NEXT GENERATION ‘FRUSTRATED LEWIS PAIRS’ by Daniel J. Scott A dissertation submitted to the Department of Chemistry of Imperial College London for the degree of Doctor of Philosophy December 2016 1 Abstract The past decade has seen the emergence of a new concept in main-group chemistry: ‘frustrated Lewis pairs’ (FLPs) are combinations of a Lewis acid (LA) and base (LB) that are prevented from forming the classically-expected adduct. By displaying simultaneously acidic and basic behaviour, these systems have been shown to be capable of activating a wide range of chemical bonds, in a manner highly reminiscent of transition-metal (TM) compounds. Chief among these reactions is the activation of H2, which can then be transferred from the FLP to an appropriate substrate. FLPs have thus provided an entirely new class of homogeneous hydrogenation catalysts, which do not require the use of TMs. Nevertheless, prior to the work described herein, such catalysis had not been successfully applied to the hydrogenation of organic carbonyl functional groups, and had been found to be extremely sensitive to the presence of moisture. This thesis describes work that has successfully overcome these limitations. Chapter 1 provides an introduction to the field of FLP chemistry, including a general summary of the topic, and a more detailed overview of catalytic hydrogenation mediated by FLPs. Chapter 2 describes the development of novel FLPs based on the combination of strong triarylborane LAs and weak ethereal solvent LBs. These systems are shown to be highly effective for the hydrogenation of a variety of substrates, including the first examples of both FLP-catalysed hydrogenation of ketones and aldehydes, and moisture-tolerant FLP-catalysed hydrogenation. Chapter 3 describes the design and preparation of alternative systems incorporating Sn(IV)-based LAs, whose use in FLP-mediated H2 activation has not previously been documented. These too are shown to be tolerant of moisture, and to be suitable for the hydrogenation of C=O, C=N and C=C bonds. Chapter 4 provides full experimental details for the procedures described in Chapter 2 and Chapter 3. 2 Declaration The work described herein was performed at Imperial College London during the period between October 2013 and October 2016 inclusive, under the supervision of Dr Andrew Ashley and Dr Matthew Fuchter. All results were obtained by the author (Mr Daniel Scott) unless explicitly stated otherwise, and have not previously been submitted in pursuit of any other degree at any institution. Daniel John Scott December 2016 Copyright The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 3 Acknowledgements First and foremost, I would like to thank my academic supervisors for getting me to this point. Without Andy and Matt’s constant support, guidance and intellectual input this thesis would not exist. I would also like to acknowledge all the various colleagues with whom I have been lucky enough to share an office during the course of this project: they have graciously expended a huge amount of effort first to teach me how to function in a lab setting, and then to help me stay (relatively) sane. Almost everybody who falls into this category has earned a special mention, but in order to avoid a rambling Oscars-style outpouring I’ll keep it generic: thank you all (you know who you are). Finally, while technical support for this project has been provided by a number of people, I have to single out Peter Haycock his assistance with NMR. For the past several years he has tolerated my frankly unreasonable demands on his time, expertise, and equipment with unfailing good humour. Without his help, this project could not have been nearly as successful. 4 Abbreviations 2-MeTHF 2-methyltetrahydrofuran APCI-MS atmospheric pressure chemical ionisation mass spectrometry Ar generic aryl group Bn benzyl; phenylmethyl Bu n-butyl col 2,4,6-collidine; 2,4,6-trimethylpyridine Cy cyclohexyl DABCO 1,4-diazabicyclo[2.2.2]octane DCB 1,2-dichlorobenzene DFB 1,2-difluorobenzene DFT density functional theory Dipp 2,6,-diisopropylphenyl DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDG electron-donating group Et ethyl EWG electron-withdrawing group FLP frustrated Lewis pair FXyl 3,5-trifluoromethylphenyl HMBC heteronuclear multiple bond correlation Hex n-hexyl HOMO highest occupied molecular orbital I nuclear spin iBu iso-butyl iPr iso-propyl J coupling constant LA Lewis acid LB Lewis base 5 LUMO lowest unoccupied molecular orbital lut 2,6-lutidine; 2,6-dimethylpyridine m/z mass/charge ratio Me methyl Mes mesityl; 2,4,6-trimethylphenyl Ms mesyl; O2SMe MS mass spectrometry MS-ToF mass spectrometry – time of flight NHC N-heterocyclic carbene NMR nuclear magnetic resonance Np neopentyl; CH2CMe3 Ph phenyl Pr n-propyl R generic organic group F R C(CF3)3 RT room temperature T1 spin-lattice relaxation time tBu tert-butyl Tf trifluoromethanesulfinate; O2SCF3 THF tetrahydrofuran TM transition metal TMP 2,2,6,6-tetramethylpiperidyl TMS tetramethylsilane Trip 2,4,6-triisopropylphenyl Ts tosyl; 4-methylphenylsulfonyl VT variable temperature XRD X-ray diffraction xs excess D-CD D -cyclodextrin G chemical shift Hr relative permittivity 6 Units °C degrees Celcius Å Ångströms atm atmospheres bar bar cal calories d days g grams h hours Hz Hertz J Joules K Kelvin L litres M molar (mol dm–3) mol moles ppm parts per million s seconds 7 Table of contents Abstract .................................................................................................................................................. 2 Declaration ............................................................................................................................................. 3 Copyright ................................................................................................................................................ 3 Acknowledgements ................................................................................................................................ 4 Abbreviations ......................................................................................................................................... 5 Units ....................................................................................................................................................... 7 Table of contents ................................................................................................................................... 8 List of Figures ....................................................................................................................................... 10 List of Schemes ..................................................................................................................................... 13 List of Tables ......................................................................................................................................... 19 Chapter 1 - Introduction ....................................................................................................................... 20 Chapter 1.1 - Putting FLPs in context: main group mimics of transition metals .............................. 20 Chapter 1.2 - Introduction to frustrated Lewis pair chemistry ........................................................ 24 Chapter 1.2.1 - Stoichiometric FLP reactivity ............................................................................... 24 Chapter 1.2.2 - Catalytic FLP reactivity ........................................................................................ 27 Chapter 1.3 - Some historical context for FLP chemistry ................................................................. 30 Chapter 1.4 - Hydrogenation catalysis using FLPs ............................................................................ 32 Chapter 1.4.1 - Stoichiometric FLP H2 activation ......................................................................... 32 Chapter 1.4.2 - Catalytic FLP H2 activation .................................................................................. 35 Chapter 1.4.3 - Aspects of FLP design .......................................................................................... 40 Chapter 1. 5 - Frontiers and limitations of FLP chemistry ................................................................ 45 Chapter 1.5.1 - FLP-mediated hydrogenation of carbonyl compounds ....................................... 46 Chapter 1.5.2 - Moisture tolerance in FLP chemistry ................................................................... 47 Chapter 1.5.3 - Thesis aims .......................................................................................................... 48 Chapter 1.6 - References for Chapter 1 ........................................................................................... 49 Chapter 2 - Boron-based FLPs .............................................................................................................. 58 Chapter 2.1 - Introduction ............................................................................................................... 58 Chapter 2.2 - Catalytic