Decarboxylative Cross-Coupling: Bimetallic Nanoparticles As Catalysts and Low-Temperature Optimisation

Decarboxylative Cross-coupling: Bimetallic Nanoparticles as Catalysts and Low-Temperature Optimisation Joseph Kyle Sheppard Submitted in accordance with the requirements for the degree of Doctor of Philosophy University of Leeds School of Chemistry September 2020 The candidate confirms the work submitted is his own and that appropriate credit has been given where reference has been made to the work of others. I Acknowledgements First and foremost, I would like to thank my supervisors Dr. Bao N. Nguyen and Prof. Patrick McGowan for providing me with the opportunity to undertake this PhD. Bao, you deserve a medal for putting up with me for four whole years! Thank you dearly for everything you have taught me. Patrick, though our meetings were few and far between, I always left them brimming with new ideas and knowledge. I must also thank the wonderful Dr. Alexander Kulak; chiefly for all of your assistance with AAS and SEM analysis but also for being a friendly face that never failed to brighten my days. I’ll deeply miss the hours we spent, shouting over the noise of the spectrometer and trying to work out why it would develop an entirely new issue every time we used it. I would also like to thank Dr. Rebecca Stones for all of her hard work running my TEM samples and teaching me how to analyse the micrographs. Special thanks must also go to Dr. Mary Bayana for her patience in teaching me how to use all of the arcane and intricate analytical machines of the iPRD and to Martin Huscroft for helping me refine my HPLC method. To the members of the BNN research group, past and present, thank you for the copious assistance navigating the enigmatic world of academia and generally being a joy to work with. Thank you, Grant and Rachel, for putting up with all of my questions at the start of my PhD. Grant, your tastes in music were… definitely something! To Rosie, your quick wit and questionable reddit adventures will always be remembered; thank you so much for your diligent proof-reading. Thank you Sam, python wizard and saxophone maestro, for stimulating computational chemistry discussions and for providing the group with all of the juicy opera society gossip. To Tom, what can I say? You put the bantz into BNN and the fear of God into me when you were behind the wheel. James, mild of manners but ruthless when it came to curve fever; thank you for your assistance with many a disastrous column. Finally, I must thank Sannia; our sprawling office chats were very dear to me and I wish you all the best in your postdoc. Without question, my largest thanks go to my family. To my dear old mum, thank you for keeping me stocked with motivational kit-kats and being there for me every step of the way. To my beloved fiancée Sophie, words are not enough to describe II everything you have done to get me to where I am now. You make me a better person and none of this would have been possible without you. Lastly, I would like to thank my grandad for always believing in me; I told you I’d do it! This thesis is dedicated to you. III Abstract Decarboxylative cross-coupling chemistry is an emerging field of research that promises the synthesis of a variety of biaryl products without the need for expensive and challenging to handle organometallic reagents. Via interaction with a transition metal catalyst, organometallic species are generated in situ from carboxylic acid functionality, eliminating carbon dioxide in the process. However, inducing the decarboxylation of even highly activated carboxylic acids often requires forcing conditions: high reaction temperatures; long reaction times; and in some cases, stoichiometric quantities of transition metal mediator. Such conditions bring with them issues regarding functional group tolerance and side reaction prevalence, which limit the broader applicability of the method. The work detailed herein explores the applicability of both monometallic and bimetallic nanoparticles as potential solutions to these problems. A wide library of bimetallic catalysts have been synthesised containing group 10 (nickel or palladium) and group 11 (copper, silver or gold) transition metals, characterised via atomic absorption spectroscopy, transition electron microscopy and energy-dispersive x-ray spectroscopy and subsequently screened against a typical decarboxylative cross- coupling protocol utilising fluorinated potassium benzoate salts. Palladium/copper bimetallic nanoparticles were found to be excellent catalysts under both the literature conditions of 130 C and the lower temperature of 100 C. Palladium rich alloys performed best, and a synergistic effect was observed – the bimetallic nanoparticles displaying greatly enhanced reactivities over their monometallic analogues. Capping agent choice was also found to have a pronounced effect on catalyst activity, with the ethylene glycol-capped palladium/copper 1:1 bimetallic nanoparticle catalyst reaching reaction completion in 1 hour at 100 C, outperforming competing homogeneous catalyst systems. Substrate scope was also explored under these conditions, utilising small scale DFT calculations to make informed substrate choices. The result of this work was the elucidation of an interesting phenomenon, wherein certain substrate parings performed considerably better than others. Through follow up experiments evidence is presented that suggests this phenomenon is kinetic in nature, with substrate choice IV affecting the rates of the group 10 and group 11 catalytic cycles – parameters that are key to a reliable decarboxylative cross-coupling reaction. Finally, scope for the replacement of toxic and harmful solvents typically used in DCC protocols was also investigated. Success was found utilising poly(ethylene glycol) both as a direct analogue for problem solvents such as diglyme and in smaller quantities as an additive in desirable but underperforming solvent systems to boost reactivity. V Table of Contents Page Acknowledgements II Abstract IV Table of Contents VI List of Figures X List of Schemes XIII List of Tables XV List of Abbreviations XVII Chapter 1: Introduction 1.1 Overview 1 1.2 Decarboxylative Cross-coupling 1 1.2.1 Background 1 1.2.2 Bimetallic Catalyst Systems 5 1.2.3 Monometallic Catalyst Systems 11 1.2.4 Protodecarboxylation 16 1.2.5 The Ortho- Effect 21 1.3 Metallic Nanoparticles 26 1.3.1 Routes to Synthesis 28 1.3.2 Monometallic Nanoparticles in Catalysis 33 1.3.3 Bimetallic Nanoparticles in Catalysis 36 1.4 Project Aims 39 Chapter 2: Investigations in Copper-catalysed Decarboxylative Cross-coupling 2.1 Introduction 40 2.2 Synthesis and Characterisation of Copper-containing Heterogeneous 41 Catalysts 2.3 Copper-catalysed Decarboxylative Cross-coupling 49 2.3.1 Reaction Optimisation 55 VI 2.3.2 Solvent Scope and the Role of Diglyme 58 2.3.3 Exploring the Effect of Varying Substrate Counter-ion 64 2.4 Induction Heating as a Novel Approach to Decarboxylative Cross- 68 coupling 2.4.1 Reactor Design 72 2.4.2 Initial Investigations and Discussion 74 2.5 Conclusions and Future Work 77 Chapter 3: Bimetallic Nanoparticles as Catalysts for Decarboxylative Cross-coupling 3.1 Introduction 82 3.2 Catalyst Synthesis and Characterisation 83 3.2.1 PVP-capped Palladium/Copper Catalyst Series 85 3.2.2 PVP-capped Palladium/Silver and Palladium/Gold Catalyst Series 90 3.2.3 EG-capped Nickel/Copper and Palladium/Copper Catalyst Series 95 3.3 PVP-capped Nanoparticles in Decarboxylative Cross-coupling 101 Reactions 3.3.1 Palladium/Copper Decarboxylative Cross-coupling 101 3.3.2 The Potential for Nanoparticle Leaching 104 3.3.3 Palladium/Silver and Palladium/Gold Catalysed Decarboxylative 107 Cross-coupling 3.4 EG-capped Nanoparticles in Decarboxylative Cross-coupling 110 Reactions 3.4.1 Palladium/Copper Catalysed Decarboxylative Cross-coupling 110 3.4.2 Nickel/Copper Catalysed Decarboxylative Cross-coupling 111 3.5 Conclusions and Future Work 112 Chapter 4: Exploration of the Scope of Decarboxylative Cross-coupling under Low Temperature Conditions 4.1 Introduction 116 4.2 Bimetallic Catalysis and Choice of Substrate 117 4.3 Screening Substrates & Catalysts in Decarboxylative Cross- 124 coupling Reactions VII 4.4 Conclusions and Future Work 131 Chapter 5: Poly(ethylene glycol) as an Additive to Promote Reactivity in Decarboxylative Cross-coupling 5.1 Introduction 134 5.2 Applying Solvent Mapping to a Typical DCC Protocol 135 5.2.1 Using Glycols to Improve Reactivity 140 5.3 Exploring the Role of Poly(ethylene glycol) in DCC Reactivity 142 5.3.1 As an Additive 146 5.3.2 As a Solvent 147 5.4 Reaction Optimisation for Substrate with Lower Degrees of 149 Fluorination 5.4.1 Design of Experiments 152 5.5 Conclusions and Future Work 161 Chapter 6: Experimental 6.1 Methods and Instrumentation 165 6.2 Experimental Details 165 6.2.1 Synthesis of Nanoparticles and Catalytic Material 165 6.2.2 Synthesis of Functionalised Potassium Benzoates 173 6.2.3 Synthesis of Functionalised Caesium Benzoates 177 6.2.4 Synthesis and Purification of Biphenyl Products 177 6.2.5 General Experimental Procedures 182 6.3 Nuclear Magnetic Resonance Spectroscopy of Purified Compounds 187 6.4 Fourier-transform Infra-red Spectroscopy of Purified Compounds 200 6.5 High Resolution Mass Spectrometry of Purified Compounds 203 6.6 High Pressure Liquid Chromatography Yield Derivation 207 Methodology 6.7 Nuclear Magnetic Resonance Yield Derivation Methodology 211 6.8 Calibration Data for Benzoate/Aryl Halide Coupling Reactions 214 6.9 Magnetochemical Analysis 220 6.10 Atomic Absorption Spectroscopy Data 222 VIII 6.11 Transition Electron

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