Trapping a Highly Reactive Nonheme Iron Intermediate That Oxygenates Strong CH Bonds with Stereoretention

An unprecedentedly reactive iron species (2) has been generated by reaction of excess peracetic acid with a mononuclear iron complex [FeII(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 [FeIII(OOAc)(PyNMe3)]2+, also by comparison with the EPR parameters of the structurally characterized hydroxamate analogue [FeIII(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 [FeV(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 [FeV(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 [FeIII(OOAc)(PyNMe3)]2+ precursor

Acid-Triggered O−O Bond Heterolysis of a Nonheme FeIII (OOH) Species for the Stereospecific Hydroxylation of Strong C−H Bonds

A novel hydroperoxoiron(III) species [FeIII(OOH)(MeCN)(PyNMe3)]2+ (3) has been generated by reaction of its ferrous precursor [FeII(CF3SO3)2(PyNMe3)] (1) with hydrogen peroxide at low temperatures. This species has been characterized by several spectroscopic techniques and cryospray mass spectrometry. Similar to most of the previously described low‐spin hydroperoxoiron(III) compounds, 3 behaves as a sluggish oxidant and it is not kinetically competent for breaking weak C−H bonds. However, triflic acid addition to 3 causes its transformation into a much more reactive compound towards organic substrates that is capable of oxidizing unactivated C−H bonds with high stereospecificity. Stopped‐flow kinetic analyses and theoretical studies provide a rationale for the observed chemistry, a triflic‐acid‐assisted heterolytic cleavage of the O−O bond to form a putative strongly oxidizing oxoiron(V) species. This mechanism is reminiscent to that observed in heme systems, where protonation of the hydroperoxo intermediate leads to the formation of the high‐valent [(Porph.)FeIV(O)] (Compound I)

Bioinspired Nonheme Iron Catalysts for C–H and CC Bond Oxidation: Insights into the Nature of the Metal-Based Oxidants

ConspectusRecent 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 <i>g</i>_max = 2.19) that leads to the hydroxylation of substrate C–H bonds or the epoxidation and <i>cis</i>-dihydroxylation of CC bonds. Surprisingly, these organic products show incorporation of ¹⁸O from H₂¹⁸O, 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 (κ²-acylperoxo)­iron­(III) species (EPR <i>g</i>_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 (κ²-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 <i>S</i> = 1/2 species just discovered by Talsi that has much less <i>g</i>-anisotropy (EPR <i>g</i>_max = 2.07) may represent either of these postulated high-valent intermediates

Palladium(IV) Monohydrocarbyls: Mechanistic Study of the Ligand-Enabled Oxidation of Palladium(II) Complexes with H₂O₂ in Water

A detailed mechanistic study of the di­(2-pyridyl)­ketone (dpk)-enabled oxidation with H₂O₂ in water of a series of monohydrocarbylpalladium­(II) complexes derived from cyclopalladated 2-(3-R-benzoyl)­pyridines (R = H, Me) and 2-(<i>p</i>-R′-phenyl)­pyridines (R′ = H, Me, MeO, F) to produce corresponding Pd^IV monohydrocarbyl hydroxo complexes has been carried out, and the Pd^IV hydrocarbyls have been characterized in detail. The study involves kinetics, isotopic labeling experiments, and the DFT calculations. A reaction mechanism has been proposed for the oxidation of dpk-supported Pd^II complexes in water that includes elimination of water from the hydrated dpk ligand of the monohydrocarbylpalladium­(II) species as the rate-limiting step. Subsequent reversible addition of H₂O₂ across the resulting ketone CO bond leads to the formation of two diastereomeric hydroperoxoketals, one of which can rapidly produce a Pd^IV monohydrocarbyl and the second is unreactive in this type of transformation. All the monohydrocarbyl Pd^IV complexes undergo clean C–O reductive elimination to form the corresponding phenols or derived palladium­(II) phenoxides. The kinetics of the C–O reductive elimination of the Pd­(IV) monohydrocarbyls derived from cyclopalladated 2-(<i>p</i>-R-phenyl)­pyridines was studied at 22 °C; the corresponding first-order rate constants were found to be only weakly dependent on the nature of the substituent R (H, Me, OMe, F). To account for these observations, a detailed DFT analysis of plausible C–O reductive elimination mechanisms in water was carried out. A direct elimination mechanism of six-coordinate complexes resulting from the oxidation above was proposed to be operational that involves an “early” C–O coupling transition state whose structure varies insignificantly among the substrates studied

Palladium(IV) Monohydrocarbyls: Mechanistic Study of the Ligand-Enabled Oxidation of Palladium(II) Complexes with H₂O₂ in Water

A detailed mechanistic study of the di­(2-pyridyl)­ketone (dpk)-enabled oxidation with H₂O₂ in water of a series of monohydrocarbylpalladium­(II) complexes derived from cyclopalladated 2-(3-R-benzoyl)­pyridines (R = H, Me) and 2-(<i>p</i>-R′-phenyl)­pyridines (R′ = H, Me, MeO, F) to produce corresponding Pd^IV monohydrocarbyl hydroxo complexes has been carried out, and the Pd^IV hydrocarbyls have been characterized in detail. The study involves kinetics, isotopic labeling experiments, and the DFT calculations. A reaction mechanism has been proposed for the oxidation of dpk-supported Pd^II complexes in water that includes elimination of water from the hydrated dpk ligand of the monohydrocarbylpalladium­(II) species as the rate-limiting step. Subsequent reversible addition of H₂O₂ across the resulting ketone CO bond leads to the formation of two diastereomeric hydroperoxoketals, one of which can rapidly produce a Pd^IV monohydrocarbyl and the second is unreactive in this type of transformation. All the monohydrocarbyl Pd^IV complexes undergo clean C–O reductive elimination to form the corresponding phenols or derived palladium­(II) phenoxides. The kinetics of the C–O reductive elimination of the Pd­(IV) monohydrocarbyls derived from cyclopalladated 2-(<i>p</i>-R-phenyl)­pyridines was studied at 22 °C; the corresponding first-order rate constants were found to be only weakly dependent on the nature of the substituent R (H, Me, OMe, F). To account for these observations, a detailed DFT analysis of plausible C–O reductive elimination mechanisms in water was carried out. A direct elimination mechanism of six-coordinate complexes resulting from the oxidation above was proposed to be operational that involves an “early” C–O coupling transition state whose structure varies insignificantly among the substrates studied

Rate-Determining Water-Assisted O–O Bond Cleavage of an Fe^III‑OOH Intermediate in a Bio-inspired Nonheme Iron-Catalyzed Oxidation

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⁺ (<b>1</b>, TPA = tris­(2-pyridylmethyl)­amine). The (TPA)­Fe^III(OOH) intermediate <b>2</b> can be observed at −40 °C and is found to undergo first-order decay, which is accelerated by water. Interestingly, the decay rate of <b>2</b> is comparable to that of product formation, indicating that the decay of <b>2</b> results in olefin oxidation. Furthermore, the Eyring activation parameters for the decay of <b>2</b> and product formation are identical, and both processes are associated with an H₂O/D₂O KIE of 2.5. Taken together with previous ¹⁸O-labeling data, these results point to a water-assisted heterolytic O–O bond cleavage of <b>2</b> as the rate-limiting step in olefin oxidation

Identification of a low-spin acylperoxoiron(III) intermediate in bio-inspired non-heme iron-catalysed oxidations

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 = 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(star)) (TPA(star) = 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, Mossbauer 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

C–H Bond Cleavage by Bioinspired Nonheme Oxoiron(IV) Complexes, Including Hydroxylation of <i>n</i>‑Butane

The development of efficient and selective hydrocarbon oxidation processes with low environmental impact remains a major challenge of the 21st century because of the strong and apolar nature of the C–H bond. Naturally occurring iron-containing metalloenzymes can, however, selectively functionalize strong C–H bonds on substrates under mild and environmentally benign conditions. The key oxidant in a number of these transformations is postulated to possess an <i>S</i> = 2 Fe^IVO unit in a nonheme ligand environment. This oxidant has been trapped and spectroscopically characterized and its reactivity toward C–H bonds demonstrated for several nonheme iron enzyme classes. In order to obtain insight into the structure–activity relationships of these reactive intermediates, over 60 synthetic nonheme Fe^IV(O) complexes have been prepared in various laboratories and their reactivities investigated. This Forum Article summarizes the current status of efforts in the characterization of the C–H bond cleavage reactivity of synthetic Fe^IV(O) complexes and provides a snapshot of the current understanding of factors that control this reactivity, such as the properties of the supporting ligands and the spin state of the iron center. In addition, new results on the oxidation of strong C–H bonds such as those of cyclohexane and <i>n</i>-butane by a putative <i>S</i> = 2 synthetic Fe^IV(O) species that is generated in situ using dioxygen at ambient conditions are presented

Equilibrating (L)Fe^III–OOAc and (L)Fe^V(O) Species in Hydrocarbon Oxidations by Bio-Inspired Nonheme Iron Catalysts Using H₂O₂ and AcOH

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 exhibit EPR signals arising from two <i>S</i> = 1/2 intermediates, a highly anisotropic g2.7 subset (<i>g</i>_max = 2.58 to 2.78 and Δ<i>g</i> = 0.85–1.2) that we assign to an Fe^III–OOAc species and a less anisotropic g2.07 subset (<i>g</i> = 2.07, 2.01, and 1.96 and Δ<i>g</i> ≈ 0.11) we associate with an Fe^V(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 <i>S</i> = 1/2 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)­Fe^II/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 stereospecific nonheme iron oxidation catalysts but also for providing insight into the mechanisms of the remarkably versatile oxidants formed by nature’s most potent oxygenases

Modeling TauD-J: A High-Spin Nonheme Oxoiron(IV) Complex with High Reactivity toward C-H Bonds

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 degrees 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