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 i 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. ii 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 iii 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. iv 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. v 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 vi 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 vii 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 viii 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 ...........................................................................................