Synthesis and Kinetics of Novel Ionic Liquid Soluble Hydrogen Atom Transfer Reagents

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Synthesis and kinetics of novel ionic liquid soluble hydrogen atom transfer reagents

Thomas William Garrard

Submitted in total fulfilment of the requirements of the degree Doctor of Philosophy

June 2018

School of Chemistry The University of Melbourne

Produced on archival quality paper

ORCID: 0000-0002-2987-0937

Abstract The use of radical methodologies has been greatly developed in the last 50 years, and in an effort to continue this progress, the reactivity of radical reactions in greener alternative solvents is desired. The work herein describes the synthesis of novel hydrogen atom transfer reagents for use in radical chemistry, along with a comparison of rate constants and Arrhenius parameters.

Two tertiary thiol-based hydrogen atom transfer reagents, 3-(6-mercapto-6-methylheptyl)-1,2- dimethyl-3H-imidazolium tetrafluoroborate and 2-methyl-7-(2-methylimidazol-1-yl)heptane-2-thiol, have been synthesised. These are modelled on traditional thiol reagents, with a six-carbon chain with an imidazole ring on one end and tertiary thiol on the other. 3-(6-mercapto-6-methylheptyl)- 1,2-dimethyl-3H-imidazolium tetrafluoroborate comprises of a charged imidazolium ring, while 2- methyl-7-(2-methylimidazol-1-yl)heptane-2-thiol has an uncharged imidazole ring in order to probe the impact of salt formation on radical kinetics. The key step in the synthesis was addition of thioacetic acid across an alkene to generate a tertiary thioester, before deprotection with either

LiAlH4 or aqueous NH3. Arrhenius plots were generated to give information on rate constants for H-atom transfer to a primary alkyl radical, the 5-hexenyl radical, in ethylmethylimidazolium bis(trifluoromethane)sulfonimide. A comparison of the results from the Arrhenius studies for both charged and uncharged t-thiols reveal no significant difference between rate constants (1.16 × 107 M-1 s-1 vs. 1.11 × 107 M-1 s-1 respectively), pre-exponential factors or activation energies. When comparing to the commonly used t-BuSH, the rate constant at 25 °C for the uncharged 2-methyl-7-(2-methylimidazol-1-yl)heptane-2-thiol is essentially identical within experimental error, while the rate constant at 25 C for the charged 3-(6-mercapto-6-methylheptyl)-1,2-dimethyl-3H- imidazolium tetrafluoroborate is marginally faster than for t-BuSH under the same conditions.

An IL-supported organostannane 1-(6-diphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium tetrafluoroborate was also synthesised, modelled on the commonly used triphenylstannane reagent. Literature precedence exists for similar tin hydride compounds, however, the synthetic route involved steps with reproducibility issues. The synthesis was dramatically improved by utilising a hydrostannylation reaction, with other steps optimised to allow easier synthesis and purification. An Arrhenius plot was also generated for 1-(6-diphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium tetrafluoroborate in ethylmethylimidazolium bis(trifluoromethane)sulfonimide and compared to the traditional tributyl and triphenylstannane Arrhenius parameters. The rate constant for hydrogen atom transfer from this novel stannane to a primary alkyl radical at 25 C was found to be

5.01 × 106 M-1 s-1. Similar to the thiol salt, this result is marginally faster than the equivalent result for the common reagent, tributylstannane.

Declaration This is to certify that: (i) the thesis comprises only my original work towards the PhD;

(ii) due acknowledgement has been made in the text to all other materials used;

(iii) the thesis is less than 100,000 words in length, exclusive of tables, bibliographies and appendices.

Thomas Garrard

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Preface The kinetic work regarding the 6,6-diphenyl-5-hexenyl radical 83 in Chapter 3, Section 3.1.1, including both preliminary cyclisation rate constants and hydrogen atom transfer rate constants from p-thiocresol, were performed by Dr Amber Hancock at the University of Melbourne.

Acknowledgements First and foremost, I wish to thank my supervisor Jonathan, who allowed me freedom in my work but gave guidance, advice and encouragement any time I needed it. Thanks also to the other members of my advisory panel, Uta and Craig, who have both given critical advice at various times.

Further to rest of the White group who make coming into work more enjoyable, in and out of the lab. Friday afternoon drinks or lunch at the pub was often the break I needed and helped keep my sanity.

The various support staff within the Bio21 Institute have also been instrumental to my success. Hamish for maintaining the NMR cave and teaching me how to run NMR on a variety of nuclei, Nick for constantly fixing the mass spec, and the store staff for ensuring solvents and consumables were never more than a few minutes away. David and Eleonore from the admin team for providing me with casual employment and a travel scholarship.

Thanks to my family and friends for their support, often listening to me complain without really understanding what I am talking about. The support and encouragement from those closest to me has been enormous, and I am especially grateful for their guiding hand in the latter stages of this PhD.

Table of contents

ABSTRACT I

DECLARATION III

PREFACE IV

ACKNOWLEDGEMENTS V

TABLE OF CONTENTS VI

TABLE OF FIGURES IX

TABLE OF SCHEMES XII

TABLE OF TABLES XIV

LIST OF ABBREVIATIONS XV

1 INTRODUCTION 1

1.1 Free radicals 1 1.1.1 Hydrogen atom transfer 2

1.2 Laboratory solvents 4 1.2.1 Ionic liquids 6 1.2.2 Task-specific ionic liquids 11

1.3 Free radicals in ionic liquids 13

1.4 Research objectives 15

2 DESIGN AND SYNTHESIS OF IONIC LIQUID SOLUBLE HYDROGEN ATOM TRANSFER REAGENTS 16

2.1 Tertiary thiol-based reagents 16 2.1.1 Introduction 16 2.1.2 Retrosynthesis 21 2.1.3 Forming functionalised tertiary carbon 22 2.1.4 Halogenation of tertiary alcohol 31 24 2.1.5 Thioester addition 30 2.1.6 Imidazole methylation 33 2.1.7 Attempted deacetylation of imidazolium t-thiol 48 34 2.1.8 Deacetylation of uncharged t-thiol 39 36 2.1.9 Methylation to form charged t-thiol 45 38 2.1.10 Further attempts toward deacetylation of imidazolium t-thiol 48 42

2.1.11 Conversion to the BF4 salt 27 44

2.2 Stannane 47 2.2.1 Introduction to organotin chemistry 47 2.2.2 Retrosynthesis of target compound 51 2.2.3 Preparation using literature method 51 2.2.4 Other methods attempted 55 2.2.5 Hydrostannylation 59 2.2.6 Functionalisation of terminal end 60 2.2.7 Salt formation 61 2.2.8 Synthesis of tin chloride 66 63

- 2.2.9 Conversion to the BF4 salt 65 2.2.10 Preparation of tin hydride 60 66

2.3 PTOC ester 68 2.3.1 Introduction to radical precursors 68 2.3.2 Synthesis 69

2.4 Conclusions 71

3 COMPETITION KINETICS 72

3.1 Introduction 72 3.1.1 Explorations into similar radical reactions 75

3.2 5-Hexenyl radical 85 reaction and IL used 79

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3.3 Response factor 81

3.4 General method 84

3.5 Tertiary thiol 46 86 3.5.1 Concentration profile 86 3.5.2 Arrhenius expression 89

3.6 Tertiary thiol salt 27 91 3.6.1 Concentration profile 91 3.6.2 Arrhenius expression 93

3.7 Stannane 60 95 3.7.1 Concentration profile 95 3.7.2 Arrhenius expression 97

3.8 Conclusions 99

4 EXPERIMENTAL 101

4.1 Instrumentation 101

4.2 General method for kinetic experiments 102

4.3 Experimental procedures 103 4.3.1 3-(6-Mercapto-6-methylheptyl)-1,2-dimethyl-3H-imidazolium tetrafluoroborate (27) 103 4.3.2 Ethyl 6-bromohexanoate (29) 103 4.3.3 7-Bromo-2-methylheptan-2-ol (30) 104 4.3.4 2-Methyl-7-(2-methylimidazol-1-yl)heptan-2-ol (31) 104 4.3.5 2-Bromo-2-methyl-7-(2-methylimidazol-1-yl)heptane (32) 104 4.3.6 3-(6-Bromo-6-methylheptyl)-1,2-dimethyl-3H-imidazolium bromide 105 4.3.7 3-(6-Bromo-6-methylheptyl)-1,2-dimethyl-3H-imidazolium iodide (34) 105 4.3.8 1,6-Dibromo-6-methylheptane (35) 106 4.3.9 2-Methyl-1-(6-methylhept-5-enyl)-1H-imidazole (major, 36) and 2-methyl-1-(6-methylhept-6- enyl)-1H-imidazole (minor, 36-2) 106 4.3.10 2,3-Dimethyl-1-(6-methylhept-5-enyl)-3H-imidazolium iodide (38) 107 4.3.11 Thioacetic acid S-[1,1-dimethyl-6-(2-methylimidazol-1-yl)hexyl] ester (39) 108 4.3.12 6-Bromohexanethioic acid O-ethyl ester (40) 108 4.3.13 2,3-Bis(tributyltinoxy) butane (43) 109

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4.3.14 4,5-Dimethyl-[1,3]dioxolane-2-thione (44) 109 4.3.15 3-(6-Mercapto-6-methylheptyl)-1,2-dimethyl-3H-imidazolium iodide (45) 110 4.3.16 2-Methyl-7-(2-methylimidazol-1-yl)heptane-2-thiol (46) 111 4.3.17 3-(6-Acetylsulfanyl-6-methylheptyl)-1,2-dimethyl-3H-imidazolium iodide (48) 112 4.3.18 1-(6-Diphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium tetrafluoroborate (60) 112 4.3.19 1-(6-Chlorohexyl)-2-methylimidazole (63) 113 4.3.20 Triphenylstannane 113 4.3.21 2-Methyl-1-(6-triphenylstannyl-hexyl)-3H-imidazole (64) 114 4.3.22 1-(6-Triphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium iodide (65) 115 4.3.23 1-(6-Chlorodiphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium iodide (66) 116 4.3.24 1-(6-Iodohexyl)-2-methylimidazole (67) 116 4.3.25 2-(6-chlorohexyloxy)-tetrahydro-2H-pyran 117 4.3.26 2-(6-iodohexyloxy)-tetrahydro-2H-pyran (70) 117 4.3.27 Triphenyl-[6-tetrahydropyran-2-yloxy-hexyl]-stannane (71) 118 4.3.28 (6-Hydroxyhexyl)triphenylstannane (73) 119 4.3.29 (6-methanesulfonyloxyhexyl)triphenylstannane 119 4.3.30 (6-iodohexyl)triphenylstannane (74) 120 4.3.31 1-(6-Chlorodiphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium tetrafluoroborate (76) 120 4.3.32 Diethyl (4-pentenyl)malonate (79) 121 4.3.33 6-Heptenoic acid (80) 121 4.3.34 Hept-6-enoic acid 2-thioxo-2H-pyridin-1-yl ester (82) 122

5 REFERENCES 123

6 APPENDIX 137

6.1 Response factor data 137

6.2 Data for t-thiol 46 139

6.3 Data for t-thiol salt 27 143

6.4 Data for stannane 60 147

Table of figures

Figure 1-1 Radical synthesis of Ebselen (1)7 ...... 1

Figure 1-2 Radical synthesis of taxane frameworks8 ...... 2 Figure 1-3 Radical synthesis of (±)-spongi-16-one (4)9 ...... 2 Figure 1-4 Radical synthesis of (±)-hirsutene (5)17 ...... 3 Figure 1-5 Radical synthesis of (±)-morphine (6, R = H) and (±)-codeine (7, R = Me)18 ...... 4 Figure 1-6 Quaternary ammonium salts mixed with glycerol form DESs43, 44 ...... 6 Figure 1-7 Common ions used in ILs ...... 7 Figure 1-8 First intentionally synthesised IL 852 and first air/water stable IL 953 ...... 7 Figure 1-9 Substitution and elimination pathways during formation of ILs79...... 9 Figure 1-10 TSILs for ATRP 10107 and radiolabelling 11108 ...... 12 Figure 1-11 TSIL 12 for heavy metal extraction109 ...... 12 Figure 2-1 Naturally occurring thiols ...... 16 Figure 2-2 Pharmaceutical drugs containing thiols140-142 ...... 17 Figure 2-3 Example of polarity reversal catalysis170 ...... 19 Figure 2-4 Thiol-containing ionic liquids175, 177-179 ...... 20 Figure 2-5 Retrosynthetic pathway towards tertiary thiol 27 ...... 22 Figure 2-6 Comparison of 1H NMR spectra between thioacetate 39 and t-thiol 46 ...... 37 Figure 2-7 Proposed zwitterion formation ...... 38 Figure 2-8 1H NMR spectra of isolated elimination products 36 and 38 compared to starting t-thiol 46 ...... 39 Figure 2-9 Example of sulfonium formation and elimination216, 217 ...... 41 Figure 2-10 Alternative methylating agents and corresponding anions ...... 42 Figure 2-11 Dithiothreitol ...... 43 Figure 2-12 1H NMR spectra of charged thioacetate 48 starting material and charged t-thiol 45 product ...... 43 Figure 2-13 Organotin drugs for cancer treatment247, 248 ...... 48 Figure 2-14 Water soluble organotin derivatives254, 255 ...... 49 Figure 2-15 Organotin complex used for biofuel production in ILs262 ...... 49 Figure 2-16 Targeted IL-supported stannane 60 ...... 51 Figure 2-17 Halide exchange between tin and anion halides ...... 64 Figure 2-18 HRMS of tin chloride 66 and tin iodide 75 ...... 64 Figure 2-19 HRMS of tin hydride 60 ...... 67 Figure 2-20 Acyloxyl radical trapped by t-BuSH prior to decarboxylation303 ...... 68 Figure 3-1 Radical chain mechanism ...... 72 Figure 3-2 Radical clocks and their rearrangement rate constants at 25 °C15, 299 ...... 73 Figure 3-3 Radical scavenging by PTOC ester312 ...... 74 Figure 3-4 Cyclisation of 6,6-diphenyl-5-hexenyl radical (83) ...... 75

Figure 3-5 Transient absorption spectra monitoring growth of cyclised product 84 in BMIM NTf2 ...... 76

Figure 3-6 Hydrogen transfer from p-thiocresol to the 6,6-diphenyl-5-hexenyl radical (83) ...... 78 Figure 3-7 Generation of 5-hexenyl radical (85) and pathways to final products (HAT step eliminated for clarity) ...... 79

Figure 3-8 Ethylmethylimidazolium bis(trifluoromethane)sulfonimide, EMIM NTf2 ...... 80 Figure 3-9 Response factor calibration curve for 1-hexene (88) and methylcyclopentane (86) ...... 81 Figure 3-10 Response factor calibration curve for methylcyclopentane (86) and 1-hexene (88) ...... 83

Figure 3-11 Spot kH values for H-transfer from t-thiol 46, at a single concentration and temperature, to

the 5-hexenyl radical in 100 % EMIM NTf2 ...... 87 Figure 3-12 Concentration profile (10× to 50×) for H-transfer from t-thiol 46 to the 5-hexenyl radical in

100 % EMIM NTf2 at 25 °C ...... 88

Figure 3-13 Arrhenius study for H-transfer from t-thiol 46 to the 5-hexenyl radical in 100 % EMIM NTf2 at various temperatures ...... 89

Figure 3-14 Spot kH values for H-transfer from t-thiol 27, at a single concentration and temperature, to

the 5-hexenyl radical in 100 % EMIM NTf2 ...... 91 Figure 3-15 Concentration profile (10× to 50×) for H-transfer from t-thiol 27 to the 5-hexenyl radical in

100 % EMIM NTf2 at 30 C ...... 92 Figure 3-16 Arrhenius study for H-transfer from IL t-thiol 27 to the 5-hexenyl radical in 100 % EMIM

NTf2 at various temperatures ...... 93

Figure 3-17 Spot kH for H-transfer from stannane 60, at a single concentration and temperature, to the

5-hexenyl radical in 100 % EMIM NTf2 ...... 95 Figure 3-18 Concentration profile (10× to 50×) for H-transfer from stannane 60 to the 5-hexenyl radical

in 100 % EMIM NTf2 at 26.13 C ...... 96 Figure 3-19 Arrhenius plot for H-transfer from stannane 60 to the 5-hexenyl radical in 100 % EMIM

NTf2 at various temperatures ...... 97

Table of schemes

111 Scheme 1-1 TSIL 13 used for CO2 capture ...... 13 Scheme 2-1 Reversibility and isomerisation following thiyl radical addition to an alkene160 ...... 18 Scheme 2-2 Thiyl radical reaction with PTOC esters162 ...... 19 Scheme 2-3 Forming a tertiary alcohol ...... 23 Scheme 2-4 Conversion of a tertiary alcohol to a tertiary bromide ...... 24 Scheme 2-5 Dibromide 35 formation and attempted substitution ...... 25 Scheme 2-6 Single step substitution and elimination with dibromide 35 ...... 26 Scheme 2-7 Elimination of tertiary alcohol 31 ...... 27 Scheme 2-8 Dibromide substitution and elimination to give charged products 37 and 37-2 ...... 27 Scheme 2-9 Unsuccessful alkene bromination attempt ...... 28 Scheme 2-10 Methylation to form charged alkene product 38...... 28 Scheme 2-11 Bromination of charged alkene 38 to give a tertiary bromide 34 ...... 29 Scheme 2-12 Thioester addition across alkene 36 ...... 30 Scheme 2-13 Attempted Grignard reaction pathway on thionester 40 ...... 31 Scheme 2-14 Attempts toward thiocarbonate 44 ...... 32

Scheme 2-15 Attempted H2S addition to alkene 38 ...... 33 Scheme 2-16 Potential thioether product following methylation ...... 33 Scheme 2-17 Formation of charged thioester 48 following methylation ...... 34 Scheme 2-18 Unsuccessful deacetylation reactions ...... 34 Scheme 2-19 Deacetylation reaction of uncharged thioacetate 39 ...... 36 Scheme 2-20 Unsuccessful imidazole methylation of tertiary thiol 46 ...... 38 Scheme 2-21 Elimation products following imidazole methylation attempts of 46 ...... 39 Scheme 2-22 Successful deacetylation of charged thioacetate 48 ...... 42

Scheme 2-23 Conversion to the BF4 salt ...... 44 Scheme 2-24 Legoupy’s synthesis of IL-supported organotin hydride 59263-268 ...... 50 Scheme 2-25 Substitution reaction to form primary chloride 63 ...... 51 Scheme 2-26 Substitution of primary chloride to insert a triphenylstannyl moiety ...... 52 Scheme 2-27 Imidazole methylation to give charged organotin derivative ...... 53 Scheme 2-28 Formation of tin chloride 66 following protodestannylation ...... 54 Scheme 2-29 Attempted Finkelstein reaction ...... 55 Scheme 2-30 Attempted Grignard reaction to insert triphenylstannyl moiety ...... 56 Scheme 2-31 Formation of difunctionalised hexane chain 70 ...... 56 Scheme 2-32 Unsuccessful Grignard reaction using THP-ether 70 ...... 57 Scheme 2-33 Unsuccessful substitution attempts using lithiation or zinc dust ...... 58 Scheme 2-34 Hydrostannylation of 5-hexen-1-ol (72) ...... 59

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Scheme 2-35 Unsuccessful hydrostannylation attempts from Legoupy and co-workers266 ...... 60 Scheme 2-36 Two step conversion of primary alcohol to iodide ...... 60 Scheme 2-37 Imidazole substitution and methylation from (6-iodohexyl)tin compound 74 ...... 61 Scheme 2-38 Single step formation of IL-supported organotin 65 ...... 62 Scheme 2-39 Protodestannylation of triphenyltin to afford tin chloride 66 ...... 63 Scheme 2-40 Anion exchange to form tetrafluoroborate salt ...... 65 Scheme 2-41 Hydride reduction to give organotin hydride 60...... 66 Scheme 2-42 Michael addition to form diester 79...... 69 Scheme 2-43 Diester hydrolylsis and subsequent decarboxylation to give monoacid 80 ...... 69 Scheme 2-44 Esterification reaction to give PTOC ester 82 ...... 70

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Table of tables

Table 2-1 - Reagents and conditions for charged thioacetate 48 deprotection...... 36 Table 3-1 Cyclisation rate constants for the 6,6-diphenyl-5-hexenyl radical (83) in various solvents ... 76 Table 3-2 Rate constants for hydrogen transfer from para-thiocresol to the 6,6-diphenyl-5-hexenyl radical (83) in various solvents ...... 78 Table 3-3 Arrhenius expressions and rate constants for H-atom transfer from novel IL-soluble HAT

reagents to a primary alkyl radical (the 5-hexenyl radical) in 100 % EMIM NTf2. Similar data has

been included for t-BuSH and n-Bu3SnH in THF and isooctane-di-tert-butyl peroxide respectively.304, 334 ...... 99 Table 4-1 Standard method parameters used in gas chromatography experiments ...... 102 Table 6-1 Raw data used to calibrate response factors for methylcyclopentane 86 and 1-hexene 88 137 Table 6-2 Raw data for single concentration and temperature kinetic study with t-thiol 46 and PTOC ester 82 ...... 139 Table 6-3 Raw concentration profile data for t-thiol 46 and PTOC ester 82 ...... 140 Table 6-4 Raw Arrhenius data for t-thiol 46 and PTOC ester 82 ...... 142 Table 6-5 Raw data for single concentration and temperature for t-thiol salt 27 and PTOC ester 82 . 143 Table 6-6 Raw concentration profile data for t-thiol salt 27 and PTOC ester 82 ...... 144 Table 6-7 Raw Arrhenius data for t-thiol salt 27 ...... 146 Table 6-8 Raw data for single concentration and temperature for stannane 60 and PTOC ester 82 ... 147 Table 6-9 Raw concentration profile data for stannane 60 and PTOC ester 82 ...... 148 Table 6-10 Raw Arrhenius data for stannane 60 ...... 150

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List of abbreviations °C degrees Celsius

δ chemical shift (ppm)

µL microlitre

A pre-exponential factor in the Arrhenius equation

Ac acetyl

AIBN azobisisobutronitrile

ATRP atom transfer radical polymerisation b.p. boiling point

BMIM butyl-methyl-imidazolium

CID collision induced dissociation cm centimetre d doublet (NMR)

DCC N,N'-dicyclohexylcarbodiimide

DES deep eutectic solvent

DMAP 4-dimethylaminopyridine

Ea activation energy

EI electron ionisation

EMIM ethyl-methyl-imidazolium

ESI electrospray ionisation

ESR electron Spin Resonance

Et ethyl g gram

GC gas chromatography

HAT hydrogen atom transfer h hour

HRMS high resolution mass spectrometry

Hz Hertz

IL ionic liquid

J Joules

xv k rate constant

K Kelvin kPa kilopascals

LDA lithium diisopropylamide m multiplet (NMR)

M Molar m.p. melting point m/z mass to charge ratio

Me methyl mg milligram

MHz Megahertz min minute(s) mL millilitre mm Hg millimetres of mercury mmol millimole mol mole

MS mass spectrometry n-Bu n-butyl nm nanometer

NMR nuclear magnetic resonance p.s.i. pounds per square inch p para

Ph phenyl ppm parts per million

PTOC N-hydroxypyridine-2-thione derivative p-TsOH para-toluenesulfonic acid

R universal gas constant r.t. room temperature

RAFT reversible addition-fragmentation chain transfer polymerisation s singlet (NMR)

xvi t triplet (NMR) t tertiary

T temperature

Tf trifluoromethanesulfonyl

THP tetrahydropyran

TSIL task-specific ionic liquid

UV/Vis ultra violet / visible light w/w weight by weight concentration

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1 Introduction

1.1 Free radicals Free radical chemistry has come a long way since the discovery of the triphenylmethyl radical by Gomberg in 1900.1 Indeed, free radical chemistry remained misunderstood for many more years following this discovery, with radicals often blamed for undesirable reaction outcomes or unknown mechanisms.2 It was not until late in the 20th century that many of the factors controlling reactivity, stereochemistry and regiochemistry had been more fully studied and understood. Nowadays, radical reactions provide efficient and convenient synthetic pathways toward a wide variety of organic molecules. Indeed, the pioneering work of Ingold, Beckwith, Walling and Barton between 1970 and 1990 fuelled much of the insight into the factors governing organic radical reactivity, promoting their acceptance into modern day synthetic applications.3-6

Figure 1-1 Radical synthesis of Ebselen (1)7

Radical methodologies have made bond formation, in particular ring construction, a simpler task, resulting in a number of novel heterocycles and ring systems. Some examples of this include the synthesis of the heterocycle Ebselen (1) which is used as an anti-inflammatory or antioxidant (Figure 1-1),7 an elegant tandem radical macrocyclisation-radical transannular cyclisation to form complex taxane frameworks 2 and 3 (Figure 1-2)8 and the cascade radical cyclisation leading to the formation of (±)-spongian-16-one (4) (Figure 1-3).9

2 3

Figure 1-2 Radical synthesis of taxane frameworks8

Radical chemistry is also used extensively in polymerisation processes, notably reversible addition- fragmentation chain transfer (RAFT)10 and atom transfer radical polymerisation (ATRP).11, 12 As is normally the case, nature has found ways to utilise radical chemistry long before we were aware of it, with the biosynthesis of deoxyribonucleotides involving radical deoxygenation of ribose units through the enzyme ribonucleotide reductase,13 as well as a plethora of other enzymatic reactions found to proceed through radical intermediates.14

Figure 1-3 Radical synthesis of (±)-spongi-16-one (4)9

1.1.1 Hydrogen atom transfer Unlike ionic and organometallic chemistry, free radical reactions are mostly under kinetic control and so a solid understanding of reaction kinetics is required to maximise the desired synthetic outcome. These reaction kinetics, typically rate constants for hydrogen atom transfer (HAT), kH, or cyclisation, kC, can be measured directly through laser flash photolysis or pulse radiolysis and indirectly through competition kinetic experiments.15 The most common mechanism involved is a radical chain reaction involving initiation, propagation and termination. Initiation is usually achieved through thermolysis or photolysis of a suitable initiator, often present as a part of the compound under investigation, as with Barton’s pyridine-2-thione (PTOC)6, or small amounts of peroxide or diazo initiator compounds. Commercial initiators are inexpensive and can be sacrificed

2 during the reaction, contrasting to homogenous transition-metal catalysts which are expensive and difficult to recover and reuse again rapidly. Thus, radical chain processes are much more advantageous from a cost and efficiency point of view and have great potential for expanding their use in chemical, pharmaceutical and agrochemical industries.16

Figure 1-4 Radical synthesis of (±)-hirsutene (5)17

The use of stannanes, such as tri-n-butyltin hydride, has been instrumental in radical chemistry and is used frequently in many types of reactions. Previous examples (Figure 1-2 and 1-3) have included a HAT step, while further examples showing the versatility of tin hydrides can be seen in Curran’s tandem radical approach to linear condensed cyclopentanoids in the total synthesis of (±)-hirsutene (5) (Figure 1-4)17 or in the total synthesis of (±)-morphine (6) and (±)-codeine (7) (Figure 1-5).18 It is critical to understand the rate constants for cyclisation reactions, and in particular HAT, as it plays a part both in propagation and termination steps in a chain mechanism. By knowing these rate constants, one can avoid using a reagent that does not fit well with the reaction.

For example, in the synthesis of hirsutene (Figure 1-4) where two new bonds must form, a HAT reagent with a very fast rate constant for H-transfer may not allow for both bonds to form prior to termination, while a very slow rate constant for H-transfer may allow time for undesired by- products to form. When looking at the synthesis of codeine and morphine below (Figure 1-5), several new bonds are needed, so knowledge of the cyclisation rate constants is also required in order to match to a HAT reagent.

6 : R = H 7 : R = Me

Figure 1-5 Radical synthesis of (±)-morphine (6, R = H) and (±)-codeine (7, R = Me)18

1.2 Laboratory solvents Radical chemistry clearly has a place in the modern practitioner’s arsenal, however, large scale syntheses can still cause problems. Aside from the common synthetic issues that plague all sorts of chemistry, radical reactions can be very sensitive to temperature and light, particularly with radical initiators. Furthermore, a loss of temperature control can arise from exothermic free radical reactions, particularly polymerisation, causing thermal runaway, which can be hazardous and also detrimental to the chemical reaction.19, 20 In order to reduce thermal runaway one of four processes may occur: venting, containment, venting with containment or inhibition. Unfortunately, radical reactions typically make use of highly toxic, flammable and volatile solvents, such as benzene, alkanes or halogenated solvents among many others. These are not only hazardous to humans, but also the environment, so desired alternatives are non-hazardous, sustainable and environmentally benign. Sustainable, or green, chemistry has a framework of twelve principles to follow to design or improve materials, products, processes and systems.21 Included in these principles are strategies for preventing waste, less hazardous chemical syntheses, safer solvents and renewable feedstocks, where alternative solvents can play a key role. However, it is well accepted that no single solvent is completely green, but rather depends on the application, its toxicological properties and the environmental impact of the solvent’s whole life cycle.22

Possibly the most ideal alternative solvent is water, as it is cheap, non-toxic and readily available. Water has many positive factors in regard to its use as a solvent. It is the natural solvent for biological processes and some organic reactions are accelerated using water, while hydrogen bonding, polarity, acidity, entropy and hydrophobicity are all able to play important roles during chemical syntheses.23-28 Indeed, water is often a great solvent for radical reactions, with the O-H bond very resistant to homolysis, which leads to high energy hydroxyl radicals.16 As the ‘solvent’ for biological processes, nature has, by necessity, learnt to handle and make extensive use of radical reactions. However, water also has its limitations due to the insolubility of non-polar compounds

4 and the reactivity with many reagents or catalysts. Furthermore, an overlooked issue with water is organic product extraction, with volumes of organic solvent exceeding that of water by factors of up to 30 times, and the residual organic matter required to be removed to very low concentrations before disposal.23, 25

Another alternative is to use a solvent-free system, often assisted by the use of focused microwave technology.29-31 In many cases, solvent-free reactions proceed more selectively and faster than similar reactions in solution, while other benefits include reduced pollution, lower cost and simpler processes and handling.32, 33 However, solvent is often required to dilute reactions, as high concentrations may have undesirable effects on the reaction or local environment, with some solvent-free reactions becoming explosive.

Supercritical solvents, in particular CO2, are compounds heated and pressurised beyond their critical point, a place where the liquid and gas phases become indistinguishable.34 These supercritical fluids are useful for extraction, chromatography and as a reaction media, especially for homogenous catalysis reactions, they can be non-toxic, non-flammable and can eliminate solvent residue.35-37 Chemical reactivity is tuneable in a supercritical fluid, as variations in pressure or temperature control phase behaviour, dissolution, precipitation, reaction rate and selectivity.38

However, supercritical CO2 solubilises a restricted number of catalysts, reagents and substrates which are generally non-polar, non-ionic and of low molecular weight,34 while other supercritical fluids, such as water, require much greater temperatures and pressures causing thermal decomposition of many compounds.38 Furthermore, in order to reach these high temperatures and pressures, specialised equipment is required.

Glycerol is another green alternative, and its use as a solvent can be extended to deep eutectic solvents (DESs). Glycerol is a by-product of biodiesel production and is generated in very large quantities such that it is now quite cheap and of high purity.39 It is non-toxic, non-flammable, immiscible with many organic solvents allowing it to be recycled, and has good solvating power, able to dissolve organic and inorganic compounds. Glycerol also has a very high boiling point of 290 °C and is biodegradable, so it has many of the qualities desired from a green solvent.40 Unfortunately, glycerol has a very high viscosity, and does not dissolve hydrophobic compounds and gasses, while the hydroxyl groups can be quite reactive under certain conditions or coordinate to transition metals. When glycerol is teamed with a quaternary ammonium salt, the hydrogen

5 bonding between the salt and glycerol lowers the melting point of the mixture relative to the individual components, affording a DES.41 These DESs containing glycerol have a far lower viscosity and density compared to glycerol itself,39 and while DESs are a promising field of study, there are a relatively few number of salts that have been explored.42

Figure 1-6 Quaternary ammonium salts mixed with glycerol form DESs43, 44

Ionic liquids (ILs) are another promising alternative to traditional solvents. ILs are comprised of salts with low melting points, traditionally an organic cation and inorganic, polyatomic anions with a melting point below 100 °C but most are liquids at close to room temperature.45 This is similar to a DES, however the number of possible salts, with varying cations and anions, that can be synthesised is far greater, thus potentially allowing for an IL to be synthesised to apply to a single task.46 Due to the strong Coulombic interactions, ILs usually exhibit non-volatility and non- flammability, while they are also thermally stable and readily recyclable.47, 48 However, ILs are expensive to purchase and their melting point can be problematic as they are notorious glass-forming materials.49 Furthermore, some varieties can form harmful by-products, particularly those with fluorinated anions which form HF on extended contact with water.47

1.2.1 Ionic liquids Due to the versatility and growing number of applications of ILs, this work chose to focus on their use for radical chemistry. Ionic liquids are composed entirely of ions and can also be called molten salts. However, the term molten salt tends to evoke a rather high temperature, viscous and corrosive media, such as molten sodium chloride. Ionic liquids, however, have a slightly different meaning that implies a melting point under 100 °C, often around room temperature, with much lower viscosity and easier to handle.50 These room temperature ILs are generally composed of an organic cation, i.e. tetraalkylammonium, tetraalkylphosphonium, trialkylsulfonium, N-alkylpyridinium or 1,3-dialkylimidazolium cations (Figure 1-7), with the melting point dependent on cation symmetry.48 The anion can also impact on the melting point, with common anions

6 including halides, tetrafluoroborates, hexafluorophosphates, alkylsulfates, dicyanamides, triflates or bis(triflyl)imides (Figure 1-7).47

Figure 1-7 Common ions used in ILs

Ionic liquids are not a new concept, as Sir William Ramsay, known for his discovery of noble gases, described the product of citric acid and picoline as an ‘uncrystallisable syrup’ in 1876.51 It was almost 40 years later in 1914 when Walden synthesised the first intentional IL, ethylammonium nitrate (8) from the neutralisation of ethylamine with concentrated nitric acid giving a melting point of just 12-14 °C.52 Many of the earlier ILs included a haloaluminate anion, which were highly moisture sensitive and with very niche uses.49 Indeed, these haloaluminate ILs persisted until Wilkes and Zaworotko published a paper on air and water stable 1-ethyl-3-methylimidazolium based ILs, such as imidazolium IL 9, in 1992 that the use of ILs expanded into a variety of different areas.53 Plechkova and Seddon estimated in a 2008 review that there are around 106 simple ILs and upwards of 1018 ILs if all ternary systems are investigated,54, 55 allowing for the properties of ILs to be manipulated toward specific tasks.

8 9

Figure 1-8 First intentionally synthesised IL 852 and first air/water stable IL 953

Although ILs were introduced as a ‘green’ solvent, this is not entirely true for all ILs. Indeed, the term green is often synonymous with ILs, but many salts have non-green character such as toxicity, or they are non-renewable or non-biodegradable.56 Furthermore, the preparation and purification of the salts often requires the use of the very same organic solvents that are avoided in the first place.57 That being said, ILs do contain a number of features that lend themselves well to green chemistry, in particular their non-volatility, non-flammability and recyclability.58, 59 Some of the other benefits of ILs include their air and water stability (particularly for imidazolium-based ILs),53 or strong solvating power, with the ability to dissolve many diverse molecules such as cellulose60 or proteins.61 Depending on salt composition, ILs are also insoluble with water and many organic solvents,46 allowing for bi or triphasic reactions.50 ILs also have good conductivity,62-64 and are used frequently in batteries65, 66 and semiconductors.67

In terms of radical chemistry, ILs have many other advantageous properties. They are excellent heat dissipaters68 and have good thermal stability (stable over 400 °C),62, 69 which is important for reducing operating temperatures and limiting explosions due to thermal runaway in exothermic radical reactions. MacFarlane and co-workers used an accelerating-rate calorimeter to assess the role of ILs in moderating the polymerisation of styrene and acrylonitrile and found that the addition of an IL drastically reduces the rate of self-heating at all temperatures compared the neat monomer.68

Although there are many advantages to using ILs, there are some disadvantages also, with their cost, melting point and potential for hazardous by-products mentioned previously. It may be argued that the cost of an IL is greatly reduced by its ability to be recycled, the choice of cheaper ions and also its purity. Seddon, a pioneer in the ionic liquid field, and his co-workers note that it is widely recognised ILs are not colourless when they should be, despite common analytical techniques displaying pure samples, with the best explanation that impurities are present in part per billion concentrations but with very high molar extinction coefficients.70 This makes IL use in spectroscopic or UV/Vis (ultraviolet/visible) monitoring applications more difficult. Indeed, there is often a ‘non-negligible absorption even beyond 300 nm’ in UV/Visible absorption spectra of imidazolium ILs, with some long absorption tails extending beyond 350 nm.71, 72 Another disadvantage in ILs is due to their relatively new development, with much toxicity and hazard related data not yet studied.73

The preparation of simple ILs is remarkably simple, typically following just two steps: quaternisation and anion metathesis.57, 74-78 With regard to imidazolium-based ILs, quaternisation is possible by alkylating an imidazole moiety to give an intermediate salt, followed by anion exchange to insert the desired anion, as shown in the substitution pathway of Figure 1-9.47 As distillation of ILs is quite difficult, impurities are often minimised by ensuring all starting materials are pure, air and moisture are rigorously excluded70 and the temperature is well controlled to avoid hot spots, which can lead to greater formation of by-products such as through the elimination pathway in Figure-1-9.79 Following IL synthesis, naming an individual IL is relatively straightforward as it is a simple combination of cation and anion. In the case of imidazolium-based ILs, the cation is labelled as 1-alkyl-3-alkylimidazolium, for example with 1-Ethyl-3-MethylIMidazolium tetrafluoroborate (9)

(Figure 1-8), which is commonly abbreviated to EMIM BF4.

Figure 1-9 Substitution and elimination pathways during formation of ILs79

The impact of using an IL solvent on reaction rate has only recently been looked at, with very little kinetic data reported for reactions carried out in ILs prior to 2005. Electron transfer process in ILs have been widely investigated and are usually slower in ILs than in water or common organic solvents. This was initially attributed to the higher viscosity of ILs for diffusion-controlled reactions, however. when processes are slower than diffusion constants, the experimental rate constants are still lower compared to the same rate constants in acetonitrile or aqueous solutions, suggesting that ILs do not behave as a highly polar solvent.80 Rather, it is a change in the energy of solvation of the reactive species that affects rates.81

Other efforts toward kinetic studies have investigated substitution reactions, such as the substitution of a chloride with either methanol or benzyl alcohol.82 Harper and co-workers showed that the rate constant for this substitution decreased with added IL with solvent reorganisation and selective solvation likely contributors to the observed rate differences. Indeed, many other studies

9 dictate the rate accelerations or decelerations are due to changes to the entropy of the reaction systems.83 Several instances of this have already been alluded to given the previous mentions of changes in energy of solvation or solvent reorganisation. Whether these entropy differences affect the starting materials, intermediates or products is dependant of the reaction itself. Harper and co- workers found rate acceleration in Menschutkin reactions when using an IL solvent and attribute this to an increase in the entropy of activation of the process, suggesting that there is increased organisation about the starting materials.84 Conversely, for a different set of reactions, it is the increased solvation of the transition state that influences reaction rate.82

A common theme in many kinetic analyses of reactions in ILs is the mole fraction of the IL used in the solvent. For example, the importance of solvent reorganisation in unimolecular substitution process with varying levels of IL in the solvent has been demonstrated, where the addition of a small amount of IL (0.02 mol fraction) had no impact on activation parameters. However, with increasing amounts (0.50 mol fraction) there are dramatic changes in these parameters, as there is a significant decrease in activation enthalpy, consistent with the stabilisation of incipient charges in the transition state.85 By varying the mole fraction of ionic liquid in some reaction mixtures, one is able to manipulate rates of reactions and possibly control the pathway a reaction proceeds through.86 In other types of reactions, such as a series of substituted benzaldehyde with hexylamine, the addition of an IL to the reaction mixture reduces the build-up of intermediate products, with further increases in the mol fraction of IL allowing rate increases in all steps of the reaction.87

With a range of effects possible when using ILs as a reaction solvent, the choice of IL becomes another point to consider, as the physical properties of ILs can vary significantly, as expected with the large range of potential cation and anion combinations. Some of the properties most affected include melting point, viscosity, density, heat capacity and polarity.88-93 The large amount of previous work on these physical properties is crucial, as there is not enough time to screen a reaction in all of the ILs, even if focussing on just one cation or anion. In this regard, understanding how the properties of an IL vary as a function of the anion or cation enable us to establish patterns and give more predictable physical properties. It is also important to recognise the impact of impurities, in particular water, as these can cause a measurable change, and unfortunately, many literature reports of IL physicochemical properties do not include water concentrations.94

The manipulation of these properties has allowed for IL use in a huge variety of areas, most commonly as a designer solvent. ILs have attracted much attention as a lubricant due to a number of their inherent properties, importantly their high thermal stability and relative inertness compared to conventional lubrication oils.95 This use is further extended to hydraulic fluids, which act both as a lubricant and power transfer medium.96 Another use is as a colourless permanent antistatic agent in polymers,97, 98 as the antistatic ability of polymers deteriorates over time and the current conductive fillers are expensive or of a different colour to the polymer. A variety of sensors also make use of ILs, as they replace membrane-covered and membrane-independent gas sensors,99 while various ion selective, voltametric and biosensors also apply IL technology.100 Evidently a large amount of IL research is on the applications of commercially available ILs, making use of their physicochemical properties, another branch of IL research is into custom-made ILs, generally called task-specific ionic liquids (TSILs).

1.2.2 Task-specific ionic liquids The term task-specific ionic liquid was introduced by Davis in 2004,101 where he described ILs with a covalently tethered functional groups to one or both ions of an otherwise ordinary IL, with the capacity to interact in specific way. This has had a significant impact on broader IL chemical use, as they initially were used to replace solid supports for chemical functionality, where the solid support, usually a functionalised polymer, was desirable due to the lack of vapour pressure and phase separation. With a TSIL, one avoids several of the issues with solid supports, in particular heterogeneous kinetics and deactivation, and from an engineering perspective, reagent mass and volume.102 Aside from just a replacement for solid supports, TSILs are also used for catalysis, organic synthesis, chiral induction or nanomaterial stabilisation103, 104 among other interesting uses such as in oral drug delivery.105, 106

A property of TSILs that is frequently exploited is their immiscibility in organic solvents and water. For example, Shen and co-workers reported the biphasic polymerisation of methyl methacrylate, catalysed by a TSIL copper catalyst 10, where the polymers produced had controlled molecular weights and low polydispersity. Importantly, as the reaction was biphasic, the TSIL was easily separated from the polymer solution and could be recycled to reform the active catalyst.107 Legoupy and co-workers have also developed a reusable catalyst which can be used in radiolabelling.108 In these experiments, an IL supported organotin reagent 11 formed a biphasic mixture which avoided time consuming purification and allowed for good yields and purities of the radiopharmaceuticals. Importantly, the radiochemical yield is similar to that from using a conventional tin reagent, but an

11 overall higher yield is found due to the time saved in purification, as no product is lost to decay or retention in chromatographic systems.

10 11

Figure 1-10 TSILs for ATRP 10107 and radiolabelling 11108

The ability of TSILs to be recycled and reused many times has increased their popularity and use, with both catalyst 10 and organotin 11 able to regenerate the active TSIL. Efforts to push TSILs toward green applications further help their standing as a green alternative solvent. For example, Rogers and co-workers have developed a TSIL incorporating thiourea (12), thioether or urea for the extraction of heavy metal ions from aqueous solutions.109 The heavy metals targeted with these TSILs were mercury(II) and cadmium(II) as they are toxic and easily transported from the environment.110

Figure 1-11 TSIL 12 for heavy metal extraction109

A second, 'green' use can be seen with Davis and co-workers' TSIL for CO2 capture (13).111 It is

noted that although molten salts are already used for CO2 separation, they are generally commercially available, non-optimised salts that frequently depend on water to function.112

Importantly, TSIL 13 was found to sequester CO2 in comparable amounts to standard sequestering amines, the process was reversible by heating at 80-100 C for several hours and the TSIL could be recycled up to five times with no loss of efficiency.

Scheme 1-1 TSIL 13 used for CO2 capture111

1.3 Free radicals in ionic liquids Despite the far-ranging applications for ILs in ionic and organometallic chemistry, their use in radical applications has not been exploited to quite the same degree. However, free radical polymerisation is one process that has made significant use of ILs. Noda and Watanabe were amongst the first to explore room temperature ILs as solvents for radical initiated polymerisation of some vinyl monomers, finding the resultant polymers to be transparent, mechanically strong and highly conductive.113 Several years later, ILs were being used frequently for radical polymerisation, with much of this work summarised by Kubisa,114, 115 who noted that "there is one important observation that may justify the interest in using ionic liquids as solvents in radical polymerisation."

Indeed, this one important observation is that there is a significant impact on reaction kinetics when radical polymerisation is performed in an IL. The importance of reaction kinetics in relation to radical chemistry has been previously mentioned (section 1.1.1), and in 2002, Haddleton and co-workers published their work detailing an unprecedented, solvent-induced, rate acceleration of methyl methacrylate by free-radical propagation.116 Despite radical polymerisation rates being a

13 composite of several rate coefficients, Haddleton found that the rate of propagation of methyl methacrylate at 25 C increased steadily as the concentration of IL was increased, as determined using the pulsed laser polymerisation technique. Although the underlying cause of the increase rate of propagation is unclear, it was not an isolated event, with Rogers finding a ten-fold increase in polymerisation rate,117 while Seddon found an enhanced rate of reaction and more narrow polydispersity.118 Yamago demonstrated a significantly increased reaction rate and improved controllability of polydispersity in organotellurium-mediated living radical polymerisation,119 Glück determined a very high propagation rate coefficient and reduced activation energy for propagation120 and Beuermann also found a strong increase in propagation rates.121, 122 However, with other radical reactions, reaction rates are often found to be slower in ILs. Neta and co-workers investigated redox reaction kinetics in ILs using pulse radiolysis, finding that rate constants for electron transfer are lower than in water or alcohols, while rate constants for hydrogen abstraction and addition reactions are of the same order of magnitude to water and acetonitrile.81, 123-126 Dunkin and co-workers have also found similar decreases in rate constants for bimolecular reactions, which they attribute to an increase in activation energies.127, 128

This conflicting information, although for different radical reactions, does not guide an understanding on how the kinetics may affect more traditional radical reactions, such as cyclisation or hydrogen transfer similar to those depicted in Figures 1-2 to 1-5. Despite the commonly held belief that radical reactions, and the corresponding kinetics and products, are essentially free from solvent effects, there are a number of synthetically valuable radical reactions that do exhibit large kinetic solvent effects.129 Such kinetic solvent effects can greatly reduce the rate of a radical chain reaction or cause formation of an unwanted by-products. Indeed, Ingold and co-workers have demonstrated that the rate of hydrogen abstraction can be solvent dependent, and in many cases, the kinetic solvent effect is directly related to hydrogen-bonding interactions with the solvent.130 Stereoselectivity following radical cyclisation has also been shown to be affected by solvent polarity.131 Given that critical rate constants and thermodynamic data for hydrogen transfer reactions, as well as key radical rearrangement reactions (radical clocks), in organic solvents are integral to our understanding and use of radical methodologies, expanding this to include ILs will allow a clearer understanding of the impact of solvent polarity on radicals.

In order to probe traditional radical reactions in ILs, in particular cyclisation or hydrogen transfer, a variety of hydrogen atom transfer reagents are required to aid in propagation and termination steps. This requires HAT reagents or initiators that are soluble in an IL with favourable spectroscopic qualities, i.e. colourless and with no absorption tail above than 300 nm. Unfortunately, many of the common HAT reagents are relatively non-polar and thus insoluble in an IL, these include stannanes, silanes or long-chained thiols, while common diazo or peroxide initiators, such as azobisisobutronitrile (AIBN) or di-tert-butylperoxide, are also insoluble. Although some HAT reagents have been found to be soluble in some ILs, such as t-butylthiol or 4-methylbenzenethiol, others are required such that a ladder of compounds with varying rate constants for HAT can be used to fit with the kinetics of diverse radical reactions.

1.4 Research objectives This project specifically aims to measure fundamental kinetic data for organic radicals in ionic liquids. Given the absence of common HAT reagents soluble in an IL, we sought to synthesise several novel HAT reagents, modelled on those that are frequently used in traditional radical chemistry such as triphenylstannane or t-dodecanethiol. A comparison of rate constants and Arrhenius parameters will dictate the potential use of these novel compounds in further radical reactions. This will also give us insight into the kinetic solvent effect for organic free radical reactions.

2 Design and synthesis of ionic liquid soluble hydrogen atom transfer reagents

2.1 Tertiary thiol-based reagents

2.1.1 Introduction There are a number of naturally occurring and biologically significant thiols with great variety and function. Indeed, the presence of thiols in living systems is integral in cellular redox potentials, protein function and structure, as well as cellular protection from reactive oxygen species.132 Some of the most biologically important thiols, depicted in Figure 2-1, include the amino acid (R)-cysteine (14) and its related tripeptide glutathione,133 and coenzymes A and M (15).134, 135 However, there are many other thiols that we interact with on an almost daily basis. Allicin (16) (from garlic),136 2-furfurylthiol (17) (roasted coffee),137 2-butene-1-thiol and 3-methyl-1-butanethiol (18) (skunks)138 and various mercapto-alcohols, such as 4-mercapto-4-methylpentan-2-ol (19), (Sauvignon Blanc wine)139 are just a few examples of these.

14 15 16

17 18 19

Figure 2-1 Naturally occurring thiols

Along with these naturally occurring thiols, there are many synthetically derived thiols used in the pharmaceutical industry for a wide range of ailments (Figure 2-2). Some pharmaceutical examples include (S)-penicillamine (20), a t-thiol derivative of cysteine which is used in the treatment of Wilson’s disease as a chelating agent for copper;140 captopril (21), a primary thiol which acts as an angiotensin converting enzyme (ACE) inhibitor in the treatment of high blood pressure;141 and sodium aurothiomalate (22), a secondary thiol bound to two gold atoms, used as a disease- modifying anti-rheumatic drug for the management of progressive rheumatoid arthritis.142 Recent

16 developments in β-lactam antibiotic resistance mediated by metallo-β-lactamase enzymes has also made use of several thiol containing drugs. β-Lactam antibiotics are widely used due to their high efficacy, broad activity range and low toxicity in humans. Thiol groups are known as good metal chelators, often with zinc or copper, and thus inhibit metallo-β-lactamases with zinc ions in their active site, restoring antibiotic effectiveness.143 Other thiols acting as metal chelators include the well-known organomercury compound thiomersal, which contains a thiol bound to mercury, and is used as an antiseptic and antifungal agent144 as well as a preservative in vaccines, causing a significant amount of mainstream controversy.145, 146

20 21 22

Figure 2-2 Pharmaceutical drugs containing thiols140-142

In general, thiols do not have the same polarity as analogous alcohol containing molecules, nor do they show the same amount of hydrogen bonding. This contributes to their lower boiling points and often limited solubility in water. As such, thiols and thioethers often have similar solubility and boiling point characteristics, while this is not true for structurally similar oxygen derivatives.147 Given their volatility, thiols are known for their strong odours, with very low detection limits in the human nose, and this has allowed low molecular weight thiols, such as t-butylthiol, to be added to odourless natural gas.147 An explosion at New London School, Texas, in 1937 was caused by a large build-up of natural gas and killed 298 students and teachers, so the addition of t-butylthiol now allows for leak detection before a deadly build up can occur.148

Synthetically, thiols can be formed in a variety of ways. Some of the more common synthetic routes include reduction of disulphides,149 thioethers150 or thioesters,151 addition across a double bond,152 conversion from an alcohol153 or halide displacement.154, 155 These routes are applicable for primary, secondary and tertiary thiols alike. However, tertiary thiols are known to be more difficult to synthesise given their steric bulk which limits some forms of synthesis, while their characteristic penetrating smell is often a deterrent to further work.156, 157

However, thiols are not just a synthetic target, they are also of great use in radical chemistry. Broadly, their use in this context can be grouped into seven main categories; thiyl-mediated hydrogen abstraction/hydrogen atom transfer, additions to alkenes, alkynes, isonitriles and the C=S bond of N-hydroxypyridine-2-thione moieties (PTOC esters or, more commonly, Barton esters), fragmentation of β-sulfanyl radicals and the generation of silyl radicals.158 Thiyl addition reactions can occur in both an inter and intramolecular fashion, generating a thioether and frequently a carbon centred radical, which may further propagate the chain reaction. It is notable that thiyl radical additions are reversible, adding to the less substituted end of a double or triple bond and are normally exothermic.159 The reversibility of thiyl addition is what gives rise to β-sulfanyl radical fragmentation, regenerating a double bond (Scheme 2-1). By manipulating the reaction conditions, one can achieve isomerisation of (Z)-alkenes to the more stable (E)-alkene160 or introduction/migration of vinyl, allyl or allenyl groups in target compounds.161

Scheme 2-1 Reversibility and isomerisation following thiyl radical addition to an alkene160

Perhaps one of the most important uses of a thiol in radical chemistry is in its reaction with C=S double bonds, in particular those from N-hydroxypyridine-2-thiones.6 Thiohydroxamic acids are excellent traps for thiyl radicals where the addition occurs on the sulfur of the C=S bond, resulting in a carbon centred radical (Scheme 2-2). Indeed, the thiocarbonyl group is very well known in radical chemistry, not just for these PTOC esters but for reactions such as the Barton-McCombie deoxygenation,162 with a substantial review from Crich and Quintero solely covering radical reactions with thiocarbonyl groups.163 However, as PTOC esters can be quite reactive, the best thiols to use with them are sterically hindered and poorly nucleophilic such as tert-butylthiol or tert-dodecanethiol.164, 165

Scheme 2-2 Thiyl radical reaction with PTOC esters162

Hydrogen atom transfer is also one of the more important functions involving thiyl radicals. Despite the relatively high bond dissociation energy of an alkyl thiol S-H bond (~87 kcal mol-1),166 they are excellent hydrogen atom donators compared to other conventional donors such as tri-n-butylstannane (Sn-H, 79 kcal mol-1)167 or α-tocopherol (O-H, 77 kcal mol-1).168 Due to this, the most common way of forming a thiyl radical is through hydrogen transfer, which occurs rapidly with most other radicals, in particular radical initiators such as peroxides or azo-compounds. Thiyl radicals themselves will also rapidly abstract hydrogen from weak X-H bonds, which can allow thiols to act as polarity reversal catalysts.169

Figure 2-3 Example of polarity reversal catalysis170

For example, hydrogen atom transfer to a stabilised alkyl radical from a trialkylsilane is usually exothermic and the low rate of reaction is likely due to unfavourable polar effects in the transition state (Figure 2-3). In cases like this, where the hydrogen is electron rich and alkyl radical is nucleophilic, the rate of reaction can be enhanced by the addition of a thiol, where the alkyl radical can abstract the electron deficient sulfhydryl hydrogen to leave an electrophilic thiyl radical. This electrophilic thiyl radical will now quickly abstract the electron rich silane hydrogen, which is then able to continue with its desired function, often hydrosilylation reactions.170

There are a number of examples of thiols used with ILs, such as Michael addition reactions of thiols with alkenes,171 IL assisted thiol removal from jet fuel,172 or thiol addition to α,β-unsaturated ketones.173 Unfortunately, thiols have not frequently been included as part of a TSIL, often present as a thioether rather than a free thiol.174 However, there are several instances of thiols on an IL scaffold. Jia and co-workers have investigated thiol-containing ILs as a modifier for styrene- butadiene rubber/silica or rubber/halloysite nanotube composites (23).175, 176 Lee has designed thiol-containing ILs for the one-phase synthesis of gold and platinum nanoparticles (24),177 while Zhao’s use is as inks for microcontact printing of ionic liquid microdroplet arrays onto gold chips (25).178 Finally, Yan uses thiol-containing ILs as a bridge to prepare multi-component soft hybrid materials of silver lanthanides and control luminescence colour (26).179 While there are other examples with rather diverse and exotic structures, it is the thiol’s ability to bind to metals that is made use of, rather than its applications in radical chemistry.

23 24

25 26

Figure 2-4 Thiol-containing ionic liquids175, 177-179

2.1.2 Retrosynthesis Despite the solvating power of ILs for a broad range of compounds, not all common thiols used as HAT reagents are soluble. In many IL common solvents, the commonly used t-butylthiol proves to be soluble while t-dodecanethiol is not, most likely due to its long non-polar chain. Given the volatility of t-butylthiol, a longer carbon chain is desired to ensure the effectiveness during higher temperature reactions. Arylthiols, such as p-thiocresol, were also investigated and although these proved to be soluble, they were not suitable for the desired kinetic experiments as they interfere with photolytically initiated radical processes.

Ideally, TSIL 27 was targeted, where a thiol moiety is separated from the cation by a six-carbon chain, ensuring solubility in common ILs hopefully without significantly impacting on the thiol group. A tertiary thiol, rather than a primary thiol, is required given the aforementioned steric hindrance and poor nucleophilicity of tertiary thiols. By tethering the thiol to an IL, compound volatility is eliminated, and it is easier to handle in other reactions, especially as TSILs such as these can be solids at room temperature. Given the cation of ILs can take a number of forms, an imidazolium cation is preferable given its overwhelming use in the literature. Further to this, as the hydrogen in the 2-position of an imidazole ring is acidic, targeting a 2-methylimidazolium derivative eliminates any potential side reactions during synthesis and kinetic experiments. Methylation of the C2 position of a 1,2-disubstituted imidazolium ring can have an enormous impact on viscosity, conductivity, surface tension and phase behaviour.180 Most relevantly, the impact of C2 methylation can be seen in significant increases in melting points and viscosities,181 however, it is considered more important to remove the chance of side-reactions than to keep the melting point low.

It is also important to consider the anion for the IL target, and much of this consideration relies on the IL solvent to be used for future kinetic studies. For these experiments it is important to use an IL which is colourless and of high purity for spectroscopy, such as ethylmethylimidazolium bis(trifluoromethane)sulfonimide. Lengthier discussions on the IL to be used can be seen in Section 3.2. However, it is important to note the anion used in the IL solvent, such as bis(trifluoromethane)sulfonimide (NTf2) and the impact of a differing anion on the synthesised IL-soluble HAT reagent. For these studies, the tetrafluoroborate anion was also targeted due to its common use, relative lack of reactivity to radical chemistry and relative cost compared to NTF2. While this does introduce two salts into kinetic experiments, previous research has indicated that a mixture of these anions can reduce the refractive index, and increase both density and viscosity.182 These points were not considered to be of great impact to the proposed kinetic studies.

Figure 2-5 Retrosynthetic pathway towards tertiary thiol 27

Retrosynthetic analysis of the target compound suggests several divergent pathways, where the key step involves the formation of a functionalised tertiary carbon. The tertiary carbon may be formed directly or following an addition reaction. Ideally, an imidazole moiety is included early in the synthesis, as the substituted imidazole product (28) is likely to be more stable compared to a primary functional group such as an alcohol or halide. Given that either end of the heptane chain can undergo varying reactions, the synthetic route can proceed through a number of pathways using the same reactions in different orders, such that the ideal reaction pathway is not immediately clear. In any case, Figure 2-5 shows the initial retrosynthetic pathway deemed most convenient toward the IL-supported t-thiol 27.

2.1.3 Forming functionalised tertiary carbon A simple method of forming a functionalised tertiary carbon is through the use of a Grignard reagent acting on an ester to form a tertiary alcohol. Thus, excess methylmagnesium bromide was added dropwise to a solution of ethyl 6-bromohexanoate (29) in anhydrous diethyl ether at 0 °C.183 After stirring for 24 hours, the solution was acidified to pH 3 until no bubbles formed, and following work-up, tertiary alcohol 30 was isolated in a 95 % yield. The formation of the tertiary alcohol was confirmed following 1H NMR spectroscopy, which showed a clear singlet resonance at 1.21 ppm corresponding to the two newly added methyl groups. Importantly, the ester signals at 4.11 and 3.40 ppm from the starting material184 were no longer present, while other characteristics agreed with those in the literature.185

29 30 31

Scheme 2-3 Forming a tertiary alcohol

Reagents and conditions: a) MeMgBr, Et2O, 0 C, 17 h; b) 2-methylimidazole, KOH, CH3CN, r.t., 17 h.

With a functionalised tertiary carbon in hand, it was then necessary to attach an imidazole derivative to the opposite end of the carbon chain which can be alkylated to form a salt. In order to do this, a suspension of sodium hydride in anhydrous THF was prepared and to this was added 2-methylimidazole and the solution stirred at room temperature for one hour. Subsequently, tertiary alcohol 30 was added and the resulting mixture stirred at room temperature overnight.76 Following aqueous workup, the desired alcohol 31 was obtained in an excellent yield of 97 %. A second method is also possible, where excess KOH was added to a solution of tertiary alcohol 30 and 2-methyimidazole in acetonitrile and stirred at room temperature overnight. The mixture was then concentrated in vacuo before being worked up and afforded the desired compound in a yield over 95 %. The product structure was confirmed by 1H NMR spectroscopy, which displayed a triplet signal at 3.81 ppm corresponding to the new CH2-N protons, while two doublet signals at 6.79 and 6.89 ppm corresponding to the protons in the 4 and 5 positions of the imidazole ring are also visible.

2.1.4 Halogenation of tertiary alcohol 31

31 32

33 34

Scheme 2-4 Conversion of a tertiary alcohol to a tertiary bromide

Reagents and conditions: a) 33 % HBr, LiBr, CHCl3, r.t., 15 h; b) 1.0 M BBr3, CH2Cl2, 0 C, 3 h; c) PBr3, CHCl3, 0 C, 72 0h; d) MeI, toluene, 110 C, 20 h.

Conversion of a tertiary alcohol to thiol may be achieved in a few ways, most commonly by converting the alcohol group to a halide before substitution with a thiol group. To this end, an excess of 33 % HBr in acetic acid was added to a solution of LiBr and tertiary alcohol 31 in CHCl3 and stirred at room temperature overnight.186 Unfortunately, following an aqueous workup and 1H NMR spectroscopy of the crude material, no characteristic product signals could be identified.

Next, a 1 M solution of BBr3 was added slowly to tertiary alcohol 31 in CH2Cl2 at 0 °C and stirred for three hours.187 No change was detected by TLC analysis and again, following aqueous workup and 1H NMR spectroscopy, no characteristic product signals were seen. Finally, PBr3 was added dropwise to alcohol 31 in CHCl3 at 0 °C, allowed to warm to room temperature and stirred for several days,188 however neither TLC nor 1H NMR spectroscopic analysis showed conversion of the starting material to the targeted t-bromide 32. The mechanism of bromination using PBr3 involves an SN2 substitution, so it is not usually used in conjunction with t-alcohols, however, Brückner describes the conversion from 2-methylbut-3-yn-2-ol to 3-bromo-3-methylbut-1-yne using PBr3 with a 60 % yield.188

Given the difficulties in bromination of alcohol 31, attention was focused toward brominating the dialkylated imidazolium 33. As such, iodomethane was added to a solution of alcohol 31 in toluene and refluxed at 110 C overnight. On completion, toluene was removed under reduced pressure and the residue washed with Et2O to give the desired imidazolium 33 in an almost quantitative yield. An alternative method was also explored where a solution of 1,2-dimethylimidazole and 7-bromo-2-methylheptan-2-ol (30) was refluxed in toluene at 110 C for 18 hours. After concentrating and washing with Et2O, the imidazolium t-alcohol 33 was obtained in a very good yield of 88 %. The 1H NMR spectrum of salt 33 displayed several characteristic resonances confirming the structure. Of note, the imidazolium proton signals were found as doublets at 7.57 and 7.64 ppm (compared to starting material at 6.76 and 6.84 ppm), the CH2-N proton signals formed a triplet at 4.23 ppm, while both methyl groups on the imidazolium moiety presented as singlet resonances at 2.81 and 4.00 ppm (starting material: 2.32 and 3.52 ppm). The triplet signal from the CH2-N protons has shifted downfield compared to those from uncharged imidazole 31 given the charged imidazolium has a larger deshielding effect. Unfortunately, when the imidazolium

33 was subjected to the same halogenation reactions described above, using 33 % HBr or 1 M BBr3, no signals resembling those that were expected for salt 34 were seen in a 1H NMR spectrum of the crude materials.

30 35 32

Scheme 2-5 Dibromide 35 formation and attempted substitution

Reagents and conditions: a) 33 % HBr in AcOH, LiBr, CHCl3, r.t., 17 h; b) NaH, 2-methylimidazole, THF, r.t., 17 h.

As bromination at this step was unsuccessful, conversion of the alcohol to the bromide was attempted with the Grignard product 30. Thus, 33 % HBr in acetic acid was added dropwise to a solution of 1-bromo-6-hydroxy-6-methylheptane (30) and LiBr in CHCl3 at 0 C and allowed to warm to room temperature and stirred overnight. The resulting solution was concentrated under reduced pressure before aqueous workup and afforded the desired 1,6-dibromo-6-methylheptane (35) in a 97 % yield. The 1H NMR spectrum of the product was in agreement with that in the literature,189 where a singlet signal shift from 1.21 ppm in starting material to 1.75 ppm in the product, corresponding to the six methyl protons, was the only significant difference.

With the dibromide 35 in hand, substitution of the primary bromide for an imidazole ring could be performed. In the same manner as earlier substitutions, 2-methylimidazole was added to a suspension of NaH in anhydrous THF and allow to stir for 1 hour before the dibromide 35 was added slowly. Upon full consumption of dibromide 35 as determined by TLC analysis, the solution was worked up and organic impurities removed by flash chromatography. The 1H NMR spectrum indicated substitution was successful, with doublet signals at 6.80 and 6.90 ppm, corresponding to the protons on the imidazole ring, and also a triplet signal at 3.81 ppm, the CH2-N protons, confirming the substitution. However, the signal for the protons on the tertiary methyl groups appeared as two distinct singlets at 1.68 and 1.59 ppm, rather than just one singlet as expected, while multiplets at 5.06, 4.70 and 4.65 ppm were not identified. Initially these unidentified multiplets were attributed to an inseparable by-product and/or perhaps a conformational bias leading to two environments for the tertiary methyl groups.

35 36 36-2

Scheme 2-6 Single step substitution and elimination with dibromide 35

Reagents and conditions: a) 2-methylimidazole, NaH, THF, r.t., 17 h; b) 2-methylimidazole, KOH, CH3CN, 82 C, 17 h.

The reaction was repeated using an alternative method, whereby dibromide 35, 2-methylimidazole and KOH were combined and refluxed in acetonitrile for 17 hours before undergoing an aqueous workup.190 Following flash chromatography, a product with identical spectral characteristics to that described earlier was isolated. Although the intended product had not been isolated, the basic conditions in the reaction mixture cause elimination of the tertiary bromide to form a mixture of alkenes, 36 and 36-2.191 When accounting for halide elimination, the previously unassigned signals in the 1H NMR spectrum at 5.06, 4.70 and 4.65 ppm can be attributed to the protons adjacent to the alkene in either major or minor product, as described by Saytzeff in 1875.192 Indeed, alkene formation does conformationally lock the terminal methyl carbons of the side chain and gives two different proton environments, accounting for the singlet resonances at 1.68 and 1.59 pm. Despite not forming a tertiary halide as planned, addition to an alkene can also lead to the desired product.

31 36 36-2

Scheme 2-7 Elimination of tertiary alcohol 31

Reagents and conditions: a) p-TsOH, toluene, 110 C, 36 h.

A third method to deliberately form these alkene products 36 and 36-2 was also achieved through an elimination reaction with t-alcohol 31. p-Toluenesulfonic acid was mixed with a solution of alclohol 31 and refluxed in toluene until TLC indicated no starting material remained.193 The solution was then concentrated under reduced pressure, dissolved in CH2Cl2, washed with a basic solution followed by water and brine to afford the alkenes 36 and 36-2. This synthetic route, substituting imidazole into molecule before undergoing hydroxyl elimination as opposed to converting the hydroxyl group to a bromide prior to substitution/dehalogenation, affords the desired alkenes 36 and 36-2 in high yields and with fewer by-products. This also removes the need to use the corrosive HBr solution which fumes in moist air and is highly damaging to Suba seals.

35 37 37-2

Scheme 2-8 Dibromide substitution and elimination to give charged products 37 and 37-2

Reagents and conditions: a) 1,2-dimethylimidazole, toluene, 100 C, 17 h.

A final method toward imidazolium t-bromide 34, bypassing the use of basic conditions, was also attempted. Thus, dibromide 35 was refluxed with 1,2-dimethylimidazole in toluene for 17 hours before an aqueous workup. Instead, similarly to reaction with 2-methylimidazole, a mixture of alkenes 37 and 37-2 were isolated with similar proton shifts seen for the alkene protons at 5.06, 4.70 and 4.65 ppm, as well as the characteristic two singlets resonances for the terminal methyl protons in the 1H NMR spectrum of the crude material. It was thought that the basic pH employed in previous substitutions to 2-methylimidazole was the cause of dehydrohalogenation, however

from the results of this experiment, 1,2-dimethylimidazole appears to be a strong enough base to cause elimination by itself.

2.1.4.1 Other methods to maintain or reform tertiary halide

36 32

Scheme 2-9 Unsuccessful alkene bromination attempt

Reagents and conditions: a) 33 % HBr in AcOH, CH2Cl2, 0 C, 17 h.

Given an alkene was not an initially desired product, attempts were made to reform a tertiary halide through an addition reaction with HCl or HBr. Thus, solutions of HX were added to alkenes 36

and 36-2 in CH2Cl2 and stirred at either 0 C or refluxed at 55 C.194 After reaction with HBr and aqueous workup, 1H NMR analysis of the crude material displayed a large singlet resonances at 1.75 ppm, which corresponds to the two terminal methyl groups now in one environment. Interestingly, but not surprisingly, the signals for the imidazole protons had shifted to 7.06 and 7.29 ppm. This shift suggests that the imidazole ring has been protonated, as similar shifts are seen with dialkylated imidazolium compounds. Unfortunately, efforts to purify or deprotonate the crude product resulted in decomposition and/or conversion back to starting material 36.

36 38

Scheme 2-10 Methylation to form charged alkene product 38

Reagents and conditions: a) MeI, toluene, 100 C, 17 h.

Formation of the charged imidazolium alkene 38 was achieved by refluxing iodomethane and alkene 36 in toluene overnight, resulting in a good yield of the desired salt. 1H NMR spectroscopic analysis confirmed the structure with both proton signals on the imidazole ring shifting downfield to 7.27 and 7.43 ppm, while the signal for the newly added methyl group can be seen at 3.97 ppm, with other resonance shifts as expected. Methylating the imidazole ring prior to halogenation of the alkene should counter issues associated with the previous reaction’s imidazole protonation. This compound could be partially purified by washing with Et2O to remove organic impurities.

38 34

Scheme 2-11 Bromination of charged alkene 38 to give a tertiary bromide 34

Reagents and conditions: a) 33 % HBr in AcOH, CH2Cl2, 0 C, 17 h.

In a similar manner to previous reactions, 33 % HBr was added slowly to charged alkene 38 in

CH2Cl2 at 0 °C and stirred for 48 hours. After concentrating the solution and then working up, the crude material was isolated and a 1H NMR spectrum revealed one large singlet resonance at 1.74 ppm corresponding to the two terminal methyl groups. By methylating the imidazole ring, no protonation is possible, so further efforts toward the desired thiol may still be achieved. However, concurrent work at this time was more promising and this route was not pursued any further.

2.1.5 Thioester addition

36 39

Scheme 2-12 Thioester addition across alkene 36

Reagents and conditions: a) AcSH, AlCl3, CH2Cl2, 0 C – r.t., 17 h.

Although the previous elimination reaction gives a mixture of inseparable alkene isomers 36 and 36-2, by adapting Markovnikov's rule195 to the addition of a thiol moiety we can expect the same product formation for reaction with either alkene, given the most stable cation formed is identical regardless of the starting alkene. Initially, alkene 36 in anhydrous 1,2-dichloroethane was added to 0.15 equivalents of aluminium trichloride under an inert atmosphere, followed by the dropwise addition of thioacetic acid before heating, using an adaptation of a method from Raz and Rademann.196 Unfortunately, only trace amounts of the product were obtained and the 1H NMR spectrum of the crude product did not show the characteristic terminal methyl signal shift, nor a resonance characteristic of the thioacetate group. Although Raz uses indium trichloride as the Lewis acid catalyst, aluminium trichloride is a common Lewis acid and was used in place of the indium variety.

Instead, a similar method from Shanmugam using the same reagents was applied. Accordingly, two equivalents of aluminium trichloride were added to anhydrous CH2Cl2 under argon at 0 C, followed by the addition of alkenes 36 and 36-2 and, finally, a large excess of thioacetic acid.197 The reaction progress was followed by mass spectrometry (MS) as the retention factor of both starting material and product by TLC are difficult to differentiate. Upon reaction completion, the solution was slowly quenched with 10 % HCl, worked up and organic impurities removed by flash chromatography to give the thioester 39 in a 69 % yield. The structure of thioester 39 was confirmed by 1H NMR and 13C NMR spectroscopy, as well as HRMS. In the 1H NMR spectrum, the previous two singlet resonances for the terminal methyl groups were now seen as one signal at

1.41 ppm with integration of six protons, while the methyl group from the newly added thioacetate can be seen as a singlet resonance at 2.23 ppm.

Importantly, all protons associated with the alkene in either starting material were not present. The 13C NMR spectrum displayed a carbonyl carbon resonance at 196.7 ppm, while a signal at 269.1721 m/z was seen in HRMS, in good agreement with the calculated m/z of 269.1688 for [M+H]+. A dark red by-product, whose signals were not visible in 1H NMR spectra, formed during this reaction, however, stirring the post aqueous workup solution over activated carbon before filtering over celite helped remove this coloured by-product. Unfortunately, this reaction was low yielding when performed on a large scale so for those times when large amounts of this product were required, the reaction was repeated several times with a maximum of 2.50 g starting alkene 36. It is also interesting to note the large excess (two equivalents) of aluminium trichloride required for this reaction, as usually only small amounts of a Lewis acid, less than 25 mol %, are required for similar

reactions.198 This could be due to the age and purity of the AlCl3, which was noticeably yellow

indicating contamination with FeCl3199 or previous reactions with water to afford [Al(H2O)6]Cl3.

2.1.5.1 Other methods of introducing the thiol

29 40 41

Scheme 2-13 Attempted Grignard reaction pathway on thionester 40

Reagents and conditions: a) Lawesson’s reagent, toluene, 110 °C, 36 h; b) MeMgBr, Et2O, 0 C, 17 h.

Several other methods towards a tertiary halide were also explored. The first method attempted was conversion of ester 29 to a thionoester 40 using Lawesson’s reagent in refluxing toluene for several days.200 Monitoring the reaction was achieved by staining TLC samples with 2,4-dinitrophenylhydrazine (Brady’s reagent),201 known for its ability to qualitatively test for aldehyde and carbonyl functionality. Unfortunately, after flash chromatography and MS analysis, the desired thionoester 40 could not be observed. Although no literature precedence for similar reactions to those in Scheme 2-13 were found, it was envisioned that the thionoester 40 might

31 undergo a simple Grignard reaction in the same manner as normal esters, instead leaving tertiary thiol 41 rather than alcohol 30, as this appeared to be a simple and quick route to the final compound.

42 44

Scheme 2-14 Attempts toward thiocarbonate 44

Reagents and conditions: a) Bu3SnCl, Na, toluene, 110 °C, 48 h; b) CS2, r.t., 17 h; c) thiourea, ZnCl2, 1,2-dichloroethane, 105 °C, 42 h.

In another approach to the thiol, following the method of Pestov and co-workers, 2,3-butandiol

(42) was mixed with thiourea and ZnCl2 in 1,2-dichloroethane at 105 °C for 48 hours before being decanted and the remaining solid washed with more 1,2-dichloroethane.202 The organic layer was concentrated in vacuo, however, 1H NMR spectroscopy and MS analysis were unable to reveal signals corresponding to the desired compound 44. Alternatively, the method was repeated proceeding through a tin intermediate 43, as detailed by Ishii and co-workers.203 As such, a mixture of 2,3-butanediol (42) and sodium metal was refluxed for 5 hours in toluene before the addition of tributyltin chloride and further reflux until TLC indicated reaction completion. The crude material was then used immediately by stirring with CS2 in minimal 1,2-dichloroethane at room temperature overnight. Unfortunately, 1H NMR spectroscopic analysis did not show any signals expected for the desired thiocarbonate 44. Mukaiyama has shown that similar thiocarbonates can react with alkenes and Lewis acid catalysts to yield tertiary thiols as desired in this work.204

38 45

Scheme 2-15 Attempted H2S addition to alkene 38

Reagents and conditions: a) Na2S•9H2O, glacial acetic acid, AlCl3, CH2Cl2, r.t., 6 h.

In a final effort toward the introduction of a tertiary thiol, H2S was generated in situ by dropping acetic acid on moist sodium sulphide and this was bubbled into a solution of imidazolium alkene 38 and AlCl3 in CH2Cl2.205 Sodium sulphide and acetic acid were added periodically to maintain a relatively steady flow of gas into the alkene solution. Unfortunately, following an aqueous workup, the desired tertiary thiol 45 was not detected by various forms of analysis, however, this process was not optimised during further experimentation.

2.1.6 Imidazole methylation

46 47

Scheme 2-16 Potential thioether product following methylation

Reagents and conditions: a) MeI, toluene, 100 C, 17 h.

While either methylation or deacetylation can be performed on thioacetate 39, it was envisaged that if deacetylation was performed first, the free thiol could potentially be methylated to form thioether 47 (Scheme 2-16), an undesirable process as thioether deprotection can be more difficult than for a thioacetate.206

39 48

Scheme 2-17 Formation of charged thioester 48 following methylation

Reagents and conditions: a) MeI, toluene, 100 C, 17 h.

Thus, in order to avoid thioether formation, imidazole methylation was performed first. A large excess of iodomethane was added to a solution of thioester 39 in toluene and refluxed at 100 C until TLC analysis showed complete consumption of starting material. After this, toluene was removed under reduced pressure, the residue washed with Et2O and then organic impurities removed by flash chromatography to afford the imidazolium thioester product 48 as a dark yellow, waxy solid in a 77 % yield. The structure was confirmed by 1H NMR spectroscopic analysis, which showed the expected imidazolium proton's doublet signal shift from 6.95 and 7.16 ppm in starting material to 7.36 and 7.47 ppm, while the signal for the newly added methyl group could be seen as a singlet at 3.97 ppm. HRMS was also used to confirm the structure, with the parent cation seen at 283.1845 m/z in excellent agreement with the calculated value 283.1844 m/z.

2.1.7 Attempted deacetylation of imidazolium t-thiol 48

48 45

Scheme 2-18 Unsuccessful deacetylation reactions

Reagents and conditions: a) various methods explored in text.

S-Acetyl thioesters are well known and often cleaved to allow the free thiol through the use of acids or bases among a variety of other methods. Indeed, simple hydrolysis initially seems the most

34 promising route to deacetylation. As such, using the method of Wittstock et al.,207 a large excess of acetyl chloride was added to a solution to charged thioacetate 48 in methanol and stirred at room temperature. No change was detected by TLC after 24 hours, so the solution was set to reflux until starting material had been completely consumed. After aqueous workup, a negligible amount of product was retrieved, and other methods were investigated.

As per Artaud's thiol deacetylation,208 2.2 equivalents of K2CO3 was added to a 0.07 M solution of thioacetate salt 48 in MeOH and the mixture stirred at room temperature overnight. No change was detected by TLC analysis and, following aqueous workup, very little product was isolated. 1H NMR spectroscopic analysis of the crude material indicated that the signal for the acetate group had been removed, however, other signals had been broadened as the product did not appear to be very soluble in CDCl3. In general, many of the IL type compounds, such as imidazolium thioacetate 48, were found to give very low yields and many by-products in reactions with acids or bases. Given the low crude yield in this case, another method was investigated.

The next method used was based on Yu's deacetylation using LiAlH4 where a solution of charged thioacetate 48 in anhydrous THF was prepared, cooled to 0 C and three equivalents of LiAlH4 added in one portion.209 In a similar manner to previous attempts, a very low crude yield was obtained. While analysis of the 1H NMR spectrum did indicate deacetylation had occurred, a number of by-products appeared to have formed, with a large singlet resonance in the 1H NMR spectrum appearing at 1.99 ppm and a multitude of signals appearing in the alkyl region between 1 - 2 ppm. Given the polarity and ionic nature of the product, starting material and any potential by-products, it was deemed inefficient to purify this reaction for minimal product.

Given the reactive nature of LiAlH4 and the potential for reducing the imidazolium moiety, it was considered that the milder reagent NaBH4 might reduce the thioester more selectively, and thus it was envisioned that fewer by-products may result. As such, an excess of NaBH4 was added at 0 C to a solution of thioacetate salt 48 in CH2Cl2, then stirred overnight at room temperature. No change was detected by TLC after 24 hours and consequently, a few drops of MeOH were added.

The reactivity of NaBH4 is known to be enhanced by MeOH, among other potential additives, and MeOH is not likely to cause any product decomposition.210 Unfortunately, no change was detected after a further 17 hours at room temperature or following reflux at 45 C, with 83 % of the starting material recovered. Given the difficulties encountered in deacetylation at this step, possibly due to

35 the charged nature of the compound, performing the reaction on the uncharged thioacetate 39 may allow higher yields and fewer by-products despite possible issues with thioether formation.

Table 2-1 - Reagents and conditions for charged thioacetate 48 deprotection.

Reagent Solvent Conditions Yield of salt 45 Starting material recovered

LiAlH4 THF r.t., 17 h 0 % 0 %

NaBH4-MeOH CH2Cl2 r.t., 17 h 0 % 100 %

NaBH4-MeOH CH2Cl2 45 C, 24 h 0 % 0 %

K2CO3 MeOH r.t. 17 h 0 % 0 % Acetyl Chloride MeOH r.t. 17 h 0 % 100 % Acetyl Chloride MeOH 65 C, 24 h 0 % 0 %

2.1.8 Deacetylation of uncharged t-thiol 39

39 46

Scheme 2-19 Deacetylation reaction of uncharged thioacetate 39

Reagents and conditions: a) LiAlH4, anhydrous THF, r.t., 72 h.

Deacetylation was attempted by adding excess LiAlH4 to uncharged thioacetate 39 in THF at 0 C, then allowing the solution to warm to room temperature and stir for 72 hours. The resulting solution was acidified to pH 4, before removing THF under reduced pressure and extracting into

CH2Cl2 to give the desired t-thiol 46 in an excellent yield of 96 %. The structure was confirmed by HRMS, which displayed a product peak at 227.1578 m/z in excellent agreement with the calculated 227.1582 m/z. 1H NMR spectroscopy also helped confirm the structure of thiol 46, with a singlet resonance at 2.74 ppm corresponding to the methyl in 2-position of imidazole ring and no evidence

36 of the acetate signal. A 13C NMR spectrum also supported the structure of the desired transformation, with the carbonyl acetate carbon signal at 196.7 ppm no longer present.

Figure 2-6 Comparison of 1H NMR spectra between thioacetate 39 and t-thiol 46

Interestingly, the aforementioned resonance at 2.74 ppm has shifted a relatively long way given the distance from the thiol, while the imidazole proton signals have also shifted further downfield to 6.97 and 7.22 ppm. This could be due the formation of zwitterion 49, where hydrogen has exchanged between the thiol and imidazole ring to leave a sulfur anion and imidazolium cation. This is possible given dissociation constants of 8 – 18 for tertiary thiols211-213 and 8.13 – 8.22 for protonated 1,2-dialkylimidazoles214 and helps to explain the larger than expected chemical shifts in the 1H NMR spectrum for the imidazole and 2-methyl protons.

46 49

Figure 2-7 Proposed zwitterion formation

With a significant amount of thiol 46 on hand we could then attempt methylation to form the desired salt 45. However, prior to this, the solubility of uncharged thiol 46 in EMIM NTf2 was tested. Pleasingly, thiol 46 proved to be soluble in this IL and, as one of the targets of this work was to provide alternative HAT reagents, thiol 46 underwent kinetic testing. The outcome of this work will be discussed in Chapter 3.

2.1.9 Methylation to form charged t-thiol 45

46 45

Scheme 2-20 Unsuccessful imidazole methylation of tertiary thiol 46

Reagents and conditions: a) MeI, toluene, 100 C, 17 h.

Initially, methylation of thiol 46 to form imidazolium salt 45 was attempted using the same method as previously described; a large excess of iodomethane was added to a solution of thiol 46 in toluene and heated for 17 hours at 110 C. Unfortunately, the desired product was not isolated following this reaction, and neither signals for methylation of the imidazole or the thiol were observed in the 1H NMR spectrum of the crude product. The boiling point of iodomethane is 42 C,215 so the reaction was repeated but heated to only 50 C to increase the amount of iodomethane in solution. After 24 hours, a 1H NMR spectrum of the product did show a very small resonance had formed just under 4.0 ppm, attributed to imidazole methylation, as well as two small signals forming downfield of 7.0 ppm, attributed to the imidazolium protons. However, after

38 continuing the reaction for a further 72 hours, no increase in signal size or integration was observed.

38 38-2

36 36-2

Scheme 2-21 Elimation products following imidazole methylation attempts of 46

Reagents and conditions: a) MeI, toluene, 100 C, 17 h.

Figure 2-8 1H NMR spectra of isolated elimination products 36 and 38 compared to starting t-thiol 46

Upon closer examination of the reaction, it appeared that elimination of the sulfur moiety had occurred. The 1H NMR spectrum of the crude materials showed two small singlet resonances at around 1.68 ppm which correspond to the tertiary methyl groups in an eliminated product. Furthermore, three new resonances were observed, one at approximately 5.0 ppm and two at close to 4.6 ppm. These can be attributed to the single proton on the alkene of the major elimination product and the two protons on the terminal alkene of the minor product respectively. Indeed, following flash chromatography two major compounds were isolated with very similar characteristics. The less polar compound (middle spectrum in Figure 2-8) had identical 1H NMR spectral characteristics as the previously described alkene 36 with the single alkenyl proton resonance on the major product appearing at 5.06 ppm, the two proton signals on the terminal alkene of the minor product at 4.70 and 4.65 ppm, and the two terminal methyl signals at 1.59 and 1.68 ppm. Notably, marginally less minor elimination product formed as ascertained by proton integration.

A 1H NMR spectrum of the more polar compound (top spectrum in Figure 2-8) is similar, with the same characteristic elimination signals apparent, namely the major and minor alkene proton signals at 5.02, 4.66 and 4.61 ppm, and the two singlet resonances from the terminal methyl groups at 1.65 and 1.56 ppm. However, also noticeable is the two doublet signals from the imidazole ring shifting to 7.40 and 7.60 ppm, a new singlet at 3.96 ppm and a slight shift downfield to 4.15 ppm for the

CH2-N triplet signal. These signal differences all indicate that methylation to form an imidazolium has occurred, as this causes a greater deshielding effect on surrounding protons, accounting for the downfield shift seen with several signals. These signals are consistent with the previous synthesis of charged alkene 38. Unfortunately, no isolated product appeared to correspond to the desired imidazolium salt 45.

Given thiol elimination is observed, a side reaction must be occurring to convert the thiol into a good leaving group, as it does not typically undergo elimination reactions. As a large excess of iodomethane was used in this methylation attempt, and the previously expected sulfur thioether formation, it is not unreasonable to suggest that sulfur is methylated twice to form a sulfonium salt. Indeed, Oppenheimer and co-workers have described an analogous reaction to form trimethylsulfonium iodide through the addition of iodomethane to methylsulfide.216 Furthermore, Schmitz and co-workers have described the basic elimination of sulfonium salts to form internal and terminal alkenes (Figure 2-9).217, 218 Although no base was added to the reaction, previous experiments mentioned earlier in this work have shown that the imidazole or imidazolium moiety

40 can act as a strong enough base to cause elimination. From this it can be assumed that demethylation and elimination of the thiol occurs prior to methylation of the imidazole ring, given no isolated products correspond to the thiol or singly methylated thioether.

Figure 2-9 Example of sulfonium formation and elimination216, 217

Z = n-Bu, OH, O-n-Bu, OPh, OAc or OCF2CFClH.

Several efforts were made to limit this elimination from occurring by varying the methylating agents, temperature and equivalencies. Firstly, the reaction was repeated using only one equivalent of iodomethane and heating in toluene at 110 C, however, this did not afford the desired product 27. Secondly, one equivalent of iodomethane was added to a solution of thiol 46 in toluene in a sealed tube and heated at 55 C for 44 hours. After this time, only a small amount of charged thiol 45 was detected and, unfortunately, after increasing the temperature to 65 C, the eliminated product was identified following analysis of a crude 1H NMR spectrum. As mentioned earlier, elimination appears to occur prior to methylation, so while these reactions were attempted, their success was not expected. A sealed tube was used to help increase the amount of iodomethane in solution in order to react with the imidazole ring without dramatically increasing the temperature.

Ensuing efforts toward methylation of t-thiol 46 were attempted using different methylating agents, dimethyl methylphosphonate 50219 and methyl trifluoroacetate 52,220 as the resulting compound can undergo anion exchange to form the final targeted t-thiol 27. As such, a slight excess of the alkylating agent was added to a sealed tube with a solution of 46 in toluene and heated at 100 C. Unfortunately, the desired product was not observed with methyl trifluoroacetate, with 50 % of starting material recovered. Reaction of dimethyl methylphosphonate resulted in a poor crude yield, less than 10 %, of the desired product and this could not be improved after varying temperature, equivalencies or time. It was intended that the larger anions, methyl methylphosphonate 51 or

41 trifluoroacetate 53, formed following methylation using these alternative agents would reduce dimethylation and elimination of the thiol. Also, the larger structures may make it more difficult to initially methylate the thiol given it is already somewhat hindered by the tertiary methyl groups, while the imidazole ring is far less sterically hindered.

50 51

52 53

Figure 2-10 Alternative methylating agents and corresponding anions

2.1.10 Further attempts toward deacetylation of imidazolium t-thiol 48

48 45

Scheme 2-22 Successful deacetylation of charged thioacetate 48

Reagents and conditions: a) 33 % NH3, MeOH, r.t., 17 h.

Although previous deacetylations of charged thioacetate 48 were unsuccessful, several other methods are available, such as using ammonia,221 hydrazine222 or dithiothreitol (Figure 2-11).223 Firstly, excess dithiothreitol, most commonly used for reducing biological disulfides,224 was mixed with charged thioacetate 48 and 10 mol % NaHCO3 in acetonitrile and stirred at room temperature overnight. Following aqueous workup and 1H NMR analysis of the crude material, it appeared no reaction had taken place due to the presence and full integration of the acetate signal at 2.24 ppm. However, the starting material was recovered in a 74 % yield.

Figure 2-11 Dithiothreitol

Next, two equivalents of 30 % aqueous solution of ammonia was added slowly to a solution of charged thioacetate 48 in MeOH and stirred for 17 hours. After acidification to pH 3 and extraction, the product could be observed in a 1H NMR spectrum of the crude material, albeit in low yields. The reaction was then repeated using only a slight excess of ammonia and monitored by HRMS over several days, pleasingly leading to good yields of over 70 %.

Figure 2-12 1H NMR spectra of charged thioacetate 48 starting material and charged t-thiol 45 product

Unfortunately, a small amount of an unidentified by-product was formed. Flash chromatography was performed to remove this by-product, however, given the highly polar nature of the charged thiol 45 and the by-product, as well as their propensity to streak on silica, it was exceedingly difficult to purify, and much material was often lost as a result. Efforts to recrystallise were attempted by dissolving the crude mixture in minimal hot MeOH and diluting with THF before storing below freezing temperature for several days.

Other attempts used included dissolving the product in CH2Cl2 and diluted with Et2O. Despite no crystallisation occurring, these methods were partially successful in removing by-products and were repeated several times to remove as much by-product as possible. This difficulty in recrystallisation is not an isolated occurrence, as it was found with all salt products formed during this project. Driesen and co-workers state that while ionic liquids can be regarded as molten salts and salts can be purified by recrystallisation, ionic liquids hamper this method due to being very viscous oils at room temperature and sometimes below. However, even ILs that do crystallise at room temperature are somewhat difficult to handle during spectroscopic measurements.225

2.1.11 Conversion to the BF4 salt 27

45 27

Scheme 2-23 Conversion to the BF4 salt

Reagents and conditions: a) NaBF4, CH2Cl2, 45 C, 48 h.

Anion exchange was easily performed by refluxing a large excess of NaBF4 with iodide salt 45 in

CH2Cl2 for 48 hours. After washing with water, the product was isolated in an almost quantitative yield.226 The reaction time was arbitrarily set at 48 hours as this was deemed more than sufficient for full conversion to the tetrafluoroborate salt. Unfortunately, this anion exchange is not easy to quantify by normal characterisation techniques. Indeed, a 1H NMR spectrum of the material shows

44 small chemical shifts compared to the starting material, while HRMS shows the same m/z values and it is difficult to glean any useful information from an IR spectrum. The exchange of an iodide anion for a tetrafluoroborate is not required for future kinetic experiments, however, these studies will involve exposure to high levels of energy and/or irradiation and iodine has a greater potential for side reactions. Other anions considered were PF6- or NTf2-, which are other commonly used anions and ones that have been seen in radical studies,118, 122, 227, 228 however, the PF6- anion can cause the IL to be partially water soluble or more hygroscopic,70, 229, 230 while NTf2 salts are quite expensive.

Despite the difficulties in determining full anion exchange, a simple starch-iodine test can establish whether iodide is present in the product solution. Other techniques are possible, such as 127I NMR spectroscopy, combustion microanalysis or ion chromatography, however each of these techniques may have issues with sensitivity or ease of obtaining information.231, 232 Regardless, the starch-iodine test is known be to very sensitive in regards to the amount of iodine required for a colour change and is easy to perform.233 Although this test is not quantitative, it has been used to detect iodine concentrations as low as 3 µM,234 so it could be said that no colour development effectively demonstrates that there is no iodine present, or at the very least, to such a negligible level that it can be ignored.235

The test was performed by dissolving both the starting material and product in minimal CH2Cl2 and a few drops of the CH2Cl2 solutions were added to separate solutions of H2O2 and AcOH in water. The addition of starch results in a dark purple colour if iodide is present, due to the formation of a starch-I3- complex, and will remain colourless with no iodide present, as expected with the desired product. The reactions shown below drive this reaction and the colour change. It should be noted that the addition of iodine (I2) negates the need to add hydrogen peroxide and acetic acid, however, this was avoided so that the sole source of iodine/iodide was from iodide salt 45. Also, CH2Cl2 is not required but was added to aid solubility and increase the dispersion of the IL products, as neither are soluble in water.236

− + 퐻2푂2 + 2 퐼 + 2 퐻 → 퐼2 + 2 퐻2푂

− − 퐼2 + 퐼 → 퐼3

− − 퐼3 + 푠푡푎푟푐ℎ → 푠푡푎푟푐ℎ 퐼3 푐표푚푝푙푒푥

Pleasingly, the solution containing the starting material turned yellow and upon standing overnight, a very dark purple/black, while the product solution remained colourless over the same time period. Although the reaction with starch is usually quite fast and in this case took several hours, this possibly indicates that excessive amounts of acid were added causing hydrolysis of starch to simpler sugars.237 Regardless of this, the yellow colour produced is a sign that triiodide anions have formed, thus iodide is present in the starting material. As no colour was seen in the product sample, it is reasonable to assume that no iodide is present. In order to confirm that the two solutions were equivalent, with the only change being the charged thiol 45 added, a small amount of KI was added to the solutions containing BF4 salt 27, which instantly turned yellow and, upon standing, dark purple.

With the desired IL-soluble thiol 27 in hand, kinetic analysis could be performed, the results and discussion of which are discussed in Chapter 3. Our attention then turned toward the synthesis of IL-soluble organostannane derivatives based on commonly used stannanes, such as triphenylstannane, and their use in HAT experiments.

2.2 Stannane

2.2.1 Introduction to organotin chemistry Organotin chemistry originates with some of the pioneers of organometallic chemistry. Frankland, a student of Bunsen, and Lowig, Bunsen’s successor at the University of Breslau, both independently described the formation of organotin derivatives in 1850 and 1852 respectively.238-240 It took another hundred years for organotin chemistry to become more mainstream while attention was focussed more toward other organometallic compounds, particularly organomagnesium derivatives. However, since then, the field of organotin chemistry has grown exponentially to become one of the most widely used classes of compound in organometallic chemistry.241

Analysis of tin compounds is an easier task than most other elements, with it said that tin can be studied by more techniques than any other element.242 Indeed, infrared, Raman and Mössbauer spectroscopy are easily applied to the analysis of tin compounds, with Mössbauer spectroscopy critical in the earlier structural elucidation of organotin compounds. Tin has ten stable isotopes, making mass spectrometry a trivial task due to the characteristic peak pattern, while three of those isotopes, 115Sn, 117Sn and 119Sn all have spin ½, and are suitable for NMR analysis.243 However, 119Sn is the nucleus most commonly probed as it has the greatest sensitivity of all isotopes, closely followed by 117Sn (sensitivity 25.7 and 19.2 times greater relative to 13C respectively), while both have similar abundances.244

The applications of organotin compounds are varied and dependent on the type of compound being used (e.g. tin hydrides, halides or oxides). Two of the more common synthetic uses include transmetallation,245 particularly with lithium, and the Stille reaction.246 Other less frequent uses of organotin compounds are directed toward the therapeutic potential as antitumor agents (pyridoxine derivative 54),247 cancer chemotherapy (steroid derivative 55),248 or antimicrobial, antiparasitic, antiviral and antihypertensive effects.249

54 55

Figure 2-13 Organotin drugs for cancer treatment247, 248

Organotin reagents are also possibly the most well-known, well understood and most widely used reagents in radical chemistry due to their versatility, predictability and functional-group tolerance.250 Since some of the pioneering work by Kuivila in the 1960s regarding the now widely use tin hydride reduction method, tin’s use has exploded.251 Indeed, Walton and Baguley describe the ‘tyranny of tin’ such is the prestige and notoriety that tin reagents possess, essentially monopolising the market place for homolytic synthetic and kinetic applications. A number of examples of tin hydride use in radical chemistry can be seen in Figures 1-2 to 1-5.7-9, 17, 18

Unfortunately, this dominance has come with a price. The perceived toxicity of organotin compounds can be a deterrent, as can the sometimes insurmountable purification problems which have limited large scale applications in the synthesis of pharmaceuticals, where strictly heavy-metal-free products are required.16 The perceived toxicity of organotin compounds largely stems from the former use of tributyltin derivates as a potent biocide in anti-fouling paints for protection of ships’ hulls, which results in adverse effects for aquatic organisms.252 Many methods have been developed to aid the removal of tin by-products from reaction mixtures, such as treating polar tin products with Me3Al or non-polar products with NaOH,253 developing water soluble tin hydride reagents (56 and 57, note the Sn-N bond in 56 is a dative covalent bond),254, 255 or a potassium carbonate-silica stationary phase for flash chromatography.256 Quintard and co-workers have also published an extensive review detailing a number of further methodologies to limit or avoid contamination by organotin residues in organic synthesis.257

56 57

Figure 2-14 Water soluble organotin derivatives254, 255

The use of organotin compounds in ILs has been relatively sporadic since the late 1990s. Gordon and McClusky were some of the first, performing allylation reactions with tetraallylstannane on aldehydes using BMIM cations with BF4 and PF6 anions,258 and the following year McClusky performed analogous reactions to form N-protected homoallylic alcohols.259 Further work by Handy and Zhang explored Stille cross coupling reactions with tributylstannane derivatives in

BMIM BF4,260 which was expanded to Suzuki cross coupling with palladium nanoparticles in quaternary ammonium salts by Montingelli et al.261 Suarez and co-workers have also synthesised biofuel from vegetable oil by transesterification using an organotin complex 58 immobilised in

BMIM InCl4.262 Many of these biphasic reactions found the IL and catalysts able to be regenerated and/or reused several times with no significant impact on reaction outcome. Unfortunately, although the two-phase system often allows for easier purification, numerous extractions with diethyl ether or petroleum spirits are required, sometimes requiring further washes with aqueous potassium fluoride to remove tin residues. Furthermore, the amount of remaining tin residue in desired products is not reported, which may restrict the application of similar reactions to pharmaceutical syntheses.257

Figure 2-15 Organotin complex used for biofuel production in ILs262

In a similar fashion to the above applications, Legoupy et al. have synthesised IL-supported organotin compounds for use in Stille cross coupling reactions, reductive amination, alkyl halide reductions and for use in the preparation of molecular imaging and therapy agents.108, 263-268 Importantly, Legoupy found that it was possible to recycle and reuse the system as products, by-products and remaining starting materials could be extracted by a non-IL miscible solvent, while the palladium catalysts and organotin reagent remained in the IL phase. Also, in Stille cross coupling reactions, by adding PhLi to the reaction mixture the required aryltin compound could be reformed to further the reaction.268 In a similar manner, for radical reduction of alkyl halides,

NaBH4 could be added to the solution to reform the active tin hydride 59, while no signals corresponding to organotin residues could be observed in 1H or 119Sn NMR spectra of the extracted products.265 Both of these factors are advantageous when working with organotin as reforming active compounds in situ allows for lower mol % of the initial organotin to be added, and no extraction into product mixtures significantly increases the applications.

Scheme 2-24 Legoupy’s synthesis of IL-supported organotin hydride 59263-268

Reagents and conditions: a) NaH, THF, r.t., 48 h; b) Bu2PhSnH, LDA, THF, -78 °C – r.t., 19 h; c) MeI, 45 °C, 17 h;

d) HCl, Et2O, r.t., 1 h; e) NaBH4, Et2O, r.t., 45 min.

2.2.2 Retrosynthesis of target compound Similar to the issue faced with common t-thiols, the traditional stannanes used for as HAT reagents, such as tri-n-butylstannane and triphenylstannane, were not soluble in the IL solvents used by our laboratory for spectroscopic purposes. This is due to the low electronegativity of tin, lower than carbon, making quite non-polar compounds.242 Although either butyl or phenyl substituents on the tin can used, phenyl groups were chosen due to the abundance of triphenyltin chloride within the laboratory, and the relative ease of cleaving a phenyl group from tin compared to a butyl group. Other structural features of the target, such as the six-carbon chain linker, 2-methylimidazole and tetrafluoroborate anion were unchanged to reduce any variables for rate constant calculations between the thiol and tin compounds. Given the synthesis of an IL-supported tin hydride by Legoupy et al. this formed our initial approach to the synthesis of stannane 60.

Figure 2-16 Targeted IL-supported stannane 60

2.2.3 Preparation using literature method

61 62 63

Scheme 2-25 Substitution reaction to form primary chloride 63

Reagents and conditions: a) NaH, THF, r.t., 5 days.

Using an adaptation of the work from Legoupy and co-workers,268 2-methylimidazole (61) was dissolved in anhydrous THF and added dropwise to a suspension of NaH in anhydrous THF at 0 C before warming to room temperature and stirring for 45 minutes. After this time, 1-bromo-6- chlorohexane (62) was added slowly and the solution stirred for 5 days. Following quenching with

51 dilute acid, typical aqueous workup and flash chromatography, the desired alkylated imidazole 63 was isolated in an 80 % yield. 1H NMR spectroscopy confirmed the structure of primary chloride 63,269 with two doublet signals from the imidazole ring present at 6.79 and 6.89 ppm and two triplet signals from CH2-Cl and CH2N at 3.52 and 3.82 ppm respectively.

63 64

Scheme 2-26 Substitution of primary chloride to insert a triphenylstannyl moiety

Reagents and conditions: a) LDA, Ph3SnH, THF, -78 C – r.t., 17 h.

Addition of the triphenylstannyl moiety could be achieved through substitution on the primary chloride. As such, LDA was prepared in situ, cooled to -78 C and to this triphenylstannane in anhydrous THF was added dropwise. The solution warmed to -60 C and stirred for one hour before a solution of alkylated imidazole 63 in anhydrous THF at -50 C was transferred to the tin- lithium solution via cannula. The resulting solution was allowed to warm to room temperature overnight before undergoing an aqueous workup to isolate the crude product. 1H NMR spectroscopy of this crude product revealed the substitution was successful, with the triplet signal at

3.52 ppm (CH2-Cl) in the starting material no longer present. This is expected as the electronegativity of tin is far less than chlorine, so there is no significant deshielding effect and the signal shifts upfield. The product was not purified given descriptions by Legoupy detailing the difficulty in purification at this stage as by-products have similar polarity to products when using 2-methylated imidazoles. Unfortunately, several further attempts to repeat this synthesis of tin-imidazole 64 were unsuccessful, likely due to issues forming the key triphenyltin anion. Altering the reaction temperature, time and concentration were not able to enhance the synthesis and yield of tin-imidazole 64.

64 65

Scheme 2-27 Imidazole methylation to give charged organotin derivative

Reagents and conditions: a) MeI, 40 C, 17 h, * yield over two steps.

Methylation to form the imidazolium derivative 65 could be easily achieved using a similar method to that described previously, with the crude tin product 64 mixed with neat iodomethane in a sealed vessel at 40 C and heated for 17 hours. Following aqueous workup, a sticky brown paste was formed, with several characteristic signals in a 1H NMR spectrum, in particular singlets at 2.70 and

3.92 ppm (CH3-C and CH3-N respectively), a triplet at 4.00 ppm (CH2-N) and a doublet at 7.10 ppm (imidazole proton). These downfield resonance shifts are expected given the formation of an imidazolium salt, causing greater deshielding to surrounding protons. Of note are the imidazole proton resonances, only one of which is visible at 7.10 ppm as the other is covered by the large multiplet signal from the aryl protons. Most organic by-products could be removed from the desired product simply by washing with Et2O.

Numerous efforts were made towards the removal of stubborn by-products, firstly by dissolving the residue in a 50:50 mix of CH2Cl2 and toluene, removing the CH2Cl2 under reduced pressure and triturating the remainder with toluene to aid removal of by-products, as the tin salt 65 is insoluble in toluene. Secondly, the sample was washed with 1 M NaOH in order to form tin hydroxides and bistin oxides which are easily removed on silica.253 Flash chromatography using 10 % w/w potassium carbonate-silica was also performed which was also successful at removing a large amount of by-products.256

65 66

Scheme 2-28 Formation of tin chloride 66 following protodestannylation

Reagents and conditions: a) 2 M HCl, CH2Cl2, r.t., 3.5 h.

Cleavage of a phenyl group from tin was achieved adding 2 M HCl in Et2O dropwise to a solution of salt 65 in anhydrous CH2Cl2 at 0 C. After stirring for several hours, aqueous workup and washing with Et2O/hexane, the desired tin chloride 66 was isolated as a waxy yellow solid in an 87 % yield. The structure was supported by HRMS, with [M-I]+ observed at 489.1077 m/z, compared to the expected 489.1120 m/z, while the integration of the aromatic proton signals in the 1H NMR spectrum also indicated that cleavage had occurred.

Tin hydride formation was achieved by adding an excess of NaBH4 and several drops of MeOH to a solution of tin chloride 66 in CH2Cl2. The reaction was monitored by TLC and, when complete, the solution underwent an aqueous workup before concentrating and storing below 0 °C under an inert atmosphere. Unfortunately, the synthesised tin-hydride was not soluble in several common deuterated solvents so NMR spectra were not obtained, however, the compound was deemed to be of sufficient purity for use in preliminary flash photolysis studies performed by Dr. Amber Hancock. The results from this preliminary study have not been included in this text as experimental procedures and techniques were subsequently improved to allow more accurate and reliable results.

2.2.4 Other methods attempted Although this literature method was successful in one instance, subsequent efforts to improve yields and synthesise greater quantities of the desired salt were unsuccessful. In particular, the critical tin-carbon bond formation reaction was found to be highly irreproducible in this work, likely due to the highly sensitive reagents and intermediate products. As such, other routes toward uncharged triphenyltin 64 were investigated, with literature detailing several alternative reaction pathways detailed below.

2.2.4.1 Finkelstein reaction

63 67

Scheme 2-29 Attempted Finkelstein reaction

Reagents and conditions: a) NaI, acetone, 60 C, 17 h.

One perceived difficulty during formation of uncharged triphenyltin 64 was assumed to be substitution on the alkyl chloride, thus, a Finkelstein reaction was performed to convert the chloride to a more reactive alkyl iodide.270 As such, excess NaI was added to a solution of alkyl chloride 63 in acetone and the mixture refluxed for 24 hours before being concentrated under

reduced pressure, dissolved in CH2Cl2 and undergoing an aqueous workup.271 A TLC of the crude reaction mixture revealed many products, while the extracted yield was poor. A 1H NMR spectrum

of the crude material was not able to show the desired product signals, such as for CH2-I, which

should present as a triplet signal further downfield to CH2-Cl in the starting material. Flash chromatography was able to isolate 10 % of the starting material, with the remaining by-products unidentified. This is possibly due to the incompatibility of the nucleophilic/basic imidazole ring and the reactive iodide leaving group, leading to elimination or substitution to give polymeric products.

2.2.4.2 Attempted Grignard synthesis of stannane

63 64

Scheme 2-30 Attempted Grignard reaction to insert triphenylstannyl moiety

Reagents and conditions: a) magnesium, iodine, Ph3SnCl, anhydrous THF, 0 C – r.t., 17 h.

Another possible formation method of uncharged triphenyltin 64 is through the use of a Grignard reaction.272 Initially, alkyl chloride 63 was reacted with activated magnesium in anhydrous THF before adding triphenyltin chloride and allowing to stir for 24 hours. Unfortunately, despite a number of different magnesium activation techniques being employed, such as vigorous stirring,

sonication, or the addition of I2 or 1,2-dibromoethane, this reaction was not successful likely due to the low reactivity of chlorides to form Grignard reagents273, 274 and gave a complex mixture of products. Given the failure of the previously described Finkelstein reaction to form an primary iodide (Scheme 2-29), other suitable compounds were investigated.

68 69 70

Scheme 2-31 Formation of difunctionalised hexane chain 70

Reagents and conditions: a) p-toluenesulfonic acid, CH2Cl2, r.t., 17 h; b) NaI, acetone, 56 C, 17 h.

In order to form the desired tin compound, the Grignard reagent must have functionality on either side of the alkyl chain. 6-Chloro-1-hexanol (68) was chosen as an adaptable molecule given the ease of which it can be manipulated to form a suitable Grignard reagent. Since Grignard reagents are highly nucleophilic, the alcohol group must be protected as the slightly acidic hydroxyl proton could protonate and destroy the Grignard reagent before it is able to react.275 As such, following the method of Padilla and co-workers,276 3,4-dihydropyran (69) was added dropwise to a solution of

6-chloro-1-hexanol (68) and catalytic p-toluenesulfonic acid in CH2Cl2 at 0 °C, and stirred at room temperature overnight before undergoing standard aqueous workup. The tetrahydropyran (THP) ether product was isolated in a 98 % yield following flash chromatography, and it’s structure confirmed by 1H NMR spectroscopy which was in agreement with literature characterisation.277 Of note is the CH proton signal between oxygen atoms at 4.54 – 4.57 ppm in the 1H NMR spectrum, which is characteristic of the product. The tetrahydropyran group was chosen in this situation given its ease of installation, removal, low cost, availability and relative stability to most non-acidic reagents.

A Finkelstein reaction was then performed in the standard manner by refluxing an excess of NaI with the primary chloride intermediate in acetone for 17 hours. Following an aqueous workup, the desired iodo compound 70 was isolated as a yellow oil in a 93 % yield and its structure confirmed by 1H NMR spectroscopy, comparing favourably with that from the literature.278 The most notable change are the CH2-X proton signals, which can be seen as a triplet signal at 3.52 ppm in the starting material and at 3.20 ppm in the THP ether 70.

70 71

Scheme 2-32 Unsuccessful Grignard reaction using THP-ether 70

Reagents and conditions: a) magnesium, iodine, Ph3SnCl, anhydrous THF, 0 C – r.t., 17 h.

In the same manner to the previous Grignard reaction, the primary iodide 70 was added slowly to activated magnesium in anhydrous THF and stirred for 30 minutes, followed by the dropwise addition of a solution of triphenyltin chloride in anhydrous THF. Unfortunately, following an aqueous workup, the desired product was not formed. Puzzlingly, although magnesium was consumed, the reaction turned grey and was visibly exothermic with the addition of the alkyl iodide, a 1H NMR spectrum of the crude product did not show the CH2-I proton signals or resonances associated with the desired product. Flash chromatography was also unable to isolate any meaningful products, possibly due to competing Wurtz coupling which frequently accompanies Grignard reagent formation.279

A test reaction using the same procedure and starting material was performed, substituting alkyl iodide 70 for benzaldehyde, which should clearly indicate whether a reaction is occurring.280 Unfortunately, a very similar outcome resulted, with the magnesium consumed, the solution turning grey in colour and becoming exothermic with the addition of alkyl iodide 70, usually indicating successful formation of a Grignard reagent, but no reaction with the benzaldehyde was observed.

Again, the CH2-I resonance in a 1H NMR spectrum was not detected but no further reaction appeared to occur.

2.2.4.3 Lithium chips and Zinc powder

70 71

63 64

Scheme 2-33 Unsuccessful substitution attempts using lithiation or zinc dust

Reagents and conditions: a) Lithium, Ph3SnCl, anhydrous THF, r.t., 17 h; b) Zinc dust, Ph3SnCl, sat. NH4Cl, anhydrous THF, r.t., 17 h.

Given the initial method involved lithiation of tin using LDA, attempts were made to lithiate with lithium metal instead. As such, strips of lithium metal were placed into anhydrous THF before

adding Ph3SnCl and allowing the mixture to stir overnight. Following this, THP-protected iodohexanol 70 or hexyl chloride 63 was added and the solution allowed to react for a further several hours. Following aqueous workup, the desired material was not obtained. The reaction was repeated several times with various changes with no significant improvements. Using the recommendation of Miller and co-workers, the lithium strips were washed quickly in anhydrous MeOH until shiny before rinsing in anhydrous THF and placing into solution.281 Extended sonication or reflux was also not able to improve the reaction, which should turn the solution a deep green colour upon formation of the tin lithium species, however only pale green solutions

58 were ever managed. Despite all care being taken to eliminate water from the synthesis, it is possible that the starting tin reagent contained moisture that reduced the effectiveness of this reaction.

Given the difficulties in the previous few methods, some of which may be due to water contamination, a method where water and oxygen presence was of no consequence was attempted. Following the work of Tagliavini et al., zinc dust was added to a mixture of THF and saturated

NH4Cl before adding a primary halide (THP-protected iodohexanol 70 or hexylchloride 63) and allowing to stir for extended periods of time.282 Unfortunately, Tagliavini states the reactions are highly exothermic and completed in around 15 minutes, however, when attempted in this instance no exothermicity was observed and the desired products were not able to be isolated.283

2.2.5 Hydrostannylation

72 73

Scheme 2-34 Hydrostannylation of 5-hexen-1-ol (72)

Reagents and conditions: a) AIBN, 110 C, 24 h.

Hydrostannylation provides a simple method for carbon-tin bond formation with few by-products and simple reaction conditions. Excess 5-hexan-1-ol (72) was added to triphenylstannane under an argon atmosphere in a sealed flask before catalytic 2,2'-azoisobutryonitrile (AIBN) was added and the reaction stirred at 110 C for approximately 24 hours.284 AIBN was added periodically to the mixture to ensure the radical reaction was maintained given the decomposition rate constant (kd) for AIBN at 100 °C is 1.5 × 10-3 s-1 and half-life is less than 10 minutes.285 On reaction completion, the mixture was dissolved in CH2Cl2 and underwent an aqueous workup before flash chromatography to give the desired hydrostannylation product 73 in a 76 % yield. The structure was confirmed using HRMS, which showed a peak for [M-Ph]+ at 375.07641 m/z, comparing favourably with a calculated peak at 375.07865 m/z. The 119Sn NMR spectrum also showed a single resonance at -99.8 ppm, a shift from -162.8 ppm for Ph3SnH,286 while all other data was in

59 accordance with the literature.287 Importantly, this reaction proved to be relatively high yielding, reproducible and simple to perform.

Scheme 2-35 Unsuccessful hydrostannylation attempts from Legoupy and co-workers266

Reagents and conditions: a) AIBN or Pd(OH)2, n-Bu2PhSnH, acetone, varied temperature and reaction time.

Hydrostannylation was not attempted at a later stage in the synthesis as previous work by Legoupy and co-workers has demonstrated difficulties performing hydrostannylation using di-n-butylphenylstannane or tri-n-butylstannane with either AIBN or Pd(OH)2 catalysts on a terminal double bonds of an ionic liquid (Scheme 2-35).266 Variations of temperature, reaction time and anion were explored with no effect on product formation.

2.2.6 Functionalisation of terminal end

73 74

Scheme 2-36 Two step conversion of primary alcohol to iodide

Reagents and conditions: a) methanesulfonyl chloride, Et3N, CH2Cl2, r.t., 1.5 h; b) NaI, acetone, 56 C, 17 h.

With the critical tin-carbon bond formation successful, and with a functionalised terminal alkyl chain, it was then required to substitute the necessary imidazole ring for IL formation. This can be achieved using a modified Finkelstein reaction through the sulfonate intermediate. To that end, excess methanesulfonyl chloride was added to a basic solution of alcohol 73 in CH2Cl2 and stirred for 1.5 hours before undergoing an aqueous workup to give the desired mesylate in an 88 % yield.288 The structure was confirmed by 1H NMR analysis, showing a singlet resonance at 2.96 ppm, corresponding to the mesylate group, while the signal for the methylene adjacent to the

60 oxygen had also shifted from 3.56 ppm to 4.14 ppm. This compound was then dissolved in acetone, excess NaI added, and the solution refluxed for 17 hours, before being cooled and worked up.289 The desired alkyl iodide 74 was isolated in a good yield of 85 % and the structure confirmed by 1H NMR spectroscopy which displayed a triplet signal at 3.09 ppm, attributed to the CH2-I protons, among other expected signals. This compound was used without further analysis or purification.

2.2.7 Salt formation

Scheme 2-37 Imidazole substitution and methylation from (6-iodohexyl)tin compound 74

Reagents and conditions: a) 2-methylimidazole, NaH, THF, r.t., 7 days; b) MeI, toluene, 110 C, 24 h.

Salt formation was initially performed by stirring 2-methylimidazole with NaH in anhydrous THF for 30 minutes before adding the tin iodide 74 and allowing to stir for a further 24 hours.268 Following aqueous workup and flash chromatography, substituted imidazole 64 was isolated in a 78 % yield. The imidazole compound was then refluxed with excess methyl iodide in toluene for 24 hours, before being worked up and undergoing flash chromatography to give the desired charged

61 tin compound 65 in a good yield of 90 %. As experienced during a large portion of this work, purification of these imidazole compounds is quite tricky as the imidazole group tends to cause the compound to stick to silica and streak during chromatography, only exacerbated following salt formation. As such, given this transformation required two steps, both needing to undergo flash chromatography, much time and solvent was wasted during purification and so a simpler method was explored.46, 70, 225 It is also worth noting that the same substitution reactions were performed with the aforementioned mesylate intermediate which proved far less effective, with substitution to form uncharged tin-imidazole 64 requiring extended reaction times and temperatures to give only 50 % yields.

74 65

Scheme 2-38 Single step formation of IL-supported organotin 65

Reagents and conditions: a) 1,2-dimethylimidazole, toluene, 110 C, 24 h.

The same transformation was accomplished in just one step by refluxing 1,2-dimethylimidazole and hexyliodide 74 in toluene for 24 hours.78 Upon reaction completion, the solution was cooled, toluene removed under vacuum and the residue washed several times with Et2O to give the desired imidazolium salt 65 in a 96 % yield. The structure of the imidazolium salt was confirmed by HRMS, which displayed a peak for the parent cation at 531.18140 m/z, in good agreement with a calculated peak of 531.18222 m/z. Also, the 1H NMR spectrum showed expected resonance shifts for the protons on imidazolium ring which appear as doublet signals, one of which is seen at 7.10 ppm, the other buried under aromatic proton resonances, while singlet resonances for the attached methyl groups can be seen at 2.70 and 3.92 ppm. No proton signals from the uncharged imidazole ring of 1,2-dimethylimidazole, at 6.76 and 6.84 ppm, or its attached methyl groups at 3.52 (N-Me) and 2.32 ppm (CH-Me), were observed.290 Other data, which includes a 119Sn NMR spectral resonance at -108.7 ppm, was in line with the structure.

2.2.8 Synthesis of tin chloride 66

65 66

Scheme 2-39 Protodestannylation of triphenyltin to afford tin chloride 66

Reagents and conditions: a) 2 M HCl, CH2Cl2, r.t., 3.5 h.

In preparation for forming the desired tin hydride, a phenyl group attached to tin must be exchanged with a halide in a process known mechanistically as protodestannylation, an electrophilic ipso substitution reaction promoted by the strong β-effect of tin.291 Using the method of Jurkschat and co-workers, I2 was added in small portions to a solution of triphenyltin salt 65 in CH2Cl2 at 0 C and stirred overnight.292 Unfortunately, following aqueous workup, a 1H NMR spectrum of the crude material did not show any characteristic product signals, such as the expected doublets from the imidazole ring.

Instead, as previously described, phenyl cleavage was achieved by the dropwise addition of 1 M

HCl in Et2O to a cooled solution of salt 65 in anhydrous CH2Cl2, which was stirred at room temperature for 3.5 hours before concentrating and working up as required. It was found that working up the solution immediately after the reaction gave significantly lower yields, however, concentrating the solution before diluting in CH2Cl2 and working up allowed for higher yields.

After washing with Et2O, the desired tin chloride 66 was isolated in a good yield of 87 % with a melting point of 134.4 – 138.8 C. HRMS confirmed the structure with the parent cation peak seen at 489.1077 m/z, compared to calculated 489.1120 m/z. The 1H NMR spectrum also showed correct integration of the aromatic proton resonances, with the imidazolium proton signals now identifiable as two doublets at 7.15 and 7.19 ppm (showing a small roofing effect) and the ortho-aryl proton resonances shifting from 7.44 – 7.60 ppm in starting material to 7.65 – 7.84 ppm in the product as expected.293, 294

66 75

Figure 2-17 Halide exchange between tin and anion halides

Figure 2-18 HRMS of tin chloride 66 and tin iodide 75

It is interesting to note that halide exchange occurs within this molecule to give a tin iodide with chloride anion 75, with a peak in the HRMS at 581.0479 m/z matching very well with the calculated peak at 581.0470 m/z. This halide exchange is not expected to affect the next steps which involve anion exchange and halide cleavage, indeed the tin iodide 75 is likely to be more reactive to reduction than the tin chloride 66. In hindsight, this is not overly unexpected as the ratio of chlorine and iodine anions is approximately the same, so in a similar manner to Finkelstein reactions, some exchange will occur. Another noteworthy product exists at 499.1408 m/z, with a greater relative abundance compared to either tin chloride 66 or tin iodide 75, and while the structure is unknown, the isotopic splitting pattern suggests a tin atom is present, as with the product at 567.1279 m/z. Given the difficulty in visualising these products by TLC analysis due to the nature of salts on silica, one cannot be completely certain that these exchanges are occurring in

64 solution and may simply be an artefact from the mass spectrum. The conditions in the mass spectrometer may be causing some exchange, however, no full analysis was performed given that subsequent steps in the synthesis involve anion exchange and halide reduction. Thus, the composition of the final product would be the same regardless of where any exchange had occurred, either in solution or the mass spectrometer. Unfortunately, extended exposure of this compound mixture to ambient laboratory conditions, in particular light, causes decomposition to occur leaving an unidentified white powder. This decomposition product was insoluble in CH2Cl2,

Et2O, toluene and water, with a structure likely to centre around tin metal with little to no organic compound remaining attached.

2.2.9 Conversion to the BF4- salt

66 76

Scheme 2-40 Anion exchange to form tetrafluoroborate salt

Reagents and conditions: a) NaBF4, CH2Cl2, 40 C, 48 h.

In the same manner as for the tertiary thiol, anion exchange was performed by refluxing the iodide salt 66 with NaBF4 in CH2Cl2 for 48 hours before being worked up and rinsed with Et2O to give the tetrafluoroborate salt 76 in a quantitative yield. Characterisation of the product salt was largely the same as for the starting material, with very small chemical shift changes observed in the 1H NMR spectrum where the imidazolium proton doublet resonances have separated slightly to 7.13 and 7.23 ppm and the ortho-aryl proton signals shifted upfield to 7.51 – 7.69 ppm. A melting point of 115.6 –116.6 C was also obtained, approximately 20 °C lower than with iodine anion. This is an expected change as tetrafluoroborate is a more weakly coordinating anion compared to iodine, leading to lower melting points for tetrafluoroborate salts such as with NaI (melting point of

660.85 °C)295 and NaBF4 (370 °C)296 or [BMIM][I] (-64 °C)297 and [BMIM][BF4] (-75 °C).298 Given these melting points, the synthesised tin salts are not room temperature ILs, but do have melting points far lower than salts with the same anion and are soluble in other ILs of interest. As discussed

65 previously, C2 methylation causes a large increase in imidazolium-based IL melting points, so lower melting point salts could be synthesised, although side reactions may be more likely.181

The starch-iodine test explained previously was used again to confirm full conversion to tetrafluoroborate. Anion exchange with this compound is required for similar reasons to the tertiary thiol, iodine has potential to be more reactive during radical reactions, however, as halide conversion occurred in the previous step, anion exchange here also serves to ensure all anions are the same.

2.2.10 Preparation of tin hydride 60

76 60

Scheme 2-41 Hydride reduction to give organotin hydride 60

Reagents and conditions: a) NaBH4, CH2Cl2, MeOH, r.t., 23 h.

With the tin chloride BF4 salt 76 in hand, reduction to form the corresponding tin hydride could be pursued. Following the procedure of Legoupy and Pham,265 excess NaBH4 was added to a cooled solution of tin chloride 76 in CH2Cl2 with several drops of methanol added to aid reduction. This was stirred overnight until TLC indicated no starting material remained, after which time the solution was washed with H2O, the aqueous phase washed with CH2Cl2, the organic layers combined and concentrated in vacuo to give an off-white highly viscous oil, reminiscent of foam following solvent evaporation, with a yield of approximately 80 %. HRMS of the final compound indicated the reaction was successful, with a peak found at 455.1513 m/z matching well with an expected peak of 455.1509 m/z for the parent cation. As expected, although the starting material comprised of both tin chloride 76 and the analogous tin iodide (from tin iodide 75), both were successfully reduced to the tin hydride 60 as well as all of the other unknown tin compounds present in the starting material. The addition of methanol to the system is known to enhance the reactivity of NaBH4 and decrease required reaction times for reductions.210 As the reactivity of the tin hydride 60 is not known, it was prepared and used immediately in the following days for kinetic experiments, stored under argon at below freezing temperatures.

Figure 2-19 HRMS of tin hydride 60

2.3 PTOC ester

2.3.1 Introduction to radical precursors PTOC esters were discussed briefly in Section 2.1.1, and their ability to propagate a radical chain reaction is illustrated in Scheme 2-2. PTOC esters can be readily formed from a carboxylic acid or acid chloride and N-hydroxy pyridine-2-thione or a corresponding salt, usually with sodium, through a typical esterification reaction. The PTOC group is a strong, long wavelength chromophore absorbing at approximately 350 nm, extending into the visible region to give these compounds a distinct yellow colour.299

PTOC esters are usually stable at room temperature when shielded from light, and with a weak nitrogen-oxygen bond, they can be initiated thermally or photolytically with visible light. In this case, radical initiators are not required as the ester itself acts as an initiator. The subsequent

decarboxylation to expel CO2 often occurs rapidly to give a variety of radicals. However, this is not true in all cases, as aryl and vinyl radicals derived from aromatic and α,β-unsaturated acids are generally not available due to the slow decarboxylation of acyloxyl radical intermediates.300, 301 Indeed, when paired with highly reactive HAT reagents, these acyloxyl radicals can be trapped in competition with decarboxylation (Figure 2-20).302, 303 PTOC esters can also be used to generate oxygen and nitrogen-centred radicals under mild conditions, allowing them great synthetic flexibility.

Figure 2-20 Acyloxyl radical trapped by t-BuSH prior to decarboxylation303

The synthetic target of 6-heptenoic acid was chosen due to the extensive amount of data regarding radical cyclisation to form methylcyclopentane and cyclohexane (in approximately 50:1 ratio respectively).4 The simplicity of this unimolecular rearrangement has allowed for its use as a radical clock reaction and while any unimolecular radical reaction may qualify as a radical clock, the 5-hexenyl radical is very well known and applied in many studies.304 5-Hexenyl type cyclisations are

68 often used with HAT reagents on the lower to middle regions of the kinetic scale, an appropriate target for use with the previously synthesised t-thiols 27 and 46 and organostannane 60.299

2.3.2 Synthesis

77 78 79

Scheme 2-42 Michael addition to form diester 79

Reagents and conditions: a) NaH, THF, r.t. – 80 C, 3 h.

Following the method of Shirbhate and Kotha, 5-bromo-1-pentene (78) was added to a cooled solution of previously refluxed diethyl malonate (77) and NaH in anhydrous THF. The reaction was quenched following consumption of staring materials and following aqueous workup and flash chromatography to remove organic impurities, the desired diester was isolated in a low yield of 25 %.305 The 1H NMR spectrum of the purified diester 79 showed the expected signals, in particular the triplet resonance at 3.32 ppm indicative of the proton adjacent to both ester groups. Although 25 % is a low yield, sufficient diester 79 was obtained such that optimisation was not required.

79 80

Scheme 2-43 Diester hydrolylsis and subsequent decarboxylation to give monoacid 80

Reagents and conditions: a) KOH, EtOH, H2O, 100 °C – 160 C, 24 h.

Conversion of the diester 79 to monoacid 80 was achieved through a two-step process following the work of Pettit and Israeli.306 Firstly, the diester was converted to the corresponding diacid by a simple hydrolysis with potassium hydroxide in refluxing aqueous ethanol. Following isolation of the diacid, it was heated neat at 160 °C overnight to afford 6-heptenoic acid (80) in a moderate yield

69 after acid-base workup. The 1H NMR spectrum was in accordance with the literature,307 with the signal for the proton adjacent to the acid now present as a triplet at δ 3.27 ppm as reported.

80 81 82

Scheme 2-44 Esterification reaction to give PTOC ester 82

Reagents and conditions: a) DCC, DMAP, CH2Cl2, 0 C – r.t., absence of light, 17 h.

The Barton ester, radical precursor was formed using a typical Steglich esterification reaction,308 where DCC and catalytic DMAP were added to 6-heptenoic acid (80) and stirred briefly at 0 °C. This was followed by the addition of N-hydroxy pyridine-2-thione (81) and the solution stirred until full consumption of the pyridine moiety was observed by TLC analysis.309 During this time, the reaction was covered in foil to exclude light as the N-O bond is susceptible to homolytic cleavage. Subsequently, the reaction was stored in a freezer overnight before filtering over celite to aid removal of both DCC and the by-product dicyclohexyl urea. Prior experience performing flash chromatography of PTOC esters has resulted in significant amounts of decomposition and it is preferable to simply flash through a short silica plug directly into a foil-wrapped round bottom flask to avoid transferring and limit exposure to light as much as possible. Less than one equivalent of N-hydroxy pyridine-2-thione (81) was added to ensure unreacted 6-heptenoic acid (80) would remain on silica and only the PTOC ester 82 would pass through. Given the reactive nature of this radical precursor, extensive analysis was not performed as, and despite TLC and 1H NMR spectroscopy not showing any impurities, the PTOC ester 82 does not need to be 100 % pure for competition kinetic experiments.

2.4 Conclusions Several novel IL-soluble compounds have been successfully synthesised that are modelled on traditional HAT reagents. Regarding the tertiary thiol-based reagents, both charged and uncharged thiol reagents, 27 and 46 respectively, were successfully synthesised with most steps being relatively high yielding. These thiol-based reagents may provide a beneficial alternative to the traditional t-BuSH as they are both solids are room temperature, with no noticeable odour (i.e. low volatility), allowing for easier use.

The synthesis of IL-supported organostannane 60 involved several challenges, however, a high yielding, reproducible pathway was established following a conventional hydrostannylation. Although the final tin hydride 60 was not fully characterised, a HRMS of the product indicated the hydride was successfully formed. Further characterisation was not performed due to solubility, as well as potential reactivity issues in conventional organic solvents. Unfortunately, this stannane was not particularly easy to work with, so it is unlikely to be of any significant use for future reactions.

Finally, a suitable PTOC ester 82 was synthesised using a well-established reaction pathway. This PTOC ester can form a desirable radical clock following thermolysis or photolysis, the 5-hexenyl radical, which has well known and understood kinetic parameters.

3 Competition kinetics

3.1 Introduction Competition kinetic experiments employ an indirect measurement of kinetics through analysis of product ratios. Early kinetic analyses of radical reactions were performed in a direct manner, making use of Electron Spin Resonance (ESR), laser flash photolysis or pulse radiolysis coupled with rapid time-resolved analysis usually through UV-visible spectroscopy.299, 310 However, these direct techniques are not always able to be used, requiring large or expensive instruments and requiring products to be visible through the time-resolved analysis method.311 Competition kinetics however, requires much more simple and common equipment or compound functionality, such as a gas chromatograph, and indirect competition methods have been studied so extensively that almost the entire range of radical kinetics in solution can be studied.15, 299

Figure 3-1 Radical chain mechanism

For competition kinetics to be effective, the radical reaction must generally proceed to two different species, one which includes the rate constant under examination, and the other with a known rate constant, allowing for the unknown rate constant data to be extracted from product analysis.15 In order to further simplify the analysis, one reaction tends to be unimolecular and the other bimolecular, while both should be irreversible. In most cases, the bimolecular reaction involves a HAT step (radical propagation), while the unimolecular reaction involves radical rearrangement (R• in Figure 3-1). Furthermore, reactions are usually designed with a large excess (more than five equivalents, but typically upwards of ten) of a trapping reagent involved in the

72 bimolecular process such that the concentration of the reactive intermediate, i.e. the radical that is formed, can be considered to be unchanged throughout the reaction, a steady-state approximation.299 This allows for simplification of the rate law from second order to pseudo-first order.

Ingold and Griller coined the term ‘radical clock’ in regards to compounds whose absolute rate constant in solution for unimolecular rearrangement is known and can be applied in competition kinetic experiments.5 Thus, for all classes of radical intermediates there is a need for calibrated clocks which cover a range of time scales. Figure 3-2 shows some examples, while Newcomb has previously compiled a larger list.15, 299 Most competition kinetic measurements make use of the tin hydride method or PTOC-thiol method. The tin hydride method involves an alkyl halide, serving as the radical precursor, and an adequately reactive metal hydride, usually tri-n-butyltin hydride, to trap the radical intermediate by hydrogen atom transfer.15 Other metal hydrides may be used to increase the dynamic range of the experiment if the unknown rate constant is far too fast or slow for HAT to adequately compete. Most thiols, while excellent hydrogen donors, are not useful in this method due to the corresponding thiyl radical’s slow halide abstraction that is inadequate to maintain a chain reaction.

Figure 3-2 Radical clocks and their rearrangement rate constants at 25 °C15, 299

It goes without saying that the PTOC-thiol method makes use of PTOC esters as radical precursors, and thiols as hydrogen donors. This method has a few advantages over the metal hydride method as PTOC esters, and the related Kim esters, are highly reactive so a wide range of propagating radicals can be used. It is also possible to generate oxygen and nitrogen-centred radicals starting with PTOC esters. However, the high reactivity of the thione group is also a disadvantage in that if the radical formed following decarboxylation is slow, it can participate in a ‘self-trapping’ reaction with a thione group (Figure 3-3), with a number of rate constants measured for the addition reaction around 1 × 106 M-1 s-1.312-314 Some acyloxyl radicals can also be trapped prior to decarboxylation, as mentioned previously.

Figure 3-3 Radical scavenging by PTOC ester312

The Arrhenius equation (Equation 1 and 2) is a well-known empirical relationship between temperature and rate constant, with Arrhenius first developing this equation in 1889.315 Arrhenius’ equation was the first introduction of the term for activation energy, Ea, and the pre-exponential factor, A. According to the Arrhenius equation, the logarithm of the rate constant of a particular reaction is expected to have a linear relationship to the inverse of temperature, and kinetic studies over a temperature range of less than 100 K usually verify this.316 Indeed, the Arrhenius equation has historically prevailed over other kinetic models as the parameters, such as activation energy, are easily understood and linked to a reaction. However, some reactions are difficult to model at all, with other effects such as tunnelling requiring correction factors or other parameters.317, 318

퐸 − 푎 푘 = 퐴푒 푅푇 (1)

퐸 ln(푘) = ln(퐴) − 푎 (2) 푅푇

Importantly, rate data for other temperatures can be extrapolated from an Arrhenius plot, but equally importantly, the pre-exponential factor and activation energy for the reaction can be determined from the y-intercept (ln(A)) and gradient (-Ea/R) respectively. It is most common when reporting kinetic experiments to give the Arrhenius function (Equation 2) as well as the rate constant at 20 °C or 25 °C. Thus, by applying a radical clock to the reaction with the previously synthesised IL-soluble hydrogen donors (27, 46 and 60), we may derive the rate constants for hydrogen transfer, the pre-exponential factors and the activation energies of the reactions.

3.1.1 Explorations into similar radical reactions

83 84

Figure 3-4 Cyclisation of 6,6-diphenyl-5-hexenyl radical (83)

The cyclisation of the 6,6-diphenyl-5-hexenyl radical (83) was monitored in several solvents

(CH3CN, CH2Cl2 and BMIM NTf2) and following laser flash photolysis a transient absorption spectrum was developed, as depicted in Figure 3-5. The derived rate constant for cyclisation was compared to the known rate constant derived by Newcomb et al.319 to determine the impact of a polar IL solvent on the reaction rate. Newcomb had also used varying solvents, such as CH3CN, in order to confirm that solvent effects on the kinetics of this radical reaction are minor. The comparison with BMIM NTf2 also served to investigate whether IL viscosity had an impact on rate constants.

Indeed, the impact of both polarity and viscosity are often debated for free radical chemistry, with a paper by Ingold, Beckwith and Litwinienko exploring the frequently overlooked importance of solvents in free radical chemistry,129 although Welton and co-workers have stressed that understanding the polarity of ILs is not a trivial pursuit.90 Ha and co-workers have also explored the impact of viscosity on rates of diffusion, finding them to be almost halved in ILs compared to conventional solvents.320 Despite this, vibrational activation theory lends itself to rate constant increases in higher viscosity ILs due to a molecule’s kinetic energy being translated to vibrational energy, promoting bond formation,321 however this is more relevant for bimolecular processes.

Table 3-1 Cyclisation rate constants for the 6,6-diphenyl-5-hexenyl radical (83) in various solvents

Solvent Cyclisation rate constant at 22 °C

CH3CN 4.2 (± 0.5) × 107 s-1

Lit. CH3CN 4.5 (± 0.1) × 107 s-1 (Reported319)

CH2Cl2 4.1 (± 0.3) × 107 s-1

BMIM NTf2 5.5 (±0.1) × 107 s-1

1.50E-01

1.00E-01 (325 nm) (325

5.00E-02 Absorbance

0.00E+00 0 50 100 150 200

Time (ns)

Figure 3-5 Transient absorption spectra monitoring growth of cyclised product 84 in BMIM NTf2

As can be seen in Table 3-1, the rate constant for cyclisation is relatively unaffected for the 6,6-diphenyl-5-hexenyl radical (83) despite solvent polarity and viscosity. It is also useful to compare the rate constant in CH3CN to that from the literature319 (entry 1 and 2 in Table 3-1), which confirms the accuracy of our measurements. The lack of variation in rate constant is expected as the transition state to form cyclised radical 84 is relatively non-polar, thus not likely to have been affected by solvent polarity. Harper and co-workers have demonstrated pericyclic reactions, with little to no charge development, undergoing rate enhancement due to preferential solvation of the transition state in an IL.322 However, in the absence of more data for radical reactions in ILs and given that no change in rate constant was seen in Table 3-1, it is reasonable to assume for other non-polar radical rearranges, with non-polar transition states, that the rate constant will be largely unaffected. Having calibrated a radical clock in an IL, we could then access competing hydrogen transfer reactions to investigate solvent effects. This was achieved using the PTOC-thiol method explained previously, with p-thiocresol as hydrogen donor (Figure 3-6).

Figure 3-6 Hydrogen transfer from p-thiocresol to the 6,6-diphenyl-5-hexenyl radical (83)

Table 3-2 Rate constants for hydrogen transfer from para-thiocresol to the 6,6-diphenyl-5-hexenyl radical (83) in various solvents

Solvent Rate constant for hydrogen transfer at 22 °C

CH3CN 1.4 x108 M-1 s-1 (Reported for PhSH323)

CH2Cl2 1.4 (± 0.1) × 108 M-1 s-1

BMIM NTf2 1.7 (± 0.3) × 108 M-1 s-1

1 BMIM NTf2 : 1 CH2Cl2 1.5 (± 0.9) × 108 M-1 s-1

Although p-thiocresol was not used in further studies, the lack of any significant variation in the rate constant for hydrogen transfer over a number of solvents allows us to assume that for alkyl radicals with non-polar transition states, neither cyclisation or hydrogen transfer is affected by the solvent. This preliminary work, including both cyclisation and hydrogen atom transfer rate constant determination, was performed by Dr. Amber Hancock of the University of Melbourne.

3.2 5-Hexenyl radical 85 reaction and IL used

86 87

82 85 88

Figure 3-7 Generation of 5-hexenyl radical (85) and pathways to final products (HAT step eliminated for clarity)

Given the preliminary work detailed above, it is assumed that the Arrhenius parameters in the literature304 are relatively unaffected moving from conventional solvents to an IL. Other preliminary

work exploring the reaction in Figure 3-7 with t-BuSH as hydrogen donor in both EMIM NTf2 (89) and tertiary-butylbenzene (t-BuPh) has been performed, with similar product ratios in each solvent found, further confirming little solvent dependence on the rate constant for cyclisation. This allows for a rough determination of the rate constant for hydrogen transfer, although the exact rate for each compound may be slightly different, it is an easier representation of their reactivity compared to traditional hydrogen donors than an analysis of the product ratio and thus ratio of rate constants. As such, the Arrhenius expressions and rate constants detailed later are not exact but assumed to be a very close approximation to their true values. Furthermore, it is critical to reinforce that these rate constants and Arrhenius parameters are given for hydrogen transfer to a primary alkyl radical, the 5-hexenyl radical 85, as these rate constants/parameters will vary depending on the type of radical.

Figure 3-8 Ethylmethylimidazolium bis(trifluoromethane)sulfonimide, EMIM NTf2

Finally, the choice of IL for this experiment was ethylmethylimidazolium bis(trifluoromethane)sulfonimide (89) or, more commonly, EMIM NTf2. This ionic liquid was of the highest quality for spectroscopic use as it was colourless and had the lowest absorption in the regions required for excitation of the PTOC ester. A known problem when using ILs for spectroscopic applications is often their long absorption tail in a UV-Visible spectrum which may interfere with the radical reaction. Seddon et al. have published a number of methods for purifying ILs for spectroscopic applications, but these methods are difficult to perform on the quantity of IL required for all kinetic studies, especially as the spectroscopic quality of the IL should remain consistent throughout its use.70 Due to this, this ionic liquid was purchased from io-li-tec, Ionic Liquid Technologies, and used without further purification, with the same batch of IL used throughout all experiments.

The importance of using the same batch of IL throughout the set of experiments is not just to ensure the same optical purity, but also to ensure residual halide content and water remained constant, as these are known to alter IL properties.324 Baker and co-workers propose a simple test to establish the relative purity of commercially purchased ILs by comparing a vial of IL to a vial of water; an IL with high purity will be indistinguishable from water,79 as is the case with the IL used in these experiments. Furthermore, both cation and anion are commonly used, ensuring that the results can be applied to other common IL solvents.

3.3 Response factor Given that a ratio of products will be measured using gas chromatography, a response factor for these compounds must first be calculated to ensure good quantitative analysis.325 In this instance, the response factor is simply the ratio between the concentrations of analytes and the signal response of the GC detector. A suitable response factor can be established by calibrating the GC with known standard concentrations and applying that response factor to experimental solutions.326 During these experiments, the important information is the ratio between methylcyclopentane (86) and 1-hexene (88), so the response factor was calculated for this ratio.327 It is also important to note that the same GC and detector was used for all experiments, eliminating differences that can arise from using different equipment. However, the response factor can change over time despite keeping all conditions the same, so periodic recalculation of the response factor was performed to ensure no significant differences were observed.

4.5

3.5

2.5 y = 0.7428x 2 R² = 0.9999

1.5

0.5 Experimental [Uncyclised 88]/[Cyclised 86] 88]/[Cyclised [Uncyclised Experimental

0 0 1 2 3 4 5 6 Known [Uncyclised 88]/[Cyclised 86]

Figure 3-9 Response factor calibration curve for 1-hexene (88) and methylcyclopentane (86)

The calibration curve in Figure 3-9 was formed by preparing solutions with varying concentrations of authentic samples of uncyclised product 1-hexene (88) and cyclised product methylcyclopentane (86) in t-BuPh. An authentic sample of cyclohexane (87) was not included as no formation is observed during experimental kinetics. GC analysis of each concentration was repeated in triplicate with new samples to ensure the data is statistically significant. The resulting graph of the known product ratio and experimentally determined ratio is highly linear and shows that the GC response is consistently 0.7428 times, or ~74 %, of the known concentration. With this knowledge, we may assume that all future GC responses for the ratio between cyclised products 88 and 86 will be ~74 % of the true amount. Thus, the results must be divided by 0.7428 to reveal the true product ratio.

When considering the impact of the response factor on the derived Arrhenius expression, note that it is only the log(A) value (Equation 2, Section 3.1) that is impacted, as this relates to the y-intercept. As all data points undergo the same transformation, the gradient is not affected, and Ea is unchanged. This response factor was recalculated several times during GC studies with no significant variation in the graph's gradient found. This response factor was also calculated for the inverse product ratio of cyclised products 86 to 88, which gives a response consistently 1.3285 times, or ~133 %, of the known concentration ratio, with this response used in Figures 3-12, 3-15 and 3-18. These response factors should be the inverse of each other, and indeed equate to equivalent values within 1.33% of the inverse experimentally determined response ratio.

8 y = 1.3285x 6 R² = 1

Experimental [Cyclised 86]/[Uncyclised 88] 86]/[Uncyclised [Cyclised Experimental 0 0 1 2 3 4 5 6 7 8 9 10 Known [Cyclised 86]/[Uncyclised 88]

Figure 3-10 Response factor calibration curve for methylcyclopentane (86) and 1-hexene (88)

3.4 General method A standard method was used for all kinetic experiments, with a detailed explanation contained in Section 4.2, Chapter 4. In general, samples were prepared with 0.01 M PTOC ester 82 in

EMIM NTf2, with 10 to 50 equivalents (~0.10 to 0.50 M) of the desired hydrogen donor 27, 46 or

60 in EMIM NTf2 with further amounts of the IL added to make the solution up to a total of 1.0 mL. More than 10 equivalents of the hydrogen donor are used during these experiments as this ensures the concentration remains much greater than the 5-hexenyl radical throughout the reaction, and a steady-state approximation of the 5-hexenyl radical may be used during analysis.299 It is

important to note that the only solvent present in the reaction vessel was EMIM NTf2, with no co- solvent added in any case prior to reaction completion. Earlier explanations in this text have explored the impact of varying the mol fraction of an IL on reaction kinetics, however, finding a suitable co-solvent for these radical reactions is not trivial. Thus any impact of solvent mixtures will not be a factor during these experiments.

After degassing, the samples were photolysed for an extended time (with a pre-heated oil bath when required), products extracted into tertiary-butylbenzene before product ratios were analysed using gas chromatography. As opposed to more traditional extraction techniques, such as dissolving

the IL layer in EtOAc before adding Et2O to form two layers as detailed by Gordon and McClusky,258 the use of t-BuPh was found to provide more reproducible and more effective extractions for methylcyclopentane (86) and 1-hexene (88) as required for this analysis. The efficacy of this extraction technique was tested with known amounts of sample by a co-worker before being deemed most reproducible and with the greatest levels of extraction. All experiments were run a minimum of three times at each concentration of hydrogen donor or temperature setting. The retention time of each product was determined using authentic samples of methylcyclopentane (86), cyclohexane (87), and 1-hexene (88) at various concentrations, and the peak identities confirmed periodically throughout all experiments by doping experimental samples with the authentic products.

All uncertainty within the results for the following kinetic experiments is minimised by performing equivalent reactions a minimum of three times each to ensure reproducibility. While the origin of errors may be from the reproducibility of the experiment (i.e. temperature variations, product extraction or data analysis) or in the uncertainty in the fit of data, by ensuring reproducibility with each experiment we avoid many problems relating to these origins.328 Further, the results from Arrhenius plots were analysed with a linest function, which produces uncertainty estimates for the

84 graphed data using the least squares method. The standard deviation, a measure of variability in data, is one of the outputs of the linest function and from this we can determine a 95 % confidence interval (two standard deviations) for the fitted data.329 As such, all results obtained from a graph, i.e. rate constants and Arrhenius parameters, are given with an error representing the 95 % confidence limit.330

3.5 Tertiary thiol 46

3.5.1 Concentration profile

Stock solutions of uncharged thiol 46 and PTOC 82 in EMIM NTf2 were prepared, followed by the preparation of five samples containing 0.01 M PTOC ester and 0.10 M thiol. Following photolysis, the solutions were extracted into t-BuPh and analysed immediately by measuring peak area in the GC spectrum. Products were identified by a comparison to authentic standards. As both thiol 46 and PTOC ester 82 are yellow in colour, all stock and sample solutions were also yellow. However, following extraction, the t-BuPh layer was colourless to the naked eye and it is assumed that little to none of the thiol was extracted from the IL and all of the PTOC ester has been consumed during the reaction. This may allow for greater recyclisation of the thiol for future experiments.

This initial experiment, keeping concentration and temperature constant, was performed to ensure that the reaction and extraction technique allowed for similar results every time it was performed. Indeed, the results from this preliminary experiment showed all results falling within 9 % and two standard deviations of the average (Figure 3-11).

1.30E+07

1.26E+07 1.25E+07

1.20E+07 1.18E+07 )

1 1.16E+07

- s

1 1.15E+07 -

1.12E+07

(M H 1.10E+07

Spot k Spot 1.06E+07 1.05E+07

1.00E+07

9.50E+06 1 2 3 4 5 Sample #

Figure 3-11 Spot kH values for H-transfer from t-thiol 46, at a single concentration and temperature, to the

5-hexenyl radical in 100 % EMIM NTf2

Given the reaction under single temperature and concentration was reproducible, the concentration was then varied to investigate whether the reaction in an IL is concentration dependent. A plot of the inverse H-donor concentration (1/[t-thiol 46], x-axis) against the product ratio ([cyclised 86]/[uncyclised 88], y-axis) will afford a linear graph if the reaction is pseudo-first order and the rate constant for H-transfer may then be isolated from the graph’s gradient.331 Non-linearity would indicate that the reaction is not pseudo-first order and that there is a dependence of the rate on the concentration of HAT reagent in an IL.331 The results from this set of experiments can be seen in Figure 3-12.

0.2

0.18

0.16

0.14

0.12

0.1 y = 0.0198x - 0.0058 R² = 0.9947 0.08

0.06

0.04 [cyclised 86]/[uncyclised 88] product ratio product 88] 86]/[uncyclised [cyclised 0.02

0 1 2 3 4 5 6 7 8 9 10 1/[t-thiol 46]

Figure 3-12 Concentration profile (10× to 50×) for H-transfer from t-thiol 46 to the 5-hexenyl radical in 100 %

EMIM NTf2 at 25 °C

Given the high degree of linearity in the concentration profile at 25 C depicted in Figure 3-12, with a coefficient of determination (R2) value of 0.9947, the reaction is confirmed to be under pseudo first order conditions and hence the gradient represents a ratio of rate constants.15 Given the cyclisation rate constant is known,304 we can determine a rate constant for H-transfer from thiol 46 of 1.11 × 107 M-1 s-1. This compares quite well with the known HAT rate constant for t-BuSH at 25 C of 7.99 × 106 M-1 s-1. While these results are not significantly different, the synthesised t-thiol 46 could be considered a preferable thiol as it is a solid at room temperature and no obvious odour was detected when in use.

3.5.2 Arrhenius expression

16.9

16.8

16.7 )

H 16.6 y = -1.5361x + 21.386

R² = 0.9822 ln(k 16.5

16.4

16.3

16.2

16.1 2.9 3 3.1 3.2 3.3 3.4 1000/T

Figure 3-13 Arrhenius study for H-transfer from t-thiol 46 to the 5-hexenyl radical in 100 % EMIM NTf2 at various temperatures

Equivalent experiments to those previously described were performed using a 10× excess of thiol 46 compared to PTOC ester 82 and at temperatures of 25 C, 40 C, 49 C, 56 C, 62 C and 68 C. Experiments were not performed at higher temperatures due to the boiling point of the reaction products (methylcyclopentane: 71.85 C and 1-hexene: 63.50 C),332, 333 where higher temperatures may alter the reaction rate as products move from solution into the headspace of the reaction vessel. The results from this study can be seen in Figure 3-13, where each point is an average of three individual experiments and an R2 value over 0.98 provides confidence that the kinetic model is correct.

The Arrhenius function can then be determined to give values for activation energy and the pre-exponential factor. Although an Arrhenius plot includes the natural log of the rate constant, it is more common for the Arrhenius equation to be written in log base 10, with the conversion possible by dividing by 2.303, giving Equation 3.

1.33 (± 0.18) log 푘 = 9.29 (± 0.28) − (3) 퐻 2.303푅푇

2.00 (± 0.09) log 푘 = 8.37 (± 0.08) − (4)334 퐻 2.303푅푇

This Arrhenius expression for thiol 46 in EMIM NTf2 is slightly different to that for t-BuSH in

THF (Equation 4),334 with a lower Ea and slightly higher logA value. However, these differences are not significant enough to have a noticeable impact, noting the errors represent a 95 % confidence limit.

3.6 Tertiary thiol salt 27

3.6.1 Concentration profile

1.60E+07 1.41E+07 1.40E+07 1.25E+07 1.22E+07 1.19E+07 1.20E+07

1.07E+07

) 1

- 1.00E+07

1 -

(M 8.00E+06 H

6.00E+06 Spot k Spot

4.00E+06

2.00E+06

0.00E+00 1 2 3 4 5 Sample #

Figure 3-14 Spot kH values for H-transfer from t-thiol 27, at a single concentration and temperature, to the

5-hexenyl radical in 100 % EMIM NTf2

Following the same method and analysis as described above, the concentration and temperature were unchanged between samples to ensure reproducibility with IL t-thiol 27, with the results depicted in Figure 3-14. All results fell within two standard deviations and 15 % of the mean.

0.3

0.25

0.2

y = 0.0228x - 0.0004 0.15 R² = 0.9997

0.1

0.05 [Cyclised 86]/[Uncyclised 88] 88] product 86]/[Uncyclised [Cyclised

0 0 2 4 6 8 10 12 1/[IL t-thiol 27]

Figure 3-15 Concentration profile (10× to 50×) for H-transfer from t-thiol 27 to the 5-hexenyl radical in 100 %

EMIM NTf2 at 30 C

In a similar manner to the uncharged t-thiol 46, a high degree of linearity in the concentration profile for t-thiol salt 27 was determined, with a correlation coefficient of 0.9997. As such, the reaction is operating in a pseudo-first order manner. Using the rate constant for cyclisation to form methylcyclopentane (86), a rate constant for HAT from salt 27 at 30 C to be 1.16 × 107 M-1 s-1 was determined. This is again very similar to the HAT rate constant for t-BuSH (7.99 × 106 M-1 s-1). IL t-thiol 27 is also very easy to work with, as a non-volatile solid.

3.6.2 Arrhenius expression

16.9

16.8

16.7

) 16.6 H y = -1.6896x + 21.871

ln(k R² = 0.9793 16.5

16.4

16.3

16.2 2.95 3 3.05 3.1 3.15 3.2 3.25 3.3 3.35

1000/T

Figure 3-16 Arrhenius study for H-transfer from IL t-thiol 27 to the 5-hexenyl radical in 100 % EMIM NTf2 at various temperatures

The Arrhenius plot shown in Figure 3-16 was formed following experiments at 30 °C, 40 °C, 45 °C, 50 °C, 55.4 °C and 60 °C. The R2 value of 0.9793 indicates that linear regression fits the data very well and the Arrhenius expression can be assumed to be a good model for this data. The derived Arrhenius expression for IL t-thiol can be seen in Equation 5.

1.46 (± 0.21) log 푘 = 9.50 (± 0.33) − (5) 퐻 2.303푅푇

When comparing the Arrhenius expressions of t-thiol 46 (Equation 3) and IL t-thiol 27 (Equation 5), and taking into account the 95 % confidence limit, we can see that the results are identical within experimental error. As there is no difference when comparing to each other, nor when comparing to t-BuSH, the impact of methylating the imidazole ring is negligible. This indicates that IL formation, and consequently the TSIL anion, have little to no impact on the rate constants or Arrhenius parameters, despite many IL solvent parameters often being impacted on by the anion.335 This is not unexpected given the distance the salt moiety is from the active thiol group.

3.7 Stannane 60

3.7.1 Concentration profile

6.00E+06 5.40E+06 5.12E+06 5.21E+06 5.00E+06 4.81E+06 4.44E+06

4.00E+06

)

- s

1 3.00E+06

(M H

2.00E+06 Spot k Spot

1.00E+06

0.00E+00 1 2 3 4 5

Sample #

Figure 3-17 Spot kH for H-transfer from stannane 60, at a single concentration and temperature, to the 5-hexenyl

radical in 100 % EMIM NTf2

As with the previous experiments, the concentration and temperature were held constant for preliminary kinetic experiments to establish whether the reaction proceeded in the expected manner using IL-supported stannane 60. The results from this can be seen in Figure 3-17, with all results falling within 12 % of the mean and well within two standard deviation.

1.4

1.2

0.8 y = 0.0459x + 0.0204 0.6 R² = 0.9991

0.4 [Cyclised 86]/[Uncyclised 88] 88] product 86]/[Uncyclised [Cyclised 0.2

0 0 5 10 15 20 25 30

1/[stannane 60]

Figure 3-18 Concentration profile (10× to 50×) for H-transfer from stannane 60 to the 5-hexenyl radical in 100 %

EMIM NTf2 at 26.13 C

Pleasingly, a very high degree of linearity was found following the concentration profile (10× to 50× excess HAT reagent) for stannane 60, with a coefficient of determination of 0.9991. Thus, the reaction is under pseudo-first order conditions in the concentration range tested. The rate constant for HAT at 26.13 °C from tin hydride 60 of 5.01 × 106 M-1 s-1 was determined from Figure 3-18, which has a negligible difference to the rate constant for HAT of Bu3SnH of 2.4 × 106 M-1 s-1 or

Ph3SnH of ~5 × 106 M-1 s-1.304, 336

3.7.2 Arrhenius expression

16.3

16.2

16.1

15.9 ) H y = -2.9661x + 25.387

ln(k 15.8 R² = 0.927

15.7

15.6

15.5

15.4

15.3 3 3.05 3.1 3.15 3.2 3.25 3.3 3.35 3.4

1000/T

Figure 3-19 Arrhenius plot for H-transfer from stannane 60 to the 5-hexenyl radical in 100 % EMIM NTf2 at various temperatures

The Arrhenius plot shown in Figure 3-19 was formed following experiments at 26 C, 40.2 C, 45 C and 50 C (represented by the solid data points). Unfortunately, several problems began to occur when the temperature of the stannane/PTOC mixtures were raised, with noticeable particulate matter forming causing the solution to become cloudy. Other experiments were performed at 55 C, 32 C and 36 C (represented by the crosses), however, these have been excluded from analysis to allow for the most linear graph. In excluding these data points, the R2 value for the graph is 0.9268, indicating that the data fits a linear graph moderately well. Thus, this figure is less reliable than the previously performed Arrhenius plots for the thiol derivates.

The formation of particles in solution has several implications, most notably that the tin moiety is decomposing to an unknown by-product. This causes two problems for the kinetic experiments, the concentration of the tin in solution cannot be adequately measured, while less light is able to hit the PTOC ester 82 due to the particles. Both of these problems do not allow for the data to be extended to include higher temperatures. Although these experiments were run several times, with newly synthesised tin hydride 60 each time, analysis at other temperature points was not possible.

However, from the data in Figure 3-19, we are still able to determine the Arrhenius parameters, which can be seen in Equation 6.

2.56 (± 1.02) log 푘 = 11.0 (± 1.63) − (6) 퐻 2.303푅푇

3.69 (± 0.32) log 푘 = 9.07 (± 0.24) − (7) 퐻 2.303푅푇

The errors in Equation 6 are quite large, however a similar trend in the Arrhenius parameters as seen with t-thiol 46 and IL-t-thiol 27 is evident, as the logA value is higher than the Arrhenius parameters for n-Bu3SnH (Equation 7), although the value for EA is identical within experimental error (95 % confidence limit).

3.8 Conclusions

Table 3-3 Arrhenius expressions and rate constants for H-atom transfer from novel IL-soluble HAT reagents to

a primary alkyl radical (the 5-hexenyl radical) in 100 % EMIM NTf2. Similar data has been included for t-BuSH

and n-Bu3SnH in THF and isooctane-di-tert-butyl peroxide respectively.304, 334

Rate constant at Compound Arrhenius expression ~25 C (M-1 s-1)

7 1.33 (± 0.18) 1.11 (± 0.09) × 10 log 푘퐻 = 9.29 (± 0.28) − 2.30푅푇

1.46 (± 0.21) 1.16 (± 0.03) × 107 log 푘 = 9.50 (± 0.33) − 퐻 2.30푅푇

2.00 (± 0.09) t-BuSH 7.99 × 106 log 푘 = 8.37 (± 0.08) − 퐻 2.30푅푇

2.56 (± 1.02) 5.01 (± 0.17) × 106 log 푘 = 11.0 (± 1.63) − 퐻 2.30푅푇

3.69 (± 0.32) n-Bu3SnH 2.36 × 106 log 푘 = 9.07 (± 0.24) − 퐻 2.30푅푇

Arrhenius parameters for the H-atom transfer from novel IL-soluble HAT reagents 27, 46 and 60

to the 5-hexenyl radical in 100 % EMIM NTF2 have been established. Each set of parameters followed the same trend, with values for the pre-exponential factor, A, slightly higher and values for

the activation energy, Ea, slightly lower than those in the Arrhenius equation for the traditional thiol or stannane reagents.

Several interesting conclusions can be derived from these results. Firstly, it is also of great interest that within the experimental parameters used for this kinetic study, no difference was seen between t-thiol salt 27 or uncharged t-thiol 46. Although no difference would not normally be an interesting point, one may have expected some difference between the rate constants and Arrhenius parameters between the two thiols. Secondly, the rate constants for H-atom transfer and radical

99 cyclisation did not change significantly in an ionic liquid vs. a conventional solvent, giving us insight into the kinetic solvent effect for organic free radical reactions.

In terms of replacing the common HAT reagents, there were no other common stannanes soluble in ionic liquids, so stannane 60 has potential to be used for other radical reactions. Unfortunately, this is likely to end at potential, as the compound was difficult to work with, both in terms of preparing for a reaction and because it decomposed with only moderate temperatures. These difficulties make stannane 60 unlikely to be an alternative worth pursuing for future IL-based radical reactions. However, both t-thiol reagents were very easy to use, being non-volatile solids that dissolved easily in EMIN NTf2, allowing them to be excellent replacements for t-BuSH for use as a HAT reagent in radical chemistry. This may allow for more modern radical chemistry involving H-atom transfer to be performed in recyclable solvents like ILs. Furthermore, given that the novel IL-soluble HAT reagents, in particular t-thiol salt 27 and stannane 60, are likely to remain in the ionic liquid layer following a reaction, they are able to be recycled themselves, reducing waste.

Having a fundamental understanding of radical reactions is critical for their application, and this work has provided alternative HAT reagents that may be used in radical reactions performed in ionic liquids. Solvent polarity did not impact the reactions investigated during this project, however, further work investigating cyclisation rate constants for radical compounds with polar transition states may give more insight into kinetic solvent effects.

100

4 Experimental

4.1 Instrumentation All moisture sensitive reactions were performed in oven-dried glassware under argon or nitrogen

gas. Anhydrous tetrahydrofuran (THF), diethyl ether (Et2O) and dichloromethane (CH2Cl2) were dried over activated neutral alumina under argon. Anhydrous ethanol (EtOH) was dried over magnesium ethoxide under nitrogen. Organic extracts are dried over anhydrous magnesium sulfate

(MgSO4) unless otherwise noted. Analytical thin layer chromatography (TLC) was performed on

precoated 0.25 mm thick Merck 60 F254 silica gel plates and visualized under 254 nm light and/or stained with 20 % w/w phosphomolybdic acid in ethanol. Flash chromatography was performed on silica gel (Merck Kieselgel 60, 230 - 400 mesh). The solvent system for TLC and flash chromatography is most commonly a mixture of dichloromethane and up to 10 % methanol.

1H NMR spectra were recorded on a Varian Inova 500 (operating at 500 MHz), a Varian Inova 600

(600 MHz) or a Varian Inova 400 (400 MHz) Spectrometer in deuterated chloroform (CDCl3) at

298 K and the residual CHCl3 signal was used as an internal reference (7.26 ppm). Chemical shifts for each signal are given in parts per million (, ppm). The multiplicity of each signal is indicated by: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), m (multiplet). The number of protons (n) for each resonance is indicated by nH. Coupling constants (J) are quoted in Hertz (Hz). 13C NMR spectra were recorded on a Varian Inova 600 (150 MHz), a Varian Inova 500 (125 MHz)

or Varian Inova 400 (100 MHz) and used the central resonance of CDCl3 as a reference (77.0 ppm). Chemical shifts for each signal are given as  in units of parts per million (ppm). 119Sn NMR spectra were recorded on a Varian Inova 500 (186 MHz) instrument with proton decoupling. Samples were

run in C6D6 or CDCl3, with chemical shifts for each signal given as  in units of ppm relative to an external standard of bis(tributyltin) oxide at 84.8 ppm or 85.6 ppm respectively.337, 338

Low resolution electrospray ionization (ESI) mass spectra were recorded at 70 eV on a Shimadzu GC/MS-QP505A spectrometer. High resolution ESI mass spectra were recorded using a hybrid linear ion trap (Finnegan LTQ-FT) mass spectrometer or a ThermoFisher Orbitrap Elite Hybrid Ion Trap-Orbitrap Mass Spectrometer with using CID fragmentation.

101

GC analysis was performed on a Shimadzu GC-17A with an AOC-20i auto injector using a Supelco SPB-Octyl fused silica capillary column (30 m × 0.25 mm × 0.25 µm film thickness). Helium (≥ 99.999 %, 105 p.s.i.), compressed air (70 p.s.i.) and hydrogen (≥ 99.999 %, 65 p.s.i) were used as the carrier gas mixture. The Shimadzu GC-17A uses an FID detector set to 280 C, with the injector port set to 260 C.

4.2 General method for kinetic experiments Stock solutions of PTOC ester 82 (~0.10 M) and HAT reagents 27, 46 or 60 (~0.50 M to 2.0 M) in

EMIM NTf2 (1.0 to 4.0 mL) were prepared. When not in use, the stock solutions were kept under argon, shielded from light and below 0 °C. Samples were prepared from these stock solutions to contain 0.01 M PTOC ester 82 and an appropriate amount of HAT reagent depending on concentration required, ranging from 0.10 M to 0.50 M, with the volume made up to 1.0 mL with

EMIM NTf2. These samples were shielded from light, degassed with argon by purging for two minutes in solution and one minute above, before being closed to the atmosphere. A low pressure, broad spectrum, mercury lamp, was set up 20 cm from the sample location.

When higher temperature reactions were performed, the lamp and transparent oil bath were equilibrated until the temperature stabilised before samples were added. Photolysis occurred for 120 minutes, with the temperature monitored every 30 minutes. On completion, the samples were allowed to cool to room temperature before being extracted with t-BuPh (5 × 1.0 mL) and passed through a very small silica column. GC analysis was performed immediately, with the product’s peak area used to establish the amount of product. The data for these experiments can be seen in the appendix.

Table 4-1 Standard method parameters used in gas chromatography experiments

Temperature Hold time at Temperature Pressure Pressure increase increase temperature 50 C - 53.0 kPa - 15 minutes 100 C 40 C / min 58.0 kPa 4.0 kPa / min 5 minutes 150 C 40 C / min 64.0 kPa 4.8 kPa / min 5 minutes

102

4.3 Experimental procedures

4.3.1 3-(6-Mercapto-6-methylheptyl)-1,2-dimethyl-3H-imidazolium tetrafluoroborate (27)

N N BF4 SH

NaBF4 (11.3 g, 103 mmol) was added to a solution of 3-(6-mercaptio-6-methylheptyl)-1,2-dimethyl-

3H-imidazolium iodide (45) (3.79 g, 10.3 mmol) in CH2Cl2 (150 mL) and the resulting mixture

refluxed at 40 °C for 48 hours. Subsequently, the solution was cooled, washed with H2O

(4 × 40 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue underwent flash

chromatography (CH2Cl2:MeOH) to afford an orange powder (3.28 g, 97 %)

H (400 MHz, CDCl3): 1.14-1.35 (m, 8H), 1.36-1.58 (m, 4H), 1.70-1.83 (m, 2H), 2.55 (s, 3H), 3.75 (s, 3H), 4.03 (t, J = 7.5 Hz, 2H), 7.19-7.31 (m, 2H).

C (100 MHz, CDCl3): 9.2, 24.6, 26.3, 29.5, 32.4, 35.0, 44.4, 46.0, 48.4, 120.8, 122.5, 143.8.

HRMS calculated for [M-BF4]+ C13H25N2OS: 241.1733 m/z, found 241.1722 m/z.

4.3.2 Ethyl 6-bromohexanoate (29) O Br O

A solution of 6-bromohexanoic acid (1.05 g, 5.38 mmol) and acetyl chloride (1.91 mL, 26.9 mmol) in EtOH (75 mL) was stirred at room temperature overnight. The solvent was removed under

reduced pressure to give a yellow residue which was then dissolved in Et2O (50 mL) and washed

with a saturated bicarbonate solution (2 × 25 mL), H2O (1 × 25 mL) and brine (1 × 25 mL) before

the organic phase was dried over anhydrous MgSO4 and reduced to a colourless solid (1.08 g, 90 %).184

H (500 MHz, CDCl3): 1.26 (t, J = 7.1 Hz, 3H), 1.43-1.52 (m, 2H), 1.61-1.70 (m, 2H), 1.83-1.93 (m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 3.41 (t, J = 6.8 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H).

103

4.3.3 7-Bromo-2-methylheptan-2-ol (30)

Br OH

3 M Methyl magnesium bromide (2.68 mL, 8.03 mmol) was added dropwise to a solution of ethyl

6-bromohexanoate (29) (0.448 g, 2.01 mmol) in anhydrous Et2O (25 mL) at 0 C under an argon atmosphere and the resulting solution stirred for 17 hours at room temperature. 10 % HCl was added slowly under no reaction observed, then the aqueous layer extracted with Et2O (3 × 20 mL), the organic fractions dried over anhydrous MgSO4 and concentrated under reduced pressure to afford a clear oil (0.383 g, 91 %).185

H (500 MHz, CDCl3): 1.21 (s, 6H), 1.35-1.50 (m, 6H), 1.56 (s, 1H), 1.85-1.92 (m, 2H), 3.42 (t, J = 6.8 Hz, 2H).

4.3.4 2-Methyl-7-(2-methylimidazol-1-yl)heptan-2-ol (31)

N N HO

2-Methylimidazole (0.110 g, 1.33 mmol), KOH (0.142 g, 2.53 mmol) and 7-bromo-2-methylheptan-

2-ol (30) (0.265 g, 1.27 mmol) were mixed together in CH3CN (25 mL) and stirred at room temperature overnight. CH3CN was removed under reduced pressure, the residue dissolved in H2O

(15 mL) and then extracted with CH2Cl2 (3 × 15 mL) to afford the title compound as a pale-yellow oil (0.258 g, 97 %).

H (500 MHz, CDCl3): 1.20 (s, 6H), 1.25-1.49 (m, 6H), 1.69-1.78 (m, 2H), 2.38 (s, 3H), 3.82 (t, J = 7.2 Hz, 2H), 6.80 (d, J = 0.9 Hz, 1H), 6.90 (d, J = 0.9 Hz, 1H).

4.3.5 2-Bromo-2-methyl-7-(2-methylimidazol-1-yl)heptane (32)

N N Br

48 % Hydrobromic acid (0.14 mL, 1.21 mmol) was added dropwise to a solution of tertiary alcohol

31 (0.127 g, 0.604 mmol) and LiBr (0.079 g, 0.091 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 15 hours, then diluted with H2O (20 mL), extracted with CH2Cl2 (3 × 10 mL), the organic fractions dried over anhydrous MgSO4 and concentrated under reduced pressure.186

104

1H NMR spectroscopy of the extracted product displayed a multitude of signals none of which could be clearly identified as originating from the desired product.

Tertiary alcohol 31 (0.318 g, 1.51 mmol) was dissolved in anhydrous CH2Cl2 (15 mL), cooled to

0 C and to this was added 1.0 M BBr3 (1.89 mL, 1.89 mmol) dropwise. The resulting solution was stirred for 3 hours at room temperature, before H2O was added slowly, the aqueous layer extracted with CH2Cl2 (3 × 10 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure.187 1H NMR spectroscopy of the extracted product displayed a multitude of signals, none of which could be clearly identified as originating from the desired product.

4.3.6 3-(6-Bromo-6-methylheptyl)-1,2-dimethyl-3H-imidazolium bromide

N N Br Br

IL-tertiary alcohol 33 (0.129 g, 0.423 mmol) was dissolved in anhydrous CH2Cl2 (5 mL), cooled to

0 C and to this was added 1.0 M BBr3 (0.53 mL, 0.423 mmol) dropwise. The resulting solution was allowed to warm to room temperature and stirred for 1.5 hours, before H2O added slowly, the aqueous layer extracted with CH2Cl2 (3 × 5 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure.187 1H NMR spectroscopy of the extracted product displayed a multitude of signals, none of which could be clearly identified as originating from the desired product.

4.3.7 3-(6-Bromo-6-methylheptyl)-1,2-dimethyl-3H-imidazolium iodide (34)

N N Br I

33 % HBr in acetic acid (0.10 mL, 0.51 mmol) was added dropwise to a solution of alkene salt 38

(0.14 g, 0.43 mmol) in CH2Cl2 (10 mL) before refluxing at 55 C for 48 hours. The mixture was concentrated in vacuo to give a dark orange solid which was washed with Et2O (3 × 5 mL), water

(3 × 5 mL), dried over anhydrous MgSO4 and filtered over celite before being concentrated in vacuo. The crude material was used immediately without characterisation or purification.

105

4.3.8 1,6-Dibromo-6-methylheptane (35)

Br Br

33 % Hydrogen bromide in acetic acid (13.6 mL, 75.3 mmol) was added dropwise to a solution of

1-bromo-6-methylheptan-2-ol (30) (7.88 g, 37.7 mmol) and LiBr (4.91 g, 56.5 mmol) in CHCl3 (200 mL) at 0 C. The mixture was stirred overnight, concentrated under reduced pressure, diluted with CH2Cl2 (150 mL), washed with H2O (1 × 50 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford the title compound as a dark oil (9.95 g, 97 %) with identical spectral character compared to that reported in the literature.189

H (500 MHz, CDCl3): 1.44-1.61 (m, 4H), 1.75 (s, 6H), 1.77-1.81 (m, 2H), 1.87-1.94 (m, 2H), 3.43 (t, J = 6.8 Hz, 2H).

4.3.9 2-Methyl-1-(6-methylhept-5-enyl)-1H-imidazole (major, 36) and 2-methyl-1-(6-methylhept-6-enyl)-1H-imidazole (minor, 36-2)

N N N N

Dibromide 35 (7.67 g, 28.2 mmol), KOH (3.16 g, 56.4 mmol) and 2-methylimidazole (2.32 g, 28.2 mmol) were mixed together in CH3CN (150 mL) and refluxed for 48 hours. Upon completion, the reaction was cooled, concentrated under reduced pressure and the residue dissolved in CH2Cl2 (50 mL) and H2O (50 mL) before extracting with CH2Cl2 (3 × 50 mL), drying over anhydrous MgSO4 and concentrating under reduced pressure.190 Following flash chromatography (CH2Cl2:MeOH) , an inseparable mixture of the title compounds (4.03 g, 74 %) was isolated as a pale yellow oil, with a 7:3 major to minor product ratio determined by 1H NMR spectroscopy.

A solution of p-toluenesulfonic acid (2.35 g, 12.4 mmol) and tertiary alcohol 31 (2.37 g, 11.3 mmol) in toluene (150 mL) was refluxed at 110 C for 36 hours. After cooling, the solution was concentrated in vacuo, dissolved in CH2Cl2 (100 mL), washed with 2 M NaOH (3 × 30 mL), water

(1 × 30 mL), brine (1 × 30 mL), then dried over anhydrous MgSO4 and concentrated in vacuo to give the desired compound mixture in a 98 % yield.

106

H (500 MHz, CDCl3): 1.31-1.39 (m, 2H), 1.44-1.50 (m, 1H), 1.60 (s, 2H), 1.69-1.76 (m, 5H), 1.99-2.04 (m, 2H), 2.38 (s, 3H), 3.82 (t, J = 7.3 Hz, 2H), 4.65-4.67 (m, 0.3H, minor product), 4.70-4.72 (m, 0.3H, minor product), 5.05-5.10 (m, 0.7H, major product), 6.81 (d, J = 1.2 Hz, 1H), 6.91(d, J = 1.2 Hz, 1H).

C (125 MHz, CDCl3): 13.0, 17.7, 22.3, 25.7, 25.8, 26.2, 26.7, 27.0, 27.4, 30.2, 30.6, 37.5, 46.0, 110.0, 119.0, 123.6, 126.8, 132.2, 144.3, 145.4.

HRMS calculated for [M+H]+ C12H20N2: 193.1705 m/z, found 193.1876 m/z.

4.3.10 2,3-Dimethyl-1-(6-methylhept-5-enyl)-3H-imidazolium iodide (38)

N N I

Alkene 36 (0.523 g, 2.87 mmol) was dissolved in toluene (2 mL) in a sealed tube under argon and to this was added iodomethane (0.90 mL, 14.37 mmol). The solution was stirred at 100 °C for 17 hours before diluting with CH2Cl2 (25 mL), washing with saturated Na2S2O3 (2 × 10 mL), H2O (1

× 10 mL), drying over anhydrous MgSO4 and concentrating under reduced pressure. The crude material was washed several times with Et2O to remove organic impurities, leaving the title compound as a pale-yellow oil (0.813 g, 85 %).

H (500 MHz, CDCl3): 1.37-1.46 (m, 2H), 1.60 (s, 3H), 1.69 (s, 3H), 1.81-1.90 (m, 2H), 2.01-2.08 (m, 2H), 2.82 (s, 3H), 3.97 (s, 3H), 4.14 (t, J = 7.6 Hz, 2H), 4.63-4.72 (m, 0.2H, minor product), 5.02-5.08 (m, 0.8H, major product), 7.26-7.28 (m, 1H), 7.43 (d, J = 2.0 Hz, 1H).

107

4.3.11 Thioacetic acid S-[1,1-dimethyl-6-(2-methylimidazol-1-yl)hexyl] ester (39)

N N S

AlCl3 (3.24 g, 24.3 mmol) was added to anhydrous CH2Cl2 (140 mL) under argon and cooled to

0 C. To this was added a solution of alkene 36 (2.34 g, 12.2 mmol) in anhydrous CH2Cl2 (20 mL) followed by the dropwise addition of thioacetic acid (3.74 mL, 48.0 mmol). The final mixture was stirred for a further 42 hours at room temperature before slowly adding 10 % HCl until no vigorous reaction occurred. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure.197 Following flash chromatography

(CH2Cl2:MeOH), the title compound was isolated as an orange oil (2.26 g, 69 %).

H (500 MHz, CDCl3): 1.24-1.39 (m, 4H), 1.41 (s, 6H), 1.69-1.76 (m, 4H), 2.23 (s, 3H), 2.39 (s, 3H), 3.81 (t, J = 7.2 Hz, 2H), 6.80 (d, J = 1.3 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H).

C (125 MHz, CDCl3): 12.8, 24.4, 26.8, 27.6, 30.5, 31.5, 41.0, 46.0, 51.5, 119.0, 126.5, 144.2, 196.7.

HRMS calculated for [M+H]+ C14H25N2OS: 269.1688 m/z, found 269.1721 m/z.

4.3.12 6-Bromohexanethioic acid O-ethyl ester (40) S Br O

Ethyl 6-bromohexanoate (29) (0.156 g, 0.698 mmol) was dissolved in toluene (3 mL) under an inert atmosphere. Lawesson’s reagent (0.283 g, 0.700 mmol) was then added and the mixture stirred at reflux for 36 hours. Subsequently, the solution was cooled, toluene was added (10 mL), the solution washed with H2O (3 × 5 mL), brine (1 × 5 mL), the organic layer dried over anhydrous MgSO4 and concentrated under reduced pressure. Following flash chromatography, 1H NMR spectroscopy and MS analysis, the desired compound could not be observed.

108

4.3.13 2,3-Bis(tributyltinoxy) butane (43)

Bu3SnO OSnBu3

A mixture of 2,3-butanediol (42) (1.00 mL, 11.1 mmol) and sodium metal (0.511 g, 22.2 mmol) were refluxed in anhydrous toluene (70 mL) for 5 hours. Subsequently, tributyltin chloride (7.24 g, 22.2 mmol) was added and the reaction refluxed until TLC indicated full consumption of starting material. After cooling, the mixture was diluted with anhydrous toluene (30 mL), the solution filtered over celite and concentrated under reduced pressure.203 The isolated compound was used immediately, and no characterisation was performed.

4.3.14 4,5-Dimethyl-[1,3]dioxolane-2-thione (44) S

O O

A mixture of ZnCl2 (0.253 g, 1.86 mmol), thiourea (0.141 g, 1.86 mmol) and 2,3-butanediol (42) (167 µL, 1.86 mmol) in 1,2-dichloroethane (20 mL) was prepared and heated at 105 °C for 48 hours. After allowing to cool, the solvent was decanted, the remaining white solid washed with 1,2-dichloroethane (3 × 10 mL), then concentrated under reduced pressure.202 1H NMR spectroscopy and MS analysis did not reveal any signals characteristic of the title compound.

2,3-bis(tributyloxy) butane (43) (0.416 g, 0.623 mmol) and CS2 (0.19 mL, 3.1 mmol) were dissolved in 1,2-dichloroethane (3 mL) and stirred at room temperature under argon for 17 hours. Following this, the mixture was concentrated in vacuo to an oil.203 1H NMR spectroscopy of the crude material did not reveal any signals attributed to the title compound.

109

4.3.15 3-(6-Mercapto-6-methylheptyl)-1,2-dimethyl-3H-imidazolium iodide (45)

N N I SH

30 % NH3 (0.20 mL, 5.1 mmol) was added slowly to a solution of charged thioacetate 48 (2.11 g, 5.14 mmol) in MeOH (50 mL) at 0 C, then allowed to warm to room temperature and stirred until HRMS indicated reaction completion. The resulting solution was acidified to pH 2 with 10 % HCl, concentrated under reduced pressure, diluted with H2O (50 mL), extracted with CH2Cl2

(6 × 25 mL) and underwent flash chromatography (CH2Cl2:MeOH)221 to afford the title compound as a brown, highly viscous, oil (1.36 g, 72 %).

Glacial acetic acid was dropped slowly over solid Na2S•9H2O (0.70 g, 2.9 mmol) and the evolved gas bubbled through a solution of charged alkene 38 (0.097 g, 0.29 mmol) and AlCl3 (0.077 g,

0.058 mmol) in CH2Cl2 (5 mL). Further amounts of Na2S•9H2O and acetic acid were added to maintain a steady flow of gas into the solution. After 5 hours, CH2Cl2 (10 mL) was added, the organic phase washed with saturated Na2S2O3 (2 × 5 mL) and H2O (2 × 5 mL) before drying over anhydrous MgSO4 and concentrating under reduced pressure.205 1H NMR spectroscopic analysis of the crude reaction product showed only starting material.

A solution of t-thiol 46 (0.092 g, 0.41 mmol) and dimethyl methylphosphonate (52 µL, 0.49 mmol) in toluene (1 mL) were heated in a sealed tube under argon at 100 °C for 17 hours. Following this, the solution was diluted with CH2Cl2 (10 mL) and concentrated under a reduced pressure to give a yellow oil.219 1H NMR spectroscopy of the crude product did not show resonances associated with the desired product.

A solution of t-thiol 46 (0.097 g, 0.43 mmol) and methyl trifluoroacetate (45 µL, 0.45 mmol) in toluene (1 mL) were heated in a sealed tube under argon at 100 °C for 17 hours. Following this, the solution was diluted with CH2Cl2 (10 mL) and concentrated under a reduced pressure to give a yellow oil.220 1H NMR spectroscopy of the crude product showed only signals relating to the starting material.

110

H (500 MHz, CDCl3): 1.37 (s, 6H), 1.38-1.54 (m, 6H), 1.86-1.94 (m, 2H), 2.83 (s, 3H). 3.98 (s, 3H), 4.18 (t, J = 7.5 Hz, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H).

C (125 MHz, CDCl3): 11.3, 22.4, 24.6, 26.4, 29.6, 32.6, 36.6, 45.9, 48.9, 121.0, 122.7, 143.6.

HRMS calculated for [M-I]+ C13H25N2S: 241.1733 m/z, found 241.1734 m/z.

4.3.16 2-Methyl-7-(2-methylimidazol-1-yl)heptane-2-thiol (46)

N N SH

LiAlH4 (1.64 g, 43.6 mmol) was added in one portion to a solution of thioester 39 (3.90 g, 14.5 mmol) in anhydrous THF (100 mL) at 0 C under argon, allowed to warm to room temperature and stirred until HRMS indicated reaction completion. 10 % HCl was then added slowly until gas evolution ceased, THF removed in vacuo, 10 % HCl (100 mL) added and the solution extracted with CH2Cl2 (6 × 30 mL).209 The combined organic fractions were dried over anhydrous MgSO4, concentrated in vacuo and underwent flash chromatography (CH2Cl2:MeOH) to give the desired thiol as a sticky orange solid (3.17 g, 96 %).

H (500 MHz, CDCl3): 1.28-1.38 (m, 8H), 1.44-1.57 (m, 4H), 1.78-1.88 (m, 2H), 2.74 (s, 3H), 3.98 (t, J = 7.3 Hz, 2H), 6.97 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H).

C (125 MHz, CDCl3): 10.6, 24.1, 25.8, 29.2, 32.1, 45.4, 46.5, 53.1, 119.4, 120.1, 142.9.

HRMS calculated for [M+H]+ C12H23N2S: 227.1582 m/z, found 227.15775 m/z.

111

4.3.17 3-(6-Acetylsulfanyl-6-methylheptyl)-1,2-dimethyl-3H-imidazolium iodide (48)

N N I S

A solution of thioacetate 39 (2.44 g, 9.08 mmol) and MeI (1.70 mL, 27.2 mmol) in toluene (75 mL) was refluxed at 110 C for 48 hours. The solution was then concentrated in vacuo and the residue washed with Et2O (20 mL). The residue was purified by flash chromatography (CH2Cl2:MeOH) to afford the title compound as a highly viscous dark yellow oil (2.87 g, 77 %).

H (500 MHz, CDCl3): 1.34-1.44 (m, 10H), 1.73-1.80 (m, 2H), 1.82-1.92 (m, 2H), 2.23 (s, 3H), 2.83 (s, 3H), 3.97 (s, 3H), 4.16 (t, J = 7.5 Hz, 2H), 7.34 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H).

C (125 MHz, CDCl3): 11.9, 24.2, 26.6, 27.7, 29.5, 31.5, 36.7, 40.6, 49.2, 51.5, 121.0, 122.8, 144.0, 197.0.

HRMS calculated for [M-I]+ C15H27N2OS: 283.1844 m/z, found 283.1845 m/z.

4.3.18 1-(6-Diphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium tetrafluoroborate (60)

SnPh H N N 2 BF4

A solution of 1-(6-chlorodiphenylstannyl-hexyl)-2,3-dimethyl-1H-imidazolium tetrafluoroborate

(76) (0.633 g, 1.10 mmol) in CH2Cl2 (30 mL) and several drops of MeOH was prepared and to this was added NaBH4 (0.208 g, 5.50 mmol) at 0 °C under argon. The solution was stirred for 22 hours, monitored by HRMS until no starting material remained. Following this, H2O was added slowly until no visible reaction occurred, the organic layer washed with H2O (2 × 10 mL) and the aqueous layer extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried over anhydrous

MgSO4 and concentrated under reduced pressure to give a foamy white solid (0.522 g, 88 %). This was of sufficient purity for use in competition kinetics.

HRMS calculated for [M-BF4]+ C23H31N2Sn: 455.1504 m/z, found 455.1513 m/z.

112

4.3.19 1-(6-Chlorohexyl)-2-methylimidazole (63)

Cl N N

NaH (60 % dispersion, 1.34 g, 56.0 mmol) was washed with anhydrous hexane (2 × 20 mL), suspended in anhydrous THF (40 mL) and cooled to 0 C. 2-Methylimidazole 61 (2.40 g, 29.2 mmol) in anhydrous THF (60 mL) was then added dropwise over 30 mins and stirred for 30 mins at 0 C then for 45 mins at room temperature. The solution was re-cooled to 0 C, 1-bromo- 6-chlorohexane (62) (4.36 mL, 29.2 mmol) was added in one portion and the solution stirred at room temperature for 5 days. The mixture was filtered, the precipitate washed with a small amount of THF and the THF removed under reduced pressure. The residue was then dissolved in CH2Cl2

(100 mL), washed with H2O (3 × 50 mL) and brine (1 × 50 mL) then the combined organic fractions dried and concentrated in vacuo.269 Following flash chromatography (CH2Cl2:MeOH), the title compound was isolated as a yellow oil (4.68 g, 80 %) with identical spectral characteristics to those described in the literature.

H (600 MHz, CDCl3): 1.31-1.36 (m, 2H), 1.45-1.50 (m, 2H), 1.71-1.79 (m, 4H), 2.36 (s, 3H), 3.52 (t, J = 6.6 Hz, 2H), 3.82 (t, J = 7.2 Hz, 2H), 6.79 (d, J = 1.3 Hz, 1H), 6.89 (d, J = 1.3 Hz, 1H).

4.3.20 Triphenylstannane

LiAlH4 (0.246 g, 6.47 mmol) was added to anhydrous ether (100 mL) at 0 °C under argon followed by the portion-wise addition of Ph3SnCl (4.99 g, 13.0 mmol). The mixture was stirred at 0 °C for 30 minutes, then at room temperature for a further four hours. The resulting solution was then re-cooled to 0 °C and hydrolysed slowly with H2O. The organic layer was washed with cold H2O (3 × 25 mL), dried and concentrated in vacuo to give the title compound as a white solid (3.00 g, 66 %).

H (500 MHz, CDCl3): 6.91 (s, 1H), 7.00-7.21 (m, 9H), 7.44-7.59 (m, 6H).339

113

4.3.21 2-Methyl-1-(6-triphenylstannyl-hexyl)-3H-imidazole (64)

SnPh N N 3

A mixture of diisopropylamine (0.70 mL, 5.0 mmol) in THF (15 mL) was cooled to -10 C and to this was added previously titrated n-butyl lithium (4.7 mmol) in a dropwise fashion. This was stirred for 15 minutes, then cooled to -78 C. Ph3SnH (1.67 g, 4.76 mmol) in THF (5 mL) was then added dropwise over 10 minutes and the resulting solution stirred at -55 °C to -65 C for 1 hour. 1-(6- Chlorohexyl)-2-methylimidazole (63) (0.689 g, 3.39 mmol) in THF (8 mL) was cooled to -78 C then added, via thick cannula, to the tin lithium species. After the addition was complete, the solution was allowed to warm to room temperature slowly and stirred overnight. Subsequently,

H2O (20 mL) was added and the solution stirred for 15 minutes, followed by addition of CH2Cl2

(50 mL). The organic layer was collected, the aqueous layer washed with CH2Cl2 (1 × 50 mL) and the combined organic fractions washed successively with H2O (2 × 30 mL) and brine (2 × 30 mL) before being dried and concentrated in vacuo (at 30 C and shielded from light) to leave a brown oil (2.30 g). The crude product was used in the next step without purification.

A large excess of lithium was cut into small strips, washed with hexane and placed into anhydrous

THF (20 mL). A solution of Ph3SnCl (1.18 g, 3.07 mmol) in anhydrous THF (20 mL) was then added and the resulting mixture stirred overnight. No visible change occurred so the solution was then sonicated for 3 hours, after which time it was a pale green colour, followed by refluxing for a further hour. Subsequently, the solution cooled before being cannulated to a solution of alkyl chloride 63 in anhydrous THF (1 mL) at -60 °C and stirred at room temperature for a further 17 hours. Following concentration under a reduced pressure, the residue was dissolved in CH2Cl2

(50 mL) and washed with H2O (3 × 20 mL), the organic fraction dried over anhydrous MgSO4 and concentrated in vacuo. Analysis of the crude product mixture by 1H NMR spectroscopy showed only starting material remaining.

114

4.3.22 1-(6-Triphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium iodide (65)

SnPh N N 3 I

Crude 2-methyl-1-(6-triphenylstannyl-hexyl)-1H-imidazole (64) (0.853 g, 1.66 mmol) was mixed with MeI (0.13 mL, 2.2 mmol) in a dry sealed tube under argon and stirred at 40 C overnight

(protected from light). The mixture was diluted with CH2Cl2 (40 mL) and washed successively with

H2O (4 × 10 mL) and brine (1 × 10 mL), dried, concentrated under reduced pressure, washed with

Et2O (3 × 10 mL) before undergoing flash chromatography (CH2Cl2:MeOH) to yield the title compound as an off-white powder (0.802 g, 74 %).

A solution of (6-iodohexyl)triphenylstannane (74) (1.13 g, 2.02 mmol) and 1,2-dimethylimidazole (0.388 g, 4.04 mmol) in toluene (25 mL) was refluxed for 24 hours. After cooling, the solvent was removed in vacuo and the residue washed with Et2O (3 × 10 mL) to remove starting materials, affording the title compound as an off-white foam (1.27 g, 96 %).

H (500 MHz, CDCl3): 1.25-1.45 (m, 4H) 1.46-1.53 (m, 2H), 1.64-1.76 (m, 4H), 2.70 (s, 3H), 3.92 (s, 3H), 4.00 (t, J = 7.4 Hz, 2H), 7.10 (d, J = 2.1 Hz, 1H), 7.29-7.42 (m, 10H), 7.45-7.60 (m, 6H).

C (125 MHz, CDCl3): 10.8, 11.8, 25.7, 26.3, 29.4, 33.3, 36.6, 49.0, 120.8, 122.8, 128.5, 128.9, 137.0, 138.8, 143.8.

Sn (186 MHz, CDCl3): -108.7.

HRMS calculated for [M-I]+ C29H35N2Sn: 531.18222 m/z, found 531.18140 m/z.

115

4.3.23 1-(6-Chlorodiphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium iodide (66)

SnPh Cl N N 2 I

2 M HCl in Et2O (2.06 mL, 4.12 mmol) was slowly added dropwise to a solution of 1-(6-triphenylstannyl-hexyl)-2,3-dimethyl-1H-imidazolium iodide (65) (2.71 g, 4.12 mmol) in dry

CH2Cl2 (75 mL) at -10 °C. The solution was allowed to warm to room temperature and stirred for a further 3.5 hours before being concentrated under reduced pressure. The residue was then dissolved in CH2Cl2 (100 mL) and washed with H2O (3 × 25 mL) before drying over anhydrous

MgSO4 and concentrating under reduced pressure. The residue was washed with Et2O (3 × 30 mL) to remove organic impurities, followed by flash chromatography (CH2Cl2:MeOH), leaving the title compound as a waxy yellow solid (2.21 g, 87 %, m.p. 134.4 – 138.8 °C).

H (500 MHz, CDCl3): 1.37-1.51 (m, 4H), 1.75-1.86 (m, 6H), 2.77 (s, 3H), 3.93 (s, 3H), 4.08 (t, J = 7.4 Hz, 2H), 7.20-7.22 (m, 1H), 7.29-7.32 (m, 1H), 7.38-7.47 (m, 6H), 7.53-7.68 (m, 4H).

C (125 MHz, CDCl3): 10.1, 25.3, 25.6, 27.1, 29.3, 32.4, 35.5, 48.4, 120.8, 122.3, 128.1, 128.7, 136.8, 143.3, 145.2.

HRMS calculated for [M-I]+ C23H30N2ClSn: 489.1120 m/z, found 489.1077 m/z. (compound 66)

HRMS calculated for [M-Cl]+ C23H30N2ISn: 581.0476 m/z, found 581.0472 m/z. (compound 75)

4.3.24 1-(6-Iodohexyl)-2-methylimidazole (67)

I N N

1-(6-Chlorohexyl)-2-methylimidazole (63) (0.633 g, 3.15 mmol) was dissolved in acetone (50 mL) and NaI (2.36 g, 15.8 mmol) was added. The resulting solution was heated at 60 °C for 17 hours, cooled to room temperature before diluting with H2O (250 mL) and extracting with CH2Cl2 (3 × 50 mL). The combined organic fractions were washed with brine (1 × 25 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The 1H NMR spectrum of the crude material did not show any characteristic signals associated with either product or starting material.

116

4.3.25 2-(6-chlorohexyloxy)-tetrahydro-2H-pyran O Cl O

3,4-Dihydropyran (69) (1.36 mL, 15.0 mmol) was added dropwise to a cooled solution of 6-chloro-

1-hexanol (68) (1.00 mL, 7.50 mmol) and catalytic p-toluenesulfonic acid in CH2Cl2 (5 mL) and the resulting solution stirred for 17 hours at room temperature. The mixture was diluted with CH2Cl2

(15 mL), washed with H2O (2 × 10 mL) and NaHCO3 (1 × 10 mL), the organic layer dried and concentrated under reduced pressure.277 Flash chromatography was performed on the residual oil (5 % EtOAc in PS) to afford the desired compound as a yellow oil (1.62 g, 98 %).

H (500 MHz, CDCl3): 1.32-1.65 (m, 10H), 1.67-1.73 (m, 1H), 1.75-1.86 (m, 3H), 3.35-3.40 (m, 1H), 3.46-3.55 (m, 3H), 3.70-3.75 (m, 1H), 3.83-3.88 (m, 1H), 4.54-4.57 (m, 1H).

4.3.26 2-(6-iodohexyloxy)-tetrahydro-2H-pyran (70) O I O

A solution of NaI (2.30 g, 15.3 mmol) and 2-(6-chlorohexyloxy)-tetrahydro-2H-pyran (0.845 g,

3.83 mmol) in acetone (15 mL) was refluxed for 17 hours. The solution was then diluted with H2O (30 mL) and extracted with pentane (3 × 15 mL), affording the title compound as a yellow oil (1.12 g, 93 %).

H (500 MHz, CDCl3): 1.35-1.64 (m, 10H), 1.68-1.75 (m, 1H), 1.76-1.89 (m, 3H), 3.20 (t, J = 7.0 Hz, 2H), 3.36-3.41 (m, 1H), 3.47-3.54 (m, 1H), 3.71-3.76 (m, 1H), 3.84-3.89 (m, 1H), 4.56- 4.58 (m, 1H).

117

4.3.27 Triphenyl-[6-tetrahydropyran-2-yloxy-hexyl]-stannane (71) O Ph3Sn O

Mg turnings (0.081 g, 3.3 mmol) and catalytic iodine were placed under argon and heated until iodine vapour had fully dispersed, then stirred vigorously for 1 hour. Subsequently, anhydrous Et2O (1 mL) was added followed by the dropwise addition of alkyl iodide 70 (0.610 g, 1.95 mmol) slowly. After 15 min the solution had turned a cloudy grey and was stirred for a further five minutes before

Ph3SnCl (0.568 g, 1.46 mmol) in anhydrous Et2O (10 mL) was added slowly. This was stirred for a further 30 min, after which time the solution had turned clear. Water was slowly added until no reaction observed, then the aqueous layer extracted with Et2O (3 × 10 mL), the organic extracts dried over anhydrous MgSO4 and concentrated under reduced pressure. 1H NMR spectroscopy of the crude material did not show any characteristic signals from the desired product.

A large excess of lithium was cut into small strips, washed briefly with anhydrous MeOH, and placed into anhydrous THF (10 mL). To this suspension was added 2-(6-iodohexyloxy)- tetrahydropyran (70) (0.391 g, 1.25 mmol) in anhydrous THF (5 mL) and the solution refluxed at 74 °C for 2.5 hours after which time the solution had turned a cloudy yellow colour. Subsequently, a solution of Ph3SnCl (0.434 g, 1.13 mmol) in anhydrous THF (5 mL) was prepared and cannulated into the hot lithium solution. The combined mixture was refluxed at 74 °C for a further 17 hours before cooling and concentrating to an oily residue, dissolving in CH2Cl2 (50 mL), washing with

H2O (3 × 20 mL), drying over anhydrous MgSO4 and concentrating under reduced pressure. NMR spectra of various nuclei did not reveal signals from the desired product.

118

4.3.28 (6-Hydroxyhexyl)triphenylstannane (73)

Sn OH

Triphenylstannane (3.00 g, 8.54 mmol), 5-hexen-1-ol (72) (1.28 mL, 10.7 mmol) and catalytic AIBN were added to a dried, sealed tube under argon and heated at 110 C for 22 hours, with AIBN added in small portions after 5 and 12 hours. CH2Cl2 (50 mL) added and the solution washed with

H2O (2 × 25 mL) and brine (1 × 25 mL), dried and concentrated under reduced pressure.287 Flash chromatography (CH2Cl2:MeOH) allowed the title compound to be isolated as a colourless oil (2.93 g, 76 %) with identical spectral character compared to the literature.

H (500 MHz, CDCl3): 1.10 (t, J = 5.5 Hz, 1H), 1.27-1.54 (m, 8H), 1.68-1.77 (m, 2H), 3.56 (m, 2H), 7.27-7.41 (m 9H), 7.45-7.61 (m, 6H).

C (125 MHz, CDCl3): 11.0, 25.1, 26.5, 32.6, 33.9, 62.9, 128.4, 128.8, 137.0, 139.1.

Sn (186 MHz, CDCl3): -99.8.

HRMS calculated for [M-Ph]+ C18H23OSn: 375.0771 m/z, found 375.07641 m/z.

4.3.29 (6-methanesulfonyloxyhexyl)triphenylstannane

Sn OMs

Methanesulfonyl chloride (0.14 mL, 1.8 mmol) was added dropwise to a solution of (6-hydroxyhexyl)triphenylstannane (73) (0.573 g, 1.28 mmol) and triethylamine (0.36 mL, 2.6 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature for 1.5 hours, water

(30 mL) added, extracted with CH2Cl2 (3 × 10 mL) and the combined organic layers washed with

10 % HCl (20 mL), 2 % NaHCO3 (20 mL) and H2O (20 mL), dried and concentrated under reduced pressure to give the title compound as a colourless oil (0.596 g, 88 %).

H (500 MHz, CDCl3): 1.34-1.54 (m, 6H), 1.61-1.76 (m, 4H), 2.96 (s, 3H), 4.14 (t, J = 6.6 Hz, 2H), 7.29-7.40 (m, 9H), 7.48-7.60 (m, 6H).

119

4.3.30 (6-iodohexyl)triphenylstannane (74)

Sn I

NaI (0.13 g, 0.86 mmol) was added to a solution of (6-methanesulfonyloxyhexyl)triphenylstannane (0.18 g, 0.34 mmol) in acetone (5 mL) and refluxed for 17 hours. The mixture was then cooled, acetone removed under vacuum, the residue dissolved in CH2Cl2 (15 mL) and washed with H2O (3 × 5 mL). The organic phase was dried and concentrated under reduced pressure to afford the title compound as a pale-yellow oil (0.19 g, 99 %).

H (500 MHz, CDCl3): 1.30-1.53 (m, 6H), 1.64-1.79 (m, 4H), 3.09 (t, J = 7.0 Hz, 2H), 7.28-7.40 (m, 9H), 7.46-7.60 (m, 6H).

4.3.31 1-(6-Chlorodiphenylstannyl-hexyl)-2,3-dimethyl-3H-imidazolium tetrafluoroborate (76)

SnPh Cl N N 2 BF4

1-(6-Chlorodiphenylstannylhexyl)-2,3-dimethyl-3H-imidazolium iodide (66) (1.15 g, 1.87 mmol) was dissolved in CH2Cl2 (50 mL) and to this was added NaBF4 (1.03 g, 9.40 mmol). The resulting mixture was refluxed for 48 hours before cooling, washing with H2O (4 × 20 mL), drying over anhydrous MgSO4, concentrating under reduced pressure before undergoing flash chromatography

(CH2Cl2:MeOH) to give the title compound as a pale yellow oil (1.08 g, 100%, m.p. 115.6 – 116.6 °C).

H (400 MHz, CDCl3): 1.20-1.42 (m, 4H), 1.56-1.68 (m, 2H), 1.71-1.94 (m, 4H), 2.43 (s, 3H), 3.64 (s, 3H), 3.87 (t, J = 7.4 Hz, 2H), 7.10 (s, 1H), 7.17 (s, 1H), 7.27-7.43 (m, 6H), 7.52-7.70 (m, 4H).

C (100 MHz, CDCl3): 9.1, 17.9, 25.0, 25.5, 28.9, 32.1, 34.7, 47.9, 120.4, 122.1, 128.5, 129.6, 135.7, 138.6, 143.3.

Sn (186 MHz, CDCl3): -47.2.

HRMS calculated for [M-BF4]+ C23H30N2ClSn: 489.1120 m/z, found 489.1116 m/z. (compound 76)

120

HRMS calculated for [M-BF4]+ C23H30N2ISn: 581.0476 m/z, found 581.0479 m/z.

4.3.32 Diethyl (4-pentenyl)malonate (79)

CO2Et

To a suspension of NaH (2.30 g, 59.0 mmol) in anhydrous THF (75 mL) was added diethyl malonate (77) (3.0 mL, 20 mmol) at 0 °C under argon. The reaction mixture was stirred for one hour at room temperaure, after which time 5-bromo-1-pentene (78) (2.56 mL, 21.6 mmol) was added and the reaction stirred until TLC indicated reaction completion. The mixture was them slowly quenched with H2O (50 mL), the THF removed under reduced pressure and the product extracted into Et2O (3 × 25 mL).305 Following flash chromatography (5 % EtOAc in PS), the title compound was isolated as a colourless oil (0.659 g, 25 %), with spectral characteristics in agreement with those from the literature.340

H (400 MHz, CDCl3): 1.26 (t, J = 7.1 Hz, 6H), 1.38-1.47 (m, 2H), 1.91 (q, J = 8.0 Hz, 2H), 2.08 (q, J = 7.0 Hz, 2H), 3.32 (t, J = 7.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 4H), 4.94-5.05 (m, 2H), 5.72- 5.84 (m, 1H).

4.3.33 6-Heptenoic acid (80)

CO2H

Diester 79 (0.456 g, 2.00 mmol) was dissolved in EtOH (3 mL) and H2O (5 mL) and to this was added KOH (0.449 g, 8.00 mmol) before the mixture was refluxed for 3 hours, then cooled and stirred at room temperature overnight. Subsequently, EtOH was removed under reduced pressure, the aqueous phase acidified to pH 3 and then solvent extracted with Et2O (3 × 5 mL). The combined organic fractions were washed with H2O (1 × 5 mL) and brine (1 × 5 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was then heated neat at 160 °C for 24 hours before undergoing an acid-base extraction to give the title compound as a clear oil (0.158 g, 62 %), with spectral characteristics in agreement with those from the literature.306, 307

H (400 MHz, CDCl3): 1.41-1.50 (m, 2H), 1.61-1.70 (m, 2H), 2.04-2.13 (m, 2H), 2.37 (t, J = 7.4 Hz, 2H), 4.91-5.07 (m, 2H), 5.69-5.86 (m, 1H).

121

4.3.34 Hept-6-enoic acid 2-thioxo-2H-pyridin-1-yl ester (82) S O N O

6-Heptenoic acid (80) (0.235 g, 1.84 mmol) was dissolved in CH2Cl2 (40 ml) under argon at 0 °C and to this was added N,N'-dicyclohexylcarbodiimide (0.417 g, 2.02 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.011 g, 0.092 mmol.). The solution was wrapped in foil to ensure complete darkness before adding N-hydroxy pyridine-2-thione (81) (0.210 g, 1.66 mmol), then stirred for 17 hours at room temperature. Following this, the mixture was cooled to -10 °C, filtered over celite and immediately pushed through a silica plug to remove excess acid. Following concentration under reduced pressure, the title compound was isolated as a yellow oil (0.189 g, 48 %).

H (400 MHz, C6D6): 1.13-1.23 (m, 2H), 1.48-1.57 (m, 2H), 1.80 (q, J = 7.2 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 4.85-4.98 (m, 2H), 5.31-5.38 (m, 1H), 5.54-5.68 (m, 1H), 5.93-6.02 (m, 1H), 6.38-6.44 (m, 1H), 7.35-7.42 (m, 1H).

122

5 References 1. M. Gomberg, J. Am. Chem. Soc., 1900, 22, 757-771. 2. A. N. Hancock and C. H. Schiesser, Chem. Commun., 2013, 49, 9892-9895. 3. C. Walling, Tetrahedron, 1985, 41, 3887-3900. 4. A. L. J. Beckwith and C. H. Schiesser, Tetrahedron, 1985, 41, 3925-3941. 5. D. Griller and K. U. Ingold, Acc. Chem. Res., 1980, 13, 317-323. 6. D. H. R. Barton, D. Crich and W. B. Motherwell, J. Chem. Soc., Chem. Commun., 1983, 939- 941. 7. M. C. Fong and C. H. Schiesser, J. Org. Chem., 1997, 62, 3103-3108. 8. S. A. Hitchcock, S. J. Houldsworth, G. Pattenden, D. C. Pryde, N. M. Thomson and A. J. Blake, Perkin Trans. 1, 1998, 3181-3206. 9. G. Pattenden, L. Roberts and A. J. Blake, Perkin Trans. 1, 1998, 863-868. 10. J. Chiefari, Y. K. Chong, F. Ercole, J. Krstina, J. Jeffery, T. P. T. Le, R. T. A. Mayadunne, G. F. Meijs, C. L. Moad, G. Moad, E. Rizzardo and S. H. Thang, Macromolecules, 1998, 31, 5559-5562. 11. M. Kato, M. Kamigaito, M. Sawamoto and T. Higashimura, Macromolecules, 1995, 28, 1721- 1723. 12. J.-S. Wang and K. Matyjaszewski, J. Am. Chem. Soc., 1995, 117, 5614-5615. 13. P. Nordlund and P. Reichard, Annu. Rev. Biochem., 2006, 75, 681-706. 14. P. A. Frey, A. D. Hegeman and G. H. Reed, Chem. Rev., 2006, 106, 3302-3316. 15. M. Newcomb, in Encyclopedia of Radicals in Chemistry, Biology and Materials, John Wiley & Sons Ltd, Hoboken, New Jersey, 2012. 16. S. Z. Zard, Org. Lett., 2017, 19, 1257-1269. 17. D. P. Curran and D. M. Rakiewicz, J. Am. Chem. Soc., 1985, 107, 1448-1449. 18. K. A. Parker and D. Fokas, J. Am. Chem. Soc., 1992, 114, 9688-9689. 19. A. Russo, G. Maschio and C. Ampelli, Macromol. Symp., 2007, 259, 365-370. 20. K. Platkowski and K. H. Reichert, Chem. Eng. Technol., 1999, 22, 1035-1038. 21. P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, Oxford, UK, 1998. 22. D. Reinhardt, F. Ilgen, D. Kralisch, B. Konig and G. Kreisel, Green Chem., 2008, 10, 1170- 1181. 23. D. G. Blackmond, A. Armstrong, V. Coombe and A. Wells, Angew. Chem. Int. Ed., 2007, 46, 3798-3800. 24. U. M. Lindström, Chem. Rev., 2002, 102, 2751-2772. 25. W. Wei, C. C. K. Keh, C.-J. Li and R. S. Varma, Clean Techn. Environ. Policy, 2004, 7, 62-69. 26. L. Chen and C.-J. Li, Adv. Synth. Catal., 2006, 348, 1459-1484.

123

27. C. I. Herrerías, X. Yao, Z. Li and C.-J. Li, Chem. Rev., 2007, 107, 2546-2562. 28. C.-J. Li, Chem. Rev., 2005, 105, 3095-3166. 29. K. Tanaka, in Solvent-Free Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2009. 30. R. S. Varma, Pure Appl. Chem., 2001, 73, 193-198. 31. R. S. Varma, Green Chem., 1999, 1, 43-55. 32. K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025-1074. 33. J. R. Cherouvrier, J. Boissel, F. Carreaux and J. P. Bazureau, Green Chem., 2001, 3, 165-169. 34. P. G. Jessop, T. Ikariya and R. Noyori, Science, 1995, 269, 1065-1069. 35. M. Wei, G. T. Musie, D. H. Busch and B. Subramaniam, J. Am. Chem. Soc., 2002, 124, 2513- 2517. 36. T. Matsuda, Y. Ohashi, T. Harada, R. Yanagihara, T. Nagasawa and K. Nakamura, Chem. Commun., 2001, 2194-2195. 37. R. Ishii and K. Ooi, Chem. Commun., 1998, 1705-1706. 38. P. G. Jessop, T. Ikariya and R. Noyori, Chem. Rev., 1999, 99, 475-494. 39. J. I. Garcia, H. Garcia-Marin and E. Pires, Green Chem., 2014, 16, 1007-1033. 40. Y. Gu and F. Jerome, Green Chem., 2010, 12, 1127-1138. 41. A. P. Abbott, G. Capper, D. L. Davies, H. L. Munro, R. K. Rasheed and V. Tambyrajah, Chem. Commun., 2001, 2010-2011. 42. D. A. Alonso, A. Baeza, R. Chinchilla, G. Guillena, I. M. Pastor and D. J. Ramón, Eur. J. Org. Chem., 2016, 612-632. 43. M. K. AlOmar, M. Hayyan, M. A. Alsaadi, S. Akib, A. Hayyan and M. A. Hashim, J. Mol. Liq., 2016, 215, 98-103. 44. N. R. Rodriguez, J. Ferre Guell and M. C. Kroon, J. Chem. Eng. Data, 2016, 61, 865-872. 45. J. S. Wilkes, in Ionic Liquids in Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2003, pp. 1-6. 46. J. H. Davis Jr., C. M. Gordon, C. Hilgers and P. Wasserscheid, in Ionic Liquids in Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2003, pp. 7-40. 47. J. P. Hallett and T. Welton, Chem. Rev., 2011, 111, 3508-3576. 48. T. Welton, Chem. Rev., 1999, 99, 2071-2084. 49. E. W. Castner, C. J. Margulis, M. Maroncelli and J. F. Wishart, Annu. Rev. Phys. Chem., 2011, 62, 85-105. 50. R. Sheldon, Chem. Commun., 2001, 2399-2407. 51. W. Ramsay, Philos. Mag. Ser. 5, 1876, 2, 269-281. 52. C. Austen Angell, Y. Ansari and Z. Zhao, Faraday Discuss., 2012, 154, 9-27. 53. J. S. Wilkes and M. J. Zaworotko, J. Chem. Soc., Chem. Commun., 1992, 965-967. 54. N. V. Plechkova and K. R. Seddon, Chem. Soc. Rev., 2008, 37, 123-150.

124

55. E. W. C. Jr. and J. F. Wishart, J. Chem. Phys., 2010, 132, 120901. 56. T. P. Thuy Pham, C.-W. Cho and Y.-S. Yun, Water Res., 2010, 44, 352-372. 57. M. Deetlefs and K. R. Seddon, in Handbook of Green Chemistry, eds. P. Wasserscheid and A. Stark, Wiley-VCH Verlag GmbH & Co. KGaA, 2010, vol. 6. 58. E. Sklavounos, J. K. J. Helminen, L. Kyllönen, I. Kilpeläinen and A. W. T. King, in Encyclopedia of Inorganic and Bioinorganic Chemistry, ed. R. A. Scott, 2016. 59. S. Abu-Eishah, Ionic Liquids Recycling for Reuse, 2011. 60. R. P. Swatloski, S. K. Spear, J. D. Holbrey and R. D. Rogers, J. Am. Chem. Soc., 2002, 124, 4974-4975. 61. K. Fujita, D. R. MacFarlane, M. Forsyth, M. Yoshizawa-Fujita, K. Murata, N. Nakamura and H. Ohno, Biomacromolecules, 2007, 8, 2080-2086. 62. P. Bonhôte, A.-P. Dias, N. Papageorgiou, K. Kalyanasundaram and M. Grätzel, Inorg. Chem., 1996, 35, 1168-1178. 63. M. Armand, F. Endres, D. R. MacFarlane, H. Ohno and B. Scrosati, Nat. Mater., 2009, 8, 621-629. 64. M. Galiński, A. Lewandowski and I. Stępniak, Electrochim. Acta, 2006, 51, 5567-5580. 65. N. Kamaya, K. Homma, Y. Yamakawa, M. Hirayama, R. Kanno, M. Yonemura, T. Kamiyama, Y. Kato, S. Hama, K. Kawamoto and A. Mitsui, Nat. Mater., 2011, 10, 682-686. 66. H. Saruwatari, T. Kuboki, T. Kishi, S. Mikoshiba and N. Takami, J. Power Sources, 2010, 195, 1495-1499. 67. F. Endres, ChemPhysChem, 2002, 3, 144-154. 68. R. Vijayaraghavan, M. Surianarayanan and D. R. MacFarlane, Angew. Chem., 2004, 116, 5477-5480. 69. J. G. Huddleston, A. E. Visser, W. M. Reichert, H. D. Willauer, G. A. Broker and R. D. Rogers, Green Chem., 2001, 3, 156-164. 70. M. J. Earle, C. M. Gordon, N. V. Plechkova, K. R. Seddon and T. Welton, Anal. Chem., 2006, 79, 758-764. 71. P. K. Mandal, A. Paul and A. Samanta, J. Chin. Chem. Soc., 2006, 53, 247-252. 72. A. Paul, P. K. Mandal and A. Samanta, J. Phys. Chem. B, 2005, 109, 9148-9153. 73. M. Petkovic, K. R. Seddon, L. P. Rebelo and C. Silva Pereira, Chem. Soc. Rev., 2011, 40, 1383-1403. 74. X. Chen, S. Kang, M. J. Kim, J. Kim, Y. S. Kim, H. Kim, B. Chi, S.-J. Kim, J. Y. Lee and J. Yoon, Angew. Chem. Int. Ed., 2010, 49, 1422-1425. 75. C. C. Weber, A. F. Masters and T. Maschmeyer, Angew. Chem. Int. Ed., 2012, 51, 11483- 11486. 76. M. Yang, B. Mallick and A.-V. Mudring, Cryst. Growth Des., 2013, 13, 3068-3077.

125

77. M. Debdab, F. Mongin and J. P. Bazureau, Synthesis, 2006, 2006, 4046-4052. 78. T. J. Geldbach and P. J. Dyson, J. Am. Chem. Soc., 2004, 126, 8114-8115. 79. A. K. Burrell, R. E. D. Sesto, S. N. Baker, T. M. McCleskey and G. A. Baker, Green Chem., 2007, 9, 449-454. 80. C. Chiappe and D. Pieraccini, J. Phys. Org. Chem., 2005, 18, 275-297. 81. J. Grodkowski and P. Neta, J. Phys. Chem. A, 2002, 106, 11130-11134. 82. B. Y. W. Man, J. M. Hook and J. B. Harper, Tetrahedron Lett., 2005, 46, 7641-7645. 83. H. M. Yau, A. K. Croft and J. B. Harper, Faraday Discuss., 2012, 154, 365-371. 84. H. M. Yau, A. G. Howe, J. M. Hook, A. K. Croft and J. B. Harper, Org. Biomol. Chem., 2009, 7, 3572-3575. 85. H. M. Yau, S. A. Barnes, J. M. Hook, T. G. A. Youngs, A. K. Croft and J. B. Harper, Chem. Commun., 2008, 3576-3578. 86. S. T. Keaveney, B. P. White, R. S. Haines and J. B. Harper, Org. Biomol. Chem., 2016, 14, 2572-2580. 87. S. T. Keaveney, R. S. Haines and J. B. Harper, Org. Biomol. Chem., 2015, 13, 8925-8936. 88. J. L. Anthony, J. F. Brennecke, J. D. Holbrey, E. J. Maginn, R. A. Mantz, R. D. Rogers, P. C. Trulove, A. E. Visser and T. Welton, in Ionic Liquids in Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2003, pp. 41-126. 89. A. P. Fröba, H. Kremer and A. Leipertz, J. Phys. Chem. B, 2008, 112, 12420-12430. 90. M. A. Ab Rani, A. Brant, L. Crowhurst, A. Dolan, M. Lui, N. H. Hassan, J. P. Hallett, P. A. Hunt, H. Niedermeyer, J. M. Perez-Arlandis, M. Schrems, T. Welton and R. Wilding, Physical chemistry chemical physics : PCCP, 2011, 13, 16831-16840. 91. T. L. Greaves and C. J. Drummond, Chem. Rev., 2008, 108, 206-237. 92. S. N. V. K. Aki, J. F. Brennecke and A. Samanta, Chem. Commun., 2001, 413-414. 93. H. Tokuda, K. Ishii, M. A. B. H. Susan, S. Tsuzuki, K. Hayamizu and M. Watanabe, J. Phys. Chem. B, 2006, 110, 2833-2839. 94. J. A. Widegren, A. Laesecke and J. W. Magee, Chem. Commun., 2005, 1610-1612. 95. F. Zhou, Y. Liang and W. Liu, Chem. Soc. Rev., 2009, 38, 2590-2599. 96. T. Regueira, L. Lugo and J. Fernández, Lubr. Sci., 2014, 26, 488-499. 97. B. Wu, Z. Hu, Y. Zhang, Y. Xiao, J. Lei and C. Zhou, Polym. Eng. Sci., 2016, 56, 629-635. 98. A. Tsurumaki, S. Tajima, T. Iwata, B. Scrosati and H. Ohno, Electrochim. Acta, 2017, 248, 556-561. 99. M. C. Buzzeo, C. Hardacre and R. G. Compton, Anal. Chem., 2004, 76, 4583-4588. 100. D. Wei and A. Ivaska, Anal. Chim. Acta, 2008, 607, 126-135. 101. J. H. Davis Jr., Chem. Lett., 2004, 33, 1072-1077.

126

102. A. W. Czarnik, in Solid‐Phase Organic Syntheses, John Wiley, New York, U.S.A., 2001, pp. 1- 157. 103. A. D. Sawant, D. G. Raut, N. B. Darvatkar and M. M. Salunkhe, Green Chem. Lett. Rev., 2011, 4, 41-54. 104. S.-g. Lee, Chem. Commun., 2006, 1049-1063. 105. Y. Sahbaz, T.-H. Nguyen, L. Ford, C. L. McEvoy, H. D. Williams, P. J. Scammells and C. J. H. Porter, Mol. Pharm., 2017, 14, 3669-3683. 106. H. D. Williams, Y. Sahbaz, L. Ford, T.-H. Nguyen, P. J. Scammells and C. J. H. Porter, Chem. Commun., 2014, 50, 1688-1690. 107. S. Ding, M. Radosz and Y. Shen, Macromolecules, 2005, 38, 5921-5928. 108. H. Rajerison, D. Faye, A. Roumesy, N. Louaisil, F. Boeda, A. Faivre-Chauvet, J.-F. Gestin and S. Legoupy, Org. Biomol. Chem., 2016, 14, 2121-2126. 109. A. E. Visser, R. P. Swatloski, W. M. Reichert, R. Mayton, S. Sheff, A. Wierzbicki, J. J. H. Davis and R. D. Rogers, Chem. Commun., 2001, 135-136. 110. R. D. Rogers and S. T. Griffin, J Chromatogr B Biomed Sci Appl, 1998, 711, 277-283. 111. E. D. Bates, R. D. Mayton, I. Ntai and J. H. Davis, J. Am. Chem. Soc., 2002, 124, 926-927. 112. R. Quinn, J. B. Appleby and G. P. Pez, J. Am. Chem. Soc., 1995, 117, 329-335. 113. A. Noda and M. Watanabe, Electrochim. Acta, 2000, 45, 1265-1270. 114. P. Kubisa, Prog. Polym. Sci., 2004, 29, 3-12. 115. P. Kubisa, J. Polym. Sci. A, 2005, 43, 4675-4683. 116. S. Harrisson, S. R. Mackenzie and D. M. Haddleton, Chem. Commun., 2002, 2850-2851. 117. K. Hong, H. Zhang, J. W. Mays, A. E. Visser, C. S. Brazel, J. D. Holbrey, W. M. Reichert and R. D. Rogers, Chem. Commun., 2002, 1368-1369. 118. A. J. Carmichael, D. M. Haddleton, S. A. F. Bon and K. R. Seddon, Chem. Commun., 2000, 1237-1238. 119. S. Feng, W. Xu, K. Nakanishi and S. Yamago, ACS Macro Lett., 2011, 1, 146-149. 120. G. Schmidt‐Naake, I. Woecht, A. Schmalfuß and T. Glück, Macromol. Symp., 2009, 275–276, 204-218. 121. S. Beuermann, Macromol. Rapid Commun., 2009, 30, 1066-1088. 122. I. Woecht, G. Schmidt-Naake, S. Beuermann, M. Buback and N. García, J. Polym. Sci. A, 2008, 46, 1460-1469. 123. D. Behar, P. Neta and C. Schultheisz, J. Phys. Chem. A, 2002, 106, 3139-3147. 124. D. Behar, C. Gonzalez and P. Neta, J. Phys. Chem. A, 2001, 105, 7607-7614. 125. J. Grodkowski and P. Neta, J. Phys. Chem. A, 2002, 106, 5468-5473. 126. J. Grodkowski and P. Neta, J. Phys. Chem. A, 2002, 106, 9030-9035.

127

127. A. J. McLean, M. J. Muldoon, C. M. Gordon and I. R. Dunkin, Chem. Commun., 2002, 1880- 1881. 128. M. J. Muldoon, A. J. McLean, C. M. Gordon and I. R. Dunkin, Chem. Commun., 2001, 2364- 2365. 129. G. Litwinienko, A. L. J. Beckwith and K. U. Ingold, Chem. Soc. Rev., 2011, 40, 2157-2163. 130. D. W. Snelgrove, J. Lusztyk, J. T. Banks, P. Mulder and K. U. Ingold, J. Am. Chem. Soc., 2001, 123, 469-477. 131. L. J. Athelstan, M. D. Cliff and C. H. Schiesser, Tetrahedron, 1992, 48, 4641-4648. 132. C. E. Hand and J. F. Honek, J. Nat. Prod., 2005, 68, 293-308. 133. A. Meister and M. E. Anderson, Annu. Rev. Biochem., 1983, 52, 711-760. 134. J. Baddiley, E. M. Thain, G. D. Novelli and F. Lipmann, Nature, 1953, 171, 76. 135. C. D. Taylor and R. S. Wolfe, J. Biol. Chem., 1974, 249, 4879-4885. 136. C. J. Cavallito and J. H. Bailey, J. Am. Chem. Soc., 1944, 66, 1950-1951. 137. P. Semmelroch and W. Grosch, J. Agric. Food Chem., 1996, 44, 537-543. 138. K. K. Andersen, D. T. Bernstien, R. L. Caret and L. J. Romanczyk, Tetrahedron, 1982, 38, 1965-1970. 139. T. Tominaga, A. Furrer, R. Henry and D. Dubourdieu, Flavour Fragr. J., 1998, 13, 159-162. 140. J. Peisach and W. E. Blumberg, Mol. Pharmacol., 1969, 5, 200-209. 141. L. Hansson, L. H. Lindholm, L. Niskanen, J. Lanke, T. Hedner, A. Niklason, K. Luomanmäki, B. Dahlöf, U. de Faire, C. Mörlin, B. E. Karlberg, P. O. Wester and J.-E. Björck, Lancet, 1999, 353, 611-616. 142. J. D. Jessop, M. M. O'Sullivan, P. A. Lewis, L. A. Williams, J. P. Camilleri, M. J. Plant and E. C. Coles, Rheumatology, 1998, 37, 992-1002. 143. F.-M. Klingler, T. A. Wichelhaus, D. Frank, J. Cuesta-Bernal, J. El-Delik, H. F. Müller, H. Sjuts, S. Göttig, A. Koenigs, K. M. Pos, D. Pogoryelov and E. Proschak, J. Med. Chem., 2015, 58, 3626-3630. 144. Y. Xu, G. Pang, D. Zhao, C. Gao, L. Zhou, S. Sun and B. Wang, Antimicrob. Agents. Chemother., 2010, 54, 536-539. 145. T. W. Clarkson and L. Magos, Crit. Rev. Toxicol., 2006, 36, 609-662. 146. S. A. Counter and L. H. Buchanan, Toxicol. Appl. Pharmacol., 2004, 198, 209-230. 147. W. H. Brown and T. Poon, Introduction to Organic Chemistry, John Wiley & Sons Inc, Hoboken, New Jersey, 5th edn., 2015. 148. R. L. Jackson, Living Lessons from the New London School Explosion, The Parthenon Press, Nashville, Tennessee, 1938. 149. R. Takagi, N. Igata, K. Yamamoto and S. Kojima, J. Organomet. Chem., 2011, 696, 1556- 1564.

128

150. G. Pattenden and A. J. Shuker, Perkin Trans. 1, 1992, 1215-1221. 151. J. I. Cunneen, J. Chem. Soc., 1947, 134-141. 152. C. G. Moore and R. W. Saville, J. Chem. Soc., 1954, 2089-2094. 153. B. A. Tkachenko, N. A. Fokina, L. V. Chernish, J. E. P. Dahl, Liu, R. M. K. Carlson, A. A. Fokin and P. R. Schreiner, Org. Lett., 2006, 8, 1767-1770. 154. D. Tsuchiya, M. Tabata, K. Moriyama and H. Togo, Tetrahedron, 2012, 68, 6849-6855. 155. R. Nicolaÿ, Macromolecules, 2012, 45, 821-827. 156. J. Voss, J. Sulfur Chem., 2009, 30, 167-207. 157. J. Clayden and P. MacLellan, Beilstein J. Org. Chem., 2011, 7, 582-595. 158. F. Dénès, M. Pichowicz, G. Povie and P. Renaud, Chem. Rev., 2014, 114, 2587-2693. 159. K. Griesbaum, Angew. Chem. Int. Ed., 1970, 9, 273-287. 160. M. Schwarz, G. F. Graminski and R. M. Waters, J. Org. Chem., 1986, 51, 260-263. 161. S. N. Lewis, J. J. Miller and S. Winstein, J. Org. Chem., 1972, 37, 1478-1485. 162. D. H. R. Barton and S. W. McCombie, Perkin Trans. 1, 1975, 1574-1585. 163. D. Crich and L. Quintero, Chem. Rev., 1989, 89, 1413-1432. 164. D. H. R. Barton, D. Crich and W. B. Motherwell, Tetrahedron, 1985, 41, 3901-3924. 165. D. H. R. Barton and D. Crich, Perkin Trans. 1, 1986, 1603-1611. 166. E. Denisov, C. Chatgilialoglu, A. Shestakov and T. Denisova, Int. J. Chem. Kinet., 2009, 41, 284-293. 167. C. Chatgilialoglu and M. Newcomb, in Advances in Organometallic Chemistry, eds. R. West and A. F. Hill, Academic Press, 1999, vol. 44, pp. 67-112. 168. M. Lucarini and G. F. Pedulli, Chem. Soc. Rev., 2010, 39, 2106-2119. 169. B. P. Roberts, Chem. Soc. Rev., 1999, 28, 25-35. 170. H.-S. Dang and B. P. Roberts, Tetrahedron Lett., 1995, 36, 2875-2878. 171. B. C. Ranu and S. S. Dey, Tetrahedron, 2004, 60, 4183-4188. 172. A. R. Ferreira, L. A. Neves, J. C. Ribeiro, F. M. Lopes, J. A. P. Coutinho, I. M. Coelhoso and J. G. Crespo, Chem. Eng. J., 2014, 256, 144-154. 173. J. S. Yadav, B. V. S. Reddy and G. Baishya, J. Org. Chem., 2003, 68, 7098-7100. 174. A. S. Shaplov, P. S. Vlasov, E. I. Lozinskaya, O. A. Shishkan, D. O. Ponkratov, I. A. Malyshkina, F. Vidal, C. Wandrey, I. A. Godovikov and Y. S. Vygodskii, Macromol. Chem. Phys., 2012, 213, 1359-1369. 175. Y. Lei, Z. Tang, L. Zhu, B. Guo and D. Jia, Polymer, 2011, 52, 1337-1344. 176. Y. Lei, Z. Tang, L. Zhu, B. Guo and D. Jia, J. Appl. Polym. Sci., 2012, 123, 1252-1260. 177. K.-S. Kim, D. Demberelnyamba and H. Lee, Langmuir, 2004, 20, 556-560. 178. R. Gondosiswanto, C. A. Gunawan, D. B. Hibbert, J. B. Harper and C. Zhao, ACS Appl. Mater. Interfaces, 2016, 8, 31368-31374.

129

179. Y. Mei and B. Yan, Inorg. Chem. Commun., 2014, 40, 39-42. 180. A. S. M. C. Rodrigues, C. F. R. A. C. Lima, J. A. P. Coutinho and L. M. N. B. F. Santos, Phys. Chem. Chem. Phys., 2017, 19, 5326-5332. 181. K. Fumino, A. Wulf and R. Ludwig, Angew. Chem. Int. Ed., 2008, 47, 8731-8734. 182. M. Larriba, S. García, P. Navarro, J. García and F. Rodríguez, J. Chem. Eng. Data, 2012, 57, 1318-1325. 183. Z. Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian and R. A. Widenhoefer, J. Am. Chem. Soc., 2006, 128, 9066-9073. 184. R. El Aissi, J. Liu, S. Besse, D. Canitrot, O. Chavignon, J.-M. Chezal, E. Miot-Noirault and E. Moreau, ACS Med. Chem. Lett., 2014, 5, 468-473. 185. N. Miyoshi, T. Matsuo and M. Wada, Eur. J. Org. Chem., 2005, 4253-4255. 186. H. Masada and Y. Murotani, Bull. Chem. Soc. Jpn, 1980, 53, 1181-1182. 187. J. D. Pelletier and D. Poirier, Tetrahedron Lett., 1994, 35, 1051-1054. 188. E. Rank and R. Brückner, Eur. J. Org. Chem., 1998, 1045-1053. 189. A. Guijarro, D. M. Rosenberg and R. D. Rieke, J. Am. Chem. Soc., 1999, 121, 4155-4167. 190. Z. Si, Z. Sun, F. Gu, L. Qiu and F. Yan, J. Mater. Chem. A, 2014, 2, 4413-4421. 191. H. E. French and A. E. Schaefer, J. Am. Chem. Soc., 1935, 57, 1576-1578. 192. A. Saytzeff, Justus Liebigs Ann. Chem., 1875, 179, 296-301. 193. Z. Du, Y. Li, Y. Wang, L. Ding and J. Gao, Synth. Commun., 2010, 40, 1920-1926. 194. M. Julia and P. Roy, Tetrahedron, 1986, 42, 4991-5002. 195. W. Markownikoff, Justus Liebigs Ann. Chem., 1870, 153, 228-259. 196. R. Raz and J. Rademann, Org. Lett., 2011, 13, 1606-1609. 197. G. Gopalakrishnan, V. Kasinath, N. Pradeep Singh, R. Thirumurugan, S. Sundara Raj and G. Shanmugam, Molecules, 2000, 5, 880. 198. B. R. Yoo, J. Hyun Kim, H.-J. Lee, K.-B. Lee and I. Nam Jung, J. Organomet. Chem., 2000, 605, 239-245. 199. D. Gudeczauskas and C. A. Natalie, Hydrometallurgy, 1985, 14, 369-385. 200. W. H. Bunnelle, B. R. McKinnis and B. A. Narayanan, J. Org. Chem., 1990, 55, 768-770. 201. O. L. Brady and G. V. Elsmie, Analyst, 1926, 51, 77-78. 202. V. A. Kuznetsov, M. G. Pervova and A. V. Pestov, Russ. J. Org. Chem., 2013, 49, 1859-1860. 203. S. Sakai, Y. Kiyohara, K. Itoh and Y. Ishii, J. Org. Chem., 1970, 35, 2347-2350. 204. M. Teruaki, S. Terunobu and J. Hideki, Chem. Lett., 2001, 30, 638-639. 205. I. S. Alferiev, N. V. Mikhalin, I. L. Kotlyarevskii and L. M. Vainer, Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1987, 36, 786-791. 206. T. W. Greene and P. G. M. Wuts, in Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY, Third edn., 1999.

130

207. A. Wichmann, G. Schnurpfeil, J. Backenköhler, L. Kolke, V. A. Azov, D. Wöhrle, M. Bäumer and A. Wittstock, Tetrahedron, 2014, 70, 6127-6133. 208. E. Bourlès, R. Alves de Sousa, E. Galardon, M. Selkti, A. Tomas and I. Artaud, Tetrahedron, 2007, 63, 2466-2471. 209. X. Yue, M. B. Taraban, L. L. Hyland and Y. B. Yu, J. Org. Chem., 2012, 77, 8879-8887. 210. N. Boechat, J. C. S. da Costa, J. de Souza Mendonça, P. S. M. de Oliveira and M. Vinıciuś Nora De Souza, Tetrahedron Lett., 2004, 45, 6021-6022. 211. W. Eckhardt and C. A. Grob, Helv. Chim. Acta, 1974, 57, 2339-2345. 212. J.-N. Li, L. Liu, Y. Fu and Q.-X. Guo, Tetrahedron, 2006, 62, 4453-4462. 213. A. Mirzahosseini, A. Szilvay and B. Noszál, Chem. Phys. Lett., 2014, 610-611, 62-69. 214. B. Lenarcik and P. Ojczenasz, J. Heterocyclic Chem., 2002, 39, 287-290. 215. M. G. Voronkov, I. P. Tsyrendorzhieva and V. I. Rakhlin, Russ. J. Org. Chem., 2010, 46, 1476-1478. 216. N. Buckley and N. J. Oppenheimer, J. Org. Chem., 1997, 62, 540-551. 217. B. Badet, M. Julia, J. M. Mallet and C. Schmitz, Tetrahedron Lett., 1983, 24, 4331-4334. 218. B. Badet, M. Julia, J. M. Mallet and C. Schmitz, Tetrahedron, 1988, 44, 2913-2924. 219. S. J. Sachnov, P. S. Schulz and P. Wasserscheid, Chem. Commun., 2011, 47, 11234-11236. 220. J. Sun, X. Yao, W. Cheng and S. Zhang, Green Chem., 2014, 16, 3297-3304. 221. M. Pignot, G. Pljevaljcic and E. Weinhold, Eur. J. Org. Chem., 2000, 549-555. 222. G. Shapiro and Y. Lavi, Heterocycles, 1990, 31, 2099-2102. 223. P. Shu, J. Zeng, J. Tao, Y. Zhao, G. Yao and Q. Wan, Green Chem., 2015, 17, 2545-2551. 224. W. W. Cleland, Biochemistry, 1964, 3, 480-482. 225. P. Nockemann, K. Binnemans and K. Driesen, Chem. Phys. Lett., 2005, 415, 131-136. 226. T. Strašák, L. Č. Šťastná, V. Bílková, V. Skoupá, J. Karban, P. Cuřínová and J. Čermák, J. Fluor. Chem., 2015, 178, 23-29. 227. T. Lanza, M. Minozzi, A. Monesi, D. Nanni, P. Spagnolo and C. Chiappe, Curr. Org. Chem., 2009, 13, 1726-1732. 228. M. A. B. H. Susan, T. Kaneko, A. Noda and M. Watanabe, J. Am. Chem. Soc., 2005, 127, 4976-4983. 229. A. G. Fadeev and M. M. Meagher, Chem. Commun., 2001, 295-296. 230. J. L. Anthony, E. J. Maginn and J. F. Brennecke, J. Phys. Chem. B, 2001, 105, 10942-10949. 231. D. Laurencin, F. Ribot, C. Gervais, A. J. Wright, A. R. Baker, L. Campayo, J. V. Hanna, D. Iuga, M. E. Smith, J.-M. Nedelec, G. Renaudin and C. Bonhomme, ChemistrySelect, 2016, 1, 4509-4519. 232. P. M. J. Szell and D. L. Bryce, in Annual Reports on NMR Spectroscopy, ed. G. A. Webb, Academic Press, 2015, vol. 84, pp. 115-162.

131

233. G. L. Hatch, Anal. Chem., 1982, 54, 2002-2005. 234. M. Thomas, F. G. Priest and J. R. Stark, J. Gen. Microbiol., 1980, 118, 67-72. 235. Z. Xiao, R. Storms and A. Tsang, Anal. Biochem., 2006, 351, 146-148. 236. H. Landolt, Ber. Dtsch. Chem. Ges., 1886, 19, 1317-1365. 237. H. Li, Y. Zhu, A. Jiao, J. Zhao, X. Chen, B. Wei, X. Hu, C. Wu, Z. Jin and Y. Tian, Int. J. Biol. Macromol., 2013, 55, 276-281. 238. E. Frankland, Q. J. Chem. Soc., 1850, 2, 263-296. 239. C. Lowig, Justus Liebigs Ann. Chem., 1852, 84, 308-333. 240. W. Caseri, J. Organomet. Chem., 2014, 751, 20-24. 241. R. K. Ingham, S. D. Rosenberg and H. Gilman, Chem. Rev., 1960, 60, 459-539. 242. A. G. Davies, Organotin Chemistry, Wiley-VCH, Weinheim, Second edn., 2004. 243. L. Pellerito and L. Nagy, Coord. Chem. Rev., 2002, 224, 111-150. 244. B. Wrackmeyer, in Modern Magnetic Resonance, ed. G. A. Webb, Springer Netherlands, Dordrecht, 2006, pp. 461-463. 245. M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Inc., Hoboken, New Jersey, Third edn., 2013. 246. J. K. Stille, Angew. Chem. Int. Ed., 1986, 25, 508-524. 247. M. Gielen, Appl. Organomet. Chem., 2002, 16, 481-494. 248. S. Tabassum and C. Pettinari, J. Organomet. Chem., 2006, 691, 1761-1766. 249. L. Niu, Y. Li and Q. Li, Inorg. Chim. Acta, 2014, 423, 2-13. 250. P. A. Baguley and J. C. Walton, Angew. Chem. Int. Ed., 1998, 37, 3072-3082. 251. H. G. Kuivila, L. W. Menapace and C. R. Warner, J. Am. Chem. Soc., 1962, 84, 3584-3586. 252. A. C. A. Sousa, M. R. Pastorinho, S. Takahashi and S. Tanabe, Environ. Chem. Lett., 2014, 12, 117-137. 253. P. Renaud, E. Lacôte and L. Quaranta, Tetrahedron Lett., 1998, 39, 2123-2126. 254. J. Light and R. Breslow, Tetrahedron Lett., 1990, 31, 2957-2958. 255. X. Han, G. A. Hartmann, A. Brazzale and R. D. Gaston, Tetrahedron Lett., 2001, 42, 5837- 5839. 256. D. C. Harrowven, D. P. Curran, S. L. Kostiuk, I. L. Wallis-Guy, S. Whiting, K. J. Stenning, B. Tang, E. Packard and L. Nanson, Chem. Commun., 2010, 46, 6335-6337. 257. E. Le Grognec, J.-M. Chrétien, F. Zammattio and J.-P. Quintard, Chem. Rev., 2015, 115, 10207-10260. 258. C. M Gordon and A. McCluskey, Chem. Commun., 1999, 1431-1432. 259. A. McCluskey, J. Garner, D. J. Young and S. Caballero, Tetrahedron Lett., 2000, 41, 8147- 8151. 260. S. T. Handy and X. Zhang, Org. Lett., 2001, 3, 233-236.

132

261. V. Calò, A. Nacci, A. Monopoli and F. Montingelli, J. Org. Chem., 2005, 70, 6040-6044. 262. B. A. DaSilveira Neto, M. B. Alves, A. A. M. Lapis, F. M. Nachtigall, M. N. Eberlin, J. Dupont and P. A. Z. Suarez, J. Catal., 2007, 249, 154-161. 263. D. Faye, M. Vybornyi, F. Boeda and S. Legoupy, Tetrahedron, 2013, 69, 5421-5425. 264. N. Louaisil, P. D. Pham, F. Boeda, D. Faye, A.-S. Castanet and S. Legoupy, Eur. J. Org. Chem., 2011, 143-149. 265. P. D. Pham and S. Legoupy, Tetrahedron Lett., 2009, 50, 3780-3782. 266. P. D. Pham, J. Vitz, C. Chamignon, A. Martel and S. Legoupy, Eur. J. Org. Chem., 2009, 3249-3257. 267. P. D. Pham, P. Bertus and S. Legoupy, Chem. Commun., 2009, 6207-6209. 268. J. Vitz, D. H. Mac and S. Legoupy, Green Chem., 2007, 9, 431-433. 269. K. Iizuka, K. Akahane, D. Momose, M. Nakazawa, T. Tanouchi, M. Kawamura, I. Ohyama, I. Kajiwara and Y. Iguchi, J. Med. Chem., 1981, 24, 1139-1148. 270. H. Finkelstein, Ber. Dtsch. Chem. Ges., 1910, 43, 1528-1532. 271. B. Shi, N. A. Hawryluk and B. B. Snider, J. Org. Chem., 2003, 68, 1030-1042. 272. H. A. Olszowy and W. Kitching, Organometallics, 1984, 3, 1670-1675. 273. D. H. Smith, J. Chem. Educ., 1999, 76, 1427-1428. 274. U. Tilstam and H. Weinmann, Org. Process Res. Dev., 2002, 6, 906-910. 275. K. Tamao, N. Ishida and M. Kumada, J. Org. Chem., 1983, 48, 2120-2122. 276. N. M. Carballeira, N. Montano and L. F. Padilla, Chem. Phys. Lipids, 2007, 145, 37-44. 277. W.-W. Zheng, Y.-H. Hsieh, Y.-C. Chiu, S.-J. Cai, C.-L. Cheng and C. Chen, J. Mater. Chem., 2009, 19, 8432-8441. 278. J. Lund, C. Stensrud, Rajender, P. Bohov, G. H. Thoresen, R. K. Berge, M. Wright, A. Kamal, A. C. Rustan, A. D. Miller and J. Skorve, Bioorganic Med. Chem., 2016, 24, 1191-1203. 279. G. J. Sormunen and D. E. Lewis, Synth. Commun., 2004, 34, 3473-3480. 280. T. Ema, Y. Nakano, D. Yoshida, S. Kamata and T. Sakai, Org. Biomol. Chem., 2012, 10, 6299-6308. 281. L. D. Hall, P. R. Steiner and D. C. Miller, Can. J. Chem., 1979, 57, 38-43. 282. D. Marton, U. Russo, D. Stivanello, G. Tagliavini, P. Ganis and G. C. Valle, Organometallics, 1996, 15, 1645-1650. 283. F. von Gyldenfeldt, D. Marton and G. Tagliavini, Organometallics, 1994, 13, 906-913. 284. B. Jousseaume, M. Lahcini, M.-C. Rascle, F. Ribot and C. Sanchez, Organometallics, 1995, 14, 685-689. 285. J. Brandrup, E. H. Immergut and E. A. Grulke, Polymer Handbook, John Wiley & Sons, New York, USA, 4th edn., 2003.

133

286. J. Pichler, A. Torvisco, P. Bottke, M. Wilkening and F. Uhlig, Can. J. Chem., 2014, 92, 565- 573. 287. M. Z. Bulatović, D. Maksimović-Ivanić, C. Bensing, S. Gómez-Ruiz, D. Steinborn, H. Schmidt, M. Mojić, A. Korać, I. Golić, D. Pérez-Quintanilla, M. Momčilović, S. Mijatović and G. N. Kaluđerović, Angew. Chem. Int. Ed., 2014, 53, 5982-5987. 288. H. R. Williams and H. S. Mosher, J. Am. Chem. Soc., 1954, 76, 2984-2987. 289. J. W. Lee, H. Yan, H. B. Jang, H. K. Kim, S.-W. Park, S. Lee, D. Y. Chi and C. E. Song, Angew. Chem. Int. Ed., 2009, 48, 7683-7686. 290. J.-W. Kim, S. M. Abdelaal, L. Bauer and N. E. Heimer, J. Heterocyclic Chem., 1995, 32, 611- 620. 291. J. Clayden, N. Greeves and S. Warren, Organic Chemistry, Oxford University Press, Oxford, U.K., Second edn., 2012. 292. G. Reeske, M. Schürmann, B. Costisella and K. Jurkschat, Eur. J. Inorg. Chem., 2005, 2881- 2887. 293. F. Caruso, M. Giomini, A. M. Giuliani and E. Rivarola, J. Organomet. Chem., 1994, 466, 69- 75. 294. G. M. Allan, R. A. Howie, J. N. Low, J. M. S. Skakle, J. L. Wardell and S. M. S. V. Wardell, Polyhedron, 2006, 25, 695-701. 295. A. Voronel, E. Veliyulin, T. Grande and H. A. Øye, J. Phys. Condens. Matter, 1997, 9, L247. 296. J. Zachara and W. Wišniewski, J. Therm. Anal. Calorim., 1995, 44, 929-935. 297. D. Rauber, F. Heib, M. Schmitt and R. Hempelmann, J. Mol. Liq., 2016, 216, 246-258. 298. T. Buffeteau, J. Grondin, Y. Danten and J.-C. Lassègues, J. Phys. Chem. B, 2010, 114, 7587- 7592. 299. M. Newcomb, Tetrahedron, 1993, 49, 1151-1176. 300. D. H. R. Barton and M. Ramesh, Tetrahedron Lett., 1990, 31, 949-952. 301. D. H. R. Barton, B. Lacher and S. Z. Zard, Tetrahedron Lett., 1985, 26, 5939-5942. 302. M. Newcomb, M. B. Manek and A. G. Glenn, J. Am. Chem. Soc., 1991, 113, 949-958. 303. P. Blom, A. X. Xiang, D. Kao and E. A. Theodorakis, Bioorganic Med. Chem., 1999, 7, 727- 736. 304. C. Chatgilialoglu, K. U. Ingold and J. C. Scaiano, J. Am. Chem. Soc., 1981, 103, 7739-7742. 305. S. Kotha and M. E. Shirbhate, Synlett, 2012, 23, 2183-2188. 306. M. Israeli and L. D. Pettit, Dalton Trans., 1975, 414-417. 307. R. Kadyrov, Chem. Eur. J., 2013, 19, 1002-1012. 308. B. Neises and W. Steglich, Angew. Chem. Int. Ed., 1978, 17, 522-524. 309. D. H. R. Barton and J. Albert Ferreira, Tetrahedron, 1996, 52, 9347-9366.

134

310. J. C. Walton, in Encyclopedia of Radicals in Chemistry, Biology and Materials, John Wiley & Sons Ltd, Hoboken, New Jersey, 2012. 311. M. Newcomb, N. Tanaka, A. Bouvier, C. Tronche, J. H. Horner, O. M. Musa and F. N. Martinez, J. Am. Chem. Soc., 1996, 118, 8505-8506. 312. M. Newcomb and J. Kaplan, Tetrahedron Lett., 1987, 28, 1615-1618. 313. J. Lusztyuk, B. Maillard, S. Deycard, D. A. Lindsay and K. U. Ingold, J. Org. Chem., 1987, 52, 3509-3514. 314. D. P. Curran, E. Bosch, J. Kaplan and M. Newcomb, J. Org. Chem., 1989, 54, 1826-1831. 315. S. Arrhenius, Zeitschrift für Physikalische Chemie, 1889, 4U, 226. 316. A. Diamanti, On the Determination of the Reaction Rate Constant and Selectivity in Gas and Liquid-Phase Organic Reactions: Temperature and Solvent Effects. Ph.D. Thesis, Imperial College London, London, UK, December 2016. 317. B. Temelso, C. D. Sherrill, R. C. Merkle and R. A. Freitas, J. Phys. Chem. A, 2006, 110, 11160-11173. 318. S. G. Chiodo, M. Leopoldini, N. Russo and M. Toscano, Phys. Chem. Chem. Phys., 2010, 12, 7662-7670. 319. C. Ha, J. H. Horner, M. Newcomb, T. R. Varick, B. R. Arnold and J. Lusztyk, J. Org. Chem., 1993, 58, 1194-1198. 320. T. H. Y. Ha, K. Rasmussen, S. Landgraf and G. Grampp, Electrochim. Acta, 2014, 141, 72- 81. 321. R. A. Firestone and M. A. Vitale, J. Org. Chem., 1981, 46, 2160-2164. 322. S. T. Keaveney, R. S. Haines and J. B. Harper, ChemPlusChem, 2017, 82, 449-457. 323. J. A. Franz, B. A. Bushaw and M. S. Alnajjar, J. Am. Chem. Soc., 1989, 111, 268-275. 324. K. Seddon, A. Stark and M.-J. Torres, Pure Appl. Chem., 2000, 72, 2275-2287. 325. H. M. McNair and J. M. Miller, Basic Gas Chromatography, John Wiley & Sons, Inc., Hoboken, New Jersey, Second edn., 2009. 326. in Journal of Chromatography Library, eds. G. Guiochon and C. L. Guillemin, Elsevier, 1988, vol. 42, pp. 587-627. 327. K. Rome and A. McIntyre, Chromatography Today, 2012, May/June, 52-56. 328. T. Nagy and T. Turányi, Int. J. Chem. Kinet., 2011, 43, 359-378. 329. D. G. Altman and J. M. Bland, BMJ, 2005, 331, 903-903. 330. K. Héberger, S. Kemény and T. Vidóczy, Int. J. Chem. Kinet., 1987, 19, 171-181. 331. P. Atkins and J. de Paula, Atkins' Physical Chemistry, W. H. Freeman and Company, New York, NY, 8th edn., 2006. 332. E. G. Foehr and M. R. Fenske, Ind. Eng. Chem., 1949, 41, 1956-1966.

135

333. S. V. Semikolenov, K. A. Dubkov, E. V. Starokon', D. E. Babushkin and G. I. Panov, Russ. Chem. Bull., 2005, 54, 948-956. 334. M. Newcomb, A. G. Glenn and M. B. Manek, J. Org. Chem., 1989, 54, 4603-4606. 335. M. Holzweber, R. Lungwitz, D. Doerfler, S. Spange, M. Koel, H. Hutter and W. Linert, Chem. Eur. J., 2013, 19, 288-293. 336. D. J. Carlsson and K. U. Ingold, J. Am. Chem. Soc., 1968, 90, 7047-7055. 337. T. P. Lockhart, Inorg. Chem., 1989, 28, 4265-4268. 338. R. Shankar, M. Kumar, R. K. Chadha and S. P. Narula, Polyhedron, 2004, 23, 71-75. 339. H. G. Kuivila and O. F. Beumel, J. Am. Chem. Soc., 1961, 83, 1246-1250. 340. J. E. H. Day, S. Y. Sharp, M. G. Rowlands, W. Aherne, P. Workman and C. J. Moody, Chem. Eur. J., 2010, 16, 2758-2763.

136

6 Appendix

6.1 Response factor data

Table 6-1 Raw data used to calibrate response factors for methylcyclopentane 86 and 1-hexene 88

Stock Vol Mw Stocks Conc g solute (L) g/cm3

methylcyclopentane 84.16 [CYP] 0.226948669 0.0955 0.005 density 0.749

1-hexene 84.16 [UCP] 0.117395437 0.0988 0.01 density 0.678 VOL CYP UCP:CYP CYC/UNCYC Standards µL VOL UCP µL VOL t-BuPh [CYP] M [UCP] M Ratio Ratio

R1 50 500 0 0.0206317 0.10672312 5.172774869 0.193319838

R2 100 700 0 0.02836858 0.10272101 3.620942408 0.276171197

R3 125 375 0 0.05673717 0.08804658 1.551832461 0.64439946

R4 300 300 0 0.11347433 0.05869772 0.517277487 1.933198381

R5 700 150 0 0.1868989 0.02071684 0.110845176 9.021592443

R6 100 400 0 0.04538973 0.09391635 2.069109948 0.483299595

Total Vol needed 4125 7275

Retention time (cyc) min 5.75-5.95

Retention time (uncyc) min 4.97-5.12

Response factor for uncyclised/cyclised REPLICA CYC 5.85 [CYP Real STD # TE Area Uncyc 5.06 Area CYC % UNCYC % %U/ %C Avg %U/C ] [UCP] [U]/[C] 0.020 1 1 88060 332160 20.9556899 79.0443101 3.771973654 3.828827382 6317 0.10672312 5.17277487

1 2 85619 325018 20.8502887 79.1497113 3.796096661

137

1 3 83039 325381 20.3317663 79.6682337 3.918411831 0.028 2 1 120233 317151 27.4891171 72.5108829 2.637803265 2.696053099 36858 0.10272101 3.62094241

2 2 115249 311692 26.994128 73.005872 2.704509367 2 3 113463 311552 26.6962343 73.3037657 2.745846664 0.056 3 1 243290 271447 47.2649139 52.7350861 1.115734309 1.144155786 73717 0.08804658 1.55183246

3 2 231069 268868 46.2196237 53.7803763 1.163583172 3 3 233660 269445 46.4435853 53.5564147 1.153149876 0.113 4 1 477672 181428 72.4733728 27.5266272 0.379817113 0.382147602 47433 0.05869772 0.51727749

4 2 467546 179390 72.2708274 27.7291726 0.383684172 4 3 469526 179801 72.3096375 27.6903625 0.38294152 0.186 5 1 785073 67009 92.1358508 7.86414923 0.085353846 0.083542384 8989 0.02071684 0.11084518

5 2 768806 63101 92.4148973 7.58510266 0.082076623 5 3 773264 64333 92.3193373 7.68066266 0.083196683 0.045 6 1 189332 295210 39.0744249 60.9255751 1.559218727 1.567305252 38973 0.09391635 2.06910995

6 2 179811 283384 38.8197196 61.1802804 1.576010366 6 3 180036 282060 38.9607354 61.0392646 1.566686663

Response factor for cyclised/uncyclised REPLICA CYC 5.85 [CYP Real STD # TE Area Uncyc 5.06 Area CYC % UNCYC % %C/ %U Avg %C/U ] [UCP] [C]/[U] 72.27 1 1 88060 332160 20.9556899 79.0443101 0.265113198 0.261249041 08274 27.7291726 0.19331984

1 2 85619 325018 20.8502887 79.1497113 0.263428487 1 3 83039 325381 20.3317663 79.6682337 0.255205436 72.30 2 1 120233 317151 27.4891171 72.5108829 0.379103329 0.371014186 96375 27.6903625 0.2761712

2 2 115249 311692 26.994128 73.005872 0.369752833 2 3 113463 311552 26.6962343 73.3037657 0.364186396

138

92.13 3 1 243290 271447 47.2649139 52.7350861 0.896270727 0.874291659 58508 7.86414923 0.64439946

3 2 231069 268868 46.2196237 53.7803763 0.859414285 3 3 233660 269445 46.4435853 53.5564147 0.867189965 92.41 4 1 477672 181428 72.4733728 27.5266272 2.632846088 2.616840383 48973 7.58510266 1.93319838

4 2 467546 179390 72.2708274 27.7291726 2.606310274 4 3 469526 179801 72.3096375 27.6903625 2.611364787 92.31 5 1 785073 67009 92.1358508 7.86414923 11.71593368 11.97312694 93373 7.68066266 9.02159244

5 2 768806 63101 92.4148973 7.58510266 12.18373718 5 3 773264 64333 92.3193373 7.68066266 12.01970995 39.07 6 1 189332 295210 39.0744249 60.9255751 0.641346838 0.638050052 44249 60.9255751 0.4832996

6 2 179811 283384 38.8197196 61.1802804 0.634513593 6 3 180036 282060 38.9607354 61.0392646 0.638289726

6.2 Data for t-thiol 46 Single concentration (10×) of t-thiol 46 with respect to PTOC ester 82 at 25 °C. Response factor = 0.7428

Table 6-2 Raw data for single concentration and temperature kinetic study with t-thiol 46 and PTOC ester 82

rep [RSH] M Uncyclised area Cyclised area Uncyc % Cyc % U %/C % / Resp fact 1/[RSH] kC (at 25 °C in C6H6) Spot kH error % 1 0.1028 674 168 80.04750594 19.95249 5.401056 9.727626 220429.7 1.16E+07 0.26 2 0.1028 802 207 79.48463826 20.51536 5.215934 9.727626 220429.7 1.12E+07 -3.18 3 0.1028 890 217 80.39747064 19.60253 5.521517 9.727626 220429.7 1.18E+07 2.49 4 0.1028 738 201 78.5942492 21.40575 4.942975 9.727626 220429.7 1.06E+07 -8.25 5 0.1028 935 215 81.30434783 18.69565 5.854654 9.727626 220429.7 1.26E+07 8.68

139

Average 0.1028 788.6666667 197.33333 79.98647735 20.01352 5.380481 9.727626 220429.7 1.15E+07

Concentration profile for t-thiol 46. Response factor = 1.3285

Table 6-3 Raw concentration profile data for t-thiol 46 and PTOC ester 82

rep 1 [RSH] M Uncyclised area Cyclised area Uncyc % Cyc % C %/U % / Resp fact 1/[RSH] kC (at 25 °C in C6H6) Spot kH

10:01 0.1028 788.7 197.3 79.98986 20.01014 0.18830146 9.727626459 220429.657 4.04E+05 20:01 0.1998 630 67 90.38737 9.612626 0.08005209 5.005005005 220429.657 8.83E+04 30:01 0.3006 691 53 92.87634 7.123656 0.05773461 3.326679973 220429.657 4.23E+04 40:01 0.4005 757 35 95.58081 4.419192 0.03480251 2.496878901 220429.657 1.92E+04 50:01 0.5004 423 21 95.27027 4.72973 0.03736951 1.998401279 220429.657 1.65E+04

Analysis

kC / kh 0.0201 from graph

kC 220429.657 in benzene

kH 1.10E+07

rep 2 [RSH] M Uncyclised area Cyclised area Uncyc % Cyc % C %/U % / Resp fact 1/[RSH] kC (at 25 °C in C6H6) Spot kH

10:01 0.1028 788.7 197.3 79.98986 20.01014 0.18830146 9.727626459 220429.657 4.04E+05 20:01 0.2015 519 72 87.81726 12.18274 0.10442478 4.962779156 220429.657 1.14E+05 30:01 0.3014 563 45 92.59868 7.401316 0.06016481 3.317850033 220429.657 4.40E+04 40:01 0.4012 651 35 94.89796 5.102041 0.04046928 2.492522433 220429.657 2.22E+04 50:01 0.5011 563 21 96.40411 3.59589 0.02807691 1.995609659 220429.657 1.24E+04

140

Analysis

kC / kh 0.0206 from graph

kC 220429.657 in benzene

kH 1.07E+07

rep 3 [RSH] M Uncyclised area Cyclised area Uncyc % Cyc % C %/U % / Resp fact 1/[RSH] kC (at 25 °C in C6H6) Spot kH

10:01 0.1028 788.7 197.3 79.98986 20.01014 0.18830146 9.727626459 220429.657 4.04E+05 20:01 0.2015 760 81 90.36861 9.631391 0.08022503 4.962779156 220429.657 8.78E+04 30:01 0.3014 620 62 90.90909 9.090909 0.07527286 3.317850033 220429.657 5.51E+04 40:01 0.4012 612 37 94.29892 5.701079 0.0455081 2.492522433 220429.657 2.50E+04 50:01 0.5011 662 39 94.43652 5.563481 0.04434504 1.995609659 220429.657 1.95E+04

Analysis

kC / kh 0.0186 from graph

kC 220429.657 in benzene

kH 1.19E+07

average [RSH] M Uncyclised area Cyclised area Uncyc % Cyc % C %/U % / Resp fact 1/[RSH] kC (at 25 °C in C6H6) Spot kH

10:01 0.1028 788.70 197.30 79.98986 20.01014 0.18830146 9.727626459 220429.657 4.04E+05 20:01 0.200933 636.33 73.33 89.66651 10.33349 0.08674715 4.97677505 220429.657 9.52E+04 30:01 0.301133 624.67 53.33 92.13373 7.866273 0.06426712 3.320788134 220429.657 4.70E+04 40:01 0.400967 673.33 35.67 94.96944 5.030559 0.03987226 2.493972899 220429.657 2.19E+04 50:01 0.500867 549.33 27.00 95.31521 4.684789 0.03699698 1.996539332 220429.657 1.63E+04

Analysis 25 degrees

141

kC / kh 0.01977789 from graph

kC 220429.657 in benzene

kH 1.11E+07 9.42E+05 2 standard deviations

Arrhenius data for t-thiol 46. Response factor = 0.7428

Table 6-4 Raw Arrhenius data for t-thiol 46 and PTOC ester 82

U %/C % Uncycl / Resp kC (at Temp Rep [RSH] M area Cyc area Uncyc % Cyc % fact 1/[RSH] C %/U % temp) Spot kH 1000/T in K ln(kH) 25 °C average 0.1028 5.442419 9.727626 0.247384 220429.7 1.11E+07 3.354016435 16.22652 220429.7 220429.7 40 °C 1 0.08216 911 375 70.83981 29.16019 3.270508 12.17137 0.411636 383753.4 1.53E+07 2 0.08216 886 374 70.31746 29.68254 3.189262 12.17137 0.422122 383753.4 1.49E+07 3 0.08216 762 341 69.08432 30.91568 3.008352 12.17137 0.447507 383753.4 1.41E+07 average 0.08216 853 363.3333 70.08053 29.91947 3.153346 12.17137 0.427088 383753.4 1.47E+07 3.193357816 16.50616 49 °C 1 0.08216 592 361 62.11962 37.88038 2.207713 12.17137 0.609797 522106 1.40E+07 2 0.08216 546 273 66.66667 33.33333 2.692515 12.17137 0.5 522106 1.71E+07 3 0.08216 636 358 63.9839 36.0161 2.391675 12.17137 0.562893 522106 1.52E+07 average 0.08216 591.333333 330.6667 64.25673 35.74327 2.420207 12.17137 0.557563 522106 1.54E+07 49 °C 0.08216 891 436 67.14393 32.85607 2.751182 12.17137 0.489338 522106 1.75E+07 0.08216 983 566 63.4603 36.5397 2.338111 12.17137 0.575788 522106 1.49E+07 0.08216 803 425 65.39088 34.60912 2.543635 12.17137 0.529265 522106 1.62E+07 average 0.08216 892.333333 475.6667 65.3317 34.6683 2.536995 12.17137 0.531464 522106 16168441 Ave of aves 0.08216 741.833333 403.1667 64.79422 35.20578 2.477709 12.17137 0.544514 522106 15807253 3.104144032 16.57598

142

56 °C 1 0.08216 712 408 63.57143 36.42857 2.349351 12.17137 0.573034 655688.3 1.87E+07 2 0.08216 777 444 63.63636 36.36364 2.35595 12.17137 0.571429 655688.3 1.88E+07 3 0.08216 727 439 62.34991 37.65009 2.229451 12.17137 0.603851 655688.3 1.78E+07 average 0.08216 738.666667 430.3333 63.1859 36.8141 2.31065 12.17137 0.582771 655688.3 1.84E+07 3.038128513 16.73046 62 °C 1 0.08216 736 450 62.05734 37.94266 2.201879 12.17137 0.611413 791065.8 2.12E+07 2 0.08216 732 444 62.2449 37.7551 2.219505 12.17137 0.606557 791065.8 2.14E+07 3 0.08216 798 534 59.90991 40.09009 2.011823 12.17137 0.669173 791065.8 1.94E+07 average 0.08216 755.333333 476 61.40405 38.59595 2.141822 12.17137 0.629048 791065.8 2.06E+07 2.983738624 16.84308 68 °C 1 0.08216 741 525 58.53081 41.46919 1.900146 12.17137 0.708502 948113.9 2.19E+07 2 0.08216 688 515 57.19036 42.80964 1.798495 12.17137 0.748547 948113.9 2.08E+07 3 0.08216 762 595 56.15328 43.84672 1.724115 12.17137 0.78084 948113.9 1.99E+07 average 0.08216 730.333333 545 57.29148 42.70852 1.805941 12.17137 0.745963 948113.9 2.09E+07 2.931261908 16.85331

6.3 Data for t-thiol salt 27 Single concentration (10×) of t-thiol 27 with respect to PTOC ester 82 at 30 °C. Response factor = 0.7428

Table 6-5 Raw data for single concentration and temperature for t-thiol salt 27 and PTOC ester 82

k (at 30 Uncyclised Cyclised U %/C % / C rep [RSH] M Uncyc % Cyc % 1/[RSH] °C in Spot k error % area area Resp fact H C6H6) 1 0.08967 4171 1333 75.78125 24.21875 4.212482846 11.152 266795.4 1.25E+07 2.01 2 0.08967 3147 896 77.83823893 22.16176 4.728428629 11.152 266795.4 1.41E+07 14.50 3 0.08967 3865 1267 75.31176929 24.68823 4.106775744 11.152 266795.4 1.22E+07 -0.55 4 0.08967 3360 1128 74.86631016 25.13369 4.010128439 11.152 266795.4 1.19E+07 -2.89 5 0.08967 7473 2802 72.72992701 27.27007 3.590500208 11.152 266795.4 1.07E+07 -13.06

Average 0.08967 4403.2 1485.2 74.7775287 25.22247 3.991274309 11.152 266795.4 1.19E+07

143

Concentration profile for t-thiol salt 27. Response factor = 1.3285

Table 6-6 Raw concentration profile data for t-thiol salt 27 and PTOC ester 82

Uncyclised Cyclised C %/U % / Resp kC (at 30 °C rep 1 [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact in C6H6) 10:01 0.08967 4403.2 1485.2 74.77753 25.22247 0.25389548 11.15200178 266795.39 7.55E+05 20:01 0.1794 3515 571 86.02545 13.97455 0.12227825 5.574136009 266795.39 1.82E+05 30:01 0.269 3730 424 89.79297 10.20703 0.08556486 3.717472119 266795.39 8.49E+04 40:01 0.3587 3741 331 91.87132 8.128684 0.06660069 2.787844996 266795.39 4.95E+04 50:01 0.4484 3836 248 93.92752 6.072478 0.04866442 2.23015165 266795.39 2.90E+04

Analysis

kC / kh 0.0227 from graph

kC 266795.39 in benzene

kH 1.18E+07

Uncyclised Cyclised C %/U % / Resp kC (at 29 °C rep 2 [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact in C6H6) 10:01 0.08967 4403.2 1485.2 74.77753 25.22247 0.25389548 11.15200178 266795.39 7.55E+05 20:01 0.1445 3949 827 82.68425 17.31575 0.15763651 6.920415225 256930.805 2.80E+05 30:01 0.2174 3887 521 88.18058 11.81942 0.10089314 4.599816007 256930.805 1.19E+05 40:01 0.2897 2111 214 90.7957 9.204301 0.07630693 3.451846738 256930.805 6.77E+04 50:01 0.3619 2063 175 92.18052 7.819482 0.06385241 2.763194253 256930.805 4.53E+04

144

Analysis

kC / kh 0.0229 from graph

kC 266795.39 in benzene

kH 1.17E+07

Uncyclised Cyclised C %/U % / Resp kC (at 30 °C rep 3 [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact in C6H6) 10:01 0.08967 4403.2 1485.2 74.77753 25.22247 0.25389548 11.15200178 266795.39 7.55E+05 20:01 0.1445 2170 460 82.50951 17.49049 0.1595646 6.920415225 266795.39 2.95E+05 30:01 0.2174 2091 270 88.56417 11.43583 0.09719595 4.599816007 266795.39 1.19E+05 40:01 0.2897 2117 228 90.27719 9.722814 0.08106855 3.451846738 266795.39 7.47E+04 50:01 0.3619 2191 214 91.10187 8.898129 0.07352073 2.763194253 266795.39 5.42E+04

Analysis

kC / kh 0.0222 from graph

kC 266795.39 in benzene

kH 1.20E+07

Uncyclised Cyclised C %/U % / Resp kC (at 30 °C average [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact in C6H6)

10:01 0.08967 4403.20 1485.20 74.77753 25.22247 0.25389548 11.15200178 266795.39 7.55E+05 20:01 0.156133 3211.33 619.33 83.83223 16.16777 0.14517021 6.404782237 263507.195 2.45E+05 30:01 0.2346 3236.00 405.00 88.87668 11.12332 0.09420739 4.262574595 263507.195 1.06E+05 40:01 0.3127 2656.33 257.67 91.15763 8.84237 0.07301534 3.19795331 263507.195 6.15E+04 50:01 0.390733 2696.67 212.33 92.70081 7.299186 0.05926924 2.559290224 263507.195 4.00E+04

145

Analysis 30 degrees

kC / kh 0.02275717 from graph

kC 264164.834 in benzene

kH 1.16E+07 2 standard 2.47E+05

deviations

Arrhenius data for t-thiol salt 27. Response factor = 0.7428

Table 6-7 Raw Arrhenius data for t-thiol salt 27

U %/C % / Resp kC (at Temp Rep [RSH] M Uncycl area Cyc area Uncyc % Cyc % fact 1/[RSH] C %/U % temp) Spot kH 1000/T in K ln(kH) 30 °C average 0.247384 266795.4 1.16E+07 3.298697015 16.2672 266795.4 266795.4 40 °C 1 0.07645 897 410 68.63045 31.36955 2.945349 13.08044 0.457079 383753.4 1.48E+07 2 0.07645 1156 554 67.60234 32.39766 2.809158 13.08044 0.479239 383753.4 1.41E+07 3 0.07645 1139 507 69.19806 30.80194 3.024432 13.08044 0.445127 383753.4 1.52E+07 average 0.07645 1064 490.3333 68.47695 31.52305 2.92445 13.08044 0.460482 383753.4 1.47E+07 3.193357816 16.50262 45 °C 1 0.07645 1737 902 65.82039 34.17961 2.592516 13.08044 0.519286 456317.9 1.55E+07 2 0.07645 2021 1007 66.74373 33.25627 2.701873 13.08044 0.498268 456317.9 1.61E+07 3 0.07645 1680 862 66.08969 33.91031 2.623796 13.08044 0.513095 456317.9 1.57E+07 average 0.07645 1812.66667 923.6667 66.21793 33.78207 2.638867 13.08044 0.510217 456317.9 1.58E+07 3.14317146 16.57261 50 °C 1 0.07645 1484 791 65.23077 34.76923 2.525722 13.08044 0.533019 539703.5 1.78E+07 2 0.07645 2470 1296 65.58683 34.41317 2.565784 13.08044 0.524696 539703.5 1.81E+07 3 0.07645 1582 924 63.12849 36.87151 2.304956 13.08044 0.584071 539703.5 1.63E+07 average 0.07645 1845.33333 1003.667 64.6487 35.3513 2.461968 13.08044 0.547262 539703.5 1.74E+07 3.09453814 16.67228

146

55.4 °C 0.07645 2014 1322 60.3717 39.6283 2.050955 13.08044 0.656405 643253.5 1.73E+07 0.07645 1876 1188 61.22715 38.77285 2.125908 13.08044 0.633262 643253.5 1.79E+07 0.07645 1225 714 63.1769 36.8231 2.309755 13.08044 0.582857 643253.5 1.94E+07 average 0.07645 1705 1074.667 61.59192 38.40808 2.158883 13.08044 0.624175 643253.5 18192893 3.043676762 16.71654 60 °C 1 0.07645 1657 1108 59.92767 40.07233 2.013311 13.08044 0.668678 743647.5 1.96E+07 2 0.07645 2095 1482 58.56863 41.43137 1.90311 13.08044 0.707399 743647.5 1.85E+07 3 0.07645 1827 1214 60.07892 39.92108 2.02604 13.08044 0.664477 743647.5 1.97E+07 average 0.07645 1859.66667 1268 59.52507 40.47493 1.979894 13.08044 0.680185 743647.5 1.93E+07 3.001650908 16.77395

6.4 Data for stannane 60 Single concentration (10×) of stannane 60 with respect to PTOC ester 82 at 26 °C. Response factor = 0.7428

Table 6-8 Raw data for single concentration and temperature for stannane 60 and PTOC ester 82

U %/C % k (at 26 Uncyclised Cyclised C rep [RSH] M Uncyc % Cyc % / Resp 1/[RSH] °C in Spot k error % area area H fact C6H6) 1 0.03552 324 633 33.85579937 66.1442 0.68908 28.15315 229125.5 4.44E+06 -11.06 2 0.03552 227 365 38.34459459 61.65541 0.837261 28.15315 229125.5 5.40E+06 8.07 3 0.03552 252 455 35.64356436 64.35644 0.745619 28.15315 229125.5 4.81E+06 -3.76 4 0.03552 487 826 37.09063214 62.90937 0.793738 28.15315 229125.5 5.12E+06 2.45 5 0.03552 503 838 37.5093214 62.49068 0.808076 28.15315 229125.5 5.21E+06 4.30

Average 0.03552 358.6 623.4 36.51731161 63.48269 0.774411 28.15315 229125.5 5.00E+06

Concentration profile for stannane 60. Response factor = 1.3285

147

Table 6-9 Raw concentration profile data for stannane 60 and PTOC ester 82

Uncyclised Cyclised C %/U % / Resp kC (at 25.4 °C in rep 1 [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact C6H6)

10:01 0.03552 358.6 623.4 36.51731 63.48269 1.30856396 28.15315315 229125.4869 8.44E+06 20:01 0.07104 858 878 49.42396 50.57604 0.77027476 14.07657658 223874.631 2.43E+06 30:01 0.10656 1136 719 61.23989 38.76011 0.47641892 9.384384384 223874.631 1.00E+06 40:01 0.14208 815 414 66.31408 33.68592 0.38236768 7.038288288 223874.631 6.02E+05 50:01 0.1776 1318 539 70.97469 29.02531 0.30783061 5.630630631 223874.631 3.88E+05

Analysis 25.4 degrees kC / kh 0.0445 from graph kC 223874.631 in benzene k H 5.03E+06

Uncyclised Cyclised C %/U % / Resp kC (at 27 °C in rep 1 [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact C6H6)

10:01 0.03552 358.6 623.4 36.51731 63.48269 1.30856396 28.15315315 229125.4869 8.44E+06 20:01 0.08987 1006 627 61.60441 38.39559 0.46914598 11.12718371 238102.9688 1.24E+06 30:01 0.1348 1432 595 70.64628 29.35372 0.31276085 7.418397626 238102.9688 5.52E+05 40:01 0.1797 1407 428 76.67575 23.32425 0.22897502 5.564830273 238102.9688 3.03E+05 50:01 0.2247 1739 452 79.37015 20.62985 0.19564885 4.450378282 238102.9688 2.07E+05

Analysis 27 degrees kC / kh 0.0475 from graph kC 238102.969 in benzene k H 5.01E+06

148

Uncyclised Cyclised C %/U % / Resp kC (at 26 °C in rep 1 [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact C6H6)

10:01 0.03552 358.6 623.4 36.51731 63.48269 1.30856396 28.15315315 229125.4869 8.44E+06 20:01 0.08987 868 643 57.4454 42.5546 0.55760889 11.12718371 229125.4869 1.42E+06 30:01 0.1348 1277 629 66.99895 33.00105 0.37076454 7.418397626 229125.4869 6.30E+05 40:01 0.1797 1362 506 72.91221 27.08779 0.27964809 5.564830273 229125.4869 3.57E+05 50:01 0.2247 1397 442 75.9652 24.0348 0.23815752 4.450378282 229125.4869 2.43E+05

Analysis 26 degrees kC / kh 0.0453 from graph kC 229125.487 in benzene k H 5.06E+06

Uncyclised Cyclised C %/U % / Resp kC (at av °C in rep 1 [RSH] M Uncyc % Cyc % 1/[RSH] Spot kH area area fact C6H6)

10:01 0.03552 358.60 623.40 36.51731 63.48269 1.30856396 28.15315315 229125.4869 8.44E+06 20:01 0.083593 910.67 716.00 55.98361 44.01639 0.59182325 11.96267645 230367.6955 1.63E+06 30:01 0.125387 1281.67 647.67 66.43055 33.56945 0.38037757 7.975329647 230367.6955 6.99E+05 40:01 0.16716 1194.67 449.33 72.66829 27.33171 0.28311334 5.982292414 230367.6955 3.90E+05 50:01 0.209 1484.67 477.67 75.65823 24.34177 0.24217785 4.784688995 230367.6955 2.67E+05

Analysis 26.1333333 degrees k / k C h 0.04593952 from graph kC 230119.254 in benzene k H 5.01E+06 2 standard 1.74E+05 deviations

149

Arrhenius data for stannane 60. Response factor = 0.7428

Table 6-10 Raw Arrhenius data for stannane 60

Uncycl Cyc kC (at 1000/T in Temp Rep [RSH] M area area Uncyc % Cyc % U %/C % / Resp fact 1/[RSH] C %/U % temp) Spot kH K ln(kH) 26.13 °C average 230276.5 5.01E+06 3.34135258 15.42678 230276.5 230276.5 40.2 °C 1 0.04623 1003 1184 45.86191 54.13809 1.140453 21.63098 1.180459 386462.1 9.53E+06 2 0.04623 954 1138 45.60229 54.39771 1.128585 21.63098 1.192872 386462.1 9.43E+06 3 0.04623 987 1267 43.78882 56.21118 1.048742 21.63098 1.283688 386462.1 8.77E+06 average 0.04623 981.333333 1196.333 45.08434 54.91566 1.105243 21.63098 1.219006 386462.1 9.25E+06 3.191319611 16.0396 45 °C 1 0.04623 862 1151 42.82166 57.17834 1.008231 21.63098 1.335267 456317.9 9.95E+06 2 0.04623 736 1053 41.1403 58.8597 0.940974 21.63098 1.430707 456317.9 9.29E+06 3 0.04623 821 1137 41.93054 58.06946 0.9721 21.63098 1.384896 456317.9 9.60E+06 average 0.04623 806.333333 1113.667 41.96417 58.03583 0.973443 21.63098 1.383623 456317.9 9.61E+06 3.14317146 16.07849 50 °C 1 0.04623 720 1093 39.71318 60.28682 0.88683 21.63098 1.518056 539703.5 1.04E+07 2 0.04623 691 1102 38.53876 61.46124 0.84416 21.63098 1.59479 539703.5 9.85E+06 3 0.04623 697 1097 38.85173 61.14827 0.85537 21.63098 1.573888 539703.5 9.99E+06 average 0.04623 702.666667 1097.333 39.03704 60.96296 0.862063 21.63098 1.56167 539703.5 1.01E+07 3.09453814 16.12447 55 °C 1 0.04623 514 985 34.28953 65.71047 0.702514 21.63098 1.916342 635070.2 9.65E+06 2 0.04623 545 1085 33.43558 66.56442 0.676231 21.63098 1.990826 635070.2 9.29E+06 3 0.04623 524 1040 33.50384 66.49616 0.678307 21.63098 1.984733 635070.2 9.32E+06 average 0.04623 527.666667 1036.667 33.73109 66.26891 0.685249 21.63098 1.964624 635070.2 9.41E+06 3.047386866 16.05764 32 °C 1 0.04623 250 381 39.61965 60.38035 0.883371 21.63098 1.524 287462.3 5.49E+06 2 0.04623 249 393 38.78505 61.21495 0.852972 21.63098 1.578313 287462.3 5.30E+06 3 0.04623 208 370 35.98616 64.01384 0.756815 21.63098 1.778846 287462.3 4.71E+06

150

average 0.04623 235.666667 381.3333 38.19557 61.80443 0.831996 21.63098 1.618105 287462.3 5.17E+06 3.277076847 15.45905 36 °C 1 0.04527 92 151 37.86008 62.13992 0.820236 22.08968 1.641304 332757.8 6.03E+06 2 0.04527 105 211 33.22785 66.77215 0.669939 22.08968 2.009524 332757.8 4.92E+06 3 0.04527 113 156 42.00743 57.99257 0.975174 22.08968 1.380531 332757.8 7.17E+06 average 0.04527 103.333333 172.6667 37.43961 62.56039 0.805675 22.08968 1.670968 332757.8 5.92E+06 3.234675724 15.59421

151

Minerva Access is the Institutional Repository of The University of Melbourne

Author/s: Garrard, Thomas William

Title: Synthesis and kinetics of novel ionic liquid soluble hydrogen atom transfer reagents

Date: 2018

Persistent Link: http://hdl.handle.net/11343/216788

File Description: Synthesis and kinetics of novel ionic liquid soluble hydrogen atom transfer reagents

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