Frontier Molecular Orbital Contributions to Chlorination versus Hydroxylation Selectivity in the Non-Heme Iron Halogenase SyrB2

The
ability of an FeIVO intermediate in SyrB2
to perform chlorination versus hydroxylation was computationally evaluated
for different substrates that had been studied experimentally. The
π-trajectory for H atom abstraction (FeIVO
oriented perpendicular to the C–H bond of substrate) was found
to lead to the S = 2 five-coordinate HO–FeIII–Cl complex with the C• of the
substrate, π-oriented relative to both the Cl– and the OH– ligands. From this ferric intermediate,
hydroxylation is thermodynamically favored, but chlorination is intrinsically
more reactive due to the energy splitting between two key redox-active
dπ* frontier molecular orbitals (FMOs). The splitting is determined
by the differential ligand field effect of Cl– versus
OH– on the Fe center. This makes chlorination effectively
competitive with hydroxylation. Chlorination versus hydroxylation
selectivity is then determined by the orientation of the substrate
with respect to the HO–Fe–Cl plane that controls either
the Cl– or the OH– to rebound
depending on the relative π-overlap with the substrate C radical.
The differential contribution of the two FMOs to chlorination versus
hydroxylation selectivity in SyrB2 is related to a reaction mechanism
that involves two asynchronous transfers: electron transfer from the
substrate radical to the iron center followed by late ligand (Cl– or OH–) transfer to the substrate.