Biocatalytic Intramolecular C−H aminations via Engineered Heme Proteins: Full Reaction Pathways and Axial Ligand Effects

Engineered heme protein biocatalysts provide an efficient and sustainable approach to develop amine‐containing compounds through C−H amination. A quantum chemical study to reveal the complete heme catalyzed intramolecular C−H amination pathway and protein axial ligand effect was reported, using reactions of an experimentally used arylsulfonylazide with hemes containing L=none, SH(−), MeO(−), and MeOH to simulate no axial ligand, negatively charged Cys and Ser ligands, and a neutral ligand for comparison. Nitrene formation was found as the overall rate‐determining step (RDS) and the catalyst with Ser ligand has the best reactivity, consistent with experimental reports. Both RDS and non‐RDS (nitrene transfer) transition states follow the barrier trend of MeO(−)<SH(−)<MeOH<None due to the charge donation capability of the axial ligand to influence the key charge transfer process as the electronic driving forces. Results also provide new ideas for future biocatalyst design with enhanced reactivities.