We then compare Fe and V intermediates of non-heme hydroxylases to those of halogenases to understand if V-mimics are more faithful in one of the two enzyme classes. We observe considerable differences between Fe and V intermediates for both hydroxylases and halogenases, but the nature of these differences is distinct in the two enzyme classes. The range of isomer energetics spanned by the native ferryl species in halogenases 88 is much smaller relative to hydroxylases, i.e., 4 kcal/mol vs 12 kcal/mol, while the opposite trend is observed for isomer energetics of their vanadyl mimics, i.e., 18 kcal/mol vs 5 kcal/mol (Figure ). This shows that while all halogenase Fe(IV)=O isomers are generally accessible and interconvertible, some of the vanadyl isomers incorrectly imply highly unfavorable energetics for the most favored native iron isomers . On the contrary, vanadyl mimics of hydroxylases incorrectly suggest favorable energetics for one of the most energetically unfavorable ferryl isomers (Figure ). The nature of differences between Fe intermediates and their V mimics for hydroxylases vs halogenases are likely the result of size difference between the coordinating carboxylate residue in hydroxylases and the active site halide in halogenases. Furthermore, the carboxylate residue in hydroxylases can bind in a monodentate or bidentate fashion which could lead to additional steric or electrostatic interactions (i.e., with respect to other active-site ligands), which are not observed in halogenases with a monodentate halide ligand, as we will explore in more detail next. For both halogenases and hydroxylases, however, vanadyl mimics of monodentate succinate isomers exhibit strongly unfavorable energies, meaning that they may not be observed experimentally, although these isomers for the native Fe(IV)=O intermediate are energetically favorable. These observations show that the energetics of the native ferryl intermediates are not accurately captured by their vanadyl mimics, suggesting that vanadyl structures are not faithful mimics of ferryl intermediates in C-H activation.