Continuous Processing for the Scale-Up of Organometallic Chemistry

Organometallic reagents are versatile carbanion synthons for the formation of new carbon-carbon and carbon-heteroatom bonds. However, their high reactivity and chemical instability can cause issues with their handling and safe generation. While at a laboratory level organometallic compounds can be handled relatively safely, scaling-up poses a challenge for industrial applications. Flow chemistry may provide a solution to these issues, and organometallic reagents have previously been successfully handled in continuous flow micro-reactors, often with improved chemoselectivity compared to reactions performed in batch mode. This is due to the rapid heat transfer, efficient mixing and precise stoichiometric control which are possible in flow. However, scale up to industrially relevant quantities is still impeded by the throughput of typical micro-reactor technology. In addition, sustainability benefits may be realized by the implementation of organometallic processes in continuous manufacturing.
The objective of this project is to investigate meso-scale (and larger) flow reactor technologies for the continuous processing of organometallic processes, with the aim of developing general processes for the synthesis and eventual manufacture of chemical intermediates, in particular aryl and heterocyclic ketones.

Initially, using a model system, parameters such as mixing, temperature control and solids management will be explored and optimized. The findings will then be applied to progressively more complex model systems which would support the synthesis of molecules of interest across all sectors of chemical industry. These studies will be supported by appropriate analytical techniques to provide a detailed picture of how reaction performance relates to the physical properties of the reactor.

The eventual realization of the project outcomes in a manufacturing environment will require technical input from appropriate stakeholders. A unique aspect of this project is that input from stakeholders will be sought throughout the duration of the project to ensure that the solutions identified are fit for purpose.

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.