Stereospecific Alkane Hydroxylation by Non-Heme Iron Catalysts: Mechanistic Evidence for an Fe^VO Active Species

High-valent iron−oxo species have frequently been invoked in the oxidation of hydrocarbons by both heme and non-heme enzymes. Although a formally FeVO species, that is, [(Por•)FeIVO]+, has been widely accepted as the key oxidant in stereospecific alkane hydroxylation by heme systems, it is not established that such a high-valent state can be accessed by a non-heme ligand environment. Herein we report a systematic study on alkane oxidations with H2O2 catalyzed by a group of non-heme iron complexes, that is, [FeII(TPA)(CH3CN)2]2+ (1, TPA = tris(2-pyridylmethyl)amine) and its α- and β-substituted analogues. The reactivity patterns of this family of FeII(TPA) catalysts can be modulated by the electronic and steric properties of the ligand environment, which affects the spin states of a common FeIII−OOH intermediate. Such an FeIII−peroxo species is high-spin when the TPA ligand has two or three α-substituents and is proposed to be directly responsible for the selective C−H bond cleavage of the alkane substrate. The thus-generated alkyl radicals, however, have relatively long lifetimes and are susceptible to radical epimerization and trapping by O2. On the other hand, 1 and the β-substituted FeII(TPA) complexes catalyze stereospecific alkane hydroxylation by a mechanism involving both a low-spin FeIII−OOH intermediate and an FeVO species derived from O−O bond heterolysis. We propose that the heterolysis pathway is promoted by two factors:  (a) the low-spin iron(III) center which weakens the O−O bond and (b) the binding of an adjacent water ligand that can hydrogen bond to the terminal oxygen of the hydroperoxo group and facilitate the departure of the hydroxide. Evidence for the FeVO species comes from isotope-labeling studies showing incorporation of 18O from H218O into the alcohol products. 18O-incorporation occurs by H218O binding to the low-spin FeIII−OOH intermediate, its conversion to a cis-H18O−FeVO species, and then oxo−hydroxo tautomerization. The relative contributions of the two pathways of this dual-oxidant mechanism are affected by both the electron donating ability of the TPA ligand and the strength of the C−H bond to be broken. These studies thus serve as a synthetic precedent for an FeVO species in the oxygen activation mechanisms postulated for non-heme iron enzymes such as methane monooxygenase and Rieske dioxygenases

Stereospecific Alkane Hydroxylation by Non-Heme Iron Catalysts: Mechanistic Evidence for an Fe^VO Active Species

High-valent iron−oxo species have frequently been invoked in the oxidation of hydrocarbons by both heme and non-heme enzymes. Although a formally FeVO species, that is, [(Por•)FeIVO]+, has been widely accepted as the key oxidant in stereospecific alkane hydroxylation by heme systems, it is not established that such a high-valent state can be accessed by a non-heme ligand environment. Herein we report a systematic study on alkane oxidations with H2O2 catalyzed by a group of non-heme iron complexes, that is, [FeII(TPA)(CH3CN)2]2+ (1, TPA = tris(2-pyridylmethyl)amine) and its α- and β-substituted analogues. The reactivity patterns of this family of FeII(TPA) catalysts can be modulated by the electronic and steric properties of the ligand environment, which affects the spin states of a common FeIII−OOH intermediate. Such an FeIII−peroxo species is high-spin when the TPA ligand has two or three α-substituents and is proposed to be directly responsible for the selective C−H bond cleavage of the alkane substrate. The thus-generated alkyl radicals, however, have relatively long lifetimes and are susceptible to radical epimerization and trapping by O2. On the other hand, 1 and the β-substituted FeII(TPA) complexes catalyze stereospecific alkane hydroxylation by a mechanism involving both a low-spin FeIII−OOH intermediate and an FeVO species derived from O−O bond heterolysis. We propose that the heterolysis pathway is promoted by two factors:  (a) the low-spin iron(III) center which weakens the O−O bond and (b) the binding of an adjacent water ligand that can hydrogen bond to the terminal oxygen of the hydroperoxo group and facilitate the departure of the hydroxide. Evidence for the FeVO species comes from isotope-labeling studies showing incorporation of 18O from H218O into the alcohol products. 18O-incorporation occurs by H218O binding to the low-spin FeIII−OOH intermediate, its conversion to a cis-H18O−FeVO species, and then oxo−hydroxo tautomerization. The relative contributions of the two pathways of this dual-oxidant mechanism are affected by both the electron donating ability of the TPA ligand and the strength of the C−H bond to be broken. These studies thus serve as a synthetic precedent for an FeVO species in the oxygen activation mechanisms postulated for non-heme iron enzymes such as methane monooxygenase and Rieske dioxygenases

Models for Amide Ligation in Nonheme Iron Enzymes

Models for Amide Ligation in Nonheme Iron Enzyme

Iron-Catalyzed Olefin Epoxidation in the Presence of Acetic Acid: Insights into the Nature of the Metal-Based Oxidant

The iron complexes [(BPMEN)Fe(OTf)2] (1) and [(TPA)Fe(OTf)2] (2) [BPMEN = N,N‘-bis-(2-pyridylmethyl)-N,N‘-dimethyl-1,2-ethylenediamine; TPA = tris-(2-pyridylmethyl)amine] catalyze the oxidation of olefins by H2O2 to yield epoxides and cis-diols. The addition of acetic acid inhibits olefin cis-dihydroxylation and enhances epoxidation for both 1 and 2. Reactions carried out at 0 °C with 0.5 mol % catalyst and a 1:1.5 olefin/H2O2 ratio in a 1:2 CH3CN/CH3COOH solvent mixture result in nearly quantitative conversions of cyclooctene to epoxide within 1 min. The nature of the active species formed in the presence of acetic acid has been probed at low temperature. For 2, in the absence of substrate, [(TPA)FeIII(OOH)(CH3COOH)]2+ and [(TPA)FeIVO(NCCH3)]2+ intermediates can be observed. However, neither is the active epoxidizing species. In fact, [(TPA)FeIVO(NCCH3)]2+ is shown to form in competition with substrate oxidation. Consequently, it is proposed that epoxidation is mediated by [(TPA)FeV(O)(OOCCH3)]2+, generated from O−O bond heterolysis of the [(TPA)FeIII(OOH)(CH3COOH)]2+ intermediate, which is promoted by the protonation of the terminal oxygen atom of the hydroperoxide by the coordinated carboxylic acid

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

Models for Amide Ligation in Nonheme Iron Enzymes

Models for Amide Ligation in Nonheme Iron Enzyme

Reactivities of Fe(IV) Complexes with Oxo, Hydroxo, and Alkylperoxo Ligands: An Experimental and Computational Study

In a previous paper [Jensen et al. J. Am. Chem. Soc. 2005, 127, 10512], we reported the synthesis of the turquoise-colored intermediate [FeIV(β-BPMCN)(OOtBu)(OH)]2+ (Tq; BPMCN = N,N′-bis(2-pyridylmethyl)-N,N′-dimethyl-trans-1,2-diaminocyclohexane). The structure of Tq is unprecedented, as it represents the only synthetic example to date of a nonheme FeIV complex with both alkylperoxo and hydroxide ligands. Given the significance of similar high-valent Fe intermediates in the mechanisms of oxygenase enzymes, we have explored the reactivity of Tq at −70 °C, a temperature at which it is stable, and found that it is capable of activating weak XH bonds (X = C, O) with bond dissociation energies ≤∼80 kcal/mol. The FeIVOH unit of Tq, and not the alkylperoxo moiety, performs the initial H-atom abstraction. However at −45 °C, Tq decays at a rate that is independent of substrate identity and concentration, forming a species capable of oxidizing substrates with stronger C−H bonds. Parallel reactivity studies were also conducted with the related oxoiron(IV) complexes [FeIV(β-BPMCN)(O)(X)]2+ (3-X; X = pyridine or nitrile), thereby permitting a direct comparison of the reactivity of FeIV centers with oxo and hydroxide ligands. We found that the H-atom abstracting ability of the FeIVO species greatly exceeds that of the FeIVOH species, generally by greater than 100-fold. Examination of the electronic structures of Tq and 3-X with density functional theory (DFT) provides a rationale for their differing reactivities

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

Sc³⁺ (or HClO₄) Activation of a Nonheme Fe^III–OOH Intermediate for the Rapid Hydroxylation of Cyclohexane and Benzene

[Fe­(β-BPMCN)­(CH3CN)2]2+ (1, BPMCN = N,N′-bis­(pyridyl-2-methyl)-N,N′-dimethyl-trans-1,2-diaminocyclo-hexane) is a relatively poor catalyst for cyclohexane oxidation by H2O2 and cannot perform benzene hydroxylation. However, addition of Sc3+ activates the 1/H2O2 reaction mixture to be able to hydroxylate cyclohexane and benzene within seconds at −40 °C. A metastable S = 1/2 FeIII–(η1-OOH) intermediate 2 is trapped at −40 °C, which undergoes rapid decay upon addition of Sc3+ at rates independent of [substrate] but linearly dependent on [Sc3+]. HClO4 elicits comparable reactivity as Sc3+ at the same concentration. We thus postulate that these additives both facilitate O–O bond heterolysis of 2 to form a common highly electrophilic FeVO oxidant that is comparably reactive to the fastest nonheme high-valent iron-oxo oxidants found to date

Spin-Crossover in an Iron(III)−Bispidine−Alkylperoxide System

The iron(II) complex of a tetradentate bispidine ligand with two tertiary amines and two pyridine groups (L = dimethyl [3,7-dimethyl-9,9‘-dihydroxy-2,4-di-(2-pyridyl)-3,7-diazabicyclo nonan-1,5-dicaboxylate]) is oxidized with tert-butyl hydroperoxide to the corresponding end-on tert-butylperoxo complex [FeIII(L)(OOtBu)(X)]n+ (X = solvent, anion). UV−vis, resonance Raman, and EPR spectroscopy, as a function of the solvent, show that this is a spin-crossover compound. The experimentally observed Raman vibrations for both low-spin and high-spin isomers are in good agreement with those computed by DFT