Recent efforts to design synthetic iron catalysts for the selective and efficient oxidation of C-H and C═C bonds have been inspired by a versatile family of nonheme iron oxygenases. These bioinspired nonheme (N4)Fe(II) catalysts use H2O2 to oxidize substrates with high regio- and stereoselectivity, unlike in Fenton chemistry where highly reactive but unselective hydroxyl radicals are produced. In this Account, we highlight our efforts to shed light on the nature of metastable peroxo intermediates, which we have trapped at -40 °C, in the reactions of the iron catalyst with H2O2 under various conditions and the high-valent species derived therefrom. Under the reaction conditions that originally led to the discovery of this family of catalysts, we have characterized spectroscopically an Fe(III)-OOH intermediate (EPR g(max) = 2.19) that leads to the hydroxylation of substrate C-H bonds or the epoxidation and cis-dihydroxylation of C═C bonds. Surprisingly, these organic products show incorporation of (18)O from H2(18)O, thereby excluding the possibility of a direct attack of the Fe(III)-OOH intermediate on the substrate. Instead, a water-assisted mechanism is implicated in which water binding to the iron(III) center at a site adjacent to the hydroperoxo ligand promotes heterolytic cleavage of the O-O bond to generate an Fe(V)(O)(OH) oxidant. This mechanism is supported by recent kinetic studies showing that the Fe(III)-OOH intermediate undergoes exponential decay at a rate enhanced by the addition of water and retarded by replacement of H2O with D2O, as well as mass spectral evidence for the Fe(V)(O)(OH) species obtained by the Costas group. The nature of the peroxo intermediate changes significantly when the reactions are carried out in the presence of carboxylic acids. Under these conditions, spectroscopic studies support the formation of a (κ(2)-acylperoxo)iron(III) species (EPR g(max) = 2.58) that decays at -40 °C in the absence of substrate to form an oxoiron(IV) byproduct, along with a carboxyl radical that readily loses CO2. The alkyl radical thus formed either reacts with O2 to form benzaldehyde (as in the case of PhCH2COOH) or rebounds with the incipient Fe(IV)(O) moiety to form phenol (as in the case of C6F5COOH). Substrate addition leads to its 2-e(-) oxidation and inhibits these side reactions. The emerging mechanistic picture, supported by DFT calculations of Wang and Shaik, describes a rather flat reaction landscape in which the (κ(2)-acylperoxo)iron(III) intermediate undergoes O-O bond homolysis reversibly to form an Fe(IV)(O)((•)OC(O)R) species that decays to Fe(IV)(O) and RCO2(•) or isomerizes to its Fe(V)(O)(O2CR) electromer, which effects substrate oxidation. Another short-lived S = 1/2 species just discovered by Talsi that has much less g-anisotropy (EPR g(max) = 2.07) may represent either of these postulated high-valent intermediates.

High-spin oxoiron(IV) species are often implicated in the mechanisms of nonheme iron oxygenases, their C-H bond cleaving properties being attributed to the quintet spin state. However, the few available synthetic S = 2 Fe(IV)═O complexes supported by polydentate ligands do not cleave strong C-H bonds. Herein we report the characterization of a highly reactive S = 2 complex, [Fe(IV)(O)(TQA)(NCMe)](2+) (2) (TQA = tris(2-quinolylmethyl)amine), which oxidizes both C-H and C═C bonds at -40 °C. The oxidation of cyclohexane by 2 occurs at a rate comparable to that of the oxidation of taurine by the TauD-J enzyme intermediate after adjustment for the different temperatures of measurement. Moreover, compared with other S = 2 complexes characterized to date, the spectroscopic properties of 2 most closely resemble those of TauD-J. Together these features make 2 the best electronic and functional model for TauD-J to date.

An unprecedentedly reactive iron species (2) has been generated by reaction of excess peracetic acid with a mononuclear iron complex [Fe(II)(CF3SO3)2(PyNMe3)] (1) at cryogenic temperatures, and characterized spectroscopically. Compound 2 is kinetically competent for breaking strong C-H bonds of alkanes (BDE ≈ 100 kcal·mol(-1)) through a hydrogen-atom transfer mechanism, and the transformations proceed with stereoretention and regioselectively, responding to bond strength, as well as to steric and polar effects. Bimolecular reaction rates are at least an order of magnitude faster than those of the most reactive synthetic high-valent nonheme oxoiron species described to date. EPR studies in tandem with kinetic analysis show that the 490 nm chromophore of 2 is associated with two S = 1/2 species in rapid equilibrium. The minor component 2a (∼5% iron) has g-values at 2.20, 2.19, and 1.99 characteristic of a low-spin iron(III) center, and it is assigned as [Fe(III)(OOAc)(PyNMe3)](2+), also by comparison with the EPR parameters of the structurally characterized hydroxamate analogue [Fe(III)(tBuCON(H)O)(PyNMe3)](2+) (4). The major component 2b (∼40% iron, g-values = 2.07, 2.01, 1.95) has unusual EPR parameters, and it is proposed to be [Fe(V)(O)(OAc)(PyNMe3)](2+), where the O-O bond in 2a has been broken. Consistent with this assignment, 2b undergoes exchange of its acetate ligand with CD3CO2D and very rapidly reacts with olefins to produce the corresponding cis-1,2-hydroxoacetate product. Therefore, this work constitutes the first example where a synthetic nonheme iron species responsible for stereospecific and site selective C-H hydroxylation is spectroscopically trapped, and its catalytic reactivity against C-H bonds can be directly interrogated by kinetic methods. The accumulated evidence indicates that 2 consists mainly of an extraordinarily reactive [Fe(V)(O)(OAc)(PyNMe3)](2+) (2b) species capable of hydroxylating unactivated alkyl C-H bonds with stereoretention in a rapid and site-selective manner, and that exists in fast equilibrium with its [Fe(III)(OOAc)(PyNMe3)](2+) precursor.

Synthetically useful hydrocarbon oxidations are catalysed by bio-inspired non-heme iron complexes using hydrogen peroxide as oxidant, and carboxylic acid addition enhances their selectivity and catalytic efficiency. Talsi has identified a low-intensity g ¼ 2.7 electron paramagnetic resonance signal in such catalytic systems and attributed it to an oxoiron(V)-carboxylate oxidant. Herein we report the use of Fe II (TPA*) (TPA* ¼ tris (3,5-dimethyl-4-methoxypyridyl-2-methyl)amine) to generate this intermediate in 50% yield, and have characterized it by ultraviolet-visible, resonance Raman, Mössbauer and electrospray ionization mass spectrometric methods as a low-spin acylperoxoiron(III) species. Kinetic studies show that this intermediate is not itself the oxidant but decays via a unimolecular rate-determining step to unmask a powerful oxidant. The latter is shown by density functional theory calculations to be an oxoiron(V) species that oxidises substrate without a barrier. This study provides a mechanistic scenario for understanding catalyst reactivity and selectivity as well as a basis for improving catalyst design.

Hydrocarbon oxidations by bio-inspired nonheme iron catalysts and H2O2 have been proposed to involve an Fe(III)-OOH intermediate that decays via a water-assisted mechanism to form an Fe(V)(O)(OH) oxidant. Herein we report kinetic evidence for this pathway in the oxidation of 1-octene catalyzed by [Fe(II)(TPA)(NCCH3)](2+) (1, TPA = tris(2-pyridylmethyl)amine). The (TPA)Fe(III)(OOH) intermediate 2 can be observed at -40 °C and is found to undergo first-order decay, which is accelerated by water. Interestingly, the decay rate of 2 is comparable to that of product formation, indicating that the decay of 2 results in olefin oxidation. Furthermore, the Eyring activation parameters for the decay of 2 and product formation are identical, and both processes are associated with an H2O/D2O KIE of 2.5. Taken together with previous (18)O-labeling data, these results point to a water-assisted heterolytic O-O bond cleavage of 2 as the rate-limiting step in olefin oxidation.

The reaction of [(PyNMe)Fe(CFSO)], 1, with excess peracetic acid at -40 °C generates a highly reactive intermediate, 2b(PAA), that has the fastest rate to date for oxidizing cyclohexane by a nonheme iron species. It exhibits an intense 490 nm chromophore associated with an S = 1/2 EPR signal having g-values at 2.07, 2.01, and 1.94. This species was shown to be in a fast equilibrium with a second S = 1/2 species, 2a(PAA), assigned to a low-spin acylperoxoiron(III) center. Unfortunately, contaminants accompanying the 2(PAA) samples prevented determination of the iron oxidation state by Mössbauer spectroscopy. Use of MeO-PyNMe (an electron-enriched version of PyNMe) and cyclohexyl peroxycarboxylic acid as oxidant affords intermediate 3b(CPCA) with a Mössbauer isomer shift δ = -0.08 mm/s that indicates an iron(V) oxidation state. Analysis of the Mössbauer and EPR spectra, combined with DFT studies, demonstrates that the electronic ground state of 3b(CPCA) is best described as a quantum mechanical mixture of [(MeO-PyNMe)Fe(O)(OC(O)R)] (∼75%) with some Fe(O)(OC(O)R) and Fe(OOC(O)R) character. DFT studies of 3b(CPCA) reveal that the unbound oxygen of the carboxylate ligand, O2, is only 2.04 Å away from the oxo group, O1, corresponding to a Wiberg bond order for the O1-O2 bond of 0.35. This unusual geometry facilitates reversible O1-O2 bond formation and cleavage and accounts for the high reactivity of the intermediate when compared to the rates of hydrogen atom transfer and oxygen atom transfer reactions of Fe(OC(O)R) ferric acyl peroxides and Fe(O) complexes. The interaction of O2 with O1 leads to a significant downshift of the Fe-O1 Raman frequency (815 cm) relative to the 903 cm value predicted for the hypothetical [(MeO-PyNMe)Fe(O)(NCMe)] complex.

Monohydrocarbyl palladium(IV) complexes bearing OH, OH(2), Br, and Cl ligands at the metal and supported by facially chelating 1-hydroxy-1,1-bis(2-pyridyl)methoxide were readily prepared in water at 0 °C. These complexes reductively eliminate Ar-X (X = OH, Br, Cl) in water at room temperature in high yield, and the corresponding first-order rate constants k(OH), k(Cl), and k(Br) are on the same order of magnitude.

Inspired by the remarkable chemistry of the family of Rieske oxygenase enzymes, nonheme iron complexes of tetradentate N4 ligands have been developed to catalyze hydrocarbon oxidation reactions using H2O2 in the presence of added carboxylic acids. The observation that the stereo- and enantioselectivity of the oxidation products can be modulated by the electronic and steric properties of the acid implicates an oxidizing species that incorporates the carboxylate moiety. Frozen solutions of these catalytic mixtures generally afford two S = ½ intermediates, a highly anisotropic g2.7 subset (gmax = 2.58 to 2.78 and Δg = 0.85 – 1.2) that we assign to an FeIII–OOAc species and the less anisotropic g2.07 subset (g = 2.07, 2.01, and 1.96 and Δg ~ 0.11) we associate with an FeV(O)(OAc) species. Kinetic studies on the reactions of iron complexes supported by the TPA (tris(pyridyl-2-methyl)amine) ligand family with H2O2/AcOH or AcOOH at −40 °C reveal the formation of a visible chromophore at 460 nm, which persists in a steady state phase and then decays exponentially upon depletion of the peroxo oxidant with a rate constant that is substrate independent. Remarkably, the duration of this steady state phase can be modulated by the nature of the substrate and its concentration, which is a rarely observed phenomenon. A numerical simulation of this behavior as a function of substrate type and concentration affords a kinetic model in which the two intermediates exist in a dynamic equilibrium that is modulated by the electronic properties of the supporting ligands. This notion is supported by EPR studies of the reaction mixtures. Importantly, these studies unambiguously show that the g2.07 species, and not the g2.7 species, is responsible for substrate oxidation in the (L)FeII/H2O2/AcOH catalytic system. Instead the g2.7 species appears to be off-pathway and serves as a reservoir for the g2.07 species. These findings will be helpful not only for the design of regio- and stereo-specific nonheme iron oxidation catalysts but also for providing insight into the mechanisms of the remarkably versatile oxidants formed by nature’s most potent oxygenases.