The proximal heme axial ligand plays an important role in tuning the reactivity of oxoiron(IV) porphyrin π-cation radical species (compound I) in enzymatic and catalytic oxygenation reactions. To reveal the essence of the axial ligand effect on the reactivity, we investigated it from a thermodynamic viewpoint. Compound I model complexes, (TMP(+•))Fe(IV)O(L) (where TMP is 5,10,15,20-tetramesitylporphyrin and TMP(+•) is its π-cation radical), can be provided with altered reactivity by changing the identity of the axial ligand, but the reactivity is not correlated with spectroscopic data (ν(Fe═O), redox potential, and so on) of (TMP(+•))Fe(IV)O(L). Surprisingly, a clear correlation was found between the reactivity of (TMP(+•))Fe(IV)O(L) and the Fe(II)/Fe(III) redox potential of (TMP)Fe(III)L, the final reaction product. This suggests that the thermodynamic stability of (TMP)Fe(III)L is involved in the mechanism of the axial ligand effect. Axial ligand-exchange experiments and theoretical calculations demonstrate a linear free-energy relationship, in which the axial ligand modulates the reaction free energy by changing the thermodynamic stability of (TMP)Fe(III)(L) to a greater extent than (TMP(+•))Fe(IV)O(L). The linear free energy relationship could be found for a wide range of anionic axial ligands and for various types of reactions, such as epoxidation, demethylation, and hydrogen abstraction reactions. The essence of the axial ligand effect is neither the electron donor ability of the axial ligand nor the electron affinity of compound I, but the binding ability of the axial ligand (the stabilization by the axial ligand). An axial ligand that binds more strongly makes (TMP)Fe(III)(L) more stable and (TMP(+•))Fe(IV)O(L) more reactive. All results indicate that the axial ligand controls the reactivity of compound I (the stability of the transition state) by the stability of the ground state of the final reaction product and not by compound I itself.

To study the effect of axial ligands on the electronic structure and reactivity of compound I of peroxidases and catalases, oxoiron(IV) porphyrin pi-cation radical complexes with imidazole, 2-methylimidazole, 4(5)-methylimidazole, and 3-fluoro-4-nitrophenolate as the axial ligands were prepared by ozone oxidation of iron(III) complexes of 5,10,15,20-tetramesitylporphyrin (TMP) and 2,7,12,17-tetramethyl-3,8,13,18-tetramesitylporphyrin (TMTMP). These complexes were fully characterized by absorption, (1)H, (2)H, and (19)F NMR, electron paramagnetic resonance (EPR), and electrospray ionization mass spectrometry (ESI-MS) spectroscopy. The characteristic absorption peak of compound I at approximately 650 nm was found to be a good marker for estimation of the electron donor effect from the axial ligand. The axial ligand effect did not change the porphyrin pi-cation radical state, the a(2u) state of the TMP complexes, or the a(1u) radical state of both the TMTMP complexes and compound I. The ferryl iron and porphyrin pi-cation radical spins were effectively transferred into the axial ligands for the a(2u) complexes but not for the a(1u) complexes. Most importantly, the reactivity of the oxoiron(IV) porphyrin pi-cation radical complex was drastically increased by the imidazole and phenolate axial ligands. The reaction rate for cyclooctene epoxidation was increased 100- to 400-fold with axial coordination of imidazoles and phenolate. A similar increase was also observed for the oxidation of 1,4-cyclohexadiene,N,N-dimethyl-p-nitroaniline and hydrogen peroxide. These results suggest extreme enhancement of the reactivity of compound I by the axial ligand in heme enzymes. The functional role of axial ligands on the compound I in heme enzymes is discussed.