Data-driven design of Next Generation Cross-Coupling catalysts by Ligand Parameterisation: A Combined Experimental and Computational Approach.

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In the synthesis of complex molecules, the ability to react already functional group rich compounds presents an ongoing challenge. This is particularly true in catalytic transformations, and a major limitation of base metal mediated reactions. Preliminary results in this collaborative work have identified highly effective copper catalysts at very low metal loadings (0.5 mol %) while displaying remarkable functional group tolerance. Our design is based on bidentate ligands containing an N-heterocyclic carbene (NHC) and a hemilabile second coordination site that produces isolable and air stable copper complexes.The main purpose of this project is to design improved ligands with broad applicability and efficiency in a range of cross-coupling reactions. Instead of tedious optimisation studies for each type of nucleophile, we propose the classification and parametrisation of bidentate ligands using novel dynamic descriptors. Predicted hits will be validated experimentally to develop a suite of copper catalysts to form aryl-O, aryl-N and aryl-CF3 bonds with high functional group tolerance. Overall, this work will provide a quantitative insight to ligand properties, an improved understanding of copper-mediated transformations and ultimately state-of-the-art catalytic systems for one of the most commonly employed transformations in fine chemical industry.