Are Vanadium Intermediates Suitable Mimics in Non-Heme Iron Enzymes? An Electronic Structure Analysis

Vanadyl intermediates are frequently
used as mimics for the fleeting
Fe­(IV)O intermediate in non-heme iron enzymes that catalyze
C–H activation. Using density functional theory and correlated
wavefunction theory, we investigate the degree to which the electronic
structure of vanadium mimics is comparable to that of catalytic iron
intermediates. Our calculations reveal crucial structural and energetic
differences between vanadyl and ferryl intermediates primarily due
to the former having a low-spin ground state and the latter having
a high-spin one. This difference in spin state leads to differences
in energetics for accessing isomers that confer activity in non-heme
hydroxylase and halogenase enzymes. While interconversion between
monodentate and bidentate succinate isomers of the key metal-oxo/hydroxo
intermediates is energetically favorable for Fe, it is strongly unfavorable
in V mimics. Additionally, isomerization of a terminal metal-oxo between
an axial and equatorial position is energetically unfavorable for
Fe but favorable for V. Analyses of binding strengths of Fe and V
intermediates to α-ketoglutarate and succinate co-substrates
reveal that both co-substrates bind more strongly to V than to Fe.
Given the increasingly frequent use by the biochemistry community
of V-based intermediates as mimics, our work highlights the limitations
of this approach in studies of non-heme iron enzymes.