Jason England

A Synthetic High‐Spin Oxoiron(IV) Complex: Generation, Spectroscopic Characterization, and Reactivity

High versus low: The high-yield generation of a synthetic high-spin oxoiron(IV) complex, [Fe(IV)(O)(TMG(3)tren)](2+) (see picture, TMG(3)tren = 1,1,1-tris{2-[N2-(1,1,3,3-tetramethylguanidino)]ethyl}amine), has been achieved by using the very bulky tetradentate TMG(3)tren ligand, in order to both sterically protect the oxoiron(IV) moiety and enforce a trigonal bipyramidal geometry at the iron center, for which an S = 2 ground state is favored.

The Crystal Structure of a High-Spin OxoIron(IV) Complex and Characterization of Its Self-Decay Pathway

[Fe(IV)(O)(TMG(3)tren)](2+) (1; TMG(3)tren = 1,1,1-tris{2-[N(2)-(1,1,3,3-tetramethylguanidino)]ethyl}amine) is a unique example of an isolable synthetic S = 2 oxoiron(IV) complex, which serves as a model for the high-valent oxoiron(IV) intermediates observed in nonheme iron enzymes. Congruent with DFT calculations predicting a more reactive S = 2 oxoiron(IV) center, 1 has a lifetime significantly shorter than those of related S = 1 oxoiron(IV) complexes. The self-decay of 1 exhibits strictly first-order kinetic behavior and is unaffected by solvent deuteration, suggesting an intramolecular process. This hypothesis was supported by ESI-MS analysis of the iron products and a significant retardation of self-decay upon use of a perdeuteromethyl TMG(3)tren isotopomer, d(36)-1 (KIE = 24 at 25 degrees C). The greatly enhanced thermal stability of d(36)-1 allowed growth of diffraction quality crystals for which a high-resolution crystal structure was obtained. This structure showed an Fe horizontal lineO unit (r = 1.661(2) A) in the intended trigonal bipyramidal geometry enforced by the sterically bulky tetramethylguanidinyl donors of the tetradentate tripodal TMG(3)tren ligand. The close proximity of the methyl substituents to the oxoiron unit yielded three symmetrically oriented short C-D...O nonbonded contacts (2.38-2.49 A), an arrangement that facilitated self-decay by rate-determining intramolecular hydrogen atom abstraction and subsequent formation of a ligand-hydroxylated iron(III) product. EPR and Mossbauer quantification of the various iron products, referenced against those obtained from reaction of 1 with 1,4-cyclohexadiene, allowed formulation of a detailed mechanism for the self-decay process. The solution of this first crystal structure of a high-spin (S = 2) oxoiron(IV) center represents a fundamental step on the path toward a full understanding of these pivotal biological intermediates.

Proton- and Reductant-Assisted Dioxygen Activation by a Nonheme Iron(II) Complex to Form an Oxoiron(IV) Intermediate

Dioxygen activation by mononuclear iron oxygenases in general requires two electrons and protons to facilitate the reductive cleavage of the O-O bond and formation of a high-valent iron oxidant.[1,2] For enzymes with an iron(III) resting state, the oxidant is postulated to have a formally FeV oxidation state, e.g. FeIV(O)(porphyrin radical) for cytochrome P450[i] and FeV(O)(OH) for the Rieske dioxygenases.[ii] On the other hand, enzymes with an iron(II) resting state often require a tetrahydropterin or an α-keto acid cofactor to form an FeIV(O) intermediate.[2] Such intermediates have recently been trapped and characterized for several enzymes.[iii]

A More Reactive Trigonal Bipyramidal High-Spin Oxoiron(IV) Complex with a cis-Labile Site

The trigonal-bipyramidal high-spin (S = 2) oxoiron(IV) complex [Fe(IV)(O)(TMG(2)dien)(CH(3)CN)](2+) (7) was synthesized and spectroscopically characterized. Substitution of the CH(3)CN ligand by anions, demonstrated here for X = N(3)(-) and Cl(-), yielded additional S = 2 oxoiron(IV) complexes of general formulation [Fe(IV)(O)(TMG(2)dien)(X)](+) (7-X). The reduced steric bulk of 7 relative to the published S = 2 complex [Fe(IV)(O)(TMG(3)tren)](2+) (2) was reflected by enhanced rates of intermolecular substrate oxidation.

Nuclear Resonance Vibrational Spectroscopy on the FeIVO S=2 Non‐Heme Site in TMG3tren: Experimentally Calibrated Insights into Reactivity

Mononuclear non-heme iron (NHFe) enzymes catalyze a number of key biological reactions including hydroxylation, desaturation, ring closure and halogenation.[1-3] The reactive intermediate that carries out many of the C–H bond activations is an S = 2 FeIV=O species that has been observed and characterized in several enzyme systems.[3-5] Synthetic efforts have yielded FeIV=O model complexes that exhibit an S = 1 ground state[6, 7] in all but three cases: (H2O)5FeIV=O[8], (H3buea)FeIV=O[9] and (TMG3tren)FeIV=O (1).[10] 1 has an FeIV=O unit ligated by TMG3tren in a C3ν trigonal bipyramidal geometry (Figure 1A), and an S = 2 ground state replicating that of enzyme intermediates.[10, 11] 1 is reactive in oxo-atom transfer and H-atom abstraction, but in the latter it is only as reactive as the approximately-C4v S = 1 (N4Py)FeIV=O (2, Figure 1B) complex where both have the same reaction rate with 1,4-cyclohexadiene (CHD).[10] Original studies from our group showed that whereas S = 1 reaction coordinates only have a □-attack pathway, involving the β-d□* orbital, available for electrophilic reactivity, S = 2 systems are predicted to possess an additional -attack pathway involving the ⟨-dz2 orbital that is lowered in energy due to spin-polarization.[12, 13] This has recently been referred to as an exchange enhancement.[14] In this study, we utilize Nuclear Resonance Vibrational Spectroscopy (NRVS) to obtain ground-state vibrational data on 1 for comparison to 2[15] and, through correlations to DFT calculations, to understand the observed similar reactivities of 1 (S = 2) and 2 (S = 1). These studies define the steric and intrinsic electronic contributions to the reaction barriers and establish that both the S = 1 and S = 2 surfaces have significant steric contributions due to the different directionalities of substrate approach and thus similar intrinsic reactivities.

π-Frontier molecular orbitals in S = 2 ferryl species and elucidation of their contributions to reactivity

S = 2 FeIV═O species are key intermediates in the catalysis of most nonheme iron enzymes. This article presents detailed spectroscopic and high-level computational studies on a structurally-defined S = 2 FeIV═O species that define its frontier molecular orbitals, which allow its high reactivity. Importantly, there are both π- and σ-channels for reaction, and both are highly reactive because they develop dominant oxyl character at the transition state. These π- and σ-channels have different orientation dependences defining how the same substrate can undergo different reactions (H-atom abstraction vs. electrophilic aromatic attack) with FeIV═O sites in different enzymes, and how different substrates can undergo different reactions (hydroxylation vs. halogenation) with an FeIV═O species in the same enzyme.

Near-stoichiometric conversion of H(2)O(2) to Fe(IV)=O at a nonheme iron(II) center. Insights into the O-O bond cleavage step.

Near-quantitative formation of an oxoiron(IV) intermediate [Fe(IV)(O)(TMC)(CH(3)CN)](2+) (2) from stoichiometric H(2)O(2) was achieved with [Fe(II)(TMC)](2+) (1) (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraaza-cyclotetradecane). This important outcome is best rationalized by invoking a direct reaction between 1 and H(2)O(2) followed by a heterolytic O-O bond cleavage facilitated by an acid-base catalyst (2,6-lutidine in our case). A sizable H/D KIE of 3.7 was observed for the formation of 2, emphasizing the importance of proton transfer in the cleavage step. Pyridines with different pK(a) values were also investigated, and less basic pyridines were found to function less effectively than 2,6-lutidine. This study demonstrates that the reaction of Fe(II) with H(2)O(2) to form Fe(IV)= O can be quite facile. Two factors promote the near-stoichiometric conversion of H(2)O(2) to Fe(IV)=O in this case: (a) the low reactivity between 1 and 2 and (b) the poor H-atom abstracting ability of 2, which inhibits subsequent reaction with residual H(2)O(2). Both factors inhibit formation of the Fe(III) byproduct commonly found in reactions of Fe(II) complexes with H(2)O(2). These results may shed light into the nature of the O-O bond cleaving step in the activation of dioxygen by nonheme iron enzymes and in the first step of the Fenton reaction.

An Inverted and More Oxidizing Isomer of [FeIV(O)(tmc)(NCCH3)]2+†

High-valent oxoiron species are often invoked as the oxidants in the catalytic cycles of dioxygen activating mononuclear nonheme iron enzymes.[1] To date, such iron(IV) intermediates have been characterized for four enzymes, lending strong support for this notion.[2] Within the same time frame, synthetic nonheme complexes containing oxoiron(IV) units have also been described that serve as models for such reactive intermediates.[3] The first crystallographically characterized and most extensively studied member of this family of synthetic oxoiron(IV) complexes is [FeIV(O)(TMC)(NCCH3)](OTf)2 (1-NCCH3)[4] (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane). Its structure features a short Fe=O bond (rFe=O = 1.646 A) with an acetonitrile bound trans to the oxo atom.[4] The macrocyclic TMC ligand adopts a trans-I (R,S,R,S) configuration, such that all four methyl groups are oriented in the same direction with respect to the FeN4 plane,[5] and anti to the oxo atom. On the other hand, monoanionic X ligands coordinate syn to the methyl groups in crystal structures of five-coordinate [FeII(TMC)(X)]+ complexes.[6] Herein, we report the unexpected preparation of an inverted isomer of 1-NCCH3 in which the oxo group binds to the site syn to the four methyl groups (Scheme 1). The conversion of 1-NCCH3 to its inverted isomer is effected by treatment with PhIO in the presence of tetrafluroborate, an otherwise inert anion. The switch in binding site of the oxo group engenders changes in the spectroscopic properties of the oxoiron(IV) complex and, more importantly, a significantly enhanced reactivity in hydrogen-atom abstraction and oxo-transfer reactions.

The trivalent copper complex of a conjugated bis-dithiocarbazate schiff base: stabilization of Cu in three different oxidation states

The new tribasic N(2)S(2) ligand H(3)ttfasbz has been synthesized by condensation of 4-thenoyl 2,2,2-trifluoroacetone and S-benzyl dithiocarbazate. On complexation with copper(II) acetate, spontaneous oxidation to the Cu(III) oxidation state is observed, and the complex [Cu(ttfasbz)] has been isolated and characterized structurally. Reduction to the EPR active Cu(II) analogue has been achieved chemically and also electrochemically, and in both cases, the process is totally reversible. The Cu(III/II) redox potential of the complex is remarkably low and similar to that of the ferrocenium/ferrocene couple. Further reduction to the formally monovalent (d(10)) dianion [Cu(I)(ttfasbz)](2-) may be achieved electrochemically. Computational chemistry demonstrates that the three redox states [Cu(ttfasbz)], [Cu(ttfasbz)](-), and [Cu(ttfasbz)](2-) are truly Cu(III), Cu(II), and Cu(I) complexes, respectively, and the potentially noninnocent ligand does not undergo any redox reactions.

An ultra-stable oxoiron(IV) complex and its blue conjugate base

Treatment of [FeII(L)](OTf)2 (4), (where L = 1,4,8-Me3cyclam-11-CH2C(O)NMe2) with iodosylbenzene yielded the corresponding S = 1 oxoiron(IV) complex [FeIV(O(L)](OTf)2 (5) in nearly quantitative yield. The remarkably high stability of 5 (t1/2 ≈ 5 days at 25 °C) facilitated its characterization by X-ray crystallography and a raft of spectroscopic techniques. Treatment of 5 with strong base was found to generate a distinct, significantly less stable S = 1 oxoiron(IV) complex, 6 (t1/2 ~ 1.5 hrs. at 0 °C), which could be converted back to 5 by addition of a strong acid; these observations indicate that 5 and 6 represent a conjugate acid-base pair. That 6 can be formulated as [FeIV(O)(L-H)](OTf) was further supported by ESI mass spectrometry, spectroscopic and electrochemical studies, and DFT calculations. The close structural similarity of 5 and 6 provided a unique opportunity to probe the influence of the donor trans to the FeIV=O unit upon its reactivity in H-atom transfer (HAT) and O-atom transfer (OAT), and 5 was found to display greater reactivity than 6 in both OAT and HAT. While the greater OAT reactivity of 5 is expected on the basis of its higher redox potential, its higher HAT reactivity does not follow the anti-electrophilic trend reported for a series of [FeIV(O)(TMC)(X)] complexes (TMC = tetramethylcyclam) and thus appears to be inconsistent with the Two-State Reactivity rationale that is the prevailing explanation for the relative facility of oxoiron(IV) complexes to undergo HAT.