C(sp3)–H Amination Catalyzed by Ir(Me)-Porphyrin: A Computational Study

In recent years, a series of elegant studies demonstrated the potential of engineered cytochrome enzymes to catalyze C(sp3)–H amination efficiently. This calls for an extensive understanding of the underlying mechanisms to assist rational design and optimization of engineered variants. This work reported a computational mechanistic study of C(sp3)–H amination catalyzed by iridium porphyrin (IrIII-Por). Two Ir-Por model systems were investigated, differing from each other in their proximal ligand (methide or methylthiolate). The results showed that the C(sp3)–H amination encompasses two stages: the azido dissociation and the nitrene insertion (combination of two elementary steps concertedly or in a stepwise manner: hydrogen migration and C–N coupling). A typical feature of this reaction is the formation of a nitrenoid intermediate upon the azido dissociation, and the proximal ligand may influence the azido dissociation and modulate the electronic structure of the nascent nitrenoid intermediate. Site selectivity relied on the hydrogen migration step. This work may enrich our understanding of the mechanisms of enzymatic reactions in the cytochrome family and benefit protein engineering for catalytic systems.