Multimetallic Nanoscale Assemblies

Based on Bifunctional Linkers

By

James McArdle

May 2017

Department of Chemistry

Imperial College London

A thesis submitted in partial fulfilment of the requirements for the

degree of Doctor of Philosophy in Chemistry from Imperial College

London.

2

Declaration

The work presented herein was conducted in the Chemistry department, Imperial College

London, between October 2012 and May 2016 and unless stated to the contrary, is entirely my

own work.

The copyright of this thesis rests with the author and is made available under a Creative

Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy,

distribute or transmit the thesis on the condition that they attribute it, that they do not use it for

commercial purposes and that they do not alter, transform or build upon it. For any reuse or

redistribution, researchers must make clear to others the licence terms of this work.

3

Publications

Multimetallic Complexes and Functionalized Nanoparticles Based on Unsymmetrical

Dithiocarbamate Ligands with Allyl and Propargyl Functionality

Venesia L. Hurtubise, James M McArdle, Saira Naeem, Anita Toscani, Andrew J. P. White,

Nicholas J. Long and James D. E. T. Wilton-Ely, Inorg. Chem., 2014, 53, 11740-11748.

Functionalized Nanoparticles in Asymmetric Catalysis

J. McArdle, J. D. E. T. Wilton-Ely and N. J. Long, Chemistry, Molecular Sciences and Chemical

Engineering (Reference Module), 2016.

4

Acknowledgments

First of all, I would like to thank my supervisors Prof. Nick Long and Dr James Wilton-Ely for

guiding me throughout my PhD. I am extremely grateful to have been given the opportunity to

work with and learn from them both. From providing frequent advice, guidance and motivation

on a daily basis to excellent pastoral care throughout, they have both provided me with the

support needed to get here.

Next, I would like to thank all members of both the Long and Wilton-Ely groups, past and

present, for making coming into work every day that much easier. Whether it was being there

for a much needed tea break after a failed reaction or blowing off some steam at the end of the

week with a pint you all kept me going. I consider myself incredibly lucky to call you my friends

and to have as many fond memories as I do. Hopefully, I can thank you all in person rather than

risk missing anyone out.

A big thank you goes to my family who have supported me over the years and helped me follow

this path. To Mum and Dad, thanks for everything but particularly for the daily support you have

provided me with over the past six months that has kept me on track and has allowed me to

work without distraction. To Sarah, thanks for being there and keeping me grounded. To my

Uncle and Aunt, Paul and Helen, a huge thanks for everything you have done for me this year – I

never would have done this without you. Izzie and Matt, thanks for providing me with much

needed comic relief and reminding me of what’s important.

Finally, I would like to say thank you to Samantha. You have kept me going this past year as I’ve

worked towards the finish line. You have provided me with support even when not present,

made me laugh when I’m stressed and most of all, have made this PhD more worthwhile than it

already was. Thank you.

5

Table of Contents Declaration ............................................................................................................................................. 2

Publications ........................................................................................................................................... 3

Acknowledgments ................................................................................................................................. 4

Abstract .................................................................................................................................................. 8

Abbreviations ........................................................................................................................................ 9

1. Introduction ................................................................................................................................. 11

1.1 Nanoparticles: Developments in Catalysis ............................................................................ 11

1.2 Outline ...................................................................................................................................... 19

1.3 References ................................................................................................................................ 22

2. Novel Unsymmetrical Dithiocarbamate Ligand with Propargyl Functionality ...................... 27

2.1 Introduction ............................................................................................................................. 27

2.2 Aims .......................................................................................................................................... 29

2.3 Results and Discussion ............................................................................................................ 34

2.3.1 Synthesis of N-methylpropargyldithiocarbamate nickel(II) complex ............................ 34

2.3.2 Intramolecular Cyclisation of N-methylpropargyl dithiocarbamate............................... 36

2.3.3 Synthesis of N-methylpropargyldithiocarbamate Ru(II) and Pd(II) complexes ............ 41

2.3.4 Hydrogenation of N-methylpropargyldithiocarbamate nickel(II) complex ................... 48

2.3.5 Alkyne-azide cycloaddition of N-methylpropargyldithiocarbamate complex ............... 53

2.3.6 Functionalisation of Gold Nanoparticles ........................................................................... 63

2.4 Conclusions .............................................................................................................................. 67

2.5 Future Work ............................................................................................................................. 69

6

2.6 References ................................................................................................................................ 71

3. Novel Unsymmetrical 1,1’-Disubstituted Ferrocene Linker .................................................... 77

3.1 Introduction ............................................................................................................................. 77

3.2 Aims .......................................................................................................................................... 82

3.3 Results and Discussion ............................................................................................................ 87

3.3.1 Synthesis of 1’-ethynylferrocene-1-carboxylic acid ......................................................... 87

3.3.2 Synthesis of 1’-Ethynylferrocene-1-carboxylate ruthenium(II) complex ...................... 89

3.3.3 Synthesis of tri-metallic complexes ................................................................................... 91

3.3.4 Reactivity of 1’-Ethynylferrocene-1-carboxylate ruthenium(II) complex in alkyne-azide

cycloaddition ..................................................................................................................................... 104

3.3.5 Synthesis of hexa- and hepta-metallic complexes .......................................................... 107

3.4 Conclusions ............................................................................................................................ 110

3.5 Future Work ........................................................................................................................... 112

3.6 References .............................................................................................................................. 114

4. Synthesis of Novel Linkers Using Thioctic Acid ...................................................................... 120

4.1 Introduction ........................................................................................................................... 120

4.2 Aims ........................................................................................................................................ 124

4.3 Results and Discussion .......................................................................................................... 127

4.3.1 Coupling of piperazine mono-dithiocarbamate ruthenium(II) complex and thioctic acid

127

4.3.2 Coupling of 1-boc piperazine and thioctic and deprotection ......................................... 132

4.3.3 Dithiocarbamate synthesis and ruthenium(II) coordination ........................................ 137

7

4.3.4 Coordination of Pd(II) and Au(I) ...................................................................................... 144

4.3.5 Coupling of 1-boc-ethylenediamine and 1-boc-1,2-diaminopropane with thioctic acid

and deprotection ............................................................................................................................... 150

4.3.6 Imine condensation ........................................................................................................... 155

4.3.7 Ruthenium(II)-functionalisation of gold nanoparticles ................................................. 156

4.4 Conclusions ............................................................................................................................ 161

4.5 Future Work ........................................................................................................................... 163

4.6 References .............................................................................................................................. 165

5. Experimental Section ................................................................................................................ 171

5.1 General ................................................................................................................................... 171

5.2 Chapter 2 Compounds ........................................................................................................... 172

5.3 Chapter 3 Compounds ........................................................................................................... 176

5.4 Chapter 4 Compounds ........................................................................................................... 180

5.5 References .............................................................................................................................. 186

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Abstract

The intermediate size of nanoscale materials with respect to bulk materials and discrete

molecular species affords them unique physical and chemical properties. Since the seminal

work of Nord in 1943 the use of nanoparticles as heterogeneous catalysis has gathered

significant interest and has led to their application in alkene hydrogenation, photocatalysis,

aerobic oxidation and Heck cross-coupling to name a few.

Due to improvements in the synthesis, stabilisation and characterisation of nanoparticles it is

now possible to functionalise the surface of nanoparticles with traditional molecular transition

metal catalysts. These species may bridge the gap between homogeneous and heterogeneous

catalysts where the nanoparticule support provides excellent recyclability yet maintains high

activity and selectivity due to the essentially molecular nature of the catalyst on its surface

In chapter 1 the development of functionalised nanoparticles and their application as catalysts

will be discussed in broad terms with a focus on the functionalisation of gold nanoparticles with

novel alkanethiol ligands. The investigation of novel ligands that provide superior stability and

potential for functionalisation will then be introduced.

Chapter 2 details the synthesis of a novel unsymmetrical dithiocarbamate with propargyl

functionality and the subsequent experiments in which the reactivity of both groups was tested.

Novel Ru(II), Ni(II) and Pd(II) complexes were synthesised despite the ligand exhibiting

unanticipated intramolecular reactivity. In chapter 3 the synthesis of an unsymmetrical

ferrocene linker is detailed and its use in the synthesis of multimetallic complexes given. This

linker proved amenable to the synthesis of two novel group 8 hexa- and hepta-metallic

complexes. Finally, chapter 4 details the work carried out on thioctic acid and its use as an

alternative to both alkanethiols and dithiocarbamates. A novel Ru(II) complex was synthesised

and used to functionalise the surface of AuNPs which were characterised fully.

9

Abbreviations

° C Degrees centigrade

μL Microlitre

AuNP Gold nanoparticle

BPDS Sulfonated bathophenanthroline

BTD 2,1,3-benzothiadiazole

COD 1,5-cyclooctadiene

COSY Homonuclear correlation spectroscopy

CuAAC Copper(I)-catalysed alkyne-azide cycloaddition

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC N,N’-dicyclohexylcarbodiimide

DCU N,N’-dicyclohexylurea

DIC N,N’-diisopropylcarbodiimide

DIPEA N,N-diisopropylethylamine

DMAP 4-Dimethylaminopyridine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

dppe 1,1’-Bis(diphenylphosphino)ethane

dppf 1,1’-Bis(diphenylphosphino)ferrocene

dppm 1,1’-Bis(diphenylphosphino)methane

DTC Dithiocarbamate

EDC (3-Dimethylamino-propyl)-ethyl-carbodiimide

EI Electron ionization

ES Electrospray

FAB Fast atom bombardment

FGI Functional group interconversion

FT-IR Fourier transform infrared

HBTU (2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)

HOBt 1-Hydroxybenzotriazole

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HPNPP 2-hydroxylpropyl-p-nitrophenyl phosphate

ICP-MS Inductively coupled plasma mass spectrometry

IR Infrared

MALDI Matrix-assisted laser desorption/ionization

mM Millimolar

MOF Metal-organic framework

MPC Monolayer-protected cluster

NHS N-hydroxysuccinimide

nm Nanometre

NMR Nuclear magnetic resonance

NP Nanoparticle

RNA Ribonucleic acid

ROMP Ring-opening metathesis polymerisation

SAM Self-assembled monolayer

TA Thioctic acid

TACN 1,4,9-triazacyclonanone

TBIA Tris(benzimidazole)methyl amine

TBTA Tris-(benzyltriazolyl)methyl amine

TBTU O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate

TEM Transmission electron microscopy

TFA Trifluoroacetic acid

TGA Thermogravimetric analysis

THF Tetrahydrofuran

TLC Thin-layer chromatography

TOAB Tetraoctylammonium bromide

TOF Turnover frequency

TPPO Triphenylphosphine oxide

TTTA Tris-(tert-butyltriazolyl)methyl amine

UV-Vis Ultraviolet-visible

XPS X-ray photoelectron spectroscopy

11

1. Introduction

1.1 Nanoparticles: Developments in Catalysis

At 10-9 m in size, nanoscale materials can be found in the void between bulk materials and

discrete atomic or molecular species wherein unique properties and applications may manifest.

The term “nanoscale material” is rather broad and encompasses a variety of systems including

nanoparticles,1-2 molecular wires,3-4 “nanozymes”,5-6 metal-organic frameworks (MOFs)7-9 and

supramolecular assemblies.10-12 At the nanometer scale interesting phenomena such as

quantum confinement grow in significance and new possibilities arise such as the formation of

single magnetic domains both of which yield unique properties: surface plasmon resonance and

superparamagnetism respectively. Although the chemical properties of nanoscale materials are

dictated by high surface area to volume ratio and correspondingly high surface energy

numerous morphologies can be achieved and employed in different ways. These properties and

the potential they present has led to the application of nanoscale materials in fields such as

medical imaging,13-14 optics,15 electronics4, 16 and catalysis1, 17 on which the presented work is

grounded.

The earliest report of a nanomaterial of any kind dates back to the 19th century when Faraday,

amongst others, showed that the aqueous reduction of bulk metals resulted in fine dispersions

of metal particles – referred to as metal colloids.18 In 1943 Rampino and Nord investigated the

relationship between the activity of polyvinyl alcohol-protected Pt or Pd colloids as

hydrogenation catalysts and found a marked increase in efficiency with decreasing particle

size,19 a result which prompted further research into the utility of nanoparticles as

heterogeneous catalysts.

It wasn’t until the early 1970s that colloidal dispersions of gold were investigated for their

catalytic activity – largely a consequence of the well-known chemical inertness of bulk gold. In

one early study Cha and Parravano used a carbon tracer to follow the rate of oxygen transfer

12

between CO and CO2 on the surface of MgO-supported gold at temperatures ranging between

300-400 °C at a total pressure of 50 Torr.20 The gold particles were synthesised by reducing

HAuCl4 at low temperature in acidic medium (a co-precipitative technique) and were then

impregnated onto the MgO support. Whilst no catalytic activity was observed below 350 °C the

activity was found to increase with decreasing particle size, a result which was attributed to

higher surface energy and higher Au-O binding affinity. In 1989, Haruta et al. further explored

the low temperature catalytic activity of metal oxide-supported gold clusters for CO and H2

oxidation.21 A parabolic relationship between rate of H2 oxidation and cluster size was found

and attributed to the interplay between available surface area and propensity to agglomerate.

Figure 1 Cooperative co-adsorption of CO and O2 onto an Au6- cluster and the formation of CO2. O2 binds to the Au6- cluster surface in its superoxo form (O2-) to form (II). Co-adsorption of CO yields the initial species, Au6CO3- (III). Surface rearrangement yields the more stable adsorbate, CO3- (IV). CO2 is eliminated from the cluster surface giving Au6O- (V). A second molecule of CO may bind to the cluster surface, eliminating a second equivalent of CO2 (VI) and regenerating the Au6- cluster. Reprinted with permission from ref 22. Copyright © 2002, American Chemical Society.

In 2002, Wallace and Whetten investigated the co-adsorption of CO and O2 anionic AuN- clusters

(N = 4-19) with the aim of further elucidating the relationship between cluster size and catalytic

activity.22 As per the work of Haruta et al. a non-linear relationship between catalytic activity

13

and cluster size was observed wherein Au6- clusters proved most reactive towards O2 (100

times more so than comparable commercial and model gold catalysts) and Au11- clusters were

most reactive towards CO2. From this result Wallace and Whetten proposed a mechanism for

the surface binding of CO/O2 and oxidation to CO2 (Figure 1) wherein a cooperative effect

operates and the cluster’s electronic properties play a crucial part alongside the surface energy

of the cluster. Gold nanoclusters have since been used as heterogeneous catalysts for the

aerobic oxidation of a large variety of substrates and remain common in the literature due to

high activity and model behaviour.23-29

The work of Wallace and Whetten also emphasised the importance of avoiding cluster

agglomeration so as to maintain optimal catalyst activity. Procedures for the reproducible

synthesis of monodisperse gold nanoclusters such as the Turkevich30-31 or Brust-Schiffrin32-33

methods have made it simple to prevent agglomeration by stabilising the gold surface with a

chosen passivating ligand, the most common of which are the alkanethiols. Beyond limiting

particle aggregation alkanethiols also make it possible to functionalise the surface of the

nanoparticles with any number of units, including catalytically active species. In this way it has

become possible to combine the strengths of heterogeneous and homogeneous catalysis into a

single species wherein solvent-induced aggregation can be used to recycle the catalyst which, at

the terminus of the passivating ligand, dissolves in the reaction medium and maintains high

activity.

The earliest example of such a species was published by Bartz et al. where catalytic gold

nanoclusters were synthesised by treating 4-methylhexa-3,5-diene-1-thiolated gold clusters

with RuCl3 and utilised in the ring-opening metathesis polymerisation (ROMP) of norbornene

(Figure 2).34 Whilst the catalyst did not prove soluble in the reaction medium (methylene

chloride) it was responsible for a marked increase in the turnover frequency (TOF) relative to

that of the analogous molecular catalyst (16 000 h-1 as opposed to 3000 h-1). In a similar study Li

et al. employed a dihydroquinone-functionalised alkanethiol to passivate gold clusters and then

14

used them as a catalyst (with OsO4) for the asymmetric dihydroxylation of β-substituted

styrene.35 The product diols were obtained in universally high yields approximating 80% and

enantiomeric excesses reaching 85-90%. Gratifyingly, upon recycling, the yield and

enantiomeric excess dropped only marginally to 72% and 79% respectively.

Figure 2 Ruthenium(II)-functionalised Au monolayer-protected cluster (MPC) catalysis for ROMP of norbornene. Reprinted with permission from ref 36. Copyright © 2012, Royal Society of Chemistry.

In a later study Belser, Stöhr and Pfaltz synthesised a novel thiol-functionalised chiral rhodium

diphosphine catalyst and incorporated it onto the surface of n-octanethiolate-protected gold

clusters synthesised prior using the Brust-Schiffrin method (Scheme 1).37 The result was a

catalyst that exhibited high conversions and good enantioselectivities in the hydrogenation of

methyl α-acetamidocinnamate comparable to that of the analogous molecular catalyst.

Critically, the colloids were easily recycled by filtration and the catalyst regenerated by treating

with 10 equivalents of 1,5-cyclooctadiene (COD) after which they were used for another three

consecutive cycles wherein the enantioselectivity did not change and the conversion dropped

only moderately from 99% to 74%. The good catalytic activity and enantioselectivity was

attributed to the fact that the rhodium catalyst extended beyond the SAM it was nestled within,

acting much like its (homogeneous) molecular analogue.

15

Scheme 1 Incorporation of chiral rhodium diphosphine ligand into n-alkanethiolate SAM. (a) [Rh(COD)Cl]2, TLBArF, CH2Cl2, 52%; (b) gold particles (2 mg ml-1), 1.5 nM solution of complex 12, CH2Cl2, 24 h, 23 °C. Reprinted with

permission from ref 37. Copyright © 2005, American Chemical Society.

16

Figure 3 Top: Transphosphorylation of HPNPP where [HEPES] = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer. Bottom: (TACN)-functionalised AuNPs: initial rate constant vs Zn(II) mole fraction. The highest catalytic

activity is achieved when the Zn(II) mole fraction is sufficiently high that the Zn(II) coordination centres begin to neighbour one another on the gold surface, allowing cooperative behaviour to arise. Reprinted with permission from

ref 39. Copyright © 2004, John Wiley and Sons.

In their 2011 work Zaupa et al. synthesised gold nanoclusters passivated with a mixed SAM of n-

octanethiolate and 1,4,9-triazacyclonanone(TACN)-terminated thiols which were then

coordinated to Zn(II) by treating with [Zn(NO3)2].38 The system was utilised for the

transphosphorylation of 2-hydroxypropyl-p-nitrophenyl phosphate (HPNPP), an RNA model

compound, and was found to exhibit a rate acceleration of over 40,000 (kcat/kuncat) as compared

to the uncatalysed reaction – making it one of the best Zn(II)-transphosphorylation catalysts

available. The most intriguing result of this work however was the fact that a sigmoidal

relationship was found between the initial rate constant and the Zn(II)-catalyst mole fraction

(Figure 3). After further investigation this result was ascribed to catalyst cooperativity wherein

at higher Zn(II) concentrations the Zn(II) centres begin to neighbour one another within the

cluster’s SAM, raising the local concentration and thereby greatly enhancing the catalytic

activity.38-39

Though remarkable, the above systems rely on functionalisation with monoalkanethiol ligands –

ligands that are known to suffer reversible desorption and cause irreversible aggregation,

17

naturally limiting their long term stability and recyclability as catalysts.40-43 In 2005 Zhao et al.

proposed the dithiocarbamate ligand to be a valid alternative wherein a range of secondary

amines could readily condense with CS2 onto nearby gold surfaces at room temperature without

the need for additional base (Figure 4).44 These ligands remained amenable to SAM formation

and proved to be extremely robust, exhibiting stability in basic and acidic media as well as

resilience towards displacement by competing surfactants.

Figure 4 Spontaneous assembly of dithiocarbamates on a flat gold surface. The wide selection of commercially available secondary amines allow for functionalised dithiocarbamate ligands of significantly different character to be

synthesised; illustrated is the variety of accessible dithiocarbamates that contain long hydrocarbon chains, heterocycles, aromatics and even macrocycles. Reprinted with permission from ref 44. Copyright © 2005, American

Chemical Society.

In the work of Knight et al. piperazine and the associated mono- and bis-dithiocarbamate were

tested in the synthesis of novel bi-metallic complexes and the knowledge gained then applied to

the functionalisation of gold nanoparticles.45-47 Through the control of reaction stoichiometry

and reaction time both the piperazinyl mono- and bis-dithiocarbamates could be isolated and

the illustrated mono-, bi- and hexa-metallic complexes synthesised (Scheme 2). In a related

approach, piperazine was treated with CS2 in a stepwise manner allowing the zwitterionic

complex cis-[Ru(S2CNC4H8NCS2)(dppm)2] to be synthesised and then attached to the surface of

18

gold nanoparticles synthesised in situ via the Brust-Schiffrin method. The nanoparticles were

found to be 3.4 ± 0.3 nm in diameter and were soluble enough in CDCl3 to be characterised by 1H

and 31P{1H} NMR spectroscopy, confirming the presence of the Ru(II) complex on the particle

surface. Presently, examples of dithiocarbamate-functionalised nanoparticles can still be found

in the literature however their applications tend to be mostly analytical or medical in nature,48-

51 highlighting untapped potential as far as catalysis is concerned.

Scheme 2 Synthesis of mono-, bi- and hexa-metallic complexes. (i) CS2, short stir; (ii) CS2, long stir; (iii) AuCl(PPh3); (iv) Et3N, CS2, AuCl(PPh3); (v) (AuCl)2dppf.

Fundamental to all of the above examples is the bifunctional nature of the ligand used to

simultaneously functionalise the gold surface at one terminus and coordinate a second

transition metal at the other. In the case of the presented alkanethiolates it is the incorporation

of a second reactive functional group that allows this to be achieved whereas with the

piperazinyl dithiocarbamate it is the controlled reactivity that permits this, despite its

symmetrical nature. Furthermore, the approach adopted by Knight et al. in which the reactivity

of the ligand is first defined by testing in the synthesis of novel mono- and multimetallic

19

coordination complexes, fully characterised by typical spectroscopic methods and then applied

to the functionalisation of gold nanoparticles presents an ideal way of optimising synthetic

procedure whilst creating unique and novel transition metal coordination complexes.

Scheme 3 Synthesis of piperazinyl bis(dithiocarbamate), complexation with cis-[RuCl2(dppm)2] and gold nanoparticle functionalisation. Piperazine readily condenses with CS2 undergoing (self-) proton exchange to yield the illustrated zwitterionic dithiocarbamate. This route is especially useful in that dithiocarbamate complexation can be confirmed prior to attachment to gold. Nanoparticles synthesised in situ by Brust-Schiffrin method. Reprinted with

permission from ref 47. Copyright © 2009, American Chemical Society.

In summary, the robust nature of dithiocarbamates and simplicity of preparation make them a

viable alternative to the much better established alkanethiol ligand. Furthermore, bifunctional

dithiocarbamates such as the piperazinyl bis(dithiocarbamate) illustrated above, allow AuNPs

to be functionalised with transition metals by first synthesising and characterising the

molecular complexes. Ultimately, this approach can provide novel routes to catalytically active

species wherein AuNPs can act as solid supports for conventional molecular transition metal

catalysts with the goal of improving stability and recyclability.

1.2 Outline

Accordingly, the aim of this project was to synthesise novel bifunctional linkers for the

coordination of the late transition metals and functionalisation of AuNPs, with catalysis as the

motivation for doing so. The approach adopted by Knight et al.45-47, 52 was used to inform the

work in the second chapter however, further relevant literature reports and details will be

covered at the beginning of each results chapter.

20

Scheme 4 Top: Planned coordination of N-methylpropargyldithiocarbamate; Bottom: Unanticipated ligand cyclisation.

The first task was to choose a suitable bifunctional linker based upon commercially available

reagents in order to begin exploring transition metal coordination and AuNP functionalisation

immediately. To this end N-methylpropargylamine and the associated dithiocarbamate were

chosen as the start point and a small number of Ru(II), Ni(II) and Pd(II) precursors selected to

test the reactivity of this linker (Scheme 4). It was quickly found however, that the

dithiocarbamate exhibited unanticipated intramolecular reactivity, complicating its use. Chapter

2 details the unexpected behaviour of N-methylpropargyl dithiocarbamate and how successful

Ru(II), Ni(II) and Pd(II) coordination and AuNP functionalisation was achieved regardless.

21

Scheme 5 Top: Literature preparation of 1’-ethynylferrocene-1-carboxylic acid; Bottom: Proposed Ru(II) and Os(II) coordination.

To avoid the difficulties faced with N-methylpropargyl dithiocarbamate an alternative

ferrocene-based bifunctional linker was proposed based upon a literature protocol (Scheme 5).

The two functional groups of this ligand showed orthogonal reactivity and allowed a selection of

novel bi-, tri-, hexa- and hepta-metallic complexes to be synthesised all of which are covered in

chapter 3.

22

Scheme 6 Proposed Pd(II)-functionalisation of AuNPs using thioctic acid.

The work presented in chapter 4 was heavily focussed on establishing a bifunctional linker that

would be more amenable to the formation of mixed SAMs and perhaps allow cooperative

catalytic affects such as those observed by Zaupa et al.38 to be investigated. In keeping with the

aim of using alternatives to monoalkanethiols for AuNP functionalisation, the commercially

available disulfide, thioctic acid was selected (Scheme 6).

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29. Soulé, J.-F.; Miyamura, H.; Kobayashi, S., J. Am. Chem. Soc. 2011, 133 (46), 18550-18553.

30. Turkevich, J.; Stevenson, P. C.; Hillier, J., Discuss. Faraday Soc. 1951, 11 (0), 55-75.

31. Frens, G., Nature Phys. Sci. 1973, 241, 20-22.

32. Brust, M.; Walker, M.; Bethell, D.; Schiffrin, D. J.; Whyman, R., J. Chem. Soc., Chem.

Commun. 1994, 801-802.

33. Brust, M.; Fink, J.; Bethell, D.; Schiffrin, D. J.; Kiely, C., J. Chem. Soc., Chem. Commun. 1995,

(16), 1655-1656.

34. Bartz, M.; Küther, J.; Seshadri, R.; Tremel, W., Angew. Chem. Int. Ed. 1998, 37 (18), 2466-

2468.

35. Li, H.; Luk, Y.-Y.; Mrksich, M., Langmuir 1999, 15 (15), 4957-4959.

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36. Pieters, G.; Prins, L. J., New J. Chem. 2012, 36, 1931-1939.

37. Belser, T.; Stöhr, M.; Pfaltz, A., J. Am. Chem. Soc. 2005, 127 (24), 8720-8731.

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4889.

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6165-9.

40. Aslan, K.; Pérez-Luna, V. H., Langmuir 2002, 18 (16), 6059-6065.

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42. Fujiwara, H.; Yanagida, S.; Kamat, P. V., J. Phys. Chem. B 1999, 103 (14), 2589-2591.

43. Kamat, P. V., J. Phys. Chem. B 2002, 106 (32), 7729-7744.

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26

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Inorg. Chem. 2008, 47 (20), 9642-9653.

27

2. Novel Unsymmetrical Dithiocarbamate Ligand with

Propargyl Functionality

2.1 Introduction

The primary interest in dithiocarbamate ligands (R2NCS2¯) has historically centred on the

formation of chelated coordination complexes of the d-block elements for which examples exist

in all of their common oxidation states. Only in the past decade has interest grown in exploring

the possibility of modifying the NR2 unit.1-8 Indeed, recent research within the group has shown

that doing so is a viable means of synthesising both symmetrical and unsymmetrical

multimetallic assemblies.9-15

Scheme 7 General synthesis of heterobimetallic assemblies using a piperazine-based dithiocarbamate. (i) CS2; (ii) cis-[RuCl2(dppm)2], 2NaBF4; (iii) 2NEt3, CS2; (iv) [Os(CH=CHR)Cl(CO)(BTD)(PPh3)2] (BTD = 2,1,3-

benzothiadiazole); (v) [Pd(C,N-C6H4CH2NMe2)Cl]2; (vi) [PtCl2(PEt3)2

Ideally, these assemblies are built in a step-wise manner whereby a second donor remains

free/inactive after coordination of the dithiocarbamate to the first transition metal, such that a

second metal may subsequently be coordinated. Synthesis in this way avoids the need for a

protection/deprotection strategy and provides a facile route to creating heterobimetallic

28

species, crucial for the success of the presented work. An example of this is the piperazine-based

dithiocarbamate that inspired the work in the final chapter (Scheme 7).13

In this case one of the amine functional groups acts as a base and the second as a nucleophile

which, following treatment with CS2, yields the illustrated zwitterionic mono-dithiocarbamate.

The fact that the second dithiocarbamate unit can be added after coordination to the first

transition metal makes piperazine a good example of a useful building block for the step-wise

construction of heterobimetallic complexes.

Scheme 8 Ring-closing metathesis of diallyldithiocarbamate complexes. The terminal allyl groups remain suitably reactive within the metal’s coordination sphere to undergo ring-closing metathesis to yield the illustrated 3-

pyrroline dithiocarbamate complexes all the while leaving the complex itself unaltered.14

In earlier work within the group, Naeem et al. 14 showed that unsymmetrical dithiocarbamate

ligands bearing allyl groups could be successfully used to introduce unsaturated groups to the

coordination sphere of a metal that remains reactive post-coordination. In particular,

diallyldithiocarbamate complexes of the type [LnMS2CN(CH2CH=CH2)2] (where M = Ru(II), Ni(II),

Pd(II), Pt(II) and Au(I)) were synthesised and their reactivity in ruthenium-catalysed ring-

29

closing metathesis investigated. It was shown that the terminal unsaturated units belonging to a

variety of the corresponding Ru(II), Ni(II), Pd(II) and Pt(II) complexes underwent ring-closing

metathesis in the presence of the catalyst [Ru(=CHPh)Cl2(SIMes)(PCy3) to form the

corresponding 3-pyrroline dithiocarbamate complexes (Scheme 8). With regards to the present

work, it is reasonable to expect that a similar approach using unsymmetrical unsaturated

dithiocarbamates could be used in the synthesis of heterobimetallic complexes, multimetallic

arrays or the functionalisation of gold nanoparticles; these aims will now be discussed.

2.2 Aims

Unsymmetrical dithiocarbamate ligands bearing pendant alkenes or alkynes were considered

for study and ultimately those illustrated in Figure 1 were chosen. N-allylmethylamine and N-

methylpropargylamine are both commercially available and have found use in organic

synthesis,16-17 though not previously for the formation of dithiocarbamates. In both cases the –

NMe group provides a useful spectroscopic handle for ease of characterisation by NMR

spectroscopy.

Figure 5 Proposed unsymmetrical dithiocarbamate ligands.

The aim was to synthesise a variety of Group 8 and 10 coordination complexes predominantly

using the N-methylpropargylamine-based dithiocarbamate (the N-allylmethyamine approach

was undertaken jointly with a co-worker). The reactivity of the terminal alkyne could then be

probed and the possibility of synthesising novel heterobimetallic complexes investigated. With

this in mind, it was decided to first prepare the coordination complexes illustrated in Scheme 9

using the starting materials discussed below.

30

Scheme 9 Synthesis of unsymmetrical dithiocarbamate complexes.

Cis-[RuCl2(dppm)2] reacts readily with a variety of symmetrical dithiocarbamate salts, R2NCS2¯

(where NR2 = NMe2, NEt2 and NC5H10)13 with the resultant complexes giving rise to

characteristic triplets in the 31P{1H} NMR spectrum due to the cis- arrangement of the ligands.

Similarly, other starting materials of the type [LnMCl2] may also be used for coordination to the

Group 10 transition metals,18-19 an approach which is particularly attractive considering the

commercial or synthetic availability of such starting materials. Furthermore, this approach

yields symmetric bis-dithiocarbamates with metal precursors of the type [MCl2L2] (where L =

PPh3, MeCN etc.) which, if the terminal alkyne remains reactive, may provide a powerful route

to wire-like oligomeric or polymeric multimetallic assemblies.

In an earlier report from the group, the complexes [Pd(S2C∙NHC)(PPh3)2](PF6)2 (NHC = IMes,

IDip) were successfully used as pre-catalysts for the oxidative functionalisation of

benzo[h]quinoline in the presence of PhI(OAc)2 and methanol.20 These complexes are readily

synthesised from [PdCl2(PPh3)2] and NaPF6 and the conversion of benzo[h]quinoline to 10-

methoxybenzo[h]quinoline itself simply requires heating under reflux overnight in the presence

of 1 mol% catalyst loading. If the terminal alkyne remains reactive after coordination (see

below) this approach could provide a facile route to the functionalisation of AuNPs with

catalytically active species.

31

Copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) would appear to be a good way of

testing the reactivity of the terminal alkyne owing to the simplicity (commercially available

catalyst, mild reaction conditions and simple product isolation) of this atom economical

transformation and the ease of characterisation of the 1,2,3-triazole product. A particularly

direct approach to metallation would be to utilise the alkyne moiety itself as a donor via

acetylide formation. Treatment with Au(I) complexes of the type [AuClL] (where L = PPh3, PCy3

etc) provides a good way of testing this whilst probing the stability of the dithiocarbamate

complex. Finally, with a view to constructing multimetallic assemblies, it would be pertinent to

test the viability of functional group interconversion (FGI) of the alkyne. Oxidation and

reduction are primary pathways for FGI and, considering the experimental simplicity in this

case (H2 over Pd/C catalyst), make for a natural starting point. Furthermore, the degree of

reduction of the alkyne may provide insight into its post-coordination reactivity. Scheme 10

highlights some of the planned experiments.

Scheme 10 Reactions to probe alkyne post-coordination reactivity.

The final aim of the presented work is to establish the utility of the N-methylpropargylamine

dithiocarbamate as a surface unit for AuNPs, particularly with regards to achieving a narrow

size distribution and long-term stability. Cheap and rapid routes to stabilised mono-disperse

32

AuNPs are always attractive however, should the experiments summarised in Scheme 10 prove

successful, then straightforward post-attachment functionalisation may also prove possible.

In this case, the AuNPs will be synthesised by the Turkevich (citrate) method owing to its

reliable nature in yielding near spherical particles over a narrow size range between 10-20

nm.21-23 Once the nanoparticles have been prepared and temporarily capped with weakly-bound

citrate units, a solution of the N-methylpropargyl dithiocarbamate (synthesised in situ) will be

added and permanent passivation achieved. Purification will simply involve washing with water

to remove excess citrate and dithiocarbamate; once dried, characterisation by 1H NMR and IR

spectroscopies, TEM and TGA will follow.

If the terminal alkyne units remain reactive after passivation, then there is scope for transition

metal functionalisation, likely via Cu(I)-catalysed azide/alkyne 1,3-dipolar cycloaddition.

Alternatively, AuNPs passivated with 11-azido-1-undecanethiol could be synthesised using a

modified Brust-Schiffrin procedure24-25 and coupled to any of the coordination complexes

featured above (Scheme 10), again via Cu(I)-catalysed cycloaddition. The propensity for

alkanethiols to suffer displacement and leeching26-27 make this route less viable however. In

Scheme 11 are examples of how both approaches may be used in this work.

33

Scheme 11 Proposed post-attachment functionalisation of AuNPs.

34

2.3 Results and Discussion

2.3.1 Synthesis of N-methylpropargyldithiocarbamate nickel(II)

complex

Scheme 12 In situ generation of N-methylpropargyl-dithiocarbamate (1).

Initially, the preparation used by Naeem et al.14 was followed. An aqueous solution of the

dithiocarbamate was generated in situ by treating N-methylpropargylamine with potassium

hydroxide and carbon disulfide. An aliquot of this mixture was then added to a solution of the

desired transition metal precursor and the reaction expected to reach completion within a

couple of hours at room temperature. For the purpose of initial experimentation cis-

[RuCl2(dppm)2] was used with NH4PF6 to provide a source of counter-ions (Scheme 13),

improving the crystallinity of the product.

Scheme 13 Synthesis of bis(diphenylphosphino)-N-methylpropargyldithiocarbamato ruthenium(II) complex 2.

35

These experiments were monitored by taking aliquots and characterising them by 31P{1H} NMR

spectroscopy, which immediately revealed little tendency for ruthenium(II) coordination to

occur with predominantly cis-[RuCl2(dppm)2] starting material still present. This lack of

reaction was accompanied by the formation of a colourless precipitate prior to addition to the

solution of cis-[RuCl2(dppm)2]. This was not observed when N-methylpropargylamine was

treated with potassium hydroxide in the absence of CS2, and thus it was speculated that

dithiocarbamate formation was problematic. Inspection of the 1H NMR spectrum showed a

series of unexpected resonances between 3.0 and 5.5 ppm which suggested that the ligand was

behaving in an otherwise unanticipated manner.

Scheme 14 Synthesis of bis(N-methylpropargyldithiocarbamato) nickel(II) complex 3.

However, when the above procedure was slightly modified and applied to the coordination of

Ni(II) the reaction proceeded successfully. A solution of the dithiocarbamate was prepared in

the same way as above, though left to stir for a shorter duration (< 10 minutes) before being

added to an aqueous solution of NiCl2·6H2O. Work-up afforded 3 as a pale green solid.

The characteristic spectroscopic features of the N-methylpropargyl moiety were identified in

the 1H NMR spectrum with resonances at 2.46 (t, 1H), 3.33 (s, 3H) and 4.46 (d, 2H) ppm

attributable to the alkynyl, methyl and methylene protons respectively. A resonance at 203.1

ppm in the 13C{1H} NMR spectrum was attributed to the –CS2 unit, showing successful formation

of the dithiocarbamate. Finally, electrospray mass spectrometry (+ve mode) gave a molecular

ion with the mass expected for 3 ([M+]). Elemental analysis showed a good agreement between

calculated and experimentally determined values, confirming the overall composition.

36

The success of this experiment was ascribed to two main factors: (i) the shorter reaction time

and (ii) the greater solubility of NiCl2·6H2O in water. If it is true that either N-

methylpropargylamine or the corresponding dithiocarbamate exhibited unexpected reactivity

then it is possible that shorter reaction times limited this or allowed coordination to occur

before this could happen. As far as the second point is concerned, in early experiments it was

noted that cis-[RuCl2(dppm)2] often exhibited poor solubility in the reaction medium and

sometimes phase separation would occur, depending upon the solvent ratio. Naturally, this

would be expected to limit coordination and possibly promote side reactions. It was clear that, if

reproducible coordination of the metal was to be achieved, then the ligand’s behaviour needed

to be elucidated. To this end an experiment was carried out in which the transition metal was

omitted entirely and the reaction between N-methylpropargylamine and carbon disulfide

monitored.

2.3.2 Intramolecular Cyclisation of N-methylpropargyl

dithiocarbamate

An aqueous solution of KOH, N-methylpropargylamine and CS2 was left to stir for an hour to

yield even more significant formation of the colourless precipitate noted before. This could be

readily collected by filtration, washed with H2O and dried under vacuum. Characterisation by 1H

NMR spectroscopy showed what appeared to be a single product with only four distinct proton

environments at 3.30 (s, 3H), 4.78 (t, 2H), 5.14 and 5.26 (m x 2, 2 x 1H). With further

characterisation provided by elemental analysis and electrospray mass spectrometry (m/z

146), a cyclic product was proposed (4). Analysis of the filtrate in the same way revealed that a

second, minor cyclic product had also formed (5). The cyclisation of the N-methylpropargyl-

dithiocarbamate is summarised below in Scheme 15.

37

Scheme 15 Cyclisation of N-methylpropargyl dithiocarbamate.

Based on the cyclic products that were identified it is apparent that the dithiocarbamate and

terminal alkyne are reacting with one another. Sulfur is a reasonable nucleophile owing to its

large, polarisable nature and its accessible lone pair of electrons. Delocalisation within

dithiocarbamate ligands makes the sulfur atoms more electron-rich and enhances the

nucleophilicity further.28 Though less common, alkynes can be susceptible to nucleophilic

addition reactions, which is in part due to hybridisation and the greater s-character afforded to

the carbon nuclei. With this in mind it is reasonable to suppose that cyclisation may proceed via

nucleophilic addition of the dithiocarbamate to the alkyne. The proposed mechanism for this

reaction is illustrated in Scheme 16.

Scheme 16 Intramolecular cyclisation of N-methylpropargyl dithiocarbamate.

As drawn in Scheme 16 it is likely that the reaction proceeded in a concerted manner wherein

nucleophilic addition and protonation occurred simultaneously. However, following this

reasoning it is apparent that the cyclization could also have proceeded to form a 6-membered

38

ring instead (Scheme 17). Experimentally, none of the 6-membered species was observed which

can be rationalised by applying Baldwin’s rules.29

Scheme 17 Alternative intramolecular cyclisation of N-methylpropargyl dithiocarbamate.

Typically, the preferred cyclization pathway is dictated by the interplay of thermodynamic and

kinetic considerations which, very generally, refer to the relative free energies of the starting

material and product (exothermic vs endothermic) and the size of the activation barrier

respectively. According to Baldwin’s rules these competing factors can be summarised as

favourable (or not) based upon the number of atoms in the newly formed ring, the

hybridisation of the attacked atom and whether or not the breaking bond falls outside (exo-) or

inside (endo-) the ring. In this case, the preference for the 5-exo-dig pathway over the 6-endo-

dig pathway must be rationalised.

For the anionic ring closure of alkynes the formation of both 5- and 6-membered rings is

permitted as neither suffer any strain, though such reactions tend to be thermoneutral or even

weakly endothermic.30 With this in mind it is unlikely that there is a significant thermodynamic

driving force for either pathway so the reaction must instead be under kinetic control. In their

revision of Baldwin’s rules, Alabugin et al. show that the kinetics of alkyne ring closure are

strongly influenced by stereoelectronics and the trajectory of attack of the incoming

nucleophile.30

39

Figure 6 Original and modified trajectories for digonal cyclizations.

Where Baldwin originally proposed an acute angle of nucleophilic attack (60°) Alabugin et al.

instead propose an obtuse angle of attack (120°) that mirrors the Bürgi-Dunitz trajectory of SN2

addition to carbonyl units, for instance. An acute angle of attack suffers from a poor matching of

orbital symmetry wherein the nucleophile meets the node of the alkyne π* anti-bonding

molecular orbital (Figure 6); this does not benefit from any stabilising interactions and does not

favour bond formation. Conversely, the obtuse trajectory does not suffer from any such

unfavourable orbital interactions and can be considered stereoelectronically favourable.

Figure 7 a) Trajectory of nucleophilic addition within N-methylpropargyl dithiocarbamate; b) Anti-periplanar arrangement of σ*C-S and σC-H.

As applied to this reaction, one may speculate that the trajectory required to form the 5-

membered ring is much closer to the Bürgi-Dunitz trajectory than that for the 6-membered ring,

which appears more acute and likely to incur the unfavourable orbital interactions mentioned

40

above (Figure 7a). Though less significant, the anti-periplanar arrangement of the C-S and C-H

bonds formed (Figure 7b) permits hyperconjugative stabilisation between the σ*C-S and σC-H

orbitals which may favour the 5-endo pathway even further.31

Following this line of reasoning it can be concluded that, of the two transition states, that of the

5-membered species is more stable and has a lower activation energy barrier to formation, i.e.

the 5-exo-dig pathway is favoured kinetically. Indeed, this is supported by the literature which

shows an overwhelming abundance of 5-exo-dig cyclisations over 6-endo-dig routes.32-37

As mentioned above, when this reaction was carried out in aqueous solution, heterocycle 4

precipitated and was isolated by filtration whilst 5 remained in solution and was obtained by

evaporating the filtrate to dryness under reduced pressure. A comparison of the relative yields

of 4 and 5 showed a clear preference for 4 with an approximate ratio of 4:1. It is apparent that 4

and 5 are isomers and differ only in the position of a single proton; i.e. this is likely an example

of prototropic tautomerism. Though tautomerism often represents a dynamic equilibrium,

tautomerism between two non-aromatic heterocycles is always slow and the individual

tautomers can be isolated,38 much like they were in this experiment.

The relative free energies of tautomers are influenced by a variety of factors including solvent

polarity, electron lone-pairs and dipolar repulsion, aromaticity, hydrogen-bonding and relative

bond energies.38-39 Of these variables, only relative bond energies and solvent effects are

relevant to this reaction. From the 4:1 ratio of products it can be inferred that heterocycle 4 has

a lower free energy than 5.

Although this reactivity did complicate the use of this ligand for transition metal coordination it

was still interesting in that it highlighted both an atom efficient and high yielding means of

synthesising thiazolidine-2-thiones. In comparison, the leading literature procedure proceeds

via the iodocyclisation of allylamines and does so with yields between 46-75% while generating

two molecules of HI in the process.40 Though interesting in its own right and of potential interest

to those involved in heterocyclic chemistry, in this work it was simply a synthetic challenge to

41

overcome. At this point future experiments were designed to achieve rapid dithiocarbamate

formation and avoid cyclisation prior to transition metal coordination.

2.3.3 Synthesis of N-methylpropargyldithiocarbamate Ru(II) and

Pd(II) complexes

Initially, the experiment was modified to reduce dilution so as to encourage intermolecular

activity over intramolecular activity and the reaction times reduced to prevent excessive

cyclisation prior to coordination. Unfortunately, this did little to reduce cyclisation so the choice

of base and reaction solvent were investigated next.

Though the syntheses of the piperazine- and N-allylmethylamine-based dithiocarbamates

proceeded in water with little issue, it is still possible that the early conversion of amine to

dithiocarbamate was limited by the poor solubility of CS2 in the reaction medium. This was

particularly apparent in the formation of the piperazine-based dithiocarbamate which required

up to an hour before any product was observed to precipitate. Naturally, if the dithiocarbamate

forms slowly and is only ever present in low concentrations, then cyclisation will be more likely

to occur.

Methanol was first tested as an alternative solvent owing to its superior miscibility with CS2 and

the retained solubility of KOH. The experiment proceeded in much the same way as before,

however, upon addition of ethanol and concentration under reduced pressure a crystalline pale

yellow solid was obtained (6). 31P{1H} NMR spectroscopy of 6 revealed the successful formation

of a new complex with complete conversion of cis-[RuCl2(dppm)2] (Figure 8). The retention of

the multiplicity of the resonances suggested the dppm ligands were still intact and maintained

their arrangement.

1H NMR spectroscopy (Figure 9) revealed only the proton environments corresponding to the

dppm ligands; neither the acetylide proton nor the N-methylpropargyl methylene protons could

be identified. It is evident that successful displacement of the chloride ligands took place

42

however the desired dithiocarbamate complex didn’t form. A literature search reveals that

when cis-[RuCl2(dppm)2] is treated with CS2 and NaOH in methanol a singly charged

ruthenium(II) xanthate forms which readily converts to the corresponding ruthenium(II)

dithiocarbonate species if the base is present in excess (Scheme 18).41

Figure 8 31P{1H} NMR spectra of 6 (red) and the cis-[RuCl2(dppm)2] starting material (blue) in CD2Cl2.

Scheme 18 Ruthenium(II) dithiocarbonate formation.

43

Figure 9 1H NMR spectrum of 6 in CD2Cl2.

Further characterisation of 6 corroborated this finding as characteristic νCO stretching bands

(1590 and 1561 cm-1) were identified in the IR spectrum and the molecular ion in the ES mass

spectrum (+ve mode) displayed an m/z of 963 ([M+H]+, 100%). Elemental analysis matched the

calculated values and showed the complete absence of nitrogen.

In response, a variety of experiments were carried out by simply repeating the original

procedure with polar aprotic solvents such as acetonitrile, DMF and DMSO or by altering the

procedure to utilise organic bases such as triethylamine and DIPEA in methylene chloride or

chloroform. Alternative sources of counter-ions were also investigated.

After much investigation the most promising procedure was as follows: A solution of N-

methylpropargylamine in methylene chloride was cooled to 0°C and a slight excess of

triethylamine was added. After stirring for five minutes, carbon disulfide was added and the

mixture stirred for an additional 20 minutes. A solution of one equivalent of cis-[RuCl2(dppm)2]

in methylene chloride and methanol (1:2 mixture) was added immediately followed by a

44

solution of KPF6 in water and the reaction stirred for 45 minutes. All solvent was removed

under reduced pressure and the crude product dissolved in the minimum volume of methylene

chloride and filtered through celite. Ethanol was added to the filtrate which, upon concentration

by rotary evaporation, yielded the product as a pale orange solid (2) which was washed with

ethanol and diethyl ether and vacuum-dried.

Figure 10 31P{1H} NMR spectrum of complex 2 in CD2Cl2.

31P{1H} NMR spectroscopy showed complete conversion of cis-[RuCl2(dppm)2] to a new species

as indicated by a pair of new pseudo-triplets at -4.7 and -18.9 ppm, with no xanthate or

dithiocarbonate formation being observed (Figure 10). The chemical shift values were in good

agreement with those in the literature for similar ruthenium(II) dithiocarbamates14 and the

signal multiplicity and pairing suggested the dppm ligands were still arranged in the same

manner as in the precursor. As Figure 10 shows, additional signal splitting relative to the

starting material occurred, suggesting an increasing degree of inequivalence between each of

the phosphorus nuclei. This is perhaps a consequence of restricted rotation about the

dithiocarbamate C-N bond, the barrier for which is estimated to vary between 65 and 88 kJ mol-

1 at 298 K.42

45

1H NMR spectroscopy provided additional evidence for the successful formation of (2) with

resonances at 2.51 (t, 1H, C≡CH), 3.08 (s, 3H, CH3), 4.12 (dd, 1H, CH2) and 4.51 (dd, 1H, CH2) all

attributable to the N-methylpropargyl moiety. The presence of this unit was further confirmed

by IR spectroscopy with a weak stretching band at 2122 cm-1 (νC≡C). A molecular ion at m/z

1014 ([M]+, 100%) in the mass spectrum (ES, +ve mode) and elemental analysis values that

matched calculated values provided firm evidence that complex 2 was synthesised successfully.

The success of this approach was attributed to the complete miscibility of CS2 with methylene

chloride and the consequent higher effective concentration of the so-formed N-methylpropargyl

dithiocarbamate which was expected to favour coordination over cyclisation. Using KPF6

instead of NH4PF6 may also have aided the reaction as the presence of slightly acidic ammonium

ions might have been an unnecessary complication in the first instance.

Scheme 19 Synthesis of N-methylpropargyldithiocarbamatobis(triphenylphosphine) palladium(II) complex 7.

The developed procedure also proved successful for the coordination of the N-methylpropargyl

dithiocarbamate to palladium(II) to yield complex 7, starting from [PdCl2(PPh3)2] and using

NaBF4 as the counter-ion source. The reaction was followed by 31P{1H} NMR spectroscopy

which highlighted slow conversion of [PdCl2(PPh3)2] and, with longer reaction times,

dissociation of triphenylphosphine and its subsequent oxidation to triphenylphosphine oxide.

Slow conversion and simultaneous ligand cyclisation somewhat limited this reaction and

accordingly yields no higher than 37% were achieved. Recrystallisation from isopropanol was

necessary to achieve high purity.

46

Figure 11 1H NMR spectrum of complex 7 in CD2Cl2.

The resonances attributed to the N-methylpropargyl unit in the 1H NMR spectrum (Figure 11)

exhibited similar shifts to 2 with signals at 2.54 (t, 1H, C≡CH), 3.31 (s, 3H) and 4.47 (d, 2H) ppm.

A single resonance at 30.4 ppm in the 31P{1H} NMR spectrum and correct integration of the 1H

NMR spectrum showed retention of the triphenylphosphine ligands. Mass spectrometry (ES, +ve

mode) corroborated this analysis with a molecular ion visible at m/z 774 ([M]+, 100%) as did

elemental analysis which closely matched the calculated values.

Scheme 20 Synthesis of carbonylhydrido-N-methylpropargyldithiocarbamatobis(triphenylphosphine) ruthenium complex 8.

47

Despite following the improved protocol, initial attempts to synthesise complex 8 failed and

appeared to be limited by the apparent lack of reactivity of RuHCl(CO)(PPh3)3 as indicated by

31P{1H} NMR spectroscopy which showed only the presence of starting material and free

triphenylphosphine. The literature corroborates this finding wherein more pressing reaction

conditions such as heating under reflux in acetone are required to coordinate even simple

dithiocarbamates such as Me2NCS2¯ and Et2NCS2¯ to [RuHCl(CO)(PPh3)3].43 With this in mind, it

was speculated that under the conditions presented in Scheme 20, dithiocarbamate cyclisation

proceeded without competition.

Greater success was met by instead using [RuHCl(CO)(BTD)(PPh3)2] (where BTD = 2,1,3-

benzothiadiazole). The increased lability of the BTD ligand was expected to readily permit

dithiocarbamate coordination and simplify the work up (BTD removed in the filtrate). In order

to gauge the reactivity of the Ru(II) precursor and the potential formation of any new complexes

the reaction was first carried out in an NMR tube and closely followed by 31P{1H} NMR

spectroscopy at regular intervals. After 10 minutes of reaction, the formation of a new species

was identified by the emergence of a doublet at 49.9 ppm (Figure 12). Unfortunately, the ratio of

starting material (36.6 ppm) to the newly formed species did not change further over the course

of two hours. 1H NMR spectroscopy of the same mixture showed the appearance of the cyclised

dithiocarbamate, 4.

When the experiment was repeated using N-allylmethylamine instead, the reaction reached

completion within 30 minutes and, after purification to remove traces of triphenylphosphine

oxide (recrystallization from EtOH), only a doublet at 49.9 ppm was observed in the 31P{1H}

NMR spectrum. From this it was inferred that the emergent doublet of the same chemical shift

from the previous experiment could be assigned to complex 8. However, once again it was

evident that dithiocarbamate cyclisation strongly limited transition metal coordination.

48

Figure 12 31P{1H} NMR spectrum in CD2Cl2 of DTC/[RuHCl(CO)(BTD)(PPh3)2] mixture after 10 minutes.

2.3.4 Hydrogenation of N-methylpropargyldithiocarbamate

nickel(II) complex

Scheme 21 Pd-catalysed hydrogenation of complex 3.

The palladium-catalysed hydrogenation of complex 3 was chosen to test the reactivity of the

terminal alkyne post-transition metal coordination. It was anticipated that a successful reaction

would be simple enough to determine as the conversion of alkyne to alkene could be followed

readily by 1H NMR spectroscopy. The homoleptic nature of complex 3 made it an ideal candidate

for this reaction and simplified the experiment further. Finally, it was hoped that this reaction

49

could provide insight into the possibility of functional group interconversion which would make

such complexes even more versatile with regards to creating multimetallic systems or

functionalising AuNPs.

In the first attempt at this experiment, 3 was dissolved in ethyl acetate and Lindlar catalyst

added. H2 was bubbled through the solution for an hour via balloon and stirred vigorously at

room temperature. The catalyst was removed by filtering through celite and the resultant

filtrate was evaporated to dryness and submitted for 1H NMR spectroscopy analysis.

Inspection of the 1H NMR spectrum of the crude product showed only complex 3; no alkene had

formed nor had any other reactions occurred. Accordingly the experiment was modified and H2

was bubbled through the solution for two hours and then an H2 atmosphere (1 bar) maintained

overnight; no hydrogenation was observed in this case either. As a control the experiment was

repeated, this time using 1-octyne and followed closely by TLC and 1H NMR spectroscopy. 1-

Octene was noted to form readily and complete conversion was achieved after leaving the

reaction to stir at room temperature overnight.

It was clear that the quality of the catalyst had not been compromised nor was the procedure at

fault; the problem instead lay with complex 3. It was speculated that the coordination to Ni(II)

had modified the character of the terminal alkyne compared to its entirely organic counterpart,

perhaps making it less reactive and rendering the Lindlar catalyst insufficient for

hydrogenation. More active palladium catalysts were investigated to begin to test this

hypothesis.

In a subsequent experiment complex 3 was dissolved in ethyl acetate and palladium on

activated charcoal (10%) added. H2 was bubbled through the solution and the mixture stirred

vigorously for two hours at room temperature. After this time the catalyst was removed by

filtration through celite. 1H NMR spectroscopic analysis of the filtrate showed successful

reduction of complex 3 to the desired alkene though incomplete conversion had been achieved.

Increasing the reaction time to four hours allowed complex 9 to be isolated in 92% yield.

50

In the 1H NMR spectrum, the signal assigned to the alkynyl proton of 9 at 2.46 ppm (t, 1H, JHH =

2.5 Hz) was no longer present and instead two signals at 5.30 (m, 4H, =CHAB) and 5.77 ppm (m,

2H, =CHC) were observed providing conclusive evidence for the successful reduction to the

alkene. A slight upfield shift was noticed for the –NCH2 protons (4.46 to 4.20 ppm). In the

13C{1H} NMR spectrum the transformation of alkyne to alkene was evidenced by the

replacement of the signals at 75.1 and 74.2 ppm with signals at 129.8 and 119.6 ppm

respectively. Electrospray mass spectrometry (+ve mode) showed the expected increase in

mass with a molecular ion of m/z 351 ([M]+, 20%). Finally, elemental analysis showed good

agreement between calculated and determined values, providing further confirmation of

successful reduction.

Typically, Lindlar catalysts are extremely effective in the hydrogenation of alkynes and, in some

cases where further poisoning is not employed, can still lead to overhydrogenation of the

substrate.44-45 With this in mind, it is interesting that no reduction of complex 3 was observed at

all, especially considering that the same conditions were suitable for the complete reduction of

1-octyne to 1-octene.

First proposed by Horiuti and Polanyi in 1934, the general mechanism for the heterogeneous

catalytic hydrogenation of saturated hydrocarbons is illustrated in Scheme 22.46 The first step of

the reaction involves the oxidative addition of H2 to the surface of the metal catalyst; this step is

rate-determining. The reaction then proceeds with adsorption of the substrate to the catalyst

surface and hydrometallation of the M-H bond with said substrate. Finally, the surface-bound

intermediates are released via reductive elimination and the catalyst surface is regenerated.44

51

Scheme 22 Proposed mechanism of heterogeneous catalytic hydrogenation of unsaturated hydrocarbons.44

Due to the nature of the control experiment in which the reaction conditions, reaction time and

catalyst loading were all kept the same and only the substrate altered it can be concluded that

the lack of reactivity was unlikely to be related to H2 adsorption/desorption and catalyst

interaction. Instead, the nature of the terminal alkyne in complex 3 must have been responsible

wherein its ability to associate to the catalyst surface or undergo either hydrometallation or

reductive elimination was compromised.

The selective hydrogenation of alkynes in the presence of palladium catalysts is

thermodynamically driven47; that is to say a higher relative chemical potential and surface

adsorption strength favours binding, allowing alkyne hydrogenation to proceed preferentially.48

A stronger and more stable carbon-carbon multiple bond might be expected to diminish the

exothermic gain of surface binding and consequently hinder or prevent hydrogenation.

Complex 3 and 1-octyne were compared by IR spectroscopy and the respective stretching

frequencies of the carbon-carbon triple bond found to be 2123 and 2107 cm-1. With such a

negligible difference in νC≡C it was concluded that the alkyne bond strength was approximately

52

the same in both complex 3 and 1-octyne proving the above argument to be invalid in

rationalising the difference in reactivity. Indeed, there is nothing about 3 that explains a

stronger carbon-carbon triple bond such as conjugation and molecular orbital mixing. If

anything, the electron-withdrawing nature of the dithiocarbamate might be expected to weaken

the alkyne π-bonds further and make it more reactive.

Although the carbon-carbon triple bond of 3 might be just as readily broken as that in the

organic molecule, this route will only be available if 3 has sufficient access to the surface’s

reactive sites; indeed it is the blocking of such sites by Pb2+ ions (and preferentially adsorbed

alkyne) that limits alkene reduction with Lindlar catalysts. Upon moving away from acetylene

towards higher homologues and in particular, more branched hydrocarbons, the addition of

hydrogen becomes limited.49 This is attributed to reduced access to reactive surface sites and

increased surface-substrate repulsion.

With linear, non-branched hydrocarbons, including 1-octyne, access to the catalyst’s surface is

not limited to a significant degree (though somewhat relative to acetylene) and consequently

adsorption and hydrogen addition proceed readily. In the case of complex 3 however it may be

the case that the unsymmetrical nature of the dithiocarbamate ligand might also prevent

surface binding and prevent subsequent hydrogen addition. Furthermore, the electron-rich

nature of the Ni(II) coordination sphere may serve to strengthen surface-substrate repulsion

and further inhibit adsorption. By utilising a more active catalyst with a poison-free surface it

may be that in spite of these constraints complex 3 is able to bind and undergo hydrogen

addition, explaining why success was met by replacing the Lindlar catalyst with palladium on

activated charcoal (10%).

53

2.3.5 Alkyne-azide cycloaddition of N-

methylpropargyldithiocarbamate complex

Scheme 23 Copper(I)-catalysed cycloaddition of 2 with benzyl azide.

Alongside the above experimentation, the reactivity of complex 2 in copper(I)-catalysed azide-

alkyne cycloadditions (CuAACs) was also tested. CuAAC reactions often give quantitative yields

and are tolerant of a variety of functional groups and reaction conditions making them an ideal

reaction with which to test the reactivity of 2.50

Initially, the stereotypical CuAAC protocol established by Sharpless and co-workers was

followed in which the copper(I) catalyst is generated by the in situ reduction of CuSO4·5H2O

with sodium ascorbate.51 Benzyl azide was used due to ready availability and for the

characteristic shift of the CH2 protons in the 1H NMR spectrum upon 1,2,3-triazole formation.

Complex 2 and benzyl azide were suspended in a 1:1 mixture of water and tert-butyl alcohol.

Solutions of sodium ascorbate (10 mol%) and CuSO4·5H2O (1 mol%) in water were then added

sequentially. The reaction mixture was stirred vigorously at room temperature overnight after

which time the solution was diluted further with water and the so-formed precipitate collected

by filtration. Analysis of the crude product was carried out by 1H NMR spectroscopy and ES

mass spectrometry.

The CH2 protons of benzyl azide are characterised by a two-proton singlet at approximately 4.3

ppm in CDCl3 which, upon 1,2,3-triazole formation, shifts downfield to approximately 5.5 ppm

in CDCl3. The triazole proton itself is characterised by a singlet around 7.7 ppm.52 1H NMR

54

spectroscopy of the crude product showed no 1,2,3-triazole formation with only complex 2 and

traces of benzyl azide present; it was clear that no reaction had occurred. All attempts to

achieve a successful reaction, starting with increased catalyst loading, failed to yield any

conversion of benzyl azide (Table 1).

Table 1 Copper-catalysed cycloaddition of 2 and benzyl azide reaction conditions. *Entries 5 and 9: reaction carried out under N2. **Entry 6: i-PrOH, THF, DMSO, MeCN and acetone all tested as co-solvents. BPDS = sulfonated bathophenanthroline.

Entry [Cu] (mol%) Solvent (ml) Temperature/°C t/hrs Additive

1 CuSO4·5H2O/Asc

(1/10)

t-BuOH/H2O

(2)

25 18 N/A

2 CuSO4·5H2O/Asc

(1/25)

t-BuOH/H2O

(2)

25 18 N/A

3 CuSO4·5H2O/Asc

(2/20)

t-BuOH/H2O

(2)

25 18 N/A

4 CuSO4·5H2O/Asc

(5/50)

t-BuOH/H2O

(2)

25 18 N/A

5* CuSO4·5H2O/Asc

(1/10)

t-BuOH/H2O

(2)

25 18 N/A

6 CuSO4·5H2O/Asc

(1/10)

**/H2O (2) 25 18 N/A

7 CuSO4·5H2O/Asc

(1/10)

t-BuOH/H2O

(2)

60 18 N/A

8 CuSO4·5H2O/Asc

(1/50)

t-BuOH/H2O

(2)

25 18 BPDS

9* CuSO4·5H2O/Asc t-BuOH/H2O 25 18 BPDS

55

(1/50) (2)

Although heterogeneity was not a problem in the original work of Sharpless et al.51 it was

thought that the poor solubility of 2 in the tert-butyl alcohol/water mixture may have been

critical considering the fact that the alkyne did not appear to be as reactive as anticipated (see

the hydrogenation of 3). The high tolerance of CuAACs to a variety of functional groups and

reaction conditions is well documented and this is also true of solvent choice where high yields

with the CuSO4.5H2O/ascorbate system may also be achieved using THF, acetone, MeCN, DMF,

DMSO and CH2Cl2/MeOH.50 However, as Table 1 illustrates, using THF, DMSO or acetone, in

which 2 was readily soluble, following the same protocol again did not yield a reaction.

Although the instability of the copper(I) oxidation state in the presence of oxygen is known not

to adversely affect this reaction53-54 it was considered worthwhile to check. Carrying the

reaction out under an inert atmosphere of N2 did nothing to affect the outcome of the

experiment, again only 2 and benzyl azide were identified in the 1H NMR spectrum. Copper(I)

oxidation tends not to be an issue with the CuSO4·5H2O/ascorbate system because ascorbate

removes dissolved O2 through rapid reduction.55 In some instances however this reaction can

quickly deplete the available reducing agent, limiting copper(II) reduction and subsequent

catalysis.55 Increasing the excess of sodium ascorbate (up to 25-fold excess relative to

CuSO4·5H2O) also resulted in no change.

Furthermore, whilst the CuSO4·5H2O/ascorbate system is generally excellent, the rate of

reaction has been shown to suffer when the concentration of reactants are especially low and in

such cases additive ligands are often required.55 Though concentration was not an issue in this

experiment it was considered that the reaction might be affected by a larger activation energy

barrier necessitating a rate-accelerating ligand.

56

Figure 13 Common CuAAC-accelerating ligands. A: i) tris-(benzyltriazolyl)methyl amine (TBTA); ii) tris-(tert-butyltriazolyl)methyl amine (TTTA); B: water-soluble analogues; C: sulfonated bathophenanthroline; D:

tris(benzimidazole)methyl amine (TBIA).

With this in mind the CuSO4.5H2O/ascorbate procedure was first modified to incorporate the

use of CuAAC-accelerating ligands, the most commonly used of which are illustrated in Figure

13. Tris-(benzyltriazolyl)methyl amine (TBTA) and its derivative tris-(tert-butyltriazolyl)methyl

amine (TTTA) have both been shown to greatly enhance the rate of CuAACs and are widely

relied upon in the bioconjugation of nucleic acids, proteins etc.56-57 TBTA and TTTA both

accelerate the rate of reaction by coordinating to free copper(I) thereby stabilising it in aqueous

mixtures.58 TBTA however is poorly soluble in water which has led to the development of more

polar derivatives (Figure 13, B) and the testing of commercially available sulfonated

57

bathophenanthroline (Figure 13, C), which is responsible for an even greater rate

enhancement.58

On account of its commercial availability, superior water solubility and remarkable rate

acceleration, sulfonated bathophenanthroline (BPDS) was used. The copper(I) complexes of

BPDS and (similar Schiff bases) are strongly electron-rich and therefore more susceptible to

oxidation under aerobic conditions.55 Accordingly, the reaction must either be carried out in an

inert atmosphere or a large excess of reducing agent must be employed.58

Complex 2 was dissolved in tert-butyl alcohol and benzyl azide added with stirring. CuSO4·5H2O

(1 mol%), sodium ascorbate (50 mol%) and sulfonated bathophenanthroline (10 mol%) in

water were then added. The reaction mixture was stirred vigorously for a day. The so-formed

precipitate was collected by filtration, washed with water, vacuum-dried and submitted for 1H

NMR spectroscopy and ES mass spectrometry (+ve mode). Once again, 1H NMR spectroscopy

showed no conversion of benzyl azide to the corresponding substituted 1,2,3-triazole and no

change to complex 2. ES mass spectrometry corroborated this finding with only 2 present.

Repeating the reaction under N2 had no effect.

For reference, the reaction between 1-octyne and benzyl azide as catalysed by CuSO4·5H2O was

carried out and found to proceed readily without any additive as determined by 1H NMR

spectroscopy. Though the robust nature of CuAACs and their procedural simplicity made it

unlikely that experimental error was responsible for the failure of 2 to react, it was important to

carry out a control experiment for confirmation. No reaction occurred when the experiment was

repeated using the palladium(II) dithiocarbamate (7). Finally, the copper catalyst itself was

investigated.

58

Figure 14 [(NHC)CuX] catalysts for CuAACs.59-61

In studying the synthesis and application of a variety of transition-metal complexes containing

N-heterocyclic carbene (NHC) ligands60, 62-65 it was found that complexes of the type

[(NHC)CuBr] are effective catalysts for CuAAC reactions that give high reaction rates and yields

under moderate conditions using a range of alkynes (varying degrees of substitution) and

azides (both isolated and generated in situ).59 Catalysts of the type [(NHC)CuX] maintain high

activity at low loading (less than 1 mol%), are stable in aqueous or organic media and can be

subjected to heating.59, 61, 66 These catalysts are even capable of catalysing the cycloaddition of

internal alkynes.67

59

Table 2 [(NHC)CuX]-catalysed azide-alkyne cycloaddition reaction conditions. *Entry 5: i-PrOH, MeOH, DMSO, THF, MeCN and acetone. **Entry 10: Et3N used as an additive.

Entry [Cu] (mol%) Solvent (ml) Temperature/° C t/hr

1 [(IPr)CuI] (1) t-BuOH/H2O (2) 25 18

2 [(IPr)CuI] (5) t-BuOH/H2O (2) 25 18

3 [(IAd)CuI] (1) t-BuOH/H2O (2) 25 18

4 [(IAd)CuI] (5) t-BuOH/H2O (2) 25 18

5 [(IPr)CuI] (1) */H2O (2) 25 18

6 [(IPr)CuI] (1) DMSO/H2O (2) 60 18

7 [(IPr)CuI] (1) CH2Cl2 (2) 25 18

8 [(IPr)CuI] (1) CHCl3 (2) 55 18

9 [(IPr)CuI] (1) C2H4Cl2 (2) 75 48

10** [(IPr)CuI] (1) t-BuOH/H2O (2) 25 18

Following the general procedure established by Nolan and co-workers59 the reaction between

2.1 and benzyl azide was repeated with [(NHC)CuI] (where NHC = IPr or IAd) in water/tert-

butyl alcohol at room temperature for 18 hours. As before, no reaction occurred as confirmed by

1H NMR spectroscopy and ES mass spectrometry (+ve mode); furthermore, varying the reaction

conditions did nothing to facilitate the reaction either (Table 2). Adding Et3N so as to facilitate

deprotonation of the alkyne’s terminal proton and allow formation of the copper(I) acetylide

complex also failed to yield a reaction. Bearing in mind the robust nature of CuAACs and the fact

that the terminal alkyne proved less reactive in other experiments (hydrogenation of 3) it was

concluded that the alkyne moiety was not amenable to cycloaddition, regardless of reaction

conditions.

60

Scheme 24 Successful azide-alkyne [3+2] cycloaddition of N-methylpropargylamine.68

Interestingly, a literature search showed that N-methylpropargylamine was capable of

undergoing an azide-alkyne [3+2] cycloaddition with the azide illustrated in Scheme 24.68 The

reaction was catalysed using the CuSO4.5H2O/ascorbate protocol and was facilitated by the use

of TBTA; completion was reached after stirring for 24 hours at room temperature. This provides

compelling evidence that dithiocarbamate-formation and transition-metal coordination

markedly reduced the reactivity of the alkyne functional group.

The first step of any CuAAC is the formation of a copper(I) acetylide complex. It is thought that

this process proceeds via π-bonding between the alkyne and copper(I) centre which enhances

the acidity of the terminal proton and thereby facilitates formation of the σ-acetylide complex.55

Next, the azide coordinates to the copper(I) centre which activates it sufficiently for C-N bond

formation to proceed. The cycloaddition proceeds via an intermediate strained copper

metallacycle to the copper(I) triazolide complex which dissociates to reveal the 1,2,3-triazole

and regenerate the copper(I) catalyst. The catalytic cycle for CuAACs is summarised in Scheme

25.

61

Scheme 25 Catalytic cycle for copper(I)-catalysed alkyne-azide cycloadditions.55

Formation of the copper(I) acetylide complex is crucial for any CuAAC to proceed successfully.

The common use of benzyl azide in CuAACs and its successful reaction with 1-octyne in the

control experiment rules out azide coordination (k4) as a limiting-step. As the formation of

copper triazolides (k5) tend to be highly exothermic and proceed with ease55 it was speculated

that this too was not a limiting-step; instead it was supposed that copper(I) acetylide formation

was the issue.

If either the alkyne failed to form a π-bond to the copper(I) centre or deprotonation failed then

the σ-acetylide complex would not have formed. In order to cast light on this the synthesis of

gold(I) acetylides was attempted using both complexes 2 and 7. [AuCl(PPh3)] was used as the

gold(I) source and a variety of bases including 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), Et3N

and NaOMe were employed and in no cases was Au(I) acetylide formation noted.

In a 2001 study, the charge density distribution of nickel and cobalt dialkyldithiocarbamate

complexes was investigated by single X-ray diffraction and theoretical quantum molecular

orbital calculations.69 It was found that the π-delocalisation exhibited in dithiocarbamates,

represented by the resonance structures illustrated in Scheme 26, is little affected by

62

complexation – the M-S bond consists mostly of σ-donation from the sulfur atoms with little π

back-bonding from the metal.69-70

Scheme 26 Resonance structures of N-methylpropargyl dithiocarbamate.

Although conjugation between the dithiocarbamate and alkyne moieties is not possible, it may

be the case that the π-systems of the two are not entirely isolated. Depending upon the

geometry of the ligand there may be some orbital overlap of the two π-systems allowing for a

small degree of molecular orbital mixing. This could have the effect of reducing the availability

of the alkyne’s π-electron density for further interaction. With regards to Cu(I) and Au(I), this

would mean no electron donation from alkyne to metal and no π-complex formation which in

turn would prevent the σ-acetylide complex from forming. Naturally, without the Cu(I) σ-

acetylide the CuAAC cannot proceed and no reaction will be observed. If it is similar such π-

association that allows alkynes to bind to the surface of heterogeneous catalysts, including Pd,

then this hypothesis may also explain the reduced reactivity of complex 3 with regards to

hydrogenation.

The application of these complexes in the construction of multimetallic assemblies or in the

functionalisation of AuNPs relies upon the reactivity of the terminal functionalities remaining

the same after transition-metal coordination. At this point it was clear that complexation of the

N-methylpropargyl dithiocarbamate did more to affect the nature of the terminal alkyne moiety

than anticipated, rendering it less reactive at best and entirely unreactive at worst. Due to time

constraints the reactivity of this ligand after coordination was not explored further, however it

would have been interesting to investigate alternative ligands in which the alkyne unit was

placed further away from the dithiocarbamate and coordination sphere of the metal.

63

2.3.6 Functionalisation of Gold Nanoparticles

Figure 15 N-methylpropargyl dithiocarbamate and N-allylmethyl dithiocarbamate-capped AuNPs.

Following the success of complexing Ru(II), Pd(II) and Ni(II) centres with both the N-

methylpropargyl and N-allylmethyl dithiocarbamates, it was logical to apply this ligand to the

passivation of AuNPs. Dithiocarbamates have proven to be an effective alternative to thiolate

ligands due to synthetic accessibility and favourable chemisorption properties.71 Furthermore,

early work within the group showed that the methodology to passivate the surface of AuNPs

with functionalised dithiocarbamates could be extended from that used to prepare molecular

systems.4, 9, 11

In order to synthesise the AuNPs the Turkevich method was followed in which trisodium citrate

(Na3Ct) was used as both the reducing agent and temporary stabilising agent for the AuNPs

formed.21-23 HAuCl4·3H2O (2 mM) was dissolved in water and heated under reflux and an

aqueous solution of Na3Ct was added. The golden colour of the Au(III) starting material quickly

dissipated to be replaced by a deep purple colouration. The mixture was heated under reflux for

10 minutes before being cooled to room temperature and stored at 0 °C overnight to allow the

NPs to settle. The intention was to reduce the solvent volume and remove excess citrate by

washing with water and centrifuging. However it was clear that the NPs had agglomerated – the

NPs had settled and the solution had entirely lost its colour nor could the NPs be re-dispersed,

64

even with sonication. As a consequence, displacement with dithiocarbamate could not be

carried out. Avoiding cooling and concentration of the reaction mixture did nothing to prevent

the NPs from agglomerating.

The formation of AuNPs is thought to proceed via a seed-mediated growth mechanism in which

an initial phase of rapid nucleation is followed by slow coalescence and reduction.72-75 This

mechanism and, by extension, the final number and size of AuNPs is affected by pH76, reaction

temperature77, order of reactant addition78 and, critically, the [AuCl4]¯/Na3Ct ratio.22-23, 74, 76, 79-83

At high concentrations of Na3Ct the seed particles can be rapidly and entirely stabilised, yielding

a smaller average particle size. Conversely, at low Na3Ct concentrations, incomplete passivation

is observed and the formation of larger, less stable NPs is more likely to occur.82 With regards to

the experiments described here it was likely that this was the issue – the concentration of Na3Ct

relative to [AuCl4]¯ was low and lead to incomplete passivation and agglomeration.

In a subsequent experiment, the Na3Ct/[AuCl4]¯ ratio was increased from 4.0 to 8.0 and

agglomeration avoided. Furthermore, the solution of Na3Ct was warmed to 40 °C prior to

addition to the boiling solution of HAuCl4·3H2O and the heat removed immediately afterwards

and replaced with an ice bath. The solution at this point was dark blue (indicative of small seed

particle size) and was stirred at 0 °C for one hour. In the second part of the experiment an

aqueous solution of N-methylpropargyl dithiocarbamate was synthesised in situ (KOH as base)

and added dropwise to the above NP solution. The reaction mixture was warmed to room

temperature and stirred for three hours after which time the stirring was halted and the

mixture stored at 5 °C overnight. Doing so caused the NPs to settle and allowed for the solvent

to be decanted. The NPs were washed excessively with water to remove Na3Ct and then dried

under vacuum to yield a fine black powder (NP1). These nanoparticles were soluble in

chlorinated solvents and could be readily characterised by 1H NMR spectroscopy.

The signals expected for the N-methylpropargyl dithiocarbamate could be identified with broad

resonances at 2.45 (1H), 3.59 (3H) and 4.78 (2H) corresponding to the ≡CH, -NMe and –NCH2

65

units respectively. The presence of metal nanoparticles is known to generate distortions in the

magnetic field about the surface chemical environments and can be responsible for significant

signal broadening and shifting.84-85 The relatively small size of N-methylpropargyl

dithiocarbamate and the close proximity of all environments of the molecule to the gold surface

explain why universal broadening and shifting was observed relative to the precursor. The 1H

NMR spectrum also showed traces of the cyclised ligand (4), however, this proved

inconsequential as trituration in diethyl ether was sufficient to remove said traces.

Figure 16 TEM image of Au@S2CN(CH2C≡CH)Me (NP1). Sample prepared by dispersing Au@S2CN(CH2C≡CH)Me in MeOH and dropping carefully onto copper square mesh TEM support grid via pipette. Sample sealed and dried

under vacuum overnight prior to imaging.

Analysis by IR spectroscopy was consistent with coverage by N-methylpropargyl

dithiocarbamate with a νC≡C absorption noted at 2120 cm-1. The spectrum also revealed no

traces of citrate indicating complete displacement of this initial coating. The nanoparticles were

found to be spherical and of size 4.8 ± 1.0 nm by transmission electron microscopy (TEM).

Typically, the average size of AuNPs synthesised by the Turkevich method does not fall below

10 nm86 however the higher relative concentration of Na3Ct and shorter reaction times

66

employed here likely favoured the rapid formation of numerous small nucleation sites, yielding

a much smaller average nanoparticle size.87 Finally, thermogravimetric analysis (TGA) showed a

28.6 % reduction in mass upon heating a 2.5 mg sample of NP1 from 30 to 700 °C at a rate of 10

°C per minute with nothing but a residue of metallic gold left at the end of the analysis. This

reduction in mass was found to be within the range of values reported previously by Angurell

and Rossell for mixed-thiolate-functionalised AuNPs.88

Figure 17 TEM image of Au@S2CN(CH2CH=CH2)Me (NP2). Sample prepared by dispersing Au@S2CN(CH2CH=CH2)Me in MeOH and dropping carefully onto copper square mesh TEM support grid via pipette.

Sample sealed and dried under vacuum overnight prior to imaging.

Interestingly, when the protocol described above was repeated but using N-allylmethyl

dithiocarbamate instead, the experiment failed – addition of the dithiocarbamate lead to rapid

agglomeration and in some cases, metallic gold was observed. Indeed, a TEM image was taken of

an aliquot of the reaction mixture an hour after adding N-allylmethyl dithiocarbamate that

showed the extent of aggregation (Figure 17); the nanoparticles were noticeably larger and

more densely packed compared to those seen in Figure 16.

67

The fact that aggregation occurred directly after adding the dithiocarbamate suggested that the

ligand was directly responsible. It may have been the case that N-allylmethyl dithiocarbamate

was only capable of partial citrate displacement yielding highly unstable particles more

susceptible to agglomeration. Perhaps greater citrate displacement was achieved however

surface coverage of N-allylmethyl dithiocarbamate may have been much poorer compared to

that of N-methylpropargyl dithiocarbamate. The molecular geometry and orientation of surface-

bound ligands play an important role in the stabilisation of AuNPs89-90 so it may have been the

difference in surface orientation of the two dithiocarbamates and, by extension, surface packing

densities that yielded the observable difference in stability of NP1 and NP2. Due to time

constraints this hypothesis could not be tested and success was not met in synthesising NP2.

2.4 Conclusions

In conclusion, N-methylpropargyl dithiocarbamate is not a suitable precursor for the synthesis

of reactive transition-metal coordination complexes which may then be used in the

functionalisation of AuNPs or the creation of multimetallic assemblies. N-methylpropargyl

dithiocarbamate is a clear illustration of the inherent challenge in selecting suitable bifunctional

synthons for the synthesis of larger multimetallic systems – both functional groups must be

amenable to transition-metal coordination however their reactivity must be balanced such that

stepwise coordination is possible all the while avoiding interaction between the two.

Figure 18 Thiazolidine-2-thione formed from adding CS2 to N-methylpropargylamine in aqueous solution of KOH.

68

Although N-methylpropargyl dithiocarbamate appeared to be an ideal building block due to its

small size and structural simplicity experimentation quickly highlighted how it was these traits

that severely limited its use. Despite the synthetic ease of adding CS2 to form the

dithiocarbamate this was enough to activate the N-terminus of the molecule which, when

combined with its small size and close proximity to the terminal alkyne, resulted in cyclisation

to form a thiazolidine-2-thione (Figure 18).

When this reaction was optimised thiazolidine-2-thione 4 could be obtained in 77% yield which

is comparable to the current leading literature route involving the iodocyclisation of allylamines

which proceeds with yields ranging between 46-75%.40 Furthermore, the synthesis described

here is entirely atom efficient unlike the leading literature route which generates two molecules

of HI in the reaction. This was a noteworthy result and highlighted how the unanticipated

behaviour N-methylpropargyl dithiocarbamate might be utilised effectively in heterocyclic

chemistry. Furthermore, this behaviour did not prevent the Ru(II), Ni(II) and Pd(II) complexes

illustrated in Scheme 15 from being successfully synthesised.

Figure 19 Coordination complexes successfully synthesised using N-methylpropargyl dithiocarbamate.

Finally, the terminal alkyne unit proved to be less reactive after transition-metal coordination

than anticipated, such that complexes 2 and 7 were not reactive towards CuAACs and acetylide

formation and complex 3 could not be hydrogenated under standard controlled conditions. The

69

fact that N-methylpropargylamine is reactive towards CuAACs68 suggests that the lack of

reactivity was a direct consequence of either dithiocarbamate formation or the subsequent

coordination. This is an interesting result and would benefit from additional experiments such

as increasing the distance of the terminal alkyne from the coordination centre.

2.5 Future Work

Figure 20 N-methylpropargylamine, N-methyl-3-butyn-1-amine and N-methyl-4-pentyn-1-amine.

With the above conclusions in mind, it would be interesting to attempt to increase the distance

between the amine and alkyne functional groups, were this work to be continued further. In

doing so, the corresponding dithiocarbamate may no longer interact with the alkyne,

prohibiting cyclisation. Additionally, if the alkyne can be distanced sufficiently from the

amine/dithiocarbamate, then it will be more likely to remain reactive towards further

coordination and allow the aim of synthesising multimetallic assemblies to be realised.

Scheme 27 Synthesis of N-methyl-4-pentyn-1-amine.

In N-methyl-3-butyn-1-amine, the alkyne is one additional carbon atom further away from the

amine, unfortunately it is extremely expensive and there appear to be few literature procedures

to synthesise it. N-methyl-4-pentyn-1-amine on the other hand can be readily synthesised from

commercially available 5-hexyn-1-ol and methylamine (Scheme 27). 5-Hexyn-1-ol is treated

70

with methanesulfonyl chloride to generate the mesylate which can then be aminated directly

with a solution of methylamine in ethanol.91

Scheme 28 Proposed repeated AuNP functionalisation.

With the N-methyl-4-pentyn-1-amine to hand, the procedure followed in this work could be

repeated. The dithiocarbamate could be synthesised (non-aqueous system preferable to account

for longer chain), coordinated to Ru(II), Ni(II) and Pd(II) and the reactivity investigated once

71

again. Should placing the alkyne unit further away from the coordination centre prove

successful in allowing it to react further, then AuNP functionalisation and multimetallic

assembly could be studied more extensively.

At this point the scope for future work would be substantial and the application of any

synthesised assemblies or functionalised NPs could be explored, including in catalysis. For

instance, if the functionalised AuNPs illustrated in Scheme 28 could be synthesised then their

respective application in the catalysis of cross-coupling reactions and oxidative

functionalisation could be investigated.

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3. Novel Unsymmetrical 1,1’-Disubstituted Ferrocene Linker

3.1 Introduction

Following its discovery in 19511-2 ferrocene was quickly found to exhibit reactivity typical of

aromatic compounds, allowing for a variety of substituted derivatives to be synthesised via

reactions such as Friedel-Crafts acylation and alkylation or direct metalation with n-butyl

lithium as well as many others.3-10 Over the ensuing decades the reactivity and flexibility of

ferrocene paved the way to a variety of 1,1’-disubstituted ferrocene derivatives of both

symmetrical11-13 and unsymmetrical14-20 nature. 1,1’-Disubstituted ferrocene compounds are

now commonly applied in fields diverse as electrochemistry, asymmetric catalysis and polymer

chemistry.21-24

Scheme 29 Synthesis of ferrocene-bridged Pd(II)/Ni(II) heterobimetallic oligomers.

78

The application of 1,1’-disubstituted ferrocene compounds in molecular electronics quickly

followed from the synthetic ease of derivatising ferrocene combined with its electron rich

aromatic character, which made it ideal for incorporation into existing rigid π-conjugated

systems. In 1996 Lavastre et al. coupled 1,1’-diiodoferrocene and 1-((triisopropylsilyl)ethynyl)-

4-ethynylbenzene under typical Sonogashira cross-coupling conditions using a

[PdCl2(PPh3)2]/Cu(OAc)2 catalyst to yield the conjugated starting material depicted in Scheme

1.25 This compound was readily desilylated by treating with (Bun4N)F and the free alkynes

metalated with either [PdCl2(PBun3)2] or [Ni(C≡CH)2(PBun3)2] in a copper(I)-catalysed reaction

to yield the illustrated organometallic oligomers.

Scheme 30 Synthesis of ferrocene-bridged Pd(II)/Pt(II) heterobimetallic via transmetallation.

In contrast, Long et al. used a transmetallation protocol to synthesise a similar oligomeric mixed

ferrocenyl/Pt(II) species.13 Trimethylsilyl-protected 1,1’-diethynylferrocene26 was lithiated and

then treated with SnCl(CH3)3 in situ to yield the anticipated trimethyltin ferrocene species in

excellent yield (Scheme 30). In the presence of a catalytic amount of CuI (5 mol%) the distannyl

ferrocene species readily underwent transmetallation with trans-[PtCl(C6H5)(PR3)2] giving

79

either a discrete trimetallic species or the associated oligomer when using two or one

equivalents respectively; polymerisation was not observed due tow of poor solubility.

Scheme 31 Synthesis of ferrocene-capped ruthenium(II) bis(acetylide) complex from cis-[RuCl(dppe)2].

Later Lebreton et al.,27 also investigating the electrochemical consequences of incorporating

organometallic species into carbon-rich π-conjugated systems, synthesised mixed

ruthenium(II)/ferrocenyl trimetallic complexes by taking advantage of the known reactivity of

ruthenium(II) towards terminal alkynes.28-29 As studied by cyclic voltammetry, the trimetallic

species was found to exhibit excellent electronic communication between the ruthenium(II) and

ferrocenyl units via the alkyne bridge.

During the same period, 1,1’-disubstituted ferrocene compounds were becoming commonplace

in the synthesis of polymetallic building blocks for coordination polymers and supramolecular

architectures wherein the combined redox activity, high conformational freedom and electron-

rich π-system of ferrocene would allow unique physical, catalytic, electronic and optical

properties to emerge.30-35 This development was no coincidence, as evidenced by the

simultaneous surge in literature reports of a multitude of novel symmetric 1,1’-disubstituted

ferrocene derivatives.

Starting with the work of Cayton et al. in 1991, a number of bifunctional covalent linkers,

including 1,1’-ferrocenedicarboxylic acid, proved useful in the synthesis of quadruply M-M

bonded tetranuclear molybdenum and tungsten carboxylate complexes with the aim of

designing novel sub-units for supramolecular assemblies.34 The ferrocene-bridged sub-unit was

simply synthesised by treating a solution of [W2(O2CtBu)4] in toluene with 1,1’-

80

ferrocenedicarboxylic acid and leaving it to react at room temperature for three days. The

desired tetranuclear complex was obtained in excellent yield (96%).

Figure 21 Novel multimetallic complexes synthesised using 1,1’-ferrocenedicarboxylic acid: (a) linked Mo2(DAniF)3 (DAniF = N,N’-di-p-anisylformamidinate) units; (b) tetranuclear Cu2Fe2 cage.

Cotton et al. published a series of related structures a decade later (Figure 21a) with a particular

focus on characterising them more fully by X-ray crystallography and elucidating their

electrochemical behaviour.33 In a different approach, Dong et al. were able to synthesise a

tetranuclear Cu2Fe2 multimetallic cage in the presence of pyridine using 1,1’-

ferrocenedicarboxylate ligands as terminating groups (Figure 21b).36 Stability of the complex

was maintained due to hydrogen bonding and π-π interactions between the pyridyl ligands and

ferrocenyl moieties of neighbouring molecules, interactions which form the basis of many

supramolecular architectures.

Fundamental to all of these studies was the symmetry of the bifunctional ferrocene spacer; a

design choice which may have been in part due to synthetic simplicity. Over the past decade

however, hetero(multi)metallic complexes containing different early or late transition metals

have garnered a lot of attention37-41 on account of unique structural features and the potential

for unique properties to emerge as a consequence of cooperative effects.42-45 Unsymmetrical

1,1’-disubstituted ferrocene derivatives have been incredibly useful in realising this goal.

81

Scheme 32 1-(carboxylic acid)-1’-(diphenylphosphanyl)ferrocene (Hdpf) in the synthesis of mixed Ru/Au/Fe/Zn heptametallic complex.

A good example is the work of Kühnert et al. in which 1-(carboxylic acid)-1’-

(diphenylphosphanyl)ferrocene (Hdpf) was a crucial linker for the heptametallic complex

illustrated in Scheme 32.46 Taking advantage of the differing soft/hard nature of the respective

phosphorous- and oxygen-based donors Au(I) was first selectively coordinated by treating Hdpf

with [AuCl(tht)] (where tht = tetrahydrothiophene). Addition of Au(I) to the ferrocene unit

proved to have little effect on its reactivity, allowing for a reaction to take place with 1-

ethynylruthenocene. Finally, the carboxylate ligand (revealed by treatment with two

equivalents of diethylamine) was coordinated to a Zn(II) centre by treating with [ZnCl2(tmeda)].

The complex was isolated in 68% yield and proved amenable to characterisation by 1H, 13C{1H}

and 31P{1H} NMR and IR spectroscopy, ES (+ve mode) mass spectrometry and elemental

analysis. Crucial to the preparation of this heteromultimetallic compound was the asymmetry of

Hdpf and the stepwise synthetic strategy that it allowed.

Figure 22

82

The 2010 work of Hildebrandt et al. provides another strong example of this sequential

synthetic approach working with an unsymmetrical ferrocene building block at its core.47 Under

typical Aldol condensation conditions, 1-(diphenylphosphino)-1’-formylferrocene was first

treated with acetylpyridine in the presence of NaOH followed by a Michael addition with a 1-[2-

oxo-2-(2-pyridyl)ethyl]pyridinium salt. After subsequent ring closing, this yielded the

anticipated terpyridyl-functionalised ferrocenyl moiety. The diphenylphosphine ligand could

then be selectively coordinated with either [AuCl(tht)] or [RhCl(COD)]2 followed by the

terpyrdine unit with [RuCl2(dmso)4] to give complexes of the type illustrated in Figure 22.

Crucially, in some of the reported complexes, interplay between the two metal centres either

side of the ferrocene spacer led to the appearance of apparent cooperative effects – enhanced C-

H activation in this case.47 With respect to the work presented here, it seems clear that

ferrocene, and in particular its unsymmetrical 1,1’-disubstituted derivatives, may be superior to

the N-methylpropargyldithiocarbamate investigated in the previous chapter wherein a stepwise

synthetic approach can be fully realised without subsequent coordination chemistry being

adversely affected.

3.2 Aims

As described above, in their 1998 work Lebreton et al. showed that ethynylferrocene remained

suitably reactive towards trans-[RuCl2(dppe)2], which under controlled reaction conditions,

yielded the mono-ferrocenylalkynyl ruthenium(II) complex (Figure 23a).27 The remaining

chloride ligand and the latent reactivity it presents makes this an ideal building block to inspire

the current work. Again, as described in the introduction, the 1,1’-ferrocenedicarboxylate ligand

exhibited the anticipated coordinative behaviour allowing a variety of polymetallic species to be

synthesised.

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Figure 23 Reactivity of substituted ferrocene compounds: (a) ethynylferrocene is reactive towards metal precursors such as trans-[RuCl2(dppe)2]; (b) 1,1’-ferrocenedicarboxylic acid is reactive towards metal

precursors such as [Ru{C(C≡CPh)=CHPh}Cl(CS)(PPh3)2].

In 2007 however, Cowley et al. showed the utility of this ligand in the formation of a smaller

monobridged bis-ruthenium(II) enynyl complex (Figure 23b).48 The similarity in the

coordinative behaviour of carboxylate and dithiocarbamate ligands makes this building block

valuable to the current work. A literature procedure has been found for the preparation of 1’-

ethynylferrocene-1-carboxylic acid, a molecule which, based upon the complexes illustrated

above and the orthogonal reactivity of the two functional groups, should be amenable to

stepwise coordination and the synthesis of novel hetero(multi)metallic complexes.

Scheme 33 Four step synthesis of 1’-ethynylferrocene-1-carboxylic acid from commercially available ferrocenecarboxylic acid.

As described in the work of Barišić et al., commercially available ferrocenecarboxylic acid can be

treated with boron trifluoride diethyl etherate in MeOH to yield methyl ferrocenecarboxylate

(Scheme 33).49 In a separate study Huber, Hubner and Gmeiner first treated methyl

ferrocenecarboxylate with acetyl chloride and AlCl3 under typical Friedel-Crafts acylation

conditions to yield the illustrated methyl 1’-acetylferrocene-1-carboxylate.50 Finally, Vilsmeier-

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type formylation followed by base-mediated elimination allowed the desired ferrocene spacer

to be isolated in moderate yield (57%).

Significantly, it was further shown that 1’-ethynylferrocene-1-carboxylate did indeed exhibit

orthogonal behaviour, permitting the ethynyl and carboxylate units to be functionalised in

separate steps. In this case, the carboxylate functional group was receptive to activation by O-

(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) and coupling to

both aminopropyl- and aminobutyl-functionalised phenylpiperazine derivatives while the

ethynyl unit remained reactive towards Cu(II)-catalysed azide-alkyne cycloaddition in a

subsequent step. This suggests that 1’-ethynylferrocene-1-carboxylate may be the bifunctional

linker needed to achieve the synthesis of novel multimetallic arrays or the functionalisation of

gold nanoparticles, while incorporating a redox-active moiety.

As Scheme 34 illustrates, if the carboxylate ligand can first be used to synthesise the

corresponding ruthenium(II) enynyl complex, similar to that reported by Cowley et al., then,

assuming the ethynyl functional group remains suitably reactive, a wide variety of novel

polymetallic coordination complexes can by synthesised. For instance, with a suitable bis-azide

or azide-functionalised thiol/disulfide, the Cu(I)-catalysed cycloaddition approach could be

used to synthesise novel tetrametallic species or even functionalise the surface of AuNPs

(Scheme 34).

The direct metallation of the ethynyl unit will provide a comparison to the surprisingly

unreactive terminal alkyne of the dithiocarbamate discussed in the previous chapter. To this

end, the ferrocenylcarboxylate ruthenium(II) enynyl complex could either be treated with

[AuCl(L)] (where L = PPh3, PCy3, PMe3 etc.) or trans-[RuCl2(dppe)2] to yield the corresponding

mono-acetylide complexes. Finally, it would allow the reactivity of the ethynyl unit towards

insertion reactions to be explored. It would be extremely useful to determine whether the

associated vinyl complexes can be synthesised when using starting materials of the type

[MHCl(BTD(CO)(PPh3)2] (where M = Ru or Os). Should such a reaction prove successful then the

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remaining labile BTD and chloride ligands present the ideal opportunity to employ a second

bifunctional linker such as the piperazinyl bis-dithiocarbamate shown earlier or even 1,1’-

ferrocenedicarboxylate as described above. If successful, this would not only allow hexa- or

heptametallic assemblies to be prepared but also permit arrays containing all three major group

eight transition metals to be generated.

86

Scheme 34

87

3.3 Results and Discussion

3.3.1 Synthesis of 1’-ethynylferrocene-1-carboxylic acid

Scheme 35 Synthesis of 1’-ethynylferrocene-1-carboxylic acid.

Methyl ferrocene-1-carboxylate was synthesised according to the protocol established by

Barišić et al. in which a solution of ferrocenecarboxylic acid in MeOH was treated with BF3·Et2O

and heated under reflux for four hours.49 After raising the pH to approximately 8-9 and

extracting with CH2Cl2, the crude product proved sufficiently pure that it was simply washed

with NaCl solution and then dried over Na2SO4, evaporated to dryness and vacuum-dried. 1H

NMR spectroscopy showed complete conversion of the carboxylic acid to the ester as evidenced

by the disappearance of the broad signal at approximately 11.0 ppm and the appearance of a

singlet at 3.82 ppm integrating to three protons relative to those of the ferrocenyl rings.

The remaining experimental steps to 1’-ethynylferrocene-1-carboxylic acid were carried out

according to the protocols followed by Gmeiner et al. starting with the synthesis of methyl 1’-

acetylferrocene-1-carboxylate. Acetyl chloride was added to a suspension of anhydrous

aluminium chloride in CH2Cl2 at 0 °C, stirred for 15 minutes and then added dropwise to a

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solution of methyl ferrocene-1-carboxylate in CH2Cl2 under N2. As before, extraction with CH2Cl2

(and drying over MgSO4) was sufficient to isolate methyl 1’-acetylferrocene-1-carboxylate in

high purity. The incorporation of the acetyl group was confirmed by the appearance of a singlet

at 2.39 ppm (3H) in the 1H NMR spectrum and a signal at 201.3 ppm in the 13C{1H} NMR

spectrum.

Methyl 1’-(1-chloro-3-oxoprop-1-enyl)ferrocene-1-carboxylate was synthesised by adding

POCl3 dropwise to anhydrous DMF at 0 °C, stirring for 15 minutes and then adding the mixture

to a solution of methyl 1’-acetylferrocene-1-carboxylate in anhydrous DMF. After warming to

room temperature the reaction was found to reach completion within three hours. After

quenching the Vilsmeier complex with sodium acetate trihydrate and extracting the crude

product with CH2Cl2 it was found that purification by flash chromatography (n-hexane:ethyl

acetate, 6:1) was necessary. A pair of doublets (1H) at 6.38 and 10.13 ppm in the 1H NMR

spectrum were assigned to the unsaturated α-proton and aldehyde proton respectively,

showing the successful formation of the ferrocenyl chloroacrolein derivative.

In the final step a solution of methyl 1’-(1-chloro-3-oxoprop-1-enyl)ferrocene-1-carboxylate in

anhydrous dioxane was heated under reflux and treated with a boiling solution of NaOH. The

mixture was heated under reflux for a further 30 minutes before being cooled and neutralised

with HCl. The product was extracted with CH2Cl2 and purified by flash chromatography. In the

literature procedure a 1:1 mixture of n-hexane and diethyl ether was used to elute the product

however, in this case, elution with a 9:1 mixture of methylene chloride and methanol was

necessary to remove the product from the column. The solubility of 1’-ethynylferrocene-1-

carboxylic acid was found to be pH-dependent with acid being necessary to permit solubility in

solvents such as diethyl ether, methylene chloride and chloroform. This was attributed to the

presence of the carboxylate (as opposed to the acid) which may have been stabilised by

conjugation with the neighbouring cyclopentadienyl ring. This would lead the product to exhibit

a high affinity for the stationary phase (silica), requiring greater polarity to elute it. Regardless,

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1H NMR spectroscopy showed complete elimination of both the unsaturated aldehyde and the

ester and, crucially, confirmed the presence of the acetylide proton, assigned to a singlet at 2.83

ppm.

3.3.2 Synthesis of 1’-Ethynylferrocene-1-carboxylate

ruthenium(II) complex

Scheme 36 Synthesis of 1’-ethynylferrocene-1-carboxylate ruthenium(II) vinyl complex 11. [Ru] = [Ru{C(C≡CPh)=CHPh}Cl(CO)(PPh3)2].

Due to the poor solubility of 1’-ethynylferrocene-1-carboxylate and the potential complications

arising from the free carboxylate unit, it was decided to first coordinate the carboxylate to the

group 8 transition metals ruthenium and osmium. Furthermore, [RuHCl(CO)(BTD)(PPh3)2] was

not suitable for direct reaction with 1’-ethynylferrocene-1-carboxylate because of its reactivity

towards alkyne insertion.51-52 To this end [RuHCl(CO)(BTD)(PPh3)2] was first treated with 1,4-

diphenylbutadiyne following the protocol established by Torres et al.51 to provide the

ruthenium(II) enynyl complex, [Ru{C(C≡CPh)=CHPh}Cl(CO)(PPh3)2].

Initially, a solution of this ruthenium complex (1.0 equiv.) in CH2Cl2 was added to a suspension

of 1’-ethynylferrocene-1-carboxylic acid (1.0 equiv.) and Et3N (excess) in CH2Cl2. After one hour

31P{1H} NMR spectroscopy showed the formation of a new species with approximately 75%

conversion; leaving the reaction for a further two hours did not lead to further conversion.

Accordingly, the mixture was treated with another 0.2 equivalents of 1’-ethynylferrocene-1-

carboxylic acid and Et3N in CH2Cl2 and stirred for another hour. This proved sufficient to achieve

100% conversion as confirmed by 31P{1H} NMR spectroscopy. All solvent was removed under

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reduced pressure, and the residue taken up in the minimum volume of CH2Cl2 and filtered

through celite. Finally, recrystallization from CH2Cl2/EtOH yielded the complex 11 as a fine

orange powder which was vacuum dried and characterised by 1H, 31P{1H} and 13C{1H} NMR and

IR spectroscopy, ES mass spectrometry (+ve mode) and elemental analysis.

Figure 24 1H NMR spectrum of complex 11 in d6-acetone.

The 31P{1H} NMR spectrum showed only one signal at 35.5 ppm, a chemical shift which matches

well with literature values for similar carboxylate ruthenium(II) vinyl complexes,53 providing

strong evidence for successful coordination. The 1H NMR spectrum corroborated this finding,

with good agreement between the relative integrations of the phenylic and ferrocenyl chemical

environments, including both the acetylide and vinyl protons (Figure 24). The carbonyl ligand

(expected as a triplet) could not be identified in the 13C{1H} NMR spectrum however a signal at

177.8 ppm was assigned to the carboxylate ligand.

However, the presence of the carbonyl ligand was confirmed by IR spectroscopy as indicated by

a very strong signal at 1908 cm-1 and the stretching frequency of the carboxylate ligand was

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found to be 1501 cm-1. Though weak (despite increasing the number of scans), signals

attributed to the stretching modes of both the enynyl and ferrocenyl alkyne triple bonds were

identified at frequencies of 2100 and 2143 cm-1, respectively. The complex proved sensitive to

the ionising conditions of ES mass spectrometry (+ve mode), fragmenting significantly - the

main peak corresponded to an m/z of 898 which may be indicative of a fragment such as [M-

(CO)-(PPh3)+2K]+. Even MALDI failed to prevent fragmentation, showing the same molecular

ion as seen in the ES mass spectrum. Finally, the experimental elemental analysis was in

excellent agreement with the calculated values, confirming the composition and the high purity

of the product.

3.3.3 Synthesis of tri-metallic complexes

Scheme 37 Synthesis of Au(I) acetylide complexes.

The subsequent experiments were designed to demonstrate that the ruthenium(II) coordination

centre and the ethynyl unit were sufficiently separated by the ferrocenyl linker that a second

transition metal could be coordinated with ease, unlike the N-methylpropargyldithiocarbamate

ruthenium(II) complex of the previous chapter. Due to the stability and facile synthesis of

ethynyl organogold(I) complexes,54-55 the first experiments involved testing the reactivity of 1’-

ethynylferrocene-1-carboxylate ruthenium(II) enynyl complex by treating directly with Au(I)

precursors of the type [AuCl(L)] where L = PPh3, PCy3 and dppf.

In a typical experiment, the 1’-ethynylferrocene-1-carboxylate ruthenium(II) enynyl complex

was dissolved in CH2Cl2 and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) and [AuCl(L)] added.

After stirring at room temperature for 18 hours, EtOH was added which, after concentration

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under reduced pressure, yielded precipitation of the products as pale yellow solids which were

collected by filtration and vacuum-dried. The products were characterised by 1H and 31P{1H}

NMR and IR spectroscopy, ES (+ve mode) mass spectrometry, MALDI and elemental analysis.

Figure 25 31P{1H} NMR spectrum of complex 12 in d6-acetone.

Both 1H and 31P{1H} NMR spectroscopy provided strong evidence that the treatment of the 1’-

ethynylferrocene-1-carboxylate ruthenium(II) complex with [AuCl(PPh3)] had led to the

anticipated ethynyl gold(I) complex with elemental analysis confirming high purity. In the

31P{1H} NMR spectrum (Figure 25) a new signal was found at 42.0 ppm, in good agreement with

the literature chemical shift values for non-functionalised ethynyl organogold(I) complexes,54

whilst sufficiently shifted from that of the [AuCl(PPh3)] starting material at approximately 34.0

ppm.56 The signal assigned to the ruthenium-bound PPh3 ligands did not shift significantly,

suggesting no interaction between the [AuCl(PPh3)] starting material and the enynyl

ruthenium(II) complex.

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Figure 26 1H NMR spectrum of complex 12 in d6-acetone.

Crucially, the 1H NMR spectrum confirmed the absence of the acetylide proton (Figure 26),

providing conclusive evidence that the ethynyl group had undergone direct metallation with the

Au(I) centre. Furthermore, the additional PPh3 ligand was accounted for, with good relative

integrations between the phenyl and ferrocenyl chemical environments. In the IR spectrum the

νCO and νOCO stretching modes were assigned to signals at 1920 and 1499 cm-1 respectively; only

the stretching mode associated with the ferrocenyl alkyne could be identified at a frequency of

2182 cm-1 (very weak). As before, severe fragmentation was observed with both ES (+ve mode)

and MALDI mass spectrometry such that the first major peak was found at an m/z of 1181,

corresponding to a fragment such as [M-enynyl-PPh3+2K]+. Finally, the experimentally

determined elemental analysis values matched the calculated values.

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Figure 27 31P{1H} NMR spectrum of complex 13 in CD2Cl2.

Treatment of the 1’-ethynylferrocene-1-carboxylate ruthenium(II) ethynyl complex with

[dppf(AuCl)2] was also found to proceed successfully as shown by 1H and 31P{1H} NMR

spectroscopy, with high purity shown by elemental analysis. In the 31P{1H} NMR spectrum

(Figure 27) a new signal appeared at 36.6 ppm, in excellent agreement with the literature value

for similar (dppf)Au(I) acetylides,57 and sufficiently shifted from the value for the starting

material.58 The 1H NMR spectrum (Figure 28) also appeared as anticipated, illustrating the

presence of the additional ferrocene unit as indicated by a pair of downfield multiplets at 4.32

and 4.80 ppm (4H x 2). The presence of the additional phenyl rings was evidenced by increased

activity in the aromatic region with an integration that matched well with that of the ferrocene

chemical environments and gave the expected number of protons (100H).

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Figure 28 1H NMR spectrum of complex 13 in CD2Cl2.

No changes were observed in the IR frequencies assigned to the νCO and νOCO stretching modes

with signals at 1921 and 1500 cm-1, respectively. Again, a very weak signal attributed to the

triple bond of the Fc(C≡CH) unit was identified at 2160 cm-1. Unfortunately, no characteristic

fragments could be assigned in either the ES (+ve mode) or MALDI mass spectra. Finally, the

experimentally determined elemental analysis values showed excellent agreement with the

calculated values.

Scheme 38 Synthesis of (dppe)Ru(II) acetylide complex 14.

As Scheme 38 illustrates, the synthesis of the mono-acetylide complex 14 was attempted

following the protocol established by Fox et al.59 A solution of the 1’-ethynylferrocene-1-

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carboxylate ruthenium(II) enynyl complex and [RuCl(dppe)2]OTf in CH2Cl2 was treated with

DBU under nitrogen. A reaction appeared to occur instantaneously as indicated by a colour

change from deep red to yellow. Concentration under reduced pressure yielded precipitation of

a yellow solid which was then analysed by 1H and 31P{1H} NMR spectroscopy.

As characterised by 31P{1H} NMR spectroscopy, the [RuCl(dppe)2]OTf starting material give rise

to a pair of multiplets at approximately 84 and 57 ppm and the associated mono-acetylide

complexes tend to give rise to a singlet at approximately 50 ppm.59 Bearing this in mind 31P{1H}

NMR spectroscopy of the crude product, 14, showed high conversion of the starting material to

a number of new species, none of which was the expected mono-acetylide complex. Only the

PPh3 ligands of the enynyl ruthenium(II) complex were readily identified, as evidenced by the

signal at 35.7 ppm.

In a second experiment, the 1’-ethynylferrocene-1-carboxylate ruthenium(II) enynyl complex

and [RuCl(dppe)2]OTf were placed in a Young’s valve NMR tube, dissolved in the minimum

volume of CD2Cl2 and submitted immediately for 31P{1H} NMR spectroscopy with no base

present. The resultant 31P{1H} NMR spectrum (Figure 29, A) was much cleaner and proved far

more insightful. First of all, both the [RuCl(dppe)2]OTf and the enynyl ruthenium(II) starting

materials could be identified by the pair of broad signals at 82.9 and 55.6 ppm and a singlet at

35.7 ppm respectively. Most interesting however was the appearance of a pair of triplets at 50.4

and 37.6 ppm with matching J-coupling values of 48 Hz, a result which was indicative of the

formation of a complex in which the dppe ligands were arranged cis- to one another.

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Figure 29 31P{1H} NMR spectrum of complex 14 and [RuCl(dppe)2]OTf in CD2Cl2 at t = 0 (A), t = 2 (B) and t = 24 (C) hr.

A second 31P{1H} NMR spectrum was obtained after two hours (Figure 29, B) which showed the

appearance of four new singlets at 44.2, 43.1, 42.9 and 34.3 ppm. The singlet at 44.2 ppm was

assigned to the trans-[RuCl(=C=CFc*)(dppe)2] vinylidene intermediate expected prior to the

addition of any base.27, 60-61 Although less clear, the remaining signals may have been due to the

presence of labile intermediates which are known for complexes of this nature, even with

bidentate phosphine ligands.62 A final 31P{1H} NMR spectrum taken after 24 hours (Figure 29, C)

showed significant consumption of both the [RuCl(dppe)2]OTf starting material and the

unidentified cis-complex (suggesting it was an intermediate). Furthermore, the remaining

signals were far more prevalent, especially that at 34.3 ppm – perhaps a consequence of poor

solution stability of the enynyl ruthenium(II) complex. Given the typically long reaction times to

form the trans-acetylide complexes61, 63 such a result was not ideal.

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Figure 30 31P{1H} NMR spectrum of complex 11 and [RuCl2(dppe)2] and KPF6 in CD2Cl2 before and after addition of Et3N (A and B respectively) and after stirring for 18 h (C).

In a final experiment, in situ chloride abstraction was tested in a similar manner to the work of

Younus et al.61 in which trans-[RuCl2(dppe)2] and the alkyne (enynyl complex 11 in this case)

were treated with KPF6 and Et3N. 31P{1H} NMR spectroscopy of the mixture prior to Et3N

addition (Figure 30, A) showed clearly that the chloride abstraction had proceeded as predicted

– the pair of triplets at 82.7 and 55.5 ppm corresponding to the five-coordinate

[RuCl(dppe)2]PF6 complex. The 31P{1H} NMR spectrum also showed the formation of the

intermediate cis-complex as evidenced by the pair of triplets at 50.2 and 38.1 ppm. This result

proved fascinating as it is well known that in solution the trans-isomer exists preferentially as a

consequence of thermodynamic stability.61 Regardless, 31P{1H} NMR spectra of the mixture after

18 hours (Figure 30, C) showed consumption of this intermediate and formation of the desired

trans-mono-acetylide complex as evidenced by the singlet at 48.6 ppm. Unfortunately, isolation

of said complex proved extremely difficult as the other by-products/impurities exhibited

identical solubility to that of the desired complex; this experiment was not taken any further.

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Scheme 39 Synthesis of ferrocenyl bis-vinyl complexes.

Next, the complex 11 and [RuHCl(CO)(BTD)(PPh3)2] were simply dissolved in CH2Cl2 and stirred

at room temperature for 30 minutes. Addition of EtOH and concentration under reduced

pressure allowed complex 15 to be collected by filtration as a crystalline red solid. Full analysis

including 1H and 31P{1H} NMR and IR spectroscopy, ES (+ve mode) mass spectrometry and

elemental analysis were carried out.

The 31P{1H} NMR spectrum of complex 15 provided strong evidence for the successful

incorporation of the second ruthenium(II) coordination centre as indicated by the appearance

of a singlet at 26.9 ppm, a value which was in good agreement with the literature for similar

ruthenium(II) vinyl species.53 The disappearance of the triplet at approximately -11.0 ppm in

the 1H NMR spectrum assigned to the hydride ligand of the starting material provided further

evidence to corroborate this conclusion, showing that alkyne addition and hydride insertion had

occurred (Figure 31). Furthermore, the signals assigned to the ferrocenyl protons integrated

well relative to those in the aromatic region, showing the presence of two additional PPh3

ligands. The α-proton of the newly formed vinyl was readily assigned to a broad signal at 7.82

ppm and the β-proton, though somewhat masked by CH2Cl2, a signal at 5.41 ppm.

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Figure 31 1H NMR spectrum of complex 15 in CD2Cl2.

The IR spectrum did not differ much from that of the starting material with retention of the

enynyl and carbonyl ligands being supported by a weak signal at 2162 cm-1 and an intense

broad signal at 1918 cm-1, respectively. The broadening and intensity of the signal assigned to

the νCO stretching modes was taken as evidence for the presence of the second carbonyl ligand

on the second ruthenium(II) centre. The anticipated molecular ion could not be identified by ES

(+ve mode) mass spectrometry with only smaller fragments associated with the 1’-

ethynylferrocene-1-carboxylate ruthenium(II) enynyl complex being found. Finally, the

experimentally determined elemental analysis values matched well with the calculated values

providing further evidence for the formation of the desired trimetallic species.

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Figure 32 1H NMR spectrum of complex 16 in CD2Cl2.

The reaction of [OsHCl(CO)(BTD)(PPh3)2] and the 1’-ethynylferrocene-1-carboxylate

ruthenium(II) enynyl complex in CH2Cl2 proved equally successful, yielding complex 16 as a

crystalline purple powder after recrystallisation from EtOH; once again full characterisation was

carried out in the same way as above. First of all, the 31P{1H} NMR spectrum provided good

evidence that the osmium(II) vinyl species had formed successfully as indicated by the

appearance of a broad singlet at -3.1 ppm, a value which was in good agreement with the

literature for similar such osmium(II) vinyl complexes.64 Interestingly, the signal assigned to the

PPh3 ligands of the ruthenium(II) coordination centre showed signs of splitting unlike that of

the bis-ruthenium(II) complex which merely exhibited slight broadening, implying a greater

degree of inequivalence.

The 1H NMR spectrum was particularly interesting, showing signs of splitting in the signals

assigned to the ferrocenyl protons (Figure 32), suggesting that the inequivalence suggested by

the 31P{1H} NMR spectrum may be a consequence of the reduced symmetry about the ferrocene

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unit. If rotation of the cyclopentadienyl rings was at all hindered then conformational change

would be slowed causing broadening to occur. Either a slight difference in the size of the

osmium coordination sphere or perhaps a slight distortion in geometry may be responsible for

this. Integration of the entire region shows the expected 8 protons relative to the 70 protons of

the aromatic region, suggesting that the osmium(II) centre and its associated pair of PPh3

ligands have been successfully added to the ferrocene unit. Finally, both the α- and β-protons of

the newly formed vinyl unit were assigned to broad doublets at 8.07 and 5.6 ppm respectively,

the downfield shifts of which are expected for such osmium(II) vinyl complexes.64

In the IR spectrum, the signals associated with the νC≡C absorptions were simply too weak to

assign, however, as was the case for complex 15, the signal assigned to the νCO stretching mode

was found to be far more intense and significantly broadened – implying the presence of more

than one stretching mode and, by extension, more than one carbonyl ligand. The molecular ion

could not be identified in the ES (+ve mode) mass spectrum nor could any distinguishable

fragments, suggesting increasing sensitivity of these larger complexes (Mw = 2025 and 1936 for

respective Os and Ru complexes) to the ionising conditions employed. Finally, the elemental

analysis values measured were close to the calculated values with minor discrepancies

attributed to the presence of a few minor impurities, seen also in the 31P{1H} NMR spectrum.

The experiment was deemed a success, however, further analysis by low temperature NMR

spectroscopy would have provided further insight into behaviour of this complex in solution

and to shed light on the greater chemical inequivalence observed in the Os analogue.

Scheme 40 Synthesis of complex 17.

103

Dialkyldithiophosphate ruthenium(II) hydride complexes of the type illustrated in Scheme 12,

synthesised by treating [RuHCl(CO)(PPh3)3] with K[S2P(OEt)2],65 are reactive towards terminal

alkynes in a similar manner to their parent ruthenium(II) hydride complexes.66 The

dialkyldithiophosphate ligand provides an excellent spectroscopic handle in 31P{1H} NMR

spectroscopy and a characteristic upfield shift is observed in the phosphorus nuclei of the PPh3

ligands upon formation of the vinyl complex, making this an ideal means of further confirming

the reactivity of the 1’-ethynylferrocene-1-carboxylate ruthenium(II) enynyl complex.

Figure 33 31P{1H} NMR spectrum in CD2Cl2 of dialkyldithiophosphate ruthenium(II) starting material (red) and product mixture (blue).

[RuH(S2P(OEt)2)(CO)(PPh3)2] and complex 11 were dissolved in CH2Cl2 and stirred at room

temperature for one hour. All solvent was removed and the crude product analysed by 1H and

31P{1H} NMR spectroscopy. Complete conversion of [RuH(S2P(OEt)2)(CO)(PPh3)2] was inferred

from the lack of a singlet in the 1H NMR spectrum assigned to the hydride ligand as well as the

singlet at 41.0 ppm in the 31P{1H} NMR spectrum (Figure 33) assigned to the PPh3 ligands of the

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dialkyldithiophosphate ruthenium(II) complex, which was observed to shift upfield to a value of

31.7 ppm. This was in good agreement with literature values for analogous

dialkyldithiophosphate ruthenium(II) vinyl complexes. The presence of O=PPh3 was inferred

from a singlet at 29.1 ppm, illustrating that undesired PPh3 dissociation was a problem in this

reaction, an unexpected result given no such lability was observed in either the enynyl complex

nor the parent [MHCl(CO)(BTD)(PPh3)2] (M = Ru, Os) complexes. Recrystallisation in methanol

proved sufficient to remove the majority of O=PPh3, however the remaining unidentified

impurities proved difficult to remove. Time constraints prevented this reaction from being

conducted on a larger scale and the desired vinyl complex isolated.

3.3.4 Reactivity of 1’-Ethynylferrocene-1-carboxylate

ruthenium(II) complex in alkyne-azide cycloaddition

Figure 34 Testing the reactivity of complex 11 with p-methoxybenzyl azide and 2-azidoethylbenzene in copper-mediated cycloaddition.

As detailed in the previous chapter, copper-mediated alkyne-azide cycloadditions provide, in

theory, a simple means of testing the reactivity of a terminal alkyne where the atom economy

makes for simple isolation and the 1,2,3-triazole product can be readily distinguished by 1H

NMR spectroscopy. In this case the chosen azide was added to a suspension of complex 11,

CuSO4·5H2O and sodium ascorbate in H2O, tBuOH and CH2Cl2 and left to stir at room

temperature for 18 hours. The crude product was isolated by extracting with additional CH2Cl2

and then analysed by 1H and 31P{1H} NMR spectroscopy.

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Figure 35 1H NMR spectrum of complex 18 in CD2Cl2 (crude).

The reaction with p-methoxybenzyl azide appeared to have proceeded successfully as

confirmed by the 1H NMR spectrum (Figure 35) which showed a significant downfield shift in

the signal assigned to the benzylic protons from 4.23 ppm67 to 5.48 ppm, a chemical shift value

which is in good agreement for purely organic 1-(p-methoxybenzyl)-1,2,3-triazoles.68 For such

1,2,3-triazoles, the triazole proton is expected to give rise to a singlet at approximately 7 ppm.68

Unfortunately, due to other features in the aromatic region of the spectrum due to the PPh3

ligands of the ruthenium(II) coordination centre, this proton proved difficult to assign. The

singlet assigned to the methoxy functional group was observed at 3.83 ppm amongst the signals

assigned to the ferrocenyl protons which were found to have shifted upfield, with the multiplet

assigned to the ferrocenyl protons closest to the 1,2,3-triazole shifting from 3.88 ppm to 3.73

ppm. The residual peaks in this region must then correspond to the unreacted ethynyl complex,

showing incomplete conversion was achieved. Unsurprisingly, the 31P{1H} spectrum showed no

change from the starting enynyl complex. Overall, this was a very promising result however a

106

longer reaction time or purification (e.g., recrystallization) was clearly necessary in order to

isolate the desired ferrocenyl 1,2,3-triazole.

Figure 36 1H NMR spectrum of complex 19 in CD2Cl2 (crude).

The reaction with 2-azidoethylbenzene also appeared to have proceeded with success as seen in

the 1H NMR spectrum (Figure 36) which showed the characteristic downfield shift of the

methylene protons neighbouring the azide/1,2,3-triazole functional group from a value of 3.50

ppm69 to 4.60 ppm, in excellent agreement with the literature values for organic phenylethyl-

1,2,3-triazoles.70 The triplet assigned to the methylene protons closest to the phenyl ring also

showed a slight downfield shift from 2.89 ppm69 to 3.26 ppm. Much like the previous

experiment conversion of the ethynyl unit into a 1,2,3-triazole resulted in a slight upfield shift of

approximately 0.2 ppm in the multiplet assigned to the nearest ferrocenyl protons. Though the

activity in the aromatic region of the spectrum was just as extensive as previously noted, the

appearance of a new series of multiplets between 7.07 and 7.18 ppm was discernible and one of

which can be reasonably assigned to the triazole proton. Though a promising result overall, it

107

was clear that only partial conversion had been achieved and that further work was required in

order to optimise this reaction. Due to time constraints the focus of the investigation moved to

concentrate on the generation of multimetallic compounds.

3.3.5 Synthesis of hexa- and hepta-metallic complexes

Scheme 41 Synthesis of piperazinyl bis-dithiocarbamate hexametallic assembly 20.

Having successfully confirmed the reactivity of the ethynyl unit in complex 11 the subsequent

experiments were conducted using the trimetallic vinyl complex 15 as the starting point for the

generation of multimetallic assemblies. This made use of the lability of the chloride and BTD

ligands towards bidentate chelates. As described in the introduction to the previous chapter, the

bis-dithiocarbamate based on piperazine functions as an excellent linker to construct

multimetallic assemblies.71-73 In the same body of work, 1,1’-ferrocenedicarboxylic acid also

proved to be an excellent linker for the same purpose.

In the first experiment a solution of the piperazinyl bis-dithiocarbamate in MeOH was treated

with a solution of complex 15 in CH2Cl2 in a 1:2 stoichiometric ratio and left to stir at room

temperature for two hours. The solution was then carefully concentrated by rotary evaporation

to yield precipitation of an off-white solid which was collected by filtration and washed with

108

H2O, MeOH and petroleum ether, vacuum-dried and submitted for analysis by 1H and 31P{1H}

NMR spectroscopy.

The 31P{1H} NMR spectrum illustrated complete conversion of the vinyl starting material with

the disappearance of the broad singlet at 26.9 ppm and the appearance of a broad signal at 39.2

ppm, which corresponds to the PPh3 ligands of the expected dithiocarbamato ruthenium(II)

vinyl coordination centres.74 As expected, the PPh3 ligands of the original ruthenium(II)

coordination centre were unaltered as confirmed by the signal at 35.4 ppm.

Figure 37 1H NMR spectrum of complex 20 in CD2Cl2.

The 1H NMR spectrum (Figure 37) was not as informative but did provide evidence that the

reaction had proceeded as hoped. Broadened resonances at 5.20 ppm (RuCH=CHR) and 5.58

ppm (enynyl Hβ) suggested the presence of both vinyl units. Comparison with literature

assignments of similar piperazinyl dithiocarbamato ruthenium(II) vinyl complexes74 and the 1H

NMR spectrum of complex 15 showed that the upfield multiplets in the 2.8-3.8 ppm region may

109

well correspond to the eight piperazine ring protons, expected of the NC4H8N unit. The

complexity of the features in this region were attributed to growing axial/equatorial

inequivalence due to complex through space interactions with neighbouring units in the

molecule. The ferrocene environments, however, were more difficult to assign due to their

broadening and overlap with the piperazine resonances. Despite this, rough estimation of the

relative integrations of the piperazine region against that of the ferrocene and aromatic protons

suggested that the piperazinyl bis-dithiocarbamate had successfully coordinated two

equivalents of complex 15.

Scheme 42 Synthesis of ferrocene dicarboxylic acid heptametallic complex 21.

In a final experiment a solution of 1,1’-ferrocenedicarboxylic acid and Et3N in CH2Cl2 and MeOH

was prepared and then treated with a solution of complex 15 in CH2Cl2 and stirred at room

temperature for two hours. The solution was then slowly concentrated by rotary evaporation to

yield precipitation of an orange solid which was collected by filtration, washed with MeOH and

petroleum ether, vacuum-dried and then submitted for analysis by 1H and 31P{1H} NMR

spectroscopy.

The 31P{1H} NMR spectrum was promising as it showed the appearance of a multiplet at

approximately 34 ppm – neighbouring that assigned to the Ru(II) enynyl complex

(approximately 35 ppm), not surprising given the only difference was the degree of saturation

110

of the vinyl/enynyl ligand. Again, substantial signal broadening was observed as well as the

presence of by-products or impurities, including O=PPh3. In this case, it is possible that arrested

rotation about the Fc-CO2 bond caused inequivalence of the phosphines. Unfortunately, this

inequivalence also made the 1H NMR spectrum difficult to interpret with any confidence – each

signal that was assigned to the ferrocenyl protons, including those of the central 1,1’-

ferrocenedicarboxylate unit, were split significantly. Further purification and subsequent

variable temperature NMR spectroscopic investigations would be needed to establish the

features of this complex further.

3.4 Conclusions

It can be concluded that 1’-ethynylferrocene-1-carboxylic acid can be readily synthesised in

good yield and purity following the literature procedure established by both Barišić et al. and

Huber, Hubner and Gemeiner.49-50 Secondly, and most crucially, 1’-ethynylferrocene-1-

carboxylic acid exhibited reliable reactivity and coordination behaviour and made an ideal

hetero-bifunctional linker.

Figure 38 Complex 11.

The orthogonality of the reactivity associated with the carboxylate and ethynyl functional

groups allowed the ethynylferrocenyl ruthenium(II) enynyl complex (Figure 38) to be

synthesised without issue and in good yield. Crucial to its further application was its excellent

solubility in a range of organic solvents including methylene chloride, chloroform, THF and

acetonitrile which also allowed it to be readily purified using solvents such as methanol and

ethanol. Furthermore, the ruthenium(II) enynyl complex proved stable, as determined by

31P{1H} NMR spectroscopy, to the reaction conditions required in the following reactions.

111

Figure 39 Complexes 15 (Ru) and 16 (Os).

The subsequent experiments showed that the ethynyl unit remained reactive as hoped, a result

that proved especially significant in the reaction with [MHCl(BTD)(CO)(PPh3)2] (where M = Ru

or Os) to form the desired vinyl complex (Figure 39). Progress of the reactions could be gauged

visually due to clear colour changes of the orange parent compound to the deep red and violet of

the respective Ru(II) and Os(II) complexes. Furthermore the solubility, whilst still excellent,

differed sufficiently from that of the parent complex, allowing simple isolation. Although typical

spectroscopic methods provided satisfactory evidence that the desired complexes had been

isolated, 1H and 31P{1H} NMR spectroscopy demonstrated that the nature of these complexes

deviated somewhat from that of their monometallic counterparts. The increased inequivalence

between the ligands was inferred from broadening and splitting of the resonances and this was

attributed to reduced conformational flexibility and symmetry. The significance of these

complexes was augmented by the lability of the remaining BTD and chloride ligands on the

newly introduced transition metal centre, which allowed this system to be used as a starting

point for further transformation.

Figure 40 Complex 20.

For example, the BTD and chloride ligands were responsive to displacement by the piperazinyl

bis-dithiocarbamate [S2CNC4H8NCS2]¯ to yield complex 20 (Figure 40). The complexity of the

system, including its likely flexibility, made characterisation by 1H and 31P{1H} NMR

112

spectroscopy difficult however the analysis obtained indicated that it had been formed

successfully. Undoubtedly with more work this complex could be isolated, characterised

entirely and perhaps its electrochemical properties investigated. Overall, 1’-ethynylferrocene-1-

carboxylate is a ligand that has proven its potential in acting as a potent bifunctional building

block for the synthesis of hexa- and hepta-metallic arrays.

3.5 Future Work

Scheme 43 The reactivity of complex 11 towards both p-methoxybenzyl azide and 2-azidoethylbenzene highlights the potential to coat the surface of AuNPs by copper(I)-catalysed alkyne-azide cycloaddition.

113

Bearing this conclusion in mind, work conducted on this project in the immediate future would

focus on completing all of the work established in the aims at the beginning of the chapter

(Scheme 43). This includes isolating and fully characterising the piperazine- and 1,1’-

ferrocenedicarboxylate-bridged multimetallic arrays as mentioned above but it also includes

returning to the 1’-ethynylferrocene-1-carboxylate ligand and also synthesising the Os(II)

enynyl complex to test its reactivity. Beyond this, it would be important to confirm successful

1,2,3-triazole formation as catalysed by Cu(I) in order to coat the surface of AuNPs with the

ferrocenyl enynyl complex using an azide-functionalised thiol or disulfide.

Also of future interest is the possibility of synthesising alternative unsymmetrical 1,1’-

disubstituted ferrocene building blocks. In the interest of bringing the ligand closer in nature to

that of the dithiocarbamates explored elsewhere in this project, it could be fruitful to synthesise

the sulfur analogue – 1’-ethynylferrocene-1-dithiocarboxylate (Scheme 44)

Scheme 44 Synthesis of ferrocenedithioether via Grignard formation. Direct lithiation of ferrocene and subsequent treatment with CS2 is a viable alternative.

In a modification of a previous literature procedure,75 Kaub et al. started with bromoferrocene

and synthesised the corresponding Grignard reagent by allowing it to react with magnesium.76

The ferocenyl Grignard reagent was then treated with CS2 in THF which, after treatment with a

weak acid and piperidine, yielded the piperidinium dithiocarboxylate salt. If the final

acidification is simply carried out in alcoholic solution then it should be possible to synthesise

the related dithioether as has long been reported in the literature.77 Critically, if this species

proves stable to Friedel-Crafts acylation conditions as well as the conditions required in the

subsequent formylation reaction, then it should be possible to synthesise 1’-ethynylferrocene-1-

dithiocarboxylate in much the same way as the carboxylate species.

114

Figure 41 Pd(II)-functionalised AuNP catalyst for the oxidative functionalisation of benzo[h]quinoline.

The softer nature of the dithiocarboxylate ligand would be exciting to explore as the synthesis of

alternative Au(I), Pt(II) and Pd(II) complexes would become possible. If the ethynyl unit

remained reactive towards Cu(II)-catalysed cycloaddition with azides then this could pave the

way for the species illustrated in Figure 41 to be synthesised. At this point it would become

possible to truly test the utility of these species as catalysts relative to purely homogeneous

species; in this case for the oxidative functionalisation of benzo[h]quinoline in the presence of

PhI(OAc)2 and methanol as mentioned at the beginning of the previous chapter78 If successful

the project could move towards attempting to bridge the gap between homogeneous and

heterogeneous catalysis.

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4. Synthesis of Novel Linkers Using Thioctic Acid

4.1 Introduction

The ability to control or modify the properties of a surface via the formation of self-assembled

monolayers (SAMs) has resulted in a variety of applications including biological and chemical

sensing, molecular electronics and catalysis.1-10 In particular, the formation of SAMs on gold

surfaces has been studied extensively and a variety of ligands have been explored including

amines, carboxylates, isocyanides, phosphines and, most notably, alkanethiols.11-16

Figure 42 Alkanethiols: a) SAM formation on a gold surface facilitated by strong bonding and dense packing; b) thiol-derivatized cobalt porphyrin; c) thiol-derivatized fullerene.17-21

Primarily, alkanethiols are utilised most commonly for the formation of SAMs on gold surfaces

due to the strong specific interaction between gold and sulfur22 and the highly organised nature

of the resulting monolayer.17, 23 They can be used in both organic and aqueous phases and are

amenable to functionalisation with a range of units, including porphyrins19-20 and C60,21 as

illustrated in Figure 42. Furthermore, the colloidal stability of AuNPs is enhanced when

alkanethiols are employed as a passivating agent, significantly limiting particle aggregation.11, 24-

26 As mentioned in the introduction, the long-term stability of alkanethiol monolayers can suffer

from reversible desorption, meaning irreversible aggregation is not always entirely

prevented.26-29

121

In a 1991 study of the electrochemical application of ferrocenyl alkanethiols on SAMs a notable

loss in electroactivity was observed and attributed to a reduction in the integrity of the

alkanethiol monolayer.30 Indeed, in 1995 Schlenoff et al. showed that the reversible nature of

alkanethiol binding and the need to maintain a pseudo-steady state equilibrium at the surface

was at least partly responsible for alkanethiol desorption.31

In a later study by Flynn et al., contact angle, electrochemical, FT-IR and XPS measurements

were used to investigate the integrity of alkanethiol monolayers over the course of 35 days.32 As

expected, loss in monolayer integrity was observed over this timeframe and interestingly, it was

also found that the use of anti-oxidants significantly halted degradation of the monolayer. Based

on their observations, Flynn et al. proposed that thiol headgroup oxidation was an additional

cause of desorption. Both Schlenoff et al. and Flynn et al. concluded that alternative ligands such

as polythiols or disulfides might be necessary to prevent surface desorption.

Figure 43 Alternatives to monoalkanethiols: a) spiroalkanedithiol;33 b) thiolated α-cyclodextrin;34 c) steroid cyclic disulfide;35 d) trithiol anchor.36

In a 1999 investigation Shon and Lee synthesised 2,2-dialkylpropanedithiol derivatives,

[CH3(CH2)n]2C[CH2SH]2 where n = 0, 3, 7 and 11-15 (Figure 43a), and characterised the resultant

122

monolayers on gold by optical ellipsometry, contact angle goniometry and polarization

modulation infrared reflection absorption spectroscopy.33 It was found that the tested

spiroalkanedithiols formed chelating SAMs which, although slightly less ordered than their

monoalkanethiol analogues, appeared to be more robust. Additional studies have since

confirmed this conclusion37-38 and the application of functionalised ligands such as thiolated

cyclodextrins,34 endocyclic disulfides35 and trithiols36 quickly followed (Figure 43).

Figure 44 Thioctic acid and dihydrolipoic acid respectively.

One endocyclic disulfide that has garnered significant interest in the literature is thioctic acid

(TA) (Figure 44). Reduction and cleavage of the disulfide reveals two thiol units which are

capable of chelating to gold surfaces, yielding greater kinetic stability than comparative

monoalkanethiol monolayers.37 TA is commercially available, non-hazardous and the presence

of a terminal carboxylic acid permits a great deal of synthetic flexibility. Indeed, it was quickly

found that through the carboxylic acid, biomolecules and biological sensors could be

immobilised on the surface of gold electrodes.39 Furthermore, it has been shown that

displacement by the disulfide proceeds efficiently when citrate-capped AuNPs are treated with

TA according to the modification of the Turkevich method reported by Frens,40 where the

terminal carboxylic acid provides electrostatic stabilization at high pH.41 Thioctic acid (TA) is

also compatible with the Brust method and is capable of displacing typical protecting

monoalkanethiols such as dodecanethiol.42

123

Scheme 45 Coupling of TA and 5,10,15,20-meso-tetrakis(o-aminophenyl)porphyrin.

A 2004 study by Beer, Cormode and Davis exemplified the synthetic potential of TA and its

amenability to the passivation of AuNPs and their application (anion sensing in this case).42

Four equivalents of TA were coupled with 5,10,15,20-meso-tetrakis(o-aminophenyl)porphyrin

in the presence of (3-dimethylamino-propyl)-ethyl-carbodiimide (EDC) and 1-benzotriazolol to

yield the corresponding amide-disulfide (Scheme 45). Treatment of coupled product with

Zn(OAc)2 was sufficient to obtain the corresponding metalloporphyrin, which was then used to

displace dodecanethiol from AuNPs which had been previously synthesised by the Brust

method.11

The modified AuNPs were washed excessively with methanol and acetone to remove any non-

covalently-bound metalloporphyrin before characterising them by 1H and 13C{1H} NMR, UV-Vis

spectroscopy, elemental analysis and mass spectrometry. The average particle diameter was

found to be 3-4 nm according to TEM. The metalloporphyrin-functionalised AuNPs were then

applied in anion sensing experiments and found to exhibit enhanced anion binding affinities

relative to the free metalloporphyrin.

In the work presented here it was anticipated that the commercial availability of TA and its

synthetic flexibility would permit a range of novel transition-metal coordination complexes to

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be synthesised readily before immobilising them on AuNPs for further characterisation and

experimentation. Below, the goals of this body of work will be discussed in greater detail.

4.2 Aims

The initial aim was to capitalise on the approach adopted by Beer, Cormode and Davis and

combine it with an approach previously conducted within the group, namely the use of

piperazine-based dithiocarbamates and their associated Ru(II) and Ni(II) complexes.43-45

Piperazine was found to be an ideal building block for the synthesis of multimetallic assemblies

or the functionalisation of AuNPs because of commercial availability and crucially, the

possibility of functionalising each end of the diamine in turn. For instance, when piperazine was

treated with CS2 the mono-dithiocarbamate was obtained through self-deprotonation and

zwitterion formation (Scheme 46). This permitted the monometallic species 22 to be

synthesised prior to coordinating a second transition-metal centre.

Scheme 46 Piperazine building block for multimetallic assemblies or functionalised AuNPs; i) CS2; ii) cis-[RuCl2(dppm)2], 2NaBF4; iii) NEt3, CS2; (iv) NEt3 (excess), CS2 and then 2 cis-[RuCl2(dppm)2], 3NaBF4.45

The stereotypical carbodiimide-mediated route46 used by Beer, Cormode and Davis will first be

employed to couple TA to 22 and, if successful, then used to passivate AuNPs. At its simplest

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these experiments will be used to confirm the availability of the terminal carboxylic acid for

coupling and subsequent transition-metal coordination as well the ability of the disulfide to

passivate gold surfaces. Should these experiments be met with success then the same

methodology can be used to obtain catalytically relevant species such as the analogous Pd(II)

dithiocarbamate complex for instance (Scheme 47, refer to Chapter 2).

Scheme 47 Proposed synthesis of Pd(II)-functionalised AuNPs and their application as a catalyst for the oxidative functionalisation of benzo[h]quinoline.

The simplicity and scope of this methodology means it could then be used to incorporate a

variety of ligands that may be applied to more common literature catalytic procedures. Scheme

4 illustrates the potential synthesis of a hemi-labile palladium(II) coordination complex used in

carbonylative Sonogashira cross-coupling reactions,48-49 inspired by earlier work within the

group on ferrocene-based P,N-bidentate ligands of the same type.

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This experiment will also prove significant in testing the suitability of simple building blocks

such as 1-Boc-ethylenediamine for increasing the chain length whilst maintaining linearity.

Namely, if a series of analogous linkers of varying length can be synthesised then the

relationship between catalytic activity and surface morphology can be investigated, as detailed

in the introduction.

Scheme 48 Synthesis of disulfide-functionalised P,N-bidentate donor ligand for palladium(II) coordination.

Finally, it would be extremely useful to explore the possibility of converting the terminal

carboxylic acid to alternative functional groups. This would allow an even greater library of

coordination complexes or multimetallic assemblies to be synthesised starting from only

commercially available reagents, including TA. As highlighted in the previous chapter, copper-

catalysed azide-alkyne cycloadditions (CuAACs) can be a facile and powerful tool to synthesise

larger multimetallic assemblies. For instance, if the terminal carboxylic acid of TA is amenable

to conversion to the corresponding azide50 then the alkyne-functionalised dithiocarbamate

complexes of the previous chapter could be readily immobilised on the surface of AuNPs

(Scheme 49).

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Scheme 49 Functional group interconversion of TA for palladium(II) coordination and AuNP functionalisation. Reagents: a) catechol borane, CH2Cl2; b) CH3SO2Cl, CH2Cl2; c) NaN3, DMF.

4.3 Results and Discussion

4.3.1 Coupling of piperazine mono-dithiocarbamate ruthenium(II)

complex and thioctic acid

Firstly, the literature procedure to synthesise the piperazinyl mono-dithiocarbamate was

followed in which piperazine was dissolved in distilled water and treated with CS2.45 After

approximately 10 minutes, a pale green precipitate was observed which was readily collected

by filtration, washed with water and dried under vacuum. Piperazine was found to act as both

the base and nucleophile in the reaction and preferentially formed the zwitterionic mono-

dithiocarbamate meaning only negligible amounts of the bis-dithiocarbamate salt,

[S2CNC4H8NCS2][H2NC4H8NH2], was formed.51

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Scheme 50 Synthesis of piperazinyl mono-dithiocarbamate and ruthenium(II) coordination.

The successful formation of the mono-dithiocarbamate was confirmed by 1H NMR spectroscopy

wherein the addition of the CS2 unit caused a noticeable down-field shift of the nearby ring

protons to 4.29 ppm (4H, m). Furthermore, the protons belonging to the ammonium ion were

also identified by a singlet at 4.25 ppm (2H). Characterisation by mass spectrometry (EI) gave

the anticipated molecular ion at an m/z of 162. Finally, the experimental elemental analysis

values agreed well with the calculated values.

Next, the zwitterion [S2CNC4H8NH2] and NaBF4 were suspended in methanol and a solution of

cis-[RuCl2(dppm)2] in methylene chloride added.45 The mixture was heated under reflux for 10

minutes and then stirred for two hours at room temperature; addition of ethanol after this time

was sufficient to obtain 22 as a colourless solid. Successful coordination of ruthenium(II) was

confirmed by characterisation by 31P{1H} NMR spectroscopy which showed the presence of a

pair of triplets at -3.8 and -17.3 ppm, substantially shifted from that of the starting material (-

1.1 and -28.0 ppm) and in good agreement with the literature values. Furthermore, the expected

molecular ion (m/z 1030) was found by mass spectrometry (FAB) and the experimental values

from elemental analysis matched the calculated values. Having successfully synthesised

complex 22, the coupling reaction with TA was tested.

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Scheme 51 Carbodiimide-mediated coupling of piperazinyl mono-dithiocarbamato ruthenium(II) complex with thioctic acid.

Carboxylic acids are not typically susceptible to nucleophilic attack as they are not especially

electrophilic, nor is the –OH unit a good leaving group, so activation is required. This is

particularly true of amide synthesis in which either the carboxylic acid must first be converted

to an acyl halide or active ester or coupling reagents such as carbodiimides or anhydrides must

be employed.52 Based on the success of Beer and Cormode’s 2004 study,42 the carbodiimide-

mediated approach was tested first.

It was first reported by Sheehan in 1955 that the presence of N,N’-dicyclohexylcarbodiimide

(DCC) in slight excess was sufficient to promote the coupling of carbobenzoxyglycyl-L-

phenylalanine and ethyl glycinate.53 Alternative carbodiimide reagents such as N,N’-

diisopropylcarbodiimide (DIC) and EDC have since been investigated thoroughly and proven to

be effective. The weakly basic nature of carbodiimides is sufficient to react with carboxylates,

enhancing their electrophilicity and thereby activating them towards nucleophilic attack.

Carbodiimides are commercially available, exhibit moderate to high activity, are soluble in most

organic solvents and the urea by-product formed in the coupling is easily removed.

Furthermore, carbodiimide-mediated peptide couplings are amenable to a range of additives

such as 1-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (NHS) that accelerate the

reaction further and reduce side reactions.52, 54-55

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In this experiment, the protocol used by Beer and Cormode was followed in which TA, HOBt and

EDC were dissolved in methylene chloride and a solution of 22 in methylene chloride added.

The reaction mixture was stirred at room temperature overnight and then washed with

aqueous solutions of both NaHCO3 and NaCl to remove any urea; the solvent was removed and

the crude product submitted for spectroscopic analysis.

The 1H NMR spectrum showed that TA was still present as the carboxylic acid proton could still

be identified by a broad singlet at 8.05 ppm. Furthermore, no signal expected of an amide

proton (between 6.0-7.0 ppm) was identified. Unsurprisingly, both the piperazinyl ring protons

and those belonging to the dppm ligands were identified and found to integrate well relative to

each other. 31P{1H} NMR spectroscopy further confirmed the piperazine dithiocarbamate unit to

still be intact with the pair of triplets associated with the dppm ligands found at -5.37 ppm and -

18.3 ppm. Finally, analysis by ES mass spectrometry (+ve mode) showed only starting materials,

no coupling product was observed at all. From this analysis it was clear that no coupling

reaction occurred between TA and 22 nor had any side reactions.

In carbodiimide-mediated peptide coupling reactions, it is the weakly basic nature of the

carbodiimide itself that first triggers a reaction with the carboxylic acid - one of the

carbodiimide nitrogen atoms abstracts a proton from the acid, revealing the carboxylate which

then attacks the central carbon atom to form the O-acylisourea (Figure 45).52, 56 The O-

acylisourea intermediate is incredibly reactive and sufficiently electrophilic to either be

attacked directly by the amine itself or first by the hydroxyl derivative additive (HOBt etc.)

before being attacked by the amine to yield the desired amide. The reactivity of the O-

acylisourea is such that it may also rearrange to the N-acylurea rendering it inert to further

reaction. The rearrangement is irreversible and highly undesirable as it serves only to consume

the starting carboxylic acid; fortunately in solvents such as methylene chloride the

rearrangement tends to be extremely slow and prevails only when carbodiimide is present in

large excess.56-57

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Figure 45 Mechanism of carbodiimide-mediated peptide coupling.

The successful coupling of TA and 5,10,15,20-meso-tetrakis(o-aminophenyl)porphyrin by Beer

and Cormode implied that both TA and EDC were sufficiently reactive to form the

corresponding O-acylisourea which itself must then have been reactive enough in the presence

of HOBt to form the desired amide. Indeed, employing alternative carbodiimides including DCC

and alternative catalytic additives such as 4-dimethylaminopyridine (DMAP)46, 54, 58 did nothing

to affect successful coupling thereby suggesting that neither the coupling conditions nor a

supposed lack of reactivity on the part of TA were responsible. Additionally, the presence of

only starting materials in both the 1H NMR and ES mass spectra of the experiments made it clear

that side reactivity, namely the formation of the N-acylurea, was also not responsible for a lack

of coupling.

Bearing this in mind, it was concluded that the lack of success in coupling TA and complex 22

must lie with complex 22 itself. Whilst the carboxylic acid must be rendered electrophilic

enough in order for the coupling reaction to proceed, this is predicated on the amine being

sufficiently nucleophilic to react in the first place. Because the successful coupling of TA and

5,10,15,20-meso-tetrakis(o-aminophenyl)porphyrin showed that TA can react with EDC and

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form an intermediate that is suitably electrophilic to be attacked by the aniline-functionalised

porphyrin it is possible that 22 simply is not sufficiently nucleophilic to react with the same

intermediate.

Scheme 52 Synthesis of piperazinyl mono-dithiocarbamato ruthenium(II) complex 2.11 utilising mono-Boc-piperazine.

A new experiment was proposed in which the amide would be synthesised prior to transition-

metal coordination with the aim of simplifying the coupling reaction and determining if complex

22 was indeed responsible for the failure of the reaction. Naturally, the reactivity of piperazine

at either nitrogen centre may have posed a problem with regards to over-coupling so 1-boc-

piperazine was instead proposed for coupling with TA.

4.3.2 Coupling of 1-boc piperazine and thioctic and deprotection

Firstly, 1-boc-piperazine was synthesised according to a literature procedure in which a

solution of di-tert-butyl dicarbonate in methylene chloride was added dropwise to a solution of

piperazine in methylene chloride at 0 °C.59 Small quantities of 1,4-di-boc-piperazine were

observed however only 1-boc-piperazine was found to be water soluble, allowing it to be easily

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isolated in high yields. High purity was confirmed by both 1H NMR spectroscopy and elemental

analysis.

Having successfully synthesised 1-boc-piperazine the carbodiimide-mediated coupling with TA

was attempted. DCC and DMAP were dissolved in methylene chloride, added dropwise to a

solution of 1-boc-piperazine in methylene chloride at 0 °C and then left to stir at room

temperature overnight. During this time a colourless precipitate was observed and attributed to

the formation of N,N’-dicyclohexylurea (DCU), the first evidence that the coupling reaction may

have proceeded successfully. The reaction was followed by TLC and by this time complete

conversion had still not been achieved; leaving the reaction for a further 24 hours did little to

effect this outcome. After 48 hours the precipitate was collected by filtration and the filtrate was

evaporated to dryness and taken up in a minimum volume of acetonitrile so as to remove

further traces of DCU. The crude product, a yellow oil at this point, was purified by silica column

chromatography, eluting with pure diethyl ether. The pure product was obtained as pale yellow

solid (44%) and was characterised by 1H and 13C{1H} NMR and IR spectroscopy, ES mass

spectrometry (+ve mode) and elemental analysis.

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Figure 46 1H NMR spectrum of compound 23 in CDCl3.

In the 1H NMR spectrum, the chemical environments belonging to both the piperazine and

disulfide moieties were identified and found to exhibit the correct integration relative to one

another, as anticipated for the coupled product, 23 (Figure 46). 1H-1H correlated spectroscopy

(COSY) was used to assign the proton environments of the disulfide linker. A down-field shift of

the signal attributed to the piperazinyl ring protons nearest the free amine in the starting

material was observed, a result consistent with conversion of the amine to the more electron-

withdrawing amide. The increased complexity of the splitting pattern of these signals was

attributed to both reduced ring flexibility and the fact that the signal assigned to the tertiary

proton of the disulfide heterocycle could be found in the same region as indicated by COSY.

Unsurprisingly, the chemical environment of the tert-butoxy carbonyl protecting group had not

changed as indicated by the nine proton singlet at 1.48 ppm. Finally, the lack of a broad singlet

at approximately 8.0 ppm showed that all unreacted acid was successfully removed in the work

up.

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Figure 47 13C{1H} NMR spectrum of compound 23 CDCl3.

The 13C{1H} NMR spectrum corroborates the fact that the amide has formed as evidenced by the

signal at 171.4 ppm. As expected, the carbonyl unit belonging to the tert-butoxy carbonyl unit

can still be identified by the signal at 154.6 ppm. Further evidence for the successful formation

of the thioctic amide was given by the ES mass spectrum (+ve mode) with a molecular ion of

m/z of 397 ([M+Na]+, 100%) and a lesser signal at an m/z of 375 ([M+H]+, 50%). Finally, the

experimental elemental analysis matched the calculated values confirming its composition and

purity.

In the next step it was necessary to remove the tert-butoxy carbonyl protecting group. Strong

acids such as HF, concentrated HCl and trifluoroacetic acid (TFA) are most commonly used to

effect the removal of tert-butoxy carbonyl groups through protonation of the Lewis basic

carbonyl unit and cleavage. Cleavage generates only CO2 and iso-butylene making the reaction

work up simple. Confirmation of complete tert-butoxy carbonyl removal was provided by 1H

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NMR spectroscopy and the disappearance of the characteristic singlet around 1.5 ppm

attributed to the tert-butyl protons.

Scheme 53 Deprotection of 1-(1’-boc-piperazine) lipoic amide with trifluoroacetic acid.

Initially, thioctic amide 23 was simply dissolved in methylene chloride and a 10-fold excess of

TFA added and the mixture left to stir overnight at room temperature. Examination by 1H NMR

spectroscopy after this time showed incomplete deprotection (less than 50% conversion) and

the need to leave the reaction for a longer period of time. Unfortunately, neither leaving the

reaction for a further 48 hours nor doubling the excess of TFA improved the extent of

deprotection.

Scheme 54 1-Boc cleavage via acid-catalysed separation of ion-molecule pair.

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It has been proposed that removal of tert-butoxycarbonyl units with acid may proceed via a

diprotonation mechanism wherein one molecule of acid is first required to protonate the tert-

butoxy carbonyl to yield an intermediate carbamate which is then protonated by a second

molecule of acid to generate CO2 and yield the free ammonium ion (Scheme 54).60 This

mechanism gives rise to a second-order rate dependence with respect to the acid wherein an

inverse relationship between acid concentration and rate of reaction operates.60 With this in

mind it is critical to maintain a high acid concentration so as to affect complete conversion and

avoid impractically long reaction times. To this end the experiment was repeated instead

dissolving the thioctic amide 23 in the minimum volume of methanol and adding a much larger

excess of TFA (30-fold). Doing so yielded complete deprotection within 24 hours as confirmed

by 1H NMR spectroscopy. The ES mass spectrum (+ve mode) showed only the deprotected

product at an m/z of 275 ([M+H]+, 100%), further confirming complete removal of tert-butoxy

carbonyl had been achieved.

4.3.3 Dithiocarbamate synthesis and ruthenium(II) coordination

Finally, the possibility of synthesising the dithiocarbamate from the free thioctic amide and

using it for the coordination of ruthenium(II) could be tested. Initially, an attempt was made to

synthesise and isolate the dithiocarbamate prior to coordination, as was the case for the

piperazinyl mono-dithiocarbamate.

Two experiments were tried: one in which a solution of the free thioctic amide in methylene

chloride/methanol was treated with CS2 and Et3N and another in which K2CO3 was instead used

as the base. In the first case the product of the reaction, still an oil at this point, proved insoluble

in all common laboratory solvents and impractical to characterise. Fortunately, the crude

product of the second experiment proved far more soluble and was isolated by simply filtering

off the excess K2CO3, evaporating to dryness and then triturating in ethanol so as to remove

traces of CS2. The crude product was submitted for characterisation by 1H and 13C{1H} NMR and

IR spectroscopy and ES mass spectrometry (+ve mode).

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Figure 48 13C{1H} NMR spectrum of crude thioctic piperazinyl dithiocarbamate.

1H NMR spectroscopy showed a down-field shift for the piperazinyl ring protons neighbouring

the free amine to 4.43 ppm, a shift which was consistent with the literature values for

introduction of CS2 to piperazine.45 Furthermore, significant down-field signals were noted in

the 13C{1H} NMR spectrum at 216.7 and 237.1 ppm (Figure 48). Whilst the signal at 237.1 ppm

can be attributed to the dithiocarbamate in accordance with the literature61 the signal at 216.7

ppm is harder to assign. The 1H NMR spectrum shows no evidence of any species associated

with a dithiocarbamate such as the corresponding dithiocarbamic acid that the signal could be

assigned to. Furthermore the signal is too far down-field to attributed to either residual CS2 or

K2CO3.

The IR spectrum was similar to that of the amine starting material with both the νCO and νCN

stretches still present at 1677 cm-1 and 1641 cm-1 (amide) respectively, however, the νCS stretch

was observed at 1431 cm-1 (dithiocarbamate). Finally, the ES mass spectrum (+ve mode)

showed only the free amine at an m/z of 275 (100%) with absolutely no evidence for a

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dithiocarbamate fragment. Although the 13C{1H} NMR spectrum showed promise the rest of the

characterisation data showed little firm evidence for the presence of the dithiocarbamate.

Furthermore, the nature and stability of the crude product was questionable as over a 48 hour

period its solubility decreased significantly and became impractical to work with. Considering

this experiment a failure, an alternative means of synthesising the dithiocarbamate was devised.

Scheme 55 Synthesis of thioctic piperazinyl dithiocarbamate ruthenium(II) complex 25.

In the follow-up experiment, no attempt was made to isolate the dithiocarbamate and instead it

was synthesised in situ and then used immediately for ruthenium(II) coordination, much like

the N-methylpropargyl dithiocarbamate of the previous chapter. The piperazinyl thioctic amide

was suspended in methylene chloride and treated with Et3N and CS2. The mixture was stirred at

room temperature for 10 minutes and then a solution of cis-[RuCl2(dppm)2] in methylene

chloride and methanol was added, immediately followed by NaBF4. After stirring at room

temperature for four hours the solvent was removed under reduced pressure and the mixture

taken up in the minimum volume of methylene chloride and filtered through celite. Addition of

ethanol to the filtrate and concentration by rotary evaporation yielded precipitation of the

product as an off-white solid which was submitted for characterisation by 31P{1H} and 1H NMR

spectroscopy, IR spectroscopy, ES mass spectrometry (+ve mode) and elemental analysis.

The 31P{1H} NMR spectrum showed a noteworthy shift in the pair of triplets of the cis-

[RuCl2(dppm)2] starting material from 0.86 and -27.1 ppm to -5.01 and -18.4 ppm, values which

are consistent with the literature for similar such ruthenium(II) dithiocarbamates.45

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Furthermore, the pair of signals no longer resolved clearly due to significant broadening relative

to the starting material (Figure 49).

Figure 49 31P{1H} NMR spectrum of thioctic piperazinyl dithiocarbamate ruthenium(II) complex 25 (blue). Cis-[RuCl2(dppm)2] starting material shown for comparison (red).

The 1H NMR spectrum provided further evidence for the successful formation of the desired

ruthenium(II) complex given that both the aromatic and bridging methylene protons of the

dppm ligands could be assigned and were found to have the correct integration relative to both

the piperazine ring protons and those of the disulfide heterocycle (Figure 49). The piperazinyl

ring protons were shifted down-field as expected for the introduction of the electron-

withdrawing dithiocarbamate unit. As Figure 50 illustrates, all signals in this spectrum also

exhibited significant broadening relative to the starting material much like the 31P{1H} NMR

spectrum.

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Figure 50 1H NMR spectrum of thioctic piperazinyl dithiocarbamate ruthenium(II) complex 25 in CD2Cl2.

It is possible that the observed signal broadening in both the 31P{1H} and 1H NMR spectra was

due to optical isomerism. Cis-[RuCl2(dppm)2] and the corresponding dithiocarbamate complex

exist as a pair of optical isomers in which the arrangement of the bidentate phosphine ligands

are mirror images of one another (Figure 51). Furthermore, thioctic acid itself exists as a pair of

enantiomers due to the chirality of the carbon atom where the aliphatic backbone and disulfide

ring meet. In complex 25, where the chirality of the backbone and the optical isomerism about

the ruthenium(II) centre are combined, diastereoisomerism arises wherein the isomers are no

longer mirror images of one another (non-enantiomeric). As Figure 51 illustrates, four

diastereoisomers are possible: (R)/Δ or (S)/Δ and (R)/Λ or (S)/Λ. Unlike enantiomers,

diastereoisomers can differ both physically and chemically, including being distinguishable by

NMR spectroscopy. Therefore it is possible that each of the four diastereoisomers contribute to

the 1H and 31P{1H} NMR spectra which, due to only a small distinction in chemical shift, appear

as overlapping signals, giving the appearance of broadening.

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Figure 51 (a) Λ and Δ optical isomers of cis-[RuCl2(dppm)2]; (b) (R) and (S) optical isomers of thioctic acid; (c) four possible diastereoisomers of complex 25.

Figure 52 Comparison of saturated proton environments in 1H NMR spectra of thioctic amide starting material (red) and ruthenium(II) complex 25 (blue).

143

Conformational changes in both the piperazine ring and aliphatic backbone provide an

alternative explanation to the severe signal broadening observed in the 1H NMR spectrum.

Unsubstituted piperazine exhibits a high degree of conformational flexibility wherein both chair

and boat conformations are accessible and within which the N-H bonds may occupy either

equatorial or axial positions.62-63 The chair conformation is most stable with both amine

hydrogen atoms held in equatorial positions and the boat conformation, again with equatorial

N-H bonds, the least stable.63 The energy difference between the two is approximately 10 kcal

mol-1 and the nitrogen inversion barrier is small such that at room temperature ring flipping

occurs readily. This is neatly evidenced by 1H NMR spectroscopy in which only one signal may

be assigned to all ring protons (400 MHz, CDCl3, 25 °C: 2.38 ppm, s, 8H).64

As the substitution at each nitrogen atom increases, so too does the overall strain on the ring,

increasing the energy difference between the most and least stable conformers such that the

barrier to ring inversion is greater. In practise this manifests as signal broadening at room

temperature wherein flux between conformers is slowed and the equatorial and axial protons

start to become chemically distinct. Only at low temperatures will the conformation become

locked and the equatorial and axial protons become entirely inequivalent and assignable to

separate signals. In almost all complexes of the [S2CNC4H8NCS2]2- ligand, the chair conformation

is observed crystallographically. However, Yu et al. reported a cyclic Au16 assembly in which this

ligand adopts the boat conformation.65 Because conformational changes can be prohibited at

lower temperatures a variable temperature NMR spectroscopy experiment would be a useful

way of determining whether the signal broadening is a consequence of conformational change

or diastereoisomerism.

Finally, in the ES mass spectrum the molecular ion was found at m/z 1219 which corresponds to

the singly-charged complex, 25. A significant peak was identified at an m/z of 977 (50%) and

attributed to the formation of a simpler N-methyldithiocarbamate-based ruthenium(II)

fragment. The experimentally determined elemental analysis values (C 57.2%; H 4.1%; N,2.5%)

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are lower than the calculated values (C 57.9%; H 5.02%; N 2.14%) and may instead correspond

to C63H65N2OP4RuS4·0.5CH2Cl2 (C 56.6%; H 4.9%; N 2.1%).

4.3.4 Coordination of Pd(II) and Au(I)

Scheme 56 Further testing of coordinating ability of thioctic piperazinyl amide.

Following on from the success of synthesising complex 25, the same methodology was applied

using a wider variety of transition metal starting materials, including [PdCl2(PPh3)2],

[RuHCl(CO)(PPh3)3] and [AuCl(PPh3)]. In the synthesis of the Au(I) complex 27 a solution of

[AuCl(PPh3)3] in methylene chloride was simply added to a mixture of the thioctic piperazinyl

amide, CS2 and Et3N and left to stir at room temperature for two hours. To avoid any potential

photo-degradation of the [AuCl(PPh3)] starting material, the reaction vessel was sealed in foil

and kept in the dark. Removal of the solvent under reduced pressure yielded an off-white solid

which was washed successively with ethyl acetate and methanol to remove any traces of

[AuCl(PPh3)] and uncoordinated dithiocarbamate. The crude product obtained was analysed by

1H and 31P{1H} NMR spectroscopy and ES mass spectrometry (+mode).

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Figure 53 1H NMR spectrum of thioctic piperazinyl dithiocarbamato gold(I) complex 27 in CDCl3.

In the 31P{1H} NMR spectrum only a single resonance was observed at 36.2 ppm which was

shifted from that of the starting material (33.2 ppm) and in good agreement with literature

values for similar dithiocarbamate gold(I) complexes.69 Crucially, this spectrum showed that no

dissociation of PPh3 had occurred, proving that neither dimeric Au(I) species69 nor larger Au(I)

aggregates70-71 had formed.

Figure 54 Alternative dithiocarbamate binding modes.

In the 1H NMR spectrum (Figure 53) both the aromatic and aliphatic regions were readily

assigned and found to integrate well relative to one another, showing the presence of only a

single PPh3 ligand relative to the dithiocarbamate. This provided further evidence that a

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monomeric Au(I) species was formed over the analogous dimeric species though it was not able

to provide any insight into the dithiocarbamate binding mode.72

Interestingly, the chemical distinction between each of the environments on the piperazine ring

became far more noticeable in this spectrum compared to that of 25 (Figure 49). The

resonances assigned to the piperazine protons nearest the dithiocarbamate were shifted much

further down-field to approximately 4.3 ppm. This is in good agreement with the literature 1H

NMR data for [(Ph3P)Au(S2CNC4H8NH2)]BF469 and is indicative of a strong interaction between

the dithiocarbamate and Au(I) centre. Each resonance assigned to the piperazine ring protons

was further split into a pair of broad multiplets that integrate to two protons each. This

illustrates that the axial and equatorial protons have become chemically distinct from one

another, suggesting that forming the dithiocarbamate Au(I) gold complex causes the piperazine

ring to become conformationally locked. It is likely that it is the preference for such Au(I)

complexes to maintain linearity73-74 and the increased steric demand associated with the PPh3

ligand that leads to such a change.

A molecular ion associated with the dithiocarbamate Au(I) complex could not be identified in

the ES mass spectrum (+ve mode) – only the free piperazinyl thioctic amide could be identified.

Alternative ionisation methods were tested including fast atom bombardment (FAB) to no avail

suggesting perhaps that complex 27 was too sensitive to observe without fragmentation. Due to

time constraints no further attempts were made to characterise this complex more fully.

To synthesise the Pd(II) complex 26 a solution of [PdCl2(PPh3)2] and NaBF4 in methylene

chloride and methanol was added to a solution of piperazinyl thioctic amide, Et3N and CS2 in

methylene chloride and methanol. The mixture was stirred at room temperature for four hours

after which time all solvent was removed under reduced pressure. The residue was dissolved in

the minimum volume of methylene chloride and filtered through a plug of celite before adding

ethanol and concentrating by rotary evaporation to yield precipitation of the product as a bright

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yellow solid. The crude product was submitted for analysis by 1H and 31P{1H} NMR spectroscopy

and ES mass spectrometry (+ve mode).

31P{1H} NMR spectroscopy of 26 showed complete conversion of [PdCl2(PPh3)2] (23.4 ppm75)

and the formation of a new species as indicated by a resonance at 30.5 ppm. This value

corresponded well to that obtained for the N-methylpropargyldithiocarbamate palladium(II)

complex described in the first chapter,76 providing strong evidence that the desired

dithiocarbamate palladium(II) complex had indeed formed. However, the 1H NMR spectrum

proved inconclusive. Whilst the aromatic region was readily assigned to the PPh3 ligands, it did

not integrate well relative to the resonances assigned to the piperazine ring protons and not all

of the signals expected of the aliphatic linker could be identified. Furthermore, ES mass

spectrometry (+ve mode) provided no insight into whether or not complex 26 had been

successfully synthesised as the anticipated molecular ion peak could not be identified. This was

expected to be for similar reasons cited for the Au(I) complex 27 (sensitive to fragmentation).

Again, time constraints prevented this complex from being investigated fully.

Finally, the synthesis of ruthenium(II) complex 28 was attempted by adding a solution of

[RuHCl(CO)(PPh3)3] in methylene chloride to a solution of piperazinyl thioctic amide, Et3N and

CS2 in methylene chloride and methanol. The mixture was stirred at room temperature for 10

minutes before removing all of the solvent under reduced pressure. The crude product,

obtained as a pale yellow solid, was submitted for analysis by 1H and 31P{1H} NMR spectroscopy.

From the 31P{1H} NMR spectrum it was clear that the reaction had neither reached completion

nor proceeded cleanly, yielding the formation of a variety of different species (Figure 55). The

major resonance at 50.2 ppm was thought to correspond to the desired dithiocarbamate

ruthenium(II) species based on the literature values for [RuH(S2CNC4H8NH)(PPh3)2(CO)].77 The

resonances at -5.6 and 27.5 ppm corresponded to free triphenylphosphine and

triphenylphosphine oxide (TPPO) respectively. The minor signals at 18.5 and 40.3 ppm

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corresponded to unreacted [RuHCl(CO)(PPh3)3].78 Overall, this NMR spectrum suggested that

the desired dithiocarbamate ruthenium(II) complex 28 had formed.

Figure 55 31P{1H} NMR spectrum of thioctic piperazinyl dithiocarbamato ruthenium(II) complex 28 in CD2Cl2.

In the wide scan 1H NMR spectrum, the hydride was readily assigned to a triplet at -11.0 ppm

the multiplicity of which also provided evidence that both PPh3 ligands were still present and

were mutually trans-. The chemical shift value was found to agree well with the literature

analysis of [RuH(S2CNC4H8NH)(CO)(PPh3)2]77 providing further evidence that complex 28 had

been successfully synthesised. Prior to carrying out further spectral analysis of 28, attempts

were made to optimise the experiment so as to achieve greater purity.

Increasing the reaction time to four hours or using chloroform or 1,2-dichloroethane as the

reaction solvent and heating under reflux did nothing to affect the complete reaction of

[RuHCl(CO)(PPh3)3]; doing so simply seemed to increase the degree of PPh3 dissociation and

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oxidation. The bis-phosphine precursor [RuHCl(CO)(BTD)(PPh3)2] (where BTD = 2,1,3-

benzothiadiazole) bearing the labile BTD ligand was expected to aid dithiocarbamate

substitution, however this did not improve conversion to the desired product.

Following these investigations, the original experiment was repeated instead followed by a

more thorough work-up. This approach involved purifying the crude product by silica column

chromatography, eluting with n-hexane/ethyl acetate in a gradient of increasing solvent

polarity. Doing so proved successful in removing unreacted [RuHCl(CO)(PPh3)3], free PPh3 and

the unassigned impurities, though not TPPO (Figure 56). Unfortunately, attempts to remove the

oxide by recrystallization from more polar solvents including methanol, ethanol and acetonitrile

mixed with methylene chloride or diethyl ether failed. Time constraints prevented the work-up

from being refined further such that complex 28 could be isolated in higher purity.

Figure 56 31P{1H} NMR spectrum of piperazinyl thioctic dithiocarbamato ruthenium(II) complex 28 after column chromatography (CD2Cl2).

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4.3.5 Coupling of 1-boc-ethylenediamine and 1-boc-1,2-

diaminopropane with thioctic acid and deprotection

Scheme 57 Carbodiimide-mediated coupling of thioctic acid and 1-boc-ethylenediamine and subsequent condensation with 2-bis(diphenylphosphino)benzaldehyde.

Having succeeded in coupling thioctic acid and 1-boc-piperazine in the presence of DCC and

DMAP it made sense to extend the utility of this reaction to other commercially available

starting materials in the hope of further extending the core ligand library. As the previous

experiments illustrated, this type of reaction appeared amenable to mono-protected diamines

so this was a sensible starting point. Additionally, this provided an opportunity to test the

viability of using primary amines instead such that alternative functional groups, including the

imine illustrated in Scheme 57 (29) could be tested; to this end ethylenediamine and 1,2-

diaminopropane were selected. The work presented in this section and the next (4.3.5 and

4.3.6) was undertaken jointly with a co-worker.

Figure 57 1-boc-ethylenediamine and 1-boc-1,2-diaminopropane.

As was the case for piperazine, it was first necessary to protect both ethylenediamine and 1,2-

diaminopropane at one of the amine functional groups in order to avoid complications in the

coupling reaction. A literature protocol was followed in which a solution of di-tert-butyl

dicarbonate in ethanol was added dropwise to a solution of the diamine in ethanol at 0°C under

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N2.79 A 10-fold excess of diamine was employed in order to ensure that only the mono-protected

product was obtained. The desired mono-boc-protected product was isolated simply by

extracting with methylene chloride and washing with 1M NaOH.

Analysis by 1H NMR spectroscopy showed that the protection of both ethylenediamine and 1,2-

diaminopropane had proceeded successfully as illustrated by the appearance of a sharp singlet

at 1.41 and 1.47 ppm. These signals integrated well relative to the ethylene protons and closely

match the literature values,80-81 indicating high purity and only the presence of the mono-

protected product. ES mass spectrometry (+ve mode) provided further evidence for the

successful formation of only the mono-protected amines with the molecular ion peaks at the

anticipated m/z ratios of 161 ([M+H]+, 80%) and 175 ([M+H]+, 50%) respectively.

Scheme 58 DCC-mediated coupling of thioctic acid with both 1-boc-ethylenediamine and 2-tert-butoxycarbonyl aminopropylamine.

In the next step, thioctic acid was coupled to both 1-boc-ethylendiamine and 2-tert-

butoxycarbonyl aminopropylamine following the same DCC/DMAP protocol established when

using 1-boc-piperazine. As before, a solution of DCC and DMAP in methylene chloride was added

dropwise to a solution of 1-boc-ethylenediamine or 2-tert-butoxycarbonyl aminopropylamine

and thioctic acid in methylene chloride at 0 °C. After stirring at 0 °C for an hour, and complete

addition of the reagents, the reaction mixture was warmed to room temperature and left

overnight. All solvent was then removed under reduced pressure and the residue taken up in

the minimum volume of acetonitrile, allowing the majority of the N,N’-dicyclohexylurea by-

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product to be removed by filtration. Purification by gradient column chromatography with silica

as the stationary phase and diethyl ether/methanol as the eluent was necessary in order to

isolate the desired coupled products (29 and 30) as crystalline yellow solids. The products were

characterised by 1H and 13C{1H} NMR and IR spectroscopy, ES mass spectrometry (+ve mode)

and elemental analysis.

1H NMR spectroscopy provided strong evidence for the successful coupling of 1-boc-

ethylenediamine and thioctic acid wherein the relative integration of the signals assigned to the

tert-butyl protons of the protecting group and the methylene protons of the disulfide matched

that of the anticipated product. The broad signal at 6.33 ppm was assigned to the amide proton,

providing further evidence that the coupling reaction had proceeded. The slight downfield shift

in the multiplet assigned to the methylene protons of the diamine neighbouring the free amine

in the starting material was expected upon converting the amine to the more electron-

withdrawing amide functional group. Unsurprisingly, the chemical shift values and

multiplicities of the signals assigned to the protons of the disulfide closely match those of the

piperazinyl thioctic amide characterised previously. The 13C{1H} NMR spectrum supports the

conclusion that the coupling reaction has proceeded successfully, as indicated by the

appearance of a new signal at 173.5 ppm, assigned to the amide functional group.

In the IR spectrum, two distinct signals were observed at 1641 and 1683 cm-1 corresponding to

the C=O stretching modes of both the carbamate and amide functional groups. The N-H

stretching mode of the amide functional group was identified by a significantly broadened peak

at 3350 cm-1. Finally, the anticipated product was confirmed by the ES mass spectrum (+ve

mode) at an m/z of 371.1 ([M+Na]+, 100%). The experimentally determined values from

elemental analysis were in close agreement with the calculated values. The coupling of N-boc-

aminopropylamine and thioctic acid was also deemed a success based upon the data collected

using the same techniques.

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The above experiments were successful in proving that simple diamines such as

ethylenediamine and 1,2-diaminopropane could be coupled to thioctic acid and the anticipated

product isolated, purified and characterised, however, the poor yields were considered

impractically low for further synthetic modification and possible nanoparticle functionalisation.

Figure 58 (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU).

The reaction between 1-boc-ethylenediamine and thioctic acid was repeated exploring the use

of alternative carbodiimide reagents such as EDC and alternative additives including HOBt and

NHS. Ultimately, the most successful approach proved to be that in which the carbodiimide was

omitted altogether and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium

hexafluorophosphate) (HBTU) used as the activating agent instead, allowing the desired amide

to be obtained in 66% yield – a significant improvement. HBTU is a uronium derivative of HOBt

(Figure 58) which, due to the presence of base (Et3N in this case), is attacked by the carboxylate,

transferring the uronium group and releasing HOBt in the process. The uronium group is an

excellent leaving group making the acid far more susceptible to attack by HOBt and

subsequently the chosen amine. The fact that the desired product was much easier to isolate

from the tetramethylurea by-product by column chromatography improved the yield further.

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Scheme 59 Deprotection of 1-boc-ethylene thioctic amide and 1-boc-propyl thioctic amide with TFA.

Next, it was necessary to remove the tert-butoxycarbonyl protecting groups from both amides

utilising the TFA-mediated protocol established previously in the deprotection of the

piperazinyl thioctic amide. As before, each of the amides were taken up in the minimum volume

of methanol and a large excess of TFA added so as to enhance the rate of reaction as much as

possible. The reactions were followed by 1H NMR spectroscopy and found to require a number

of days in order to reach completion (as indicated by the disappearance of the singlet around

1.47 ppm assigned to the tert-butyl protons), much like the deprotection of the piperazinyl

thioctic amide.60 After complete removal of the solvent and excess TFA, the crude products were

extracted with methylene chloride and washed with aqueous solutions of saturated NaHCO3 and

NaCl in turn so as to neutralise residual TFA and remove any salts. Concentration under reduced

pressure and layering with ethanol allowed the products to be collected as yellow oils in both

cases.

In order to convert both the aminoethylene and aminopropyl thioctic amides into ligands

suitable for palladium(II) coordination, it was necessary to affix one further functional group to

the molecule. Based upon literature reports on utilising hemi-labile P,N- and N,N’-bidentate

ligands for the synthesis of palladium(II) cross-coupling catalysts48-49, 82 the reactions illustrated

in Scheme 16 were tested.

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4.3.6 Imine condensation

Scheme 60 Condensation of aminoethylene thioctic amide or aminopropyl thioctic amide with both 2-bis(diphenylphosphino)benzaldehyde and 2-pyridinecarboxaldehyde.

In both cases the reactions were carried out by simply dissolving equimolar quantities of either

2-bis(diphenylphosphino)benzaldehyde or 2-pyridinecarboxaldehyde and either thioctic amide

in THF and then heating under reflux. 1H NMR spectroscopy was used to follow the reactions

wherein the consumption of the aldehyde was gauged by the disappearance of the characteristic

resonance at approximately 10.0 ppm and the formation of the imine by the appearance of a

new signal between 6.0 and 7.0 ppm. As corroborated by ES mass spectrometry (+ve mode), it

appeared that in all cases the imine formed in only small quantities, indeed, less than 10%

conversion of the aldehyde was noted after 18 hours of reaction and increasing the duration did

little to affect this outcome.

In follow-up experiments, the reactions were repeated either in the presence of activated

molecular sieves or using a Dean-Stark trap (DMSO/toluene) in order to remove any water

formed during the condensation reaction, potentially driving the equilibrium towards imine

formation and maintaining imine stability.83 However, this failed to yield any enhancement in

the percentage conversion.

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Scheme 61 Test condensation of benzylamine and 2-pyridinecarboxaldehyde.

In order to determine if the failure of the reaction to proceed to completion was due to

procedural error or poor reactivity of the thioctic amide, a test condensation between

benzylamine and 2-pyridinecarboxaldehyde was attempted following literature procedures.84-85

According to this protocol, MgSO4 was a sufficient dehydrating agent to aid in driving the

equilibrium towards imine formation. Indeed, the reaction was found to proceed to completion

within 24 hours at room temperature, as reported in the cited literature. The desired imine was

obtained in near quantitative yield and required no further purification. The success of this

experiment suggested that neither procedural error nor unsuitable reaction conditions were

responsible for the poor conversion of aldehyde to imine in the previous experiments. It must

instead be a consequence of poor reactivity of the thioctic amides or potentially poor stability of

the imine. Due to time constraints this hypothesis could not be tested further nor could an

attempt be made to coordinate these ligands to any transition-metal centres.

4.3.7 Ruthenium(II)-functionalisation of gold nanoparticles

The experiments detailed above show the potential of thioctic acid as a commercially available

and versatile linker which, when used in conjunction with other commercially sourced starting

materials, can be used to coordinate both ruthenium(II) and palladium(II) centres; including

potentially catalytically active centres. In order to exploit the concept of using thioctic acid to

functionalise AuNPs with catalytically active transition metals, it was necessary to explore the

possibility of synthesising AuNPs and passivating them with complex 25 (Scheme 62).

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Scheme 62 Synthesis and passivation of AuNPs with thioctic piperazinyl dithiocarbamate ruthenium(II) complex 2.12 via modified Brust-Schiffrin method.

As described in the introduction, there are two main literature routes to stabilising AuNPs with

thioctic acid. In one route, citrate-capped AuNPs are synthesised using Frens’ modification40 of

the Turkevich method and then treated with thioctic acid at pH 11, providing both steric and

electrostatic stabilisation.41 In the second route the Brust-Schiffrin method is instead used to

synthesise AuNPs passivated with dodecanethiol which can then be readily displaced by thioctic

acid or its derivatives.42

Due to the insolubility of complex 25 in aqueous media and the need for the functionalised NPs

to be soluble in organic media for catalytic applications, the Brust-Schiffrin method was first

tested. The original Brust-Schiffrin method involves a biphasic system in which

tetrachloroaurate anions are transferred from water to toluene using tetraoctylammonium

bromide (TOAB) with NaBH4 as the reducing agent and a long-chain alkanethiol such as

dodecanethiol as the passivating agent.11 Unfortunately, residual TOAB is extremely difficult to

remove and can negatively affect the properties of the AuNP clusters formed in this way.86-87 A

modification of the Brust-Schiffrin method can be employed which avoids the use of TOAB

altogether by simply treating a solution of HAuCl4·3H2O and the stabilising thiol in methanol or

ethanol with a solution of NaBH4.88

To this end, the thioctic piperazinyl dithiocarbamate ruthenium(II) complex 25 and

HAuCl4·3H2O were suspended in anhydrous ethanol and a solution of NaBH4 (excess) in

158

anhydrous methanol added dropwise with vigorous stirring. The resultant deep purple mixture

was stirred at room temperature for 15 minutes and then concentrated by rotary evaporation

allowing the AuNPs to be isolated by centrifugation, triturated in H2O and dried under vacuum

to yield a black powder. The AuNPs were readily soluble in methylene chloride, chloroform,

ethanol, 2-propanol and acetonitrile and proved re-dispersible after evaporating to dryness

multiple times and storing in air. The clusters were characterised by 1H and 31P{1H} NMR

spectroscopies and transmission electron microscopy (TEM).

Figure 59 TEM image of NP3. Sample prepared by dispersing Au@25 in MeOH and carefully dropping onto copper square mesh TEM support grid via pipette. Sample placed in sealed vessel and vacuum dried overnight prior to

imaging.

The nanoparticles were found to be essentially spherical with an average diameter of 4.4 ± 1.7

nm (Figure 59), showing greater polydispersity relative to the DTC-capped AuNPs of Chapter 2

synthesised by the Turkevich method, a result which is consistent with the literature for AuNPs

prepared in this way.88 Finally, in the electron micrograph it could be seen that the particles

exhibited a propensity to pack closely unlike the N-methylpropargyldithiocarbamate-passivated

AuNPs of the previous chapter, which remained well separated in all cases.

159

Brust et al. found that the concentration of NaBH4 relative to Au(III) is critical to the success of

the reaction using this procedure.88 At higher concentrations of NaBH4 the clusters formed are

more susceptible to decomposition, even after purification. When a 7-fold excess is used

irreversible precipitation of the Au clusters is observed during the reaction itself. In this

experiment, a 6-fold stoichiometric excess of NaBH4 was employed which may have

compromised the stability of the AuNPs enough to cause them to pack closely and show early

signs of aggregation, all the while remaining stable enough to avoid irreversible precipitation. In

order to test this hypothesis the experiment would need to be repeated using a decreasing

excess of NaBH4 and the electron micrographs of the resultant NPs compared.

Alternatively, the nature of the passivating ligand itself may be responsible for the observed

close packing of the AuNPs. The length of the aliphatic backbone of this ligand may be too short

to affect self-assembly which, when combined with the steric bulk about the ruthenium(II)

coordination centre, may limit surface coverage and the degree of passivation. Poor surface

coverage of the AuNPs will inevitably lead to clustering and eventual aggregation as the

particles strive to reduce their overall surface energy.

With more time this could have been tested by analysing the AuNPs by either inductively-

coupled plasma mass spectrometry (ICP-MS) or X-ray photoelectron spectroscopy (XPS) to

calculate the Au:S ratio which, when combined with the particle size obtained by TEM, could be

used to determine ligand packing density.89 The obtained value could then be compared to the

literature packing density for thioctic acid-passivated AuNPs90 in order to infer whether or not

the presence of ruthenium(II) on the gold surface reduces packing density and stability by

extension.

In the 31P{1H} NMR spectrum (Figure 60), the pair of multiplets attributed to dppm ligands

about the ruthenium(II) centre can still be found at -5.0 and -18.2 ppm showing that the no

change about the Ru(II) coordination centre occurred during NP synthesis. Likewise, the 1H

NMR spectrum (Figure 61) matches that of complex 25 further suggesting that both the Ru(II)

160

coordination centre and aliphatic backbone remain unchanged during AuNP synthesis. Though

promising, further analysis by ICP-MS and XPS would be required in order to confirm the

successful anchoring of Ru(II) to the AuNP surface.

Figure 60 31P{1H} NMR spectrum of ruthenium(II)-functionalised NP3 in CD2Cl2.

161

Figure 61 1H NMR spectrum of ruthenium(II)-functionalised AuNPs NP3 in CD2Cl2.

4.4 Conclusions

In conclusion, thioctic acid is a suitable commercially available starting material for the

synthesis of larger multi-functional ligands wherein the terminal carboxylic acid is sufficiently

reactive that additional commercially sourced starting materials can be affixed with ease. Doing

so allows the chain length to be increased as required, allowing appropriate separation between

the potential coordination sphere of the transition metal catalyst and the AuNP surface to be

achieved, a problem which plagued the much smaller N-methylpropargyldithiocarbamate

complexes of the second chapter. Crucially, the disulfide moiety of thioctic acid remained intact

during both chain lengthening, when harsh reagents were employed (TFA for instance), and the

subsequent transition metal coordination, when the disulfide itself could have potentially acted

as a ligand through oxidative addition for instance.

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Figure 62 Thioctic piperazinyl ruthenium(II) dithiocarbamate-functionalised AuNPs. TEM proved that the disulfide remained amenable to AuNP passivation allowing stable clusters to obtained. 1H and 31P{1H} NMR

spectroscopic analysis proved that the ruthenium(II) coordination centre remained intact in the process.

Although time constraints prevented the full coordination chemistry potential of the thioctic

acid-derived ligands from being explored, it was clear from crude spectroscopic analysis that

the amine-terminating ligands were suitable for dithiocarbamate formation and subsequent

coordination of both ruthenium(II) and palladium(II). Accordingly, a novel ruthenium(II)

complex was isolated and found to be useful in the functionalisation of AuNPs. Attempts to

utilise the terminal amine group to introduce alternative functionalities failed to provide

sufficiently promising results however, with more time and a wider selection of building blocks

available, substantial progress could be made.

The most valuable outcome of the work presented here is the success in synthesising the

functionalised gold cluster illustrated above (Figure 62). Not only does this result build upon

existing work that presents thioctic acid as a valid alternative to the more commonly used

mono-alkanethiolates but it also highlights the robust nature of this ligand and the experimental

flexibility it presents.

The piperazinyl thioctic amide was largely designed with convenience and established protocol

in mind, making the clusters of the type illustrated in Figure 62 less attractive in terms of SAM

stability, ligand packing density and control over nanoparticle size, let alone application to

catalysis. If a seemingly simple ligand such as this can be met with success, then it paves the way

163

for more sophisticated systems in which the ligand’s nature can be tailored specifically to

maximise the aforementioned properties.

4.5 Future Work

Given the conclusion above, there remains much work which could be done in order to fully

exploit this ligand for simultaneous nanoparticle passivation and catalyst coordination. Before

exploring the possibility of fine-tuning the surface chemistry of the AuNPs, it would first make

sense to ensure that catalytically active species could be attached to the surface of such clusters.

As stated above, the carboxylic acid of the thioctic acid proved amenable to coupling with amine

functional groups and, with more work into selecting appropriate building blocks, could no

doubt be employed as a linker in a variety of different ways. What was tested, as presented in

the aims, was the suitability of the carboxylic acid for functional group interconversion. This

would serve to greatly expand the library of ligands that could be accessed starting from thioctic

acid as a commercially available source.

Scheme 63 Functional group interconversion of carboxylic acid to azide. In theory a copper-mediated cycloaddition could be used to incorporate the ferrocene ligand designed in the previous chapter and obtain the

illustrated (catalytically active) ruthenium(II)-functionalised AuNPs. Reagents: a) catechol borane, CH2Cl2; b) CH3SO2Cl, CH2Cl2; c) NaN3, DMF.

164

For instance, a literature procedure to convert the carboxylic acid to an azide50 could be

followed to allow the disulfide to act as a linker in a variety of different ways. If combined with a

catalytically active derivative of the ferrocenecarboxylate ruthenium(II) complexes of the

previous chapter, then a system such as that illustrated in Scheme 63 may be synthesised. If

successfully isolated and characterised, the application of these clusters to the reduction of

unsaturated hydrocarbons could then be tested.

As described in the introduction, Scrimin, et al. synthesised 2 nm diameter AuNPs using a

mixture of 1-octane thiolate and a zinc(II)-triazacyclanone complex to passivate the surface.

These clusters were successfully used to catalyse the transphosphorylation of 2-hydroxypropyl-

p-nitrophenyl phosphate, an RNA model compound.91 Interestingly, this catalyst proved to be

more active than any other Zn(II)-based transphosphorylation catalyst, a result which was used

to infer that the mixed ligand composition on the gold surface led to the formation of catalytic

pockets, essentially increasing the effective catalyst concentration.92

In a different pair of studies by Paluti and Gawalt, it was found that three different SAM

orientations could be achieved through careful control of an alkanethiol and Cu(II)-aza-

bis(oxazoline) ligand mixture.93-94 The three SAM orientations were convex, level and concave,

wherein the Cu(II) catalyst was, respectively embedded above, even with or below the

monolayer. Depending upon the orientation of the SAM, the catalyst’s stereoselectivity and

regioselectivity in the cyclopropanation of ethyldiazoacetate and styrene was found to be

superior to analogous homogeneous catalysts.

Through utilising new synthetic building blocks other than piperazine and ethylenediamine or

by utilising FGI in a similar way to Scheme 63, thioctic acid could be used to synthesise a

number of ligands of varying hydrocarbon chain length (all capable of self-assembly) allowing

surface composition to be explored more fully. If such thioctic acid-based ligands provide

control over SAM orientation, then this would pave the way towards more active catalysts such

as those presented by Scrimin et al. and Paluti and Gawalt, without the drawbacks associated

165

with alkanethiols (discussed in the introduction). Furthermore, more complex catalysts may

even be designed such as asymmetric catalysts the selectivity of which arises from distinctly-

shaped catalytic pockets on the AuNP surface.

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5. Experimental Section

5.1 General

Unless explicitly stated, all experiments were carried out in air and the resultant products stable

toward the atmosphere, both in solid and solution state. All reagents and solvents were used as

received from commercial sources without further purification unless stated otherwise. TLC

was performed on Kieselgel 60 F254 plates (Merck) and any spots were visualised under UV

fluorescence (254 and 366 nm) or I2 vapour. Unless stated otherwise column chromatography

was carried out using silica gel 60 (Merck) under gentle pressure applied by hand bellows.

References to petroleum ether refer to the fraction boiling in the range 40-60 °C. The following

compounds were synthesised as described elsewhere: [RuHCl(CO)(PPh3)3],1

[RuHCl(CO)(BTD)(PPh3)2],2 [OsHCl(CO)(BTD)(PPh3)2],3 cis-[RuCl2(dppm)2],4 [AuCl(PPh3)],5

[AuCl]2(dppf),6 [CuI(IAd)],7 [CuI(IPr)],7 cis[PdCl2(PPh3)2],8 [RuCl(dppe)2]OTf,9 trans-

[RuCl(dppe)2],10 [RuH(S2P(OEt)2)(CO)(PPh3)2],11 [RuCl(C(=CHPh)C≡CPh)(CO)(BTD)(PPh3)2],12

1-boc-piperazine,13 1-boc-ethylenediamine,14 1-boc-aminopropylamine,14 methylferrocene-1-

carboxylate,15 1’-ethynylferrocene-1-carboxylic acid,16 p—methoxybenzylazide,17 2-

azidoethylbenzene18 and 2K[S2CNC4H8NCS2].19

Electrospray (ES) and fast atom bombardment (FAB) mass data were obtained using Micromass

LCT Premier and Autospec Q instruments, respectively. Infrared data were obtained with a

PerkinElmer Spectrum 100 FT-IR spectrometer. NMR spectroscopy was carried out at 25 °C

using Bruker AV400 spectrometers. All coupling constants are quoted in Hertz. Elemental

analysis data were obtained from London Metropolitan University. TEM images were obtained

using a JEOL 2010 high-resolution TEM (80-200 kV) equipped with an Oxford Instruments INCA

EDS 80 mm X-Max detector system. All TEM samples were prepared by suspending AuNPs in

MeOH and then carefully dropping onto a copper square mesh TEM grid via pipette or syringe

and then sealing in a vessel and drying under vacuum overnight. Thermogravimetric analysis

172

(TGA) was performed on a PerkinElmer Pyris 1 thermogravimetric analyser, using a platinum

sample holder.

5.2 Chapter 2 Compounds

KS2CN(CH2C≡CH)Me (1)

N-methylpropargylamine (84 μL, 1.00 mmol) and CS2 (72 μL, 1.20 mmol) were stirred in the

presence of KOH (67 mg, 1.20 mmol) in water (5 mL) at 0 °C for 5 minutes. This solution was

used immediately (in slight excess) for the subsequent additions to the metal precursors.

[Ru{S2CN(CH2C≡CH)Me}(dppm)2]PF6 (2)

A solution of N-methylpropargylamine (10 μL, 0.120 mmol) in methylene chloride (2 mL) was

cooled in an ice bath and triethylamine (21 μL, 0.150 mmol) added. After stirring for five

minutes, carbon disulfide (10 μL, 0.170 mmol) was added and the reaction stirred for a further

20 minutes. A solution of cis-[RuCl2(dppm)2] (98 mg, 0.100 mmol) in a mixture of methylene

chloride (3 mL) and methanol (6 mL) was added followed by KPF6 (31 mg, 0.170 mmol) in

water (1 mL) and the reaction stirred for 45 minutes. All solvent was removed under reduced

pressure and the crude product dissolved in the minimum volume of methylene chloride and

filtered through celite. Ethanol (20 mL) was added and the orange product obtained by rotary

evaporation. This was washed with ethanol (10 mL) and n-hexane (10 mL) and dried under

vacuum. Yield: 42 mg (35%). IR (solid state): 2122 (νC≡C), 1484, 1434, 1189, 1097, 999, 834,

727, 694 cm-1. 1H NMR (CD2Cl2): 2.51 (t, 1H, C≡CH, 4JHH = 2.3 Hz); 3.08 (s, 3H, CH3); 4.12 (dd, 1H,

NCH2,4JHH = 17.6, 2.3 Hz); 4.49 (m, 2H, PCH2P); 4.51 (dd, 1H, NCH2, 4JHH = 17.6, 2.3 Hz); 6.50, 7.00,

7.11 (m x 3, 3 x 4H, C6H5); 7.25-7.50 (m, 24H, C6H5); 7.69 (m, 4H, C6H5). 31P{1H} NMR (CD2Cl2): -

4.7 (t, dppm, JPP = 33.5 Hz), -18.9 (td, dppm, JPP = 33.5 Hz). MS (ES +ve) m/z (abundance) = 1014

(100) [M]+. Anal. Calcd. for C55H50F6NP5RuS2: C 57.0%, H 4.4%, N 1.2%. Found: C 57.3%, H 4.4%,

N 1.3%.

173

[Ni{S2CN(CH2C≡CH)Me}2] (3)

An aqueous solution (5 mL) of KS2CN(CH2C≡CH)Me (1.00 mmol) was added to an aqueous

solution (5 mL) of NiCl2.6H2O (119 mg, 0.500 mmol) and the reaction stirred for three hours. All

solvent was removed under reduced pressure and the residue dissolved in the minimum

volume of methylene chloride and filtered through celite to remove KCl. Ethanol (10 mL) was

added and the solvent volume reduced slowly by rotary evaporation to yield precipitation of the

product as a pale green product which was collected by filtration, washed with petroleum ether

(10 mL) and dried under vacuum. Yield: 107 mg (62%). IR (solid state): 3261, 2123 (νC≡C), 1518,

1440, 1412, 1396, 1338, 1254, 1201, 1095, 991, 959, 938, 876, 685, 657 cm-1. 1H NMR (CDCl3):

2.46 (t, 1H, C≡CH, 4JHH = 2.5 Hz); 3.33 (s, 3H, CH3); 4.46 (d, 2H, NCH2, 4JHH = 2.5 Hz) ppm. 13C{1H}

NMR (CD2Cl2): 203.1 (s, CS2), 75.1 (s, C≡CH), 74.2, 39.5 (s, NCH3), 35.7 (s, NCH2) ppm. MS (ES

+ve) m/z (abundance) = 346 (14) [M]+. Anal. Calcd. for C10H12N2S4Ni: C 34.6%, H 3.5%, N 8.1%.

Found: C 34.7%, H 3.4%, N 8.1%.

H2C=CCH2N(Me)C(=S)S (4)

An aqueous solution (20 mL) of N-methylpropargylamine (84 μL, 1.00 mmol) and KOH (56 mg,

1.00 mmol) was stirred for five minutes. Carbon disulfide (72 μL, 1.20 mmol) was added to the

solution and the reaction stirred for one hour. Additional water (10 mL) was added to the

solution and the white precipitate filtered and dried under vacuum. Yield 112 mg (77%). IR

(solid state): 2914, 1755, 1625, 1501, 1432, 1406, 1388, 1286, 1228, 1182, 1094, 1021, 872 cm-

1. 1H NMR (CDCl3): 3.30 (s, 3H, CH3); 4.78 (t, 2H, NCH2, 4JHH = 2.6 Hz); 5.14, 5.26 (m x 2, 2 x 1H,

=CH2) ppm. MS (ES +ve) m/z (abundance) = 146 (100) [M]+. Anal. Calcd. for C5H7NS2: C 41.4%, H

4.9%, N 9.6%. Found: C 41.3%, H 4.8%, N 9.5%.

MeC=CHN(Me)C(=S)S (5)

The aqueous filtrate from the synthesis of H2C=CCH2N(Me)C(=S)S was evaporated under

reduced pressure to obtain a yellow oil. Yield: 30 mg (21%). IR (solid state): 3091, 2940, 1600,

1439, 1420, 1353, 1332, 1216, 1157, 1105, 1046, 932, 781 cm-1. 1H NMR (CDCl3): 2.19 (s, 3H,

174

CH3); 3.62 (s, 3H, CH3); 6.75 (s, 1H, =CH) ppm. MS (ES +ve) m/z (abundance) = 146 (100) [M]+.

Anal. Cald. for C5H7NS2: C 41.4%, H 4.9 %, N 9.6%. Found: C 41.4%, H 4.7%, N 9.6%.

[Ru(κ2-S2C=O)(dppm)2] (6)

KOH (7 mg, 0.12 mmol) was dissolved in methanol (5 mL) and CS2 (7 μL, 0.120 mmol) was

added. After stirring at room temperature for 15 minutes a solution of cis-[RuCl2(dppm)2] (98

mg, 0.100 mmol) and NaBF4 (14 mg, 0.130 mmol) in methylene chloride (5 mL) and methanol

(5 mL) was added and the mixture stirred for a further two hours. All solvent was removed

under reduced pressure and the residue dissolved in the minimum volume of methylene

chloride and filtered through a plug of celite. Ethanol (20 mL) was added to the filtrate which,

upon concentration under reduced pressure, yielded precipitation of the product as a crystalline

yellow solid. Yield: 84 mg (87%). 31P{1H} NMR (CD2Cl2): -5.74 (t, JPP = 88.0 Hz, dppm), -18.0 (t,

JPP = 88.0 Hz, dppm).

[Pd{S2CN(CH2≡CH)Me}(PPh3)2]BF4 (7)

N-methylpropargylamne (12 μL, 0.140 mmol) was mixed with methylene chloride (2 mL) and

cooled in an ice bath. Triethylamine (24 μL, 0.170 mmol) was added and the mixture stirred for

five minutes. Carbon disulfide (10 μL, 0.170 mmol) was added and the mixture stirred for a

further 15 minutes. The resulting dithiocarbamate was added to a solution of cis-[PdCl2(PPh3)2]

(94 mg, 0.130 mmol) and NaBF4 (26 mg, 0.240 mmol) in methylene chloride (30 mL) and

methanol (10 mL). After stirring at room temperature for two hours all solvent was removed

under reduced pressure and the residue dissolved in the minimum volume of methylene

chloride and filtered through celite. Isopropanol (30 mL) was added to the filtrate which was

then concentrated by rotary evaporation and cooled in an ice bath to yield precipitation of the

desired compound as a pale yellow solid. Yield: 43 mg (37%). A further slightly less pure crop

(contaminated by approximately 5% starting material) was obtained by leaving the filtrate in

the freezer overnight. IR (solid state): 2172 (νC≡C), 1969, 1906, 1813, 1672, 1531, 1480, 1435,

1094, 998, 751, 689 cm-1. 1H NMR (CD2Cl2): 2.54 (t, 1H, C≡CH, 4JHH = 2.5 Hz); 3.31 (s, 3H, CH3);

175

4.47 (d, 2H, NCH2, 4JHH = 2.5 Hz); 7.33-7.53 (m, 30H, C6H5) ppm. 31P{1H} NMR (CD2Cl2): 30.4 (s,

PPh3) ppm. MS (ES +ve) m/z (abundance) = 774 (100) [M]+. Anal. Cald. for C41H36BF4NP2PdS2: C

57.1%, H 4.3%, N 1.6%. Found: C 57.0%, H 4.3%, N 1.6%.

[RuH{S2CN(CH2CH=CH2)Me}(CO)(PPh3)2] (8) (Attempted)

N-methylpropargylamine (2μL, 0.026 mmol) was mixed with methylene chloride (2 mL) and

cooled in an ice bath. Triethylamine (4μL, 0.029 mmol) was added and the mixture stirred for

five minutes. Carbon disulfide (2μL, 0.029 mmol) was added and the mixture stirred for a

further 15 minutes. The resulting dithiocarbamate was added to a solution of

[RuHCl(CO)(BTD)(PPh3)2] (50 mg, 0.024 mmol) in methylene chloride (20 mL) and stirred for

two hours. Methanol (20 mL) was added to the solution which was then concentrated by rotary

evaporation to yield precipitation of the crude product as a brown solid. 31P{1H} NMR (CD2Cl2):

36.6 (s, [RuHCl(CO)(BTD)(PPh3)2]); 49.9 (d, {Me(H2C=CHCH2)NCS2}Ru(PPh3)2, JPP = 52 Hz) ppm.

[Ni{S2CN(CH2CH=CH2)Me}2] (9)

A solution of [Ni{S2CN(CH2C≡CH)Me}2] (26 mg, 0.0750 mmol) in ethyl acetate (10 mL) was

treated with 5 mg of 10% Pd on carbon and hydrogen gas was passed through solution for four

hours at room temperature. The solution was filtered through celite and the solvent removed

under reduced pressure to yield the dark green product. Yield 24 mg (92%). IR (solid state):

1641, 1515, 1382, 1252, 1209, 1143, 1075, 987, 929, 679 cm-1. 1H NMR (CDCl3): 3.14 (s, 6H,

NCH3); 4.20 (d, 4H, NCH2, 4JHH = 4.8 Hz); 5.30 (m, 4H, =CHAB); 5.77 (m, 2H, =CHC) ppm. 13C{1H}

NMR (CD2Cl2): 207.5 (s, CS2), 129.8 (s, NCCH2), 119.6 (s, =CH2), 53.3 (s, NCH3), 35.9 (s, NCH2)

ppm. MS (ES +ve) m/z (abundance) = 351 (20) [M]+. Anal. Calcd. for C10H16N2NiS4: C 34.2%, H

4.6%, N 8.0%. Found: C 34.3%, H 4.5%, N 7.9%.

Au@S2CN(CH2C≡CH)Me (NP1)

An aqueous solution (200 mL) of HAuCl4.xH2O (230 mg, 0.677 mmol) was heated under reflux.

An aqueous solution (200 mL) of trisodium citrate dihydrate (1570 mg, 5.34 mmol) was added

and the solution was immediately removed from the heat and stirred in an ice bath for 40

176

minutes. The solution changed from yellow to black as nanoparticles formed. In a separate flask,

an aqueous solution (200 mL) of freshly prepared KS2CN(CH2≡CH)Me (2.64 mmol) was

immediately added dropwise to the nanoparticle solution. The solution was stirred at room

temperature for five hours and then stored at 5 °C for 18 hours to allow the nanoparticles to

settle. The water was decanted and the nanoparticles were washed with water (5 x 120 mL). All

water was then removed under vacuum and the black powder triturated in diethyl ether (4 x 50

mL), collected and dried under vacuum. Yield: 50 mg (41%). %). IR (solid state): 2120 (νC≡C),

1740, 1626, 1469, 1371, 1199, 1078, 1019, 935, 815 cm-1. 1H NMR (CD2Cl2): 2.45 (br, 1H, ≡CH);

3.59 (br, 3H, NCH3); 4.78 (br, 2H, NCH2) ppm. TEM analysis of 300 nanoparticles gave a size of

4.8 ± 1.0 nm. EDS indicated the presence of gold and sulfur. TGA analysis revealed 28.6%

surface units, 71.4% gold.

5.3 Chapter 3 Compounds

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (11)

1,1’-Ethynylferrocene carboxylate (132 mg, 0.520 mmol) was suspended in methylene chloride

(100 mL), triethylamine (0.3 mL, 2.15 mmol) and the mixture stirred until complete dissolution

occurred (30 minutes approximately). [RuCl{C(C≡CPh)CHPh}(CO)(BTD)(PPh3)2] (489 mg,

0.420 mmol) was added and the mixture stirred for a further three hours. All solvent was

removed under reduced pressure and the resultant crude product dissolved in minimum

volume of methylene chloride and filtered through celite. Ethanol (100 mL) was added and the

bright orange product obtained by rotary evaporation. This was washed with cold ethanol (20

mL) and n-hexane (20 mL) and dried under vacuum. Yield: 330 mg (69%). IR (solid state): 3298,

2143 (νC≡C), 2100 (νC≡C), 1908 (νC≡O), 1501, 1433, 1187, 1093 cm-1. 1H NMR (d6-acetone): 3.23

(s, 1H, C≡CH); 3.38 (s, 2H, C5H4); 3.88 (s, 2H, C5H4); 4.01 (s, 2H, C5H4), 4.12 (s, 2H, C5H4), 5.61 (br,

1H, C(C≡CPh)HPh); 6.94-7.67 (m, 40H, C6H5) ppm. 31P{1H} NMR (d6-acetone): 35.5 (s, PPh3)

ppm. MS (ES +ve) m/z (abundance) = 898 (100) [M-CO-PPh3+2K]+. Anal. Calcd. for

C66H50FeO3P2Ru: C 71.4 %, H 4.5%, N 0.0%. Found: C 71.3%, H 4.4%, N 0.0%.

177

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CAuPPh3)(CO)(PPh3)2] (12)

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (50 mg, 0.045 mmol) was dissolved in

methylene chloride (20 mL) and [AuCl(PPh3)] (22 mg, 0.045 mmol) and a few drops of 1,8-

diazabicyclo[5.4.0]undec-7-ene added. The mixture was stirred in the dark for 18 hours after

which time ethanol (20 mL) was added and the product obtained as a pale yellow solid by

rotary evaporation. This was washed with cold ethanol (10 mL) and n-hexane (10 mL) and

dried under vacuum. Yield: 37 mg (52%). IR (solid state): 2182 (νC≡C), 1920 (νC≡O), 1593, 1499,

1435, 1095 cm-1. 1H NMR (d6-acetone): 3.26 (s, 2H, C5H4); 3.76 (s, 2H, C5H4); 3.94 (s, 2H, C5H4);

4.10 (s, 2H, C5H4); 5.15 (br, 1H, C(C≡CPh)HPh); 6.92-7.81 (m, 55H, C6H5) ppm. 31P{1H} NMR (d6-

acetone): 35.3 (s, Ru(PPh3)2); 42.0 (s, Au(PPh3)) ppm. MS (ES +ve) m/z (abundance) = 1181

(100) [M – {(C≡CPh)CCHPh} – PPh3 + 2K]+. Anal. Cacld. for C84H64AuFeO3P3Ru: C 64.3%, H 4.1%,

N 0.0%. Found: C 64.4%, H 4.0%, N 0.0%.

[Ru{C(C≡CPh)CHPh}(O2CFcC≡C)(CO)(PPh3)2]2Au(dppf) (13)

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (50 mg, 0.045 mmol) was dissolved in

methylene chloride (20 mL) and [(AuCl)2dppf] (23 mg, 0.023 mmol) and a few drops of 1,9-

diazabicyclo[5.4.0]undec-7-ene added. The mixture was stirred in the dark at room temperature

for 18 hours after which time ethanol (20 mL) was added and the product obtained as a pale

yellow solid by rotary evaporation. This was washed with cold ethanol (10 mL) and n-hexane

(10 mL) and dried under vacuum. Yield: 30 mg (21%). IR (solid state): 2160 (νC≡C), 1921 (νC≡O),

1594, 1500, 1482, 1435, 1094 cm-1. 1H NMR (CD2Cl2): 3.22 (s, 4H, C5H4); 3.87 (s, 4H, C5H4); 3.98

(s, 4H, C5H4); 4.15 (s, 4H, C5H4); 4.32 (s, 4H, C5H4); 4.80 (s, 4H, C5H4); 6.95-7.65 (m, 100H, C6H5)

ppm. 31P{1H} NMR (CD2Cl2): 35.7 (s, RuPPh3); 36.6 (s, AuPPh3) ppm. Anal. Calcd. for

C166H126Au2Fe3O6P6Ru2: C 63.0%, H 4.0%, N 0.0%. Found: C 63.0%, H 3.9%, N 0.0%.

[Ru{C(C≡CPh)CHPh}{O2CFcC≡C(RuCl(dppe)2)}(CO)(PPh3)2] (16) (Attempted)

Trans-[RuCl2(dppe)2] (15 mg, 0.015 mmol) was dissolved in methylene chloride (10 mL) and

then [Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (50 mg, 0.0450 mmol), KPF6 (8 mg, 0.045

178

mmol) and a few drops of triethylamine were added. The solution was stirred at room

temperature for 18 hours after which time the solution was concentrated under reduced

pressure and filtered through a plug of celite. Addition of ethanol (10 mL) resulted in

precipitation of the crude product as a brown solid. 31P{1H} NMR (CD2Cl2): 35.7 (s, Ru(PPh3)2);

48.6 (s, dppe) ppm.

[Ru{C(C≡CPh)CHPh}{O2CFcCH=CH(RuCl(CO)(BTD)(PPh3)2)}(CO)(PPh3)2] (15)

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (62 mg, 0.056 mmol) was dissolved in

methylene chloride (25 mL) and [RuHCl(CO)(BTD)(PPh3)2] (40 mg, 0.057 mmol) added. The

mixture was stirred for 30 minutes after which time ethanol (25 mL) was added and the

product obtained as a dark red solid by rotary evaporation. This was washed with cold

methanol (5 mL), cold ethanol (5 mL) and petroleum ether (10 mL) and dried under vacuum.

Yield: 57 mg (56%). IR (solid state): 2162 (νC≡C) , 1918 (νC≡O), 1593, 1572, 1481, 1433, 1092 cm-

1 . 1H NMR (CD2Cl2): 3.08 (s, 2H, C5H4); 3.32 (s, 2H, C5H4); 3.52 (s, 2H, C5H4); 3.86 (s, 2H, C5H4);

5.41 (s, 1H, RuCH=CH); 5.60; 6.96-7.65 (m, 70H, C6H5); 7.82 (br, 1H, RuCH=CH); 7.95 (br, 2H, Ar-

H (BTD)) ppm. 31P{1H} NMR (CD2Cl2): 26.9 (s, HC=CHRu(PPh3)2); 35.4 (s, CO2Ru(PPh3)2 ) ppm.

Anal. Calcd. for C109H85ClFeN2O4P4Ru2S: C 67.6%, H 4.4%, N 1.5%. Found: C 67.7%, H 4.6%, N

1.6%.

[Ru{C(C≡CPh)CHPh}{O2CFcCH=CH(OsCl(CO)(BTD)(PPh3)2)}(CO)(PPh3)2] (16)

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (61 mg, 0.055 mmol) was dissolved in

methylene chloride (25 mL) and [OsHCl(CO)(BTD)(PPh3)2] (48 mg, 0.052 mmol) added. The

mixture was stirred for one hour after which time ethanol (20 mL) was added and the product

obtained as a dark purple solid by rotary evaporation. This was washed with cold methanol (10

mL), cold ethanol (10 mL) and petroleum ether (10 mL) and dried under vacuum. Yield: 50 mg

(50%). IR (solid state): 1921 (νC≡O), 1594, 1573, 1503, 1482, 1434, 1395, 1093 cm-1. 1H NMR

(CD2Cl2): 3.08 (s, 1H, C5H4); 3.28 (s, 1H, C5H4); 3.63 (s, 1H, C5H4); 4.00 (s, 1H, C5H4); 4.13 (s, 1H,

C5H4); 5.61 (m, 1H, OsCH=CH); 6.99-7.66 (m, 70H, C6H5); 8.07 (m, 1H, OsCH=CH); 8.46 (m, 1H,

179

Ar-H(BTD)) ppm. 31P{1H} NMR (CD2Cl2): -3.1 (s, Os(PPh3)2); 35.4 (s, Ru(PPh3)2) ppm. Anal. Calcd.

for C109H85ClFeN2O4OsP4RuS: C 64.6%, H 4.2%, N 1.4%. Found: C 64.7%, H 4.4%, N 1.5%.

[Ru{C(C≡CPh)CHPh}{O2CFcCH=CH(Ru(S2P(OEt)2)(CO)(PPh3)2)}(CO)(PPh3)2 (17) (Attempted)

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (50 mg, 0.0450 mmol) and

[RuH(S2P(OEt)2)(CO)(PPh3)2 (38 mg, 0.045 mmol) were dissolved in methylene chloride (20

mL) and stirred at room temperature for one hour. All solvent was removed under reduced

pressure to give the crude product as an off-white solid. 31P{1H} NMR (CD2Cl2): 36.0 (s,

Ru(PPh3)2); 94.4 (s, S2P(OEt)2) ppm.

[Ru{C(C≡CPh)CHPh}{O2CFc(p-methoxy-1-benzyl-1,2,3-triazolyl)}(CO)(PPh3)2 (18) (Test)

p-methoxybenzyl azide (1.5 mg, 0.009 mmol) was added to a suspension of

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (10 mg, 0.009 mmol), CuSO4∙5H2O (1 mol%),

sodium ascorbate (10 mol%) in methylene chloride (2 mL), tert-butyl alcohol (2 mL) and water

(2 mL) and stirred at room temperature for 18 hours. The mixture was washed with additional

methylene chloride (10 mL) and the combined organic extracts evaporated to dryness under

reduced pressure to yield the crude product as an orange solid. 1H NMR (CD2Cl2): 3.38 (pt, 1H,

C5H4); 3.73 (pt, 1H, C5H4); 3.83 (s, 2H, -OCH3); 3.99 (pt, 2H, C5H4); 4.11 (pt, 2H, C5H4); 5.48 (s, 1H,

triazole); 6.97 (m, 5H, C6H5); 7.08 (m, 3H, C6H5); 7.26-7.50 (m, 30H, C6H5); 7.64 (m, 15H, C6H5)

ppm. 31P{1H} NMR (CD2Cl2): 35.4 (s, Ru(PPh3)2) ppm.

[Ru{C(C≡CPh)CHPh}{O2CFc(2-azidoethylbenzene)}(CO)(PPh3)2 (19) (Test)

2-azidoethylbenzene (1.3 mg, 0.009 mmol) was added to a suspension of

[Ru{C(C≡CPh)CHPh}(O2CFcC≡CH)(CO)(PPh3)2 (10 mg, 0.009 mmol), CuSO4∙5H2O (1 mol%),

sodium ascorbate (10 mol%) in methylene chloride (2 mL), tert-butyl alcohol (2 mL) and water

(2 mL) and stirred at room temperature for 18 hours. The mixture was washed with additional

methylene chloride (10 mL) and the combined organic extracts evaporated to dryness under

reduced pressure to give the crude product as an orange solid. 1H NMR (CD2Cl2): 3.26 (t, 2H, Ar-

CH2, 3JHH = 4 Hz); 3.36 (s, 1H, C5H4); 3.68 (s, 2H, C5H4); 3.99 (s, 2H, C5H4); 4.11 (s, 2H, C5H4); 4.60

180

(t, 2H, Ar-CH2CH2, 3JHH = 4 Hz); 6.98 (m, 3H, C6H5); 7.08 (m, 3H, C6H5); 7.28-7.35 (m, 27H, C6H5);

7.66 (m, 13H, C6H5) ppm. 31P{1H} NMR (CD2Cl2): 35.4 (s, Ru(PPh3)2) ppm.

[Ru{{C(C≡CPh)CHPh}{O2CFcCH=CH(Ru(CO)(PPh3)2}}2(S2CNC4H8NCS2)] (20) (Attempted)

A solution of complex 15 (20 mg, 0.010 mmol) in methylene chloride (5 mL) was added to a

solution of [KS2CNC4H8NCS2K] (6 mg, 0.020 mmol) in methanol (5 mL) and stirred at room

temperature for two hours. The solution was then concentrated under reduced pressure to yield

precipitation of the crude product as an off-white solid which was then washed with water (5

mL), methanol (5 mL) and petroleum ether (5 mL) and dried under vacuum. 1H NMR (CD2Cl2):

2.74-2.78 (m, 3H, S2CNC4H8NCS2); 2.93-3.02 (m, 6H, S2CNC4H8CNS2); 3.22-3.33 (m, 8H, C5H4);

3.80 (m, 5H, C5H4); 5.20 (br, 1H, RuCH=CHFc); 5.58 (br, 2H, RuC(C≡CPh)CHPh); 6.99 (m, 4H,

C6H5); 7.08 (m, 3H, C6H5); 7.27-7.65 (m, 128H, C6H5) ppm. 31P{1H} NMR (CD2Cl2): 34.0 (s); 35.4

(s, Ru(PPh3)2); 39.2 (s, NCS2Ru(PPh3)2) ppm.

[Ru{{C(C≡CPh)CHPh}(CO)(PPh3)2{O2CFcCH=CH(Ru(CO)(PPh3)2}2{O2CFcCO2}] (21) (Attempted)

A solution of complex 15 (20 mg, 0.010 mmol) in methylene chloride (5 mL) was added to a

solution of 1,1’-ferrocenedicarboxylic acid (5.5 mg, 0.020 mmol) and triethylamine (few drops)

in methylene chloride (5 mL) and methanol (10 mL) and stirred at room temperature for two

hours. The solution was concentrated under reduced pressure to yield precipitation of the crude

product as an orange solid which was collected by filtration, washed with methanol (5 mL) and

petroleum ether (5 mL) and dried under vacuum.

5.4 Chapter 4 Compounds

1-(4-Boc-piperazine)thioctic amide (23)

A solution of N,N’-dicyclohexylcarbodiimide (1.21 g, 5.90 mmol) and 4-

(dimethylamino)pyridine (0.18 g, 1.50 mmol) in dry methylene chloride (10 mL) was added

dropwise to a solution of thioctic acid (1.0 g, 4.90 mmol) and 1-boc-piperazine (1.0 g, 5.40

mmol) in dry methylene chloride under N2 at 0 °C. After complete addition the mixture was

181

warmed to room temperature and stirred for 45 hours over which time the precipitation of a

colourless solid was observed. The precipitate was removed by filtration and the filtrate washed

with water (3 x 30 mL), dried over magnesium sulfate and evaporated to dryness. The crude

product was further purified by column chromatography eluting with diethyl ether (RF = 0.33)

to yield the desired product as a crystalline yellow solid. Yield: 0.50 g (26%). IR (solid state):

2979, 2927, 2863, 1685 (νC=O), 1637 (νC=O), 1420, 1237, 1165 cm-1. 1H NMR (CDCl3): 1.44 (s, 1H,

C(O)CH2CH2CH2); 1.48 (s, 9H, -CO2C(CH3)3); 1.54 (m, 1H, C(O)CH2CH2CH2); 1.64-1.78 (m, 4H,

C(O)CH2CH2CH2CH2); 1.89-1.97 (m, 1H, CH2(S)HCHCH(S)); 2.35 (t, 2H, C(O)CH2, 3JHH = 8.0 Hz);

2.44-2.52 (m, 1H, CH2(S)HCHCH(S)); 3.10-3.23 (m, 2H, CH2(S)HCHCH(S)); 3.41-3.45 (m, 6H, -

NC4H8N-); 3.56-3.63 (m, 3H, CH2(S)CH2CH(S) and –NC4H8-) ppm. 13C{1H} NMR (CDCl3): 171.4 (s, -

CONC4H8N-) , 154.6 (s, NCO2tBu), 80.3, 56.4, 45.4, 41.4, 40.3, 38.5, 34.8, 33.1, 29.1, 28.4, 24.9

ppm. MS (ES +ve) m/z (abundance) = 397 (100) [M + Na]+. Anal. Calcd. for C17H30N2O3S2: C

54.5%, H 8.0%, N 7.5%. Found: C 54.6%, H 8.1%, N 7.4%.

(1-Piperazine)thioctic amide (24)

Trifluoroacetic acid (5 mL, 65.3 mmol) was added to a solution of 1-(4-boc-piperazine) thioctic

amide (0.84 g, 2.15 mmol) in methanol (2 mL) and the solution stirred for 96 hours. The solvent

and excess trifluoroacetic acid were removed under reduced pressure using an N2(l) trap. The

residue was washed with methanol (3 x 10 mL) and then dissolved in methylene chloride and

washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic extracts

were combined and dried under vacuum to yield a dark yellow oil. Yield 0.37 g (43%). IR (solid

state): 2932, 2830, 1674 (νC=O), 1634 (νC=O), 1433, 1200, 1130, 1025 cm-1. 1H NMR (CD3OD):

1.45-1.78 (m, 5H, C(O)CH2CH2CH2CH2); 2.07 (br, 1H, CH2(S)HCHCH(S)); 2.50 (br, 2H, C(O)CH2);

2.91 (br, 2H, CH2(S)HCHCH(S)); 3.25 (br, 1H, CH2(S)HCHCH(S)); 3.33 (br, 2H, NC4H8N); 3.85 (br,

3H, NC4H8N) ppm. 13C{1H} NMR (CD3OD): 56.9, 38.1, 33.9, 32.3, 26.4, 24.7 ppm. MS (ES +ve) m/z

(abundance) = 275 (100) [M + H]+. Anal. Calcd. for C12H23N2OS2: C 52.4%, H 8.4%, N 5.1%.

Found: C 42.1%, H 6.8%, N 6.4%.

182

1-(4-Thioctic amide)piperazinyldithiocarbamato-bis(diphenylphosphinomethane)-ruthenium(II)

(25)

1-Piperazine thioctic amide (71 mg, 0.259 mmol) was suspended in methylene chloride (2 mL)

and triethylamine (51 μL, 0.363 mmol) added. The suspension was stirred for five minutes and

then carbon disulfide (22 μL, 0.363 mmol) added and the suspension stirred for a further five

minutes. A solution of cis-[RuCl2(dppm)2] (236 mg, 0.250 mmol) in methanol (2 mL) and

methylene chloride (4 mL) was then added, followed immediately by sodium tetrafluoroborate

(46 mg, 0.419 mmol). The mixture was stirred for four hours and then all solvent removed

under reduced pressure. The resultant residue was dissolved in the minimum volume of

methylene chloride and filtered through celite. Ethanol (25 ml) was added and the filtrate

concentrated by rotary evaporation to yield the product as an off-white solid. This was washed

with petroleum ether (2 x 10 mL) and vacuum dried. Yield: 102 mg (34%). 1H NMR (CD2Cl2):

1.45-1.80 (br, 8H, C(O)CH2CH2CH2CH2 and CH2(S)HCHCH(S)); 2.06 (br, 2H, CH2(S)HCHCH(S));

2.41 (br, 2H, C(O)CH2); 2.86 (br, 2H, CH2(S)HCHCH(S)); 3.34 (br, 2H, CH2(S)CH2CH(S)); 3.66 (br,

2H, NC4H8N); 4.54 (br, 2H, dppm); 4.99 (br, 2H, dppm); 6.52, 6.94-7.70 (m, 40H, C6H5) ppm.

31P{1H} NMR (CD2Cl2): -18.4 (m, dppm); -5.01 (m, dppm) ppm. MS (ES +ve) m/z (abundance) =

1219 (100) [M]+. Anal. Calcd. for C63H65BF4N2OP4RuS4: C 57.9%, H 5.0%, N 2.1%. Found: C

57.2%, H 4.0%, N 2.5%.

Au@1-(4-thioctic amide)piperazinyldithiocarbamatobis(diphenylphosphinomethane)-

ruthenium(II) (NP3)

Complex 25 (69 mg, 0.0566 mmol) and HAuCl4.xH2O (21 mg, 0.0618 mmol) were suspended in

dry methanol (50 mL). A solution of sodium borohydride (17 mg, 0.449 mmol) in methanol (30

mL) was added dropwise over 30 minutes. The solution changed from yellow to dark purple as

the nanoparticles formed. The solution was stirred for 15 minutes after which time the solvent

was removed under reduced pressure and the resultant black powder suspended in ethanol (25

mL) and filtered through celite. The solvent was removed entirely a second time and the black

powder triturated in water (3 x 10 mL), collected by centrifugation and dried under vacuum. 1H

183

NMR (CD2Cl2): 1.12 (br, 2H); 1.41-1.83 (br, 8H, C(O)CH2CH2CH2CH2); 2.06 (br, 2H,

CH2(S)HCHCH(S)); 2.51 (br, 2H, C(O)CH2); 2.80 (br, 2H, CH2(S)HCHCH(S)); 3.32 (br, 2H,

CH2(S)CH2CH(S)); 4.50 (br, 2H, dppm); 5.00 (br, 2H, dppm); 6.52, 6.91-7.70 (m, 40H, C6H5) ppm.

31P{1H} NMR (CD2Cl2): -18.0 (m, dppm); -5.06 (m, dppm) ppm. TEM analysis of 100

nanoparticles gave a size of 3.9 ± 1.4 nm. EDS indicated the presence of gold and sulfur.

1-(4-Thioctic amide)piperazinyldithiocarbamato-bis(triphenylphosphine)palladium(II) (26)

(Attempted)

A solution of [PdCl2(PPh3)2] (20 mg, 0.028 mmol) and NaBF4 (4.3 mg, 0.039 mmol) in methylene

chloride (5 mL) and methanol (5 mL) was added to a solution of thioctic amide 24 (7.7 mg,

0.028 mmol), triethylamine (5 μL, 0.034 mmol) and carbon disulfide (2 μL, 0.034 mmol) in

methylene chloride (5 mL) and methanol (5 mL). The solution was stirred at room temperature

for four hours and then all solvent was removed under reduced pressure. The residue was

dissolved in the minimum volume of methylene chloride and filtered through a plug of celite

before adding ethanol to the filtrate and concentrating by rotary evaporation to yield

precipitation of the crude product as a yellow solid. 31P{1H} NMR (CD2Cl2): 30.5 (s, Pd(PPh3)2)

ppm.

1-(4-Thioctic amide)piperazinyldithiocarbamato(triphenylphosphine)gold(I) (27) (Attempted)

A solution of [AuCl(PPh3)] (20 mg, 0.040 mmol) in methylene chloride (10 mL) was added to a

solution of thioctic amide 24 (11 mg, 0.040 mmol), triethylamine (7μL, 0.048 mmol) and carbon

disulfide (3μL, 0.048 mmol) in methylene chloride (10 mL). The reaction vessel was covered

entirely in aluminium foil and kept in the dark. After stirring at room temperature for two hours

all solvent was removed under reduced pressure and the off-white residue washed with ethyl

acetate (10 mL) and methanol (10 mL) and dried under vacuum. 31P{1H} NMR (CD2Cl2): 36.2 (s,

Au(PPh3)) ppm.

184

1-(4-Thioctic amide)piperazinyldithiocarbamato-carbonylhydridobis(triphenylphosphine)

ruthenium(II) (28) (Attempted)

A solution of [RuHCl(CO)(PPh3)3] (20 mg, 0.021 mmol) in methylene chloride (10 mL) was

added to a solution of thioctic amide 24 (5.8 mg, 0.021 mmol), triethylamine (4μL, 0.025 mmol)

and carbon disulfide (2μL, 0.025 mmol) in methylene chloride (10 mL) and methanol (5 mL).

The solution was stirred at room temperature for 10 minutes and then all solvent was removed

under reduced pressure to yield the crude product as a pale yellow solid. 31P{1H} NMR (CD2Cl2):

-5.6 (s, PPh3); 27.5 (s, O=PPh3); 50.2 (s, Ru(PPh3)2) ppm.

1-(2-Boc-ethylenediamine)thioctic amide (29)

1-boc-ethylenediamine (1.80 g, 11.0 mmol), thioctic acid (2.30 g, 11.0 mmol) and triethylamine

(2.2 mL, 15.0 mmol) were dissolved in dry methylene chloride (50 mL) under N2 and cooled in

an ice bath. A solution of HBTU (4.60 g, 12.0 mmol) in methylene chloride (200 mL) was added

dropwise over a period of 45 minutes. The reaction was stirred at 0 °C for one hour before

warming to room temperature and stirring for 18 hours. All solvent was removed under

reduced pressure and the residue purified by column chromatography eluting with diethyl

ether/methanol (95:5)to yield the desired product as a crystalline yellow solid. Yield: 2.50 g

(66%). IR (solid state): 3350, 3325, 2941, 1685 (νC=O), 1643 (νC=O), 1533 cm-1. 1H NMR (CDCl3):

1.45 (s, 9H, CO2C(CH3)3); 1.48 (m, 2H, C(O)CH2CH2CH2); 1.68 (m, 4H, C(O)CH2CH2CH2CH2); 1.92

(m, 1H, CH2(S)HCHCH(S)); 2.20 (m, 2H, C(O)CH2); 2.48 (m, 1H, CH2(S)HCHCH(S)); 3.16 (m, 2H,

CH2(S)CH2CH(S)); 3.28 (m, 2H,CH2NHBoc); 3.35 (m, 2H, CH2CH2NHBoc); 3.57 (m, 1H,

CH2(S)CH2CH(S)); 5.28 (br, 1H, NHBoc ); 6.33 (br, 1H, HN(CH2)2NHBoc) ppm. 13C{1H} NMR

(CDCl3): 173.5 (s, CONR), 79.7, 77.4, 77.1, 76.8, 56.4, 40.8, 40.2, 38.5, 36.4, 34.6, 31.0, 28.9, 28.4,

25.4 ppm. MS (ES +ve) m/z (abundance) = 371 (100) [M + Na]+, 349 (25) [M + H]+. Anal. Calcd.

for C15H28N2O3S2: C 51.7%, H 8.1, N 8.0%. Found: C 51.9%, H 8.2%, N 7.9%.

185

1-(2-Boc-propylenediamine)thioctic amide (30)

1,2-propylenediamine (0.5 mL, 3.0 mmol) and thioctic acid (0.6 g, 3.0 mmol) were dissolved in

dry methylene chloride (30 ml) under N2 and cooled in an ice bath. A solution of N,N’-

dicyclohexylcarbodiimide (0.54 g, 3.5 mmol) and 4-(dimethylamino)pyridine (0.11 g, 0.9 mmol)

in dry methylene chloride (30 mL) was added dropwise over a period of 30 minutes. The

reaction was stirred at 0 °C for one hour and then warmed to room temperature and stirred for

18 hours. All solvent was removed under reduced pressure and the residue dissolved in

acetonitrile (30 mL) and stored at -5 °C overnight. After filtration, the crude product was

obtained as a yellow crystalline solid which was purified further by column chromatography,

eluting with diethyl ether/methanol (95:5). Yield: 0.24 g (22%). IR (solid state): 3342, 3312,

2978, 2929, 1683 (νC=O), 1641 (νC=O), 1537 cm-1. 1H NMR (CDCl3): 1.17 (d, 3H,

HNCH(CH3)CH2NHBoc, 3JHH = 6.7 Hz); 1.24 (t, 1H, CH2NHBoc, 3JHH = 7.0 Hz); 1.46 (s, 9H,

COC(CH3)3); 1.63 (s, 3H, C(O)CH2CH2CH2CH2): 1.70 (m, 3H, C(O)CH2CH2CH2CH2); 1.93 (m, 1H,

CH2(S)HCHCH2(S)); 2.17 (m, 2H, C(O)CH2); 2.48 (m, 1H, CH2(S)HCHCH2(S)); 3.17 (m, 2H,

CH2(S)CH2CH2(S)); 3.52 (s, 1H, C(O)NHCH(CH3)); 3.60 (m, 1H, C(O)NHCH); 4.93 (br, 1H, NHBoc);

6.10 (br, 1H, NHCO) ppm. 13C{1H} NMR (CDCl3): 77.4, 73.0, 76.7, 56.4, 46.9, 45.7, 40.2, 38.5, 36.6,

34.6, 28.9, 28.4, 25.4, 18.3 ppm. MS (ES +ve) m/z (abundance) = 363 (100) [M + H]+. Anal. Calcd.

for C16H30N2O3S2: C 53.0%, H 8.3%, N 7.7%. Found: C 52.9%, H 8.4%, N 7.7%.

(1,2-Ethylenediamine)thioctic amide (31)

1-(2-boc-ethylenediamine)thioctic amide (2.50 g, 7.20 mmol) was dissolved in trifluoroacetic

acid (7.0 mL, 92.0 mmol) and stirred for five days. All trifluoroacetic acid was removed under

reduced pressure using an N2(l) trap. The resultant residue was dissolved in methylene chloride

(10 mL) and washed with aqueous saturated sodium hydrogen carbonate (3 x 10 mL). The

organic layer was evaporated to dryness to yield the product as a yellow oil. Yield: 1.40 g (80%).

1H NMR (CD3OD): 1.35-1.68 (m, 5H, C(O)CH2CH2CH2CH2); 1.91 (m, 1H, CH2(S)HCHCH(S)); 2.05

(br, 1H, C(O)CH2CH2CH2CH2); 2.27 (t, 2H, C(O)CH2, 3JHH = 7.5 Hz); 2.48 (m, 1H, CH2(S)HCHCH(S));

186

2.87 (br, 1H, CH2(S)CH2CH(S)); 3.05-3.23 (m, 2H, CH2(S)CH2CH(S)); 3.34 (m, 2H, H2NCH2); 3.46

(m, 1H, C(O)NHCH2) ppm.

(1,2-Propylenediamine)thioctic amide (32)

1-(2-Boc-propylenediamine)thioctic amide (140 mg, 0.400 mmol) was dissolved in

trifluoroacetic acid (5 mL, 66.0 mmol) and stirred for five days. All trifluoroacetic acid was

removed under reduced pressure using an N2(l) trap. The resultant residue was dissolved in

methylene chloride (10 mL) and washed with aqueous sodium hydrogen carbonate (3 x 10 mL).

The organic layer was evaporated to dryness to yield the product as a yellow oil. Yield: 94 mg

(95%). 1H NMR (CD3OD): 1.25 (d, 3H, C(O)NHCH(CH3), 3JHH = 6.6 Hz); 1.33 (m, 1H, CH2NH2);

1.48-1.67 (m, 5H, C(O)CH2CH2CH2CH2); 1.91 (m, 1H, CH2(S)HCHCH(S)); 2.24 (m, 2H, C(O)CH2);

2.46 (m, 1H, CH2(S)HCHCH(S)); 2.92 (br, 1H, CH2(S)CH2CH(S)); 3.15 (m, 2H, CH2(S)CH2CH(S));

3.58 (m, 1H, C(O)NHCH(CH3) ); 4.15 (br, 1H, -NH2) ppm.

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