Automating the Understanding of Catalytic Aldehyde Synthesis

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Aldehydes are key intermediates in the chemical synthesis of active pharmaceutical ingredients (APIs). Aryl aldehydes are typically made by the metalation of an aryl halide with an s-block reagent followed by addition to dimethylformamide (Bouveault synthesis). This approach has its disadvantages: it requires the formation of organometallic intermediates, shows limited functional group tolerance, and it generates considerable waste. A more efficient alternative is the catalytic formylation of aryl halides with CO/H2 mixtures. Despite the potential of this catalytic approach, it does not find widespread use due to the limited understanding of the reaction. Currently, it is not clear what the best process is to screen for new catalysts, it is not obvious which variables to focus on to expand the substrate scope, and open questions remain as to how best to scale the process up. If a detailed mechanistic understanding of catalytic formylation could be developed it could be used to underpin a broader application of this method in the synthesis of APIs. In this project, we will use a combination of automation, kinetic analysis (VTNA), DFT calculations and synthetic chemistry to develop deep insight into the palladium catalysed formylation