aliphatic fluorination

04/09/23 1 Dr. S.Iyengar, R & D Chennai,

14th JUly. 2011Slide -1

.We always find a better way

C-F Bond formation in aliphatic

Compounds





• There are 2 ways in which organo- fluorine compounds can be prepared .

A. One is to convert existing organo fluorine compound into another by group transformation

CF3CH2CN CF3CH2COOH

C-F bond are strong and are not cleaved by most of the reagents used for transformation of other groups

H2O/ H+





B. Second way is to introduce fluorine at specific sites

example:-

(CH3CH2CH2)3N (CF3CF2CF2)3N

We do not cover the first type but would focus on the

Second type only.

ECF





• In general organic reactions can be classified into:-– Substitution reaction– Elimination reaction.– Addition reaction.– Rearrangement – Or a combination of these to reach a goal.

• Synthesis of organo fluorine compound follow similar pattern but catalyst and reactant differ from other aliphatic halo- compounds in one way or other.

• Substitution and addition rtn are by far most important for synthesis of organo fluorine compounds.




General Methods of Fluorination

Fluorine Gas

Hydrogen Fluoride

Alkali Metal Fluorides

Metal Fluorides Fluorination

Electrophilic Transition

Sulfur Tetrafluoride and Safer Equivalents

Trifluoromethylating Agents




Fluorination with Fluorine gas




Sources of Fluorine

CaF2 HF (anhydrous)

Metal Fluorides

F2 (gas)

Transition Metal Complexes

(Fluorspar)




Direct Fluorination using Fluorine Gas

Fluorine, F2, is a diatomic molecule existing as a pale yellow gas.

It liquefies at –188oC to produce a yellowish orange liquid, and solidifies at –220oC to give a yellow solid.

Its name derives from the Latin verb “fluere” (to flow) that explains the given name to fluorite (fluorspar) since CaF2 exhibits

good fluxing abilities.

Fluorine is the most reactive element, and the most powerful oxidizing element.It readily reacts with almost all organic and inorganic materials.




Typically reaction with elemental fluorine is an exothermic, free radical chain process

CH4 CH3 + H-F CH3F + FF F2

CF4

(difficult to proceedthis far along)

Further fluorination becomes progressively more difficultF is an electrophilic radical, and therefore as we increase the fluorine content in the molecule, further fluorination becomes progressively difficult




Reaction steps of Free radicalInitiation:-

F2 2F.

H = 158kj mol-1

F2 + RH R. + HF + F

.

Propagation :-

RH + F. R

. + HF

R. + F2 RF + F

.

Termination :-

R. + F

. RF

R. + R

. R2




Consider the thermodynamics of the reaction

C-H +F2 C-F +H-F H = -99kcal/mol

Compare this to C-H +Cl2 C-Cl +H-Cl H = -23 kcal/mol

Bear in mind that a C-C bond = ~70kcal, so the heat given out is enough to break C-C bonds (i.e. destroy the molecule). So we need to control the heat evolved.




We can achieve this through dilution of the F2 in an

inert gas.( N2, He , Ar) 1-3% F2 in N2.One may use fluorinated solvents like CCl3F or a blend of CCl3F with CHCl3.Temp of reaction -40 to -78 deg C This enables fluorinations to proceed in “normal’ lab settings.

How can we use fluorine gas?




Also bear in mind that addition of F2 to double bonds is

also highly exothermic. C=C + F2 CF-CF(H = - 104kcal/mol)

For Cl2 H = -31kcal/mol

Again sufficient to smash C-C bonds when using elemental fluorine.

Addition of Fluorine to C=C




Why HF is not used for Fluorine Generation?

Fluorine gas is generated by the electrolysis of anhydrous potassium bifluoride (KHF2, or KF.HF) in HF.

The fluoride anion is oxidized at the anode to liberate F2 gas.

At the cathode, protons are reduced to hydrogen gas. (Best to make sure the two compartments are kept separate!) Anhydrous HF has a very low electrical conductivity, and so cannot be used as the electrolyte by itself. That’s why the molten fluoride salt electrolyte is used.




Some Industrial example

• CH3-CO- CH3 CF3-CO-CF3

(Hexafluoroacetone is used for ANESTHETICS)

• C3 H8 C3F8(C3F8 is used in electronic industry for plasma

etching )




Fluorination using AHF




Fluorinations using Hydrogen Fluoride

These can be divided into two sections

Halogen Exchange Reactions (HALEX)

Oxidative Fluorinations




Halogen Exchange using Hydrogen Fluoride (HALEX)

C-X C-F

is not oxidative, just a formal nucleophilic substitution. Most commonly C-Cl C-F This process works best for systems able to easily form carbocations




Flourination using AHF

A. Halogen exchange C- X to C-F

( Where X= Cl, main preoccupation commercially), Br, I

AHF/ SbCl5 using liquid phase methodology.The order of reactivity of Sb Halide is

SbF5>SbF3Cl2>SbF3/SbCl5

Example :-

CCl4 CCl3F CCl2F2 CClF3




AHF/ Chromia catalyst ( vapour phase)

Reaction at the surface of catalyst.

Active species is chromium oxyfluoride.

Reaction at High temperature .

Reaction of per-fluorination/ higher fluorination.

Example :-

CCl3 – CCl3 CFCl2- CCl3 CFCl2- CF2Cl

CF3- CF2Cl

Flourination using AHF




Fluorination using AHFB. In Allylic activated position

Allylic chlorine is exchanged more readily than chlorine in polychlorination.

Vinylic chlorine is seldom exchanged.

Example :-

CCl3CCl=CCl2 CF3CCl=CCl2

C6H5CCl3 C6H5CF3




Fluroro dehydroxylation - AHF

• In general the classic reaction of R-OH + HX R-X + H2O

Fails or gives low yield when X- Cl, and when X- F tarry material is produced.

Use of AHF in conjugation with Lewis base such as pyridine, THF improves the yield remarkably.

The ease of handling gets improved due to solvent. Example :- C8H17OH C8H17F




Fluorination with Olah’s Reagent

Fluoro Dehydroxylation :-

Olah’s Reagent is Pyridinium Poly hydrogen fluoride (PPHF) C6H5NH+(HF2)-.

It is also known as “TAMED” HF.

It is normally encountered as C6H5N. 9HF .

This is a mixture of 30 :70 %w/w of pyridine to HF.

It is quite stable and does not lose HF upto 50 deg C.

Reacts with 30 alcohol more readily at 0 deg c, 20 at 20-50, 10 Need to add fluoride NaF for reaction to proceed smoothly.

CH3CH2CH(OH)CH3 CH3CH2CHFCH3




Deaminative Fluorination• Nitrogen Replacement. C-NH2 C- N2

+ C-F

Provides simple convenient route for flurocarboxylic acid

Reagent used is AHF/ NaNO2 & Pyridine .

Skeletal rearrangement ( cationic ) occurs giving beta fluoro carboxylic acid .

High Pyridine : HF ratio favors alpha fluorocarboxylic acid

C2H5CH(NH2)COOH C2H5CHFCOOH

(CH3)2CHCH(NH2)COOH (CH3)2CHCHFCOOH + (CH3)2CFCH2COOH




Oxidative Fluorinations

Electrochemical Fluorination, E.C.F. (Simon’s Cell)

Using a solution of hydrogen fluoride, electrolysis is performed at a voltage lower (5-6V) than that required to generate Fluorine gas.

At the Nickel anode (oxidation occurs at the anode):

C-H C-F

The reaction is usually performed at 0oC, and solubility in HF can be a limiting factor.

Fluorine is not generated at the anode, but hydrogen is generated at the cathode.




H3C C

O

ClE.C.F.

F3C C

O

F F3C C

O

OHH2O

H3C S

O

ClE.C.F.

F3C S

O

F F3C S

O

OHH2O

O O O

E.C.F.N(CH3)3 N(CF3)3

trifilic acid - a very strongorganic acid

shows no significant basic character - isused as an inert fluid

Examples of Electro chemical fluorination.




The Simon’s cell process is believed to involve high valency Nickel Fluorides (NiF3 and NiF4).

Indeed workers were able to generate NiF3 and NiF4 in situ,

and these were demonstrated to be powerful fluorinating agents

K2NiF6 + 2 BF3aH-F

NiF4 + 2 KBF4

< -20oC

0oC

NiF3 + 1/2 F2

Actually NiF3 was later shown to be NiIVNiIIF6




E.g. allylic / benzylic chlorides

Ph-CCl3H-F

40oCPh-CF3

H-F

R.T.Ph3CCl Ph3CF




This reaction is industrially important in the manufacture of Refrigerants (i.e. CFC’s / Freons).

The Swarts Reaction

CCl4 CCl3F + CCl2F2 + CClF3

9% 90% trace

HF, SbF5

100oC

Systems that don’t easily form cations require a Lewis Acid Catalyst




Since Fluorine is so electronegative and a powerful inductive electron withdrawing substituent, it makes successive Chlorines worse donors to the Lewis Acid catalyst (SbF5), hence halogen

exchange becomes progressively difficult. There is also a decrease in steric assistance to ionization as each larger chlorine is replaced by a smaller fluorine.

+

109.5o 120o

The Swarts Reaction




Industrial Use of Swarts Reagent

The Bayer Company developed a one-pot synthesis of trifluorotoluene from benzene based on this type of reaction

C6H6 + CCl4HF, SbF5

C6H5-CF3

CCl3 Cl L.A.

(HF or SbF5) H CCl3

etc.

-H+

+

CCl3

HF, SbF5

CF3

L.A.-Cl-




R Cl + SbF5 R Cl SbF5

+ _R+ (SbF5Cl)-

H-F

R-F + H+(SbF5Cl)-

H-F

H-Cl + H+(SbF6)-

Cl

R

F

SbF4

H-F

(concerted)

(ionic)

General Mechanistic Process:




Alternatives to using Elemental Fluorine

Transition Metal Fluorides Oxidation Fluorination

C H C F

is a formal oxidation on the carbonSome transition metal fluorides can accomplish this type of transformation, with cobalt trifluoride CoF3 being one of the most

commonly used.




Mechanism of Oxidative Fluorination Co3+ goes to Co2+, i.e. Co (III) to Co (II), which is a gain of electrons. Cobalt is reduced

the organic gets oxidized

CoF3 is an Oxidizing agent.




Cobalt trifluoride is generated by reaction of Cobalt Difluoride with elemental Fluorine.

2CoF2 + F2 2CoF3

For CH C-F, H = - 58 kcal/mol, which is much less exothermic than direct fluorination




C H-1e

Co(III) Co(II)

C H C-H+

-1e

Co(III)

Co(II)

C+F-

C F

etc.

Recall 2CoF3 + C-H C-F + H-F + 2 CoF2

Saturated Systems




+- 1e-F-

F

- 1e-

F+F-

FF

Unsaturated Systems




Alkali Metal Fluorides for Creating C-F bonds

C XF- CF X-

Typically:

Fluoride ion is a very poor nucleophile in aqueous solution, but a very strong nucleophile in aprotic solvents.

The difference is the solvation of the fluoride ion. If the fluoride ion is solvated it is much less accessible to perform nucleophilic attack.




S

N

H3CO

OCH3

OO

O

CH3

H3C N

CH3

C

O

H H3C N

CH3

C

O

CH3

n

"glymes"n=2 diglymen=3 triglymen=4 tetraglyme

sulpholane(sulfolan)

N.M.P. D.M.F. D.M.A.

Common Aprotic Solvents include:

They have a high dielectric constant. (i.e. polar)

They act by solvating the metal cation.

These are solvents without protic hydrogens (esp. O-H, N-H, etc)




Metal Fluoride Reactivity in aprotic solvents: CsF > KF >> NaF > LiF As the lattice energy of the solid increases the reactivity decreases.(CsF has the lowest lattice energy, whilst LiF has the larger lattice energy Or CsF has the “free-est” fluoride ion). Potassium fluoride is the most frequently used fluoride ion source based on the combination of cost and availability versus its reactivity.




Sulfur Tetrafluoride and Safer Equivalents

Sulfur Tetrafluoride is best known for its fluorodeoxygenation ability.

R OH

R

R CO2H

O

R'

R F

R CF2-R'

R CF3

SF4 by itself is not a fantastic fluorinating agent, but in the presence of

hydrogen fluoride it is highly active.




Reaction of Alcohols

The mechanism of R-OH R-F can be represented by the following:




Reaction of Carboxylic Acids

The conversion of carboxylic acid to trifluoromethyl is the most demanding of the fluorodeoxygenation transformations

The mechanism of this transformation is as above, with the reaction proceeding from carboxylic acid acid fluoride trifluoromethyl.Use of high temp and plenty of HF as solvent and Lewis acid is required to perform this transformation.

The technique is used in commercial synthesis of Desflurane ( CF3CHF-O CHF2) from CHCl2OCHClCOCl .




Drawbacks of using sulfur tetrafluoride

It is a gas ( Boiling point -38 degC)

Its inhalation toxicity is comparable to that of phosgene

On exposure to moisture (air, skin) it liberates HF

Reaction with SF4 usually requires HF as solvent / LA

(which precludes use of glassware)




SF4 Alternatives

Recently, “friendlier” fluorodeoxygenation reagents have become commercially available. These are really just substituted sulfur fluorides. The most common one being DAST (Diethylaminosulfur trifluoride).

(CH3CH2)2N-SF3DAST

DAST is a milder fluorinating agent that can convert hydroxyl to fluorine and carbonyls to CF2’s.

It cannot convert carboxylic acids to trifluoromethyls.




DAST is a liquid that is stable to distillation, and can be stored in plastic bottles, and is stable in dry conditions at room temperature or with refrigeration for long periods of time.

It has a boiling point of 45-46 degree C at 10mm Hg.

DAST will decompose at 50oC, and can explode if heated to much higher temperatures .Normal reaction is done lower than 20 deg C in presence of solvents like MDC, Toluene or THF.It is highly moisture sensitive.It is widely used in carbohydrate chemistry for converting –OH to F.

DAST




Preparation of DAST

• DAST is prepared by reaction of sulfur tetrafluoride with diethylaminotrimethylsilane at –78oC, followed by warming to room temperature, and then distillation.

(CH3CH2)2NSi(CH3)3+ SF4 (CH3CH2)2NSF3 + FSi(CH3)3




DAST operates by a similar mechanism to that for sulfur tetrafluoride:




Whilst DAST is still the market leader of this type of reagent, safer versions of DAST are currently being marketed.

E.g. BAST (CH3OCH2CH2)2NSF3

Bis(2-methoxyethyl)aminosulfur trifluoride.

BAST is thermally more stable and decomposes less exothermically and with less gaseous byproducts.

Other Fluorinating agents




TAS Fluorides

Other Fluorinating agents

Modification of the DAST preparation can lead to a useful alternate product:

SF4 + (CH3CH2)2NS(CH3)3 DAST

SF4 +3 (CH3)2NS(CH3)3 ((CH3)2N)3S+ (CH3)3SF2

-

Tris(dimethylamino)Sulphonium (TAS) salts are usually very soluble in organic solvents. The (CH3)3SF2

- anion

acts as a fluoride ion source.




Trifluoromethylating Agents Trifluoromethyl radicals can be generated by various means




• THANKS FOR YOUR ATTENTION.

aliphatic fluorination

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