Oxygen Activation by Nonheme Iron(II) Complexes: α-Keto Carboxylate versus Carboxylate

Mononuclear iron(II) α-keto carboxylate and carboxylate compounds of the sterically hindered tridentate face-capping ligand Tp^Ph2 (Tp^Ph2 = hydrotris(3,5-diphenylpyrazol-1-yl)borate) were prepared as models for the active sites of nonheme iron oxygenases. The structures of an aliphatic α-keto carboxylate complex, [Fe^II(Tp^Ph2)(O₂CC(O)CH₃)], and the carboxylate complexes [Fe^II(Tp^Ph2)(OBz)] and [Fe^II(Tp^Ph2)(OAc)(3,5-Ph₂pzH)] were determined by single-crystal X-ray diffraction, all of which have five-coordinate iron centers. Both the α-keto carboxylate and the carboxylate compounds react with dioxygen resulting in the hydroxylation of a single ortho phenyl position of the Tp^Ph2 ligand. The oxygenation products were characterized spectroscopically, and the structure of the octahedral iron(III) phenolate product [Fe^III(Tp^Ph2*)(OAc)(3,5-Ph₂pzH)] was established by X-ray diffraction. The reaction of the α-keto carboxylate model compounds with oxygen to produce the phenolate product occurs with concomitant oxidative decarboxylation of the α-keto acid. Isotope labeling studies show that ¹⁸O₂ ends up in the Tp^Ph2* phenolate oxygen and the carboxylate derived from the α-keto acid. The isotope incorporation mirrors the dioxygenase nature of the enzymatic systems. Parallel studies on the carboxylate complexes demonstrate that the oxygen in the hydroxylated ligand is also derived from molecular oxygen. The oxygenation of the benzoylformate complex is demonstrated to be first order in metal complex and dioxygen, with activation parameters ΔH^⧧ = 25 ± 2 kJ mol^-1 and ΔS^⧧ = −179 ± 6 J mol^-1 K^-1. The rate of appearance of the iron(III) phenolate product is sensitive to the nature of the substituent on the benzoylformate ligand, exhibiting a Hammett ρ value of +1.3 indicative of a nucleophilic mechanism. The proposed reaction mechanism involves dioxygen binding to produce an iron(III) superoxide species, nucleophilic attack of the superoxide at the α-keto functionality, and oxidative decarboxylation of the adduct to afford the oxidizing species that attacks the Tp^Ph2 phenyl ring. Interestingly, the α-keto carboxylate complexes react 2 orders of magnitude faster than the carboxylate complexes, thus emphasizing the key role that the α-keto functionality plays in oxygen activation by α-keto acid-dependent iron enzymes.