Copper-Catalysed Aryl-Chloride Amination: A Quality-by-Design Approach Based on Improved Mechanistic Understanding

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Recently copper salts and complexes have shown themselves to be Green, economical and versatile reagents for cross-coupling reactions with breadth of scope similar to that of palladium, and reported applications in carbon-carbon, carbon-heteroatom, and even carbon-hydrogen and carbon-metal bond formation. However, the use of copper in coupling protocols has mainly been limited to small-scale studies in research labs and has not commonly been employed on larger-scale batch preparations. Underpinning this is a current lack of understanding of the mechanism of these reactions, and questions on the role of the ligand and base in both the rate determining step and catalyst deactivation pathways. This project will seek to address these shortfalls with the following main objectives:Build a deeper mechanistic understanding of copper catalysed amination reactions using a wide range of experimental, spectroscopic, and kinetic methodsDetermination of the roles and interdependencies of the ancillary ligand, base, and solvent in both the catalytic cycle and off-cycle events including catalyst deactivationUtilise mechanistic and rate information to develop new and improved ancillary ligand systems for copper-catalysed aryl-chloride activation, initially focussing upon oxalic diamide ligandsTransition learning to systems of high interest including the application of amine, amide, sulphonamide, and nucleophilic carbon substrates and progression towards scaled-up processes