Electron-catalysed C-C coupling: an integrated experimental and computational approach

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It has been estimated that more than 75% all C-C bonds in the pharmaceutical industry are made using transition-metal (TM) catalysis (J. Med. Chem. 2016, 59, 4443). This reliance on costly, finite, precious-metal resources has therefore raised serious concerns about the long-term sustainability of this life-changing industry. This project aims to address this crucial problem by developing a general, sustainable, TM-free approach to C-C bond formation using electron-catalysed radical-nucleophilic substitution (Nat. Chem. 2014, 6, 765). A key challenge in this emerging area of chemocatalysis (electron catalysis) is that, unlike conventional modes of catalysis where the source of the catalyst is obvious (e.g. as in Bronsted acid catalysis), the source of electrons in electron-catalysed reactions is often ambiguous. This project will seek to resolve this ambiguity by employing an integrated experimental and computational approach to study the overlooked role of weak intermolecular interactions in these reactions. This approach will merge the multidisciplinary expertise in the James Group on electron-catalysed reactions (Chem. Sci. 2021, 12, 14641; ChemRxiv 10.26434/chemrxiv-2022-9l5gq) and Trujillo Group using computational predictions to improve reaction design (WIREs Comput Mol Sci. 2022, e1616). This synergistic collaboration will ultimately enable longstanding mechanistic questions to be answered and empower the development of new electron-catalysed synthetic methodologies.Ethan will receive excellent training in organic synthesis using state-of-theart electron-catalysed chemistry. In addition to the experimental preparation, purification, and characterization of small organic molecules, he will also develop a diverse skillset using computational methods to study reaction mechanisms. Finally, the student will have the opportunity to attend organic problem classes, present their research at national or international meetings and interactwith industrial project partners.Methods for the formation of new C-C bonds are fundamental to the discovery of new bioactive molecules. To date, advances in this area have largely been driven by the development of new TM-catalysed coupling reactions. However, there are notable disadvantages associated with the use of TMs in synthesis, such as their cost, sustainability, and toxicity. Additionally, the supply of TMs can fluctuate dramatically as they must be imported from international mines, which also raises significant environmental and ethical concerns. There is therefore an urgent need to develop alternative TM-free coupling strategies that can circumvent these issues.This work will have a significant impact on the chemical and pharmaceutical industry (the second largest manufacturing sector in the UK) by providing a powerful new tool to be utilised in the cost-effective manufacture of next generation medicines and agrochemicals. By expediting research in this industry, untreated patients, or communities facing famine, who are waiting for new drugs or plant protection products to be developed will be indirect beneficiaries of this work.This work will also inspire wider developments in catalysis as innovation in this field is invariably driven by advances in our mechanistic understanding. This project will harness the full power of computational modelling to obtain new mechanistic insight and dramatically reduce the amount of time and resources that go into developing a new catalytic reaction. In addition to efficiency, this approach will encourage the synthetic community to widely re-evaluate what we truly know about seemingly "simple" reactions.Academically, this project will have a major impact on the career trajectories of newly appointed lectures Dr Michael James and Dr Cristina Trujillo, who will use this work to fuel future collaborations and the growth of an undeveloped field of catalysis