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

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 interact
with 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

iCAT will work with industry partners to create an holistic approach to the training of students in biocatalysis, chemocatalysis, and their process integration. Traditional graduate training typically focuses on one aspect of catalysis and this approach can severely restrict innovation and impact. Advances in technology and fundamental reaction discovery are rendering this silo-approach obsolete, and a new training modality is needed to produce the next generation of chemists and engineers who can operate across a far broader chemical continuum. iCAT will meet this challenge with a state-of-the-art CDT, equipping the next generation of scientists and engineers with the skills needed to develop future catalytic processes and create the functional molecules of tomorrow.

The UK has one of the world's top-performing chemical industries, achieving outstanding levels of growth, exports, productivity and international investment. The UK's chemical industry is a significant provider of jobs and creator of wealth, with a turnover in excess of £50 billion and a contribution of over £15 Billion of value to the UK economy [2015 figures]. iCAT will deliver highly skilled people to lead this industry across its various sectors, achieving impact through the following actions:

1. Equip the next generation of science and engineering leaders with the interdisciplinary skills and knowledge needed to work across the bio and chemo catalytic remit and build the functional molecules we need to structure society.

2. Provide a highly skilled workforce and research base, skilled in the latest methodologies, strategies and techniques of catalysis and engineering that is crucial for the UK's Chemical Industry.

3. Build the critical mass necessary to support effective cohort-based training in a world-class research environment.

4. Develop and disseminate new catalytic technologies and processes that will be taken up by industrial and academic teams around the world.

5. Encourage Industry to promote research challenges within the CDT that are of core relevance to their business.

6. Provide cohesion in the integration of biocatalysis, engineering and chemocatalysis to create a more unified voice for strategic dialogue with industry, funders and policy makers, and more generally outreach and public engagement.

7. Draw-in and bring together Industrial partners to facilitate future Industrial collaborations.

8. Benefit Industrial scientists through interactions with the CDT (e.g. training and supervisory experience, exposure to cutting-edge synthesis and catalysis etc).

9. Link with other activities in the landscape: bringing unique expertise in catalysis to, for example, externally-funded University-led initiatives, EPRSC Grand Challenge Networks, and the National Catalysis Hub.