Achieving mono-selective palladium(II)-catalysed C–H activation of arenes with protein ligands

Achieving mono-selectivity in C–H activation reactions is a considerable challenge when multiple identical C–H bonds coexist. Despite recent rapid advances in site-selective and enantioselective C–H activation, a large number of C–H activation reactions still suffer from poor mono-selectivity. Here we report the use of commercial enzymes as ligands for palladium catalysts, enabling enhanced reactivity and exceptionally high mono-selectivity (up to 99%) in both ortho- and meta-C–H activation of arenes, which originally used bifunctional mono-N-protected amino acid ligands but with poor mono-selectivity. Notably, the Pd–enzyme complex was identified as the active catalyst species. Mechanistic investigations and structural analyses of the enzymes suggest that the enzyme primary structure, the sequence length and the percentage of amino acids with hydrophobic side chains are critical for achieving mono-selectivity. By leveraging these findings, we further developed a glycine-containing oligopeptide capable of achieving similarly high mono-selectivity. Molecular organometallic catalysts typically struggle to activate only one of two identical C–H bonds in arenes for mono-selective C–H activation. Now mono-selectivity has been achieved for Pd(II)-catalysed ortho- or meta-C–H activations using commercial proteins or designed peptides as ligands.