Predicting and switching the site of heteroaromatic C-H functionalisation

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Heterocyclic CH functionalisation reactions have gathered much interest over the last decade as viable green alternatives to classic cross-coupling reactions, requiring fewer steps and producing less waste. Despite the increasing advances in this field, the issue of regioselectivity remains mostly unsolved. Though some direct heterocyclic CH functionalisations do occur selectively at one position, this is often at the "natural site" of reactivity and does not demonstrate any real regiocontrol. In a recent publication, Bedford et al. proved that it was possible to control the site selectivity of these heteroaromatic CH functionalisation reactions by switching the mechanism the reaction proceeded by. DFT was used to predict the most acidic and electron rich positions of the heterocycle and then these positions were targeted through base assisted deprotonation (BAD) and electrophilic palladation (EP) mechanisms respectively, allowing full regiocontrol between these two positions. Having proven that this strategy is effective, it is now of interest to apply this to other heterocycles and further evaluate both the predictive capabilities and regiochemical control. This project will undertake preliminary investigations, using DFT to identify the acidic and electron rich sites of other common heterocycles and then subjecting them to the BAD or EP conditions. If this proves successful, the next step will be to target other positions of the heterocycles, exploiting different innate properties to ensure regiocontrol. Once these investigations are complete, the project will then aim to try and consolidate the vast amount of DFT data that will have been collected and apply machine learning to speed up the computational prediction.