Substrate-Triggered Activation of a Synthetic [Fe₂(μ-O)₂] Diamond Core for C–H Bond Cleavage

An [FeIV2(μ-O)2] diamond core structure has been postulated for intermediate Q of soluble methane monooxygenase (sMMO-Q), the oxidant responsible for cleaving the strong C–H bond of methane and its hydroxylation. By extension, analogous species may be involved in the mechanisms of related diiron hydroxylases and desaturases. Because of the paucity of well-defined synthetic examples, there are few, if any, mechanistic studies on the oxidation of hydrocarbon substrates by complexes with high-valent [Fe2(μ-O)2] cores. We report here that water or alcohol substrates can activate synthetic [FeIIIFeIV(μ-O)2] complexes supported by tetradentate tris(pyridyl-2-methyl)amine ligands (1 and 2) by several orders of magnitude for C–H bond oxidation. On the basis of detailed kinetic studies, it is postulated that the activation results from Lewis base attack on the [FeIIIFeIV(μ-O)2] core, resulting in the formation of a more reactive species with a [X–FeIII–O–FeIVO] ring-opened structure (1–X, 2–X, X = OH– or OR–). Treatment of 2 with methoxide at −80 °C forms the 2–methoxide adduct in high yield, which is characterized by an S = 1/2 EPR signal indicative of an antiferromagnetically coupled [S = 5/2 FeIII/S = 2 FeIV] pair. Even at this low temperature, the complex undergoes facile intramolecular C–H bond cleavage to generate formaldehyde, showing that the terminal high-spin FeIVO unit is capable of oxidizing a C–H bond as strong as 96 kcal mol–1. This intramolecular oxidation of the methoxide ligand can in fact be competitive with intermolecular oxidation of triphenylmethane, which has a much weaker C–H bond (DC–H 81 kcal mol–1). The activation of the [FeIIIFeIV(μ-O)2] core is dramatically illustrated by the oxidation of 9,10-dihydroanthracene by 2–methoxide, which has a second-order rate constant that is 3.6 × 107-fold larger than that for the parent diamond core complex 2. These observations provide strong support for the DFT-based notion that an S = 2 FeIVO unit is much more reactive at H-atom abstraction than its S = 1 counterpart and suggest that core isomerization could be a viable strategy for the [FeIV2(μ-O)2] diamond core of sMMO-Q to selectively attack the strong C–H bond of methane in the presence of weaker C–H bonds of amino acid residues that define the diiron active site pocket

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

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 (2) rather than the previously reported species [Fe2(μ-O)­(OH)­(H2O)­(R3TPA)2]­(ClO4)3 (1). Facile conversion of the (μ-oxo)­(μ-hydroxo)­diiron­(III) core of 2 to the (μ-oxo)­(hydroxo)­(aqua)­diiron­(III) core of 1 occurs in the presence of water and at low temperature. When 2 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 (10). The identity of 10 was confirmed by comparison of its spectroscopic properties with those of an independently prepared sample. To evaluate whether or not 1 and 2 are capable of generating the diiron­(IV) species [Fe2(μ-O)­(OH)­(O)­(R3TPA)2]3+ (4), 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 2 reacts rapidly with hydrogen peroxide in CH3CN but not in CH3CN/H2O, conditions that favor conversion to 1, complex 1 is not a likely precursor to 4. Compound 4 also forms in the reaction of 2 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

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

Spectroscopic and Theoretical Investigation of a Complex with an [OFe^IV–O–Fe^IVO] Core Related to Methane Monooxygenase Intermediate <b>Q</b>

Previous efforts to model the diiron­(IV) intermediate <b>Q</b> of soluble methane monooxygenase have led to the synthesis of a diiron­(IV) TPA complex, <b>2</b>, with an O=Fe^IV–O–Fe^IV–OH core that has two ferromagnetically coupled S_loc = 1 sites. Addition of base to <b>2</b> at −85 °C elicits its conjugate base <b>6</b> with a novel OFe^IV–O–Fe^IVO core. In frozen solution, <b>6</b> exists in two forms, <b>6a</b> and <b>6b</b>, that we have characterized extensively using Mössbauer and parallel mode EPR spectroscopy. The conversion between <b>2</b> and <b>6</b> is quantitative, but the relative proportions of <b>6a</b> and <b>6b</b> are solvent dependent. <b>6a</b> has two equivalent high-spin (<i>S</i>_loc = 2) sites, which are antiferromagnetically coupled; its quadrupole splitting (0.52 mm/s) and isomer shift (0.14 mm/s) match those of intermediate <b>Q</b>. DFT calculations suggest that <b>6a</b> assumes an anti conformation with a dihedral OFe–FeO angle of 180°. Mössbauer and EPR analyses show that <b>6b</b> is a diiron­(IV) complex with ferromagnetically coupled <i>S</i>_loc = 1 and <i>S</i>_loc = 2 sites to give total spin <i>S</i>_t = 3. Analysis of the zero-field splittings and magnetic hyperfine tensors suggests that the dihedral OFe–FeO angle of <b>6b</b> is ∼90°. DFT calculations indicate that this angle is enforced by hydrogen bonding to both terminal oxo groups from a shared water molecule. The water molecule preorganizes <b>6b</b>, facilitating protonation of one oxo group to regenerate <b>2</b>, a protonation step difficult to achieve for mononuclear Fe^IVO complexes. Complex <b>6</b> represents an intriguing addition to the handful of diiron­(IV) complexes that have been characterized

Hydrogen-Bonding Effects on the Reactivity of [X–Fe^III–O–Fe^IVO] (X = OH, F) Complexes toward C–H Bond Cleavage

Complexes <b>1</b>–OH and <b>1</b>–F are related complexes that share similar [X–Fe^III–O–Fe^IVO]³⁺ core structures with a total spin <i>S</i> of ¹/₂, which arises from antiferromagnetic coupling of an <i>S</i> = ⁵/₂ Fe^III–X site and an <i>S</i> = 2 Fe^IVO site. EXAFS analysis shows that <b>1</b>–F has a nearly linear Fe^III–O–Fe^IV core compared to that of <b>1</b>–OH, which has an Fe–O–Fe angle of ∼130° due to the presence of a hydrogen bond between the hydroxo and oxo groups. Both complexes are at least 1000-fold more reactive at C–H bond cleavage than <b>2</b>, a related complex with a [OH–Fe^IV–O–Fe^IVO]⁴⁺ core having individual <i>S</i> = 1 Fe^IV units. Interestingly, <b>1</b>–F is 10-fold more reactive than <b>1</b>–OH. This raises an interesting question about what gives rise to the reactivity difference. DFT calculations comparing <b>1</b>–OH and <b>1</b>–F strongly suggest that the H-bond in <b>1</b>–OH does not significantly change the electrophilicity of the reactive Fe^IVO unit and that the lower reactivity of <b>1</b>–OH arises from the additional activation barrier required to break its H-bond in the course of H-atom transfer by the oxoiron­(IV) moiety

Mössbauer and DFT Study of the Ferromagnetically Coupled Diiron(IV) Precursor to a Complex with an Fe^IV₂O₂ Diamond Core

Recently, we reported the reaction of the (μ-oxo)diiron(III) complex 1 ([FeIII2(μ-O)(μ-O2H3)(L)2]3+, L = tris(3,5-dimethyl-4-methoxypyridyl-2-methyl)amine) with 1 equiv of H2O2 to yield a diiron(IV) intermediate, 2 (Xue, G.; Fiedler, A. T.; Martinho, M.; Münck, E.; Que, L., Jr. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 20615−20). Upon treatment with HClO4, complex 2 converted to a species with an FeIV2(μ-O)2 diamond core that serves as the only synthetic model to date for the diiron(IV) core proposed for intermediate Q of soluble methane monooxygenase. Here we report detailed Mössbauer and density functional theory (DFT) studies of 2. The Mössbauer studies reveal that 2 has distinct FeIV sites, a and b. Studies in applied magnetic fields show that the spins of sites a and b (Sa = Sb = 1) are ferromagnetically coupled to yield a ground multiplet with S = 2. Analysis of the applied field spectra of the exchange-coupled system yields for site b a set of parameters that matches those obtained for the mononuclear [LFeIV(O)(NCMe)]2+ complex, showing that site b (labeled FeO) has a terminal oxo group. Using the zero-field splitting parameters of [LFeIV(O)(NCMe)]2+ for our analysis of 2, we obtained parameters for site a that closely resemble those reported for the nonoxo FeIV complex [(β-BPMCN)FeIV(OH)(OOtBu)]2+, suggesting that a (labeled FeOH) coordinates a hydroxo group. A DFT optimization performed on 2 yielded an Fe−Fe distance of 3.39 Å and an Fe−(μ-O)−Fe angle of 131°, in good agreement with the results of our previous EXAFS study. The DFT calculations reproduce the Mössbauer parameters (A-tensors, electric field gradient, and isomer shift) of 2 quite well, including the observation that the largest components of the electric field gradients of FeO and FeOH are perpendicular. The ferromagnetic behavior of 2 seems puzzling given that the Fe−(μ-O)−Fe angle is large but can be explained by noting that the orbital structures of FeO and FeOH are such that the unpaired electrons at the two sites delocalize into orthogonal orbitals at the bridging oxygen, rationalizing the ferromagnetic behavior of 2. Thus, inequivalent coordinations at FeO and FeOH define magnetic orbitals favorable for ferromagnetic ineractions

Mössbauer, Electron Paramagnetic Resonance, and Density Functional Theory Studies of Synthetic <i>S</i> = ¹/₂ Fe^III−O−Fe^IVO Complexes. Superexchange-Mediated Spin Transition at the Fe^IVO Site

Previously we have characterized two high-valent complexes [LFeIV(μ-O)2FeIIIL], 1, and [LFeIV(O)(μ-O)(OH) FeIVL], 4. Addition of hydroxide or fluoride to 1 produces two new complexes, 1-OH and 1-F. Electron paramagnetic resonance (EPR) and Mössbauer studies show that both complexes have an S = 1/2 ground state which results from antiferromagnetic coupling of the spins of a high-spin (Sa = 5/2) FeIII and a high-spin (Sb = 2) FeIV site. 1-OH can also be obtained by a 1-electron reduction of 4, which has been shown to have an FeIVO site. Radiolytic reduction of 4 at 77 K yields a Mössbauer spectrum identical to that observed for 1-OH, showing that the latter contains an FeIVO. Interestingly, the FeIVO moiety has Sb = 1 in 4 and Sb = 2 in 1-OH and 1-F. From the temperature dependence of the S = 1/2 signal we have determined the exchange coupling constant J (ℋ = JŜa·Ŝb convention) to be 90 ± 20 cm−1 for both 1-OH and 1-F. Broken-symmetry density functional theory (DFT) calculations yield J = 135 cm−1 for 1-OH and J = 104 cm−1 for 1-F, in good agreement with the experiments. DFT analysis shows that the Sb = 1 → Sb = 2 transition of the FeIVO site upon reduction of the FeIV−OH site to high-spin FeIII is driven primarily by the strong antiferromagnetic exchange in the (Sa = 5/2, Sb = 2) couple