Synthetic Electrochemistry: Carboxylic Acid Derivatives as Radical Precursors

Lead Research Organisation: University College London
Department Name: Chemistry

Abstract

The use of radical chemistry in organic synthesis is widespread, yet typical radical reactions are not without their problems: preparation of radical precursors can require additional synthetic steps, while the reactions themselves frequently need elevated temperatures and utilize highly toxic tin reagents. In this project, we will use electrochemical techniques to develop green synthetic radical procedures which proceed at room temperature and use readily available and cheap precursors.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509577/1 01/10/2016 30/09/2021
1922092 Studentship EP/N509577/1 25/09/2017 30/09/2021 Isobel Wilson
 
Description The main objective of this award was to develop an electrochemical trifluoromethylation reaction, the key step of which would be the formation of a trifluoromethyl (CF3) radical via reduction at an electrode. Ideally, the trifluoromethylation would be achieved using cheap and readily available starting materials, whilst being simple and easy to replicate. This would help to highlight the potential of such electrosynthetic reactions to organic chemists in academia and industry, two areas which have so far been slow in the uptake of electrochemistry as a synthetic tool. Current, non-electrosynthetic, methods for trifluoromethylation either use toxic or expensive materials to achieve the same products. Therefore, if successful, the work done for this award should provide a cheaper and greener alternative to a widely used reaction.

During this award the formation of a trifluoromethyl ketone product has successfully been achieved via an electrosynthetic pathway. This was possible due the reduction of a pyridinium ion formed from 4-methylpyridine and trifluoroacetic acid (TFAA). The formation of this pyridinium ion was crucial as it provided a source of trifluoromethyl radicals via reduction at low potentials (within the potential window of acetonitrile). As far as we are aware, a pyridinium ion of this type has not been used for the production of trifluoromethyl radicals via an electrosynthetic method before.

After the initial formation of the trifluoromethyl radical, in the presence of styrene and air, the reaction proceeded to form a trifluoromethyl ketone. This is exciting as it is a novel reaction, however we have so far been unsuccessful in obtaining a yield greater than 32%. This yield is too low to convince the organic chemistry community that this electrosynthetic technique would be worth pursuing. Therefore, current and future work is focused on obtaining a higher yield. To do this many parameters will be examined including the effect of the electrolyte, solvent, electrode material and the current or potential supplied by the potentiostat. Hopefully this will allow us to gain insight into the reaction and allow us to obtain a higher yield of product. If this can be achieved, the next step will then be to demonstrate the substrate scope of the reaction by using materials other than styrene to trap the trifluoromethyl radical.
Exploitation Route Now that trifluoromethylation, via the electrochemical reduction of a CF3-containing pyridinium ion, has been proved possible it has opened up a wide array of possibilities. On an academic scale, future PhD students can work on developing the reaction using alternative starting materials and pathways. Another possibility would be to test the substrate scope of the reaction on materials that would be useful for the pharmaceutical or agrochemical industry as the CF3 group is a common motif used in these areas. If the reduction of pyridinium ions to produce CF3 radicals can be demonstrated on a large scale, as well as part of a multi-step synthesis then this also increases the likelihood of this reaction being used in industry.
Sectors Chemicals,Environment,Pharmaceuticals and Medical Biotechnology