Pathways for Arene Oxidation in Non-Heme Diiron Enzymes: Lessons from Computational Studies on Benzoyl Coenzyme A Epoxidase

Oxygenation
of aromatic rings using O2 is catalyzed
by several non-heme carboxylate-bridged diiron enzymes. In order to
provide a general mechanistic description for these reactions, computational
studies were carried out at the ONIOM­(B3LYP/BP86/Amber) level on the
non-heme diiron enzyme benzoyl coenzyme A epoxidase, BoxB. The calculations
revealed four possible pathways for attacking the aromatic ring: (a)
electrophilic (2e–) attack by a bis­(μ-oxo)-diiron­(IV)
species (Q pathway); (b) electrophilic (2e–) attack via the σ* orbital of a μ-η2:η2-peroxo-diiron­(III) intermediate (Pσ* pathway); (c) radical (1e–) attack via
the π*-orbital of a superoxo-diiron­(II,III) species (Pπ* pathway); (d) radical (1e–) attack of
a partially quenched bis­(μ-oxo)-diiron­(IV) intermediate (Q′ pathway). The results allowed earlier work of de
Visser on olefin epoxidation by diiron complexes and QM-cluster studies
of Liao and Siegbahn on BoxB to be put into a broader perspective.
Parallels with epoxidation using organic peracids were also examined.
Specifically for the BoxB enzyme, the Q pathway was found
to be the most preferred, but the corresponding bis­(μ-oxo)-diiron­(IV)
species is significantly destabilized and not expected to be directly
observable. Epoxidation via the Pσ* pathway represents
an energetically somewhat higher lying alternative; possible strategies
for experimental discrimination are discussed. The selectivity toward
epoxidation is shown to stem from a combination of inherent electronic
properties of the thioacyl substituent and enzymatic constraints.
Possible implications of the results for toluene monooxygenases are
considered as well.