Uncovering the Unwritten-Rules in Photoredox Catalysis for Late Stage Functionalisation

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Photoredox catalysis offers new ways to construct bonds to already complex molecules such as drugs and lead-like compounds. This reaction manifold uses visible light and a photocatalyst to generate reactive intermediates under much milder reactions conditions that circumvent the use of strong oxidants and reductants. Such reaction pathways enable broader functional group compatibility, open-up new options for molecular design and accelerate the synthesis of derivatives. Photoredox catalysis therefore has enormous potential to be broadly applied in the drug discovery process as an enabling technology for the discovery of new medicines. Despite its potential, a detailed contemporary understanding of photoredox catalytic processes is limited. Reactions can be notoriously difficult to reproduce owing to the technical nature of this chemistry and the number of variables involved for these light driven reactions. Crucial factors such as the reaction temperature are either rarely reported or poorly controlled, and the combination of variables is unusually large involving: photocatalyst, light source, wavelength, reagent concentration, solvent, reactor design and reactor material. The interplay of many of these variables, effect of wavelength and temperature for example, has not been studied. This project aims to study these multiple factors in batch and continuous flow processes in order to generate a greater understanding of photoredox catalysis and the underpinning reaction conditions. We will begin by investigating CH functionalization reactions of heterocycles - an important challenge both academically and relevant to pharma. By using batch and flow photo-reactors it will be possible to study the reaction conditions in greater detail, to generate much more data on the factors and to map out the 'reaction space' that will lead to successful reactions. Building on work within the Bull group we aim to develop new batch photoreactor that will enable the accurate control of reaction temperatures. Beyond this we will leverage this understanding to generate 'data rich' reactions through the use of a continuous flow droplet based micro reactors. This will enable us to perform large numbers of reactions with precise control and provide much more extensive data than is currently possible. This will allow wide exploration of reaction variables, and also substrates, to map reactivity of different substrates under different conditions and develop clear selectivity guides towards the controlled late stage functionalisation of complex molecules.Keywords: Photoredox catalysis; heterocycle synthesis; flow chemistry; late stage functionalisation.