Reagent-Free Flow Chemistry: The Generation and Trapping of Reactive Intermediates

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Traditionally the small-scale synthesis of organic compounds has been carried out using batch processes (the ubiquitous 'round bottom flask'). In comparison most large-scale industrial synthesis are continuous processes where the substrates are flowed through various reaction conditions and purifications. Recently equipment has been developed to allow 'flow synthesis' on the scale typically carried out in a research laboratory. Industry has enthusiastically adopted the new technology but there is a lack of people familiar with the method entering the job market as academia has, largely due to the cost of the equipment, not made much use of flow chemistry. Flow synthesis has one advantage which we believe makes it the future of synthetic organic chemistry - the output is a constant reflection of the conditions being used. To optimise a traditional batch process many separate reactions have to be carried out under various conditions and the product of each analysed in order to gradually converge on the best conditions. Using flow reactors dynamically varying the conditions and observing the output allows the equivalent of thousands of experiments to be carried out in a very short time under highly controlled conditions allowing fast optimisation. It should be possible to automate this optimisation process - an objective that this project takes the first steps towards.Our project is a collaboration between synthetic organic chemists and engineers which aims to: develop new flow technologies; develop new chemical processes which make the best use of flow techniques; promote the use of flow chemistry in the academic community by providing access to equipment and expert help; and provide three highly trained postgraduates who can take the field forward. The students carrying out the work spend half their time with our industrial partner ensuring rapid exchange of knowledge between industry and academia.The new flow technologies and chemical processes we aim to develop are unified by the overlapping concepts of 'Synthesis without Reagents' and 'Reactive Intermediate Trapping'. The former concept is driven by the desire to be able to achieve multi-step synthesis by sequencing a number of flow reactions where any by-products from the reagents used in a step might interfere with subsequent stages. The second concept is driven by the particular advantages of flow systems for the generation and trapping of reactive intermediates. Batch processes require both additional components, and the products of reaction, to be stable to the conditions used to generate the reactive intermediate. By allowing rapid combination of the 'reactive intermediate' stream with second 'component' stream under mild conditions flow systems overcome this limitation. Flow chemistry is little used for synthesis of the large number of diverse compounds needed for the discovery of new pharmaceuticals - its strength is traditionally the synthesis of large amounts of single compounds due to the effort involved in developing each flow synthesis route. We believe that we can achieve the synthesis of many different compounds by optimising a flow process to produce a reactive intermediate which may then be efficiently trapped by a wide range of reaction partners to produce the desired compounds. We plan to use either very high temperatures for a short time, or exposure to high energy Ultra-Violet light to generate the reactive intermediates.