Heme-based catalysis for sustainable carbene transfer chemistry: computational mechanistic investigations

Recently, engineered heme proteins have been developed as excellent catalysts for carbene transfer reactions to facilitate sustainable chemical synthesis. Computational mechanistic investigations provide significant insights into the understanding of various aspects of these reactions. Both density functional theory (DFT) calculations with accurate predictions of many experimental spectroscopic properties and high-level computational studies were employed to elucidate the electronic structures of key heme carbene reaction intermediates. Effects of heme catalysis, coordination modes, and structural components on heme carbene formation via diazo and non-diazo precursors were revealed. Besides the basic mechanisms discovered for multiple heme carbene transfer reactions such as cyclopropanations and X-H insertions (X = Si, C, N) with many experimental features reproduced, details of how the carbene substituent, axial ligand, porphyrin substituent, and substrate substituent influence the reactivity were also examined to help future reaction design. In addition, the mechanistic origins of stereoselectivities and chemoselectivities for some important experimental heme carbene transfer reactions were disclosed to further advance this field. The interesting mechanistic results summarized in this review will facilitate the application of new-to-nature heme based biocatalysis.