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

Abstract

Mononuclear iron(II) alpha-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 alpha-keto carboxylate complex, [Fe(II)(Tp(Ph2))(O(2)CC(O)CH(3))], and the carboxylate complexes [Fe(II)(Tp(Ph2))(OBz)] and [Fe(II)(Tp(Ph2))(OAc)(3,5-Ph(2)pzH)] were determined by single-crystal X-ray diffraction, all of which have five-coordinate iron centers. Both the alpha-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-Ph(2)pzH)] was established by X-ray diffraction. The reaction of the alpha-keto carboxylate model compounds with oxygen to produce the phenolate product occurs with concomitant oxidative decarboxylation of the alpha-keto acid. Isotope labeling studies show that (18)O(2) ends up in the Tp(Ph2) phenolate oxygen and the carboxylate derived from the alpha-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 DeltaH++ = 25 +/- 2 kJ mol(-1) and DeltaS++ = -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 rho 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 alpha-keto functionality, and oxidative decarboxylation of the adduct to afford the oxidizing species that attacks the Tp(Ph2) phenyl ring. Interestingly, the alpha-keto carboxylate complexes react 2 orders of magnitude faster than the carboxylate complexes, thus emphasizing the key role that the alpha-keto functionality plays in oxygen activation by alpha-keto acid-dependent iron enzymes.

Intermediates in the oxygenation of a nonheme diiron(II) complex, including the first evidence for a bound superoxo species

“…Such species have been found in the reactions of O 2 with heme proteins and models (6,7) as well as with one copper enzyme (8) and several synthetic copper and nickel complexes (9)(10)(11)(12)(13)(14)(15)(16). Such species have also been invoked in the mechanisms for nonheme iron enzymes, but only indirect evidence has been obtained to date (39)(40)(41). The best evidence derives from the observed formation of Fe-NO adducts analogous to the related iron-superoxo complexes in the enzyme mechanisms (42)(43)(44)(45)(46)(47).…”

Incorporation of oxygen into the succinate co‐product of iron(II) and 2‐oxoglutarate dependent oxygenases from bacteria, plants and humans

“…1) [6,7]. The incorporation of oxygen from dioxygen into the alcohol product during hydroxylation reactions by this class of enzymes is well documented [8]. Further, incubations of prokaryotic 2OG oxygenases under an 18 O 2 atmosphere have demonstrated that, during hydroxylation reactions, a less than stoichiometric incorporation of oxygen into the hydroxyl group of the product can occur in some cases (e.g., hydroxylation of some substrates catalysed by clavaminic acid synthase and deacetoxy/deacetyl cephalosporin C synthase) [9,10].…”

Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase

“…This mechanism has served well as a general working hypothesis for the mechanisms of all of the ␣KG-dependent dioxygenases: extensive studies on several family members, and inorganic models thereof have failed to reveal significant inconsistencies (1)(2)(3)(26)(27)(28)(29)(30)(31). However, the first direct evidence for any of the several oxidized iron intermediates invoked in this mechanism came relatively recently, with the detection by stopped-flow (SF) absorption and freeze-quench (FQ) Mössbauer spectroscopies of two transient states in the catalytic cycle of taurine:␣KG dioxygenase (TauD) (see Scheme 1) (32).…”