New strategies for Bi-mediated C-C bond formation

Project background (identification of the problem and its importance and relevance to sustainability)

Carbon to carbon (C-C) bonds are abundant and important in both natural and synthetic molecules, for example amino acids in our bodies, and medicines. Various methods are available to form these types of bonds, but many use metals such as palladium that are toxic, rare and/or very expensive. Therefore, it is desirable to make these reactions more sustainable by using 'green' chemicals. Bismuth-based compounds could potentially fulfil such a role. Bismuth is a non-toxic waste product of the mining industry, making it an inexpensive and sustainable material. Additionally, typical C-C bond-forming methods combine complex building blocks, the preparation of which requires additional steps that generate additional waste. A more sustainable process is to avoid this step altogether.

C-H functionalisation enables direct C-C bond formation between simple, unfunctionalized partners. The overall process is potentially less wasteful than traditional C-C bond forming methods (lower process mass intensity, PMI) as fewer steps are required to synthesise the substrates and less waste is produced in the coupling reaction itself. The Ball group have previously developed a rapid and user-friendly method for C-H functionalisation that is promoted by bismuth. At the end of the process, the bismuth-containing co-product can be recovered in high yields, and recycled for re-use in further reactions.

This project seeks to extend the remit of the Ball group's prior art, making it more sustainable and applicable to a wider range of pharmaceutically- and agrochemically-valuable target molecules.




Proposed solution and methodology

The objective of the project is to make bismuth-promoted C-H functionalisation more sustainable and more general. To do this, we will study the relationship between the structure / properties of the bismuth-based reagents, and their efficiency in C-H functionalisation reactions. The resulting insight will allow rational design of more efficient bismuth-based reagents and processes. The new reagents will be applied to the preparation of a wide range of target molecules that are valued by industry, or that are otherwise currently challenging to access in an environmentally responsible way.

This CDT will deliver impact aligned to the following agendas:

People
A2P will provide over 60 PhD graduates with the skill sets required to deliver innovative sustainable products and processes into the UK chemicals manufacturing industry. A2P will inspire and develop leaders who will:
- understand the needs of industrial end-users;
- embed sustainability across a range of sectors; and
- catalyse the transition to a more productive and resilient UK economy.

Economy
A2P will promote a step change towards a circular economy that embraces resilience and efficiency in terms of atoms and energy. The benefits of adopting more sustainable design principles and smarter production are clear. For example, the global production of active pharmaceutical ingredients (APIs) has been estimated at 65,000-100,000 tonnes per annum. The scale of associated waste is > 10 million tonnes per annum with a disposal cost of more than £15 billion. Consequently, even a modest efficiency increase by applying new, more sustainable chemical processes would deliver substantial economic savings and environmental wins. A2P will seek and deliver systematic gains across all sectors of the chemicals manufacturing industry. Our goals of providing cross-scale training in chemical sciences with economic and life- cycle awareness will drive uptake of sustainable best practice in UK industry, leading to improved economic competitiveness.

Knowledge
This CDT will deliver significant new knowledge in the development of more sustainable processes and products. It will integrate the philosophy of sustainability with catalysis, synthetic methodology, process engineering, and scale-up. Critical concepts such as energy/resource efficiency, life cycle analysis, recycling, and sustainability metrics will become seamlessly joined to what is considered a 'normal' approach to new molecular products. This knowledge and experience will be shared through publications, conferences and other engagement activities. A2P partners will provide efficient routes to market ensuring the efficient translation and transferal of new technologies is realised, ensuring impact is achieved.

Society
The chemistry-using industries manufacture a rich portfolio of products that are critical in maintaining a high quality of life in the UK. A2P will provide highly trained people and new knowledge to develop smarter, better products, whilst increasing the efficiency and sustainability of chemicals manufacture.
To amplify the impacts of our CDT, effective public engagement and technology transfer will become crucially important. As a general comment, 'sustainability' styled research is often regarded in a positive light by society, however, the science that underpins its effective implementation is often poorly appreciated. The University of Nottingham has developed an effective communication portfolio (with dedicated outreach staff) to tackle this issue. In addition to more traditional routes of scientific communication and dissemination, A2P will develop a portfolio of engagement and outreach activities including blogs, webpages, public outreach events, and contribution of material to our award-winning YouTube channel, www.periodicvideos.com.

A2P will build on our successful Sustainable Chemicals and Processes Industry Forum (SCIF), which will provide entry to networks with a wide range of chemical science end-users (spanning multinationals through to speciality SMEs), policy makers and regulators. We will share new scientific developments and best practice with leaders in these areas, to help realise the full impact of our CDT. Annual showcase events will provide a forum where knowledge may be disseminated to partners, we will broaden these events to include participants from thematically linked CDTs from across the UK, we will build on our track record of delivering hi-impact inter-CDT events with complementary centres hosted by the Universities of Bath and Bristol.