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

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.

Academic impact:
Recent advances in data science and digital technology have a disruptive effect on the way synthetic chemistry is practiced. Competence in computing and data analysis has become increasingly important in preparing chemistry students for careers in industry and academic research.

The CDT cohort will receive interdisciplinary training in an excellent research environment, supported by state-of-the-art bespoke facilities, in areas that are currently under-represented in UK Chemistry graduate programmes. The CDT assembles a team of 74 Academics across several disciplines (Chemistry, Chemical Engineering, Bioengineering, Maths and Computing, and pharmaceutical manufacturing sciences), further supported by 16 industrial stakeholders, to deliver the interdisciplinary training necessary to transform synthetic chemistry into a data-centric science, including: the latest developments in lab automation, the use of new reaction platforms, greater incorporation of in-situ analytics to build an understanding of the fundamental reaction pathways, as well as scaling-up for manufacturing.

All of the research data generated by the CDT will be captured (by the use of a common Electronic Lab Notebook) and made openly accessible after an embargo period. Over time, this will provide a valuable resource for the future development of synthetic chemistry.

Industrial and Economic Impact:
Synthetic chemistry is a critical scientific discipline that underpins the UK's manufacturing industry. The Chemicals and Pharmaceutical industries are projected to generate a demand for up to 77,000 graduate recruits between 2015-2025. As the manufacturing industry becomes more digitised (Industry 4.0), training needs to evolve to deliver a new generation of highly-skilled workers to protect the manufacturing sector in the UK. By expanding the traditional skill sets of a synthetic chemist, we will produce highly-qualified personnel who are more resilient to future challenges. This CDT will produce synthetic chemists with skills in automation and data-management skills that are highly prized by employers, which will maintain the UK's world-leading expertise and competitiveness and encourage inward investment.

This CDT will improve the job-readiness of our graduate students, by embedding industrial partners in our training programme, including the delivery of training material, lecture courses, case studies, and offers of industrial placements. Students will be able to exercise their broadened fundamental knowledge to a wide range of applied and industrial problems and enhance their job prospects.

Societal:
The World's population was estimated to be 7.4 billion in August 2016; the UN estimated that it will further increase to 11.2 billion in the year 2100. This population growth will inevitably place pressure on the world's finite natural resources. Novel molecules with improved effectiveness and safety will supersede current pharmaceuticals, agrochemicals, and fine chemicals used in the fabrication of new materials.

Recent news highlights the need for certain materials (such as plastics) to be manufactured and recycled in a sustainable manner, and yet their commercial viability of next-generation manufacturing processes will depend on their cost-effectiveness and the speed which they can be developed. The CDT graduates will act as ambassadors of the chemical science, engaging directly with the Learned Societies, local council, general public (including educational activities), as well as politicians and policymakers, to champion the importance of the chemical science in solving global challenges.