Conversion of Aldehyde to Alkane by a Peroxoiron(III) Complex: A Functional Model for the Cyanobacterial Aldehyde-Deformylating Oxygenase

Cyanobacterial aldehyde-deformylating oxygenase (cADO) converts long-chain fatty aldehydes to alkanes via a proposed diferric-peroxo intermediate that carries out the oxidative deformylation of the substrate. Herein, we report that the synthetic iron­(III)-peroxo complex [Fe^III(η²-O₂)­(TMC)]⁺ (TMC = tetramethylcyclam) causes a similar transformation in the presence of a suitable H atom donor, thus serving as a functional model for cADO. Mechanistic studies suggest that the H atom donor can intercept the incipient alkyl radical formed in the oxidative deformylation step in competition with the oxygen rebound step typically used by most oxygenases for forming C–O bonds

Dioxygen Activation by Nonheme Diiron Enzymes: Diverse Dioxygen Adducts, High-Valent Intermediates, and Related Model Complexes

A growing subset of metalloenzymes activates dioxygen with nonheme diiron active sites to effect substrate oxidations that range from the hydroxylation of methane and the desaturation of fatty acids to the deformylation of fatty aldehydes to produce alkanes and the six-electron oxidation of aminoarenes to nitroarenes in the biosynthesis of antibiotics. A common feature of their reaction mechanisms is the formation of O₂ adducts that evolve into more reactive derivatives such as diiron­(II,III)-superoxo, diiron­(III)-peroxo, diiron­(III,IV)-oxo, and diiron­(IV)-oxo species, which carry out particular substrate oxidation tasks. In this review, we survey the various enzymes belonging to this unique subset and the mechanisms by which substrate oxidation is carried out. We examine the nature of the reactive intermediates, as revealed by X-ray crystallography and the application of various spectroscopic methods and their associated reactivity. We also discuss the structural and electronic properties of the model complexes that have been found to mimic salient aspects of these enzyme active sites. Much has been learned in the past 25 years, but key questions remain to be answered

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

Characterization of an O₂ Adduct of an Active Cobalt-Substituted Extradiol-Cleaving Catechol Dioxygenase

The first example of an O₂ adduct of an active Co-substituted oxygenase has been observed in the extradiol ring cleavage of the electron-poor substrate 4-nitrocatechol (4NC) by Co­(II)-homoprotocatechuate 2,3-dioxygenase (Co-HPCD). Upon O₂ binding to the high-spin Co­(II) (<i>S</i> = ³/₂) enzyme–substrate complex, an <i>S</i> = ¹/₂ EPR signal exhibiting ⁵⁹Co hyperfine splitting (<i>A</i> = 24 G) typical of a low-spin Co­(III)–superoxide complex was observed. Both the formation and decay of the new intermediate are very slow in comparison to the analogous steps for turnover of 4NC by native high-spin Fe­(II)-HPCD, which is likely to remain high-spin upon O₂ binding. A similar but effectively stable <i>S</i> = ¹/₂ intermediate was formed by the inactive [H200N-Co-HPCD­(4NC)] variant. The observations presented shed light on the key roles played by the substrate, the second-sphere His200 residue, and the spin state of the metal center in facilitating O₂ binding and activation

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

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

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

¹H‑ENDOR Evidence for a Hydrogen-Bonding Interaction That Modulates the Reactivity of a Nonheme Fe^IVO Unit

We report that a novel use of 35 GHz ¹H-ENDOR spectroscopy establishes the presence in <b>1</b> of an Fe^IVO···H–O–Fe^III hydrogen bond predicted by density functional theory computations to generate a six-membered-ring core for <b>1</b>. The hydrogen bond rationalizes the difference in the C–H bond cleavage reactivity between <b>1</b> and <b>4</b>(OCH₃) (where a CH₃O group has replaced the HO on the Fe^III site). This result substantiates the seemingly paradoxical conclusion that the nonheme Fe^IVO unit of <b>1</b> not only has the electrophilic character required for H-atom abstraction but also retains sufficient nucleophilic character to accept a hydrogen bond from the Fe^III–OH unit

Oxygen Atom Exchange between H₂O and Non-Heme Oxoiron(IV) Complexes: Ligand Dependence and Mechanism

Detailed studies of oxygen atom exchange (OAE) between H₂¹⁸O and synthetic non-heme oxoiron­(IV) complexes supported by tetradentate and pentadentate ligands provide evidence that they proceed by a common mechanism but within two different kinetic regimes, with OAE rates that span 2 orders of magnitude. The first kinetic regime involves initial reversible water association to the Fe^IV complex, which is evidenced by OAE rates that are linearly dependent on [H₂¹⁸O] and H₂O/D₂O KIEs of 1.6, while the second kinetic regime involves a subsequent rate determining proton-transfer step between the bound aqua and oxo ligands that is associated with saturation behavior with [H₂¹⁸O] and much larger H₂O/D₂O KIEs of 5–6. [Fe^IV(O)­(TMC)­(MeCN)]²⁺ (<b>1</b>) and [Fe^IV(O)­(MePy₂TACN)]²⁺ (<b>9</b>) are examples of complexes that exhibit kinetic behavior in the first regime, while [Fe^IV(O)­(N4Py)]²⁺ (<b>3</b>), [Fe^IV(O)­(BnTPEN)]²⁺ (<b>4</b>), [Fe^IV(O)­(1Py-BnTPEN)]²⁺ (<b>5</b>), [Fe^IV(O)­(3Py-BnTPEN)]²⁺ (<b>6</b>), and [Fe^IV(O)­(Me₂Py₂TACN)]²⁺ (<b>8</b>) represent complexes that fall in the second kinetic regime. Interestingly, [Fe^IV(O)­(PyTACN)­(MeCN)]²⁺ (<b>7</b>) exhibits a linear [H₂¹⁸O] dependence below 0.6 M and saturation above 0.6 M. Analysis of the temperature dependence of the OAE rates shows that most of these complexes exhibit large and negative activation entropies, consistent with the proposed mechanism. One exception is complex <b>9</b>, which has a near-zero activation entropy and is proposed to undergo ligand-arm dissociation during the RDS to accommodate H₂¹⁸O binding. These results show that the observed OAE kinetic behavior is highly dependent on the nature of the supporting ligand and are of relevance to studies of non-heme oxoiron­(IV) complexes in water or acetonitrile/water mixtures for applications in photocatalysis and water oxidation chemistry

Evaluating the Identity and Diiron Core Transformations of a (μ-Oxo)diiron(III) Complex Supported by Electron-Rich Tris(pyridyl-2-methyl)amine Ligands

The composition of a (μ-oxo)­diiron­(III) complex coordinated by tris­[(3,5-dimethyl-4-methoxy)­pyridyl-2-methyl]­amine (R₃TPA) ligands was investigated. Characterization using a variety of spectroscopic methods and X-ray crystallography indicated that the reaction of iron­(III) perchlorate, sodium hydroxide, and R₃TPA affords [Fe₂(μ-O)­(μ-OH)­(R₃TPA)₂]­(ClO₄)₃ (<b>2</b>) rather than the previously reported species [Fe₂(μ-O)­(OH)­(H₂O)­(R₃TPA)₂]­(ClO₄)₃ (<b>1</b>). Facile conversion of the (μ-oxo)­(μ-hydroxo)­diiron­(III) core of <b>2</b> to the (μ-oxo)­(hydroxo)­(aqua)­diiron­(III) core of <b>1</b> occurs in the presence of water and at low temperature. When <b>2</b> is exposed to wet acetonitrile at room temperature, the CH₃CN adduct is hydrolyzed to CH₃COO^–, which forms the compound [Fe₂(μ-O)­(μ-CH₃COO)­(R₃TPA)₂]­(ClO₄)₃ (<b>10</b>). The identity of <b>10</b> was confirmed by comparison of its spectroscopic properties with those of an independently prepared sample. To evaluate whether or not <b>1</b> and <b>2</b> are capable of generating the diiron­(IV) species [Fe₂(μ-O)­(OH)­(O)­(R₃TPA)₂]³⁺ (<b>4</b>), which has previously been generated as a synthetic model for high-valent diiron protein oxygenated intermediates, studies were performed to investigate their reactivity with hydrogen peroxide. Because <b>2</b> reacts rapidly with hydrogen peroxide in CH₃CN but not in CH₃CN/H₂O, conditions that favor conversion to <b>1</b>, complex <b>1</b> is not a likely precursor to <b>4</b>. Compound <b>4</b> also forms in the reaction of <b>2</b> with H₂O₂ in solvents lacking a nitrile, suggesting that hydrolysis of CH₃CN is not involved in the H₂O₂ activation reaction. These findings shed light on the formation of several diiron complexes of electron-rich R₃TPA ligands and elaborate on conditions required to generate synthetic models of diiron­(IV) protein intermediates with this ligand framework