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 vanadium mimic electronic structure is comparable to catalytic iron intermediates. Our calculations reveal crucial structural and energetic differences between vanadyl and ferryl intermediates primarily due to differences in ground spin states of low spin and high spin, respectively. 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. Electronic structure analyses to quantify differences in binding strength of Fe and V intermediates to –ketoglutarate and succinate cosubstrates reveal that both cosubstrates bind more strongly to V than Fe. Our work highlights the limits of using low- or intermediate-spin V-based intermediates as mimics in studies of fleeting high-spin Fe intermediates in non-heme iron enzymes.