Electrochemical Deoxygenative Functionalisation of Alcohols

Alcohols are a useful functionality in organic synthesis due to the wide range of reactions to and from them, and due to their prevalence in natural products and synthetic targets. The deoxygenation and deoxygenative functionalisation of alcohols are often-employed synthetic steps.

Conventional methods for the deoxygenation of alcohols involve an initial derivatisation of the alcohol to form a more labile functionality, which is subsequently cleaved in a second step. Classic examples of this chemistry include the reduction of tosylates, the Barton-McCombie deoxygenation and the Markó-Lam deoxygenation. These methods for the reduction of alcohols often use hazardous or toxic reagents, and the use of a two-step process is inherently more wasteful than a one-step reduction. In a 1994 publication, Ohmori et al. disclosed a one-step electrochemical deoxygenation of alcohols, but the scope and functional group tolerance explored was limited, and the mechanism of this transformation was not determined.

The most notable protocols for the deoxygenative substitution of alcohols include the Appel reaction and the Mitsunobu reaction. However, the Appel reaction is limited to halide nucleophiles, and in the Mitsunobu reaction hazardous reagents are required to activate the alcohol. Typical deoxygenative functionalisations of alcohols require stoichiometric quantities of oxidant, which result in the production of stoichiometric waste. Following the electrochemical deoxygenation disclosed by Ohmori et al., a few examples of electrochemical deoxygenative substitutions have been published, however the scope of alcohols and substituting nucleophiles is extremely limited.

Proposed solution and methodology

The development of new synthetic methods for late-stage functionalisation addresses the pressing need for delivering complex molecules swiftly and sustainably. New methodologies for functionalisation of alcohols at the late stage permit rapid access to libraries of related compounds, in less time and fewer chemical steps than de novo syntheses. The generation of synthetically useful reactive species from alcohols using electrosynthetic techniques remains underdeveloped. In this project, methods for the electrochemical deoxygenation of alcohols and for the electrochemical deoxygenative functionalisation of alcohols will be explored and developed. Using anodic oxidation, the use of toxic and/or hazardous oxidising agents is avoided, as is the generation of stoichiometric waste from spent oxidant.

This project aims to deduce the mechanism of the electrochemical deoxygenation developed by Ohmori et al., improve its scope and functional group tolerance, and will explore its applications to complex molecules for late-stage functionalisation. Following determination of the reaction mechanism, the scope of alcohols and functional groups compatible with the electrochemical deoxygenation methodology will be expanded. With greater functional group tolerance and selectivity, the deoxygenation of complex molecules will demonstrate the applications of this methodology in late-stage functionalisation.

With mechanistic understanding of the electrochemical deoxygenation and optimised conditions, general deoxygenative functionalisation reactions will be developed. Depending on the reaction mechanism this could be via alkyl bromide or alkoxyphosphonium intermediates or via alkyl radical intermediates. Ideally, the chemistry developed will be applicable to a wide scope of alcohol substrates including complex molecules, will incorporate a range of nucleophiles, and will exhibit broad functional group tolerance.

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.