Cluster model study of the mechanism and origins of enantio- and chemoselectivity in non-heme iron enzyme-catalyzed C–H azidation

The mechanisms and enantio- and chemoselectivities of non-heme iron enzyme-catalyzed C-H azidation were investigated using density functional theory (DFT) calculations. A detailed active site cluster model comprising 337 atoms was constructed, incorporating essential features of the first- and second-coordination spheres and substrate-binding pockets. The catalytic cycle involves N-F bond activation, hydrogen atom transfer (HAT), and radical rebound steps. DFT calculations suggest that the observed enantioselectivity arises from steric effects between the substrate and key active-site residues. Additionally, in the non-heme Fe(N₃)F complex, the Fe-N₃ bond, which has a lower diabatic bond dissociation energy, preferentially rebounds to form the azidation product.