Improving Iron Catalysed Kumada Couplings in Flow

This project is focused on developing a methodology to improve iron catalysed alkyl-alkyl Kumada cross couplings. This type of reaction is a promising sustainable alternative to traditionally palladium catalysed reactions, but improving the efficiency, selectivity, and catalyst turnover is important to make the reaction more sustainable and viable for industry. This will be done by developing and using flow apparatus to explore kinetics and reaction pathway.
This type of reaction has been previously reported in the literature using Fe(II) acetate, and a xantphos or N-heterocyclic carbene (NHC) ligand; these reactions have achieved yields up to 64% for the xantphos system after 15 mins, and 67% after a total of 27 hours for the NHC reaction. Whilst these yields are promising further optimisation of the catalyst and reaction conditions would make the reaction a cheap, sustainable, and viable option for large-scale chemical production; in particular for the pharmaceutical, agrochemical, and fine chemicals industries , where more expensive and environmentally costly palladium catalysts are commonly relied upon.
We plan to exploit the fact that reactions carried out in continuous flow reactors can be probed at steady state to better insight into the reaction and aid the optimisation process. It is anticipated that the additional control over the reaction that can be achieved using flow equipment will also aid in this process. Additionally, this project will focus on expanding the substrate scope to enable the synthesis of beta-functionalised amines, such as functionalised piperadines, azetidines, and man-made amino acids. These are valuable building blocks e.g. for fragment based drug discovery and the synthesis of active pharmaceutical intermediates (APIs). The project will focus on developing a model reaction and general method that can used and applied by other research groups and industry.
Finally, throughout this project we will investigate designing a flow reactor system that will include both in-line analysis and reaction workup steps. This will enable the reaction to be used in a continuous set up as part of a longer synthesis. Furthermore, we would like to investigate the possibility of incorporating into the system a loop to recycle the catalyst as a proof of concept to spur of further development in this area.
The benefits of this project are three-fold, first of all the Kumada cross coupling is often used for the synthesis of fine chemicals and pharmaceuticals. Replacing commonly used palladium catalysts with iron will increase the sustainability and decrease the overall cost of the reaction.
Second of all by focusing on alkyl-alkyl cross couplings we will help provide methods to open up under explored chemical space by providing scalable methods to synthesize saturated structures. In particular we are interested in the synthesis of saturated beta-functionalised amines, which are common moieties in APIs. Expanding the scope of saturated structures accessible for drug development is important to continuously enable the discovery and manufacture of new medicines typically neglected in this area.
Finally, due to the reactivity of some of the components used in this reaction, in particular the Grignard reagent, it is critical to ensure that they are both synthesized and reacted safely and in a way where their reactivity can be controlled to maximise the yield of the desired product. By developing flow methodologies for this reaction we hope to demonstrate that the Grignard reagent can be used safely and with a high degree of control suitable for modern sustainable chemical manufacturing.

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.