Axial Ligand Effect On The Rate Constant of Aromatic Hydroxylation By Iron(IV)–Oxo Complexes Mimicking Cytochrome P450 Enzymes

The cytochromes P450 are important iron-heme based monoxygenases that catalyze a range of different oxygen atom transfer reactions in nature. One of the key bioprocesses catalyzed by these enzymes is the aromatic hydroxylation of unactivated arenes. To gain insight into axial ligand effects and, in particular, how it affects aromatic hydroxylation processes by P450 model complexes, we studied the effects of the axial ligand on spectroscopic parameters (trans-influence) as well as on aromatic hydroxylation kinetics (trans-effect) using a range of [Fe<sup>IV</sup>(O)(Por<sup>+•</sup>)X] oxidants with X = SH<sup>–</sup>, Cl<sup>–</sup>, F<sup>–</sup>, OH<sup>–</sup>, acetonitrile, GlyGlyCys<sup>–</sup>, CH<sub>3</sub>COO<sup>–</sup>, and CF<sub>3</sub>COO<sup>–</sup>. These systems give red-shifted Fe–O vibrations that are dependent on the strength of the axial ligand. Despite structural changes, however, the electron affinities of these oxidants are very close in energy, but sharp differences in p<i>K</i><sub>a</sub> values are found. The aromatic hydroxylation of the para-position of ethylbenzene was tested with these oxidants, and they all show two-state-reactivity patterns although the initial low-spin C–O bond formation barrier is rate determining. We show, for the first time, that the rate determining barrier for aromatic hydroxylation is proportional to the strength of the O–H bond in the corresponding iron(IV)–hydroxo complex, i.e., BDE<sub>OH</sub>, hence this thermochemical property of the oxidant drives the reaction and represents the axial ligand effect. We have rationalized our observed barrier heights for these axially ligated systems using thermochemical cycles and a valence bond curve crossing diagram to explain the origins of the rate constants.