A Bioinspired Nonheme FeIII-(O22-)-CuII Complex with an St = 1 Ground State.

Cytochrome c oxidase (CcO) is a heme copper oxidase (HCO) that catalyzes the natural reduction of oxygen to water. A profound understanding of some of the elementary steps leading to the intricate 4e-/4H+ reduction of O2 is presently lacking. A total spin St = 1 FeIII-(O22-)-CuII (IP) intermediate is proposed to reduce the overpotentials associated with the reductive O-O bond rupture by allowing electron transfer from a tyrosine moiety without the necessity of any spin-surface crossing. Direct evidence of the involvement of IP in the CcO catalytic cycle is, however, missing. A number of heme copper peroxido complexes have been prepared as synthetic models of IP, but all of them possess the catalytically nonrelevant St = 0 ground state resulting from antiferromagnetic coupling between the S = 1/2 FeIII and CuII centers. In a complete nonheme approach, we now report the spectroscopic characterization and reactivity of the FeIII-(O22-)-CuII intermediates 1 and 2, which differ only by a single -CH3 versus -H substituent on the central amine of the tridentate ligands binding to copper. Complex 1 with an end-on peroxido core and ferromagnetically (St = 1) coupled FeIII and CuII centers performs H-bonding-mediated O-O bond cleavage in the presence of phenol to generate oxoiron(IV) and exchange-coupled copper(II) and PhO• moieties. In contrast, the µ-η2:η1 peroxido complex 2, with a St = 0 ground state, is unreactive toward phenol. Thus, the implications for spin topology contributions to O-O bond cleavage, as proposed for the heme FeIII-(O22-)-CuII intermediate in CcO, can be extended to nonheme chemistry.

Identification, Characterization, and Electronic Structures of Interconvertible Cobalt-Oxygen TAML Intermediates.

The reaction of Li[(TAML)CoIII]·3H2O (TAML = tetraamido macrocyclic tetraanionic ligand) with iodosylbenzene at 253 K in acetone in the presence of redox-innocent metal ions (Sc(OTf)3 and Y(OTf)3) or triflic acid affords a blue species 1, which is converted reversibly to a green species 2 upon cooling to 193 K. The electronic structures of 1 and 2 have been determined by combining advanced spectroscopic techniques (X-band electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), X-ray absorption spectroscopy/extended X-ray absorption fine structure (XAS/EXAFS), and magnetic circular dichroism (MCD)) with ab initio theoretical studies. Complex 1 is best represented as an S = 1/2 [(Sol)(TAML•+)CoIII---OH(LA)]- species (LA = Lewis/Brønsted acid and Sol = solvent), where an S = 1 Co(III) center is antiferromagnetically coupled to S = 1/2 TAML•+, which represents a one-electron oxidized TAML ligand. In contrast, complex 2, also with an S = 1/2 ground state, is found to be multiconfigurational with contributions of both the resonance forms [(H-TAML)CoIV═O(LA)]- and [(H-TAML•+)CoIII═O(LA)]-; H-TAML and H-TAML•+ represent the protonated forms of TAML and TAML•+ ligands, respectively. Thus, the interconversion of 1 and 2 is associated with a LA-associated tautomerization event, whereby H+ shifts from the terminal -OH group to TAML•+ with the concomitant formation of a terminal cobalt-oxo species possessing both singlet (SCo = 0) Co(III) and doublet (SCo = 1/2) Co(IV) characters. The reactivities of 1 and 2 at different temperatures have been investigated in oxygen atom transfer (OAT) and hydrogen atom transfer (HAT) reactions to compare the activation enthalpies and entropies of 1 and 2.

Origin of Unprecedented Formation and Reactivity of FeIV═O Species via Oxygen Activation: Role of Noncovalent Interactions and Magnetic Coupling.

Emulating the capabilities of the soluble methane monooxygenase (sMMO) enzymes, which effortlessly activate oxygen at diiron(II) centers to form a reactive diiron(IV) intermediate Q, which then performs the challenging oxidation of methane to methanol, poses a significant challenge. Very recently, one of us reported the mononuclear complex [(cyclam)FeII(CH3CN)2]2+ (1), which performed a rare bimolecular activation of the molecule of O2 to generate two molecules of FeIV═O without the requirement of external proton or electron sources, similar to sMMO. In the present study, we employed the density functional theory (DFT) calculations to investigate this unique mechanism of O2 activation. We show that secondary hydrogen-bonding interactions between ligand N-H groups and O2 play a vital role in reducing the energy barrier associated with the initial O2 binding at 1 and O-O bond cleavage to form the FeIV═O complex. Further, the unique reactivity of FeIV═O species toward simultaneous C-H and O-H bond activation process has been demonstrated. Our study unveils that the nature of the magnetic coupling between the diiron centers is also crucial. Given that the influence of magnetic coupling and noncovalent interactions in catalysis remains largely unexplored, this unexplored realm presents numerous avenues for experimental chemists to develop novel structural and functional analogues of sMMO.

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes.

Cytotoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C terminus of these CTL epitopes is considered to be produced by the proteasome. Here we demonstrate that the cytosolic endopeptidases nardilysin and thimet oligopeptidase (TOP) complemented proteasome activity. Nardilysin and TOP were required, either together or alone, for the generation of a tumor-specific CTL epitope from PRAME, an immunodominant CTL epitope from Epstein-Barr virus protein EBNA3C, and a clinically important epitope from the melanoma protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing, and nardilysin contributed to both the C-terminal and N-terminal generation of CTL epitopes. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.

A New Thiolate-Bound Dimanganese Cluster as a Structural and Functional Model for Class Ib Ribonucleotide Reductases.

In class Ib ribonucleotide reductases (RNRs) a dimanganese(II) cluster activates superoxide (O2 ⋅- ) rather than dioxygen (O2 ), to access a high valent MnIII -O2 -MnIV species, responsible for the oxidation of tyrosine to tyrosyl radical. In a biomimetic approach, we report the synthesis of a thiolate-bound dimanganese complex [MnII 2 (BPMT)(OAc)2 ](ClO)4 (BPMT=(2,6-bis{[bis(2-pyridylmethyl)amino]methyl}-4-methylthiophenolate) (1) and its reaction with O2 ⋅- to form a [(BPMT)MnO2 Mn]2+ complex 2. Resonance Raman investigation revealed the presence of an O-O bond in 2, while EPR analysis displayed a 16-line St =1/2 signal at g=2 typically associated with a MnIII MnIV core, as detected in class Ib RNRs. Unlike all other previously reported Mn-O2 -Mn complexes, generated by O2 ⋅- activation at Mn2 centers, 2 proved to be a capable electrophilic oxidant in aldehyde deformylation and phenol oxidation reactions, rendering it one of the best structural and functional models for class Ib RNRs.

Evidence of Sulfur Non-Innocence in [CoII (dithiacyclam)]2+ -Mediated Catalytic Oxygen Reduction Reactions.

In many metalloenzymes, sulfur-containing ligands participate in catalytic processes, mainly via the involvement in electron transfer reactions. In a biomimetic approach, we now demonstrate the implication of S-ligation in cobalt mediated oxygen reduction reactions (ORR). A comparative study between the catalytic ORR capabilities of the four-nitrogen bound [Co(cyclam)]2+ (1; cyclam=1,5,8,11-tetraaza-cyclotetradecane) and the S-containing analog [Co(S2 N2 -cyclam)]2+ (2; S2 N2 -cyclam=1,8-dithia-5,11-diaza-cyclotetradecane) reveals improved catalytic performance once the chalcogen is introduced in the Co coordination sphere. Trapping and characterization of the intermediates formed upon dioxygen activation at the CoII centers in 1 and 2 point to the involvement of sulfur in the O2 reduction process as the key for the improved catalytic ORR capabilities of 2.

Spectroscopic Properties of a Biologically Relevant [Fe2 (µ-O)2 ] Diamond Core Motif with a Short Iron-Iron Distance.

Diiron cofactors in enzymes perform diverse challenging transformations. The structures of high valent intermediates (Q in methane monooxygenase and X in ribonucleotide reductase) are debated since Fe-Fe distances of 2.5-3.4 Šwere attributed to "open" or "closed" cores with bridging or terminal oxido groups. We report the crystallographic and spectroscopic characterization of a FeIII 2 (µ-O)2 complex (2) with tetrahedral (4C) centres and short Fe-Fe distance (2.52 Å), persisting in organic solutions. 2 shows a large Fe K-pre-edge intensity, which is caused by the pronounced asymmetry at the TD FeIII centres due to the short Fe-µ-O bonds. A ≈2.5 ŠFe-Fe distance is unlikely for six-coordinate sites in Q or X, but for a Fe2 (µ-O)2 core containing four-coordinate (or by possible extension five-coordinate) iron centres there may be enough flexibility to accommodate a particularly short Fe-Fe separation with intense pre-edge transition. This finding may broaden the scope of models considered for the structure of high-valent diiron intermediates formed upon O2 activation in biology.

Transition metal-mediated O-O bond formation and activation in chemistry and biology.

Oxygen evolution and reduction reactions are fundamental processes in biological energy conversion schemes, which represent an attractive method for artificial energy conversion for a world still largely depending on fossil fuels. A range of metalloenzymes achieve these challenging tasks in biology by activating water and dioxygen using cheap and abundant transition metals, such as iron, copper, and manganese. High-valent metal-oxo/oxyl, metal-superoxo, and/or metal-(hydro)peroxo species are common reactive intermediates that are found in the O-O bond formation and activation reactions. The transient nature of the metal-oxygen intermediates has, however, prevented their isolation and characterization in most cases. As a consequence, unambiguous mechanistic assignments in the O-O bond formation and cleavage processes in biological and chemical entries remain elusive, especially for the intermediates and mechanisms involved in the O-O bond formation reactions. This viewpoint article aims at summarizing the information obtained to date in enzymatic and biomimetic systems that fuels the debate regarding the nature of the active oxidants and the mechanistic uncertainties associated with the transition metal-mediated O-O bond formation and cleavage reactions.

Ligand-Constraint-Induced Peroxide Activation for Electrophilic Reactivity.

µ-1,2-peroxo-bridged diiron(III) intermediates P are proposed as reactive intermediates in various biological oxidation reactions. In sMMO, P acts as an electrophile, and performs hydrogen atom and oxygen atom transfers to electron-rich substrates. In cyanobacterial ADO, however, P is postulated to react by nucleophilic attack on electrophilic carbon atoms. In biomimetic studies, the ability of µ-1,2-peroxo-bridged dimetal complexes of Fe, Co, Ni and Cu to act as nucleophiles that effect deformylation of aldehydes is documented. By performing reactivity and theoretical studies on an end-on µ-1,2-peroxodicobalt(III) complex 1 involving a non-heme ligand system, L1, supported on a Sn6 O6 stannoxane core, we now show that a peroxo-bridged dimetal complex can also be a reactive electrophile. The observed electrophilic chemistry, which is induced by the constraints provided by the Sn6 O6 core, represents a new domain for metal-peroxide reactivity.

A Pseudotetrahedral Terminal Oxoiron(IV) Complex: Mechanistic Promiscuity in C-H Bond Oxidation Reactions.

S=2 oxoiron(IV) species act as reactive intermediates in the catalytic cycle of nonheme iron oxygenases. The few available synthetic S=2 FeIV =O complexes known to date are often limited to trigonal bipyramidal and very rarely to octahedral geometries. Herein we describe the generation and characterization of an S=2 pseudotetrahedral FeIV =O complex 2 supported by the sterically demanding 1,4,7-tri-tert-butyl-1,4,7-triazacyclononane ligand. Complex 2 is a very potent oxidant in hydrogen atom abstraction (HAA) reactions with large non-classical deuterium kinetic isotope effects, suggesting hydrogen tunneling contributions. For sterically encumbered substrates, direct HAA is impeded and an alternative oxidative asynchronous proton-coupled electron transfer mechanism prevails, which is unique within the nonheme oxoiron community. The high reactivity and the similar spectroscopic parameters make 2 one of the best electronic and functional models for a biological oxoiron(IV) intermediate of taurine dioxygenase (TauD-J).

Spectroscopic Characterization of a Reactive [Cu2 (µ-OH)2 ]2+ Intermediate in Cu/TEMPO Catalyzed Aerobic Alcohol Oxidation Reaction.

CuI /TEMPO (TEMPO=2,2,6,6-tetramethylpiperidinyloxyl) catalyst systems are versatile catalysts for aerobic alcohol oxidation reactions to selectively yield aldehydes. However, several aspects of the mechanism are yet unresolved, mainly because of the lack of identification of any reactive intermediates. Herein, we report the synthesis and characterization of a dinuclear [L12 Cu2 ]2+ complex 1, which in presence of TEMPO can couple the catalytic 4 H+ /4 e- reduction of O2 to water to the oxidation of benzylic and aliphatic alcohols. The mechanisms of the O2 -reduction and alcohol oxidation reactions have been clarified by the spectroscopic detection of the reactive intermediates in the gas and condensed phases, as well as by kinetic studies on each step in the catalytic cycles. Bis(µ-oxo)dicopper(III) (2) and bis(µ-hydroxo)dicopper(II) species 3 are shown as viable reactants in oxidation catalysis. The present study provides deep mechanistic insight into the aerobic oxidation of alcohols that should serve as a valuable foundation for ongoing efforts dedicated towards the understanding of transition-metal catalysts involving redox-active organic cocatalysts.

Stoichiometric Formation of an Oxoiron(IV) Complex by a Soluble Methane Monooxygenase Type Activation of O2 at an Iron(II)-Cyclam Center.

In soluble methane monooxygenase enzymes (sMMO), dioxygen (O2) is activated at a diiron(II) center to form an oxodiiron(IV) intermediate Q that performs the challenging oxidation of methane to methanol. An analogous mechanism of O2 activation at mono- or dinuclear iron centers is rare in the synthetic chemistry. Herein, we report a mononuclear non-heme iron(II)-cyclam complex, 1-trans, that activates O2 to form the corresponding iron(IV)-oxo complex, 2-trans, via a mechanism reminiscent of the O2 activation process in sMMO. The conversion of 1-trans to 2-trans proceeds via the intermediate formation of an iron(III)-superoxide species 3, which could be trapped and spectroscopically characterized at -50 °C. Surprisingly, 3 is a stronger oxygen atom transfer (OAT) agent than 2-trans; 3 performs OAT to 1-trans or PPh3 to yield 2-trans quantitatively. Furthermore, 2-trans oxidizes the aromatic C-H bonds of 2,6-di-tert-butylphenol, which, together with the strong OAT ability of 3, represents new domains of oxoiron(IV) and superoxoiron(III) reactivities.

Trapping of a Highly Reactive Oxoiron(IV) Complex in the Catalytic Epoxidation of Olefins by Hydrogen Peroxide.

The generation of a nonheme oxoiron(IV) intermediate, [(cyclam)FeIV (O)(CH3 CN)]2+ (2; cyclam=1,4,8,11-tetraazacyclotetradecane), is reported in the reactions of [(cyclam)FeII ]2+ with aqueous hydrogen peroxide (H2 O2 ) or a soluble iodosylbenzene (sPhIO) as a rare example of an oxoiron(IV) species that shows a preference for epoxidation over allylic oxidation in the oxidation of cyclohexene. Complex 2 is kinetically and catalytically competent to perform the epoxidation of olefins with high stereo- and regioselectivity. More importantly, 2 is likely to be the reactive intermediate involved in the catalytic epoxidation of olefins by [(cyclam)FeII ]2+ and H2 O2 . In spite of the predominance of the oxoiron(IV) cores in biology, the present study is a rare example of high-yield isolation and spectroscopic characterization of a catalytically relevant oxoiron(IV) intermediate in chemical oxidation reactions.

ECOSTBio: Explicit Control Over Spin States in Technology and Biochemistry.

Within the framework of the COST program, ECOSTBio is a European network of both experimental and theoretical researchers that tackle a diversity of chemical problems in which electronic spin is a key factor. In this special issue, the ECOSTBio researchers, as well as the invited external guests from Europe and abroad, highlight the importance of spin states and reactivity.

Observation of Carbodicarbene Ligand Redox Noninnocence in Highly Oxidized Iron Complexes.

To probe the possibility that carbodicarbenes (CDCs) are redox active ligands, all four members of the redox series [Fe(1)2 ]n+ (n=2-5) were synthesized, where 1 is a neutral tridentate CDC. Through a combination of spectroscopy and DFT calculations, the electronic structure of the pentacation is shown to be [FeIII (1.+ )2 ]5+ (S= 1 / 2 ). That of [Fe(1)2 ]4+ is more ambiguous, but it has significant contributions from the open-shell singlet [FeIII (1)(1.+ )]4+ (S=0). The observed spin states derive from antiferromagnetic coupling of their constituent low-spin iron(III) centres and cation radical ligands. This marks the first time redox activity has been observed for carbones and expands the diverse chemical behaviour known for these ligands.

Nucleophilic versus Electrophilic Reactivity of Bioinspired Superoxido Nickel(II) Complexes.

The formation and detailed spectroscopic characterization of the first biuret-containing monoanionic superoxido-NiII intermediate [LNiO2 ]- as the Li salt [2; L=MeN[C(=O)NAr)2 ; Ar=2,6-iPr2 C6 H3 )] is reported. It results from oxidation of the corresponding [Li(thf)3 ]2 [LNiII Br2 ] complex M with excess H2 O2 in the presence of Et3 N. The [LNiO2 ]- core of 2 shows an unprecedented nucleophilic reactivity in the oxidative deformylation of aldehydes, in stark contrast to the electrophilic character of the previously reported neutral Nacnac-containing superoxido-NiII complex 1, [L'NiO2 ] (L'=CH(CMeNAr)2 ). According to density-functional theory (DFT) calculations, the remarkably different behaviour of 1 versus 2 can be attributed to their different charges and a two-state reactivity, in which a doublet ground state and a nearby spin-polarized doublet excited-state both contribute in 1 but not in 2. The unexpected nucleophilicity of the superoxido-NiII core of 2 suggests that such a reactivity may also play a role in catalytic cycles of Ni-containing oxygenases and oxidases.

Temperature Dependence of the Catalytic Two- versus Four-Electron Reduction of Dioxygen by a Hexanuclear Cobalt Complex.

The synthesis and characterization of a hexanuclear cobalt complex 1 involving a nonheme ligand system, L1, supported on a Sn6O6 stannoxane core are reported. Complex 1 acts as a unique catalyst for dioxygen reduction, whose selectivity can be changed from a preferential 4e-/4H+ dioxygen-reduction (to water) to a 2e-/2H+ process (to hydrogen peroxide) only by increasing the temperature from -50 to 25 °C. A variety of spectroscopic methods (119Sn-NMR, magnetic circular dichroism (MCD), electron paramagnetic resonance (EPR), SQUID, UV-vis absorption, and X-ray absorption spectroscopy (XAS)) coupled with advanced theoretical calculations has been applied for the unambiguous assignment of the geometric and electronic structure of 1. The mechanism of the O2-reduction reaction has been clarified on the basis of kinetic studies on the overall catalytic reaction as well as each step in the catalytic cycle and by low-temperature detection of intermediates. The reason why the same catalyst can act in either the two- or four-electron reduction of O2 can be explained by the constraint provided by the stannoxane core that makes the O2-binding to 1 an entropically unfavorable process. This makes the end-on µ-1,2-peroxodicobalt(III) intermediate 2 unstable against a preferential proton-transfer step at 25 °C leading to the generation of H2O2. In contrast, at -50 °C, the higher thermodynamic stability of 2 leads to the cleavage of the O-O bond in 2 in the presence of electron and proton donors by a proton-coupled electron-transfer (PCET) mechanism to complete the O2-to-2H2O catalytic conversion in an overall 4e-/4H+ step. The present study provides deep mechanistic insights into the dioxygen reduction process that should serve as useful and broadly applicable principles for future design of more efficient catalysts in fuel cells.

A New Domain of Reactivity for High-Valent Dinuclear [M(µ-O)2 M'] Complexes in Oxidation Reactions.

The strikingly different reactivity of a series of homo- and heterodinuclear [(MIII )(µ-O)2 (MIII )']2+ (M=Ni; M'=Fe, Co, Ni and M=M'=Co) complexes with ß-diketiminate ligands in electrophilic and nucleophilic oxidation reactions is reported, and can be correlated to the spectroscopic features of the [(MIII )(µ-O)2 (MIII )']2+ core. In particular, the unprecedented nucleophilic reactivity of the symmetric [NiIII (µ-O)2 NiIII ]2+ complex and the decay of the asymmetric [NiIII (µ-O)2 CoIII ]2+ core through aromatic hydroxylation reactions represent a new domain for high-valent bis(µ-oxido)dimetal reactivity.

A Highly Reactive Oxoiron(IV) Complex Supported by a Bioinspired N3 O Macrocyclic Ligand.

The sluggish oxidants [FeIV (O)(TMC)(CH3 CN)]2+ (TMC=1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) and [FeIV (O)(TMCN-d12 )(OTf)]+ (TMCN-d12 =1,4,7,11-tetra(methyl-d3 )-1,4,7,11-tetraazacyclotetradecane) are transformed into the highly reactive oxidant [FeIV (O)(TMCO)(OTf)]+ (1; TMCO=4,8,12-trimethyl-1-oxa-4,8,12-triazacyclotetradecane) upon replacement of an NMe donor in the TMC and TMCN ligands by an O atom. A rate enhancement of five to six orders of magnitude in both H atom and O atom transfer reactions was observed upon oxygen incorporation into the macrocyclic ligand. This finding was explained in terms of the higher electrophilicity of the iron center and the higher availability of the more reactive S=2 state in 1. This rationalizes nature's preference for using O-rich ligand environments for the hydroxylation of strong C-H bonds in enzymatic reactions.

A High-Valent Non-Heme µ-Oxo Manganese(IV) Dimer Generated from a Thiolate-Bound Manganese(II) Complex and Dioxygen.

This study deals with the unprecedented reactivity of dinuclear non-heme MnII -thiolate complexes with O2 , which dependent on the protonation state of the initial MnII dimer selectively generates either a di-µ-oxo or µ-oxo-µ-hydroxo MnIV complex. Both dimers have been characterized by different techniques including single-crystal X-ray diffraction and mass spectrometry. Oxygenation reactions carried out with labeled 18 O2 unambiguously show that the oxygen atoms present in the MnIV dimers originate from O2 . Based on experimental observations and DFT calculations, evidence is provided that these MnIV species comproportionate with a MnII precursor to yield µ-oxo and/or µ-hydroxo MnIII dimers. Our work highlights the delicate balance of reaction conditions to control the synthesis of non-heme high-valent µ-oxo and µ-hydroxo Mn species from MnII precursors and O2 .