lawlor, J. Am. Chem. Soc., 1957, 79, 2549.

219 J. Balague, B. Ameduri, B. Boutevin and G. Caporiccio, J. Fluorine Chem., 1995, 74, 49.

219a G. Hougham (ed.) Fluoropolymers, Academic/Plenum Publishers, New York, 1999.

220 A.E. Feiring in Organofluorine Chemistry. Principles and Commercial Applications, ed.


221 H.S. Eleuterio, US Pat 2 958 685 (1960); Chem. Abstr., 1961, 55, 6041.

222 M. Nakamura, N. Sugiyama, Y. Etoh, K. Aosaka and J. Endo, J. Chem. Soc. Jpn, Chem. Ind.Chem., 2001, 659.

223 A.L. Logothetis in Organofluorine Chemistry. Principles and Commercial Applications, ed.


224 B.E. Smart in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and

A.E. Pavlath, ACS Monograph 187, Washington DC, 1995, p. 767.

225 M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd (revised) edition, Ellis Hor-

wood, Chichester, 1992.

226 J. Harmon, US Pat. 2 404 374 (1946); Chem. Abstr., 1946, 40, 7234.

227 A.B. Shtarov, P.J. Krusic, B. Smart and W.R. Dolbier, J. Am. Chem. Soc., 2001, 123,

9956.

228 J.D. Park, K.V. Holler and J.R. Lacher, J. Org. Chem., 1960, 25, 990.

229 M. Hauptschein, A.H. Fainberg and M. Braid, J. Am. Chem. Soc., 1958, 80, 842.

230 D.C. Coffman, P.L. Barrick, R.D. Cramer and M.S. Raasch, J. Am. Chem. Soc., 1949, 71, 490.

231 J.L. Anderson, R.E. Putnam and W.H. Sharkey, J. Am. Chem. Soc., 1961, 83, 382.

232 P. Tarrant, R.W. Johnson and W.S. Brey, J. Org. Chem., 1962, 27, 602.

233 R.D. Chambers, T. Sheppard, M. Tamura and M.R. Bryce, J. Chem. Soc., Chem. Commun.,1989, 1657.

234 W.R. Dolbier, M. Seabury, D. Daly and B.E. Smart, J. Org. Chem., 1986, 51, 974.

235 P.D. Bartlett and J.J.B. Mallet, J. Am. Chem. Soc., 1976, 98, 143.

236 B. Atkinson and A.B. Trenwith, J. Chem. Soc., 1953, 2082.

237 S.J. Getty and W.T. Borden, J. Am. Chem. Soc., 1991, 113, 4334.

238 D.W. Roberts, Tetrahedron, 1985, 41, 5529.

239 P.D. Bartlett, G.M. Cohen, S.P. Elliot, K. Hummel, R.A. Minns, C.M. Sharts and

J.Y. Fukunaga, J. Am. Chem. Soc., 1972, 94, 2899.

240 P.D. Bartlett, K. Hummel, S.P. Elliot and R.A. Minns, J. Am. Chem. Soc., 1972, 94, 2898.

241 C. DeCock, S. Piettre, F. Lahousse, Z. Janousek, R. Merenyi and H.G. Viehe, Tetrahedron,

1985, 41, 4183.

242 W.T. Miller, R.J. Hummel and L.F. Pelosi, J. Am. Chem. Soc., 1973, 95, 6850.

243 W.T. Miller and L.F. Pelosi, J. Am. Chem. Soc., 1976, 98, 4311.

244 R. Huisgen and R. Bruckner, Tetrahedron Lett., 1990, 31, 2553.

245 W.R. Dolbier in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and

A.E. Pavlath, ACS Monograph 187, Washington DC, 1995, p. 797.

246 D.R.A. Perry, Fluorine Chem. Rev., 1967, 1, 253.

247 W.H. Sharkey, Fluorine Chem. Rev., 1968, 2, 1.

248 P.D. Bartlett, G.E.H. Wallbillich, A.S. Wingrove, J.S. Swenton, L.K. Montgomery and

B.D. Kramer, J. Am. Chem. Soc., 1968, 90, 2049.

249 J.J. Drysdale, W.W. Gilbert, H.K. Sinclair and W.H. Sharkey, J. Am. Chem. Soc., 1958,

80, 245.



250 P.D. Bartlett, Quart. Rev., 1970, 24, 473.

251 V.A. Albekov, A.F. Benda, A.F. Gontar, G.A. Sokolskii and I.L. Knunyants, Bull. Acad.Sci. USSR (Div. Chem. Sci.), 1988, 37, 777.

252 V.A. Albekov, A.F. Benda, S.G.A. Gontar, and I.L. Knunyants, Bull. Acad. Sci. USSR(Div. Chem. Sci.), 1988, 37, 785.

253 A.E. Bayliff, M.R. Bryce, R.D. Chambers, J.R. Kirk and G. Taylor, J. Chem. Soc., PerkinTrans. 1, 1985, 1191.

254 Y. He, C.P. Junk, J.J. Cawley and D.M. Lemal, J. Am. Chem. Soc., 2003, 125, 5590.

255 D.J. Burton and D.A. Link, J. Fluorine Chem., 1983, 22, 397.

256 B.E. Smart, J. Am. Chem. Soc., 1974, 96, 929.

257 P.B. Sargeant and C.G. Krespan, J. Am. Chem. Soc., 1969, 91, 415.

258 M.R. Bryce, R.D. Chambers and G. Taylor, J. Chem. Soc., Chem. Commun., 1983, 5.

259 Y.V. Zeifman and L.T. Lantseva, Bull. Acad. Sci., USSR, 1986, 35, 248.

260 I.L. Knunyants and G.A. Sokolski, Angew. Chem. Int. Ed. Engl., 1972, 11, 583.

261 D. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 2532.

262 J. Mohtasham, G.L. Gard, Z.Y. Yang and D.J. Burton, J. Fluorine Chem., 1990, 50, 31.

263 A.Y. Yakubovich, S.M. Rozenshstein, S.E. Vasyukov, B.I. Tetel’baum and V.I. Yakutin,

J. Gen. Chem. USSR, 1966, 36, 740.

264 L.P. Anderson, W.J. Feast and W.K.R. Musgrave, J. Chem. Soc. (C), 1969, 2559.

265 D.J. Burton, Z.Y. Yang and P.A. Morken, Tetrahedron, 1994, 50, 2993.

266 G.S. Krashnikova, L.S. German and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.),1973, 22, 459.

267 G. Apsey, R.D. Chambers and M. Salisbury, J. Fluorine Chem., 1988, 40, 261.

268 V. Dedek and Z. Chvatal, J. Fluorine Chem., 1986, 31, 363.

269 V.A. Petrov, G.G. Belenkii and L.S. German, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1981,

30, 1920.

270 M.W. Briscoe, R.D. Chambers, S.J. Mullins, T. Nakamura, J.F.S. Vaughan and F.G. Drake-

smith, J. Chem. Soc., Perkin Trans. 1, 1994, 3115.

271 Y. Lou, Y. He, J.T. Kendall and D.M. Lemal, J. Org. Chem., 2003, 68, 3891.

272 R.N. Haszeldine, J. Chem. Soc., 1954, 4026.

273 R.L. Soulen, S.K. Choi and J.D. Park, J. Fluorine Chem., 1973, 3, 141.

274 D. Lemal in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam,

2000, p. 297.

275 D.J. Burton and S.W. Hansen, J. Am. Chem. Soc., 1986, 108, 4229.

276 A.A. Stepanov, G.Y. Bekker, A.P. Kurbakova, L.A. Leites and I.N. Rozhkov, Bull. Acad. Sci.USSR (Div. Chem. Sci.), 1981, 21, 2746.

277 R.D. Chambers, W.K.R. Musgrave and D.A. Pyke, Chem. Ind., 1964, 564.

278 M.W. Briscoe, R.D. Chambers, W. Clegg, V.C. Gibson, S.J. Mullins and J.F.S. Vaughn,


279 I. Linhart and V. Dedek, Collect. Czech. Chem. Commun., 1985, 50, 1737.

280 M.R. Bryce, R.D. Chambers, A.A. Lindley and H.C. Fielding, J. Chem. Soc., Perkin Trans.1, 1983, 2451.

281 R.D. Chambers, J.F.S. Vaughan and S.J. Mullins, J. Chem. Soc., Chem. Commun., 1995, 629.

282 Z. Chvatal and V. Dedek, J. Fluorine Chem., 1993, 63, 185.

283 N.B. Kazmina, A.P. Kurbakova, L.A. Leitas, B.A. Kvasov and E.J. Mysov, Zh. Org. Khim.,1986, 55, 1500.

284 P.W.L. Bosbury, R. Fields and R.N. Haszeldine, J. Chem. Soc., Perkin Trans. 1, 1978, 422.

285 G.B. Blackwell, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc., Perkin Trans. 1, 1983, 1.

286 G.B. Blackwell, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc., Perkin Trans. 1, 1982,

2207.

287 B.E. Smart in The Chemistry of Functional Groups. Supplement D, Fluorocarbons, ed.

S. Patai and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 613.


234 Chapter 7

288 R.E. Banks, M.G. Barlow, W.D. Davies, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc. (C),1969, 1104.

289 M.I. Bruce and W.R. Cullen, Fluorine Chem. Rev., 1969, 4, 79.

290 H. Muramatsu and K. Inukai, J. Synth. Org. Chem. Jpn., 1973, 31, 466.

291 E.S. Turbanova and A.A. Petrov, Russ. Chem. Rev., 1991, 60, 501.

292 A.L. Henne and W.G. Finnegan, J. Am. Chem. Soc., 1949, 71, 298.

293 R.D. Chambers, C.G.P. Jones, G. Taylor and R.L. Powell, J. Chem. Soc., Chem. Commun.,1979, 964.

294 A.K. Brisdon and I.R. Crossley, J. Chem. Soc., Chem. Commun., 2002, 2420.

295 R. Sauvetre and J.F. Normant, Tetrahedron Lett., 1982, 23, 4325.

296 J.J. Mielcarek, J.G. Morse and K.W. Morse, J. Fluorine Chem., 1978, 12, 321.

297 D.J. Burton and T.D. Spawn, J. Fluorine Chem., 1988, 38, 119.

298 R.D. Chambers, T. Shepherd, M. Tamura and P. Hoare, J. Chem. Soc., Perkin Trans. 1, 1990,

983.

299 S. Matsubara, M. Mitani and K. Utimoto, Tetrahedron Lett., 1987, 28, 5857.


301 G. Meazza, L. Capuzzi and P. Piccardi, Synthesis, 1989, 331.

302 T. Umemoto and Y. Gotoh, Bull. Chem. Soc. Jpn., 1986, 59, 439.

303 H.C. Brown, H.L. Gewanter, D.M. White and W.G. Woods, J. Org. Chem., 1960, 25, 634.

304 H.C. Brown, J. Org. Chem., 1957, 22, 1256.

305 J.F. Harris, R.J. Harder and G.N. Sausen, J. Org. Chem., 1960, 25, 633.

306 J.L. Boston, D.W.A. Sharp and G. Wilkinson, J. Chem. Soc., 1962, 3488.

307 J.F. Harris, US Pat. 2 923 746 (1960); Chem. Abstr., 1962, 54, 9799a.

308 H.C. Brown and H.L. Gewanter, J. Org. Chem., 1960, 25, 2071.

309 R.D. Chambers, C.G.P. Jones, M.J. Silvester and D.B. Speight, J. Fluorine Chem., 1984,

25, 47.

310 C.G. Krespan, Tetrahedron, 1967, 23, 4243.

311 R.D. Chambers, W.K.R. Musgrave and S. Partington, Chem. Commun., 1970, 1050.

312 W.T. Flowers, R.N. Haszeldine and P.G. Marshall, Chem. Commun., 1970, 371.

313 R.D. Chambers and C.G.P. Jones, J. Fluorine Chem., 1981, 17, 581.

314 W.T. Miller, R. Hummel and L.F. Pelosi, J. Am. Chem. Soc., 1973, 95, 6850.

315 R.D. Chambers, S. Partington and D.B. Speight, J. Chem. Soc., Perkin Trans. 1, 1974, 2673.

316 R.D. Chambers, S. Nishimura and G. Sandford, J. Fluorine Chem., 1998, 91, 63.

317 R.W. Kaesler and E. LeGoff, J. Org. Chem., 1982, 47, 4779.

318 N.P. Stepanova, N.A. Orlova, V.A. Galishov, E.S. Turbanova and A.A. Petrov, Zh. Org.Khim., 1985, 51, 979.

319 C.G. Krespan, B.C. McKusick and T.L. Cairns, J. Am. Chem. Soc., 1961, 83, 3428.

320 R.D. Chambers, A.J. Roche and M.H. Rock, J. Chem. Soc., Perkin Trans. 1, 1996, 1095.

321 W.J. Feast in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam,

2000, p. 142.

322 R.D. Chambers and A.R. Edwards, Tetrahedron, 1998, 54, 4949.

323 W. Mahler, J. Am. Chem. Soc., 1962, 84, 4600.

324 W.R. Cullen and M.C. Waldman, Inorg. Nucl. Chem. Lett., 1968, 4, 205.

325 B. Verkoczy, A.G. Sherwood, I. Safarik and O. Strausz, Can. J. Chem., 1983, 61, 2268.

326 C.G. Krespan, J. Am. Chem. Soc., 1961, 83, 3434.

327 R.D. Chambers, C.G.P. Jones and M.J. Silvester, J. Fluorine Chem., 1986, 32, 309.

328 R. Fields, R.N. Haszeldine and I. Kumadaki, J. Chem. Soc., Perkin Trans. 1, 1982, 2221.



Chapter 8

Functional CompoundsContaining Oxygen, Sulphuror Nitrogen and their Derivatives

This chapter contains only a brief survey of the chemistry of a range of derivatives that are

of interest to the organic chemist; further aspects have been discussed in detail and may be

referred to elsewhere [1, 2]. Because of the extreme electronegativity of fluorine and

fluorocarbon groups, the acidities of various functions are increased by introduction of

these groups. Some examples are given in Table 8.1: it is clear that fluorocarbon groups

have a dramatic effect on the acidities of alcohols and carboxylic acids. Moreover, the

CF3SO2 group is one of the most electron-withdrawing groups known [3] and conse-

quently the carbon acid ðCF3SO2Þ2CH2 is more acidic than trifluoroacetic acid. Also, the

sulphonamide ðCF3SO2Þ2NH is a strong acid [4].

Conversely, fluorine or fluorocarbon groups have a major effect in reducing the base

strength of amines, ethers and carbonyl compounds; for example, 2,2,2-trifluoroethylamine

(pKb ¼ 3:3) is ca. 105 times less basic than ethylamine. Also, pentafluoropyridine is only

protonated in strong acid [6], whereas hexafluoroacetone is not protonated even in

superacids [7–9] and perfluorinated tertiary amines and ethers are sufficiently non-basic

for them to be used as inert fluids interchangeably with perfluorocarbons.

I OXYGEN DERIVATIVES

A Carboxylic acids

1 Synthesis

The electrochemical fluorination process [10] (see Chapter 2, Section IVA) is particularly

effective for the synthesis of polyfluoroalkanoic acids and is applied on an industrial

Table 8.1 Acidities of fluorinated systems [3, 5]

Acid pKa

CH3COOH 4.76

CF3COOH 0.52

ðCH3Þ2CHOH 16.1

ðCF3Þ2CHOH 9.3

ðCF3Þ3COH 5.4

ðCF3SO2Þ2CH2 �1.0

ðCF3SO2Þ2NH 1.7



scale, although hydrolysis of chlorofluoroalkanes can also be a useful process [11, 12].

Dicarboxylic acids may be obtained by oxidation of cyclic alkenes; examples are shown

in Table 8.2.

Table 8.2 Preparation of fluorinated carboxylic acids

Reaction Ref.

RCOClE C F RFCOF RFCOOH

H2O

e.g. RF = CF3, C4F9

[13]

CF3CCl3i

CF3COOH

i, SO3, BF3

[14]

C8F17Ii

C7F15COF 83%

i, Fuming H2SO4, PCl5

[15]

CF2=CF2 (CF2)n(COOMe)2i, ii

i, K2S2O8, FeSO4, H2Oii, Esterification

n = 1−11

[16]

CF3(CF2)6I(Br)i

CF3(CF2)5COONa 83%

i, HOCH2SO2Na, NaHCO3, DMF, H2O, 90�C

[17]

(CF2)4(CH2CH2OH)2i

(CF2)4(CH2COOH)2 69−95%

i, CrO3−H2SO4

[18]

H(CF2)6CH2OHi

H(CF2)6COOH 65%

i, HNO3, FeCl2.nH2O[19]

CHF2COF + Br2hν

BrCF2COF [20]

CF2ClCFClCCl3i

CF2ClCFClCOOCl

ii

CF2ClCFClCOOCD3iii

CF2=CFCOOCD3

i, Oleumii, CD3ODiii, Zn

[21]

Contd


Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 237

2 Properties and derivatives

Boiling points of perfluoroalkanoic acids are lower than for corresponding alkanoic acids,

which indicates a significant reduction in intermolecular forces for the fluorocarbon acids.

They are very strong in comparison with other organic acids (see Chapter 4, Section IIIA,

Subsection 1) and, correspondingly, most of the metal salts, e.g. those of trifluoroacetic

acid, are water- and alcohol-soluble whilst the silver salts are soluble in ether and

benzene. Alkali-metal salts of higher acids are used as emulsifying agents.

A range of normal functional-group chemistry may be carried out with perfluoroalk-

anoic acids, little modified by the perfluoroalkyl group [2, 25, 26]. Acid chlorides are

readily obtained with thionyl chloride or phosphorus chlorides and may be converted to

the fluorides using potassium fluoride or, where a volatile product is obtained, by

exchange with benzoyl fluoride (see Chapter 3, Section IIB); anhydrides are produced

by reaction of the acid with phosphorus pentoxide [27]. To illustrate some of the

chemistry of perfluoroalkanoic acids, a selection of reactions is contained in Table 8.3.

Table 8.2 Contd

Reaction Ref.

ClSbF5

X

X

(CF2)4(COOH)2

X = Cl, F

Fi

i, Alk. KMnO4

[22, 23]

O

Cl Cl

O(CF2COOH)2

i, SbF3.SbCl5.

i ii

ii, KMnO4

Cl F

O[24]

Table 8.3 Reactions of perfluoroalkanoic acids and derivatives

Reaction Ref.

OH

O

OH

O

O

O

CF3

i

i, CF3COOH

[28]

Contd


238 Chapter 8

Pyrolysis of alkali-metal salts does not lead to simple decarboxylation but, instead,

elimination of fluoride also occurs; this is a useful synthetic method [36], commercialised

in the synthesis of monomer for the manufacture of Nafiont [37] (Figure 8.1); see

Chapter 7, Section IIB for the preparation of fluoroalkenes.

Decomposition of sodium salts of dicarboxylic acids is more complicated [38]

(Figure 8.2).

Table 8.3 Contd

Reaction Ref.

CF3COOH + C6H5COX CF3COX + C6H5COOH

X = Cl, F

[29]

CF3COONa + POCl3 CF3COCli

i, 100�C, 24 h

90% [30]

CF3COOH + P2O5 (CF3CO)2O[27]

CF3COOC2H5 + NH3 CF3CONH2 99%i

i, (C2H5)2O, 0�C

[31]

C2F5CONH2i

C2F5Br

i, Br2, NaOH[32]

CF3COOC2H5 + NH3 CF3CONH2 99%i

i, (C2H5)2O, 0�C[33]

CF3COOC4H9 + LiAlH4 CF3CH2OH 76%i

i, (C2H5)2O, Reflux

[34]

CF3COCl CF3COCHN2 CF3CH2COOC2H5

i ii

i, CH2N2, 0−20�C; ii, Ag2O, C2H5OH

62% 40%[35]

CF3CONH2 CF3CN 74%i

i, P2O5, 150−200�C

[31]



FCO[CF(CF3)OCF2]2CF2SO2FNa2CO3

Heat

CF2=CFOCF2CF(CF3)OCF2CF2SO2F

CF2=CF2

CF2F2C

O

SO3 FFCOCF2SO2F

OCF2CF2SO2FOCF2CF(CF3)OCF2CF2SO2FHFPO

HFPO

HFPO =O

CF2CF3CFCF2=CF2

Co-polymer

F

SO2

½37�

Figure 8.1

(CF2)4(COONa)2 CF2=CF(CF2)2COONa (CF2=CF-)2

61%

i ii

i, 460�C, 10−2mm ii, 160−450�C, 10−2mm

½38�

Figure 8.2

The Hunsdiecker method has been applied effectively for the replacement of carboxyl

by bromine and iodine [39–42] (Figure 8.3) but on an industrial scale the products are

more effectively obtained by other processes [43]. Routes starting from alkenes are

particularly significant (Figure 8.4). It is important to note that the toxicities of these

iodoalkanes appear to be increased dramatically from that of trifluoroiodomethane, which

is relatively harmless (and has unwisely been considered as a fire-extinguishing agent), to

those of the tertiary iodides, which are dangerously toxic [44].

CF3CO2NaAgNO3

CF3CO2AgI2

HeatCF3I 91% ½40�

Figure 8.3

The particular toxicity of perfluoro-t-butyl iodide is most probably related to the

efficiency of the iodide as a one-electron acceptor in reactions with nucleophilic sites in

the body.

3 Trifluoroacetic acid

The advantages of trifluoroacetic acid as a very strong organic acid have, of course, been

appreciated for a long time; they include its unusual properties as a solvent for kinetic


240 Chapter 8

CF2=CF2

IF5/I2

IF5/I2

C2F5I 86%

CF2=CFCF3

CF2=CFCF3

(CF3)2CFI

(CF3)2CFI

(CF3)3CFI

99%

F

i, KF, I2, CH3CN, 100�C

61%

F CF2=C(CF3)2 61%

i

i, KF, I2, CH3CN, 130�C

i

½45, 46�

½45, 46�

½47�

½48�

Figure 8.4

studies, e.g. for electrophilic aromatic substitution reactions [49] or solvolysis studies

[50]. The acid is a good ionising medium but appears to have a surprisingly low solvating

effect, or nucleophilicity, towards cations, apparently because of the high internal stabil-

isation of the CF3COO� ion. Conversely, the medium is highly efficient in solvating

anions through hydrogen bonding. As a consequence of these effects, trifluoroacetic acid

provides a useful medium for solvolytic reactions of pronounced SN1 character because

this allows inductive and anchimeric assistance effects to play a more important part in

carbocation generation than is observed using more nucleophilic solvents [50]. The acid

may be used as a solvent for promoting the formation of strong electrophiles, e.g. for

nitration. Trifluoroacetamide has been used in an alternative procedure to the Gabriel

synthesis for amines [51] (Figure 8.5).

RX + NaNHCOCF3 RNHCOCF3 RNH2

NaBH4

e.g. RX = n-C8H17I, Yield = 79%

½51�

Figure 8.5

The field of fluorinated amino acids and peptides is already established and recent

developments are important to both chemistry and biology. The reader is directed to an

excellent entry volume [52] and reviews [53].

4 Perfluoroacetic anhydride

The utility of perfluoroacetic anhydride as a medium for promoting esterifications is well

known [54] and, again, is based on the stability of the trifluoroacetate ion (Figure 8.6).

RCOOH + R'OH + (CF3CO)2O

RCOOR' + 2 CF3COOH

½54�

Figure 8.6



It is probable that on addition of a carboxylic acid to the alcohol/anhydride mixture

trifluoroacetic acid is formed, together with a mixed anhydride that is either highly polar

or actually ionised to give an acylium ion in solution (Figure 8.7).

RCOOH + (CF3CO)2O

CF3COO− + RCO

+

CF3COOH + CF3CO.OCOR

Figure 8.7

Esterification of a wide range of compounds has been achieved, often under very mild

conditions. Trifluoroacetates are also formed readily using perfluoroacetic anhydride and

are subsequently easily hydrolysed; consequently the trifluoroacetate group finds

common usage in carbohydrate and peptide chemistry [54] for blocking OH and NH2

groups. The anhydride has been used to form N-(trifluoroacetyl)succinimide, which is

claimed to be a convenient trifluoromethylating agent [55].

5 Peroxytrifluoroacetic acid

The uses of this reagent were developed by Emmons. It is prepared by mixing the

anhydride with 90–95% hydrogen peroxide [56] (Figure 8.8); although a mixture of

hydrogen peroxide and trifluoroacetic acid is sometimes used, it is less effective. It is

claimed that the use of sodium percarbonate and the anhydride is also an effective

methodology [57].

(CF3CO)2O + H2O2 CF3COOH CF3 C

O

O OHδ+δ−

½56�

Figure 8.8

Peroxytrifluoroacetic acid is a powerful peroxy-acid and only the expense of the

reagent inhibits its more widespread use. It will efficiently bring about the oxidations

for which peracids are normally used, such as the Baeyer–Villiger oxidation of ketones to

esters [58] and the conversion of alkenes to glycols [59] or, when a buffer is present, to

epoxides [60] and nitrosamines to nitramines [56, 61]. However, the reagent will also

convert aromatic amines to nitro compounds [62], even with amines containing electron-

withdrawing substituents [63]. Similarly, oxidation of perfluorodibenzothiophene to the

dioxide occurred [64] where other reagents had failed. Peroxytrifluoroacetic acid reacts

with aromatic systems by effecting electrophilic hydroxylation [65] leading to phenols,

quinones or cyclohexadienone derivatives [65, 66], and the efficiency of the reagent is

significantly increased by the addition of boron trifluoride [66] (Figure 8.9).


242 Chapter 8

CF3CO2OH

S

F F

i, CF3COOH, H2O2

S

F

O O

H3C CH3CH3

CH3CH3

CF3CO2OH

H3COH

CF3CO2OH/BF3

O

90%

C6F5NH2 C6F5NO2

i

(CH3)6 (CH3)6

½63�

½64�

½66�

½66�

Figure 8.9

B Aldehydes and ketones

1 Synthesis

Selective fluorination of aldehydes and ketones has been carried out by a variety of

electrophilic procedures [67–70] and enantiomerically enriched forms have been

achieved in a number of cases. A range of polyfluoroalkyl ketones has been synthesised

but, generally, by methods quite distinct from those that would be used to synthesise

corresponding hydrocarbon derivatives. Some examples are given in Table 8.4. Hexa-

fluoroacetone [67] and chlorofluoroacetones are commercially available and are made by

exchange of chlorine in hexachloroacetone by fluorine, using a Cr(V) or Cr(III) catalyst,

and fluoral, CF3CHO, has also been made on a commercial scale by analogous catalytic

processes, starting with chloral, CCl3CHO [71]. Preparations of trifluoromethyl ketones

have been reviewed [72].

2 Reactions [93–96]

The carbonyl group in a perfluorinated ketone is clearly very electron-deficient and this

feature dominates the chemistry of these compounds. It is reflected in, for example, the

rise in vibrational frequency of the carbonyl group in polyfluoro-ketones [97, 98] from

normal values and by the fact that hexafluoroacetone is not protonated in the superacidic

FSO3H=SbF5 mixture [8].



Table 8.4 Syntheses of perfluorinated aldehydes and ketones

Reaction Ref.

CF3CHBrCli

(CF3CHSO3)ii

CF3CHO

i, Oleum, HgO, reflux; ii, H2O

[73]

CF3Br

i, Electrochem. Red'n, DMF, Bu4NBr, Al anode, Lewis acid or Me3SiCl (trace).

ii, (CH3CO)2O, HCl, Pyridine

i, iiCF3CH(OCOCH3)2 ca. quant.

[74]

RF(CF2)nCOOH RF(CF2)nCH(OH)2 CF3(CF2)nCHOi, ii iii

i, LiAlH4; ii, H2SO4; iii, P2O5 n = 0, 1, 2

[75]

i, Swern Oxidation or Pyridinium Chlorochromate

RF(CH2)nCH2OHi

RF(CH2)nCHOF

R'F

CHO

H

RF = C4F9, R'F = C3F7, n = 1−4

[76]

FCO(CF2)3COF CF2=CFCF3

i, CH3CN, KHF2, 120−125 �C

(CF3)2CFCO(CF2)3COCF(CF3)2

75% Conversion

i[77]

CF3CF2CF=C(OMe)CF3SbF5 CF3CF=CFCOCF3

[78]

FCO(CF2)nCOF Me3SiCF3 CF3CO(CF2)nCOCF3

i, ii

i, KF; ii, Heat, Vacuum

n = 2,3 (ca. 90%)[79]

(C2H5O)2CO (n-C3F7)2CO

88%

(n-C3F7)2C(OH)2P2O5

[80]

CF3CCl=CClCF3

i, CrO3, fum. H2SO4, 60−70�C, 1.5 h

CF3COCOCF3

31%

i

[81]

Contd


244 Chapter 8

Table 8.4 Contd

Reaction Ref.

OF

F3C F

F

Cr2O3 or Al2O3 (CF3)2CO [82, 83]

OF F

i, CsF, Pt, 150−300�C, 1.5h, 300�C, 2h

Oi

[84]

CF2=CF2 CF2=CFOCH3

OCH3175�C

F

H2SO4

OH

F OHP2O5

HeatF

O

[85]

(CF2)n

F

F

OCH3 (CF2)n

OCH3

F

CoF3 (CF2)n

F

F

OCH3

F

H2SO4

(CF2)n

OH

F

OH

F

P2O5(CF2)n

F

F

O

[86, 87]

CF2=C(CF3)2 (CF3)2CHCOOH (CF3)2C=C=OH2O

THF

P2O5

77%[88]

RF C

OH

H

CF=CF2

Br2 RF C

OH

H

CFBrCF2Br

Na2Cr2O7.2H2OH2SO4

RFCOCFBrCF2Br RFCOCF=CF2

Zn/Dioxane

RF = CF3; C2F5

[89]

Contd



Addition to C5O: Synthesis of homochiral systems is an important aim [99, 100] and the

steric requirements of hexafluoroacetone may lead to quite different stereochemical

outcomes from other carbonyl systems [101] (Figure 8.10).

X CO CH2CH3

iX

Et2BO

H

CH3 ii

Re

X

O OHCF3

CF3

i, Et2BOTf, i-Pr2NEt, −5�C, 30min.

ii, (CF3)2CO, −78 to 5�CX =

NSO2

½101�

Figure 8.10

Because of the ready reaction of fluorinated ketones with nucleophiles there is

a considerable literature on this subject, although it is dominated by that of hexafluoro-

acetone. Burger and co-workers have prepared a variety of heterodienes, 8.11A

(Figure 8.11), from hexafluoroacetone and developed an extensive chemistry of these

derivatives, especially the formation of heterocycles [95, 96].

A significant feature in this chemistry is the presence of low-lying HOMOs in

the heterodienes; this has made possible a range of cycloaddition reactions [95, 96]

Table 8.4 Contd

Reaction Ref.

C

F3C OH

C CF

OF

F

iC

F3C OH

CF2

i, Nitrobenzene, 200�C

CF2HCOCF3

45%

NaO

[90]

C6F13(CH2)2Ii, ii

RFCO(CH2)2C6F13

i, t-BuLi, −78�C

ii, RFCO2Et, −78�C

RF = CF3 (89%)RF = C7F15 (68%)

[91]

RFCOCl + (i-Pr)3SiH RFCHO + (i-Pr)3SiCli

i, Pd/C, 25 to 30�C RF = C7F15 90%RF = n-C3F7 60%

[92]


246 Chapter 8

R1 X

YC(CF3)2

X = O, S, NR2

Y = N, CH

8.11A

e.g. (CF3)2CO

R1 NR2

NH2

R1 NR2 NR2

HNC(CF3)2OH

R1

NC(CF3)2

i

i, POCl3, Pyridine

80−90%

(CF3)2CO

R1 NH

CNON

F3C CF3

R1 NH

i

i, Et2O, −30�C - room temp.

75−84%

R1 = CH3, CH(CH3)2

½95, 96�

Figure 8.11

(Figure 8.12). The heterodienes are useful traps for a variety of reactive intermediates and

they are good one-electron acceptors. For example, reaction with SnCl2 leads to defluor-

ination and cyclisation [95] (Figure 8.13).

R1 NR2

NC(CF3)2

C NR3N

F3C CF3

R1

NR2

NR3

77−93%

i

i, Toluene, 50−70�C, 24−36 hr.

½95, 96�

Figure 8.12

SnCl2

R1 X

NC(CF3)2

X = O, S, NR2

R1 X

NC=CF2

F3CF3C

N

X R1F

− F

SnCl2F2

½95�

Figure 8.13



Hexafluoroacetone reacts with amino acids to give heterocyclic systems (Figure 8.14)

which are highly volatile and may be used for GLC analysis. They also show potential for

synthesis of natural and unnatural amino acids [96, 102].

OHN

HOOCO

F3C CF3

½96, 102�

Figure 8.14

Addition of amino compounds to hexafluoroacetone occurs very readily indeed, but

subsequent dehydration to form, for example, oximes or semicarbazones from the corres-

ponding adducts does not normally occur. Special procedures usually have to be

employed, the most effective being elimination of amines from adducts to form imines

that are derived from the ketone, as illustrated in Figure 8.15.

(CF3)2C=NPh + H2NNHCONH2 (CF3)2CNHNHCONH2

NHPh

∆ or HCl (− PhNH2)

(CF3)2C=NNHCONH2

½103, 104�

Figure 8.15

Haloform-type cleavage of fluoro-ketones occurs in the presence of excess base

but intermediate metal salts of the gem-diols can be isolated in some cases [105]

(Figure 8.16).

MOH + (RF)2CO C

OM

RF

RF

OH

RFCOOM + RFH ½105�

Figure 8.16

Reaction of hexafluoroacetone with water occurs exothermically to give a stable solid

gem-diol that is acidic (pKa ¼ 6:58) [94], or a liquid sesquihydrate; an adduct is formed

with hydrogen peroxide that functions as a peroxy-acid [106] and, on thermal decom-

position, gives the interesting peroxide CF3OOH [93, 107]. Reaction of CF3COCH3

with 30% hydrogen peroxide gave a stable tetroxane [108] (Figure 8.17). In recent

developments, the hydrogen peroxide is generated in situ, in a catalytic process using

N-hydroxyphthalimide and oxygen, in the presence of hexafluoroacetone or its hydrate.

The system is useful for epoxidation of alkenes, which occurs in a regio- and stereo-

selective manner [109]. Also, the use of Oxonet (KHSO5 � KHSO4 � K2SO4) with

CF3COC6H13, in aqueous ðCF3Þ2CHOH as solvent, has been developed [91]. Oxonet


248 Chapter 8

in combination with ðCF3Þ2CO is a very powerful oxidant, proceeding by the intermediate

formation of the corresponding dioxirane [110] (Figure 8.18). Catalytic diastereoselective

epoxidation of chiral allylic alcohols, using hexafluoroacetone hydrates, has also been

reported [111]. Some additions are shown in Figure 8.19.

CF3COCH3 + H2O2O

O O

O

F3C

F3C

CH3

CH3

½108�

Figure 8.17

CF3COCF3 C

O

O

Oxidation reactions

F3C

F3C

½110�

Figure 8.18

CF3COCF3

CF3COCF3

(CF3)2C(OH)2H2O

H2O2 (CF3)2C(OH)OOH

∆

CF3COOH

CF3COCF3H2S (CF3)2C(OH)SH

½112�

½106, 107�

½113�

Figure 8.19

Even though protonation of hexafluoroacetone has not been observed, reaction with

aromatic compounds may be achieved in the presence of Lewis acids, suggesting at least

some degree of co-ordination of the Lewis acid [93]. The orientation of substitution

depends on the catalyst but, using weaker systems, e.g. boron trifluoride or hydrogen

fluoride, the cross-linking agent bisphenol AF is obtained (Figure 8.20).

Wittig reagents, including apparently even the normally unreactive derivatives, give

the corresponding alkene derivative on reaction with hexafluoroacetone [114], as for

example in Figure 8.21. Unusually, intermediates may be isolated; these may then be

converted to the alkene by gentle heating [115, 116].



OH

CF3COCF3 HO C(CF3)2 OHi

i, BF3, or HF

½93�

Figure 8.20

CF3COCF3 + (C6H5)3P=CHCOCH3 (CF3)2C=CHCOCH3 ½114�

Figure 8.21

Some unusual reactions can occur between fluorinated ketones and trialkylphosphines

[117] or trialkylphosphites [118] (Figure 8.22).

C6H5COCF3 + (n-C4H9)3PC6H5

CF3C

CH

(CH2)2CH3

(C2F5)2CO + P(OC2H5)3 C2F5C(OC2H5)=CFCF3

+ FPO(C2H5)2

½117�

½118�

Figure 8.22

Uncatalysed reactions with alkenes or alkynes will occur and cycloaddition products

may be obtained (Figure 8.23).

(C2F5)2CO + CH2=C(CH3)C(CH3)=CH2

O

C2F5

C2F5

H3C

H3C

100−200�C

F

O

CH2=CH CH=CH2

CH2 CH=CH2

OHF

½119�

½85�

Figure 8.23

Carbonyl groups are normally resistant to radical attack but fluorinated ketones appear

to be exceptional in that an extensive free-radical chemistry is possible [93] (Figure 8.24).

Copolymers are obtained by free-radical copolymerisation of hexafluoroacetone with,

for example, alkenes, tetrafluoroethene and epoxides.

Highly fluorinated ketones show some unusual keto–enol phenomena [122]. Remark-

ably, the pair 8.25A and 8.25B in Figure 8.25 cannot be equilibrated by acid or base;

the enol 8.25A, for example, can be distilled from concentrated sulphuric acid. In the

presence of base, aldol condensation occurs faster than equilibration.


250 Chapter 8

(CF3)2CO + (CH3)2CHOH (CF3)2COH (CF3)2CHOH2

(CF3)2CO + CCl3SiH

(CF3)2CO

hν

hν

hν

(CF3)2CHOSiCl3

OC(CF3)2H C(CF3)2OH

C(CF3)2OH

C(CF3)2OH

½120�

½121�

½93�

Figure 8.24

2 CF2=C(OH)CF3

Slow

CF2HCOCF3

CF2 C

O

CF3

CF3COCF2C(CF3)(CF2H)OH

8.25A

8.25B

8.25C 8.25B

Fast

8.25C

Base½122�

Figure 8.25

Clearly, the tautomerism is inhibited by a kinetic barrier and this could be the relative

instability of the anion 8.25C, where electron-pair repulsion involving non-bonding pairs

on fluorine could be significant. Enols of cyclic systems are also unusually stable [123]

and the equilibrium constant depends on the solvent (Figure 8.26).

F F

OCH2Ph

F

OH

Stable in THF

½123�

Figure 8.26

Reactions with fluoride ion: With the exception of CF3OH (see the next section),

fluorinated alcohols of the type RFCF2OH are not known [124] but complexes of

K, Rb, Cs, Ag or ðC2H5Þ4Nþ fluorides with hexafluoroacetone have been isolated [125,

126], following from the earlier isolation of some similar complexes with carbonyl

fluoride [127]. These complexes have been reasonably formulated as fluorinated alkox-

ides (Figure 8.27), but the use of these salts in synthesis is often difficult because the

complexes may also act as fluoride-ion donors [128].



MF + (CF3)2CO (CF3)2CFOM

Figure 8.27

More stable complexes have been obtained by using ‘TAS’ fluoride [129], and X-ray

data on the salt (8.28A) are quite revealing (Figure 8.28). Carbon–fluorine bonds are

exceptionally long in CF3O� while the C–O distance is quite short; these observations

have been advanced as evidence for negative hyperconjugation (Chapter 4, Section IIIB)

(Figure 8.29).

COF2 + (Me2N)3S+Me3SiF2

− THF

−75�CCF3O

− (Me2N)3S

+

8.28A'TAS' fluoride

½129�

Figure 8.28

CF3 O−

F− CF2=O

Figure 8.29

Other stable alkoxide salts have been prepared [130] using hexamethylpiperidinium

fluoride, and X-ray structural data for these systems are also consistent with negative

hyperconjugation (Figure 8.30).

N F−

(CF3)2C=O (CF3)2CF O−

N

½130�

Figure 8.30

Reaction of a mixture containing hexafluoroacetone and caesium fluoride with allyl

bromide or chloride occurs readily [131, 132] (Figure 8.31) but the mixture does not react

with trimethylchlorosilane [131].

(CF3)2CO + CH2=CHCH2Br CH2=CHCH2OCF(CF3)2

i, CsF, Diglyme, 55�C, 12hr

i

½131, 132�

Figure 8.31

Difficulties undoubtedly arise because perfluorinated alkoxides are very weak nucleo-

philes but they are also potentially fluoride-ion donors and therefore, at the temperatures

necessary for reaction, the alkoxides are probably significantly dissociated and conse-

quently undergo competing side-reactions. Perfluoro-esters RFCO2R1F have been made

[133] in reactions using ðRFÞ2CFOM carried out at low temperatures, with the products

being isolated before they are allowed to warm up. Otherwise, fluoride ion attacks the

ester itself, giving the reverse reactions, because (it must be remembered) the correspond-

ing alkoxide ion RFO� will be quite a good leaving group in a nucleophilic displacement

process (Figure 8.32).


252 Chapter 8

(CF3)2CO + MF RFCO2CF(CF3)2 + F−RFCOF

−78�C½133�

Figure 8.32

Likewise, perfluoroalkoxytriazines may be isolated at low temperatures [134] (Figure

8.33).

(CF3)2CON N

N

ClN N

NRF RF

RF

RF = OCF(CF3)2

KF½134�

Figure 8.33

Perfluoroalkoxyanions are also generated by reaction of fluoride ion with acid fluorides

and with epoxides (see Section IIIB, below). Reaction of the ðCF3Þ2CO�CsF complex

with tetrafluoroethene [135] gives alkoxide 8.34A, not a carbanion 8.34B (Figure 8.34).

In the presence of iodine, however, ethers are formed [126], indicating the formation of

intermediate hypoiodites, RFOI (Figure 8.35).

CF2=CF2 + F− + (CF3)2CO

CF3CF2−

(CF3)2CO

(CF3)2CFO

CF2=CF2

CF3CF2C(CF3)2O−

(CF3)2CFOCF2CF2 etc

8.34A 8.34B

½135�

Figure 8.34

CF2=CF2 + (CF3)2CO + KF + I2 (CF3)2CFOCF2CF2I

ca. 98% yield17% conversion

½126�

Figure 8.35

A hypochlorite has been obtained by reaction of ðCF3Þ3COH with ClF at low tempera-

ture [136]. In an analogous way, hypofluorites may be formed by reactions of intermedi-

ate perfluoroalkoxide ions with elemental fluorine; this chemistry is being exploited in

industry for the manufacture of important monomers [137] (Figure 8.36).



CO CF3OF CF3OCFClCF2Cl

CF3OCF=CF2CF3CF2CF2OF

C3F7OCFClCF2Cl C3F7OCF=CF2

i, ii iii

∆i, iiCF3CF2CF=O

iii

i, F2ii, MF (M = K, Rb, Cs), −78�Ciii, CFCl=CFCl

½137�

Figure 8.36

It appears that hypofluorite formation occurs by nucleophilic attack via the very weakly

nucleophilic perfluoroalkoxide ions on elemental fluorine, regenerating fluoride ion,

because the process is catalytic in alkali-metal fluoride (Figure 8.37).

F + RFCF=O RFCF2O + F RFCF2OF + FF

Figure 8.37

Hypofluorites are also formed by similar catalytic formation of perfluoroalkoxide ions

from the corresponding oxiranes (Figure 8.38).

CF3CF CF2

OCF3CF2CF2OFF

F2F ½137�

Figure 8.38

The chemistry of fluorinated 1,3-diketones has been reviewed [138].

C Perfluoro-alcohols

1 Monohydric alcohols

The 2CF2OH system is thermodynamically unstable, by an estimated 80�160 kJmol�1,

with respect to formation of C5O and hydrogen fluoride. Nevertheless, a remarkable

low-temperature synthesis of trifluoromethanol [139] led to a system that is sufficiently

kinetically stable at low temperatures to be characterised, and a gas-phase IR spectrum

has been obtained (Figure 8.39).

CF3OCl + HCl CF3OH + Cl2−120�C ½139�

Figure 8.39


254 Chapter 8

The driving force for forming C5O via elimination of hydrogen fluoride is much

reduced in strained systems, and therefore the alcohols in Figure 8.40 are more stable

[140]. Systems of the form RFCH2OH are, however, quite stable and are extremely useful

solvents [141] because of their high polarity [142].

O

HX

OH

X

X = F, Cl, Br, I

½140�

Figure 8.40

Perfluoro-t-alcohols are quite stable and are very strongly acidic; for example, compare

ðCF3Þ3OH and ðCH3Þ3OH which have pKa values of 5.4 and 19.0 respectively [143,

144]); see Chapter 4, Section IIA. Perfluoro-t-butanol is obtained most easily from

hexafluoroacetone when it is heated with caesium fluoride in diglyme containing traces

of moisture [145] (Figure 8.41). The first stage involves a carbanion transfer and can be

formulated in a manner similar to the benzil–benzilic acid rearrangement although it

occurs, in this case, by an intermolecular process (Figure 8.42).

(CF3)2CO CF3COF + (CF3)3COCs (CF3)3COH

34%i, CsF, 150�C, Diglyme. ii, H2SO4

iii

½145�

Figure 8.41

(CF3)2COCsF

CF3

CF3 CF3 CF3

CF3CF

O

Cs

O

CF

O O

C(CF3)3

Cs δ−δ−δ+ δ+

C

Figure 8.42

Some other routes to fluorinated alcohols are shown in Figure 8.43a.

Trifluoroethanol has become a much-used ‘building-block’ [150] for a wide range of

synthetic procedures (see also Chapter 6, Section II) (Figure 8.43b), and sigmatropic

rearrangements have been exploited to move the fluorine labels to ‘internal’ sites [151].

2 Dihydric alcohols

Perfluorinated ketones form stable hydrates, ðRFÞ2CðOHÞ2, and these diols are very

acidic. Hexafluoroacetone hydrate is known to be a very good solvent and is particularly

useful for certain polymers [112, 152]. Perfluoropinacol may be obtained from

hexafluoroacetone by photolytic reduction (Figure 8.44), whilst classical reduction with

magnesium amalgam gives only low yields [112]. The same pinacol is also obtained by

heating 8.44A, which is produced as shown in Figure 8.44 [153].



CCl3Li + (CF3)2CO (CF3)2C(CCl3)OH (CF3)3OHi, ii iii

50% 60%i, THF, −100�Cii, H2SO4iii, SbF5

CF3CH2Cl + H2O CF3CH2OHi

i, 400−500�C, Catalyst

CH3OH + CF2=CF2

hνHCF2CH2OH

(CF3)2CO

CH2 HX XCH2C(CF3)2OH

X = FSO2O, CF3SO2O, Cl, I

½146�

½147�

½148�

½149�

Figure 8.43a

CF3CH2OTs CF2=C

CF2=C

CF2=C

CF2=C

i

1,2 shift

ii

i, n-BuLi ii, R3Biii, CuI, HMPA

Li

iii

CF3CH2OMEM

MEM = CH2OCH2CH2OCH3

F

F

OMEM

OH

i, ii F

F

OMEM

O

F

F

OMEM

O

F OMEMO

iii

i, LDA, THF, −78�C; ii, EtCHO; iii, Hg(OAc)2, Ethyl vinyl ether, reflux

OTs

Li

OTs

BR3

BR2

ROTs

Cu

½150�

½151�

Figure 8.43b


256 Chapter 8

(CF3)2CO

(CH3)2CO + (CF3)2C(OH)C(OH)CF3)2

POO

F3C F3C

CF3

CF3

CF3

CF3

CF3CF3

OEtOEtEtO

POO

OHOHHO

i

ii

iii

iv

i, (CH3)2CHOH/hνii, P(OC2H5)3iii, H2SO4iv, H2O, Boil

8.44A

½112�

½153�

Figure 8.44

Diols may also be used in free-radical additions to fluorinated alkenes [154] (Figure

8.45).

OH

OH

CF3CF=CF2

HO RFH

RFHHO

i

RFH = CF3CFHCF2

i, γ rays, rt

83%

½154�

Figure 8.45

3 Alkoxides

The formation of polyfluoroalkoxyanions from perfluoroketones was discussed, along

with other addition reactions of perfluoroketones, in Section IB, Subsection 2; similar

anions can also be generated from acid fluorides and epoxides (oxiranes), as represented

in Figure 8.46.

F + RFR1FCO RFR1

FCFO

F + RFCOF RFCF2O

F + RFFC CFR1F RFCF2CFR1

F

OO

Figure 8.46

Examples of fluoride-ion-initiated reactions involving perfluorinated epoxides are

shown in Figure 8.47 [155–158]. Hexafluoropropene oxide (HFPO) and tetrafluoroethene

oxide will polymerise under certain conditions in the presence of fluoride ion. The process

involves an extending alkoxide and it is terminated by elimination of fluoride ion to give



an acid fluoride. This reactive end-group may be converted by a variety of procedures

[156] into the well-known stable fluids Krytoxt and Fomblint [159].

CF3COF [CF3CF2O ]FF2C CF2

O

C2F5O(CF2CF2O)nCF2COF

F [CF3CF2](CF3)2CO

CF3CF2C

CF3

CF3

O

[CF3CF2C(CF3)2OCF(CF3)CF2O]CF3CF2C(CF3)2OCF(CF3)COF

F3CFC CF2

O

(CF3CF2CF2O)

i, MF, Tetraglyme

CF3CF2COF

CF3CF2CF2O[CF(CF3)CF2O]nCF(CF3)COF n = 1−4

i −F

HFPO

HFPO

(R4NF)

CF2�CF2

HFPO

½155�

½155, 156�

½158�

Figure 8.47

D Fluoroxy compounds [137]

An interesting series of compounds RFOF [160, 161] has been synthesised and found to

be reasonably stable; for example, the O2F bond energy in CF3OF has been calculated

to be 183 kJmol�1 [162]. Compounds containing more than one fluoroxy group may be

obtained but these can be very unstable [163, 164]; indeed, all fluoroxy compounds

should be treated with caution. Fluoroxy derivatives of hydrocarbons are less stable,

probably due to easy elimination of hydrogen fluoride from these systems. Some synthe-

ses of fluoroxy derivatives are given in Figure 8.48.

Fluoroxy compounds are very strong oxidising agents [169]; this may be attributed to

the ‘positive halogen’ character of fluorine in an O2F group. Such an approach

[170–172] led to the application of CF3OF as a selective electrophilic fluorinating

agent, but the hazards associated with this system have precluded its development as a

laboratory reagent. For example, the system is prone to explosive reaction with organic

reagents. In fact, a complex interplay of radical and polar intermediates has been

indicated for reactions of hypofluorites with electron-rich alkenes [137].

Some hypofluorites may be susceptible to spontaneous exothermic decomposition

(Figure 8.49) but, in spite of this, industry has mastered the application of intermediate


258 Chapter 8

CO + F2 (COF2) CF3COFF2

i, Cu Tube, 350�C

(CF3)2CO + F2CsF

−78�C(CF3)2CFOF 98%

CO2 + F2CsF

−78�CCF2(OF)2 99%

(CF3)3OH + F2

−20�C(CF3)3COF

CH3OH + F2 [CH3OF] CF3CFClOCH3

i ii

i, CH3CH2CN, −40�C, 1hrii, CF2=CFCl, −75�C to rt

i ½165, 166�

½167�

½168�

½169�

½170�

Figure 8.48

CF2(OF)2 CF4 + O2 ∆H0 = −360 kJ mol−1−184�C

N2

Figure 8.49

hypofluorites to make new perfluorinated ethers and industrially significant monomers.

Indeed, this chemistry illustrates well the view that an essential part of the skill of science

is to be able to operate potentially hazardous procedures while ensuring the complete

safety of the operators. For example, addition of RFOF to fluorinated alkenes (Figure 8.50)

has been exploited for the synthesis of important monomers (Figure 8.51) for copolymer-

isation (See Figure 8.78, page 269).

2 CF2=CF2 + CF2(OF)2 CF2(OCF2CF3)2 80−90% ½173�

Figure 8.50

Additions of CF3OF to sulphur dioxide and trioxide [165], at high temperatures, and to

carbon monoxide [174], on photolysis, have been described (Figure 8.52).

E Perfluoro-oxiranes (epoxides) [156, 158, 175]

Some reactions of epoxides with fluoride and perfluoroalkoxide ions were referred to in

Section IB, Subsection 2 (above), and the importance of polymers of these systems was

stressed. There are numerous publications or patents concerning the synthesis of these



FSO2CF2COF FSO2CF2CF2O−

FSO2CF2CF2OFi, ii

FSO2CF2CF2OCFClCF2ClFSO2CF2CF2OCF=CF2

iii

i, CsF; ii, F2; iii, CFCl=CFCl

i½137�

Figure 8.51

CF3OF + SO3 CF3OOSO2F + SO2FOOSO2F

CF3OF + CO CF3OCOF 86%hν

½165�

½174�

Figure 8.52

compounds [156, 158]. The most general process involves reaction of a fluoroalkene with

alkaline hydrogen peroxide at low temperatures [176–178]. This method may be used for

oxidising hexafluoropropene and higher fluoroalkenes, as well as for cyclic systems

(Figure 8.53), but not for tetrafluoroethene, in which case various procedures involving

direct reaction with oxygen have been employed [156, 179, 180] (Figure 8.54). It is useful

to note that some of the products of these reactions, especially those involving

tetrafluoroethene, may be extremely hazardous [179].

CF3CF=CF2

i, KOH, H2O/CH3OH, 30%H2O2, −78�C

CF3

OF F

F

25%i ½178�

Figure 8.53

CF2=CF2 + O2 (containing O3)

OF

F

F

F+ CF2CF2O

n

46% 18%

½181�

Figure 8.54

Bleaching powder has proved to be a very effective reagent for various epoxidations

[158, 182–184], and lithium t-butyl peroxide has been used as an epoxidising agent [185]

with electron-deficient alkenes (Figure 8.55).

A very unusual, but efficient, rearrangement of the dioxirane 8.56A to a diether 8.56B

occurs on heating, but the mechanism of the process is uncertain [186] (Figure 8.56).

An interesting use of trimethylamine as catalyst in combination with m-chloroperben-

zoic acid (mCPBA) or iodobenzene has been reported and is effective with alkenes having

perfluoroalkyl groups attached to the double bond [187] (Figure 8.57).


260 Chapter 8

CF3CF2

F3C

CF3

CF2CF3

CF3CF2

F3C

F3C

F3C F3C F3C

F3C

F3C

F3C

F3C

F3C

CF3

CF2CF3

CF2CF3

O

Cl

CF3CF2 CF3

CF3

CF3

CF3 CF3

CF3

CF3

CF3

O

74%

Z : E = 1:1

OCl

O

Z + E

O

F

F

O

F CF3

F O

O

F F

O

O

F

i

i, t-BuOOLi, THF, −78�C to rt F

½158, 182�184�

½186�

Figure 8.55

F

F

O

O

F

F

OO

FF96%

i

ii

i, t-BuOOLi, THF, −78�C to rtii, Sealed tube, 220�C, 19 days

8.56A

8.56B

F3C

F3CF3C

F3C

F3C

F3C

CF3

CF3

CF3

CF3

CF3

CF3

½186�

Figure 8.56

Fluorinated oxiranes undergo a variety of ring-opening reactions with nucleophiles, the

most simple of which is formation of an acid fluoride. In most cases, terminal oxiranes

open to give an acid fluoride 8.58B rather than a ketone [156, 158] (Figure 8.58) and this

specificity of a ring opening is a puzzling feature; it may well be that, in forming an acid

fluoride, the strongest set of carbon–fluorine bonds is produced because the 2CF2O�



m-ClC6H4CO3H

m-ClC6H4CO2H

Me3N

Me3N-O

O

F

RFRF

RFRF

F CF3

CF3

RF = CF(CF3)2

½187�

Figure 8.57

RFCFCF2Nuc

O OF3C

F

F

F

RFCFCF2O

Nuc

−F− −F

−

RFCOCF2Nuc RFCFCOF

Nuc8.58A

8.58B

½156, 158�

Figure 8.58

group is isoelectronic with 2CF3. This would then be consistent with the well-known

order of decreasing carbon–fluorine bond strengths in the series 2CF3 >

2CF22 >CF2; see Chapter 7, Section IB.

Ring-opening oligomerisation of the oxirane derived from hexafluoropropene (see

Figure 8.47) forms the basis of the production of Krytoxt fluids (DuPont Co.), with

end-group stabilisation by direct fluorination etc. Clearly, achieving high-molecular-

weight material by this process is not easy.

For comparison, oxetanes are oligomerised in an analogous way to give intermediate

polyfluoro-polyethers that are then further fluorinated to give perfluoro-polyethers in the

process for the production of Demnumt fluids (Daikin Co.) [188] (Figure 8.59).

CF2=CF2 + (CH2O)nO

F

F

F

FH

H

F CH2CF2CF2O CH2CF2COFn-1

F CF2CF2CF2On

ii

i

iii

i, HFii, e.g. CsFiii, F2, 100−120�C

F

½188�

Figure 8.59


262 Chapter 8

Examples of other ring-opening reactions are illustrated in Figure 8.60.

F F

F

F

(CH3)3N

CH3OH +

F

FF

F3C

i, KF, 80�C, 4hr

+ F−

F−

[CF3CF2O]−

(CF3)2CFCOF

(CF3)2CCOFCF3CFCF2O−

N(CH3)3

CH3OH

[CF3CF(OCH3)COF]

CF3CF(OCH3)COOCH3

96%

N(CH3)3

++

97%

i, (CH3)3N, 100�C, 30hr

CF3COF + F−i

i

FF O

O

FF3C O

½179�

½189�

½178�

Figure 8.60

So far, the only case where attack occurs at the CF2 position in hexafluoropropene

oxide involves reaction with butyl lithium [156] (Figure 8.61).

FF

FF3C O

CF3C(C4H9)(OH).CF2C4H9

i, ii

[CF3C(O)CF2C4H9]C4H9Li+

i, BuLi, ii, H+

½156�

Figure 8.61

Ring opening with a strong protonic acid gives the corresponding alcohol [190] and this

is consistent with the idea that an intermediate carbocation, 8.62A, would be more stable

than 8.62B, where CF3 groups would certainly raise the energy of an adjacent carbocation

centre (Figure 8.62).

Conversely, cleavage with a Lewis acid catalyst gives a ketone [191, 192] (Figure

8.63). These are interesting reactions because they involve a 1,2-fluorine shift to a

positive centre (Figure 8.64), a process that is, of course, very well known for hydride

shifts. The conversion of hexafluoropropene oxide to hexafluoroacetone is probably the



F

FF3C

F3C

O

H+

F

+ HF250�C

64hr(CF3)3COH

(CF3)2CCF2OH (CF3)2C(OH)CF2

++

8.63B 8.62A

FF3C

F3C

O

H+

½190�

Figure 8.62

OF

i, Al2O3, 150−300� C

OF

OC5F11

F

F

F

i, SbF5, 150� C, 18hr

i

iC5F11CO.CF3

½191�

½192�

Figure 8.63

O

F

Acid

C C

O

F

Acid

Figure 8.64

preferred industrial route to this compound (N.B. The ketone is much more toxic than

the epoxide [67].)

Carbene formation on pyrolysis of epoxides was discussed earlier: see Chapter 6,

Section IIIA.

F Peroxides [193, 194]

Some examples of formation of fluorinated peroxides are given in Figure 8.65.

It has been demonstrated by labelling studies that, in reactions with caesium trifluoro-

methoxide, ring-opening occurs by attack at the peroxide bond [197] (Figure 8.66).

A direct, but mechanistically obscure, synthesis of trifluoromethyl hydroperoxide has

been developed, involving the decomposition of the adduct formed between hexafluoro-

acetone and hydrogen peroxide [107] (Figure 8.67).


264 Chapter 8

2 CO + 3 F2AgF2

CF3OOCF3

2 (CF3)3COH + ClF3 (CF3)3COOC(CF3)3

C3F7COCl + t-BuOOH C3F7C(O)OOt-Bu

FC(O)OF + CsF CF2

O

O

O

F

F

(CF3)2C(OLi)2 + F2O

OF3C

F3C

O F

½194�

½194�

½194�

½195�

½196�

Figure 8.65

13COF213CF3O

OO

F F

13CF3O(OCF2O)nOC(O)F

13CF3OOC(O)FF

−F

nA

n = 1-3

13CF3OOCF2O

A

½197�

Figure 8.66

(CF3)2C(OH)OOH CF3OOH + CO2 + O2 ½107�

Figure 8.67

Also, intermediate peroxides are formed in the oxidation of perfluorinated alkenes,

e.g. in the photo-oxidation of perfluoroethene and perfluoropropene for the formation of

Fomblint (Ausimont Co.) perfluoro-polyether fluids [198, 199].

II SULPHUR DERIVATIVES [5, 7, 200, 201]

A Perfluoroalkanesulphonic acids

Trifluoromethanesulphonic acid is commercially available and is the most readily

obtained member of this series by electrochemical fluorination [202–205] (Figure 8.68),

since the yields of perfluoroalkanesulphonic acids decrease as the size of the alkyl group

increases.

The acids are very thermally stable; longer straight-chain derivatives are surface-active

[206]. This combination of properties appears to be responsible for the application of



CH3SO2ClEletrochemical

FluorinationCF3SO2F CF3SO2OH 87% ½203�

Figure 8.68

these systems as the basis for textile treatment leading to grease resistance. However,

the discovery of traces of perfluoro-octane sulphonic acid in the blood of workers in the

industry has caused the removal of these products from the market. Clearly, the long-term

stability of sulphonamides derived from perfluorinated sulphonic acids is not as complete

as had previously been believed.

Of course, the most outstanding property of perfluoroalkanesulphonic acids is that they

are extremely useful strong acids, in the ‘super acid’ range [207, 208]; compare the Hammett

acidity functions ðH0Þ: CF3SO2OH (�13.8); FSO3H (�15.1); FSO3H=20%SbF5,

‘Magic Acid’ (�20); and H2SO4 (�11.1). Furthermore, the extreme electron-withdrawing

capacity of the CF3SO2 group [5, 209] is such that ðCF3SO2Þ2NH is the most acidic

amide known [4] and it leads to systems with remarkable C2H acidity, e.g.

ðCF3SO2Þ22CH2ðpKa ¼ �1Þ is more acidic than CF3CO2HðpKa ¼ 0:52Þ. Consequently,

perfluoroalkanesulphonic acids are outstanding Friedel–Crafts catalysts [208, 210]. More-

over, esters of trifluoromethanesulphonic acid, i.e. ‘triflates’, are super leaving groups

in nucleophilic displacement reactions and, as such, are extremely important in both

mechanistic and synthetic organic chemistry [208]. Significantly, the first example of

generating an aryl cation utilised both a triflate leaving group and the ionising ability of

trifluoroethanol as solvent [211] (Figure 8.69).

X

OSO2CF3

X X X X

OCH2CF3

X

i

i, 120�C, K2CO3, CF3CH2OHX = SiMe3

½211�

Figure 8.69

Moreover, the outstanding leaving-group ability of the nonofluorobutylsulphonyl

group, ‘nonaflate’, allows the conversion of hydroxyl to fluorine in some cases using

n-C4F9SO2F [212], which itself is obtained by electrochemical fluorination (Figure 8.70).

Triflate salts are important catalysts because the anions are poorly co-ordinating [214,

215] (Figure 8.71).

S

O O

C4F9SO2F 45%i

i, HF, E.C.F.

Ph(CH2)3OHii

Ph(CH2)3F 79%

ii, n-C4F9SO2F

½213�

½212�

Figure 8.70


266 Chapter 8

Me3SiCH2Li CH2(SO2CF3)2

[(CF3SO2)3C]3 M

[(CF3SO2)3CLi]i ii

i, (CF3SO2)2O, pentane, 0� Cii, t-BuLi (2 equiv), (CF3SO2)2O, −78� C

M2O3

M = Y, Sc

½214�

Figure 8.71

Trifluoromethyltriflate can be made easily but nucleophilic attack does not occur on

carbon and therefore the system does not act as a source of ‘electrophilic CF3’ [216, 217]

(Figure 8.72).

(CF3SO2)2O CF3SO2OCF3

90%

Nuc-CF3

Nuci

i, Cat. SbF4(OSO2CF3)

½216�

Figure 8.72

Trifluoromethanesulphonic acid forms a very stable crystalline hydrate [205, 218] and

reacts vigorously with alcohols, ethers and ketones. Oxonium salts are formed and further

reaction may occur on heating (Figure 8.73).

CF3SO2OH + (C2H5)2O (C2H5)2OH(CF3SO3)

Figure 8.73

Perfluoralkanesulphonyl chlorides may be obtained from the corresponding iodides

[219] (Figure 8.74), and they will act as a source of perfluoroalkyl radicals under

pyrolysis or photolysis, by losing sulphur dioxide [220] (Figure 8.75).

n-C4F9I n-C4F9SO2Cl 80%i

i, SO2,Cl2,DMF,Ni

½219�

Figure 8.74

RFSO2Cl +RF Cl

SO2

CF3SO2Cl∆

∆

CF3Cl + SO2

CF3(CH3)3C

(CH3)3C�N=O

i

i, hν, or peroxides

N

O

CF3

½221�

½220�

Figure 8.75



Trifluoromethyl radicals may also be generated by electrolysis of salts of trifluoro-

methanesulphinic acid [222] (Figure 8.76).

CF3SO2 K−1e

E = 1.05VCF3SO2 CF3 + SO2

+1e

E = −0.8v

SO2

OMe OMe

OMe

OMe

OMeOMe

CF3

CF3

Total yield = ca.47%

½222�

Figure 8.76

Sulphur-containing compounds are also obtained from reactions involving fluoroalk-

enes. Polyfluoro-b-sultones are produced in reactions of fluoroalkenes with freshly

distilled sulphur trioxide [223, 224]; these sultones have a varied chemistry, including

nucleophilic ring opening to give sulphonic acid derivatives (Figure 8.77) (see

also Chapter 7, Section IID). This ring-opening reaction is important in the synthesis

of co-monomers for the production of Nafiont-type (DuPont) membranes [37]

(Figure 8.78). Resins of this type have allowed membrane cells to displace the ill-

famed mercury cells for chlor-alkali production. Also, Nafiont resin is a useful strong

acid and has been developed for solid-phase catalytic processes [225–227] (Figure 8.79).

CF2=CF2 + SO3

F

F

F

F 61%

i, F , (C2H5)3N

F

O

F

SO2

F

F

N(C2H5)3F

CO.FCF2SO2F

F (C2H5)3N

F

F

F

F 1, NaOH

2, Ion Exchange

F2CCO2H

SO2OH

F

F

F

F i

O

O

SO2

SO2

O SO2

½223�

½223�

½37, 223, 224�

Figure 8.77


268 Chapter 8

FCOCF2SO2F + F OCF2CF2SO2F

CF2=CFOCF2CF(CF3)OCF2CF2SO2F

i

ii

iii

Co-polymer

CF3

F

O

F

F

ii,

iii, CF2=CF2

i,

FCOCF(CF3)OCF2CF(CF3)OCF2CF2SO2F

iv, Hydrolysis

ivMembrane

∆, Na2CO3

½37�

Figure 8.78

n-BuONO2

R

NO2

15-98%i

R

+

i, Nafion H

C6H6 + CH2=CH2

i

i, Nafion H

C6H5C2H5

RSO3H ArH+i

RSO2Ar

30-82%R = alkyl or aryl

i, Nafion H, Reflux

½225�

½226�

½227�

Figure 8.79

Salts of polyfluoroalkanesulphonic acids may be obtained directly from fluoroalkenes

simply by reaction of aqueous sodium sulphite in an autoclave, in some cases in the

presence of benzoyl peroxide [228–230] (Figure 8.80).

CF2=CF2 + NaHSO3120�C

CHF2CF2SO3Na

CF3CF=CF2 + NaHSO3i

i, (C6H5COO)2, 120�C

CF3CFHCF2SO3Na 64%

½228�

½229�

Figure 8.80



B Sulphides and polysulphides

A general method for making perfluoroalkyl sulphides and perfluoroalkyl polysulphides

involves heating a perfluoroalkyl iodide with sulphur in a sealed vessel, as illustrated in

Figure 8.81.

Sx + (CF3)2CFI243�C

[(CF3)2CF]2S 11% + [(CF3)2CF]2S2 34%

+ [(CF3)2CF]2S3 18%

½231�

Figure 8.81

Many interesting sulphides have been formed [7, 200, 201] by reactions of sulphur with

other iodides or certain di-iodides, or by other procedures [232, 233] (Figure 8.82).

CF3SSH + CF3SCl CF3SSSCF3120�C ½232�

Figure 8.82

A series of cyclic sulphides is produced in reactions of fluoroalkenes and fluoroalkynes

with sulphur or sulphur halides [234–238]; some examples have been discussed in

Chapter 7 (Figure 8.83).

Sx + CF2=CF2

SS

SS

S

S

S

F

44% 10%

S

S

F 56%

N2

445�C

300�C 10hr

F ½234�

Figure 8.83

The reaction between tetrafluoroethene and sulphur is activated by iodine, presumably

via the intermediate formation of a di-iodide [236] (Figure 8.84).

Sx + CF2=CF2 + I2

S S

S

FF

39%

½236�

Figure 8.84

Direct syntheses of fluorocarbon–sulphur compounds from non-fluorinated starting

materials are limited, but bis(trifluoromethyl) disulphide may be obtained from carbon


270 Chapter 8

disulphide using iodine pentafluoride [239], or from thiophosgene using sodium fluoride

[240] (Figure 8.85).

CS2

IF5

195�C(CF3)2S2

76%

(CF3)2S3

7%

CSCl2

i, NaF, Sulpholan, 245�C

(CF3)2S2 + CS2

37%

i

½239�

½240�

Figure 8.85

Fluorination of thiophene and derivatives and of 1,4-dithiane [241] with KCoF4 gives a

series of fluorinated derivatives. Chlorine–fluorine exchange in sulphides is also possible

in some cases [242] (Figure 8.86).

CH3SCH3 CCl3SCH3

PCl5 SbF5CF3SCH3

½242�

Figure 8.86

Base-induced [243] addition of thiols to fluoroalkenes yields polyfluoroalkyl sulphides,

which have also been further fluorinated (Figure 8.87).

CH3SH + CF2=CFCl

i, NaOCH3, 5−70�C

CH3SCF2CFClH

90%

ii, (CH3)2SO, KOH

CH3SCF=CFCl

CH3SCFClCFCl2CH3SCF2CF3iii, SbF3/SbF5

Cl2

i ii

iii

½243�

Figure 8.87

Reaction of arylmagnesium halides with trifluoromethanesulphenyl chloride, or simply

condensation of the latter with aromatic systems, has been exploited successfully [244,

245] (Figure 8.88).

CCl3SClNaF

SulpholanCF3SCl

PhMgBr + CF3SCl PhSCF3

Et2O52%

PhN(CH3)2 CF3SCl p-CF3SC6H4N(CH3)2 58%

½240�

½244�

½245�

Figure 8.88



C Sulphur(IV) and sulphur(VI) derivatives

Electrochemical fluorination of dialkyl sulphides leads to sulphur(VI) derivatives

(see Chapter 2, Section III), and oxidation of sulphur also occurs [246] in cobalt fluoride

or direct fluorination reactions (Figure 8.89).

(CH3)2SElectrochemical

FluorinationCF3SF5 + (CF3)2SF4

CH3SHCoF3

250−275�CCF3SF5

CS2

F2/N2

48�CCF3SF5 CF3SF3 etc.

½246�

½247�

½248�

Figure 8.89

An effective route to some sulphur(IV) compounds involves fluoride-ion-initiated

reactions of a fluoroalkene with sulphur(IV) fluoride [249] (Figure 8.90). Alternatively,

similar reactions with sulphuryl fluoride give perfluorodialkylsulphones or perfluoroalk-

anesulphonyl fluorides [250] (Figure 8.91).

CF3CF=CF2 + SF4 (CF3)2CFSF3 + [(CF3)2CF]2SF2CsF

100�C½249�

Figure 8.90

CF2=CF2 + SO2F2CsF

100�C(C2F5)2SO2 83%

CF3CF=CF2 + SO2F2CsF

Diglyme, 100�C(CF3)2CFSO2F etc

½250�

Figure 8.91

It has been shown that perfluoroalkylsulphur(II) compounds can be oxidised to corres-

ponding sulphur(IV) and sulphur(VI) compounds [251–254] (Figure 8.92).

Free-radical reactions of SF5Br provide a useful approach to sulphur(VI) compounds

[256] (Figure 8.93).

D Thiocarbonyl compounds

The most simple member of this class of compounds is thiocarbonyl fluoride [257, 258],

which is obtained from the thiophosgene dimer 8.94A, and then pyrolysis of 8.94B, to the

corresponding fluoro monomer [233] (Figure 8.94).


272 Chapter 8

CF3SRF + ClF CF3SF2RF + Cl2−78�C

RF = CF3, C2F5, n-C3F7

(CF3)2SF2, −196�C

C2F6

(CF3)2SF2(CF3)2SO

Ar2S2i, ii, iii

ArSF5

Ar =

NO2

i, F2/N2(1:9 v/v), MeCN, −5�C

ii, F2, CH3CN, Micro-reactor

Ar =

F

NO2

iii, AgF2, CF2ClCFCl2, 60−130�C, Cu

½251�

½255�

½252�254�

Figure 8.92

SF5Br + CF2=CFPhhν

SF5CF2CFBrPh SF5CF2CF2PhAgBF4 ½256�

Figure 8.93

S

SCl

Cl

Cl

Cl S

SF

F

F

F2 CF2=S

i ii

i, SbF3/90�Cii, 457−500�C

8.94A 8.94B

½233�

Figure 8.94

A general route to perfluorothioketones has been developed [258] involving reaction of

appropriate bis-organomercurials with sulphur vapour (contact at lower temperatures

gives polysulphides) (Figure 8.95).

(CF3)2CFHgCF(CF3)2 + S445�C

(CF3)2C=S + HgF2

60%

½258�

Figure 8.95

Thioketones may also be obtained by heating perfluoroalkyl iodides with phosphorus

pentasulphide [258] (Figure 8.96).



C2F5CFICF3 (C2F5)CF3C=S

i, P2S5, 550�C

i ½258�

Figure 8.96

Hexafluorothioacetone does not readily form a hydrate, but dimerises readily, particu-

larly in the presence of base; high temperatures are then required to reverse the process

[258] (Figure 8.97).

600� C

Base

S

SF3C

F3C

CF3

CF3

2(CF3)2C�S ½258�

Figure 8.97

The dimer of hexafluorothioacetone may also be obtained from hexafluoropropene

[259] and the former has now been used in a route to a sulphene [260] (Figure 8.98).

CF3CF=CF2 + F−

(CF3)2CF− Sx

(CF3)2CFS−

(CF3)2C=S

S

S

S

SO2F3CF3C

F3CF3C

CF3CF3

CF3CF3

(CF3)2C=SO2

ii, Quinuclidine

½259, 260�

Figure 8.98

Bistrifluoromethylthioketene has been obtained as a monomer; that is very unusual,

since thioketenes generally dimerise [261] (Figure 8.99).

EtOOC

EtOOC

COOEt

COOEt

i, SF4, HF, 125−200�C

S

S(CF3)2C C(CF3)2 70%

(CF3)2C=C=S 70%

750�C/1mm

i½261�

Figure 8.99

The nickel–dithiolene complex (Figure 8.100) is considered as a potential means of

recovering ethene, because it is capable of binding ethene reversibly by a redox-switch

process [262].


274 Chapter 8

S

S S

Ni

S

F3C F3C

F3CF3C

CF3 CF3

CF3CF3

CH2=CH2

S

S S

Ni

S

½262�

Figure 8.100

III NITROGEN DERIVATIVES

A Amines

Primary and secondary perfluoroalkylamines are relatively unstable systems with respect

to the elimination of hydrogen fluoride, although the situation is not as extreme as that

obtained with the corresponding alcohols. Consequently, CF3NH2 has been characterised

when generated at low temperatures [139] (Figure 8.101).

CF3NCl2 + HCl CF3NH2.HCl CF3NH2

Base ½139�

Figure 8.101

Ammonia reacts readily with fluoroalkenes (see Chapter 7) but amines are not isolated

from these reactions [230] (Figure 8.102)

CF2=CF2 + NH3 HCF2CF2NH2

−2HFHCF2CN

N N

NR

R

R

R = CF2H

½230�

Figure 8.102

Addition of hydrogen fluoride [263, 264] to the imine CF3N5CF2 occurs and this

secondary system is reasonably stable, allowing some further reactions to be carried out

[263–265] (Figure 8.103). Other perfluorinated secondary amines have also been isolated

[266–268].

CF3N=CF2 + HF (CF3)2NH

(CF3)2NH

i, HNO3, (CF3CO)2O

(CF3)2N NO2i

½263, 264�

½264�

Figure 8.103



Systems in which the nitrogen is attached to carbon bearing only perfluoroalkyl groups,

rather than fluorine, are particularly stable but weak bases; for example, perfluoro-

t-butylamine is practically devoid of basic properties [269] (Figure 8.104). Diazotisation

of the amine gives a mixture of the alcohol and the nitroso derivative [270] (Figure

8.105).

(CF3)3CNO

i, H2/Pd black; ii, HI, Red P

(CF3)3CNHOHii

(CF3)3CNH2

i½269�

Figure 8.104

(CF3)3CNH2

i, HNO2, 0�C

(CF3)3COH + (CF3)3CNOi ½270�

Figure 8.105

Fluoroalkylbenzylamines are obtained by the Lewis-acid-catalysed reactions of fluoro-

alkylimines with aromatic compounds [270], and reactions also occur with alkenes [270,

271] (Figure 8.106).

(CF3)2C=NH + CH3OC6H5 CH3O C(CF3)2NH2

(CF3)2C=NH + CH2=CHCH3

i, AlCl3, 150�C

i, AlCl3, 100�C

CH2=CHCH2C(CF3)2NH2

(CF3)2C=NH + CH2=CHCH=CH2N

H

CF3

CF3i, 100�C, 13hr; ii, 150�C, 6hr

i

i

i, ii

½270�

½270�

½271�

Figure 8.106

The fluoroalkylbenzylamines are characterised by their particular inertness [270],

being devoid of the tendency towards oxidative decomposition that is generally charac-

teristic of amines. In fact, oxidation of methyl will occur in preference to that of an amino

group in these systems (Figure 8.107).

H3C C(CF3)2NH2 HOOC

i, Na2Cr2O7, H2SO4

C(CF3)2NH2

i½270�

Figure 8.107


276 Chapter 8

Perfluoro tertiary amines ðRFÞ3N are very inert systems and are more akin to perfluoro-

alkanes than amines. They are most directly obtained by electrochemical fluorination

[272, 273] (see Chapter 2, Section III) and, as inert volatile fluids, they are used

commercially as evaporation coolants for electronic apparatus.

Electron-diffraction studies on ðCF3CF2Þ3N have suggested susceptibility to attack at

the CF2 positions by electrophiles [274].

B N–O compounds

1 Nitrosoalkanes

Trifluoronitrosomethane may be obtained from photolysis of a mixture of trifluoroiodo-

methane and nitric oxide [275, 276] or from pyrolysis of trifluoroacetyl nitrite [277, 278]

(Figure 8.108).

CF3I + NO CF3NO 80%hν, Hg

(CF3CO)2O + N2O3 CF3COONO 92%

190�C

CF3NO + CO2

56%

½276�

½277, 278�

Figure 8.108

Trifluoronitrosomethane is unusual among nitroso compounds in that it exists as a

monomer that is deep blue and is therefore one of the few highly coloured simple

polyfluoro compounds. On photolysis, a species derived from radical coupling is formed

[276] (Figure 8.109).

CF3NOhν

CF3

NO

CF3NO

CF3

(CF3)2NO

(CF3)2NO CF3NO (CF3)2NONO + CF3

½276�

Figure 8.109

A series of nitroso rubbers has been formed by reaction of trifluoronitrosomethane with

fluoroalkenes [279]; with tetrafluoroethene an oxazetidine and a 1:1 copolymer are

obtained (Figure 8.110), the polymer being formed in preference at lower temperatures

[279–281]. It is claimed that the mechanism involves electron transfer [282].

CF3NO + CF2=CF2

N OF3C

F CF2CF2N(CF3)O n½280�

Figure 8.110



2 Bistrifluoromethyl nitroxide

Bistrifluoromethyl nitroxide, ðCF3Þ2NO, is a stable purple gas and is of particular interest

because, of course, nitroxides are stable free radicals. The nitroxide is prepared from

bistrifluoromethylhydroxylamine [283] by reaction with, for example, silver oxide [284]

(Figure 8.111) or potassium permanganate [285].

CF3NOhν

(CF3)2NONO (CF3)2NOH (CF3)2NOHCl, H2O AgO

Quantitative

½284�

Figure 8.111

A range of products containing ðCF3Þ2NO groups may be obtained by addition to

unsaturated compounds [286–289] (Figure 8.112).

(CF3)2NO + CF2=CFCF3 (CF3)2NOCF2CF(CF3)ON(CF3)2

i, 15 min., rt

F + (CF3)2NO C6F6-n[ON(CF3)2]n

n = 2,4,6i, Sealed tube, 150�C, 1−4hr

i

i½287�

½288�

Figure 8.112

C Aza-alkenes

In contrast to the limited chemistry of fluorinated amines, a large number of aza-alkenes

and -dienes have been synthesised and these have an extensive chemistry. Some routes to

aza-alkenes and -dienes [96] are illustrated in Table 8.5; some were included earlier

(Section IB) in the variety of heterodienes that are obtained from hexafluoroacetone.

Table 8.5 Preparation of aza-alkenes and -dienes

Reaction Ref.

N OF3C

F

i, Si tube, 550�C, 5mm

CF3N=CF2

i[280]

(CF3)2NCOF CF3N=CF2 96%

i, Ni tube, 576�C

i[290]

(C2H5)2NH

i, Electrochem. fluorination; ii, (C5H5)2Fe

(C2F5)2NF C2F5N=CFCF3

i ii

[291]

Contd


278 Chapter 8

Table 8.5 Contd

Reaction Ref.

(CF3)2C=NH + CCl4 (CF3)2CClN=CCl2 82%

ii

(CF3)2C=NCF3 + (CF3)2CFN=CF2

70 : 30 92% total

i

i, AlCl3, 65−100�C;ii, KF, Sulpholan

[292]

N

F

i, Mild Steel, 400−600�C

N

FN

CF3

F CF3CF2CF2CF=NCF3

i[293]

CF3CHFCF2N3 CF3CHFN=CF2 CF3CH=NCF3F

i, Pt, 270−280�C

i

[294, 295]

CBr2=NN=CBr2i, AgF2, 100�C

CF3N=NCF3 92%

AgF 70�C

CF2=NN=CFBr

i, AgF, 125�C

CF2=NN=CF2 33% overall

i

i

[296]

CCl2N=CCl2 2

HF NaF, 50�C

2CF2NHCF3 CF=NCF3 2

[297]

N

N

F

i, CoF3.CaF2, 80�CN

N

Fi

[298]

N

NF

i

N

NF

+F

N

NF

N

NF

N

NF

N

NF

N

NF

+ F2

i, CoF3.CaF2, 175�C[298]

N

NF

RF

RF

i

N

NF

RF

RF

83%

RF = CF(CF3)2i, CoF3.CaF2, 172�C

[299]

Contd



Polyfluoroaza-alkenes are even more susceptible to nucleophilic attack than

polyfluoroalkenes. Hydrolysis of CF25NCF3 occurs readily giving the isocyanate [302,

303], and a variety of reactions with nucleophiles have been recorded (Figure 8.113).

CF3N=CF2 CF3NCO 50%

i, H2O, 20�C, 24hr

CF3N=CF2 + CH2=CHCH2OH CF3NHCO2CH2CH=CH2 52%i

i, aq KF, Et2O

CF3N=CF2 + CH2=CHCH2OH CF3N=C(OCH2CH=CH2)2Et3N

i½302�

½304�

½304�

Figure 8.113

Anions may be generated by reaction of fluoride ion with polyfluorinated aza-alkenes

in a manner similar to that described earlier for fluoroalkenes (see Chapter 7, Section IIC,

Subsection b) but, not being as readily available as fluoroalkenes, the chemistry is less

well developed. Some examples of reactions induced by formation of aza-anions from

aza-alkenes are shown in Figure 8.114.

CF3N=CF2

F(CF3)2N

i

ii

(CF3)2NCF=NCF3

(CF3)2COF

i, CF3N=CF2;ii, CsF, COF2, 100−150�C, 2hr

CF3N=CF2 + HgF2100�C, 15hr

[(CF3)2N]2Hg

½124, 305�

½264�

Figure 8.114

Contd

Table 8.5 Contd

Reaction Ref.

CF3CONHNHCOCF3 CF3CCl=NN=CClCF3

i

i, PhNMe2.HCl, POCl3

[300]

CF2=CFCF3

i, Et4N+N3

−, −5�C

CF3CHFCF2N3 + CF3CF=CFN3

Distil

N

F

FN

FF3C F3C

F

25%

<5% 25%

[301]


280 Chapter 8

i

CF3N CF3N

CF3N

F

F

F

N

F3C F3C

F

F N

F

CF=NCF3

FN

CF3

N

NF

F

CF=NCF3

F

CF3

CF3

94%

ii

i, CsF, Sulpholan, −23�C

ii, CF3N=CFCF=NCF3

N

RF RF RF

F

N

F

N

F

Cs

i i

i, CsF, Sulpholan;ii, CH3I;iii, BF3.Et2O

RF = (CF3)2CF

8.114A 8.114B

ii iii

N

RF

F

CH3

8.114A + 8.114B Ratio 4:1

−F

CF3N=CF22 ½306�

½307�

Figure 8.114 Continued.

A remarkable rearrangement occurs in the conversion of 8.115A to 8.115B and a

mechanism has been advanced for the formation of a trifluoromethyl group [308] (Figure

8.115).

Stable salts of the ðCF3Þ2N�

anion have been described [309].

Oxaziridines have been obtained from perfluorinated aza-alkenes using a variety of

approaches, and they have been used in oxygen transfer and other reactions [310] (Figure

8.116).

Remarkably, perfluoroazapropene (8.117A) reacts with SbF5 to produce oligomers

[311, 312] (Figure 8.117). Further reaction of the cyclic trimer with SbF5 leads to the

loss of CF4 to give the stable cation 8.117B whereas, if the reaction is carried out in



N NF

N NF

N

N

N

N

F CF3

F F

F

N NF

N NF

F

N N

N

N

F F

F

F

FN N

N

N

F

F

F1

2

2

F

1

N N

N

N

FF3C

F

F

i

i, CsF, 150�C, 16hr

8.115A

8.115 B

½308�

Figure 8.115

CF3N=CF2 + CF3OOH CF3NHCF2OOCF3N

O

F3CF

F

+ COF2

BrCF2CF2N=CFCF3

O

NBrCF2CF2

CF3

F

O

NCF3CF2

CF3

F55 45:

i

i, m-CPBA, Sulpholan, 22�C

O

NRF

F

RF

R1SR2 R1SOR2 + RFN=CFRF

RF = n-C4F9

½310�

½310�

½310�

Figure 8.116


282 Chapter 8

CF3N=CF2 + SbF5

N

N

N

CF3

CF3

F (CF3)2NCF=NCF3

(CF3)2NCF2N=CFN(CF3)2

i, SbF5

N

N

NF3C CF3

−CF4, −F−

(CF3)2NCF

N

CFN(CF3)2

i, SbF5, SO2

−2CF4

2hr, 20�C

N

N

N

F3C CF3

CF3

F

F

F F

N

CF2F2C

F2C

NCF2

N

CF3

CF2

F2C

NC

N

CF3

CF3

F

F2CN

CN

CF3

CF3

F

N

N

NF3C CF3

CF3

F

CF2

NCF

NNF2C

CF3CF3

CF3

8.117B

8.117C

CF3N=CF2

8.117A

i

i

CF3N=CF2

F3C

F

½311�

½312�

½312�

Figure 8.117

sulphur dioxide as solvent, then the major product is the cation 8.117C. The reactions

probably proceed via the aza-allyl cation, following reaction paths similar to those

described for the oligomerisation of hexafluoropropene, via the perfluoroallyl cation

outlined in Chapter 7, Section IID.



D Azo compounds

A synthesis of hexafluoroazomethane from tetrabromoazomethane has already been

referred to [296], and some other routes to polyfluoroazoalkanes are illustrated in Figure

8.118.

CF3CN C2F5N=NC2F5 90%i

i, AgF2, Ambient Temp.

C2F5CN C2F5CF2NCl2

i, ClF, −78 to −0�C

205�CC3F7N=NC3F7

85%

CF2(CN)2ClF

Cl2NCF2CF2CF2NCl2200−250�C

N NF

95%

i

½313�

½314�

½314�

Figure 8.118

Like the hydrocarbon analogues, highly fluorinated azo compounds break down

on photolysis and pyrolysis to give nitrogen and corresponding organic radicals [315]

(Figure 8.119).

CF3N=NCF3hν 2CF3 + N2

2CF3 C2F6

½315�

Figure 8.119

E Diazo compounds and diazirines [316]

Stable diazoalkanes and diazirines (Figure 8.120, where X and Y are fluoroalkyl groups)

have been isolated, but no authenticated report is available of a diazoalkane where X or Y

is a fluorine atom, although difluorodiazirine is now well documented [316]. It has been

suggested that this is probably yet another result of the propensity of fluorine to favour the

formation of F2Cðsp3Þ bonds, rather than F2Cðsp2Þ, thus making the diazirine structure

thermodynamically preferred, although calculations have suggested that the diazo-

methane structure is slightly preferred for CF2N2 [317].

XC

Y

N NX

C

Y

N N

Diazoalkane

N

NX

Y

Diazirine

Figure 8.120


284 Chapter 8

Oxidation of fluorinated hydrazones with lead tetra-acetate forms a useful method for

the synthesis of bis(perfluoroalkyl)diazomethanes [318] (Figure 8.121).

(CF3)2CO + NH3

i, Pyridine, −25 to −30�C

(CF3)2C=NH 70%

(CF3)2C=NH + NH2NH2

i, P2O5, 0�C

(CF3)2C=NNH2 68%

(CF3)2C=NNH2

i, Pb(OAc)4, C6H5CN, 0�C

(CF3)2CN2 77%i

i

i

½103�

½103�

½318�

Figure 8.121

Diazotisation of hexafluoroisopropylamine has also been achieved [319] (Figure

8.122).

CF3CF=CF2 (CF3)2CFNO2

i, HF/HNO3; ii, H2, Pd, 70�C, 100atm

(CF3)2CHNH2 75%

(CF3)2CHNH2.HCl (CF3)2CN2 48%

i ii ½319�

½319�

Figure 8.122

Bis(perfluoroalkyl)diazoalkanes are surprisingly stable; for example, deliberate at-

tempts to detonate 2-diazoperfluoropropane failed [318]. It has been emphasised [316,

319] that this compound is less readily attacked by electrophilic reagents than diazoalk-

anes but is unusually susceptible to nucleophilic attack, which is a consequence of

electron withdrawal by trifluoromethyl (Figure 8.123).

(CF3)2CN2 + N (CF3)2CHN=N N ½318�

Figure 8.123

Additions to some unsaturated compounds occur [318] (Figure 8.124).

In the case of diazirines, both difluorodiazirine and bis(trifluoromethyl)diazirine

have been obtained. Difluorodiazirine was originally prepared by reductive defluorination

of bis(difluoroamino)difluoromethane [320, 321], but it can also be obtained by an

interesting fluoride-ion-induced rearrangement of difluorocyanamide [322] (Figure

8.125). Bis(trifluoromethyl)diazirine [318, 323] is best obtained by the oxidation of

2,2-diaminohexafluoropropane, prepared from hexafluoroacetone, with sodium hypo-

chlorite (Figure 8.126).

Loss of nitrogen from these aziridines occurs on photolysis and pyrolysis, and a number

of the subsequent reactions have been formulated as reactions of the carbenes F2C : and

CF3Þ2C : ,�

which have also been discussed earlier; see Chapter 6, Section IIIA.



(CF3)2CN2 + CH2=CHCN

NN

F3C

F3C

F3C

F3C

CN

NH

N

CN

(Quant.)

(CF3)2CN2 + CH3C CCH3

60�C

NN

F3C

F3C

F3C

CH3

CH3

H3C

H3C

150�C

400�C

CF3

56%

½318�

½318�

Figure 8.124

CF2(NF2)2

i, (C5H5)2Fe, (C2H5)4NCl (or I)

N

NF

F

H2NCN(H2O)

i, F2, He, Buffered, 5−9�C

F2NCN 20%

F2NCN

N

N

F

F

F

F

N

NF

F

F

N

NF

F

CsF/24�C

i

i

½321�

½322�

½322�

Figure 8.125


286 Chapter 8

N

NF

F(CF3)2C(NH2)2

i, NaOCl, NaOH, 40−60�C

78%i

½323�

Figure 8.126

REFERENCES

1 Houben-Weyl: Methods of Organic Chemistry, Vol. E10, Organo-fluorine Compounds, ed.

B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999.


Chichester, 1992.

3 L.M. Yagupol’skii, A.Y. Il’chenko and N.V. Kondratenko, Russ. Chem. Rev., 1974, 43, 32.

4 J. Foropoulous and D.D. DesMarteau, Inorg. Chem., 1984, 23, 3720.

5 L.M. Yagupol’skii, J. Fluorine Chem., 1987, 36, 1.

6 S.L. Bell, R.D. Chambers, W.K.R. Musgrave and J.G. Thorpe, J. Fluorine Chem., 1971/72, 1,

51.

7 R.E. Banks and R.N. Haszeldine in The Chemistry of Organic Sulphur Compounds, ed.

N. Karasch, Pergamon, Oxford, 1966, p. 137.

8 G.A. Olah and C.U. Pittman, J. Am. Chem. Soc., 1966, 88, 3310.

9 J.F. Liebman in Fluorine-containing Molecules, ed. J.F. Liebman, A. Greenberg and

W.R. Dolbier, VCH, Weinheim, 1988.

10 Y.W. Alsmeyer, W.V. Childs, R.M. Flynn, G.G.I. Moore and J.C. Smeltzer in OrganofluorineChemistry: Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and

J.C. Tatlow, Plenum, New York, 1994, p. 121.

11 L.O. Brockway, J. Phys. Chem., 1937, 41, 185.

12 S.K. Kim, J. Org. Chem., 1967, 32, 3673.

13 H.M. Scholberg and H.G. Brice, US Pat. 2 717 871 (1955).

14 W. Hirsch, Ger. Offen. 2 947 376 (1981); Chem. Abstr., 1981, 95, 42398c.

15 Jap. Pat. 58 152 839 (1983); Chem. Abstr., 1984, 100, 51105d.

16 I.M. Robinson, Eu., Pat. Appl. 112 714 (1984); Chem. Abstr., 1985, 102, 5704s.

17 B.N. Hang, A. Haas and M. Lieb, J. Fluorine Chem., 1987, 36, 49.

18 T. Takakura, M. Yamabe and M. Kato, Nippon Kagaku Kaishi, 1985, 2208; Chem. Abstr.,

1987, 105, 171822k.

19 K. Ichihara and H. Aoyama, Int. Pat. WO 99 62 859 (1999); Chem. Abstr., 2000, 132, 22694a.

20 K. Ooharu and S. Kumai, Jap. Pat. 08 27 058 (1996); Chem. Abstr., 1996, 124, 316530t.

21 B. Boutevin, Y. Pietrasanta, A. Rousseau and D. Bosc, J. Fluorine Chem., 1987, 37, 151.

22 J. Burdon and J.C. Tatlow, J. Appl. Chem. (London), 1958, 8, 293.

23 N. Lui and J. Fischer-Lui in Houben-Weyl: Methods of Organic Chemistry, Vol. E10b, Pt. 1,Organo-fluorine Compounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme,

Stuttgart, 1999, p. 691.

24 N. Reeves, W.J. Feast and W.K.R. Musgrave, J. Chem. Soc., Chem. Commun., 1970, 67.

25 A.M. Lovelace, W. Postelnek and D.A. Rausch, Aliphatic Fluorine Compounds, Reinhold,

New York, 1958.

26 R.E. Banks, Fluorocarbons and their Derivatives, Macdonald, London, 1970.


28 E. Pop, F. Soti and M.E. Brewster, Synth. Commun., 1995, 4099.

29 G.A. Olah and A. Pavlath, Acta Chim. Acad. Sci. Hung., 1953, 3, 191.



30 S.G. Cohen, H.T. Wolosinski and P.J. Scheuer, J. Am. Chem. Soc., 1949, 71, 3439.

31 H. Gilman and R.G. Jones, J. Am. Chem. Soc., 1943, 65, 1458.

32 D.R. Husted and W.L. Kohlase, J. Am. Chem. Soc., 1954, 76, 5141.

33 O.R. Pierce and T.G. Kane, J. Am. Chem. Soc., 1954, 76, 300.

34 K.N. Campbell, J.O. Knobloch and B.K. Campbell, J. Am. Chem. Soc., 1950, 72, 4380.

35 F. Brown and W.K.R. Musgrave, J. Chem. Soc., 1953, 2087.

36 J.D. LaZerte, L.J. Hals, T.S. Reid and G.H. Smith, J. Am. Chem. Soc., 1953, 75, 4525.

37 M. Yamabe and H. Miyake in Organofluorine Chemistry: Principles and Commercial Appli-cations, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 403.


39 A.L. Henne and W.G. Finnegan, J. Am. Chem. Soc., 1950, 72, 3806.


41 M. Hauptschein and A.V. Grosse, J. Am. Chem. Soc., 1951, 73, 2461.

42 T.J. Brice and J.H. Simons, J. Am. Chem. Soc., 1951, 73, 4016.

43 C. Wakselman and A. Lantz in Organofluorine Chemistry: Principles and CommercialApplications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 177.

44 K. Ulm in Houben-Weyl: Methods of Organic Chemistry, Vol. E10, Organo-fluorine Com-pounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 33.


46 M. Hauptschein and M. Braid, J. Am. Chem. Soc., 1961, 83, 2383.

47 C.G. Krespan, J. Org. Chem., 1962, 27, 1813.

48 A. Probst, K. Raab, K. Ulm and K. von Werner, J. Fluorine Chem., 1987, 37, 223.

49 H.C. Brown and R.A. Wirkkala, J. Am. Chem. Soc., 1966, 88, 1447.

50 J.E. Nordlander and W.J. Kelly, J. Am. Chem. Soc., 1969, 91, 596.

51 P.A. Harland, P. Hodge, W. Maughan and E. Wildsmith, Synthesis, 1984, 941.

52 V.P. Kukar and V.A. Soloshonok (eds.), Fluorine-containing Amino Acids, John Wiley and

Sons, Chichester, 1995.

53 K. Uneyama, T. Katagiri and H. Amii, Yuki Gosei Kagaku Kyokaishi, 2002, 60, 1069.

54 J.M. Tedder, Chem. Rev., 1955, 55, 787.

55 A.R. Katrizky, B.Z. Yang, G.F. Qiu and Z.X. Zhang, Synthesis, 1999, 55.

56 W.D. Emmons, J. Am. Chem. Soc., 1954, 76, 3468.

57 H.J. Kang and H.S. Jeon, Bull. Korean Chem. Soc., 1996, 17, 5; Chem. Abstr., 1996, 124,

259989y.

58 W.D. Emmons and G.B. Lucas, J. Am. Chem. Soc., 1955, 77, 2287.

59 W.D. Emmons, A.S. Pagano and J.P. Freeman, J. Am. Chem. Soc., 1954, 76, 3472.

60 W.D. Emmons and A.S. Pagano, J. Am. Chem. Soc., 1955, 77, 89.



63 G.M. Brooke, J. Burdon and J.C. Tatlow, J. Chem. Soc., 1961, 802.

64 R.D. Chambers, J.A. Cunningham and D.J. Spring, J. Chem. Soc. (C), 1968, 1560.

65 R.D. Chambers, P. Goggin and W.K.R. Musgrave, J. Chem. Soc., 1959, 1804.

66 H. Hart, C.A. Buehler and A.J. Waring, ACS Adv. Chem. Ser. No. 51, 1965, pp. 1–9.

67 W.K. Appel, B.A. Blech and M. Stobbe in Organofluorine Chemistry: Principles andCommercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York,

1994, p. 413.

68 J. Hutchinson and G. Sandford in Organofluorine Chemistry: Fluorinated Alkenes and React-ive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 1.

69 F.A. Davis and P.V.N. Kasu, Org. Prep. Proc. Int., 1999, 31, 125.

70 F.A. Davis, H. Qi and G. Sundarababu in Enantiocontrolled Synthesis of Fluoro-organicCompounds, ed. E.V. Soloshonok, John Wiley and Sons, Chichester, 1999, p. 1.

71 Y. Tasaka and T. Nakasora, Jap. Pat. 03 184 933 (1991); Chem. Abstr., 1991, 115, 231698t.

72 J.P. Beguet and D. Bonnet-Delpon, Tetrahedron, 1991, 47, 3207.


288 Chapter 8

73 A. Posta, O. Paleta, F. Liska, V. Dedek, K. Klauda and J. Svoboda, Czech. Pat. 183 467

(1980); Chem. Abstr., 1981, 94, 156316j.

74 S. Sibille, J. Perichon and J. Chaussard, Synth. Commun., 1989, 19, 2449.

75 M. Braid, H. Iserson and F.E. Lawlor, J. Am. Chem. Soc., 1954, 76, 4027.

76 L. Leveque, M. LeBlanc and R. Pastor, Tetrahedron Lett., 1998, 39, 8857.

77 R.D. Smith, F.S. Fawcett and D.D. Coffman, J. Am. Chem. Soc., 1962, 84, 4285.

78 D.C. England and J.S. Piecara, J. Fluorine Chem., 1985, 28, 417.

79 J.D.O. Anderson, W.T. Pennington and D. DesMarteaux, Inorg. Chem., 1993, 32, 5079.

80 D.W. Wiley, US Pat. 3 091 643 (1963); Chem. Abstr., 1963, 59, 11266.

81 L.O. Moore and J.W. Clark, J. Org. Chem., 1965, 30, 2472.

82 Jap. Pat. 5 862 130 (1981); Chem. Abstr., 1984, 100, 5861z.

83 Jap. Pat. 5 862 131 (1981); Chem. Abstr., 1984, 100, 5862a.

84 Fr. Pat. 3 213 134 (1965); Chem. Abstr., 1966, 64, 6502.

85 D.C. England, J. Am. Chem. Soc., 1961, 83, 2205.

86 A.B. Clayton, J. Roylance, D.R. Sayers, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1965,

7358.

87 A.B. Clayton, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1965, 7370.

88 D.C. England and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 5582.

89 B.C. Anderson, J. Org. Chem., 1968, 33, 1016.

90 U. Utebaev, E.G. Abduganiev, E.M. Rokhlin and I.L. Knunyants, Izv. Akad. Nauk SSSR, Ser.Khim., 1974, 387 (Engl. Trans. p. 352).

91 J. Legros, B. Crouse, D. Bonet-Delpon and J.P. Begue, Tetrahedron, 2002, 58, 3993.

92 W.B. Farnham and S.G. Zane in Inorganic Fluorine Chemistry; Towards the 21st Century,

American Chemical Society, Washington DC, 1994, p. 209.

93 C.G. Krespan and W.J. Middleton, Fluorine Chem. Rev., 1967, 1, 145.

94 M. Witt, K.S. Dhathathreyan and H.W. Roesky, Adv. Inorg. Chem. Radiochem., 1986, 30,

223.

95 K. Burger, B. Helmreich, O. Jendrewski, R. Hecht, G. Maier and O. Nuyken in Macromol-ecular Symposium: Fluorinated Polymers, 82, Huthig and Wepf, Basel, 1994, p. 143.

96 K. Burger, N. Sewald, C. Schierlinger and E. Brunner in Chemistry of Organic FluorineCompounds II, ed. M. Hudlicky and A.E. Pavlath, American Chemical Society, Washington

DC, 1995, p. 840.

97 L.J. Bellamy and R.L. Williams, J. Chem. Soc., 1957, 4294.

98 J.K. Brown and K.J. Morgan, Adv. Fluorine Chem., 1965, 4, 284.

99 V.A. Soloshonok (ed.), Enantiocontrolled Synthesis of Fluoro-organic Compounds, John

Wiley and Sons, New York, 1999.

100 P. Bravo and G. Resnati, Tetrahedron: Asymmetry, 1990, 1, 661.

101 K. Iseki, S. Oishi and Y. Kobayashi, Chem. Lett., 1994, 1135.

102 N. Sewald and K. Burger in Fluorine-containing Amino-acids, ed. V.P. Kukhar and

V.A. Soloshonok, John Wiley and Sons, Chichester, 1994, p. 139.

103 W.J. Middleton and C.G. Krespan, J. Org. Chem., 1965, 30, 1398.

104 W.J. Middleton and C.G. Krespan US Pat. 3 226 439 (1965); Chem. Abstr., 1966, 64, 9597.

105 J.H. Prager and P.H. Ogden, J. Org. Chem., 1968, 33, 2099.

106 R.D. Chambers and M. Clark, Tetrahedron Lett., 1970, 2741.

107 C.T. Radcliffe, C.V. Hardin, L.R. Anderson and W.B. Fox, J. Chem. Soc., Chem. Commun.,1971, 784.

108 W. Adam, G. Asensio, R. Curci, J.A. Marco, M.E. Gonzalez-Nunez and R. Mello, Tetrahe-dron Lett., 1992, 33, 5833.

109 T. Iwahama, S. Sakaguchi and Y. Ishii, J. Chem. Soc., Chem. Commun., 1999, 727.

110 S.E. Denmark and Z. Wu, Synlett, 1999, 847.

111 H.-G. Degan, A. Pastor, C.R. Saha-Moller, S.B. Schambony and C.-G. Zhao in PeroxideChemistry, ed. A. Waldemar, Wiley–VCH, Weinheim, 2000, p. 78.



112 W.J. Middleton and R.V. Lindsey, J. Am. Chem. Soc., 1964, 86, 4948.

113 J.F. Harris, J. Org. Chem., 1965, 30, 2190.

114 V.F. Plakhova and N.P. Gambaryan, Bull. Acad. Sci. USSR, 1962, 633.

115 C.F. Jewell, J. Brinckman, R.C. Petter and J.R. Wareing, Tetrahedron, 1994, 50, 3849.

116 K. Iseki, S. Oishi, T. Taguchi and Y. Kobayashi, Tetrahedron, 1993, 34, 8147.

117 D.J. Burton, F.E. Herkes and K.J. Klabunde, J. Am. Chem. Soc., 1966, 88, 5042.

118 D.W. Wiley and H.E. Simmons, J. Org. Chem., 1964, 29, 1876.

119 W.J. Linn, J. Org. Chem., 1964, 29, 3111.

120 A.F. Janzen and C.J. Willis, Can. J. Chem., 1965, 43, 3063.

121 E.G. Howard, P.B. Sargeant and C.G. Krespan, J. Am. Chem. Soc., 1967, 89, 1422.

122 H. Hart, Z. Rappoport and S.E. Biali in The Chemistry of Enols. The Chemistry of FunctionalGroups, ed. S. Patai and Z. Rappoport, John Wiley and Sons, New York, 1990, p. 481.

123 P.E. Lindner and D.M. Lemal, J. Am. Chem. Soc., 1997, 119, 3259.

124 J.A. Young, Fluorine Chem. Rev., 1967, 1, 359.

125 A.G. Pittman and D.L. Sharp, Textile Res. J., 1965, 35, 190.

126 F.W. Evans, M.H. Litt, A.M. Weidler-Kubanek and F.P. Avonda, J. Org. Chem., 1968, 33,

1837.

127 M.E. Redwood and C.J. Willis, Can. J. Chem., 1965, 43, 1893.

128 A.G. Pittman and D.L. Sharp, J. Org. Chem., 1966, 31, 2316.

129 W.B. Farnham, B.E. Smart, W.J. Middleton, J.C. Calabrese and D.A. Dixon, J. Am. Chem.Soc., 1985, 107, 4565.

130 X. Zhang and K. Seppelt, Inorg. Chem., 1997, 36, 5689.

131 M.E. Redwood and C.J. Willis, Can. J. Chem., 1967, 45, 389.

132 A.G. Pittman, D.L. Sharp and R.E. Lundin, J. Polym. Sci. Part A-1, 1966, 4, 2637.

133 D.A. Couch, R.A. deMarco, and J.M. Shreeve, J. Chem. Soc., Chem. Commun., 1971, 91.

134 R.W. Anderson, US Pat. 3 525 745 (1970).

135 D.P. Graham and V. Weinmayr, J. Org. Chem., 1966, 31, 957.

136 F. Haspel-Hentrich and J.M. Schreeve, Inorg. Synth., 1986, 24, 58.

137 W. Navarrini, V. Tortelli, A. Russo and S. Corti, J. Fluorine Chem., 1999, 95, 27.

138 K.C. Joshi and R. Joshi, J. Indian Chem. Soc., 2001, 78, 653.

139 G. Kloeter and K. Seppelt, J. Am. Chem. Soc., 1979, 101, 347.

140 S. Andreades and D.C. England, J. Am. Chem. Soc., 1961, 83, 4670.

141 T.W. Bentley, G. Llewellyn and Z.H. Ryu, J. Org Chem., 1998, 63, 4654.

142 B.K. Freed, J. Biesecker and W.J. Middleton, J. Fluorine Chem., 1990, 48, 63.

143 M.H. Abraham, P.L. Grellier, D.V. Prior, P.P. Duce, D.V. Morris and P.J. Taylor, J. Chem.Soc., Perkin Trans. 2, 1989, 699.

144 M.H. Abraham, P.L. Grellier, D.V. Prior, D.V. Morris and P.J. Taylor, J. Chem. Soc., PerkinTrans. 2, 1990, 521.

145 V. Weinmayr, US Pat. 3 317 616 (1967); Chem. Abstr., 1967, 67, 63753.

146 R. Filler and R.M. Schure, J. Org Chem., 1967, 32, 1217.

147 C. Doussain, M. Gubelmann and P. Tirel, Fr. Pat. 2 635 101 (1990); Chem. Abstr., 1990, 113,

77682h.

148 O. Paleta, J. Guenter, F. Liska and V. Dudek, Czech. (1988); Chem. Abstr., 1989, 109,

210518v.

149 V.A. Petrov, Synthesis, 2002, 2225.

150 J.M. Percy in Organofluorine Chemistry; Techniques and Synthons, ed. R.D. Chambers,

Springer, Berlin, 1997, p. 132.

151 J.M. Percy and M.E. Prime, J. Fluorine Chem., 1999, 100, 147.

152 Technical Report DP-1, E.I. DuPont de Nemours, Freon Development Products Division,

1965.

153 N.P. Gambaryan, Y.A. Cheburkov and I.L. Knunyants, Bull. Acad. Sci. USSR, 1964,

1433.


290 Chapter 8

154 R.D. Chambers, P. Diter, S.N. Dunn, C. Farren, G. Sandford, A.S. Baksanov and J.A.K.

Howard, J. Chem. Soc., Perkin Trans. 1, 2000, 1639.

155 J.L. Warnell, US Pat. 3 250 806 (1966); Chem. Abstr., 1966, 65, 48031.

156 P. Tarrant, C.G. Allison, K.P. Barthold and E.C. Stump, Fluorine Chem. Rev., 1971, 5, 77.

157 H.S. Eleuterio, J. Macromol. Sci. – Chem., 1972, A6(6), 1027.

158 H. Millaur and G.S. Siegmund, Angew. Chem., Int. Ed. Engl., 1985, 24, 161.

159 Technical Bulletins on ‘Krytox’ fluorinated oils and greases, E.I. DuPont de Nemours,

Wilmington, Delaware, USA.

160 G.H. Cady, Proceedings of the Seventeenth Int. Congress on Pure and Applied Chemistry,Vol. 1, Butterworths, London, 1960, p. 205.

161 C.J. Hoffman, Chem. Rev., 1964, 64, 91.

162 J. Czarnowski, E. Castellano and H.J. Schumacher, J. Chem. Soc., Chem. Commun., 1968,

1255.

163 P.G. Thompson and J.H. Prager, J. Am. Chem. Soc., 1967, 89, 2263.

164 R.L. Cauble and G.H. Cady, J. Am. Chem. Soc., 1967, 89, 5161.

165 W.P.V. Meter and G.H. Cady, J. Am. Chem. Soc., 1960, 82, 6005.

166 G.H. Cady, Inorg. Synth., 1966, 8, 165.

167 M. Lustig, A.R. Pitochelli and J.K. Ruff, J. Am. Chem. Soc., 1967, 89, 2841.

168 F.A. Hohorst and J.M. Shreeve, Inorg. Synth., 1968, 11, 143.

169 J.H. Prager and P.G. Thompson, J. Am. Chem. Soc., 1965, 87, 230.

170 T. Suzuta, T. Abe and A. Sekiya, J. Fluorine Chem., 2003, 119, 3.

171 D.H.R. Barton, L.S. Godinho, R.H. Hesse and M.M. Pechet, J. Chem. Soc., Chem. Commun.,1968, 804.


173 F.A. Hohorst and J.M. Shreeve, Inorg. Chem., 1968, 7, 624.

174 P.J. Aymonino, J. Chem. Soc., Chem. Commun., 1965, 241.

175 A. Paleta in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath,

Washington DC, 1995, p. 321.

176 GB Pat. 12 513 (1963); Chem. Abstr., 1963, 58, 12513.

177 H.S. Eleuterio and R.W. Meschke, US Pat. 3 358 003 (1968); Chem. Abstr., 1968, 68, 29573.

178 D. Sianesi, A. Pasetti and F. Tarli, J. Org. Chem., 1966, 31, 2312.

179 F. Gozzo and G. Camaggi, Tetrahedron, 1966, 22, 1765.

180 D. Cordischi, M. Lenzi and A. Mele, Trans. Farad. Soc., 1964, 60, 2047.

181 Montecantini, GB Pat. 1 130 836 (1968); Chem. Abstr., 1969, 70, 4795.


183 P.L. Coe, A. Sellars and J.C. Tatlow, J. Fluorine Chem., 1983, 23, 102.


185 O. Meth-Cohn, C. Moore and H.C. Taljaard, J. Chem. Soc., Perkin Trans. 1, 1988, 2663.

186 R.D. Chambers, J.F.S. Vaughan and S.L. Mullins, Res. Chem. Intermed., 1996, 22, 703.

187 T. Ono and P. Henderson, Tetrahedron Lett., 2002, 43, 7961.

188 Y. Ohsaka in Organofluorine Chemistry; Principles and Commercial Applications, ed.


189 I.L. Knunyants, V.V. Shokina, U.V. Tyuleneva, Y.A. Cheburkov and Y.E. Aronov, BullAcad. Sci. USSR, 1966, 54, 1764.

190 F. Pavlik, US Pat. 3 385 904 (1968); Chem. Abstr., 1968, 69, 26753.

191 E.D. Moore and A.S. Milian, US Pat. 3 321 515 (1967); Chem. Abstr., 1967, 66, 116587.

192 D.E. Morin, US Pat. 3 213 134 (1965); Chem. Abstr., 1965, 62, 18029.

193 M. Yoshida and N. Kamigata, J. Fluorine Chem., 1990, 49, 1.

194 H. Sawada, Chem. Rev., 1996, 96, 1779.

195 A. Russo and D.D. DesMarteau, Angew. Chem., Int. Ed. Engl., 1993, 32, 905.

196 R.W. Murray, Chem. Rev., 1989, 89, 1187.

197 Q. Huang and D.D. DesMarteau, J. Chem. Soc., Chem. Commun., 1999, 1671.



198 D. Sianesi, G. Marchionni and R.J. Pasquale in Organofluorine Chemistry. Principles andCommercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York,

1994, p. 431.

199 M. Malavasi and D. Sianesi, J. Fluorine Chem., 1999, 95, 19.

200 W.J. Middleton in The Chemistry of Bivalent Sulphur, ed. E.E. Reid, Chemical Publishing

Co., New York, 1966, p. 331.

201 R.D. Dresdner and T.R. Hooper, Fluorine Chem. Rev., 1969, 4, 1.



204 T.J. Brice and P.W. Trott, US Pat. 2 732 398 (1956); Chem. Abstr., 1956, 50, 13982.

205 J. Burdon, I. Farazmand, M. Stacey and J.C. Tatlow, J. Chem. Soc., 1957, 2574.

206 N.S. Rao and B.E. Baker in Organofluorine Chemistry. Principles and Commercial Applica-tions, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 321.

207 R.J. Gillespie and J. Liang, J. Am. Chem. Soc., 1988, 110, 6053.

208 G.A. Olah, G.K.S. Prakash and J. Sommer, Superacids, John Wiley and Sons, New York,

1985.

209 L.M. Yagupolskii, A.Y. Illchenko and N.V. Kondratenko, Usp. Khim., 1974, 43, 64; Chem.Abstr., 1974, 80, 94766.


211 Y. Himeshima, H. Kobayashi and T. Sonoda, J. Am. Chem. Soc., 1985, 107, 5286.

212 R. Zimmer, M. Webel and H.U. Reissig, J. Prakt. Chem., 1998, 340, 274.

213 V. Beyl, H. Niederprum and P. Voss, Liebigs Ann. Chem., 1970, 731, 58.

214 F.J. Waller, A.G.M. Barrett, D.C. Braddock, D. Ramprasad, R.M. McKinnell, A.J.P. White,

D.J. Williams and R. Ducray, J. Org Chem., 1999, 64, 2910.

215 R.M. Marshman, Aldrichim. Acta, 1995, 28, 77.

216 S.L. Taylor and J.C. Martin, J. Org Chem., 1987, 52, 4147.

217 P. Johncock, J. Fluorine Chem., 1974, 4, 25.


219 K. von Werner, Ger. Offen. 2 915 800 (1980); Chem. Abstr., 1981, 94, 120860.

220 GB Pat. 849 061 (1960); Chem. Abstr., 1961, 55, 16452.

221 M. Oudrhiri-Hassani, D. Brunel, A. Germain and A. Commeyras, J. Fluorine Chem., 1984,

25, 491.

222 J.-B. Tomasino, A. Brondex, M. Medebielle, M. Thomalla, B. Langlois and T. Billard, Syn.Lett., 2002, 1697.

223 D.C. England, M.A. Dietrich and R.V. Lindsey, J. Am. Chem. Soc., 1960, 82, 6181.

224 M.A. Dimitriev, G.A. Sokol’skii and I.L. Knunyants, Dokl. Akad. Nauk SSSR, 1959, 124, 581;

Chem. Abstr., 1959, 53, 11211.

225 G.A. Olah in NATO ASI Ser. C, Vol. 444, Acidity and Basicity of Solids, ed. J. Fraissard and

L. Petrakis, Kluwer Academic Publishers, Dortrecht, 1994, p. 305.

226 F.J. Waller and R.W. Scoyol, CHEMTECH, 1987, 17, 438.

227 G.A. Olah, T. Mathew and G.K.S. Prakash, J. Chem. Soc., Chem. Commun., 2001, 1696.

228 P.L. Barrick, US Pat. 2 403 207 (1946); Chem. Abstr., 1946, 40, 6497.

229 R.J. Kosher, P.W. Trott and J.D. LaZerte, J. Am. Chem. Soc., 1953, 75, 4595.

230 D.D. Coffman, M.S. Raasch, G.W. Rigby, P.L. Barrick and W.E. Hanford, J. Org. Chem.,1949, 14, 747.


232 M. Gaensslen, R. Minkwitz, W. Molzbeck and H. Oberhammer, Inorg. Chem., 1992, 31,

4147.

233 A. Haas, J. Fluorine Chem., 1999, 100, 21.

234 C.G. Krespan and W.R. Brasen, J. Org. Chem., 1962, 27, 3995.


236 C.G. Krespan and C.M. Langkammerer, J. Org. Chem., 1962, 27, 3584.


292 Chapter 8

237 W.R. Brasen, H.N. Cripps, C.G. Bottomley, M.W. Farlow and C.K. Krespan, J. Org. Chem.,1965, 30, 4188.

238 G.V.D. Tiers, J. Fluorine Chem., 1998, 90, 97.

239 R.N. Haszeldine and J.M. Kidd, J. Chem. Soc., 1953, 3219.

240 C.W. Tullock and D.D. Coffman, J. Org. Chem., 1960, 25, 2016.

241 J. Burdon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 655.

242 W.E. Truce, G.H. Birum and E.T. McBee, J. Am. Chem. Soc., 1952, 74, 3594.

243 R.D. Chambers and R.H. Mobbs, Adv. Fluorine Chem., 1965, 4, 50.

244 W.A. Sheppard, J. Org. Chem., 1964, 29, 895.

245 S. Andreades, J.F. Harris and W.A. Sheppard, J. Org. Chem., 1964, 29, 898.

246 A.L. Clifford, H.K. El-Shamy, H.J. Emeleus and R.N. Haszeldine, J. Chem. Soc., 1953, 2372.

247 G.A. Silvey and G.H. Cady, J. Am. Chem. Soc., 1950, 72, 3624.

248 E.A. Tyczkowski and L.A. Bigelow, J. Am. Chem. Soc., 1953, 75, 3523.

249 R.M. Rosenberg and E.L. Muetterties, Inorg. Chem., 1962, 1, 756.

250 S. Temple, J. Org. Chem., 1968, 33, 34.

251 D.T. Sauer and J.M. Shreeve, J. Chem. Soc., Chem. Commun., 1970, 1679.

252 R.D. Bowden, P.J. Comina, M.P. Greenhall, A. Loveday and D. Philip, Tetrahedron, 2000,

56, 3399.

253 R.D. Chambers and R.C.H. Spink, J. Chem. Soc,. Chem. Commun., 1999, 883.

254 A.M. Sipyagin, C.P. Bateman, Y.-T. Tan and J.S. Thrasher, J. Fluorine Chem., 2001,

112, 287.

255 E.W. Lawless, Inorg. Chem., 1970, 9, 2796.

256 R.W. Winter, R. Dodean, J.A. Smith, R. Anilkumar, D.J. Burton and G.L. Gard, J. FluorineChem., 2003, 122, 251.

257 W. Sundermeyer and W. Meize, Z. Anorg. Allg. Chem., 1962, 317, 334.

258 W.J. Middleton, E.G. Howard and W.H. Sharkey, J. Org. Chem., 1965, 30, 1375.

259 D.C. England, J. Org. Chem., 1981, 46, 153.

260 U. Hartwig, H. Pritzkow, K. Rall and W. Sundermeyer, Angew. Chem., Int. Ed. Engl., 1989,

28, 221.

261 M.S. Raasch, J. Org. Chem., 1970, 35, 3470.

262 K. Wang and E.I. Stiefel, Science, 291, 106.

263 D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 2532.

264 J.A. Young, S.N. Tsoukalas and R.D. Dresdner, J. Am. Chem. Soc., 1958, 80, 3604.

265 F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Chem. Eng. Data, 1965, 10, 398.

266 R.E. Banks and G.J. Moore, J. Chem. Soc. (C), 1966, 2304.

267 R.E. Banks, R.N. Haszeldine and R. Hatton, J. Chem. Soc. (C), 1967, 427.


269 I.L. Knunyants, B.L. Dyatkin and E.P. Mochalina, Bull. Acad. Sci. USSR, 1965, 1056.

270 D.M. Gale and C.G. Krespan, J. Org. Chem., 1968, 33, 1002.

271 Y.V. Zeifman, N.P. Gambaryan and I.L. Knunyants, Bull. Acad. Sci. USSR, 1965, 1431.

272 S. Nagasi, Fluorine Chem. Rev., 1967, 1, 77.

273 F.G. Drakesmith in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers,


274 M. Gaensslen, U. Gross, H. Oberhammer and S. Rudiger, Angew. Chem., Int. Ed. Engl., 1992,

31, 1467.


276 A.H. Dinwoodie and R.N. Haszeldine, J. Chem. Soc., 1965, 1675.

277 C.W. Taylor, T.J. Brice and R.L. Wear, J. Org. Chem., 1962, 27, 1064.

278 R.E. Banks, M.G. Barlow, R.N. Haszeldine and M.K. McGrath, J. Chem. Soc. (C), 1966,

1350.



279 M.C. Henry, C.B. Griffis and E.C. Stump, Fluorine Chem. Rev., 1967, 1, 1.


281 J.M. Birchall, A.J. Bloom, R.N. Haszeldine and C.J. Willis, J. Chem. Soc., 1962, 3021.

282 V.A. Tinsburg, A.N. Medvedev, S.S. Dubov, P.O. Gitelv, V. Smolyanitskaya and

G.E. Nikolaneko, J. Gen. Chem. USSR, 1969, 39, 262.

283 R.N. Haszeldine and B.J.H. Mattinson, J. Chem. Soc., 1957, 1741.

284 W.D. Blackley and R.R. Reinhard, J. Am. Chem. Soc., 1965, 87, 802.

285 S.P. Makarov, A.Y. Yakubovich, S.S. Dubov and A.N. Medvedev, Zh. Vses. Khim.Obshchestva im. D.I. Mendeleeva, 1965, 10, 106; Chem. Abstr., 1965, 62, 16034.

286 S.P. Makarov, M.A. Englin, A.F. Videiko, V.A. Tobolin and S.S. Dubov, Dokl. Akad. Nauk.SSSR, 1966, 168, 344; Chem. Abstr., 1966, 65, 8742.

287 R.E. Banks, R.N. Haszeldine and M.J. Stevenson, J. Chem. Soc. (C), 1966, 901.

288 M.A. Englin and A.V. Mel’nikova, Zh. Vses. Khim. Obshchest., 1968, 13, 594; Chem. Abstr.,1969, 70, 28503.

289 R.E. Banks, R.N. Haszeldine and T. Myerscough, J. Chem. Soc. (C), 1971, 1951.

290 J.A. Young, T.C. Simmons and F.W. Hoffman, J. Am. Chem. Soc., 1956, 78, 5637.

291 R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 328.

292 V.A. Petrov, J. Fluorine Chem., 2001, 109, 123.


294 I.L. Knunyants, E.G. Bykhovskaya and V.N. Frosin, Dokl. Akad. Nauk. SSSR, 1960, 132, 357;

Chem. Abstr., 1960, 54, 20841.

295 R.E. Banks, D. Berry, M.J. McGlinchey and G.J. Moore, J. Chem. Soc. (C), 1970, 1017.

296 R.A. Mitsch and P.M. Ogden, J. Org. Chem., 1966, 31, 3833.

297 H.J. Scholl, E. Klauke and D. Lauerer, J. Fluorine Chem., 1972/73, 2, 205.

298 R.D. Chambers, D.T. Clark, T.F. Holmes, W.K.R. Musgrave and I. Richie, J. Chem. Soc.,Perkin Trans. 1, 1974, 114.

299 R.N. Barnes, R.D. Chambers, R.D. Hercliffe and W.K.R. Musgrave, J. Chem. Soc., PerkinTrans. 1, 1981, 2059.

300 M. Barlow, D. Bell, N.J. O’Reilly and A.E. Tipping, J. Fluorine Chem., 1983, 23, 293.

301 C.S. Cleaver and C.G. Krespan, J. Am. Chem. Soc., 1965, 87, 3716.


303 J.A. Young, W.S. Durrell and R.D. Dresdner, J. Am. Chem. Soc., 1959, 81, 1587.

304 V.G. Andreev, A.F. Kolomiets and G.A. Sokolskii, Izv. Akad. Nauk. SSSR, Ser. Khim., 1990,

1643; Chem. Abstr., 1990, 113, 1643.

305 F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Am. Chem. Soc., 1962, 84, 4275.

306 R.N. Barnes, R.D. Chambers, M.J. Silvester, C.D. Hewitt and E. Klauke, J. Fluorine Chem.,1984, 24, 211.

307 R.N. Barnes, R.D. Chambers and R.S. Mathews, J. Fluorine Chem., 1982, 20, 307.

308 R.N. Barnes, R.D. Chambers and C.D. Hewitt, J. Fluorine Chem., 1986, 34, 59.

309 U. Heider, M. Schmidt, P. Sartori, N. Ignatyev and A. Kucheryna, Eur. Pat. 1 081 129 (2001);

Chem. Abstr., 2001, 134, 207547.

310 V.A. Petrov and G. Resnati, Chem. Rev., 1996, 96, 1809.

311 I.L. Knunyants, A.F. Goutar and A.S. Vinogradov, Izv. Akad. Nauk. SSSR, Ser. Khim., 1983,

476; Chem. Abstr., 1983, 99, 53706k.

312 G. Pawelke and H. Burger, J. Fluorine Chem., 1984, 26, 321.

313 J.K. Ruff, J. Org. Chem., 1967, 32, 1675.

314 J.B. Hynes and T.E. Austin, Inorg. Chem., 1966, 5, 488.

315 M.E. Jacox, Chem. Phys., 1984, 83, 171.

316 C.G. Krespan and W.J. Middleton, Fluorine Chem. Rev., 1971, 5, 57.

317 C. Glidewell, D. Higgins and C. Thompson, J. Comput. Chem., 1987, 8, 1170.

318 D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617.

319 E.P. Mochalina and B.L. Dyatkin, Bull Acad. Sci. USSR, 1965, 899.


294 Chapter 8

320 R.A. Mitsch, J. Heterocycl. Chem., 1966, 3, 245.

321 R.A. Mitsch, J. Org. Chem., 1968, 33, 1847.

322 M.D. Meyers and S. Frank, Inorg. Chem., 1966, 5, 1455.

323 R.B. Minasyan, E.M. Rokhlin, N.P. Gambaryan, Y.V. Zeifman and I.L. Knunyants, Bull.Acad. Sci. USSR, 1965, 746.



Chapter 9

Polyfluoroaromatic Compounds

This chapter will deal mainly with the chemistry of highly fluorinated compounds,

although this will be prefaced by a more general summary of synthetic methods for the

introduction of fluorine into an aromatic system. A review of this topic by Brooke [1]

covers the area in considerable detail and we can only be selective in our discussion here.

I SYNTHESIS [1, 2]

A General considerations

An ideal process would, in principle, be one where elemental fluorine could be used as

indicated in Figure 9.1. Recent work with elemental fluorine has demonstrated that this is

a reasonable approach in some circumstances, e.g. when the opportunity for forming

isomers is limited. However, nucleophilic displacement of other halogens, or mobile

groups such as nitro, by fluoride ion, when the aromatic compound is susceptible to

nucleophilic attack, is a more versatile approach at the present time (Figure 9.2).

2ArH + F2 2ArF + HF

2HFElectrolysis

F2 + H2

Figure 9.1

Ar L + F Ar F + L

Figure 9.2

We are mainly concerned here with general processes but two specific reactions are of

some interest. Fragmentation occurs in the pyrolysis of CFBr3, giving perfluorobenzene

(Figure 9.3) [3–5]; this was probably the first synthesis of this compound, although it was not

reported for some time. Trimerisation of hexafluoro-2-butyne leads to hexakis(trifluoro-

methyl)benzene [6, 7], a reaction that was referred to in Chapter7, Section IIIB, Subsection 1.

6 CFBr3Pt

630−640� C9 Br2 + C6F6 55%

3 CF3C CCF3 C6(CF3)6

½4�

½6, 7�

Figure 9.3



B Saturation/re-aromatisation

Examples of saturation and then re-aromatisation by dehydrohalogenation and

dehalogenation are given in Figure 9.4. Use of cobalt trifluoride [8] to form perfluorinated

C6Cl6i

i, F2, CF2ClCFCl2

C6ClxF12-x C6F6

C6F5ClC6F4Cl2C6F3Cl3ii, Fe, 330� C

x = mainly 5, 6, and 7

C6H6 C6H3F9 etc C6F6

KOH

C6H3F7 C6F5H

CH3

CoF3

CF3

CF3

FFe

460� C

CF3

CF3

F

H

H

H

H

Fi

i, Hg Cathode

2F−

CoF3

F

F

F

Fe

410� C

F

F

F

N NF

F

N

Fiii

i, Electrochemical Fluorinationii, Fe/600�C/,1mm

25%

ii

CH3

F

½16�

½17�

½18�

½13�

½19�

½15�

Figure 9.4


Polyfluoroaromatic Compounds 297

saturated systems as inert liquids is an industrial process operated by F2 Chemicals Ltd.; a

variety of benzenoid derivatives have been fluorinated in this way. Re-aromatisation may

be achieved by essentially two procedures: either elimination of hydrogen fluoride [9, 10]

using base, or defluorination over heated iron or nickel [11, 12]. The latter is a very

effective process for defluorination and is frequently overlooked in more recent literature

on processes for ‘activating’ carbon–fluorine bonds. An electrochemical process has also

been used to defluorinate fluorocyclohexadienes [13]. Several condensed ring benzenoids

have been prepared by the fluorination/defluorination procedure [1] but less success has

been achieved using heterocyclic systems, although pentafluoropyridine has been made in

a low-yield sequence [14, 15].

Re-aromatisation by elimination of hydrogen fluoride has been used as a route to

thiophene and furan derivatives [20, 21] (Figure 9.5).

S

H H

OH H

O

H H

H

SF

KOH

OF

KOH

O

KOH

H H

F

F

F F

½20�

½21�

½21�

Figure 9.5

C Substitution processes [22]

1 Replacement of H by F

Reactions that lead to replacement of hydrogen by fluorine could, in principle, proceed by

any of the processes outlined in Figure 9.6, and it is frequently difficult to make any

meaningful distinction between the possibilities.

Various electrophilic fluorinating reagents, including fluorine itself, are capable of

transferring ‘Fþ’ to an appropriate nucleophilic centre to give a s-complex 9.6A, but

these electrophilic fluorinating agents are also strong oxidising agents. Consequently, the

sequence could begin with a single-electron transfer [23], giving a radical cation 9.6B

which, in turn, could receive a fluorine atom from the reagent, thus reaching 9.6A by two

steps. Alternatively, the radical cation 9.6B could receive fluoride ion and then give a

radical s-complex 9.6C. All of these processes are feasible and probably arise in different

circumstances [24], albeit difficult to establish. Some examples of what might be reason-

ably regarded as electrophilic fluorinations are given in Figure 9.7. In the examples


298 Chapter 9

indicated, and others, the orientation of substitution is quite consistent with an electro-

philic aromatic substitution process.

F

"F" H

F H

H

F

F

9.6A

9.6B 9.6C

F H

Figure 9.6

COOH

F

F2

Solvent

COOH

FF

Solvent

98% H2SO4CH3CNCF2ClCFCl2

Yield, %

84530

NO2 NO2 NO2

Xi, F2, HCOOH, 10� C

X XF F F

X = OHX = F

70%53%

8%Trace

NO2 NO2 NO2

Me

i

Me MeF F F

81% 2%

i

i, F2, H2SO4, 10� C

½25�

½26�

½26�

Figure 9.7

Substitution in pyridine is more consistent with an addition–elimination process

(Figure 9.8).



N N N

F

H

F F

i

i, F2, CFCl3, −78�C

−HF

N

i

NF

H

I

−HI

NCl Cl Cl F

N

I

Cl N F

F

b

b

a

70%

14%

i, IF5/2I2

a

½27�

½28�

Figure 9.8

The occurrence of radical intermediates is evident from the product of the fluorination

of benzene [29] and of tetrafluoropyrimidine [30] (Figure 9.9).

Xenon difluoride is reactive towards aromatic compounds [31], and selective fluoro-

desilylation using this reagent has also been reported [32] (Figure 9.10).

2 Replacement of 2Nþ2 by F: the Balz–Schiemann reaction [33, 34]

In this classical reaction the leaving group, molecular nitrogen, is lost on pyrolysis and the

mechanism appears to involve formation of an aryl cation which then abstracts fluoride

ion [35] (Figure 9.11).

This reaction has been carried out on an industrial scale in spite of the fact that the

decomposition stage is potentially hazardous. Consequently, techniques have been de-

veloped that avoid isolating a solid diazonium salt [2] (Figure 9.12).

3 Replacement of 2OH or 2SH by F

Another alternative to the Balz–Schiemann reaction is now available through the thermal

decomposition of aryl fluoroformates or aryl thiofluoroformates [36–38], as indicated in

Figure 9.13. Fluoroformates are obtained in high yields but the pyrolysis step is quite

variable.

4 Replacement of Cl by F [39]

The most practicable and versatile laboratory and industrial route to polyfluoroaromatic

compounds involves the use of potassium fluoride in nucleophilic displacement of


300 Chapter 9

F F F F

n

F F F

n = 0, 20%n = 1, 40%

5% 8%

F

7%

N

NF

i

i, CoF3, CaF2, 183� C

N

NF

N

N

F

N

NF

+F

N

NF

Coupling etc

½29�

½30�

Figure 9.9

SiMe3 SiMe3

R

XeF

R

F

R

FXe

R

XeF2

CF3C6H5

XeF2meta-CF3C6H4F 71% para-CF3C6H4F 3% ½31�

½32�

Figure 9.10

ArH ArNO2 ArNH2

ArN2 BF4

HNO3

Ar BF4∆

−N2ArF + BF3

Figure 9.11



NH2COOH

N2COOH

F FCOOH

OHCOOH

i

i, NaNO2, HF/H2Oii, 58� C

ii ½2�

Figure 9.12

COCl2

i, AsF3, SbF3, or SiF4

COClF

ArXHCOClF

ArXCOF∆

ArF + COX

(X = O, S)or ArXCOCl

F

C6H5OH

i, COClF, Bu3N; ii, Pt Gauze, 800� C

C6H5OCOF

99%

iiC6H5F 70%

α-naphth.-OCOF∆

680� Cα

i

i

-naphth.-F 25%

½36�

½37�

Figure 9.13

chloride by fluoride from systems activated towards nucleophilic attack. This is

often referred to as the ‘Halex’ (halogen exchange) process [2, 39] (Figure 9.14).

Thermodynamic data for hexafluorobenzene with potassium and sodium fluorides

(Figure 9.15) [40] illustrate the feasibility of the reaction in the case of potassium

fluoride.

The process was pioneered by Finger and co-workers, who appreciated at an early stage

the advantages of using a dipolar aprotic solvent [41–43] (see Chapter 2, Section IIB,

Subsection 1, for a fuller discussion of ionic fluorides in aprotic solvents). Examples of

halogen exchange using a dipolar, aprotic solvent are shown in Figure 9.16.

Hexachlorobenzene gave 1,3,5-trifluorotrichlorobenzene when DMF or DMSO2 [41]

was used as solvent, although the use of N-methyl-2-pyrrolidone (NMP) [42, 43] gave

some tetrafluorodichlorobenzene that could not be fluorinated further in this mixture

(Figure 9.17).


302 Chapter 9

ArCl + KF ArF + KCl ½2�

Figure 9.14

C6Cl6(g) + 6KF(s) C6F6(g) + 6KCl(s)

∆H298 = −126 kJmol−1

C6Cl6(g) + 6NaF(s) C6F6(g) + 6NaCl(s)

∆H298 = +63 kJmol−1

½40�

Figure 9.15

NO2 NO2

Cl

Cl

F

F

71%i

i, KF, DMSO, phase transfer agent, heat

NO2 NO2

Cl F

82%i

i, KF, DMF, heat

Cl Cl

½2�

½2�

Figure 9.16

Cl F

i, KF, 195� C, NMP

Cl

Cl Cl

+ C6F4Cl2 + C6F5Cl

23% 34% trace

i ½42, 43�

Figure 9.17

The significance of obtaining only the 1,3,5-trifluorotrichlorobenzene will become

clear in later discussion of orientation of nucleophilic aromatic substitution. However, a

higher temperature, permitted by the use of Sulpholan as solvent [44], gave perfluoro-

naphthalene from the perchloro compound (Figure 9.18).



Cl Cl

i, KF, 235� C, Sulpholan

F F 52%i

½44�

Figure 9.18

In contrast, with Sulpholan as solvent the very reactive cyanuric chloride is converted

to the fluoride, even with sodium fluoride [45]. Indeed, if the system is sufficiently

activated, then hydrogen fluoride may be used for the conversion [46], and the halogen

exchange step probably occurs on the protonated system (Figure 9.19).

N

N

NCl

N

N

NCl

H

F

N

N

N

H

Cl

Cl

Cl

F

−HCl

N

N

N

Cl

Cl

F

N

N

NF

HF etc

N N

N

ClN N

N

F

i, NaF, 245� C, Sulpholan

74%

HF

i½45�

½46�

Figure 9.19

Nevertheless, reaction of perchloropyridine with potassium fluoride in Sulpholan leads

mainly to 2,4,6-trifluorodichloropyridine [47] (Figure 9.20). The feature limiting the

extent of fluorination is, essentially, the thermal stability of the solvent. This has been

circumvented by two techniques: (a) using a melt of potassium fluoride–potassium

chloride at temperatures in the region of 7508C [40]; and, more successfully, (b)

employing autoclaves at high temperatures for reactions in the absence of a solvent, a

technique used first to fluorinate perchlorobenzene [48, 49] and perchloropyridine [47,

50, 51] (Figure 9.21).

N

Cl

N

F

N

F

ClCl Cli

10 : 1i, KF, 200� C, Sulpholan

½47�

Figure 9.20


304 Chapter 9

C6F3Cl3 C6F6 11% + C6F5Cl 34% + C6F4Cl2 28%

+ C6F3Cl3 18% + C6F2Cl4 0.4%

C6Cl6 C6F6 21% + C6F5Cl 20% + C6F4Cl2 14%

+ C6F3Cl3 12%

i

i, KF, Autoclave, 450−500� C

N

Cl

N

F

N

F

Cl

68% 7%

i

i, KF/KCl Melt, 780� C

i, KF, Autoclave, 480� C

i

½40�

½48�

½47�

Figure 9.21

A general process has now evolved for the synthesis of highly fluorinated azabenzenoid

compounds, involving (a) synthesis of the perchloro compound by further chlorination of

partly chlorinated compounds with phosphorus pentachloride, and (b) subsequent reaction

of the perchloro compound with potassium fluoride. The method is illustrated for per-

fluoroquinoline [52] (Figure 9.22), but the technique has also been applied to other

systems (Figure 9.22b). Thus, a novel field of heterocyclic chemistry is available that is

still relatively unexplored.

N N

Cl4

N

Cl Cl

N

F F

Cl2, AlCl3

140−160� C87%

78%

71%KF

480˚C

PCl5 315� C

½52�

Figure 9.22a



N

F F

F F F F F F

F F

N

FN

N

NF

N

NF

N

N

F

N

N

N

N

N

N

N

N

NF

NN

NF

NN

NF

Figure 9.22b Perfluorinated heterocyclic systems obtained by Halex procedures [53]

II PROPERTIES AND REACTIONS

A General

Perfluorobenzene and perfluorobenzenoid compounds have boiling points that parallel

those of the corresponding hydrocarbons but, for perfluoropyridine and other perfluoro-

azabenzenoid compounds, the values are significantly lower than for their hydrocarbon

counterparts (Table 9.1).

The base strength of nitrogen in these perfluorinated systems is very considerably

reduced compared with their hydrocarbon counterparts so that, in the nitrogen systems, it

is clear that substitution of hydrogen for fluorine usually produces an overwhelming

reduction of intermolecular forces, which more than offsets the increase in molecular

weight.

Table 9.1 Boiling points of perfluoroaromatic compounds in comparison with hydrocarbon

counterparts

Compound Boiling point (8C) [54]

Boiling point of

perfluorinated derivative (8C) Ref.

Benzene 80.1 80.2 [55]

Toluene 110.6 102–103 [11]

p-Xylene 138 117–118 [11]

Pyridine 115.5 83.3 [55]

Quinoline 237.1 205 [52]

Isoquinoline 243.2 212 [52]

Pyridazine (1,2-diazine) 208 117 [56]

Pyrimidine (1,3-diazine) 123.5 89 [55]


306 Chapter 9

The effect of fluorocarbon groups on the strengths of various acids and bases was

discussed in Chapter 4, Section IIIA, where it was pointed out that pentafluorophenyl and

pentachlorophenyl are similar in electron-withdrawing properties but are much less

effective than trifluoromethyl [57]. Complexes are formed between hexafluorobenzene

and aromatic hydrocarbons [58] or amines [59], and the 1:1 complex formed between

hexafluorobenzene and mesitylene is stable enough to allow recrystallisation [58]. Much

has been written about the nature of these complexes, e.g. dispensing with the idea that

they may involve charge transfer; a recent study concludes that the complexes are formed

principally through van der Waals forces [60]. X-ray crystal structures of complexes of

hexafluorobenzene with various cyclic aromatic hydrocarbons reveal 1:1 alternating

stacks [61]. Electron affinities for perfluoroaromatic compounds indicate that they are

good electron acceptors [62].

B Nucleophilic aromatic substitution

A considerable number of highly fluorinated aromatic compounds have now been pre-

pared that undergo various nucleophilic aromatic substitution reactions. Taking perfluoro-

benzene as an example, we have the two basic requirements for nucleophilic substitution

to occur readily: (a) electron-withdrawing substitutents to lower the energy of a transition

state leading to the intermediate 9.23A (Figure 9.23); and (b) an atom that can leave with

the bonding electron pair, which in this case is F�. Indeed, just as hydrocarbon aromatic

compounds provide the framework for studying electrophilic aromatic substitution, it is

obvious that polyfluoroaromatic compounds are particularly appropriate systems for

studying nucleophilic aromatic substitution. As we will see, problems of orientation

arise that are just as fundamental to nucleophilic aromatic substitution as the classical

orientation problems are to electrophilic aromatic substitution, and it should be particu-

larly evident in this area how the chemistry of fluorocarbon systems helps to extend the

mechanistic framework of organic chemistry.

NucF

F Nuc

F

Nuc

F

9.23A

k1

k−1

k2

F5

Figure 9.23

1 Benzenoid compounds [1]

Hexafluorobenzene will react with a wide range of nucleophilic reagents, leading to

pentafluorophenyl compounds; some of these are given in Table 9.2, together with

some similar chemistry of other benzenoid systems. From these direct substitution

products, which are generally obtained in high yield, routes have been developed to

other important functional derivatives (Table 9.3). Some of these are included but other

important reactions, e.g. formation of organometallic compounds, will be covered in later

discussion and are not illustrated in this table.



Table 9.2 Reactions of perfluorobenzenoid compounds with nucleophilic reagents and some simple

interconversions

Reaction Ref.

Reactions starting from hexafluorobenzene

i, NaOCH3, MeOH; ii, AlCl3, 120� C

C6F5OCH3ii

C6F5OH

72% 58%

i

[63]

C6F5OH

i, KOH, t-BuOH 71%

i[5]

ii, Raney Ni, n-BuOHi, NaSH, Pyridine;

C6F5SH C6F5Hiii

[64]

ii, Cl2, H2O2

C6F5SO2Clii

[65]

ii, Me-nitrosourea, KOH, Et2O; iii, H2O2, CH3COOH

C6F5SCH3 C6F5SO2Meiiiii

[65]

ii, CF3CO3H, CH2Cl2i, aq. NH3, EtOH, 167� C;

C6F5NH2 C6F5NO2 85%i ii

[66, 67]

ii, HCl, Et2O

C6F5NH2HClii

[68]

NaOClC6F5N=NC6F5

[69]

ii, HCO3H, CH2Cl2

C6F5NO2 48%ii

[70]

ii, NaNO2, 80% HF; iii, Cu2Br2, HBr

C6F5N2 Fiii

C6F5Brii

[68]

Contd


308 Chapter 9

Table 9.2 Contd

i, NH2NH2.H2O, EtOH; ii, Ca(OCl)2, C6H6

C6F5NHNH2

71%

C6F5C6H5

74%

i ii

[71]

NaOH

H

H

F 90% [72]

NO2Cl52%C6F5N3 [71]

LiAlH4C6F5H

[73]

i, (CH2OH)2, NaOH; ii, K2CO3, DMF, Reflux

F

OCH2CH2OH

ii

O

O

Fi [74]

Reactions of other perfluorobenzenoid compounds

i, NH2NH2, aq. EtOH; ii, LiAlH4, Et2O; iii, Fehling�s soln.

NHNH2

F F F F

ii

H

F F

iii

i

[75]

F F

i, LiAlH4, THF

F F

H

Hi

[76]

F F

i, C6F5O , DMAC

F F OC6F5

90 %

i[77]

Contd



Table 9.2 Contd

F F

i, NH2NH2, aq. EtOH

F FH2NHN NHNH2

F FH2NHN

18%

72%

i

[78, 79]

a DMAC, dimethylacetamide.

Table 9.3 Nucleophilic substitution in C6F5X compounds

Orientation of product(%)

Substituent, X Nucleophile Ortho Meta Para Reference

H LiAlH4 7 1 92 [80]

NaOMe/MeOH 3 — 97 [81]

Me MeLi — — 100 [82]

MeO� — — 100 [83]

NH3 — — 100 [83]

CF3 LiAlH4 — — 100 [84]

NH3 — — 100 [84]

EtO� — — 100 [84]

NH2 NH3 — 100 — [66, 73]

NH3 — 87 13 [85, 86]

MeNH2 — 88 12 [86]

NO2 NH3 (ether) 70 — 30 [67]

NH3 (liq.) 33 — 67 [87]

MeNH2 (benzene) 77 — 23 [88]

MeOH ðEt2OÞ 8 — 92 [89]

MeOH ðEt2OÞ 50 — 50 [88]

NH2 NH3 — 100 — [66, 73]

NH3 — 87 13 [85, 86]

MeNH2 — 88 12 [86]

OH KOH — 100 — [73, 83, 90]

Orientation and reactivity: [1, 91]: Reactions of pentafluorophenyl derivatives are

particularly interesting because of the unusual orientation of substitution observed. This

area was pioneered by workers at the University of Birmingham (UK) [1, 17] and, in most

cases, for substitution in C6F5X derivatives the main (>90%) product arises from

displacement of a fluorine atom that is para to the substituent group X (for example,

where X ¼ H, CH3, SCH3, CF3, NðCH3Þ2, SO2CH3, NO2, C6F5, OC6F5, etc.). In a few

cases ðX ¼ NH2, O�Þ meta replacement predominates, whilst (for X ¼ OCH3 and

NHCH3) comparable amounts of meta and para replacement occur (Figure 9.24).

The effects of substituents on rate constants are, however, in the direction expected for

nucleophilic aromatic substitution; electron-donating groups deactivate while electron-

withdrawing groups activate; for example, C6F5NH2 and C6F5O� are strongly deacti-

vated. The magnitude of these effects, such as the relative reactivities of

NaOCH3ðCH3OH at 608C), have been recorded [92] and some relative rates towards

sodium pentafluorophenoxide (dimethylacetamide, 1068C) are shown in Table 9.4 [93].


310 Chapter 9

F

X Nuc

Nuc

F

X

F

X

Nuc

Nuc

+ F

+ F

e.g. X = H, CH3, CF3

e.g. X = NH2, O

Figure 9.24

Table 9.4 Relative rates of reaction of

C6F5X towards NaOC6F5, DMAC [93]

X Relative reaction rate

CF3 2.4 � 104

CO2C2H5 2.9 � 103

C6F5 7.3 � 102

Br 39

Cl 32

H 1

F 0.91

Clearly, therefore, there is a very wide spread in reactivity, as in electrophilic substitu-

tion in benzene derivatives, but here we have the contrasting feature that the orientation

pattern is relatively insensitive to the substituent. Consequently, it is important to estab-

lish the nature of this unusual orientating influence arising from the five fluorine

atoms.

Mechanism [91, 94]: It is reasonable to assume the normal two-step mechanism (Figure

9.23) of nucleophilic attack in these systems, with the first stage k1 being rate-limiting.

The type of evidence that allows this assumption to be made is that perfluorobenzene is

much more reactive than perchlorobenzene, and this is only consistent with there being

little or no bond breaking in the rate-determining stage. The reason for this greater

reactivity of C2F over C2Cl lies in the fact that the C2F bond is more polarised

and hence ion–dipole interactions with the incoming nucleophile are greater for C2F

and lead to a corresponding lowering of the activation energy. Of course, a similar

argument is necessary to account for the often greater reactivity of acid fluorides

RCOX (X ¼ F) over acid chlorides (X ¼ Cl) towards nucleophiles, although this is rarely

emphasised.

We are then left with the influence of the remaining ring fluorine atoms on the

substitution process. In reality, halogen atoms that are at positions ortho, meta and para

to the site of nucleophilic attack (Figure 9.25) have different effects; these separate

activating influences have been derived from the data contained in Table 9.5 [91, 94].



F

Fδ

Nuc δ

ortho

meta

para

F

Nuc

ortho

meta

para

+ F

Figure 9.25

In the benzenoid system, therefore, the activating effects of fluorine vary in the order

meta-F > ortho-F� para-F, although this can also vary with the system (see Table 9.6).

Clearly, the para-F is slightly deactivating but is not very different from H at the same

position.

Our problem then is to rationalise these data on the basis of the known effects of F on

carbanion stabilities, which we have described earlier (see Chapter 4, Section VII)

(Figure 9.26).

Table 9.5 Ratios of measured rate constants (CH3O�=CH3OH, 588C) [91, 94]

Benzene derivatives compared kF=kH

F vs

F

F

H

para-F / para-H

(ie k/6)a

(Position of nucleophilic attack)

0.43

F vs

H

F

H

ortho-F / ortho- H

F H

57

F vs

H

F

H

meta- F / meta- H

F H

106

a Statistically corrected.


312 Chapter 9

C C F F

Strongly Stabilising Slightly de-stabilisingfor a planar system

Nuc F

F

δ −

δ −

δ −

F

Nuc F F

δ + F

δ −

meta-F para-F ortho-F

9.26A 9.26B 9.26C

Nuc

C

Figure 9.26

Taking the Meisenheimer complex as a model for the transition state associated with step

k1 (Figure 9.23), we can easily see why meta-F, which is adjacent to centres of high charge

density, is strongly activating. Likewise, the slightly deactivating influence of fluorine at

the para position (9.26B) is entirely consistent with the effect of fluorine directly attached

to a planar carbanion centre. However, we would have expected ortho- and para-F to have

similar effects, whereas this is clearly not the case. Consequently, it has been argued that the

effect of ortho-F (9.26C) is predominantly a polar influence, enhancing the electrophilic

character or ‘hardness’ of the carbon atom under attack. We might expect that the influence

of this ortho-F effect would diminish as the reactivity or ‘hardness’ of the nucleophile is

reduced, and the data contained in Table 9.6 support this case.

We can see, therefore, that nucleophilic attack para to the substituent in C6F5X

compounds (Table 9.3) stems from maximising the number of activating fluorine atoms

[95] (Figure 9.27), where attack para to X involves all of the ring fluorine substituents in

the positions that maximise their activating influence.

X

Fo o

m m

X

Fp o

m

o

4- activating F 3- activating F

Figure 9.27

Table 9.6 Comparison of kF=kH

Ortho Meta Para

MeO�=MeOH, 588CBenzene derivatives 57 106 0.43

Pyridine derivatives 79 30 0.33

NH3/dioxane, 258CPyridine derivatives 31 23 0.26



These simple arguments may be extended [76] to account for the orientation of

substitution in perfluoronaphthalene, where pm indicates ‘pseudo-meta’ (activating),

and pp ‘pseudo-para’ (slightly deactivating) (Figure 9.28).

pm

pp para

meta

ortho

F Nucpm

δ −

δ − δ −δ −

δ −pp

pm meta

ortho

orthopp

δ −δ −

δ −δ −

δ −

F

Nuc

pmF F F F

4- activating F 5- activating F

Figure 9.28

Clearly, attack at the b-position maximises the influence of fluorine substituents. These

same approaches can be used to account for the orientation of substitution in other

systems (Figure 9.29).

FF

F

F

FF

F

F

F F

F

F F

Figure 9.29

Ortho attack [1] can occur, however. Although nucleophilic substitution at sites para to

X in C6F5X compounds generally predominates, there are cases where specific binding

interactions between the incoming reagent and the substituent X are sufficient to direct the

reagent to the ortho position. Hydrogen bonding [96] (Figure 9.30) and co-ordination of X

to organometallic reagents are particularly significant [97] (Figure 9.31).

NO O

H

NH2

F

½96�

Figure 9.30


314 Chapter 9

C6F5COOH

C

OBrMgO

F

MgBr

NHPh2PhNHMgBr

C

OBrMgO

F

MgBr

F

NH

Ph

C

OHO

F

NHPh

H

½97�

Figure 9.31

2 Heterocyclic compounds

Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds: Polyfluoroaro-

matic nitrogen heterocyclic systems are all activated, relative to the corresponding

benzenoid compounds, towards nucleophilic aromatic substitution. The magnitude of

this activation is illustrated by the effects of a ring nitrogen, relative to C2F at the

same position, for attack by ammonia [91] (Figure 9.32).

NN

N

N

N N

N

NF F FF

1 37.4 2000 >105

Figure 9.32 Ratio of rate constants for attack by NH3 / aq. dioxane, 258C

It is clear from these data that ring N is a major factor affecting reactivity and

orientation of attack in these systems. Nevertheless, pentafluoropyridine reacts with

various nucleophiles to give products arising from exclusive attack at the 4-position

(Table 9.7), whereas 3H-tetrafluoropyridine gives a mixture of both 4- and 6-attack

Table 9.7 Nucleophilic attack on pentafluoropyridine and related heterocyclic compounds, and some

interconversion reactions

Reaction Ref.

Pentafluoropyridine

N

F

OCH3 OCH3

OCH3 CH3O OCH3

OCH3

N

F

N

F

i, CH3ONa, CH3OH

i i[98, 99]

Contd



Table 9.7 Contd

N

F

NH2

aq. NH3

N

F

N2 F

N

F

Br

CuBr

i, aq. HF, NaNO2, −20 to −25� C

N

F

NO2

CF3COOOH

N NF F

Cu, 230� C

i

[98, 100, 101]

N

F

OH

N

F

OH

10 1

N

F

OCH3

N

F

OCH3

i, KOH, t-BuOH; ii, KOH, CH3I, 100� C

i ii[102]

N

F

I

i, NaI, DMF, 150� C

i[103]

N

F

i, [π−C5H5Fe(CO)2]

π−C5H5Fe(CO)2

i [104]

Perfluoroisoquinoline

NF FLiAlH4

H

[105]

Contd


316 Chapter 9

Table 9.7 Contd

NF F

OCH3

NF F

OCH3

CH3ONa

CH3O

CH3OH

[105]

NF Faq. NaOH

OH

NHF F

O

[106]

Perfluoroquinoline

N

F F

N

F F

i, CH3ONa, CH3OHOCH3

OCH3

AlCl3, 120� C AlCl3, 120� C

N

F F

N

F F

OH

NH

F F

O N

F F

O

OH

CH3

N

F F

OCH3

CH2N2, Et2O

i, H2SO4

ii, H2O

i

[52, 105, 106]

Contd



(Figure 9.33). Since 4-attack (one ortho-F, two meta-F) and 6-attack (one ortho-F, two

meta-F) have approximately the same activation by F substituents, it is clear that the ring N

only discriminates by a factor of ca. 3.7 in favour of the 4-position. Therefore, it is clear

that the F substituents determine the generally specific attack at the 4-position on penta-

fluoropyridine (Figure 9.34).

Table 9.7 Contd

Miscellaneous

Perfluoro-3,3’-bipyridyl

i

OCH3

F

N N

F 88%

i, CNH3ONa, CH3OH

[107]

Perfluoropyridazine

i

N

NF

CH3O

N

NCH3O

CH3O

F also tri- andtetra-methoxyderivatives

i, CH3ONa, CH3OH

[108]

C6H5SNa

N

N 85%(SC6H5)4[108]

H+, H2O

N

NF

OH

N

NF

OH

Polymer[109]

Perfluoropyrimidine

aq NH3

N

N

NH2 NH2

F

N

NFor

H2N

[110]

N

N

OCH3

F

H3CO

i, CH3OH, Na2CO3

i[110]


318 Chapter 9

N

F

H

NH3/Dioxane

N

F

H

N

F

H

NH2

H2N

3.7 1

½76�

Figure 9.33

N

FNuc

F

δ+

δ−

o

m

o

m

N

Fo

m

o

m

F Nuc

N

F

Nuc

F

Figure 9.34 The activating influence of the F-substituent is maximised

The positions of the most favourable monosubstitution in attack by nucleophiles are

shown in Figure 9.35 for various systems; it is clear that directing effects by F have a

major influence on the orientation of attack.

N

F

N

FFN

FF FF

N

NF

N

NF

N

N

F

N

NFF

N

N

FF

N

N

FF F

cf

Figure 9.35

Of course, when bromine or chlorine is at the 4-position in the pyridine system, then

attack at the 2-position is favoured (Figure 9.36).

N

F

Br

aq NH3

N

F

Br

NH2

½100�

Figure 9.36



A rare case of preferential 2-attack occurs with potassium hydroxide in t-butanol. Here,

this result has been attributed to the large steric requirement of the solvated nucleophile,

and the fact that the 4-position is the most crowded site. Consequently, it is observed that

3,5-dichlorotrifluoropyridine gives preferential 2-attack with this reagent [102] (Figure

9.37).

N

F

i, KOH, t-BuOHN

F

OH

X X X X

N

F

X X

OH

i

X = F, 90 10

X = Cl, 30 70

½102�

Figure 9.37

In the case of 4-nitrotetrafluoropyridine, a 4-nitro group is in competition with ring

nitrogen as an orientating influence [101]. As in the benzene series, however, the effect of

the nitro group is very dependent on the nucleophile and is also affected by solvent. Much

more attack adjacent to the nitro group occurs with ammonia (Figure 9.38) and, again, this

can be attributed to hydrogen bonding. Displacement of the nitro group itself also occurs

readily.

N

F

i, NH3, Et2O

N

F

NH2

N

F

NH2i

N

F

NH2

NO2

27% 48% 25%

NO2 NO2

½101�

Figure 9.38

There are other cases [102, 107] where the subtle interplay of solvent and steric effects

has a profound effect on orientation of substitution.

Polysubstitution: Most groups introduced by nucleophilic substitution are subsequently

electron-donating and therefore deactivating towards further attack; for example, attack

on perfluoropyridine by methoxide becomes progressively more difficult but eventually

leads to 2,4,6-trisubstitution [98, 99] (Table 9.7). In this case R in 9.39A and 9.39B

(Figure 9.39) is electron-donating and so 9.39A is preferred. Examples will be discussed

later where the substituent is electron-withdrawing, for example, R ¼ CF2CF3, and then

2,4,5-trisubstitution occurs, indicating that in this case 9.39B is preferred to 9.39A.

The fact that the order of nucleophilic substitution is as indicated in Figure 9.40

allows the use of polyhalopyridines for synthesis of heterocyclic systems with unusual

substitution patterns [111]. Moreover, when this methodology is applied in combination

with palladium chemistry, the possibilities are extensive [112, 113] (Figure 9.41).


320 Chapter 9

N

F

RF F

F

Nuc R

9.39A

N

F

RF F

F R

9.39B

Nuc

Figure 9.39

N

F

1

23

Figure 9.40

Remarkably, we note that orientation of substitution in 2,4,6-tribromodifluoropyridine

depends critically on the nature of the nucleophile. So-called ‘hard’ nucleophiles, e.g.

�OCH3 and NH3, give exclusive attack at the ‘hard’ electrophilic centres, i.e. C2F,

whereas ‘soft’ nucleophiles displace bromine. This is further evidence for the importance

of ion–dipole interactions, regarding attack at C2F bonds. Reactions of perfluoro-quinoline

and -isoquinoline with hard and soft nucleophiles have also revealed a sensitivity towards a

change in orientation of attack with the nature of the nucleophile [114] (Figure 9.42).

To account for these results, it has been suggested that the 1-position, i.e. the position

adjacent to the ring N, is the harder electrophilic site [114].

In the quinoline system the nature of the substituent groups also can govern the position

of entry of a nucleophile. When R in 9.43A (Figure 9.43) is electron-donating, methoxyl

for example, then a 2,4,7-trisubstituted compound 9.44A is obtained (Figure 9.44),

because 9.43A is preferred to 9.43B; but when R is electron-withdrawing, CFðCF3Þ2 for

example, then a 2,4,6-trisubstituted compound 9.44B is obtained [115] because perfluoro-

alkyl groups stabilise 9.43B relative to 9.43A.

Acid-induced processes: Although perfluoroaromatic nitrogen heterocyclic compounds

are only weak bases, nucleophilic substitution can be induced by protonic or Lewis acids,

as outlined in Figure 9.45, and interesting contrasts in orientation can sometimes be

achieved because attack ortho to nitrogen is often preferred under these conditions.

It is clear from the striking tendency for the protonated systems, as shown in Figure

9.46, to give attack ortho to nitrogen that, again, polar influences are extremely important

in governing the reactivity of a C2F bond, at least with hard nucleophiles. In both of the

examples contained in Figure 9.46, the orientation of entry of the nucleophile is changed

in comparison with reaction with the neutral system. We may conclude, here, that in

systems containing structure 9.47A (Figure 9.47) the positive pole involving nitrogen has

significantly enhanced the reactivity of adjacent C2F bonds. It will be clear, therefore,

that this is similar to the argument advanced for the activating influence of an ortho-C2F

for nucleophilic attack on an adjacent 5C2F bond (9.47B).



N

Fi

N

F

Br Br

Br

N

F

H H

H

ii

i, HBr/AlBr3, 150� C; ii, Pd/C/H2(4Bar), Et3N, CH2Cl2, rt

N

F

Br Br

Br

Nuc

NBr Br

BrX1 X2

Nuc = NaOMe X1 = X2 = OMe

Nuc = NH3 X1 = F, X2 = NH2

N

F

Br Br

Br

i

N

F

Br

i, CuI/(Ph3P)3PdCl2, Et3N, RC CH (R = C3H7 or Ph)

C CRRC C

N

FNuc

N

F

Br Y2

Y1

Nuc = Et2NH; Y1 = Et2N, Y2 = Br

Y1 = Br, Y2 = Et2N

Y1 = PhS, Y2 = Br

3 :

2

Nuc = PhSH;

Br

Br Br

½112�

½112�

½112�

½112�

Figure 9.41

Hydrogen halides give products where substitution para to nitrogen occurs almost as

readily as at the ortho position [117], whilst Lewis acids usually give polysubstitution

[118] (Figure 9.48).


322 Chapter 9

NF F

NF F

NF F

NF F

X

X X

X

9.42A 9.42B 9.42C

Nucleophile

HS , DMF/(CH2OH)2 100%

PhS , EtOH 99% 1%

MeO , MeOH 93% 7%

4-NO2C6H4O , EtOH 100%

(X = SH)

(X = SPh)

(X = MeO)

(X = 4-NO2C6H4O)

Nuc

½114�

Figure 9.42

N

F F

N

F F

Nuc

9.43A 9.43B

FNuc

F etc

R R

etc

Figure 9.43

N

F F

OCH3

OCH3

OCH3

OCH3N

F F

CH3O

i, CH3O , CH3OH

N

F F

CF(CF3)2

CF(CF3)2 N

F F

CF(CF3)2

CF(CF3)2

CH3O

i

i, CH3O , CH3OH

i

9.44A

9.44B

½116�

Figure 9.44



N F

Acc

N F

Acc.

Nuc

N F

Acc.

Nuc

−F

N Nuc

Acc.

Acc. = Electron Acceptor

F F F

F

Figure 9.45

N

NF

N

NF

N

NF

N

NF

N

NF

N

NF

H

H2SO4

MeOMeOH

Et3OBF4

OMe

OMe

Et

MeO

MeO

70%

H2O

MeOH 35%

N

F F

N

F F

OMe N

F F

OMe

N

F F

H

N

F F

OMe

i

ii

iii

i, = MeONa/MeOH ii, = c. H2SO4 iii, = MeOH/Slow dilution

O

Et

½108, 109�

Figure 9.46


324 Chapter 9

9.47A 9.47B

CN

H F

NucCC

F F

Nucδ+

δ −

Figure 9.47

N

F F F F FF

N NCl

Cl

Cl

23% 57%

i, HCl, 100� C, Sulpholan

N

F Fxs BCl3

140� C

xs BBr3

150� CN

F

N

F

Br

F

Br

Cl

F

Cl

88% 91%

i½117�

½118�

Figure 9.48

As explained above, these are potentially important processes because introduction of

bromine by these simple procedures allows access to the powerful range of palladium

chemistry that is now available [112] (Figure 9.49).

3 Fluoride-ion-induced reactions

Polyfluoroalkylation: Some of the chemistry of polyfluoroalkyl anions, generated by

reaction of fluoroalkenes with fluoride ion, was discussed in Chapter 7, where the analogy

between the role of fluoride ion in fluorocarbon chemistry and the role of the proton in

hydrocarbon chemistry was emphasised. This analogy has been extended to include

reactions of polyfluorinated anions, generated in the same way, with activated poly-

fluoro-aromatic systems in what may be regarded as the nucleophilic counterpart of

Friedel–Crafts reactions [119] (Figure 9.50).

Polysubstitution raises some complications for three reasons: (a) when two polyfluoro-

alkyl groups are already present these can, in some cases, control the position of further

substitution; (b) some of the reactions are reversible; and (c) substitution at the position

most activated to attack sometimes results in crowding and therefore not the most

thermodynamically stable system. This can lead to a competition between kinetic and

thermodynamic control of reaction products [116, 122–128].



N

N

F

Br

Br

i

iiN

N

F

C CC3H7

C CC3H7

i, CuI, (Ph3P)3PdCl2, Et3Nii, C3H7C CH

½112�

Figure 9.49

CF3CF=CF2

N

F

i, KF, Sulpholan

N

F

N

F

RF

RF RF

RF

RF

RF

F CF2=C CF3 C

CF3 C ArF F CF C Ar F

cf C ArH C Ar H

i

CF2=CF2

N

F

N

F

N

F

i, KF, Sulpholan

i

RF = CF(CF3)2

RF = CF2CF3

½120�

½121�

Figure 9.50

The rather complicated system that results in the pyridine system, after the trisubstitu-

tion stage has been reached using perfluoroisopropyl anions [116, 122–124, 128], is shown

in Figure 9.51. At lower temperatures, after disubstitution, further attack on 9.51D is

kinetically preferred at the 5-position through 9.51B, with the perfluoroalkyl groups now

controlling the orientation, as explained earlier. However, at higher temperatures, the

process becomes reversible with attack by fluoride ion occurring at the 5-position in

9.51A, leading to displacement of a perfluoroisopropyl group that can then re-enter, at

higher temperatures, at the 6-position via 9.51F. Attack by fluoride ion can also occur at the

4-position in 9.51A, giving the 2,5-derivative 9.51C. Finally, the situation is further


326 Chapter 9

complicated by the fact that the perfluoroisopropyl anion is in equilibrium with the

perfluoroalkene and this produces oligomers (see Chapter 7). The crowding that arises

from a perfluoroisopropyl group is reflected by the 19F NMR spectra where, for example,

for the compound 9.51D at �408C two geometric isomers 9.51D1 and 9.51D2 may be

detected [125, 126, 129], with the 4-substituent being essentially in two conformations.

−F−

F−

N

F

F−

N

F

F

N

FF

N

F

N

FCF(CF3)2 CF(CF3)2

RF

RF

RF

RF

RF

RF

RFRF

RF

RF

RF RF

RF RF

RF

RF

RF

RF

RF

N

F

N

FF

F

9.51A

9.51B

9.51C 9.51D

9.51E 9.51F

(CF3)2CF−F

−

CF3CF=CF2

Dimers and Trimers

RF = CF(CF3)2

CF3CF=CF2

½116, 122, 123�

Figure 9.51

Contd



N

F

CF CF3

CF3

CF3F3C

F N

F

C

CF3

F

F3C

F3C

F3C

F

9.51D1 9.51D2

½125, 126, 129�

Figure 9.51 Continued.

The 2-substituent is aligned preferentially with the CF3 groups towards nitrogen and it is

understandable, therefore, that the trisubstituted isomer 9.51E is more stable than 9.51A.

Tetrafluoroethene leads only to the 2,4,5-trisubstituted compound [124], which does

not rearrange, whilst perfluoroisobutene gives only the 2,4,6-trisubstituted compound; the

2,4,5-isomer, in this case, is probably very crowded. This variation in the orientation of

trisubstitution products obtained with the alkene used is related to the reversibility of the

process and to the crowding occurring in the 2,4,5-isomer. Carbanion stabilities decrease

in the series ðCF3Þ3C� > ðCF3Þ2CF� > CF3CF�2 and therefore reversibility and crowding

also follow this series (Figure 9.52).

CF2=CF2

N

F

i, CsF, Tetraglyme, 80�C

N

F

RF

RF

RF

N (RF)n

CF2=C(CF3)2

N

F

N

F

RF

RF RF

i

i

i, CsF, Tetraglyme

RF = CF2CF3

RF = C(CF3)3

½121, 124�

½124�

Figure 9.52

Fluoride-ion-induced rearrangements of perfluoro(alkyl-aromatic) compounds may be

regarded as a further stage in the analogy between fluoride-ion- and proton-induced

reactions [124, 127]. Those that have been established so far occur by intermolecular

processes, as indicated by, for example, crossover experiments [116, 122, 123], whereas

proton-induced rearrangements of alkylbenzenes may be intermolecular or intramolecu-

lar, depending on the system. However, intramolecular anionic migrations of polyfluoro-

alkyl groups remain to be found but are very unlikely.

Only in the case of triazines have perfluoroalkyl groups been introduced directly

from the perchloro compounds [130]. The 1,2,3triazine system gave an unusual product,


328 Chapter 9

arising from nucleophilic attack at N in 9.53B, accompanied by loss of fluorine from a

tertiary site (Figure 9.53). A similar process occurs in the reaction of 2,3-dimethylbuta-

diene with 9.53B, giving the unusual spiro system 9.53D [131] (Figure 9.53), but without

the loss of fluorine.

NN

NCl

RF

RFRF

RF

RFRF RF

RF

RF

NN

NN

NN NN

N

CCF3F3C

F

9.53A 9.53B 9.53C

RF = C(CF3)3

NN

N

RFRF RF

RF

RF

RFRF

RF

RF

9.53B

i

i, CH2=CH(CH3)CH(CH3)=CH2

9.53D

NN

N

H3C CH3

NN

N

H3C CH3

½130�

½131�

Figure 9.53

Recent methodology, using amines as initiators to provide the active fluoride ion, inthe absence of a solvent, has made access to these sytems on a large scale quite

feasible [115].

A recent exciting development [132, 133] of this chemistry involves conversion of

perfluoro(4,5-di-isopropyl)phthalonitrile to corresponding metal perfluorophthalocyanine

complexes; for example, when perfluoro(4,5-di-isopropyl)phthalonitrile was melted with

zinc acetate at 1808C, a blue-green solid was obtained which was established as the

phthalocyanine derivative. These perfluoroalkyl derivatives are much more soluble than

other halogenated phthalocyanines and, moreover, they appear to be excellent sensitisers

for the production of singlet oxygen.

Reactions involving chlorotrifluoroethene and bromotrifluoroethene introduce further

complexities which are summarised in Figure 9.54 [134]. Direct substitution may occur

giving 9.54A, but this is frequently accompanied by loss of Cl or Br from the side chain

to give a pentafluoroethyl derivative 9.54B. Exchange is also possible (when X ¼ Br) to

give 9.54C, together with a vinyl anion that may then react to give 9.54F, which is also

able to form an anion 9.54E, and this anion can finally give a diaryl derivative 9.54D.

Results relating to this scheme are shown in Table 9.8.



CF2=CFXF

CF3CFX

X = Cl, Br

CF3CFX

F + ArFCFXCF3F

ArFCF2CF3

ArFF

CF2=CFX

CF3CFX2 + CF2CF

ArFF

ArFCF=CF2ArFCFCF3

F(ArF)2CFCF3

9.54A 9.54B

9.54C

9.54D 9.54E 9.54F

½134�

Figure 9.54

Table 9.8 Polyfluoroalkylations and related reactions

Reaction Ref.

N N

N

C3F6N N

N

F [CF(CF3)2]nF3−n

CsF

200−300�C

n = 1, 39%; n = 2, 51%; n = 3, 5%

[135]

N

N5 C3F6F


N

NF

RF

RFN

NF

RF

RF RFN

N

RF

RF RF

RF

6% 81% 3%

RF = CF(CF3)2

i+ +

[136]

N

F CF3CF=CFCF3

N

F

RF

RF

i

i, CsF, Sulpholan, 100� CRF = CF(CF3)CF2CF3

[137]

Contd


330 Chapter 9

Table 9.8 Contd

N

NF CF2=CFCl

N

NF

CF3CF2

N

NCF3CF2

F

CF3CF2

i

i, CsF, Sulpholan, 90�C 57% 19%

[134]

N

F CF2=CFBri


N CFCF3F

2

+ CF3CFBr2 [134]

N

NF CF2=CFBr

i


N

NF

CF3CF2

N

NF

CF3CF2

CF3CF2

[134]

N

F CF3C CCF3i

N

F

CF3CC

F

CF3

N

F

CF3CC

CF3

Fn

n = 2 and 3i, CsF, Sulpholan, 110� C

[138]

i, CsF, SulpholanN

F EtO2CC CCO2Eti

N

F

EtCO2C

F

CO2Et

[138, 139]

Fi F

CF3CC

CF3

Fn

CN CN

i, CsF, DMF, 125� C

CF3C CCF3 [140]



The mechanism of displacement of chlorine and bromine by fluoride from the side

chain of these systems is of interest. It has been suggested that an SN20 type of displace-

ment of fluorine from 3-trifluoromethylquinoline occurs in reactions with sodium eth-

oxide [141] (Figure 9.55), and a similar process could account for the displacements of

chloride or bromide by fluoride from 9.54A that were indicated in Figure 9.54.

N

CF3

N

CF2

HEtOOEt

i

i, NaOEt/EtOH/Reflux

N

CF2OEt

−F

N

CF=OEt

N

C(OEt)3

EtO etc

H2O

N

CO2Et

½141�

Figure 9.55

A striking example of an intramolecular nucleophilic displacement of tertiary F is

shown in Figure 9.56 [142].

Further examples of polyfluoroalkylation are given in Table 9.8.

Other systems: Additions of perfluoro-2-butyne [143] and acetylene dicarboxylic ester

[139] to perfluoro-aromatics will also occur (see Table 9.9 and Chapter 7, Section IIIB).

The extending anion may be trapped, and the more reactive the aromatic compound used,

the more effective the competition with polymer formation (Figure 9.57) [144].

Cyanuric chloride, rather than the fluoride, is used for the formation of polyfluoroalkoxy

derivatives [145]: the probable advantage of using the perchloro compound lies in reducing

the possibility of a back-reaction when X ¼ Cl in the sequence shown in Figure 9.58.

4 Cyclisation reactions

Many procedures are now available for forming cyclic systems [147] and several will be

dealt with later; this section is concerned with procedures that, at some stage, involve

nucleophilic aromatic substitution. In the examples shown in Figure 9.59 the addition and

cyclisation occur in a single process, whereas, in other cases (Figure 9.60), an intermedi-


332 Chapter 9

ate is isolated before cyclisation. Polycyclic systems may be obtained from ortho-difunc-

tional compounds (Figure 9.61).

N

NF

RF RF

RF

N

N

RF

NMe2

Me2NN

NC

RF

NMe2

Me2N

CF3

F3C

F

N

NC

RF

N

Me2N

CF3

F3C

N

NC

RF

NMe2

N

CF3

F3C

H3C CH3

BF4 H2C

H3C

N

N

N

NMe

RFCH3

H

H

F3CCF3

i ii

iii

iv

(Yellow)

(Purple)

(Colourless)

i, Me2NH/DMF/Room Temp.ii, Standing or on addition of wateriii, BF3.Et2Oiv, Moist Acetone

RF = CF(CF3)2

½142�

Figure 9.56

CF3C CCF3 CF3CF=CCF3

CF3C CCF3

CF3CF=C(CF3)C(CF3)=CCF3

ArFF

ArFFCF3C CCF3

C(CF3)=CF(CF3)n

Polymer

+ F

Figure 9.57



RFO + ArX ArORF + X (X + Cl or F)

N N

N

Cl (CF3)2CO.KFDiglyme

−10� C N N

N

[OCF(CF3)2]3

86% conversion

½146�

Figure 9.58

F

SH

F

SC

C

COOEt

COOEt

F

SC

C

COOEt

COOEt

iii, −Fiv, H2SO4

i, ii

i, n-BuLi ii, EtOOCC CCOOEt

F

SCH

CH Cu

Quinoline

F CH3COCHCOOEt NaNaH

THFF

C

C

O CH3

H

COOEt

FC

C

HO CH3

COOEt

BaseFC

C

O CH3

COOEt

FC

C

O CH3

H

H

i, NaH.1THF, 2DMF reflux

FC

C

O CH3

Hi

½148�

½149�

½146, 150�

Figure 9.59


334 Chapter 9

FC

C

O CH3

H

H FC

C

HSCH3

H

FC

CS

H

i, H2S, EtOH, O� C

H

SH

CH3

ii, Pyridine, NaOH, Reflux

i

ii

½148�

Figure 9.60

Li Li

+ SCl2 or S2Cl2

F F F F

S

i

i, Et2O, hexane, −78� C

½151�

Figure 9.61

More recently, it has been demonstrated [152] that polyhalopyridines may be used to

synthesise a series of macrocycles, making use of the fact that, if the 4-position is blocked,

then the remaining 2,6-sites are available to react with difunctional derivatives (Figure

9.62).

N

F

X N

F

X

N

F

X

N

F

X

N

F

X

O

O

O

O

O

O

O

O O

O

i ii

i, Me3SiOCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days

X = CF(CF3)2, 94%X = OMe, 80%

X = CF(CF3)2, 64%X = OMe, 85%

ii, Me3SiOCH2CH2OCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days

½152�

Figure 9.62



C Reactions with electrophilic reagents

Displacement of Fþ from an aromatic system by electrophiles is obviously not a very

favourable process; indeed, fluorine might be considered as the worst possible leaving

group in a non-concerted process. Nevertheless, reactions of concentrated nitric acid with

perfluoro-aromatic compounds, for example perfluoronaphthalene, give quinones, or

addition products may be obtained using HNO3 in HF or NO2BF4 in Sulpholan [153].

Thus, perfluorinated systems will undergo reactions with some strong electrophiles to

give products that formally arise from electrophilic displacement of fluorine, whatever the

detailed mechanism may be (Figure 9.63).

F Fi

F F F F

CH3CH3

i, CH3F, SbF5, SO2ClF, 20� C

½1, 154�

Figure 9.63

Ring fission to the phthalic acid derivative has been observed [155] (Figure 9.64).

F F F

F NO2

F

F NO2

F

F

F

FF FF

COOH

COOH

F F

F

F

O

O

c. HNO3 H2O

F

F

O

F

O

i F

61%

71%

i, NO2+ (NO2BF4 or HNO3.HF)

½153, 155�

Figure 9.64

Sigma-complexes have been generated, and their NMR spectra observed, by reaction of

various dienes with antimony pentafluoride [156, 157] (Figure 9.65).

Under certain conditions, radical cations have been observed [158] using ESR, and

stable radical-cation salts have been fully characterised [159, 160] (Figure 9.66).

Fluorine in the side chain can, of course, be hydrolysed under acidic conditions [18],

whilst the polyfluorobenzyl cation may be obtained by removal of fluorine from per-

fluorotoluene [161] (Figure 9.67).


336 Chapter 9

O

O

FSF4

F

O

O

F

O

F

SbF5

SbF6

H2O

F F

F5

½156, 157�

Figure 9.65

F FSO3.SbF5

Oleum F F SO3.SbF5

C6F6 + O2AsF6 C6F6 AsF6 + O2

NO

C6F6 + NO AsF6

½158�

½159, 160�

Figure 9.66

CF3

CF3

F

i, H2SO4, SO3, 150� C, 12hr

CF3

Fi

COOH

COOH

F

CF2

F

CF3CF=CF2

CF2CF(CF3)2

F

i

i, SbF5, HF, 50-60� C

½18�

½161�

Figure 9.67



Hydrogen in a highly fluorinated system can often be displaced surprisingly readily

using electrophilic reagents (Figure 9.68); this reflects the fact that a transition state

resembling that in Figure 9.69 is stabilised by fluorine atoms at the ortho and para sites by

donation of electron density from the non-bonding p-orbitals on fluorine. Indeed, a

perfluorinated arenium salt has been generated from perfluorocyclohexa-1,4-diene

(Figure 9.65).

Electrophilic cleavage of pentachlorophenylpentafluorophenylmercury provides a

useful direct competition between pentafluorophenyl and pentachlorophenyl, for electro-

philic attack. Exclusive attack at pentafluorophenyl occurs, showing that the cumulative

activating effect of the ortho- and the para-fluorine substituents is dominant [168]

(Figure 9.70).

D Free-radical attack [169]

Photochemical chlorination of perfluorobenzene [170] and perfluoropyridine [171], and

reactions with bistrifluoromethyl nitroxide [171], give addition products, although the

C5N bond is very resistant to radical attack (Figure 9.71).

It is well known that free-radical aromatic substitution occurs readily when aryl

radicals are used, and extensive studies have been made using diaryl peroxides as the

source of these radicals. The effect of fluorine on the process may be considered in two

parts: first, most substituents may be expected to encourage the formation of radical

intermediate 9.72A in Figure 9.72; second, in reactions with hydrocarbon radicals, polar

effects should also increase reactivity, since the ring would be made more electrophilic.

The converse would be expected to apply with electrophilic radicals, e.g. CF3� or C6F5�.By contrast, it is not easy to predict the fate of radical 9.72A, once formed; fluorine atoms

are unlikely to be generated, but transfer of a fluorine atom to another species is possible.

Arylation of perfluorobenzene does indeed occur when dibenzoyl peroxide is used, but

ðC6F5COOÞ2 gives only tar: the scheme shown in Figure 9.73 has been proposed

[172–174].

In contrast, perfluoronaphthalene gives a mixture of products with benzoyl peroxide,

but they mainly arise from attack by C6H5CðOÞO� [173].

Cyclisation may be achieved in some electrochemical oxidations. These have been

formulated as radical substitutions [176, 177] (Figure 9.74).

Electrochemical reduction of polyhalopyridines has been observed; the position of

H-transfer corresponds with calculated spin and charge densities [179] (Figure 9.75).

Reductive defluorination will also occur under relatively mild conditions, in some

circumstances by electron transfer from metals, e.g. zinc [180, 181] (Figure 9.76).

1 Carbene and nitrene additions

Additions of carbenes to perfluorobenzene have been reported [182, 183] and tropylidene

structures for the products have been proposed (Figure 9.77).

Addition of difluorocarbene to perfluorobenzene has been proposed to account for the

formation of perfluorotoluene and other perfluoromethylbenzenes in the pyrolysis of

perfluorobenzene with potassium fluoride, or with polytetrafluoroethene as a difluoro-

carbene source [184, 185]. Indeed, Russian workers have studied the pyrolysis and


338 Chapter 9

F

H

F CH

3i, CHCl3, AlCl3, 150� C

F

H

i, Br2 (or I2), Oleum, 60−65� C

F

Br

F

H

F

NO2

i, HNO3, Sulpholan, BF3, 60−70� C

F

H

F

CH(CH3)2

i, C3H6, CBr4, AlBr3, 0� C

F F

Br

i, FeBr2.CCl4, Reflux

F F

NO2

i, HNO3, Oleum, 70� C

90-94%

F

H

3 F

C6F5

C6F5 C6F5

SbF5,F

i

i

i

i

i

i

½162�

½163�

½164, 165�

½166�

½1, 154�

½167�

½167�

Figure 9.68



E H

F5

Figure 9.69

C6F5HgC6Cl5

i, HCl, 100� C, 65hr, Sealed tube

C6Cl5Hg

C6Cl5HgCl + C6F5Hi

Cl−

+

F5

H

½168�

Figure 9.70

FCl2, hn

48hr

ClF

F

Cl

F Cl

Cl

F

Cl

F

Cl F

N

FCl2, hn

35hrN

ClF

F

Cl F

Cl

F

Cl F

½170�

½171�

Figure 9.71

R F

R F

F

R

F ?

9.72AF5

Figure 9.72

co-pyrolysis of systems containing perfluoro-aromatic compounds and developed an

extensive chemistry where a variety of substituents appear to be eliminated, frequently

in preference to fluorine [186–188] (Figure 9.78).

Elimination of difluorocarbene from a s-complex 9.79A has been proposed, although

the fate of the rest of the molecule is not clear, and the addition could involve either an

insertion reaction (a) or formation of a tropylidene (b) (Figure 9.79).

Similar processes can be proposed to account for the formation of trifluoromethyl

derivatives in the pyrolysis of heterocyclic compounds [189–193] (Figure 9.80).

In contrast, a stable carbene has been synthesised having a push–pull combination of

electron donation and withdrawal [194] (Figure 9.81).


340 Chapter 9

F Ar

Ar F

F

Ar

ArCOOArCOOF

Ar F

Ar

Coupling

FF F

F5

½172, 174, 175�

Figure 9.73

C6F5NH2−e

C6F5NH2−H

C6F5NH

C6F5NH2

N

H2N

H

F F F

N

N

F F−e

etc

C

H2N

O

F F

N

C

F F

O

H

½177�

½178�

Figure 9.74

Insertion of nitrenes occurs readily and may lead to ring expansion and a variety of

rearrangements [195, 196] (Figure 9.82).

Cyanotetrafluorophenylnitrene gives very high yields of C2H insertion compounds

[197] (Figure 9.83).

E Reactive intermediates

1 Organometallics

Fluorocarbon organometallic compounds [198, 199] are discussed more generally in

Chapter 10, but polyfluoroaryl-lithium, -magnesium and -copper compounds are particu-

larly important in organic synthesis, as outlined below.



N

X

F

N

X

N

X

N

X

N

H

F

i

ii

i, Hg Cathode, DMF, Et4NBF4, −1.8V (SCE)ii, Hydroquinone

X = Cl, F

F4 F4

F4

H

½179�

Figure 9.75

F

CF3

CF3 CF3 CF3 CF3

CF3CH3

F

CF2(CH2)5CH3

F F

Hi

i, Zn (Cu), DMF, H2O, 1-Hexene, 65� C

COOH

F F

COOH

F F

H

i

i, Zn, aq.NH3, rt, 2hr

½180�

½181�

Figure 9.76

C6F6 + N2

hνF 30%

C6F6 + (CF3)2CN2

hνF

CF3

CF3

20%

½182�

½183�

Figure 9.77

Lithium and magnesium derivatives: Bromopentafluorobenzene forms a Grignard reagent

readily [163] which can be used in conventional ways in syntheses [200, 201] (Figure

9.84). The tetrafluoropyridyl compound can be obtained in a similar way [98, 100, 103].


342 Chapter 9

C6F6 + CF2CF2 n550�C

C6F6 + C6F6-n(CF3)n

n = 1,2,3

C6F5XCF2

C6F5CF2

CF2=CF2 C6F5CF2CF2CF2

F F

−F (?)

½185�

½186�

Figure 9.78

C6F6F

(KF)

F F

CF2

(a) Insertion

(b) Addition

C6F6

C6F6

C6F5CF3

F

F

F

FF

F

F

F

9.79A

F5

Figure 9.79

N

F CF2CF2 n

550� C

N

F

N

F

CF3 CF3F3C

60% 6%

N

F

CF3

85−90% +2- and 4- isomers N

F

i, KF, 8hr, 550−560� C

i

½193�

½189�

Figure 9.80



CNH3C

R

F3C

F3C

½194�

Figure 9.81

C6F5N3i

[C6F5N:]

N

F

N

N

F F

i, Flash Vac. Pyrolysis/300� C

C6F6 + N3CN45� C N NCF ½195�

½196�

Figure 9.82

CN

N3

F hν

CN

N

F

CN

N

F

H C6H11

75−80%

c-C6H12 ½197�

Figure 9.83

C6F5MgBrC6F5Br C6F5COOH

67%i, Mg, Et2O, or THF

CO2i

C6F5CH2CH2OH

O

½200�

½201�

Figure 9.84

Lithium derivatives [202] are more versatile and more convenient to use than the

Grignard reagents, although the report of serious explosions occurring with pentafluoro-


344 Chapter 9

phenyl-lithium [203] emphasises the extreme care that must be taken. Although many and

varied reactions using pentafluorophenyl-lithium and other polyfluoroaryl-lithiums have

been carried out in the author’s laboratory, without incident, it is clear that all polyfluor-

oaryl-lithium or polyfluoroarylmagnesium derivatives should be treated as poten-

tially hazardous, particularly when hydrocarbon solvents are used at low temperatures, at

which the lithium derivative may be precipitated.

In general, polyfluoroaryl-lithiums are best obtained by metal–halogen exchange [204]

using, for example, commercially available butyl-lithium, or by metallation of hydro

compounds [205–207], the hydrogen being especially acidic when flanked by two fluor-

ine atoms. The latter method has the advantage of not generating alkyl bromides that can

be difficult to separate from some products (Figure 9.85).

C6F5Br + n-BuLiEt2O

−78� CC6F5Li + n-BuBr

H

X

F

X = H or F

+ n -BuLiEt2O

−78� C

Li

X

F

½204�

½205, 208�

Figure 9.85

The use of some polyfluoroaryl-lithiums in organic synthesis is illustrated in Table 9.9;

these reagents have, of course, been used to make many corresponding derivatives of

other elements, but this will be illustrated in the next chapter.

Table 9.9 Some organic syntheses using polyfluoroaryl-lithiums

Reaction Ref.

C6F5Li

i, B(OMe)3, H2O2

C6F5OH 39%i

[209]

C6F5Li

i, S8; ii, H2O

C6F5SH 46%i, ii

[210]

C6F5Li

i, CO2; ii, H, E+t2O, <55� C

C6F5COOH 99%i

[205]

C6F5LiHCO(NMe2) C6F5CHO 61% [211]

Contd



Copper compounds [215]: An interesting contrast occurs between phenyl- and penta-

fluorophenyl-copper compounds, in that the fluorinated derivatives are considerably more

stable [216–220] and are useful reagents in organic synthesis (Figure 9.86).

A remarkable double insertion of difluorocarbene, derived from trifluoromethyl

copper, has been reported [227] (Figure 9.87).

2 Arynes

Polyfluoroaryl-lithiums and, to a lesser extent, the Grignard reagents will decompose by a

b-elimination of metal fluoride, leaving an aryne whose properties are considerably

affected by the remaining fluorine atoms. The highly electrophilic nature of these species

leads to some reactions, e.g. with benzene derivatives, that are not shown by benzyne

itself [228] (Figure 9.88).

Table 9.9 Contd

C6F5Li(MeO)2CO

(C6F5)2CO 70% + (C6F5)3COH [212]

OH

H

Fn-BuLi

OLi

Li

F

OH

COOH

Fi, CO2

ii, H+ 84% [209]

H

Br

Br

HF

F

Li

Br

Br

HF

FHOMe2C

Br

Br

HF

F

i ii

i, LDA, THF, −78� C; ii, Me2CO, −78� C

[207, 213]

NH

H

F

FCl

NH

Li

F

FCl

H

COOH

F

FCl

F

i ii, iii

i, LDA, THF, −78�C; ii, Me2CO, −78�C; iii, H+

[214]

Li Li

F FSCl2

F F

S

66% [212]


346 Chapter 9

C6F5MgBr + CuIEt2O [C6F5Cu]

DioxaneC6F5Cu.Dioxane

130� C −Dioxane

[C6F5Cu]4PhI

MeI200�C

C6F5C6H5

C6F5Me

C6F5C6F5

87%

39%

C6F5ClCu(I)Cl, Mg

THF

[C6F5Cu]MeCOCl

−5� CC6F5COMe 72%

C6F5C CC6F5

CBr2=CHBr

43%

C6F5Cl

i, n-BuLi, THF, −70� C

C6F5Li [C6F5Cu]Cu(I)I CF2=CFI

C6F5CF=CF2

55%

C6F5I + 2Cu C6F5Cu + CuIMonoglyme

rt

C6F5Cu + CH2I2 CH2(C6F5)2

i

½221�224�

½216, 219, 220�

½225�

½217�

½226�

Figure 9.86

C6F5Cu + CF3Cu C6F5CF2CF2Cu−30� C

DMF½227�

Figure 9.87

F

Li

F F S

X

X

X

X

XF

SX

−SX = H, Cl

½228�

Figure 9.88



In addition to these cycloaddition reactions with nucleophilic p-donors, tetrafluoro-

benzyne is very susceptible to more general nucleophilic attack. Biphenyl derivatives

often occur as by-products in reactions of pentafluorophenyl-lithium, formed by addition

to the benzyne [204, 229] (Figure 9.89).

F

Li

FC6F5Li

F

Li

C6F5 C6F5

F

H

H½204�

Figure 9.89

A similar process, but involving further attack on the biphenyl and polyphenyls initially

produced, may account for the high-molecular-weight materials formed in the decom-

position of pentafluorophenylmagnesium bromide at elevated temperatures in THF solu-

tion [230, 231] (Figure 9.90).

C6F5MgBr FC6F5MgBr

F F

MgBr

F F

MgBr

C6F5MgBr

C6F5F F

MgBr

C6F5

n

½230, 231�

Figure 9.90

This type of process appears to occur even more easily with trifluoropyridyne [232]

(Figure 9.91).

N

F

Br

i, n-BuLi, Et2O, −78� C

N

F

Li

N

F

Furan

n-BuLi

Polymer

i ½232�

Figure 9.91

The addition of lithium pentafluorothiophenate to tetrafluorobenzyne leads to

perfluorodibenzothiophene by a novel cyclisation [233] (Figure 9.92).

Trapping with a 1,3-dipole has also been described [234] (Figure 9.93).


348 Chapter 9

F F

SH

i, n-BuLi, Et2O, C6H8, 0�C

Br

F F

S

F

S

FF

S

F

70%

i ½233�

Figure 9.92

F

Li

FPhCH=N(Ph)O

O

NF

H

Ph

Ph

½234�

Figure 9.93

Tetrafluorobenzyne may be involved in a number of other reactions, as outlined in

Figure 9.94. The p-benzyne (9.94A) has been observed using matrix isolation techniques

[236].

3 Free radicals

Free-radical aromatic substitutions were described earlier in this chapter (Section IID);

the generation of polyfluoroaryl radicals may be achieved by conventional procedures and

the effect of fluorine is mainly in making the radical more electrophilic in comparison

with the hydrocarbon counterparts. This has been illustrated for pentafluorophenyl rad-

icals in a quantitative fashion by competition for the radicals between chlorobenzene and

benzene [237], giving kðC6H5Cl=C6H6Þ ¼ 0:72 in comparison with a value for phenyl

radicals kðC6H5Cl=C6H6Þ ¼ 1:06. This lower relative rate for pentafluorophenylation,

coupled with a greater tendency towards ortho, para substitution than with phenyl, is a

quite clear indication of the electrophilic character of the fluorocarbon radical. This is also

clear from other substituent effects, e.g. the greater proportion of meta substitution with

nitrobenzene shown in Figure 9.95. Other reactions involving polyfluoroaryl radicals are

shown in Figure 9.96.

Thermal reactions of iodo compounds provide some useful direct syntheses of various

sulphur and selenium compounds [240, 241], presumably involving radicals, and radicals

are also produced from iodo derivatives by photolysis [242] (Figure 9.97).

The photo-reduction of perfluorobenzophenone in isopropanol [243] provides an inter-

esting contrast with the classical reduction of benzophenone to benzopinacol under the

same conditions (Figure 9.98). This difference between the two systems has been attrib-

uted to the greater resonance stabilisation of the radical 9.98A in comparison with 9.98B

and to electron-pair repulsions inhibiting the dimerisation of 9.98A.



F

O

O

O

OHg

300� CHg

Hg

HgF

F

F

83%

Hg

Hg

HgF

F

F

F F 39%Ag

~255� C

OF

O

O

F F 24%750� C

0.6mmHg

I

I

Fi

F

i, hν, Ne matrix, 3K

9.94A

½155�

½155�

½235�

½236�

Figure 9.94

C6F5NH2 + C5H11ONO C6F5

C6F5 + C6H5CH3 C6F5 C6H4CH3

o-(62.1), m-(21.5), p-(16.4)%

C6F5 + C6H5NO2 C6F5 C6H4NO2

o-(20.8), m-(53.4), p-(25.8)%

½237�

Figure 9.95

Pentafluorophenol is oxidised by lead tetra-acetate, giving products arising from

intermediate C6F5O� radicals [244, 245] (Figure 9.99).


350 Chapter 9

i, Bleaching Powder, C6H6

C6F5COCl

i, NaOH, H2O2; ii, C6H6, 80� C

(C6F5COO)2 C6F5COOH+ C6F5C6F5

+ C6F5COOC6F5

C C6F5C6H5

i

i ii

6F5NHNH2½198�

½238, 239�

Figure 9.96

C6F5IS, 230� C

(C6F5)2S 70%

I

I

F S, 250� C

S

S

F F 60%

C6F5INMe Me

H

NMe Me

H

C6F5

70%hν

CH3CN

½241�

½241�

½242�

Figure 9.97

(C6F5)2COhν

(C6F5)2OH CC6F5

HO

(C6F5)2CHOH + Me2CO

etc

cf (C6H5)2C=O (C6H5)2COH

9.98A

9.98B

PhPh

OH

PhPhHO

Me2CHOH

Me2CHOH

F ½243�

Figure 9.98

4 Valence isomers [246–248]

Photochemistry of fluorinated aromatic systems has made an important contribution to the

study of valence isomers because it has been possible to isolate and characterise

some species on which there had previously only been speculation. Some of these, as

might be expected, are very unstable (sometimes, treacherously so) towards reverting to



C6F5OH C6F5Oi ii

O

F OC6F5

OF

OC6F5FF

iii

OF

OC6F5F

C6F5O

i, Pb(OAc)4ii, Dimerisationiii, C6F5O etc.

½244�

Figure 9.99

the corresponding aromatic form. This is the case with perfluorobenzene but, when

perfluoroalkyl groups are present, valence isomers have been isolated that are remarkably

stable and thus present some fascinating systems to organic chemistry.

Let us consider the possible effects of fluorine or fluorocarbon groups as substituents

on the transformation of a benzene derivative to a para-bonded species 9.100A, a

benzvalene 9.100B or a prismane 9.100C (Figure 9.100).

X = F or perfluoroalkyl

+ +

9.100A 9.100B 9.100C

X6

X6

X6 X6

Figure 9.100

We established in Chapter 7, Section IIA, that fluorine prefers to be attached to

saturated carbon and it is useful to recall the greater heat of polymerisation of tetrafluoro-

ethene than ethene (by about 73 kJmol�1). In the same way, fluorine in a benzenoid

system may encourage the formation of 9.100A–C, where unsaturation is progressively

decreasing. The most obvious effect of a perfluoroalkyl group is to increase the crowding.

This is not necessarily relieved in the valence isomers and indeed it could be increased,

since C–C–C bond angles are reduced from 1208, in the aromatic form, when the valence

isomer is formed. However, crowding could have a profound effect on the the resonance

energy of the aromatic isomer by reducing planarity, whereas no such consideration

applies to the valence isomers 9.100A–C. Activation energies of reversion to the aromatic

isomer vary in the range 96� 128 kJmol�1 [249] but the enthalpy changes DH� for

photoisomerisation are much more varied, e.g. 214 [C6F6], 117 [C6ðCF3Þ6] and

35 kJmol�1½C6ðC2F5Þ6�. It appears that the thermal stability of valence isomers increases

with the number of perfluoroalkyl substituents. Not the least advantage of fluorocarbon


352 Chapter 9

systems is the stability of carbon–fluorine bonds. In this sense fluorine or fluorocarbon

groups are useful as ‘passive’ substituents [192], where skeletal rearrangements are being

observed, in order to obtain a minimum of side-reactions.

t-Butylfluoroacetylene is an extremely reactive compound that undergoes thermal

oligomerisation, giving a benzene derivative and valence isomers [250] (Figure 9.101).

F +

F F

F F

F

F

+

F

∆∆

(CH3)3CC CF½250�

Figure 9.101

The para-bonded isomer of perfluorobenzene may be formed by irradiation, in the

vapour phase, using 254 nm radiation [251–254] (Figure 9.102). Substituted benzenes,

C6F5XðX ¼ H, CH3, CF3, OCH3Þ [255], and trifluorobenzenes, C6H3F3 [256], all form

para-bonded species on irradiation.

Fhn

F6

½254�

Figure 9.102

Valence isomer 9.103A undergoes various reactions as a strained fluoroalkene (Figure

9.103).

Very stable valence isomers have been isolated by irradiation of hexakis(trifluoro-

methyl)benzene and hexakis(pentafluoroethyl)benzene [257–259] in the gas phase or in

solution. The sequence of formation of the isomers is shown in Figure 9.104.

Kinetic and thermodynamic data for valence isomers have been compared [249, 260].

The bicyclopropenyl isomer (Figure 9.105) has been prepared by a carbene addition

process; therefore, this system is quite unique in that all of the valence isomers are

known and fully characterised.

Nitrogen derivatives: A remarkable series of transformations has been discovered with

fluorinated pyridazines, giving pyrimidines and small amounts of pyrazines on pyrolysis

[262, 263] and pyrazines on photolysis [264]. Highly specific substituent labelling occurs

on pyrolysis and diazabenzvalenes, or vibrationally excited species approaching these,



+

F6

F6

9.103A

9.103A

9.103A

F6

F6

F4 F5

NaOMe

MeO OMe OMe

Br2 Br

Br

O3

H2OF F

F

F

COOH

COOH

P2O5

O

O

O

O

i, iii

i, hνii, hν, furan

½254�

½254�

½248�

Figure 9.103

(CF3)6

(CF3)6

>200nm<270nm

170� C

t1/2 9hr

170� Ct1/2 135hr

>200nm

>200nm

170� C

t1/2 129hr

(F3C)6

(CF3)6½258, 259�

Figure 9.104

CF3C CCF3 + CN

NF3C

Cl

(CF3)3 (CF3)3½261�

Figure 9.105


354 Chapter 9

have been suggested [192] in order to account for the results, although no valence isomers

have actually been isolated. Cycloaddition processes have been ruled out by N-15

labelling experiments. Furthermore, rearrangement is encouraged by free-radical promo-

tors, leading to the conclusion that these processes involve free-radical-promoted forma-

tion of diazabenzvalene derivatives [263] (Figure 9.106).

N

NF

RF RF RF

RFRFRF

RFRF

RF

RFRF

RF

N

NF

R

R

N

NF

R

N

NF

−R

NNF

N

NF

½263�

Figure 9.106

The situation is quite different in the photolysis reactions, where valence isomers of an

aromatic diazine have been isolated, together with the pyrazines (Figure 9.107). From the

structures of the isolated and characterised valence isomers, and the highly specific

substituent labelling, a very unusual mechanistic pathway may be drawn as indicated in

Figure 9.108. This appears to be the first case where substituent labelling has allowed

each stage in a photochemical aromatic rearrangement to be identified through various

intermediate valence isomers.

N

N

F

RF

RF

RF

RF RF

RF

RF

RFRF

RF

RFRF

RF

F

254nm

gas phase

NN

F

FN

NF

F

+i

i

i = hν or heat

N

N

F

F

254nm

gas phase N

NF

RF

F

+

i

i = hν or heat

RF = F , CF(CF3)2 , CF2CF3 , CF(CF3)(C2F5)

N

NF

F

N

N

F

F

½264, 265�

½264, 265�

Figure 9.107



N

N

1

2

3

4

6

5

1

2

3

4

56

N

N

1

2

3

4

6

5 N

N

1

2

3

4

6

5

N

N

N

N

1

2

3

4

5

6

9.108A

Figure 9.108

Some of the valence isomers (e.g. 9.108A) have a half-life of a few minutes at 1008C.

In contrast, valence isomers of some polyfluorinated pyridine derivatives have substantial

stability [266] (Figure 9.109).

N

N N

(CF3CF2)5 (CF3CF2)5 (CF3CF2)5

>200nm >200nm

270nm½266�

Figure 9.109

Again, substituent labelling studies have enabled photochemical rearrangement mech-

anisms to be clearly associated with the intermediate valence isomers, in this case

involving azaprismane derivatives (Figure 9.110).

a

b b b

a

a

ab b

b c b a b c

b

c

c a c c a c

c

b

c

c

b b b b

c c ccN

N

N N N

N Nhν

heat

+ +

x x

xx

y

y

heatcleavage, x

heat cleavage, yheat cleavage, x

a = CF3CF2-; b = CF3-; c = (CF3)2CF

Rearrangement

½267�

Figure 9.110

In some cases, photochemically induced eliminations occur; in the case of fluorinated

1,2,3-triazines, this has generated azetes [268, 269] which have been trapped and even

observed by low-temperature isolation techniques [269] (Figure 9.111).


356 Chapter 9

F

F

F

F

−RFCN

N N N

N

iii

F

N N

N

Adduct

N

i

ii

NN

RFRF

RF

RFRF

F

F

RF

RF

RF

RF

RF

RF

RF

RF

RF

F

N

FF

RF

RF

RF

RF

i = hv; ii = furan; iii = 350� C

RF = CF(CF3)2

RF ½268, 269�

Figure 9.111

Thermal elimination of nitrogen presents a route to fluorinated alkyne derivatives [270]

(Figure 9.112).

N

N

YX

XY

∆XC CY

X = Y = C6F5 (90%);X = CF3CF2; Y = C6F5 88%

½270�

Figure 9.112

Dewar thiophene (9.113A) and, from this, Dewar pyrrole derivatives have been isolated

[246]. In contrast, photolysis of furan derivatives only promoted cyclopropenyl ketone

rearrangements [271] (Figure 9.113).

S S

F3C

S

i

ii

i, hν; ii, heat or Pd Catalyst

O X

hνX

O

9.113A

X = F or CF3

(CF3)4

(CF3)4 (CF3)3

(CF3)3(CF3)3

½246�

½271�

Figure 9.113



REFERENCES

1 G.M. Brooke, J. Fluorine Chem., 1997, 86, 1.

2 J.S. Moilliet in Organofluorine Chemistry: Principles and Commercial Applications, ed.

R.E. Banks, B. E. Smart and J.C. Tatlow, Plenum Press, New York, 1994, p. 195.

3 Y. Desirant, Bull. Acad. Roy. Belg. Classe Sci., 1955, 41, 759.

4 M. Hellmann, E. Peters, W.J. Pummer and L.A. Wall, J. Am. Chem. Soc., 1957, 79, 5654.

5 J.M. Birchall and R.N. Haszeldine, J. Chem. Soc., 1959, 13.

6 H.C. Brown, H.L. Gewanter, D.M. White, and W.G. Woods, J. Org. Chem., 1960, 25, 634.

7 H.C. Brown, J. Org. Chem., 1957, 22, 1256.

8 J. Bordon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorineCompounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 655.

9 J.A. Godsell, M. Stacey and J.C. Tatlow, Tetrahedron, 1958, 2, 193.

10 E. Nield, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1959, 159.

11 B. Gething, C.R. Patrick, M. Stacey and J.C. Tatlow, Nature, 1959, 183, 588.

12 P.L. Coe, C.R. Patrick and J.C. Tatlow, Tetrahedron, 1960, 9, 240.

13 A.M. Doyle, A.E. Pedler and J.C. Tatlow, J. Chem. Soc. (C), 1968, 2740.

14 J. Burdon, J.D. Gilman, C.R. Patrick, M. Stacey and J. C. Tatlow, Nature, 1960, 186, 231.

15 R.E. Banks, A.E. Ginsberg and R.N. Haszeldine, J. Chem. Soc., 1961, 1740.

16 G.M. Brooke, R.D. Chambers, J. Heyes and W.K.R. Musgrave, J. Chem. Soc., 1964, 729.

17 J.C. Tatlow, Endeavour, 1963, 22, 89.

18 B. Gething, C.R. Patrick and J.C. Tatlow, J. Chem. Soc., 1961, 1574.

19 D. Harrison, M. Stacey, R. Stephens and J.C. Tatlow, Tetrahedron, 1963, 19, 1893.

20 J. Burdon, I.W. Parsons and J.C. Tatlow, J. Chem. Soc. (C), 1971, 346.

21 J. Burdon, G.E. Chivers and J.C. Tatlow, J. Chem. Soc. (C), 1970, 2146.

22 Various authors in Houben-Weyl: Methods of Organic Chemistry, Vol. E10, Organo-fluorine Compounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart,

1999.

23 E. Differding and M. Wehrli, Tetrahdron Lett., 1991, 32, 3819.

24 J. Hutchinson and G. Sandford in Organofluorine Chemistry: Techniques and Synthons, ed.

R.D. Chambers, Springer Verlag, Berlin, 1997, p. 1.

25 R.D. Chambers, C.J. Skinner, J. Hutchinson and J. Thomson, J. Chem. Soc., Perkin Trans. 1,

1996, 605.

26 R.D. Chambers, J. Hutchinson, M.E. Sparrowhawk, G. Sandford, J.S. Moilliet, and J. Thom-

son, J. Fluorine Chem., 2000, 102, 169.

27 T. Ono, K. Yamanouchi, R. Fernandez and K.V. Scherer, J. Fluorine Chem., 1995, 75, 197.

28 R.D. Chambers, M. Parsons, G. Sandford, C.J. Skinner, M.J. Atherton and J.S. Moilliet,


29 I.J. Hotchkiss, R. Stephens and J.C. Tatlow, J. Fluorine Chem., 1975, 6, 135.

30 R.N. Barnes, R.C. Chambers, R.D. Hercliffe and W.R.K. Musgrave, J. Chem. Soc., PerkinTrans. 1, 1981, 2059.

31 M.J. Shaw, H.H. Hyman and R. Filler, J. Am. Chem. Soc., 1970, 92, 6498.

32 C.A. Ramsden and R.G. Smith, J. Am. Chem. Soc., 1998, 120, 6842.

33 A. Roe, Org. Reactions, 1949, 5, 193.

34 B. Langlois in Houben-Weyl: Methods of Organic Chemistry, Vol E10a, Organo-fluorineCompounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999,

p. 686.

35 H. Suschitzky, Advan. Fluorine Chem., 1965, 4, 1.

36 K.O. Christe and A.E. Pavlath, J. Org. Chem., 1965, 30, 3170.




358 Chapter 9

39 L.R. Subramanian and G. Siegemund in Houben-Weyl: Methods of Organic Chemistry, Vol.E10a, Organo-fluorine Compounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg

Thieme, Stuttgart, 1999, p. 548.

40 H.C. Fielding, L.P. Gallimore, H.L. Roberts and B. Tittle, J. Chem. Soc. (C), 1966, 2142.

41 G.C. Finger and C.W. Kruse, J. Am. Chem. Soc., 1956, 78, 6034.


43 G.W. Holbrook, L.A. Loree and O.R. Pierce, J. Org. Chem., 1966, 31, 1259.

44 G. Fuller, J. Chem. Soc., 1965, 6264.

45 C.W. Tullock and D.D. Coffman, J. Org. Chem., 1960, 25, 2016.

46 E. Kysela, E. Klauke and H. Schwarz, Germ. Pat. 2 729 762 (1979); Chem. Abstr., 1979, 90,

168649a.


48 N.N. Vorozhtsov, V.E. Platonov and G.G. Yakobson, Bull. Acad. Sci. USSR, 1963, 1389.

49 G.M. Brooke in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam,

2000, p. 67.

50 R.E. Banks, R.N. Haszeldine, J.V. Latham and I. M. Young, J. Chem. Soc., 1965, 594.

51 R.D. Chambers in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Amsterdam, 2000,

p. 123.

52 R.D. Chambers, M. Hole, B. Iddon, W.K.R. Musgrave and R.S. Storey, J. Chem. Soc. (C),1966, 2328.

53 R.D. Chambers, T. Shepherd and M. Tamura, Tetrahedron, 1988, 44, 2583 and earlier parts in

the series.

54 Handbook of Chemistry and Physics, The Chemical Rubber Co., Cleveland, Ohio, USA.

55 A.K. Barbour, M.W. Buxton and G. Fuller, Encyclopedia of Chemical Technology, Wiley-

Interscience, New York, 1966.

56 J.A.H. McBride, unpublished results.


58 C.R. Patrick and G.S. Prosser, Nature, 1960, 187, 1021.

59 T.G. Beaumont and K.M.C. Davis, Nature, 1968, 218, 865.

60 S. Lorenzo, G.R. Lewis and I. Dance, New J. Chem., 2000, 24, 295.

61 J.C. Collings, K.P. Roscoe, E.G. Robins, A.S. Batsanov, L.M. Stimson, J.A.K. Howard,

S.J. Clark and T.B. Marder, New J. Chem., 2002, 26, 1740.

62 Y. Xie, H.F. Schaefeer and F.A. Cotton, J. Chem. Soc., Chem. Commun., 2003, 102.

63 E.J. Forbes, R.D. Richardson, M. Stacey and J.C. Tatlow, J. Chem. Soc., 1959, 2019.

64 P. Robson, M. Stacey, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1960, 4754.

65 P. Robson, T.A. Smith, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1963, 3692.

66 G.M. Brooke, J. Burdon, M. Stacey and J.C. Tatlow, J. Chem. Soc., 1960, 1768.


68 G.M. Brooke, E.J. Forbes, R.D. Richardson, M. Stacey and J.C. Tatlow, J. Chem. Soc., 1965,

2088.

69 J. Burdon, C.J. Morton and D.F. Thomas, J. Chem. Soc., 1965, 2621.

70 G.M. Brooke, J. Burdon and J.C. Tatlow, Chem. Ind., 1961, 832.

71 J.M. Birchall, R.N. Haszeldine and A.R. Parkinson, J. Chem. Soc., 1962, 4966.

72 D.G. Holland, G.J. Moore and C. Tamborski, J. Org. Chem., 1964, 29, 3042.

73 L.A. Wall, W.J. Pummer, J.E. Ferne and J.M. Antonucci, J. Res. Natl. Bur. Stand., Sect. A,

1963, 67, 481.

74 J. Burdon, V.A. Damodaran and J.C. Tatlow, J. Chem. Soc., 1964, 763.

75 B. Gething, C.R. Patrick and J.C. Tatlow, J. Chem. Soc., 1962, 186.

76 R.D. Chambers, M.J. Seabury, D.L.H. Williams and N. Hughes, J. Chem. Soc., Perkin Trans.1, 1988, 251.

77 R.J.d. Pasquale and C. Tambroski, J. Org. Chem., 1969, 34, 1736.

78 D.G. Holland, G.J. Moore and C. Tamborski, J. Org. Chem., 1964, 29, 1562.



79 D.G. Holland, G.J. Moore and C. Tamborski, Chem. Ind., 1965, 1376.


81 J. Burdon, P.L. Coe, C.M. Marsh and J.C. Tatlow, Tetrahedron, 1966, 22, 1183.

82 A.K. Barbour, M.W. Buxton, P.L. Coe, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1961,

808.

83 J. Burdon, W.B. Hollyhead, and J.C. Tatlow, J. Chem. Soc., 1965, 5152.

84 D.J. Alsop, J. Burdon, and J.C. Tatlow, J. Chem. Soc., 1962, 1801.

85 G.G. Yakobson, V.D. Shteingarts, G.G. Furin and N.N. Vorozhtsov, Zh. Obshch. Khim., 1964,

34, 3514.

86 J.G. Allen, J. Burdon and J.C. Tatlow, J. Chem. Soc., 1965, 6329.

87 G.A. Selivanova, T.V. Chuikova, A.A. Shtark and V.D. Shteingarts, Zh. Org. Khim., 1988, 24,

2513.

88 L.S. Kobrina, G.G. Furin and G.G. Yakobson, Zh. Org. Khim., 1970, 6, 512.

89 J. Burdon, D. Fisher, D. King and J.C. Tatlow, J. Chem. Soc., Chem. Commun., 1965, 65.

90 R.H. Mobbs, J. Fluorine Chem., 1970/1971, 1, 365.

91 R.D. Chambers, Dyes and Pigments, 1982, 3, 183.

92 J. Burdon, W.B. Hollyhead, C.R. Patrick and K.V. Wilson, J. Chem. Soc., 1965, 6375.

93 R.J. de Pasquale and C. Tamborski, J. Org. Chem., 1967, 32, 2163.

94 R.D. Chambers, M.J. Seabury and D.L.H. Williams, J. Chem. Soc., Perkin Trans. 1, 1988, 255

and earlier parts in the series.

95 R.D. Chambers, J.S. Waterhouse and D.L.H. Williams, J. Chem. Soc., Perkin Trans. 2, 1977,

585.

96 J.G. Allen, J. Burdon and J.C. Tatlow, J. Chem. Soc., 1965, 1045.

97 T.N. Gerasimova, N.V. Semikolenova, N.A. Orlova, T.V. Fomenko and E.P. Fokin, Izv. Sib.Otd. Akad. Nauk SSSR, Ser. Khim. Nauk., 1975, 14, 54.

98 R.D. Chambers, J. Hutchinson, and W.K.R. Musgrave, J. Chem. Soc., 1964, 3736.

99 R.E. Banks, J.E. Burgess, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1965, 575.


101 R.D. Chambers, J. Hutchinson and W.K.R. Musgrave, J. Chem. Soc. (C), 1966, 220.

102 R.D. Chambers, J. Hutchinson and W.K.R. Musgrave, J. Chem. Soc., Suppl. 1, 1964, 5634.

103 R.E. Banks, R.N. Haszeldine, E. Phillips and I. M. Young, J. Chem. Soc. (C), 1967, 2091.

104 J. Cooke, M. Green and F.G.A. Stone, J. Chem. Soc. (A), 1968, 173.

105 R.D. Chambers, M. Hole, W.K.R. Musgrave, R.A. Storey and B. Iddon, J. Chem. Soc. (C),1966, 2331.

106 R.D. Chambers, M. Hole, W.K.R. Musgrave and R.A. Storey, J. Chem. Soc., (C), 1967, 53.

107 R.D. Chambers, D. Lomas and W.K.R. Musgrave, J. Chem. Soc. (C), 1968, 625.

108 R.D. Chambers, J.A.H. MacBride and W.K.R. Musgrave, J. Chem. Soc. (C), 1968, 2116.


110 R.E. Banks, D.S. Field and R.N. Haszeldine, J. Chem. Soc. (C), 1967, 1822.

111 R.D. Chambers, P.R. Hoskin and G. Sandford, Coll. Czech. Chem. Commun., 2002, 67, 1277.

112 R.D. Chambers, C.W. Hall, J. Hutchinson and R.W. Millar, J. Chem. Soc., Perkin Trans. 1,

1998, 1705.

113 R.D. Chambers, P.R. Hoskin, G. Sandford, D.S. Yufit and J.A.K. Howard, J. Chem. Soc.,Perkin Trans. 1, 2001, 2788.

114 G.M. Brooke, R.D. Chambers, C.J. Dury and M.J. Bower, J. Chem. Soc., Perkin Trans. 1,

1993, 2201.

115 R.D. Chambers, W.K. Grey and S.R. Korn, Tetrahedron, 1995, 51, 13167.

116 R.D. Chambers, R.P. Corbally, W.K.R. Musgrave, J.A. Jackson and R.S. Matthews, J. Chem.Soc., Perkin Trans. I, 1972, 1286.

117 R.D. Chambers, M. Hole, W.K.R. Musgrave and J.G. Thorpe, J. Chem. Soc., 1971, 61.

118 W.K.R. Musgrave, Chem. Ind., 1969, 943.


360 Chapter 9

119 R.D. Chambers, R.A. Storey and W.K.R. Musgrave, J. Chem. Soc., Chem. Commun., 1966,

384.

120 R.D. Chambers, J.A. Jackson, W.K.R. Musgrave and R.A. Storey, J. Chem. Soc. (C), 1968,

2221.

121 H.C. Fielding, G.B. Pat. 1 133 492 (1968).

122 R.D. Chambers, R.P. Corbally, J.A. Jackson and W.K.R. Musgrave, J. Chem. Soc., Chem.Commun., 1969, 127.

123 R.D. Chambers, R.P. Corbally, J.A. Jackson and W.K.R. Musgrave, J. Chem. Soc., PerkinTrans. 1, 1972, 1281.

124 R.D. Chambers, R.P. Corbally, M.Y. Gribble and W.K.R. Musgrave, J. Chem. Soc., Chem.Commun., 1971, 1345.

125 R.D. Chambers, J.A. Jackson, W.K.R. Musgrave, L.H. Sutcliffe and G.J.T. Tiddy, J. Chem.Soc., Chem. Commun., 1969, 178.

126 R.D. Chambers, J.A. Jackson, W.K.R. Musgrave, L.H. Sutcliffe and G.J. Tiddy, Tetrahedron,

1970, 26, 71.

127 R.D. Chambers, Y.A. Cheburkov, J.A.H. MacBride and W.K.R. Musgrave, J. Chem. (C),1971, 532.

128 C.J. Drayton, W.T. Flowers and R.N. Haszeldine, J. Chem. Soc., Chem. Commun., 1970, 662.

129 R.D. Chambers, L.H. Sutcliffe and G.J.T. Tiddy, Trans. Farad. Soc., 1970, 66, 1025.

130 R.D. Chambers, T. Shepherd and M. Tamura, Tetrahedron, 1988, 44, 2583.

131 M.R. Bryce, R.D. Chambers, T. Shepherd, M. Tamura, J.A.K. Howard and O. Johnson,


132 B.A. Bench, A. Beveridge, W.M. Sharman, G.J. Diebold, J.E.V. Lier and S.M. Gorun, Angew.Chem., Int. Ed., 2002, 41, 747.

133 B.A. Bench, W.W. Brennessel, H.-J. Lee and S.M. Gorun, Angew. Chem., Int. Ed., 2002, 41,

750.

134 R.D. Chambers and M.Y. Gribble, J. Chem. Soc., Perkin Trans. 1, 1973, 1411.

135 R.L. Dressler and J.A. Young, J. Org. Chem., 1967, 32, 2004.

136 C.J. Drayton, W.T. Flowers and R.N. Haszeldine, J. Chem. Soc. (C), 1971, 2750.

137 R.D. Chambers, J.A. Jackson, S. Partington, P.D. Philpot and A.C. Young, J. Fluorine Chem.,1975, 6, 5.

138 R.D. Chambers, W.K.R. Musgrave and S. Partington, J. Chem. Soc., Chem. Commun., 1970,

1050.

139 R.D. Chambers and M.P.G. Greenhall, J. Fluorine Chem., 2001, 107, 171.

140 W.T. Flowers, R.N. Haszeldine and P.G. Marshall, J. Chem. Soc., Chem. Commun., 1970,

391.

141 Y. Kobayashi, I. Kumadaki and S. Taguchi, Chem. Pharm. Bull. (Tokyo), 1970, 18, 2334.

142 R.D. Chambers, M.J. Silvester, M. Tamura and D.A. Wood, J. Chem. Soc., Chem. Commun.,1982, 1412.

143 R.D. Chambers, S. Partington and D.B. Speight, J. Chem. Soc., Perkin Trans. 1, 1974, 2673.

144 R.D. Chambers, D.T. Clark, D. Kilcast and S. Partington, J. Polym. Sci., 1974, 12, 1647.

145 R.W. Anderson, U.S. Pat. 3 525 745 (1970).

146 G.M. Brooke, Tetrahedron Lett., 1968, 2029.

147 R.D. Chambers and C.R. Sergent, Adv. Heterocyclic Chem., 1981, 28, 1.

148 G.M. Brooke, Tetrahedron Lett., 1968, 4049 and earlier parts in the series.

149 G.G. Yakobson, T.D. Petrova, L.I. Kann, T.I. Savchenko, A.K. Petrov and N.N. Vorozhtsov,

Dokl. Akad. Nauk SSSR, 1964, 158, 926.

150 G.M. Brooke, W.K.R. Musgrave and T.R. Thomas, J. Chem. Soc. (C), 1971, 3596.

151 R.D. Chambers, J.A. Cunningham and D.J. Spring, Tetrahedron, 1968, 24, 3997.

152 R.D. Chambers, P.R. Hoskin, A. Khalil, P. Richmond, G. Sandford, D.S. Yufit and

J.A.K. Howard, J. Fluorine Chem., 2002, 116, 19.



153 V.D. Shteingarts, G.G. Yakobson and N.N. Vorozhtsov, Dokl. Acad. Nauk SSSR, 1966, 170,

1348.

154 V.D. Shteingarts in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S.

Prakash, John Wiley and Sons, New York, 1992, p. 259.

155 P. Sartori and A. Golloch, Chem. Ber., 1968, 101, 2004.

156 V.D. Shteingarts, Y.V. Pozdnyakovich and G.G. Yakobson, J. Chem. Soc., Chem. Commun.,1969, 1264.

157 V.D. Shteingarts and Y.V. Pozdnyakovich, Zhur. Org. Khim., 1971, 7, 734.

158 N.M. Bazin, N.E. Akhmetova, L.V. Orlova, V.D. Shteingarts, L.N. Shchegoleva and G.G.

Yakobson, Tetrahedron Lett., 1968, 4449.

159 T.J. Richardson, F.L. Tanzella and N. Bartlett, J. Am. Chem. Soc., 1986, 108, 4937.

160 K. Zuchner, T.R. Richardson, O. Glemser and N. Bartlett, Angew. Chem., Int. Ed. Engl., 1980,

19, 944.

161 V.A. Petrov in Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates,


162 W.F. Beckert and J.U. Lowe, J. Org. Chem., 1967, 32, 1212.

163 E. Nield, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1959, 166.

164 P.L. Coe, A.E. Jukes and J.C. Tatlow, J. Chem. Soc. (C), 1966, 2323.

165 P.L. Coe and A.E. Jukes, Tetrahedron, 1968, 24, 5913.

166 A. Orlinkov, I. Akrem, S. Vitt and M. Vol’pin, Tetrahedron Lett., 1996, 37, 3363.

167 P.L. Coe, G.M. Pearl and J.C. Tatlow, J. Chem. Soc. (C), 1971, 604.

168 R.D. Chambers and D.J. Spring, J. Organometal Chem., 1971, 31, C13.

169 L.S. Kobrina, J. Fluorine Chem., 1989, 42, 301.

170 J.A. Godsell, M. Stacey and J.C. Tatlow, Nature, 1956, 178, 199.

171 R.E. Banks, W.M. Cheng, R.N. Haszeldine and G. Shaw, J. Chem. Soc. (C), 1970, 55.

172 P.A. Claret, G.H. Williams and J. Coulson, J. Chem. Soc. (C), 1968, 341.

173 G.H. Williams, Intra-Science Chem. Reports, 1969, 3, 229.

174 P.H. Oldham, G.H. Williams and B.A. Wilson, J. Chem. Soc. (B), 1970, 1346.

175 H. Sawada, Chem. Rev., 1996, 96, 1779.

176 A.G. Hudson, M.L. Jenkins, A.E. Pedler and J.C. Tatlow, Tetrahedron, 1970, 26, 5781.

177 A.G. Hudson, A.E. Pedler and J.C. Tatlow, Tetrahedron, 1970, 26, 3791.

178 C.M. Jenkins, A.E. Pedler and J.C. Tatlow, Tetrahedron, 1971, 27, 2557.

179 R.D. Chambers, D.T. Clark, C.R. Sargent and F.G. Drakesmith, Tetrahedron Lett., 1979, 20,

1917.

180 V.I. Krasnov, V.E. Platonov, I.V. Beregovaya and L.N. Shchegoleve, Tetrahedron, 1997, 53,

1797.

181 S.S. Laev and V.D. Shteingarts, Tetrahedron Lett., 1997, 38, 3765.

182 M. Jones, J. Org. Chem., 1968, 33, 2538.

183 D.M. Gale, J. Org. Chem., 1968, 33, 2536.

184 V.E. Platonov, N.V. Ermolenko, G.G. Yakobson and N.N. Vorozhtsov, J. Gen. Chem. USSR,

1968, 2606.

185 N.N. Vorozhtsov, N.V. Ermolenko, S.A. Mazalov, O.M. Osina, V.E. Platonov, V.S. Tyurin

and G.G. Yakobson, J. Gen. Chem. USSR, 1969, 195.

186 V.E. Platonov and G.G. Yakobson, Soviet Scientific Reviews, Section B, Chem. Rev., 1984, 5,

297.

187 V.E. Platonov, G.G. Furin, N.G. Malyuta and G.G. Yakobson, Zh. Org. Khim., 1972, 8, 430.

188 N.G. Malyuta, V.E. Platonov, G.G. Furin and G.G. Yakobson, Tetrahedron, 1975, 31, 1201.

189 V.E. Platonov, N.V. Ermolenko and G.G. Yakobson, Bull. Acad. Sci. USSR, 1970, 2685.

190 T.D. Petrova, V.E. Platonov, M.I. Gorfinkel, I.S. Isaev and G.G. Yakobson, J. Org. Chem.,USSR, 1971, 7, 1311.

191 R.E. Banks, D.S. Field and R.N. Haszeldine, J. Chem. Soc. (C), 1970, 1280.



362 Chapter 9

193 R.D. Chambers, R.P. Corbally, T.F. Holmes and W.R.K. Musgrave, J. Chem. Soc., PerkinTrans. 1, 1974, 108.

194 S. Sole, H. Gornitzka, W.W. Schoeller, D. Bournisson and G. Bernard, Science, 2001, 292,

1901.

195 F.D. Marsh and H.E. Simmons, J. Am. Chem. Soc., 1965, 87, 3529.

196 R.E. Banks, N. Venayak and T.A. Hamor, J. Chem. Soc., Chem. Commun., 1980, 900.

197 R.S. Pandurangi, K.V. Katti, C.L. Barnes, W.A. Volkert and R.R. Kunrz, J. Chem. Soc.,Chem. Commun., 1994, 1841.

198 R.D. Chambers and T. Chivers, Organometal. Chem. Rev., 1966, 1, 279.

199 S.C. Cohen and A.G. Massey, Advan. Fluorine Chem., 1970, 6, 83.

200 R.J. Harper and C. Tamborski, Chem. Ind., 1962, 1824.

201 G. Fuller and D.A. Warwick, Chem. Ind., 1965, 651.

202 J. Jappy, Specialty Chemicals, 1995, 15, 58.

203 E. Kinseella and A.G. Massey, Chem. Ind., 1971, 1017.

204 D.E. Fenton, A.J. Park, D. Shaw and A.G. Massey, J. Organometal. Chem., 1964, 2, 437.

205 R.J. Harper, E.J. Soloski and C. Tamborski, J. Org. Chem., 1964, 29, 2385.

206 A.J. Bridges, W.C. Patt and T.M. Stickney, J. Org. Chem., 1990, 55, 773.

207 P.L. Coe, A.J. Waring and T.D. Yarwood, J. Chem. Soc., Perkin Trans. 1, 1995.

208 C. Tamborski and E.J. Soloski, J. Org. Chem., 1966, 31, 743.

209 G.M. Brooke and B.S. Furniss, J. Chem. Soc. (C), 1967, 869.

210 G.M. Brooke, B.S. Furniss, W.K.R. Musgrave and M.A. Quasem, Tetrahedron Lett., 1965,

2991.

211 P.L. Coe, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1962, 3227.

212 R.D. Chambers and D.J. Spring, J. Chem. Soc. (C), 1968, 2394.

213 T.D. Yarwood, A.J. Waring and P.L. Coe, J. Fluorine Chem., 1996, 78, 113.

214 C. Bobbio and M. Schlosser, Eur. J. Org. Chem., 2001, 4533.

215 D.J. Burton and L. Lu in Organofluorine Chemistry: Fluorinated Alkenes and ReactiveIntermediates, ed. R.D. Chambers, Springer Verlag, Berlin, 1997, p. 45.

216 A. Cairncross and W.A. Sheppard, J. Am. Chem. Soc., 1968, 90, 2186.

217 C. Tamborski, E.J. Soloski and R.J. de Pasquale, J. Organometal. Chem., 1968, 15, 494.

218 S.S. Dua, A.E. Jukes and H. Gilman, J. Organometal. Chem., 1968, 12, 24.

219 A. Cairncross, H. Omura and W.A. Sheppard, J. Am. Chem. Soc., 1971, 93, 248.

220 A. Cairncross, W.A. Sheppard and E. Wonchoba, Org. Synth., 1980, 122.

221 R.D. Rieke and L.D. Rhyne, J. Org. Chem., 1979, 44, 3445.

222 G.W. Ebert and R.D. Rieke, J. Org. Chem., 1984, 49, 5280.

223 G.W. Ebert and R.D. Rieke, J. Org. Chem., 1988, 53, 4482.

224 D.J. Burton, Z.Y. Yang and K.J. MacNiel, J. Fluorine Chem., 1991, 52, 251.

225 A.F. Webb and H. Gilman, J. Organometal. Chem., 1969, 20, 281.

226 D.J. Burton and L. Lu in Organofluorine Chemistry: Fluorinated Alkenes and ReactiveIntermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 75.

227 Z.Y. Yang, D.M. Wiemers and D.J. Burton, J. Am. Chem. Soc., 1992, 114, 4402.

228 D.D. Callender, P.L. Coe, J.C. Tatlow and A.J. Uff, Tetrahedron, 1969, 25, 25.

229 D.D. Callender, P.L. Coe and J.C. Tatlow, Tetrahedron, 1966, 22, 419.

230 J. Thrower and M.A. White, Abstracts., 148th Meeting, American Chemical Society, Wash-ington DC, 1964, p. 19K.

231 C. Tamborski, E.J. Soloski and J.P. Ward, J. Org. Chem., 1966, 31, 4230.

232 R.D. Chambers, F.G. Drakesmith, J. Hutchinson and W.K.R. Musgrave, Tetrahedron Lett.,1967, 1705.

233 R.D. Chambers and D.J. Spring, Tetrahedron Lett., 1969, 2481.

234 M.A. Bigneli and A.E. Tipping, J. Fluorine Chem., 1992, 58, 101.

235 D.V. Gardner, J.F.W. McOmie, P. Albriktsen and R.K. Harris, J. Chem. Soc. (C), 1969,

1994.



236 H.H. Wenk, A. Balster, W. Sander, D. Hrovat, W.T. Borden and T. Weston, Angew. Chem.,Int. Ed., 2001, 40, 2295.

237 P.H. Oldham, G.H. Williams and B.A. Wilson, J. Chem. Soc. (B), 1971, 1094.

238 J. Burdon, J.B. Campbell and J.C. Tatlow, J. Chem. Soc. (C), 1969, 822.

239 P.H. Oldham and G.H. Williams, J. Chem. Soc. (C), 1970, 1260.

240 S.C. Cohen, M.L.N. Reddy and A.G. Massey, J. Chem. Soc., Chem. Commun., 1967, 451.

241 S.C. Cohen, M.L.N. Reddy and A.G. Massey, J. Organometal. Chem., 1968, 11, 563.

242 Q.-Y. Chen and Z.-T. Li, J. Chem. Soc., Perkin 1, 1993, 1705.

243 N. Filipescu, J.P. Pinion and F.L. Minn, J. Chem. Soc., Chem. Commun., 1970, 1413.

244 L.S. Kobrina, V.N. Kovtonyuk and G.G. Yakobson, Zh. Org. Khim., 1977, 13, 1447; Chem.Abstr., 1977, 87, 151814r.

245 V.N. Kovtonyuk, L.S. Kobrina and G.G. Yakobson, Izv. Sib. Otd. Akad. Nauk SSSR, Ser.Khim. Nauk, 1984, 2, 119.

246 Y. Kobayashi and I. Kumadaki, Acc. Chem. Res., 1981, 14, 76.

247 D. Lemal in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam,

2000, p. 297.

248 D. Lemal, Acc. Chem. Res., 2001, 34, 662.

249 B. Sztuba and E. Ratajzak, J. Chem. Soc., Perkin Trans. 2, 1982, 823.

250 H.G. Viehe, Angew. Chem., Int. Ed. Engl., 1965, 4, 746.

251 G. Camaggi, F. Gozzo and G. Cevidalli, J. Chem. Soc., Chem. Commun., 1966, 313.

252 I. Haller, J. Am. Chem. Soc., 1966, 88, 2070.

253 I. Haller, J. Chem. Phys., 1967, 47, 1117.

254 G. Camaggi and F. Gozzo, J. Chem. Soc. (C), 1969, 489.

255 P. Cadman, E. Ratajczak and A.F. Trotman-Dickenson, J. Chem. Soc. (A), 1970, 2109.

256 G.P. Semeluk and R.D.S. Stevens, J. Chem. Soc., Chem. Commun., 1970, 1720.

257 M.G. Barlow, R.N. Haszeldine and R. Hubbard, J. Chem. Soc., Chem. Commun., 1969, 202.

258 D.M. Lemal, J.V. Staros and V. Austel, J. Am. Chem. Soc., 1969, 91, 3374.

259 M.G. Barlow, R.N. Haszeldine and R. Hubbard, J. Chem. Soc. (C), 1970, 1232.

260 D.M. Lemal and L.H. Dunlap, J. Am. Chem. Soc., 1972, 94, 6562.

261 M.W. Grayston and D.M. Lemal, J. Am. Chem. Soc., 1976, 98, 1278.

262 R.D. Chambers, M. Clark, J.R. Maslakiewicz, W.R.K. Musgrave and P.G. Urben, J. Chem.Soc., Perkin Trans. 1, 1976, 1513.

263 R.D. Chambers, W.K.R. Musgrave and C.R. Sergent, J. Chem. Soc., Perkin Trans. 1, 1981,

1071.

264 R.D. Chambers, J.A.H. MacBride, J.R. Maslakiewicz and K.C. Srivastava, J. Chem. Soc.,Perkin Trans. 1, 1975, 396.

265 R.D. Chambers, J.R. Maslakiewicz and K.C. Srivastava, J. Chem. Soc., Perkin Trans. 1, 1975,

1130.

266 M.G. Barlow, J.G. Dingwall and R.N. Haszeldine, J. Chem. Soc., Chem. Commun., 1970,

1580.

267 R.D. Chambers and R. Middleton, J. Chem. Soc., Perkin Trans. 1, 1977, 1500.

268 R.D. Chambers, T. Shepherd and M. Tamura, J. Chem. Soc., Perkin Trans. 1, 1990, 975.

269 R.D. Chambers, T. Shepherd, M. Tamura and P. Hoare, J. Chem. Soc., Perkin Trans., 1, 1990,

983.

270 R.D. Chambers, M. Clark, J.A.H. MacBride, W.K.R. Musgrave and K.C. Srivastava, J. Chem.Soc., Perkin Trans. 1, 1974, 125.

271 R.D. Chambers, A.A. Lindley and H.C. Fielding, J. Fluorine Chem., 1978, 12, 337.


364 Chapter 9

Chapter 10

Organometallic Compounds

Organometallic compounds have been referred to at various points in this book and their

role as reactive intermediates, where significant, has been outlined. Frequent comparisons

have been made between the chemistry of functional-hydrocarbon and corresponding

functional-fluorocarbon systems with the aim of building up a picture of the effect of

fluorine as a substituent on the chemistry of various functional groups, reactive centres

and the like. Needless to say, a similar consideration of the effect of fluorine on the

properties of carbon–metal bonds is fascinating in itself and, over the years, striking

developments in this novel field of organometallic chemistry have been made. This book

is about organic chemistry and it cannot cover this field of inorganic chemistry as a whole.

What follows, therefore, is a discussion of systems that are largely of interest to, or useful

to, the organic chemist.

There are a number of reviews available [1–19], and other key references will be given

in the text. The earliest and still one of the most dramatic contrasts between hydrocarbon

and the corresponding fluorocarbon organometallic systems is that between dimethyl-

and bistrifluoromethyl-mercury [20]. The latter is a white crystalline solid (melting point

1638C) that is slightly soluble in water, whereas dimethylmercury is a covalent liquid

(boiling point 928C). In a less dramatic but more useful way, transition-metal compounds

[21] are generally more thermally stable with fluorocarbon groups attached. Attached

fluorocarbon groups often enhance the acceptor properties of a metal and the metal

generally becomes more susceptible to nucleophilic attack. The converse also applies:

that is, electrophilic attack becomes more difficult, especially in cases where a metal is

attached only to perfluoroalkyl or perfluoroaryl groups, although the situation is more

complicated with mixed derivatives.

I GENERAL METHODS OF SYNTHESIS

It will become clear that, in some cases, the classical routes to organometallics are not

available but, compensating for this, the different chemistry of, for example, unsaturated

fluorocarbons has often been exploited to provide quite new synthetic approaches.

A From iodides, bromides and hydro compounds

1 Perfluoroalkyl derivatives

Fluorocarbon organometallic chemistry began with the first syntheses of perfluoroalkyl

iodides (see Chapter 7, Sections IIC, Subsection 7, and IIE, Subsection 2, for current

methods). On the basis of classical methods, this might have been expected to lead

logically to the corresponding lithio derivatives and these, in turn, to a considerable



array of perfluoroalkyl derivatives of other elements. However, perfluoroalkyl-lithiums,

as well as the corresponding magnesium compounds, too readily undergo elimination of

metal fluoride; although the route has been used in some cases, the method is inevitably

seriously restricted (Figure 10.1).

n-C4H9Li + i-C3F7I i-C3F7Li + n-C4H9I

−LiF

CF3CF=CF2

CH3Li + C2F5I [C2F5Li] C2F5C(OH)PhCH3ii

88%

i, Et2O, −78�C

i

ii, PhCOCH3, H+ etc.

i

½22�

½23�

Figure 10.1

A warning has been given [24] about carrying out exchange reactions to form

pentafluoroethyl-lithium at very low temperatures, where violent decomposition has

been observed. The most likely explanation for these events is that solid perfluoroethyl-

lithium is precipitated at the low temperature and, of course, this is extremely unstable

with respect to formation of the metal fluoride. The same cautionary note may be made

for all fluorinated alkyl- or aryl-lithium compounds (see Chapter 9, Section IIE,

Subsection 1)

The carbon–iodine bond in perfluoroalkyl iodides is usually susceptible to homolytic

fission; this was exploited in early work on the synthesis of mercurials and in later work

relating to group IVB and transition-metal derivatives (Figure 10.2).

CF3I + Hg∆

CF3HgI

(CH3)3SnSn(CH3)3 + CF3I (CH3)3SnI + (CH3)3SnCF3

hν

½20�

½25�

Figure 10.2

2 Derivatives of unsaturated systems

Perfluoropropynyl [15, 26, 27] and perfluorovinyl [16, 28–30]-lithium and -magnesium

are considerably more stable than perfluoroalkyl derivatives, whilst the corresponding

perfluoroaryl derivatives may be used as effectively as in the hydrocarbon series, and

direct syntheses involving iodo compounds are also possible (Figure 10.3).

This quite definite trend towards increasing stability in a series from CF3Li, which may

have little more than a fleeting existence when generated, to RFLiðRF5C2F5, n- and

i-C3F7), CF5CFLi and C6F5Li is probably a reflection of the ease of elimination of metal

fluoride decreasing in this series; see also Chapter 6, Sections II and IIIA, Subsection 3

(Figure 10.4).


366 Chapter 10

C6F5Hn-BuLi

C6F5LiHgCl2

(C6F5)2Hg

C6F5I

i, Zn (200�C) or Cd (230�C)

(C6F5)2M M = Zn or Cd

CF3CH2CF2Hi

(−LiF)[CF3CH=CFH]

i

(−LiF)

i

CF3C CLiii

Ph3SnC CCF3

i, n-BuLi; ii, Ph3SnCl

84%

CF3CFH2i

(−LiF)[CF2=CFH]

iCF2=CFLi

PhCH(OH)CF=CF2

iii, n-BuLi; ii, PhCHO, H

+ etc.

i

[CF3C CH] ½27�

½30�

½11�

½11�

Figure 10.3

CF3Li−LiF

[ CF2]etc

CF2=CFLi−LiF or [CF2=C ]

F

Li

−LiF F

[CF CF]

Figure 10.4

B From unsaturated fluorocarbons

The most obvious feature of the chemistry of highly fluorinated aromatic compounds and

alkenes which can be exploited is their susceptibility to nucleophilic attack. Therefore,

reactions with anionic species containing metals can be useful and the most significant

examples of this type involve transition-metal carbonyl anions [6, 10] (Figure 10.5).

1 Fluoride-ion-initiated reactions

Reactions which partly compensate for the unsuitability of the perfluoroalkyl-lithium

route involve addition of fluoride ion to an unsaturated site giving corresponding carb-

anions (Cs or K derivatives) that may be used in synthesis (see Chapter 7, Section IIC,


Organometallic Compounds 367

F + [Re(CO)5]− F

Re(CO)5

N

NF + [πC5H5Fe(CO)2]

− N

NF

Fe(CO)2πC5H5

½6�

½6�

Figure 10.5

Subsection 6). Mercurials have been obtained by fluoride-ion-initiated reactions of per-

fluoroalkenes with mercury(II) chloride [31], and it is probable that the process could be

extended considerably (Figure 10.6).

F− + CF2=CFCF3 (CF3)2CF

−Hg[CF(CF3)2]2

i

i, HgCl2

½31�

Figure 10.6

II LITHIUM AND MAGNESIUM

A From saturated compounds

Some polyfluoroalkyl-lithium and polyfluoroalkyl-Grignard reagents have been described

[14] but, as already mentioned, elimination of metal fluoride seriously restricts the use of

these compounds in synthesis. Perfluoroalkylmagnesium reagents are prepared either

directly from perfluoroalkyl iodides and magnesium, or by exchange between perfluoro-

alkyl iodides and a Grignard reagent, but perfluoroalkyl-lithiums can only be made by an

exchange process. Typical reactions of these reagents are given in Figure 10.7.

i-C3F7Li

i-C3F7Li

i, H2SO4, Et2O

CF3CF=CF2 N.B. Little or no i-C3F7H formed

i, EtCHO, H2SO4

EtCH(i-C3F7)OH 53%

ICF2CF2I + [n-C4F9Li + MeCHO] [MeCH(OH)CF2-]2

i

i

i, ii

i, −80� C to −85� C ii, H+

66%½22�

½22�

½32�

Figure 10.7

The fact that exchange occurs to produce, in each case, the fluorocarbon derivative is

quite consistent with the general observation that exchange generally proceeds to give a

product where the metal is bonded preferentially to the most electronegative group [33].


368 Chapter 10

The perfluoro-n- and -i-propyl and -n-heptyl derivatives [22, 34–36] are the most stable of

the simple alkyl series.

Outstandingly different in character from the perfluoroalkyl derivatives described above

are the lithium and magnesium compounds derived from highly fluorinated bicyclo-

[2.2.1]heptanes [37, 38]. Some reactions of the lithio derivative are shown in Figure

10.8, illustrating that it can be utilised in the normal synthetic procedures with much less

competition from elimination.

H

FEt2O, −40�C

MeLi

Li

F

D

FD2O

F

O

Furan

I

F

Me

F

CH(OH)Me

F

I2i, MeCHO

MeIii, H

+

F

10.8A

½37�

Figure 10.8

This difference is obviously due to the difficulty in producing a double bond at a

bridgehead position. Nevertheless, elimination of lithium fluoride does occur, especially

at reflux temperatures; the bridgehead alkene 10.8A, which probably has only a transitory

existence or may even be more appropriately described as a diradical, may be trapped

with furan.

B From alkenes

Several perfluoroalkene derivatives have been made and used successfully in synthesis.

Trifluorovinylmagnesium bromide and the lithium derivative may be obtained [39–41]

from bromotrifluoroethene but preparation from HFC 134a, which involves metallation of

trifluoroethene generated in situ, is now the more accessible route (see Section IA).

However, direct metallation of fluorinated alkenes and fluorinated cycloalkenes has

also been reported [26, 28] (Figure 10.9).



CF2=CFBr

i, Mg + I2, THF, ~ −22�C

CF2=CFMgH2SO4 CF2=CFH 43%

Me2SnCl2 + Mg

i, CF2=CFBr, THF, 0�C

Me2Sn(CF=CF2)2 65%

CF2=CFH + n-BuLi

i, Et2O or THF, −78�C

ii, CO2

iii, H+

CF2=CFLi + C4H10

ii

iii

CF2=CFCOOH 65%

(CF2)n (CF2)n

(CF2)n

F + MeLi−70�C

Et2OCH4 +

i, MeCHO

ii, H+

CH(OH)Me

n = 1, 23%n = 2, 42%n = 3, 63%

i

i

H

F

Li

F

i

½40�

½42�

½28�

½26�

Figure 10.9

C From trifluoropropyne [15]

The C2H bond in trifluoropropyne is sufficiently acidic to allow ready metallation via

Grignard or lithium reagents (Figure 10.10). However, the route from CF3CH2CF2H [27]

(Section IA, Subsection 2) is more direct.

CF3C CH + n-BuLi

i, C5H10, Et2O, −78�C

C4H10 + CF3C CLi

Et3SiCl

Et3SiC CCF3

i ½43�

Figure 10.10

A number of derivatives of metals have been synthesised [15]; the lithium and magne-

sium derivatives, especially, are capable of quite wide application.


370 Chapter 10

D From polyfluoro-aromatic compounds [7, 17, 18, 21]

The generation of Grignard reagents and lithium derivatives was discussed in Chapter 9,

Section IIE, Subsection 1, and these reagents have already provided an impressive

number of derivatives, which are discussed in detail in reviews [7, 17, 18, 21]. Some

examples are shown in Figure 10.11 but more will be found in the following text.

The steric requirements of the ligands in 10.11A are considerable and this feature has

allowed a number of unusual systems to be synthesised [48].

C6F5MgBr

i, SiCl4, Et2O

(C6F5)4Si

C6F5MgBr i (C6F5)2Hg 73%

C6F5Li

i, BCl3, Pentane/Hexane, −78�C to rt

(C6F5)3B 50%

i

i, HgCl2, Et2O

i

F3C

CF3

CF3

F3C

CF3

CF3

F3C

CF3

CF3

Lin-BuLi MX2

2

M = Zn, Cd, Hg.

M

10.11A

½44�

½45�

½46�

½47, 48�

Figure 10.11

Metallation of less highly fluorinated systems has been reviewed [49].

III ZINC AND MERCURY

A Zinc

Less work had been done with zinc compounds, but enough to indicate a contrast with

lithium and magnesium derivatives. For example, perfluoro-n-propyl zinc iodides [50, 51]

and perfluoroisopropyl zinc iodides [22] can be obtained, and the n-propyl derivative

is even stable in dioxane at reflux. It should be noted that these compounds are stable

largely because they are solvated and it has not been possible to remove the solvent

completely. Zinc under these circumstances appears to be a very strong acceptor and

therefore the compounds decompose much more readily when formed in the free state

[52] (Figure 10.12).

Ultrasonic radiation of perfluoroalkyl iodides may be used to form zinc reagents which

undergo standard reactions (Figure 10.13).

Fluorovinylzinc reagents are especially useful [14] (Figure 10.14).



n-C3F7I

i, Zn, Dioxane, 100�C,ii, Removal of Solvent

n-C3F7ZnI CF3CF=CF2~155�C

n-C3F7Ii

n-C3F7ZnI n-C3F7ZnI/dioxane

n-C3F7H 96%

H2O 100�C

n-C3F7ZnI/dioxanen-C3F7COCl

(n-C3F7)2CO

15%

i

ii

i, Zn, Dioxane, 100�C,ii, Removal of Solvent

ii

½51�

½50�

Figure 10.12

C3F7I +Ph

Br

Ph

C3F7

66%

i, Pd(Ph3P)4, Zn, THF

C3F7I +Ph Ph

71%BrC3F7

CF3I + HOCH2C CHi

CF3CH=CHCH2OH 61%

C2F5I + 51%C2F5

CF3I + PhCHODMF

PhCH.OHCF3 72%

CF3CCl3 + PhCODMF

Ph

OH

CCl2CF3

86%

i

i, Pd(Ac)2, Zn, THF

i

i, CuI, Zn, THF

i, Cp2TiCl2, Zn, THF

i

Zn

Zn

½53�

½53�

½53�

½53�

½53�

½54�

Figure 10.13

CF2=CFBrDMF

[CF2=CFZnBr]Me3SiCl

CF2=CFSiMe3 65%Zn ½55�

Figure 10.14


372 Chapter 10

Perfluoroarylzinc derivatives may be obtained directly from the corresponding iodide

and, sometimes, the chloride; they are also sufficiently stable to be produced by de-

carboxylation procedures (Figure 10.15).

C6F5I + Zn

C6F5Li + ZnCl2

(C6F5CO2)2Zn

(C6F5)2Zn

N

F

Cl

N

F

ZnCl

25%

½14�

½56�

Figure 10.15

Surprisingly, zinc has been inserted directly into C2F bonds using ultrasound tech-

niques, and in the presence of metal salts, e.g. SnCl2. The reactivity of the system appears

to depend at least partly on the electron affinity of the aromatic system, because hexa-

fluorobenzene is relatively unreactive in the process [57] (Figure 10.16).

F

CF3

iF

CF3

ZnCl

Br2 F

CF3

Bri, Zn, SnCl2, DMF, Ultrasound

½57�

Figure 10.16

B Mercury


Perfluoroalkyl derivatives of mercury were the first fluorocarbon–organometallic com-

pounds to be reported. Alkylmercurials are valuable in that they are able to alkylate other

metals, but the toxicity of mercurials greatly inhibits the use of these systems. Perfluoro-

alkyl iodides react with mercury on heating or irradiation with ultraviolet light to give

perfluoroalkylmercury(II) iodides [58–60] (Figure 10.17).

An effective route to a number of bis(perfluoroalkyl)- and bis(perfluorocycloalkyl)-

mercurials involves fluoride-ion-induced reactions of fluoroalkenes [31]; this follows an

earlier method involving addition of mercury(II) fluoride to fluoroalkenes, e.g. using

anhydrous hydrogen fluoride as solvent [62] (Figure 10.18).



CF3I + Hg

i, hν (150�C), or ii, ~275�C

CF3HgI80% (i)

22% (ii)

(CF3COO)2Hg

i, K2CO3, 120 to180�C

(CF3)2Hg

i or ii

i

½20�

½61�

Figure 10.17

CF3CF=CF2 + HgF2

i, Anhyd HF, 110�C

[(CF3)2CF]2Hg 60%

CF3CF=CF2 + HgCl2 [(CF3)2CF]2Hg 65%

i, KF, DMF, 40�C

(CF3)2C=CF2 + HgF2 [(CF3)3C]2Hg 66%i

i

i

i, KF, DMF, −78�C

½62�

½31�

½31�

Figure 10.18

2 Unsaturated derivatives

Alkenyl [63], alkynyl [26], and aryl [7, 8, 11] derivatives can be obtained by standard

procedures (Figure 10.19).

CF2=CFLi + HgCl2Et2O (CF2=CF)2Hg 52%

C6F5MgBr + HgCl2Et2O (C6F5)2Hg 73%

N

F

COO Hg

2

∆

N

F

Hg

2

½41�

½45�

½64�

Figure 10.19

Pentafluorophenylmercurials can also be made by interesting direct mercuration pro-

cedures, e.g. with mercury(II) trifluoroacetate [65] and by a base-catalysed process [66]

(Figure 10.20).


374 Chapter 10

C6F5H + Hg(OCOCF3)2150�C C6F5HgOCOCF3 85%

(C6F5)2Hg 72%

i

C6F5H + HgBr42−

+ 2 OH−

(C6F5)2Hg + 4Br− + 2H2O

i, EtOH, NaI, rt

½65�

½66�

Figure 10.20

These polyfluoroaryl groups enhance the acceptor properties of mercury and neutral

1:1 coordination complexes can be isolated with bipyridyl, 1,2-bis(diphenylphosphi-

no)ethane, 1,10-phenanthroline, and so on [45, 63].

Whereas bis(perfluoroalkyl)mercurials are cleaved by alkali, nucleophilic aromatic

substitution occurs with bis(pentafluorophenyl)mercury [67] (Figure 10.21).

(C6F5)2Hg + KOHt-BuOH

100�C(4-HOC6F4)2Hg ½67�

Figure 10.21

Also, unlike bis(perfluoroalkyl)mercurials, bis(pentafluorophenyl)mercury may be

used in a number of transformations at high temperature [68] (Figure 10.22).

(C6F5)2HgS

250�C(C6F5)2S

(C6F5)2HgSn

260�C(C6F5)4Sn

82%

60%

½68�

½68�

Figure 10.22

3 Cleavage by electrophiles

Generally, polyfluoro-aromatic compounds and polyfluoroalkenes are not particularly

susceptible to electrophilic attack and, consequently, electrophilic cleavage of these

groups from metals, which in some cases occurs very rapidly, is of considerable interest.

Unsymmetrical phenylpentafluorophenyl and methylpentafluorophenyl compounds are

obtained from the appropriate mercury(II) halide [45], or by decarboxylation procedures

[69], and these mixed derivatives are particularly susceptible to attack. Nevertheless,

bis(pentafluorophenyl)mercury is very resistant to acid cleavage; for example, it can be

recrystallised from concentrated sulphuric acid, but the well-known ligand-exchange

process, e.g. with mercury(II) chloride, occurs very rapidly and presumably by a four-

centre process [45] (Figure 10.23).

An order of susceptibility to electrophilic attack may be formulated as C6H5 >

C6F5 > C6Cl5 > CH3, which correlates with similar cleavage reactions of tin derivatives.

These reactions have applications in the synthesis of boron and aluminium compounds.



(C6F5)2Hg + HgCl2

C6F5Hg

Cl

HgCl

F2 C6F5HgCl

C6F5HgCH3

HCl (g)C6F5H + CH3HgCl

C6F5HgC6H5

HCl (g)C6H6 + C6H5H (trace) + C6F5HgCl

δ−

δ+

½45�

½45�

½45, 70�

Figure 10.23

IV BORON AND ALUMINIUM

A Boron


A considerable effort was expended in attempting to prepare a compound with a per-

fluoroalkyl group attached to boron before success was achieved. Difficulty arises from

the propensity of a fluorine atom for migration from carbon to boron; for example, the

compound CF3BF2 has been isolated in low yields [71, 72] and delightfully described as

‘enduringly metastable’, with respect to formation of BF3. It is not clear, however,

whether this decomposition is intermolecular (10.24A), intramolecular (10.24B) or both

(Figure 10.24).

CF3BF2 CF

F

F

BF2or CF

F

F

BF2

10.24A 10.24B

Figure 10.24

This ease of migration of fluorine from carbon to boron has inhibited the development

of hydroboration techniques in fluorinated systems. However, when the carbon–fluorine

bond is sufficiently remote from the boron, then hydroboration works well and Markov-

nikov or anti-Markovnikov additions may be obtained, depending on the hydroborating

system; dicyclohexylborane, ChxÞ2BH�

, is less electrophilic but sterically more

demanding than dihaloboranes (Figure 10.25).

At the root of the instability of fluoroalkylboron compounds is the availability of a

vacant orbital on boron; it will be seen that when boron is co-ordinately saturated, as in

four-covalent boron derivatives (10.26A), or partially saturated by p bonding with

attached oxygen- or nitrogen-containing groups (10.26B), then the stability of perfluoro-

alkylboron compounds increases (Figure 10.26).


376 Chapter 10

RF

OHRF

RFCHOH.CH3iii, ii i,ii

i, HBCl2, Hexane; ii, H2O2, alkaline; iii, (Chx)2BH, THF

86% yield (RF = C6F13) 90% yield (RF = C6F13)

95% Regioselective 99% Regioselective

80% yield (RF = CF3) 82% yield (RF = CF3)

94% Regioselective 99% Regioselective

½73, 74�

Figure 10.25

B RF

X

B

X

RF

10.26A 10.26B

X = O- or N<

X

B

X

RF

Figure 10.26

Several salts containing the anion ½RFBF3�� ðe:g: RF ¼ CF3, C2F5Þ have been isolated

[75a], as indicated below, while the tri-covalent derivatives 10.27A and 10.27B are not

readily decomposed; for example, 10.27A is recovered unchanged after heating to 1208C.

Furthermore, thermal decomposition of 10.27A or 10.27B gives n-C3F7H and not per-

fluoropropene, which would be formed if migration of fluorine to boron was still

important [76] (Figure 10.27).

2 Unsaturated derivatives

There is a marked increase in stability, with respect to formation of boron trifluoride,

along the series CF3BF2 � CF25CFBF2 < C6F5BF2 [71, 77, 78] and this can be related

to partial co-ordinative saturation of boron.

Trifluorovinylboron and pentafluorophenylboron halides are synthesised by electro-

philic cleavage from unsymmetrical tin compounds or mercurials [7, 17, 18] (Figure

10.28).

The formation of C6F5BF2 rather than ½C6F5BF3�� indicates that C6F5BF2 is a weaker

Lewis acid than BF3, i.e. CF3BF2 > BF3 > C6F5BF2. A complex salt 10.29A can,

however, be obtained by addition of C6F5BF2 to an aqueous solution of potassium

fluoride; the salt undergoes a novel elimination process on pyrolysis, giving polyphenyl-

enes 10.29B [79] (Figure 10.29).

Trifluorovinylboron derivatives are only stable for short periods when heated at 1008C,

and their partial decomposition to boron trifluoride occurs even on standing at room

temperature [77, 80].

Heating pentafluorophenylboron difluoride leads to disproportionation and not aryne

formation [78] (Figure 10.30).



Me3SnCF3 Me3Sn(CF3BF3)

i, BF3, CCl4, −196 to −20�C

aq. KFK(CF3BF3) + Me3SnF

∆

[ CF2] + KBF4CF2=CF2 F F+ +

O

B

O

i, n-C3F7Li, −50�C, Et2O

O

B

O

Cl C3F7

30%

10.27A

120�C, 3hr

172�C,12hr

Unchanged

n-C3F7H

25%

n-C3F7Li(Me2N)2BC3F7(Me2N)2BX

10.27B

i

i

½75�

½76�

½76�

Figure 10.27

Me2Sn(CF=CF2)2

i, BCl3, rt

CF2=CFBCl2 + Me2SnCl2

93%

SbF3

CF2=CFBF2 59%

Me3SnC6F5

i, BF3 CCl4

Me3SnBF2 + C6F5BF2

Me3SnC6F5

BCl3C6F5BCl2 C6F5BF2

i

i

½77�

½78�

½78�

Figure 10.28

C6F5BF2 + KFH2O K(C6F5BF3)

300�CKBF4 + -(C6F4)-n

10.29B10.29A

½79�

Figure 10.29


378 Chapter 10

F

194�C

18hrBF3 + (C6F5)2BF

H2O

(C6F5)2BOH

71%

C6F5BF2 ½78�

Figure 10.30

The increased susceptibility to hydrolysis of the fluorocarbon derivatives over their

hydrocarbon analogues is illustrated by pentafluorophenylboronic acid which is stable in

acid solution, whilst pentafluorophenyl is rapidly lost in neutral or basic solution [78]

(Figure 10.31).

C6F5BCl2

i, H2O, Acetone, −78�C

C6F5B(OH)2

89%

H2OC6F5B(OH)2.OH2

H2O Base

C6F5B(OH)3C6F5H + H3BO3

i ½78�

Figure 10.31

Tris(pentafluorophenyl)boron forms etherates but it can also be obtained unco-

ordinated in a hydrocarbon solvent (Figure 10.32).

3 C6F5Li + BCl3

i, Pentane/Hexane, −78�C to rt

(C6F5)3B 50%

3 C6F5MgBr + BF3.OEt2

i, Toluene, Reflux

(C6F5)3B 80%

(C6F5)3B

i, C6F5Li, Et2O, Hexane, −78� Cii, Pyridine

(C6F5)4BLii

ii

(C6F5)3B.NC5H5

i

i

½46�

½81�

½46�

Figure 10.32

The contrast in thermal stability between ðC6F5Þ3B and CF3BF2 is significant; for

example, the pentafluorophenyl compound was recovered largely unchanged after heating

at 2708C for 168 h [82]. Tris(pentafluorophenyl)boron is, in effect, a novel Lewis acid

and it is a curious fact that this compound, which was first made over 40 years ago, has



only in the last few years become important as a co-catalyst for polymerisation [18].

Similarly, pentafluorophenylaluminium compounds have been developed for the same

purpose (see below), a salutary lesson to those who feel confident in predicting which

basic research areas will yield great practical returns on the sums invested.

B Aluminium

Factors analogous to those which limit the stability of perfluoroalkylboron compounds are

even more dominant in the case of aluminium. Indeed, no perfluoroalkyl derivatives of

tri-covalent aluminium have been obtained, although salts of the type Li½ðn-C3F7Þ2AlI2�are produced [83] in reactions of perfluoroalkyl iodides with LiAlH4.

Tris(trifluorovinyl)aluminium may be obtained as the trimethylamine complex, as

indicated in Figure 10.33.

3(CF2=CF)2Hg + 2Me3N.AlH3Et2O

(CF2=CF)3Al.NMe3 + 3H2 + 3Hg

½84�

Figure 10.33

Tris(pentafluorophenyl)aluminium is obtained as the etherate from either the Grignard

reagent in ether or the lithium derivative in ether/hexane [81, 85], whereas only complex

materials are obtained from pentafluorophenyl-lithium in hexane (Figure 10.34). At-

tempts to remove the ether from the etherate, 10.34A, inevitably led to explosions.

3C6F5MgBr + AlBr3Et2O

−20 to 0�C(C6F5)3Al.OEt2

10.34A

½81, 85�

Figure 10.34

However, two pentafluorophenylaluminium derivatives, 10.35A and 10.35B, have been

isolated [85] by cleavage of the mercurial (Figure 10.35). Both 10.35A and 10.35B

eventually explode violently on heating and this occurs with 10.35A at about 1958C.

Nevertheless, the relative stability of these uncomplexed fluorocarbon derivatives may be

attributed to bromine bridging, which saturates the covalency of aluminium and inhibits

migration of fluorine from carbon to aluminium. Evidence from NMR spectra indicates

either structure shown in Figure 10.36 for compound 10.35A.

C6F5HgMe + AlBr3

i, Petroleum, 70�C, 5days

C6F5AlBr2 + MeHgBr

C6F5HgMe

(C6F5)2AlBr + MeHgBr

10.35A

10.35B

i ½85�

Figure 10.35


380 Chapter 10

C6F5

AlBr

Br

BrAl

Br

C6F5

C6F5

AlC6F5

Br

BrAl

Br

Br

Figure 10.36

Pentafluorophenylaluminium dibromide reacts with acid halides to form ketones [85],

but more significant are its reactions with propene; an insertion reaction occurs, giving a

polymer containing fluorine, after hydrolysis. Additionally, there is evidence to suggest

the intermediacy of a p-bonded species 10.37A, since addition of toluene displaces some

propene [86] (Figure 10.37).

C6F5AlBr2 + MeCH=CH2 C6F5Al(C3H6)Br2 +

Hydrolysis

AlCHMe

CH2

Toluene

MeCH=CH2C6F5(C3H6)nH + C3H6 + C6F5H

10.37A

½86�

Figure 10.37

Tris(pentafluorophenyl)aluminium has been prepared by metathesis, [87] (Figure

10.38), and the toluene complex is used as a co-catalyst for alkene polymerisation.

Me3Al + B(C6F5)3 Me3B + (C6F5)3Al ½87�

Figure 10.38

V SILICON AND TIN

A Silicon

The Grignard or lithium route is of limited value for the preparation of perfluoroalkyl

derivatives. Much of the early work was concerned with the addition of silanes to

fluorinated alkenes [88, 89], leading to the preparation of important fluorinated poly-

siloxanes, manufactured by Dow Corning Co. (Figure 10.39).

The siloxane 10.39A chars at 150–2008C and 10.39B decomposes above 2008C to

give vinyl fluoride, while 10.39C only decomposes at temperatures in excess of 4008C.

Trapping experiments (see Chapter 6, Section IIIA) have shown that a-elimination occurs

to give carbenes, and therefore both of the elimination processes shown in Figure 10.40

must be factors which limit the thermal stability of siloxanes 10.39A and 10.39B.

Trimethyltrifluoromethylsilane, which is now generally referred to as ‘Ruppert’s re-

agent’ [92], has been widely investigated [93–96] as an intermediate for transferring the

trifluoromethyl group as a nucleophile, thus compensating for the deficiencies of poly-

fluoroalkyl Grignard or lithium derivatives. This approach also complements other

methods for transfer of trifluoromethide ion. A variety of procedures have now been

developed for the synthesis of this compound but the electrochemical procedure [93]



(Figure 10.41), or simply heating bromotrifluoromethane with ðCH3Þ3SiCl and alumin-

ium powder, is particularly effective [97] (Figure 10.42).

Et2SiCl2 + n-C3F7Li~−50�C

Et2Si(n-C3F7)2 10%

+

Et2Si(n-C3F7)Cl 17%

MeSiHCl2hν

MeCl2Si + H

MeCl2Si + CF2=CF2 MeCl2SiCF2CF2

MeSiHCl2

MeCl2SiCF2CF2H + MeCl2Si etc[MeSi(CF2CF2H)O]nH2O

SiHCl3 + CF2=CF2hν

HCF2CF2SiCl3H2O [HCF2CF2SiO1.5]n

SiHCl3 + CF2=CH2hν

HCF2CH2SiCl3H2O [HCF2CH2SiO1.5]n

SiHCl3 + CF3CH=CH2hν

CF3CH2CH2SiCl3H2O [CF3CH2CH2SiO1.5]n

10.39A

10.39B

10.39C

½34�

½90�

½91�

½91�

½91�

Figure 10.39

Si C

F

∆Si F + C

SiC

C

F

∆ Si F +

Figure 10.40

CF3Bri

Me3SiCF3

i, Me3SiCl, anisole - HMPA (5 : 1)Sacrificial Al anode, Bu4NPF6 ( electrolyte)

CF3Br + 2e CF3− + Br

−

CF3− + Me3SiCl Me3SiCF3 + Cl

−

Anode: 2/3 Al0 2e 2/3 Al3+

½93�

Figure 10.41


382 Chapter 10

CF3Br + Me3SiCl Me3SiCF3 62%i

i, Al powder, NMP, Heat

½97�

Figure 10.42

Displacement of perfluoroalkyl from silicon occurs, initiated by catalytic amounts of

added fluoride ion, and reaction is especially effective with carbonyl sites as electrophiles.

The process that has been established is outlined in Figure 10.43 [94].

C

R1 R2

O

CF3SiMe3+

NBu4 F−

FSiMe3

R1 R2

O NBu4F3C

CF3SiMe3

R1 R2

OF3C NBu4

SiMe

F3CMe

Me

C

R1 R2

O

R1 R2

TMSF3C

H+

R1 R2

OHF3C

½94�

Figure 10.43

Examples of the application of Ruppert’s reagent are shown in Figure 10.44, including

the especially interesting diastereoselective procedures.

The process and mechanism for nucleophilic transfer from Me3SiCF3 to electrophilic

sites are analogous to the clever use of DMF as a reservoir for trifluoromethide (10.45A),

formed by reaction of fluoroform with a base [96], in a process outlined in Figure 10.45;

they are also analogous to the use of iodoperfluoroalkanes with tetrakis(dimethylami-

no)ethene [99] (Figure 10.46).

Not surprisingly, trifluorovinyl groups are cleaved by aqueous potassium hydroxide

from, for example, ðCF25CFÞ4Si, Et2SiðCF5CF2Þ2 and Et3SiCF5CF2, which may be

obtained by the Grignard or lithium routes [100–104] (Figure 10.47).

However, with other nucleophiles attack also occurs at carbon in 10.48A, leading to

displacement of fluorine [102] (Figure 10.48).



RCOOCH3i, ii

RCOCF3

i, Me3SiCF3, THF, TBAF, −78�C

ii, H+ R = Ph 78% = C6H11 72%

N

Ph R1

R2

N

R1

R2

Ph

F3C

SiMe3

41 − 86%

i

i, Me3SiCF3, THF, TBAF

t-BuS

N

H

R1 R1

Oi

t-BuS

N

CF3O

Hi, Me3SiCF3, THF, TBAF, −55�C

R1 = p-ClC6H4 95%

= Ph 80%

= t-Bu 75%

(RS1S)/(RS1R)Yield

>99

97 : 3

99 : 1

½94�

½94�

½94, 98�

Figure 10.44

Ph2CO + CF3H Ph2C(OH)CF3 72%i

i, (Me3Si)3N / Me4NF, DMF

O R

R1

R1

CF3O

M

NO

F3C R

O

F3CNMe2

H

O

R R1

O

H

N(SiMe3)2

N(SiMe3)3O

Me2N

Me2N

H

CF3H

F

Me3SiF

OSiMe3

F3C RR1

N(SiMe3)3

10.45A +

½96�

Figure 10.45


384 Chapter 10

RFI + TDAE [RFI] RFSiMe3

55−81%

RF = C2F5, n-C3F7, n-C4F9

i

i, (Me2N)2C=C(NMe2)2 ii, Me3SiCl

+1e

ii

RF Transfer½99�

Figure 10.46

CF2=CFMgISiCl4

−15�C(CF2=CF)4Si

15%KOH

−110�CCF2=CFH ½100�

Figure 10.47

Et3SiCF=CF2 + RLiEt2O Et3SiCF=CFR + LiF

R = Ph 76%

= C4H9 79%

10.48A

½102�

Figure 10.48

B Tin [15]

Some syntheses of perfluoroalkyl and polyfluoroalkyl derivatives are shown in Figure

10.49.

Me3SnSnMe3 + RFIhν

or ∆Me3SnRF + Me3SnI

RF = CF3, C2F5, etc

n-Bu2SnH2 + 2CF2=CF2

90�C

4hrn-Bu2Sn(CF2CF2H)2 28%

Me3SnSnMe3 + CF2=CF2hν

Me3SnCF2CF2SnMe3

Me2SnCl2 + Mg

i, C2F5I, THF, rt

Me2Sn(C2F5)2 34%i

½25, 105�

½106�

½107�

½108�

Figure 10.49

A few general trends can be traced from reactions of these compounds. Hydrolytic

cleavage occurs readily and this may well involve a two-step process, that is, via a five-

co-ordinate species, such as 10.50A, rather than an SN2-type process (Figure 10.50).

Nucleophilic displacement of trifluoromethyl also occurs with iodide ion and this is a

useful method for generating difluorocarbene [109] (Figure 10.51) (see Chapter 6, Section



HO + Me3SnCF3 [(Me3Sn(OH)CF3]

CF3H + Me3SnOH + OH

10.50A

Figure 10.50

I + Me3SnCF3

i, NaI, DME, 80�C

Me3SnI + CF3

−F

CF2

F F

MeMe

MeMe

ii

ii, Me2C=CMe2

i ½109�

Figure 10.51

IIIA), although other perfluoroalkyltin compounds are not sources of the corresponding

carbenes [110].

Thermal decomposition, again, occurs readily and, in the case of ðCH3Þ3SnCF3,

difluorocarbene is probably formed (Figure 10.52); see Chapter 6, Section IIIA,

Subsection 3.

Me3SnCF3150�C

Me3SnF + CF2

CF2=CF2

F

Figure 10.52

Trifluorovinyl and pentafluorophenyl derivatives of tin [11, 15] can be obtained readily

via magnesium or lithium derivatives. It is interesting that the stability of ðCH3Þ3SnC6F5

to hydrolysis is very dependent on purity; in the presence of fluoride ion, rapid hydrolysis

occurs and a process involving initial co-ordination of fluoride ion, and other halide ions,

to tin has been suggested [111] (Figure 10.53).

Me3SnC6F5 + X−

[Me3(C6F5)SnX]−

[Me3(C6F5)SnX (H2O)]−

Me3SnOH + C6F5H + X−

½111�

Figure 10.53


386 Chapter 10

Perfluorovinyl [112] and perfluoromethyl derivatives apparently undergo similar cleav-

age with aqueous alcoholic potassium fluoride. Fluorocarbon tin compounds may be used

effectively in Stille coupling processes [15] (Figure 10.54).

Bu3SnCF=CF2 +

I

Y

i

CF=CF2

Y

15−87%i = Pd catalyst

½15�

Figure 10.54

Electrophilic cleavage of perfluorovinyl [42] and perfluorophenyl [111] from mixed

compounds occurs quite readily, although electrophilic attack is much more difficult in

the tetrakis derivatives such as tetrakis(pentafluorophenyl)tin. The order of ease of

electrophilic cleavage from tin has been established as CF25CF � C6H5 >

CH25CH > alkyl > perfluoroalkyl [42], and p-MeC6H4 > C6H5 > C6F5 > Me [111],

illustrating the effect of electron withdrawal by fluorine; nevertheless, quantitative work

on the acid cleavage of Me3SnC6F5 indicates a rate greater than might be expected from

the combined effects of the atoms on an additive basis [113]. The well-known exchange

reaction between tetra-alkyl- or tetra-aryl-tin compounds and tin(IV) is much more

difficult with tetrakis(pentafluorophenyl)tin [114] (Figure 10.55).

3(C6F5)4Sn + SnCl4 3(C6F5)3SnCl160�C

7days

(C6F5)4Sn + 3 SnCl4 4 C6F5SnCl3140�C

11 weeks

½114�

½114�

Figure 10.55

The trichloride is more effectively made by cleavage of methylpentafluorophenylmer-

cury [111] (Figure 10.56).

C6F5HgMe + 3 SnCl4 C6F5SnCl3 + MeHgCl20�C

20 hours½111�

Figure 10.56

Cleavage of tetrakis(pentafluorophenyl)tin does not occur with boron halides, but

pentafluorophenylboron halides can be obtained from ðCH3Þ3SnC6F5 [79].

VI TRANSITION METALS

Factors affecting the stability of transition-metal bonds to carbon are of continued interest

and fluorocarbon transition-metal derivatives are especially interesting [115–117] be-

cause of their generally enhanced stability, relative to hydrocarbon analogues. Factors



that could enhance stability include the electronegativity of fluorocarbon groups, which

will tend to increase the energy gap between s and s� orbitals in the bonds to transition

metals. Also, a factor which may limit stability in some hydrocarbon systems is the ease

of migration of hydrogen to the metal, e.g. in platinum or palladium derivatives, whereas

migration of fluorine may be more difficult if the strength of the carbon–fluorine bond is

the rate-limiting step.

Alkenyl and aryl derivatives of transition metals are generally more stable than the

corresponding alkyl derivatives. This has been attributed to the unsaturated groups being

able to accept charge from the metal via p� orbitals. This process should be enhanced by

the introduction of fluorine or fluorocarbon groups into the alkene or aromatic compound.

For a wider discussion of fluorocarbon–transition-metal derivatives, and aspects such

as their bonding, the reader is referred to other sources [115–117].

A Copper [14, 15]

Fluorocarbon derivatives of copper have been studied quite widely, probably because

there is little evidence for the elimination of metal fluoride being a limitation in these

systems. Early work [118] showed that when perfluoroiodoalkanes are heated with copper

in DMSO or DMF, then the copper compounds are formed in solution and these have been

successfully applied in a variety of coupling reactions. High-dielectric media are essential

to the success of these processes (Figure 10.57).

Alternative procedures involve intermediate formation of copper derivatives via de-

carboxylation of salts of carboxylic acids [123–125] (Figure 10.58).

It was concluded, from the establishment of a crude r-value of þ0.46 for the reaction,

that the process may involve ½CF3CuI�� as an intermediate. A similar process may be

involved in the reaction of trifluoromethanesulphonyl chloride with copper (Figure

10.59).

Burton and co-workers, as part of a series of ground-breaking studies on fluorinated

organometallic systems [14], have established that trifluoromethyl derivatives may be

obtained by reaction of halofluoromethanes with copper and other metals. The process

involves electron transfer from the metal, with subsequent loss of halogen to form

difluorocarbene which, in turn, generates very active fluoride ion by reaction with the

solvent. The full process is indicated in Figure 10.60.

In an analogous manner trifluoromethylcopper has been generated from sulphonyl

fluorides (Figure 10.61).

Trifluorovinylcopper reagents are also stable and have been used in various useful

coupling reactions [15], especially in the synthesis of polyenes, where stereospecific

systems may be obtained (Figure 10.62).

Several procedures have been used to obtain pentafluorophenylcopper and this reagent

(again, much more stable than phenylcopper) may be used in coupling procedures (Figure

10.63).

B Other metals

Various approaches to other transition-metal derivatives have been applied which are not

covered here, but some involve reactions that exploit the properties of the fluorocarbon


388 Chapter 10

CF3I + Cui

[CF3Cu]PhI

PhCF3

NBr Br

n-C6F13I

Nn-C6F13 n-C6F13

i

i = Cu, DMSO, 125−130�C

I(CF2)3I + 2 ICH�CHCli

ClHC�CH(CF2)3CH�CHCl

i = Cu, Pyridine, 100� C

CHF2Cu + CH CCMe2Cl HCF2CH�C�CMe2

78%

i

i = DMF, −55� C

CF3Cu +

S S

i

i = DMF, HMPA, 70� C

N

NN

N

NH2

O

OAcOAc

AcO

Ii

CF3Cu +N

NN

N

NH2

O

OAcOAc

AcO

F3C

i = HMPA

i = DMF, ~135� C

I

CF3

½118�

½119�

½120�

½121�

½14�

½122�

Figure 10.57

CF3CF2CO2Na + p-ClC6H4I p-ClC6H4CF2CF3

i

i = DMF, HMPA, 170� C, Cu2I254%

½125�

Figure 10.58

systems, particularly the propensity of unsaturated fluorocarbons to undergo nucleophilic

attack as illustrated in Figure 10.64.

Oxidative additions to iodoperfluoroalkanes proceed readily, whilst the additions to

fluorinated alkenes shown in Figure 10.65 may well be radical processes.

The important range of palladium-induced coupling processes [137] is not lost to

fluorine chemistry: some illustrations are given in Figure 10.66.



CF3SO2Cl + Cu +

ClNO2

NO2

CF3

NO2

NO2

i

i = DMAC, Heat

½126�

Figure 10.59

CF2XY + M (Zn, Cd, Cu) MXY +

Me2NCHO Me2NCHF2 + CO

Me2NCHF2

F +

CF3

CF3

+ MXY CF3MX + (CF3)2M

[ CF2]

[ CF2]

[ CF2]

Me2N�CHF F

½14�

Figure 10.60

FSO2CF2I + PhIi

PhCCF3

i = Cu, DMF, 60−80� C. ~6Hr.

80%

FSO2CF2COOMei

[CuCF3]ii

PhCH�C(CF3)2

55 %i, CuI, DMF/HMPA, Pd(PPh3)4ii, PhCH�CBr2

½127�

½128�

Figure 10.61

The effect of fluorinated systems on the reaction process shown in Figure 10.67 is of

interest [139]; it is to be noted that insertion of the palladium catalyst into the carbon–

halogen bond may be considered as a nucleophilic attack by the palladium centre, albeit a

soft nucleophile, which prefers to attack C2Br over C2F [138]. This process is, of

course, aided by the presence of electron-withdrawing groups (EWG) in the organic

system. It is likely, however, that co-ordination of the other reactant, e.g. alkyne, to the

palladium is the rate-determining step [137], but this will be aided by EWGs attached to

the metal.

It also appears that the metal can act as a nucleophile in reactions of certain nickel

complexes with polyfluoro-aromatic compounds [145–147]. Surprisingly, with penta-

fluoropyridine, insertion occurs at the 2-position [145], which is in direct contrast

with reactions of most other nucleophiles with this system (see Chapter 9), where


390 Chapter 10

F3C

F

F

Cu

F3C F3C

Ph

F

I F

F

F

Ph

CF3

54%

CF2=CFCu CF3C CCF3

F3C

Cu

CF3

I2

63%

(CF2)n(CF2)n

I I

(CF2)n

(CF2)n

(CF2)n (CF2)nCu

F

F

F

F3C

I

CF3

F

F

F

n = 2, 3

½15�

½15�

½129�

Figure 10.62

C6F5M + CuX C6F5Cu

C6F5I

Activated Cu

60� C

C6F5COOCu

C6F5H + LiCuMe2

M = Li, MgBr, CdXX = Cl, Br, I

C6F5Cu + CF2�CFI C6F5CF�CF2

C6F5Cu + CH2I2 (C6F5)2CH2

88%

70%

½15�

½15�

½15�

Figure 10.63



CF3CF=CF2 π-C5H5Fe(CO)2Na

CF3CF=CF�Fe(CO)2πC5H5 + NaF

THF

(CO)5Mn M CF2=CFCF2Cl (CO)5MnCF2CF=CF2

(CO)5MnCF=CFCF3

M = Li, Na

C6F6 + [π-C5H5Ru(CO)2] C6F5Ru(CO)2π-C5H5

½130�

½131; 132�

½133�

Figure 10.64

π-C5H5Co(CO)2 + CF3I π-C5H5Co(CO)(CF3)I + COBenzene

MeRe(CO)5 + CF2=CF2

hνMeCF2CF2Re(CO)5

Benzene(Ph3P)2Pt(CF=CFCl)2(Ph3P)4Pt + CF2=CFCl

½134�

½135�

½136�

Figure 10.65

N

FX

Br Br

F

X = Br, CF(CF3)2

i

N

FX

RC C C CR

F

R = Ph, C3H7

i = RC CH, CuI, (Ph3P)3PdCl2 , Et3N

CF3CFH2 + ZnCl2i

[CF2=CFZnCl]ii

CF=CF2

R

61−86%

i = LDA, THF, 15−20� Cii = RC6H4I, Pd(PPh3)4, Heat

½138, 139�

½140�

Figure 10.66

Contd


392 Chapter 10

Ar

H

F

Br

i Ar

H

F

Ph

E/Z ~1:1 100% Z isolated, 73%

Ar = p-FC6H4-

i, −20� C, 7 daysii, PhSnBr3, Pd[(PPh3)]4, CuI, DMF, rt

F

Bu3Sn

F

SiMe3

+ CF2=CFIi F

CF2�CF

F

SiMe3

i, Pd[(PPh)3]4, CuI, DMF, rt

Ph

H

F

Br

i, ii Ph

H

Br Ph

H

F

H

+

i, iii

Ph

H

F

COO n-Bu

F

i, Cl2Pd(PPh3)2ii, HCOOH, n-Bu3N, DMF, 35� Ciii, CO, 160psi, n-BuOH, n-Bu3N, 70� C

E/Z 1:1 100% Z

Ar

H

F

Br

High E/Z ratio

ii ½141�

½142�

½143�

RF

I

R 4

RF

R

4

i

i, PdCl2[PPh3]2 , Et3N, CuI

½144�

Figure 10.66 Contd

selective 4-attack occurs. It is tempting to invoke interaction with the ring nitrogen as a

directing influence in these processes, even though the nitrogen is essentially non-basic in

the ground state, although this will change as the reaction proceeds and charge develops

on the nitrogen atom. Consequently, these processes may be used to approach aromatic

substitution patterns that would be difficult to obtain with other systems, and the potential

would be considerable if these processes could be achieved in a catalytic way (Figure

10.68).



N

F

L2Pd(II) Br

F

X

N

F

Br Br

F

X

N

F

Br

F

X

R

L2Pd(0)

N

F

L2Pd(II) Br

F

X

Br

Et3NHBr

Et3N

H

X = Br, CF(CF3)2

N

F

L2Pd(II) Br

F

X

Br

L = Ph3P

R

H

R

R

½139�

Figure 10.67

i, Ni(COD)(PEt3)2

N

F

N

F

NiEt3P

PEt3

F

N

F

H

HCli

F F [Complex] F F

NiEt3P

PEt3

F

Heati

i, Ni(COD)(PEt3)2

½145�

½146�

Figure 10.68


394 Chapter 10

Selective insertion into C2Cl occurs in competition with C2F, leading to further

useful processes (Figure 10.69).

[Ni(COD)2]

N

Cl

F

Ni PEt3Et3P

Cl

NF

N

I

F

I2−[Ni]

PEt3

MeLi

N

FMe

O

N

FMe

OHPEt3

Ni PEt3Et3P

Me

NF

CO−[Ni]

½147�

Figure 10.69

REFERENCES

1 J.J. Lagowski, Quart. Rev., 1959, 13, 233.

2 R.E. Banks and R.N. Haszeldine, Advan. Inorg. Chem. Radiochem., 1961, 3, 337.

3 H.J. Emeleus, Angew. Chem., Int. Ed. Engl., 1962, 1, 129.

4 H.C. Clark, Advan. Fluorine Chem., 1963, 3, 19.

5 P.M. Treichel, M.A. Chaudhari and F.G.A. Stone, J. Organometal. Chem., 1964, 2, 206.

6 F.G.A. Stone, Endeavour, 1966, 33.

7 R.D. Chambers and T. Chivers, Organometal. Chem. Rev., 1966, 1, 279.

8 C. Tamborski, Trans. New York Acad. Sci., Ser. II, 1966, 28, 601.

9 M.D. Rausch, Trans. New York Acad. Sci., Ser. II, 1966, 28, 111.

10 M.I. Bruce and F.G.A. Stone, Angew. Chem., Int. Ed. Engl., 1968, 7, 747.

11 S.C. Cohen and A.G. Massey, Advan. Fluorine Chem., 1970, 6, 185.

12 R.S. Nyholm, Quart. Rev., 1970, 24, 1.

13 M.A. McClinton and D.A. McClinton, Tetrahedron, 1992, 48, 6555.

14 D.J. Burton and Z.-Y. Yang, Tetrahedron, 1992, 48, 189.

15 D.J. Burton, Z.-Y. Yang and P.A. Morken, Terahedron, 1994, 50, 2993.

16 D.J. Burton in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers,




17 W.E. Piers and T. Chivers, J. Chem. Soc. Reviews, 1997, 345.

18 T. Chivers, J. Fluorine Chem., 2002, 115, 1.

19 Z. Fei, A.K. Fischer and F.J. Edelmann, J. Fluorine Chem., 2003, 121, 79.

20 H.J. Emeleus and R.N. Haszeldine, J. Chem. Soc., 1949, 2948.

21 F.G.A. Stone, J. Fluorine Chem., 1999, 100, 227.


23 P.G. Gassman and N.J. O’Reilly, Tetrahedron Lett., 1985, 26, 5243.

24 D.M. Roddick, C & N News, 1997 (6 Oct.), 6.

25 R.D. Chambers, H.C. Clark and C.J. Willis, Chem. Ind., 1960, 76.

26 M.I. Bruce and W.R. Cullen, Fluorine Chem. Rev., 1969, 4, 79.

27 A.K. Bridson and I.R. Crossley, J. Chem. Soc., Chem. Commun., 2002, 2420.

28 F.G. Drakesmith, R.D. Richardson, O.J. Stewart and P. Tarrant, J. Org. Chem., 1968, 33, 286.

29 J.M. Bainbridge, S.J. Brown, P.N. Ewing, R.R. Gibson and J.M. Percy, J. Chem. Soc., PerkinTrans. 1, 1998, 2541.

30 J. Burdon, P.L. Coe, I.B. Hazlock and R.L. Powell, J. Fluorine Chem., 1999, 99, 127.

31 B.L. Dyatkin, S.R. Sterlin, B.I. Martynov, E.I. Mysov and I.L. Knunyants, Tetrahedron, 1971,

27, 2843.

32 P. Johncock, J. Organometal. Chem., 1966, 6, 433.

33 G.E. Coates, M.L.H. Green and K. Wade, Organometallic Compounds, Methuen, London,

1967.

34 O.R. Pierce, E.T. McBee and G.F. Judd, J. Am. Chem. Soc., 1954, 76, 474.

35 J.A. Beel, H.C. Clark and D. Whyman, J. Chem. Soc., 1962, 4423.

36 S. Andreades, J. Am. Chem. Soc., 1964, 86, 2003.

37 S.D. Campbell, R. Stephens and J.C. Tatlow, Tetrahedron, 1965, 21, 2997.

38 S.F. Campbell, J.M. Leach, R. Stephens and J.C. Tatlow, Tetrahedron Lett., 1967, 4269.

39 H.D. Kaesz, S.L. Stafford and F.G.A. Stone, J. Am. Chem. Soc., 1959, 81, 6336.

40 I.L. Knunyants, R.N. Sterlin, R.D. Yatsenko and L.N. Pinkina, Izvest. Akad. Nauk SSSR, Otdel.Khim. Nauk, 1958, 1345; Chem. Abstr., 1959, 53, 6987.

41 P. Tarrant, P. Johncock and J. Savory, J. Org. Chem., 1963, 28, 839.

42 H.D. Kaesz, S.L. Stafford and F.G.A. Stone, J. Am. Chem. Soc., 1960, 82, 6232.

43 F.G. Drakesmith, O.J. Stewart and P. Tarrant, J. Org. Chem., 1967, 22, 280.

44 L.A. Wall, R.E. Donadio and W.J. Pummer, J. Am. Chem. Soc., 1960, 82, 4846.

45 R.D. Chambers, G.E. Coates, J.G. Livingstone and W.K.R. Musgrave, J. Chem. Soc., 1962,

4367.

46 A.G. Massey, A.J. Park and F.G.A. Stone, J. Organometal. Chem., 1964, 2, 245.

47 G.E. Carr, R.D. Chambers, T.F. Holmes and D.G. Parker, J. Organometal. Chem., 1987,

13, 325.

48 F.T. Edelmann, Comments Inorg. Chem., 1992, 12, 259.

49 M. Schlosser, Eur. J. Org. Chem., 2001, 3975.

50 R.N. Haszeldine and E.G. Walaschewski, J. Chem. Soc., 1953, 3607.

51 W.T. Miller, E. Bergmann and A.H. Fainberg, J. Am. Chem. Soc., 1957, 79, 4159.

52 K.F. Klabunde, M.S. Key and J.Y.F. Low, J. Am. Chem. Soc., 1972, 94, 999.

53 T. Kitazumi and N. Ishikawa, J. Am. Chem. Soc., 1985, 107, 5186.

54 M. Fujuta and T. Hiyama, Bull. Chem. Soc. Japan, 1987, 60, 4377.

55 V. Jairaj and D.J. Burton, J. Fluorine Chem., 2003, 121, 75.

56 V.I. Kraznov and V.E. Platonov, J. Fluorine Chem., 1992, 58, 246.

57 A.O. Miller, V.I. Krasnov, D. Peters, V.E. Platonov and R. Miethchen, Tetrahedron Lett.,2000, 41, 3817.

58 A.A. Banks, H.J. Emeleus, R.N. Haszeldine and V. Kerrigan, J. Chem. Soc., 1948, 2188.

59 H.J. Emeleus and R.N. Haszeldine, J. Chem. Soc., 1949, 2953.

60 H.J. Emeleus and J.J. Lagowski, J. Chem. Soc., 1959, 1497.

61 R. Eujen, Inorg. Synth., 1986, 24, 52.


396 Chapter 10

62 P.E. Aldrich, E.G. Howard, W.J. Linn, W.J. Middleton and W.H. Sharkey, J. Org. Chem.,1963, 28, 184.

63 A.J. Canty and G.B. Deacon, Austral. J. Chem., 1971, 24, 489.

64 R.D. Chambers, F.G. Drakesmith, J. Hutchinson and W.K.R. Musgrave, Tetrahedron Lett.,1967, 1705.

65 G.B. Deacon and F.B. Taylor, Austral. J. Chem., 1968, 21, 2675.

66 G.B. Deacon, H.B. Albrecht and M.J. Osborne, Inorg. Nucl. Chem. Lett., 1969, 5, 985.

67 J. Burdon, P.L. Coe, M. Fulton and J.C. Tatlow, J. Chem. Soc., 1964, 2673.

68 J. Burdon, P.L. Coe and M. Fulton, J. Chem. Soc., 1965, 2094.

69 J.E. Connett, A.G. Davies, G.B. Deacon and J.H.S. Green, J. Chem. Soc. (C), 1966, 106.

70 R.D. Chambers and D.J. Spring, J. Organometal. Chem., 1971, 31, C13.

71 T.D. Parsons, E.D. Baker, A.B. Burg and G.L. Juvinall, J. Am. Chem. Soc., 1961, 83, 250.

72 T.D. Parsons, J.M. Self and L.H. Schaad, J. Am. Chem. Soc., 1967, 89, 3446.

73 P.V. Ramachandran and M.P. Jennings, Org. Lett., 2001, 3, 3789.

74 P.V. Ramachandran and M.P. Jennings, J. Chem. Soc., Chem. Commun., 2002, 386.

75 R.D. Chambers, H.C. Clark and C.J. Willis, J. Am. Chem. Soc., 1960, 82, 5298.

75a Z.B. Zhou, M. Takeda and M. Ue, J. Flourine Chem., 2003, 123, 127.

76 T. Chivers, J. Chem. Soc., Chem. Commun., 1967, 157.

77 S.L. Stafford and F.G.A. Stone, J. Am. Chem. Soc., 1960, 82, 6238.

78 R.D. Chambers and T. Chivers, J. Chem. Soc., 1965, 3933.

79 R.D. Chambers, T. Chivers and D.A. Pyke, J. Chem. Soc., 1965, 5144.

80 P.M. Treichel and F.G.A. Stone, Advan. Organometal. Chem., 1964, 1, 143.

81 J.L.W. Pohlmann and F.E. Brinckman, Z. Naturf., 1965, 20b, 5.

82 A.G. Massey and A.J. Park, J. Organometal. Chem., 1966, 5, 218.

83 M. Hauptschein, A.J. Saggiomo and C.S. Stokes, J. Am. Chem. Soc., 1956, 78, 680.

84 B. Bartocha and A.J. Bilbo, J. Am. Chem. Soc., 1961, 83, 2202.

85 R.D. Chambers and J.A. Cunningham, J. Chem. Soc. (C), 1967, 2185.

86 R.D. Chambers and J.A. Cunningham, Tetrahedron Lett., 1967, 3813.

87 C.H. Lee, S.J. Lee, J.W. Park, K.H. Kim, B.Y. Lee and J.S. Oh, J. Mol. Catal. A: Chemical,1998, 132, 231.

88 S. Smith in Preparation, Properties and Industrial Applications of Organofluorine Com-pounds, ed. R.E. Banks, Ellis Horwood, Chichester, 1982, p. 235.

89 B. Ameduri and B. Boutevin in Organofluorine Chemistry. Fluorinated Alkenes and ReactiveIntermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 165.

90 A.M. Geyer and R.N. Haszeldine, J. Chem. Soc., 1957, 3925.

91 T.N. Bell, R.N. Haszeldine, M.J. Newlands and J.B. Plumb, J. Chem. Soc., 1965, 2107.

92 I. Ruppert, K. Schlich and W. Volbach, Tetrahedron Lett., 1984, 25, 2195.

93 G.K.S. Prakash and A.K. Yudin, Chem. Rev., 1997, 97, 757.

94 G.K.S. Prakash and M. Mandal, J. Fluorine Chem., 2001, 112, 123.

95 R.P. Singh and J.M. Shreeve, Tetrahedron, 2000, 56, 7613.

96 B.R. Langlois and T. Billard, Synthesis, 2003, 185.

97 J. Grose and J. Hegge, Synlett, 1995, 641.

98 G.K.S. Prakash and M. Mandal, J. Am. Chem. Soc., 2002, 124, 6538.

99 V.A. Petrov, Tetrahedron Lett., 2001, 42, 3267.

100 R.N. Sterlin, I.L. Knunyants, L.N. Pinkina and R.D. Yatsenko, Izv. Akad. Nauk SSSR, Otdel.Khim. Nauk, 1959, 1492; Chem. Abstr., 1960, 54, 1270.

101 D. Seyferth, D.W. Welch and G. Raab, J. Am. Chem. Soc., 1962, 84, 4266.

102 D. Seyferth and T. Wada, Inorg. Chem., 1962, 1, 78.

103 P. Tarrant and W.H. Oliver, J. Org. Chem., 1966, 31, 1143.

104 F.G. Drakesmith, O.J. Stewart and P. Tarrant, J. Org. Chem., 1968, 33, 472.

105 H.C. Clark and C.J. Willis, J. Am. Chem. Soc., 1960, 82, 1888.

106 G.B. Deacon and R.S. Nyholm, J. Chem. Soc., 1965, 6107.



107 M.A.A. Beg and H.C. Clark, Chem. Ind., 1962, 140.

108 F.G.A. Stone and P.M. Triechel, Chem. Ind., 1960, 837.

109 D. Seyferth, H. Dertouzos, R. Suzuki and J. Y.-P. Mui, J. Org. Chem., 1967, 32, 2980.

110 W.R. Cullen, J.R. Sams and M.C. Waldman, Inorg. Chem, 1970, 9, 1682.

111 R.D. Chambers and T. Chivers, J. Chem. Soc., 1964, 4782.

112 D. Seyferth, G. Raab and K.A. Brandle, J. Org. Chem., 1961, 26, 2934.

113 C. Eaborn, J.A. Treverton and D.R.M. Walton, J. Organometal. Chem., 1967, 9, 259.

114 J.M. Holmes, R.D. Peacock and J.C. Tatlow, J. Chem. Soc. (A), 1966, 150.

115 F.G.A. Stone in Fluorine Chemistry at the Millenium, ed. R.E. Banks, Elsevier, Amsterdam,

2000, p. 449.

116 J.A. Morrison, Adv. Inorg. Radiochem., 1983, 27, 293.

117 R.P. Hughes, Adv. Organometallic Chem., 1990, 31, 183.

118 Y. Kobayashi, I. Kumadaki, S. Sato, N. Hara and E. Chikami, Chem. Pharm. Bull. (Tokyo),1970, 18, 2334.

119 G.J. Chen and C. Tamborski, J. Fluorine Chem., 1990, 46, 137.

120 P.L. Coe, N.E. Milner and J.A. Smith, J. Chem. Soc., Perkin Trans. 1, 1975, 654.

121 D.J. Burton, G.A. Hargraves and J. Hsu, Tetrahedron Lett., 1990, 31, 3699.

122 Y. Kobayashi, K. Yamamoto, T. Asai, M. Nakano and I. Kumadaki, J. Chem. Soc., PerkinTrans. 1, 1980, 2755.

123 K. Matsui, E. Tobita, M. Ando and K. Koudo, Chem. Lett., 1981, 1719.

124 J.N. Freskos, Synth. Commun., 1988, 18, 965.

125 G.E. Carr, R.D. Chambers and T.F. Holmes, J. Chem. Soc., Perkin Trans. 1, 1988, 921.

126 C.A. Heaton and R.L. Powell, J. Fluorine Chem., 1989, 45, 86.

127 Q.-Y. Chen and S.-W. Wu, J. Chem. Soc., Perkin Trans. 1, 1989, 2385.

128 F.-L. Qing, X. Zhang and Y. Peng, J. Fluorine Chem., 2001, 111, 185.

129 F.W.B. Einstein, A.C. Willis, W.R. Cullen and R.L. Soulen, J. Chem. Soc., Chem. Commun.,1981, 526.

130 P.W. Jolly, M.I. Bruce and F.G.A. Stone, J. Chem. Soc., 1965, 5830.

131 W.R. McClennen, J. Am. Chem. Soc., 1961, 83, 1598.

132 H.D. Kaesz, R.B. King and F.G.A. Stone, Z. Naturforsch, 1960, 15b, 763.

133 T. Blackmore, M.I. Bruce and F.G.A. Stone, J. Chem. Soc. (A), 1968, 2158.

134 R.B. King, P.M. Treichel and F.G.A. Stone, J. Am. Chem. Soc., 1961, 83, 3593.

135 J.B. Wilford, P.M. Treichel and F.G.A. Stone, Proc. Chem. Soc., 1963, 218.

136 M. Green, R.B.L. Osborn, A.J. Rest and F.G.A. Stone, J. Chem. Soc. (A), 1968, 2525.

137 J. Tsuji, Palladium Reagents and Catalysts. Innovations in Organic Synthesis, Wiley-

Interscience, New York, 1995.

138 R.D. Chambers, C.W. Hall, J. Hutchinson and R.W. Millar, J. Chem. Soc., Perkin Trans. 1,

1998, 1705.

139 R.D. Chambers, P.R. Hoskins, G. Sandford, D.S. Yufit and J.A.K. Howard, J. Chem. Soc.,Perkin Trans. 1, 2001, 2788.

140 R. Anikumar and D.J. Burton, Tetrahedron Lett., 2002, 43, 2731.

141 J. Xu and D.J. Burton, Tetrahedron Lett., 2002, 43, 2887.

142 C. Lim, D.J. Burton and C.A. Wesolowski, J. Fluorine Chem., 2003, 119, 21.

143 J. Xu and D.J. Burton, Org. Lett., 2002, 4, 831.

144 M.P. Jennings, A.E. Cook and P.V. Ramachandran, J. Org. Chem., 2000, 65, 8763.

145 S.J. Archibald, T. Braun, J.A. Gaunt, J.E. Hobson and R.N. Perutz, J. Chem. Soc., DaltonTrans., 2000, 2013.

146 T. Braun, L. Cronin, C.L. Hoggitt, J.E. McGrady, R.N. Perutz and M. Reinhold, New J. Chem.,2001, 25, 19.

147 M.I. Sladek, T. Braun, B. Newmann and H.-G. Stammler, New J. Chem., 2003, 27, 313.


398 Chapter 10

Index

acid fluorides

elimination of COF2, 146

acid strengths, 93, 98

aerosol fluorination, 37

alcohols, 254–7

acidity, 93

diols, 255–6

aldehydes

reactions, 243

synthesis, 243

alkali metal fluorides

use in synthesis, 27–31, 47–9

alkenes

acidities, 115

addition of 1,3-dipoles, 212–13

addition of fluorine, 77–9

addition of HF, 76–7

addition of radicals, 196

cycloadditions, 205

electrophilic addition, 101, 191–6

nucleophilic attack, 174

oxidation, 200–201

polymerisation, 203–5

rearrangement, 176

alkoxides, 251–4, 257–8, 269

alkynes

synthesis, 218–22

allenes, 218

allylic cations, 102–3

aluminium, see organometallics

amides, 241

amine hydrofluorides, 62

reactions with epoxides, 69

amino-acids

diazotisation, 74

reaction with hexafluoroacetone, 248

amorphous polymers, 204–5

anaesthetics, 6

anhydrides, 241–2

aromatic compounds, 296

carbene additions, 338

free radical attack, 338

introduction of fluorine, 297–300

nitrene additions, 338

arynes, 346–9

aza-alkenes, 278–84

azabenzenoid compounds, 304–6, 315–32

azo compounds, 284

photolysis, 284

Balz-Schiemann reaction, 73, 108, 300–301

base strengths, 94

biological applications, 5

biotransformations, 9

bis(perfluoroalkyl)alkynes, 218

bistrifluoromethyl nitroxide, 278

bistrifluoromethylcarbene

reactions of, 155–6

structure, 158

bistrifluoromethylthioketene, 274

bond energies, 13

boron derivatives, see organometallics

bromine trifluoride, 51

bromofluoroalkanes

reaction with phosphines, 123

synthesis, 41

bromopentafluorobenzene, 339

Burton, 123

caesium fluoroxysulphate, 57, 79, 82

capto-dative substituents, 209

carbanions, 15, 96, 107–10

effects of F, 109

formation by addition of fluoride ion, 186,

241

H/D exchange, 107, 109, 111, 114

internal return, 108

pentakis(trifluoromethyl)cyclopentadienyl,

111, 114

perfluorocyclopentadienyl, 110, 114

pKa values for methane derivatives, 109

s-complexes, 112

stable salts, 112, 113, 173

stereochemistry, 110



carbanions, (cont’d)

synthesis of iodo derivatives, 241, 253

trapping of intermediates, 173, 186–7, 241

see polyfluoroalkylation

carbenes

fluorocarbenes, 147–59

from haloforms, 147

from halo-ketones and -acids, 149

from organometallic compounds, 149, 157,

386

from organophosphorus compounds, 151

(perfluoroalkyl)carbenes, 154–6, 158

push-pull stabilisation, 344

structure, 156

via pyrolysis and fragmentation reactions,

151

carbocations, 15, 99

long-lived, 102–5

polyconjugated systems, 105

polyfluorobenzenium, 104

trifluoromethyl, 104–5

carbonyl compounds

reactions with SF4 and derivatives, 66

fluorination, 58–60, 66

carboxylic acids, 236

pKa values, 93, 98, 236

strengths, 92, 98, 236

synthesis, 237–40

CFCs, 4

Charlton n valves, 91–2

chlorine-fluorine exchange, 24–7

catalysts, 24, 25

chlorine monofluoride, 51

chlorofluorocarbons, 4

synthesis, 24–7

chlorotrifluoroethene

polymer, 6

ciprofloxacin, 7

cobalt trifluoride, 32, 297–8, 301

copper

compounds, 346

coupling reactions, 216, 389–91

organometallics, 387–91

cubane derivatives, 210

cuneane derivative, 209–10

cycloadditions, 205–12

cyclobutadiene intermediates, 210, 354

cyclo-octatetraene derivatives, 210, 216, 354,

391

cyclopolymerisation, 205

Cytopt, 6

DAST, 63–5, 70

decarboxylation, 145–6, 171

defluorination

electrochemical, 297

of perfluoroalkanes and cycloalkenes, 164–5

of trifluoroethanol derivatives, 146

using phosphorus compounds, 250

using SnCl2, 247

using tetrakis(dimethylamino)ethene, 215

Demnumt fluids, 5, 262

Desflurane, 6

DFI, 65, 67

diazirines, 147, 284,

diazo compounds, 147, 284,

diazonium salts, 73, 108, 301

dications, 104–5

Diels-Alder reactions, 209–12, 214, 218

dienes, 214–18, 391

charge transfer salts, 218

electrophilic attack, 339

epoxidation, 217

heterodienes, 247

nucleophilic attack, 176, 217

photolysis, 218

strain, 176

diethylaminosulphur trifluoride, see DAST

difluorocarbene, 148–51, 156–8

2,2-difluoro-1,3-dimethylimidazoline, see DFI

diols, 255–6

dioxirane formation, 249

1,3-dipoles, 213

displacement of fluorine

from aromatic compounds, 307–36

from fluorinated alkenes, 132–3

dithionylium salts, 73, 300

DOPA, 9

dyes, 12

ECF, 33–5, 61, 171

electrochemical fluorination, 33–5, 61, 266

electronegativity, 13

electronic effects, 13, 16, 169

electron pair repulsion, 109, 110

electron transfer processes

formation of cyclopentadienylides, 114

oxidative fluorination, 61

see also single electron transfer

electrophilic aromatic substitution, 94, 99, 100,

299

in pentafluorobenzene, 339

electrophilic fluorinating agents


400 Index

containing N–F bonds, 58

containing O–F bonds, 56

FITS reagents, 126

fluorine, 52, 299

electrophilic perfluoroalkylation, 126–9

elimination reactions, 137

a-eliminations, 147

b-eliminations, 137–47

conformational effects, 140–41, 143

effect of leaving halogen, 137

ElcB processes

elimination of hydrogen halide, 137

elimination of metal fluorides, 144

formation of alkenes, 169–71

formation of aromatics, 297–8

formation of carbenes, 147

formation of di-enes, 215–8

norbornyl systems, 145

polyfluorinated cyclic systems, 142

regiochemistry, 139

syn-/anti-elimination, 140

from trifluoroethanol, 146

enols, 251

epoxides, see oxiranes

ethers

iodoethers, 253

synthesis, 253

FAR reagents, see fluoroalkylamine reagents

FEP, 6

FITS reagents, 126, 222

Flemiont, 5, 6

fluoride ion

acid catalysis, 129–30

addition to alkenes, 77, 173

addition to alkynes, 77, 185

catalysts, 47–9

F/Cl rate constant ratios, 129

induced reactions, 185–91

as a leaving group, 128–31

oligomerisation of F-alkenes, 188–91

reactions with fluoroalkenes, 174, 253, 367

reactions with ketones, 251–4, 257–8

reactions with oxiranes, 257–8

rearrangements induced, 174, 187–8

solvents, 28, 48

source, 28, 49

synthesis of iodoperfluoroalkanes, 241

use in synthesis, 28–31, 47–50

see HALEX reactions

see polyfluoroalkylation reactions with

alkynes, 331–3

fluorinase, 10, 11

fluorinated alkenes

LUMOs, 175

reactions with nucleophiles, 132, 171–85

reactions with transition metal anions, 368

reactivity order, with nucleophiles, 174

rearrangement by fluorine, 174

synthesis, 166

fluorinated alkynes

stability, 169, 218

synthesis, 218–22

fluorinated allenes

reactions, 219

synthesis, 218–19

fluorination

alcohols, 62–6

alkenes, 56, 77–80

amino-acids, 54, 55

aromatic systems, 53, 57, 63

carbanions, 58

carbohydrates, 65

carbonyl compounds, 66–9

decalin, 53, 55

dicarbonyl comounds, 55, 57, 59, 62

esters, 58, 127

nitro compounds, 57

nitrogen-containing functional groups, 275

nucleosides, 59

oxidative, 61

phosphonates, 58

selective, 47

steroids, 53, 63, 66, 78, 79

thioethers, 72

fluorine

aerosol fluorination, 37

bond energy, 35

control of reactivity, 36

as an electrophile, 52–4, 299

fluorine-18, 2

mechanism of fluorination, 35, 53–4

reaction with hydrazones, 75–6

replacement of hydrogen by fluorine, 51–5

selective fluorination, 51–5

stereochemistry of substitution, 53–5

use in synthesis of highly fluorinated

compounds, 35–40

use of microreactors, 38

fluorine displacement

addition-elimination mechanism, 131

F/Cl reactivity ratios at unsaturated sites,

131–2

influence of O and N substituents, 131


Index 401

fluorine displacement (cont’d)

from unsaturated sites, 131–5

see nucleophilic aromatic substitution

fluoroalkylamine reagents, 65–6

enantioselectivity, 65

mechanism, 66

use in supercritical CO2, 65

fluoroalkynes, 218

fluoroaromatics

aryne generation, 346–9

free radicals, 349–51

lithium derivatives, 345

synthesis, 296

valence isomers, 351–7

see nucleophilic aromatic substitution

fluorodediazotisation, see Balz-Schiemann

reaction

2-fluorodeoxyglucose, 7, 9

fluorodesulphurisation, 71–3

fluoroformates

decarboxylation, 70, 71, 300, 302

fluoromethyl cations, 104

5-fluorouracil, 6, 7, 8

fluorous biphase techniques, 166

fluoroxy compounds, 258

synthesis, 259

fluorspar, 23, 24

Fluothanet (halothane), 6

Fomblint fluids, 5

frontier orbitals, 98

graphite fluoride, 39

HALEX process, 300, 303–6

halofluorination, 80–82

halogen exchange, 300, 303–6

halogen fluorides, 40, 80, 77, 72, 64, 62, 80–82

halonium ions, 105–7

halophilic processes, 123

halothane, 6

Hammett s values, 94–5, 100

heteroaromatic compounds

boiling points, 306

polyfluoroalkylation, 327

synthesis, 298, 300–306

via cyclisation reactions, 332–5

heterodienes

synthesis, 247, 355–7

hexachlorobenzene

reaction with KF, 297

hexachlorobutadiene, 27

hexafluoro-2-butyne, 31, 220, 222

cycloadditions, 222, 224–6

formation of poly-enes, 331–3

free-radical additions, 226–7


reaction with carbenes, 354

reactions with sulphur, 226

trimerisation, 296

hexafluoroacetone, 27–8, 243

cleavage, 248

formation of a dioxirane, 249

formation of heterodienes, 247

formation of peroxides, 248–9

reaction with water, 248

Wittig reaction, 250

hexafluorobenzene, 296–7

reaction with carbenes, 342–3

hexafluoropropene

cycloadditions, 206, 211

formation of oligomers, 188

in polyfluoroalkylation, 327–8

radical additions, 197–204

reaction with SbF5, 102

reaction with SO2F2, 272

reactions with electrophiles, 193–6

reactions with nucleophiles, 174, 177

sodium sulphite addition, 269

synthesis, 170–71

hexafluorothioacetone, 274

hexakis(trifluoromethyl)benzene, 296

HFCs, 4

high valency metal fluorides, 31

Hunsdiecker reaction, 240

hydrogen-deuterium exchange, 138–9

hydrogen fluoride, 23

additions to alkenes and alkynes 76–7, 193

amine hydrofluorides, 62, 68–70

cleavage of ethers and epoxides, 69, 71

diazonium salts, 73–4

electrochemical fluorination, 33–5

hazards, 23

reactions with azirenes and aziridines, 74–5

use in synthesis, 24

use with lead tetra-acetate, 61

hypofluorites, 56, 82

formation, 254

Ip effect, 98

imaging techniques, 7

imines, 275–6, 278–83

inductive effects, 94, 97, 169

industrial applications, 3

inert fluids, 4


402 Index

iodine pentafluoride, 271

fluorination of dicarbonyl compounds, 62

see iodoperfluoroalkanes

iodoperfluoroalkanes

formation of copper compounds, 389–91

formation of organometallics, 365–6, 368,

372–3

reactions with nucleophiles, 123–6, 194

synthesis, 41, 202–3, 241, 253

synthesis of alkynes, 221

2-iodoperfluorobutane, 125

2-iodoperfluoropropane, 241

Ishikawa reagent, 65, 66

Isofluranet, 6

ketones

addition of fluoride ion, 251

enantioselective reduction, 10, 11

formation of heterodienes, 247

free-radical reactions, 250–51

protonation, 105

reactions, 243–54

synthesis, 243–5

kinetic acidities, 96, 111, 109, 113, 115

Krytoxt fluids, 5, 262

LaMar process, 36

lead tetra-acetate-hydrogen fluoride, 61

lithium derivatives, 345, 366–9

from alkenes, 369

from trifluoropropyne, 370

norbornyl derivatives, 145, 369

vinyl compounds, 370

lubricants, 5

Lumiflont, 5

macrocycles, 335

magnesium derivatives, 368

Meisenheimer s-complexes, 113

mercurials, 366, 373–6

generation of carbenes, 150

metal fluorides

eliminations, 145

as fluorinating agents, 23–32, 47–9

microreactors, 38

Moissan, 2

monofluoroacetate, 9

Nafiont, 5, 6, 268

naturally occurring compounds containing

C–F, 1

negative hyperconjugation, 16, 94–7

in perfluoroalkanes, 163

nickel insertion reactions, 394–5

nitrenes, 344

nitro groups

displacement by fluoride ion, 75

nitrogen derivatives, 236, 275

nitrosoalkanes, 277

nitroxides, 278

nomenclature, 16–19

nonaflates, 265

norbornyl cation, 106

nucleophilic aromatic substitution

from alkenes and cycloalkenes, 171–85

attack on nitrogen, 329

benzenoid compounds, 307–15

effect of acid, 324–5

effect of ring N, 315

fluoride-ion-induced reactions, 325–31

HOMO-LUMO interaction, 175

mechanism, 134, 307

orientation of substitution, 312–14, 319,

321–5

pyridine derivatives, 315–25

substituent effects of F, 312–14

nucleophilic displacement of halogen from

fluorocarbon systems, 122

from alkanes, 132, 171–85

from arenes, 133, 307

from cycloalkenes, 171–85

effect of F substituents, 123

HOMO-LUMO interaction, 175

mechanisms, 123, 124

SN1 SN2 processes, 122

nucleosides

fluorination, 59

Olah

generation of stable carbocations, 102

Olah’s reagent, 62

oligomerisation

of fluorinated alkenes, 188–91

organometallic compounds

aluminium, 380–81

boron, 376–80

cleavage reactions, 366, 375–6, 380–81

copper, see copper

from cyclo-alkanes, 369

mercury, 373–6

nickel insertion reactions, 394–5

norbornyl derivatives, 369

palladium coupling, 392–4

polyfluoroaryl, 367, 371


Index 403

organometallic compounds (cont’d)

from polyfluoroiodoalkanes, 365–7, 368

tin, 366, 370, 375, 378, 385

transition metals, 387

via fluoride addition, 367

vinyl derivatives, 370

zinc, 371–3

oxetanes, 262

oxidation

of F-alkenes, 260–61

using bis(trifluoromethyl)dioxirane, 249

using fluoroketones, 248–9

using peroxytrifluoroacetic acid, 242

oxiranes

reactions with hydrogen fluoride, 69, 71, 180,

217, 254, 255

ring opening, 257, 263–4

synthesis, 259–61

oxygen derivatives, 236

ozone depletion, 4

palladium coupling, 392–4

PCTFE, 6

pentafluorophenyl compounds from

hexafluorobenzene, 307

pentafluorophenyl group

acidifying effect, 115

pentafluorophenyl lithium, 366

pentafluoropyridine

carbene addition, 343

electrochemical reduction, 342

free radical attack, 340–41


synthesis, 297, 304

perchloryl fluoride, 60

perfluoro-2-butyne, 31

perfluoroacetic anhydride, 241

perfluoroacetone, see hexafluoroacetone

perfluoroalcohols, 254–7

perfluoroalkanes, 162

by addition of fluorine to F-alkenes, 78

defluorination, 164–5

by direct fluorination, 35

fragmentation, 166

hydrolysis, 163

physical properties, 163

reaction with thiols, 127

structure and bonding, 162–3

using cobalt trifluoride, 32

perfluoroalkenes

electrophilic attack, 191–6

epoxidation, 180

nucleophilic attack, 171–85

oligomerisation, 189

oxidation, 260


radical addition, 196–205

structure and bonding, 167

synthesis, 164, 169–71

perfluoroalkyl effect, 97

perfluoroalkylation

electrophilic, 126, 222

nucleophilic, 325

perfluoroallene, 219

Perfluorocycloalkenes

cycloadditions, 210–14


photochemistry, 189

radical additions, 200–201, 204

reactions with nucleophiles, 183–5

ring-opening, 168

perfluorocyclobutene, 168, 170, 201

perfluorocyclopentene, 31, 170, 200

perfluorodecalin

defluorination, 165

reaction with thiols, 127, 165

perfluoroisobutene

addition of diazamethane, 213

reactions with nucleophiles, 180

synthesis, 166, 170

perfluorooctyl bromide, 9

perfluorophenol, 98

perfluoropolyethers, 4, 5, 258, 269

perfluoroquinoline, see quinoline derivatives

perfluoro-t-butanol, 71, 255

peroxides, 242, 264

peroxytrifluoroacetic acid, 242

PET scanning, 7, 9

PFA, 6

pharmaceuticals, 7

effects of F substitution, 7

phosphate mimics, 11

phosphonates, 11

phosphorus acids, 93

photochemistry

formation of valence isomers, 351–7

photoelectron spectroscopy of fluorinated

alkenes, 98

phthalocyanine complexes, 329

physical properties, 3

pi-inductive effect, 98

plant protecting agents, 9, 10


polyfluoroalkylcarbenes, 154–6


404 Index

polyfluorobenzenium cations, 104

polymers, 5, 203–5

polysulphides, 270

polytetrafluoroethene, 5, 6, 204, 260, 262

positron emission tomography, 7, 9

potassium fluoride, see HALEX process

proton sponge, 49–50, 63

Prozact, 7, 8

PTFE defluorination, 164

see polytetrafluoroethene

Pummerer-type processes, 51, 61

PVF, 6

pyridinium poly(hydrogen fluoride), 62, 68–9

pyrimidines, 13

pyrolysis

of CHClF2, 151

formation of carbenes, 151–4, 343

quinoline derivates

perfluoroquinoline, 305–6

radical additions to fluorinated alkenes,

196–205

examples, 199

orientation, 197

rearrangement, 201

radical clock experiments, 54, 59–60

radicals

addition to F-alkenes, 196–205

polarity effects, 117

relative stabilities, 116

Scherer radical, 117

stereochemistry, 116

substituents effects, 115–7

rearrangements

Claisen, 256

of di-enes using SbF5, 217

induced by fluoride, 185, 187–8

radicals, 201

see SN20 processes

thermal, 355

via valence isomers, 351–7

resonance effects, 94, 100

Ruppert’s reagent, 382–4

safety

toxicity of fluorinated alkenes, 172

use of hydrogen fluoride, 23

use of perchloryl fluoride, 60

Scherer radical, 117

Scotchgardt, 12

Selectfluort, 58–60

Sevofluranet, 6

sigma, s, sþ values, 95, 100

silicon derivatives, 381–5

silver fluoride, 47

silver fluorine, 23

Simons, 2, 23

single electron transfer processes, 124,

125–6

SN2 processes

effect of substituents, 122

F/Cl rate constant ratios, 129

fluoride as a leaving group, 128

transition-states, 128

SN20 processes, 176, 185

solvolysis reactions, 106

source of fluorine, 23

squaric acid, 130

stable radicals, 117

stereoselectivity

addition of fluorine to alkenes, 56, 78–9

addition to enolates, 246

in direct fluorination, 53–4

in H/D exchange, 112

using DAST, 64–5

steric effects, 91, 246, 328, 371

in b-eliminations, 141

in SN2 processes, 123

sulphides, 270–71

sulphonic acids, 265

by ECF, 266

polymerisable monomers, 260

sulphur derivatives, 265, 272

use in ethene recovery, 275

sulphur pentafluoride derivatives, 273

sulphur tetrafluoride, 63, 64, 66, 69–70

sulphur trioxide, cycloaddition, 214

surfactants, 12

Swarts, 2, 24

Taft Es values, 91–2

TAS-F, see tris(dimethylamino)sulphonium

difluorotrimethylsiliconate

tautomers, 251

Teflont, see PTFE

Teflont AF, 6

telomerisation, 202–3

tetrabutylammonium fluoride, 49

tetrafluoroethene

addition of electrophiles, 193–5

addition of sulphur trioxide, 268

cycloaddition, 205–12, 268, 277



Index 405

tetrafluoroethene (cont’d)

in polyfluoroalkylation, 328

radical additions, 198, 202–4

reactions with nucleophiles, 173–4, 177

reaction with SO2F2, 272

reaction with sulphur, 270

sodium sulphite addition, 269

synthesis, 170

in triazine synthesis, 275

tetrakis(dimethylamino)ethene, 215

textile treatment, 12, 13

thiete formation, 226

thiocarbonyl compounds, 272

thiols

fluorination, 272

tin, see organometallics

toxicity, see safety

transition metal derivatives, 368

triazines, 13, 275, 304, 329–30

1,2,3-triazines

photolysis, 221

triflates, 265

triflic acid, 265–6

strength, 92

trifluoroacetic acid, 240

trifluoroethanol

formation of CF2 derivatives, 146, 250

trifluoroiodomethane

nucleophilic attack, 123

trifluoromethanesulphonic acid, see triflic acid

trifluoromethanesulphonyl chloride, 267

trifluoromethanesulphonyl group, 267

trifluoromethoxide salts, 96

trifluoromethyl

formation, 24

hydrolysis, 332

s values, 94–6

size, 92

transfer from CF3H, 384

transfer from silicon, see Ruppert’s reagent

trifluoromethylation

transfer from CF3H, 384

using Ruppert’s reagent, 382–4

trifluoromethylcarbene, 158

trifluoropropene

electrophilic addition, 102

trifluoropropyne, 221

trioxide, 265

tris(dimethylamino)sulphonium

difluorotrimethylsiliconate, 49–50

valence isomers, 222, 351–7

van der Waals radii, 91

volumes, 92

vinyl radicals, 117

vinyllithium derivatives, 366

Vitont, 6

wartime developments, 2

Wittig reaction, 250

xenon difluoride, 60, 80, 301

Yaravenko reagent, 65

ylides, 123


406 Index

fluorine in organic chemistry - журнал Химия и...

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