Studies of Intermolecular Asymmetric Halofunctionalisations of Alkenes

Description of the chemistry and potentially issues in the field
Alkene halofunctionalisations, namely the addition of an electrophilic halogen and a nucleophile across a double bond, are fundamental carbon-heteroatom bond-forming reactions in organic chemistry. These reactions facilitate the conversion of a prochiral alkene moiety into two new stereogenic carbon centres with predictable regiocontrol and diastereoselectivity, and are therefore attractive routes towards a diverse array of enantiopure, heteroatom-bearing vicinal disubstituted compounds. However, although the stereochemical course of alkene halofunctionalisations has been well-established over the past century, developing catalytic, asymmetric variants of these reactions has presented a significant challenge for the modern synthetic community. In the last decade, several examples of enantioselective intramolecular halofunctionalisation (involving capture of a halonium ion by a covalently tethered nucleophile) have emerged, many of which utilise chiral bisalkaloids or BINOL-phosphoric acids as organocatalysts. In contrast, there are very few examples of successful enantioselective intermolecular halofunctionalisation reactions (utilising a nucleophile extraneous to the starting alkene) using either of these organocatalysts. This is because of a generally poor mechanistic understanding of the intermolecular systems relative to their intramolecular counterparts. Inspired by results of Li et al., this project intends to elucidate the mechanisms of organocatalytic intermolecular halofunctionalisation, with comparisons being made between different organocatalytic systems. This will involve thorough optimisation experiments using factorial designs, chemometrics for the analysis of kinetic data, all tied in with a computational approach to develop theories surrounding our experimental data.

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.