Reductive Aminations and Amidations, a Self-Optimising Reactor

Lead Research Organisation: University of Nottingham
Department Name: Sch of Chemistry


Project background (identification of the problem and its importance and relevance to sustainability)
In the pharmaceutical industry over 90% of products contain nitrogen based functional groups, many of these are in the form of amines and amides. Reductive amidations and direct amidations often require several additives in stoichiometric amounts that reduce overall atom economy. Reducing the waste involved is of significant interest to the chemical industry in the UK.

In recent years there has been significant work in developing C-N bond forming reactions with reduced waste by exchanging the classical ketones and aldehydes for carboxylic acids. These acids have the advantage of being more abundant and can be sustainably sourced however are less reactive.

Recent work in this area has made use of silanes as an efficient reagent in both direct amidations and reductive aminations. Recently Stoll et al. demonstrated a reductive amination process using phenyl silane and zinc acetate, and while it did show excellent results its performance is limited by an inability to be immobilised for use in flow.1 Morisset et al. developed a direct amidation reaction using only phenyl silane at room temperature which showed significant results and the potential for further development into a flow platform.2

1 E. L. Stoll, T. Tongue, K. G. Andrews, D. Valette, D. J. Hirst and R. M. Denton, Chem. Sci., 2020, 11, 9494-9500.
2 E. Morisset, A. Chardon, J. Rouden and J. Blanchet, European J. Org. Chem., 2020, 2020, 388-392.

Proposed solution and methodology
Proposed solution
We propose to develop reductive amination and direct amidation protocols that make use of the dual functionality of silanes as both a coupling agent in direct amidations, and as a reductant in reductive aminations. We intend to deploy these protocols for both as a batch process and in a self-optimising flow reactor. To develop the process for the flow platform we will explore more sustainable polymer-based scaffolds to support and immobilise the silanes, as well as looking at how to regenerate and reuse these supported silanes. We also wish to employ machine learning techniques in order to make predictions around the reaction conditions to gain further understanding and control of the reaction. In addition, we wish to employ our machine learning process to the flow reactor.

We intend to realise our preposed solution by the following steps
1. Develop reductive amination and direct amidation protocols using silanes supported on a polymer
2. Explore the scope and limitations of the reactions through empirical and machine learning techniques
3. Further develop polymer scaffold to optimise porosity and retention times
4. Build a self-optimising flow platform to use reductive amination and direct amidation protocols
5. Apply the reductive amination and direct amidation protocols to exemplar APIs

Planned Impact

This CDT will deliver impact aligned to the following agendas:

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.

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.

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.

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,

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.


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