Seungwoo Hong

Dioxygen Activation by a Non-Heme Iron(II) Complex: Formation of an Iron(IV)−Oxo Complex via C−H Activation by a Putative Iron(III)−Superoxo Species

Iron(III)-superoxo intermediates are believed to play key roles in oxygenation reactions by non-heme iron enzymes. We now report that a non-heme iron(II) complex activates O(2) and generates its corresponding iron(IV)-oxo complex in the presence of substrates with weak C-H bonds (e.g., olefins and alkylaromatic compounds). We propose that a putative iron(III)-superoxo intermediate initiates the O(2)-activation chemistry by abstracting a H atom from the substrate, with subsequent generation of a high-valent iron(IV)-oxo intermediate from the resulting iron(III)-hydroperoxo species.

Dioxygen activation by mononuclear nonheme iron(II) complexes generates iron-oxygen intermediates in the presence of an NADH analogue and proton.

One primary goal in biomimetic research is to understand mechanisms of dioxygen activation, structures of reactive intermediates, and reactivities of the intermediates involved in catalytic oxidation reactions by metalloenzymes, such as heme and nonheme iron oxygenases. In this communication, we have reported the first example of generating nonheme iron(III)-hydroperoxo and iron(IV)-oxo complexes by activating O(2) with a biologically important electron donor, an NADH analogue, and an acid. The formation of iron(III)-hydroperoxo and iron(IV)-oxo complexes was found to depend on the supporting ligands. We have also demonstrated that high-spin nonheme iron(II) complexes with a low oxidation potential are able to bind and activate O(2) to generate the iron-oxygen intermediates.

Comparison of High-Spin and Low-Spin Nonheme Fe III −OOH Complexes in O−O Bond Homolysis and H‑Atom Abstraction Reactivities

The geometric and electronic structures and reactivity of an S = 5/2 (HS) mononuclear nonheme (TMC)Fe(III)-OOH complex are studied by spectroscopies, calculations, and kinetics and compared with the results of previous studies of S = 1/2 (LS) Fe(III)-OOH complexes to understand parallels and differences in mechanisms of O-O bond homolysis and electrophilic H-atom abstraction reactions. The homolysis reaction of the HS [(TMC)Fe(III)-OOH](2+) complex is found to involve axial ligand coordination and a crossing to the LS surface for O-O bond homolysis. Both HS and LS Fe(III)-OOH complexes are found to perform direct H-atom abstraction reactions but with very different reaction coordinates. For the LS Fe(III)-OOH, the transition state is late in O-O and early in C-H coordinates. However, for the HS Fe(III)-OOH, the transition state is early in O-O and further along in the C-H coordinate. In addition, there is a significant amount of electron transfer from the substrate to the HS Fe(III)-OOH at transition state, but that does not occur in the LS transition state. Thus, in contrast to the behavior of LS Fe(III)-OOH, the H-atom abstraction reactivity of HS Fe(III)-OOH is found to be highly dependent on both the ionization potential and the C-H bond strength of the substrate. LS Fe(III)-OOH is found to be more effective in H-atom abstraction for strong C-H bonds, while the higher reduction potential of HS Fe(III)-OOH allows it to be active in electrophilic reactions without the requirement of O-O bond cleavage. This is relevant to the Rieske dioxygenases, which are proposed to use a HS Fe(III)-OOH to catalyze cis-dihydroxylation of a wide range of aromatic compounds.

Ligand topology effect on the reactivity of a mononuclear nonheme iron(IV)-oxo complex in oxygenation reactions.

Mononuclear nonheme iron(IV)-oxo complexes with two different topologies, cis-α-[Fe(IV)(O)(BQCN)](2+) and cis-β-[Fe(IV)(O)(BQCN)](2+), were synthesized and characterized with various spectroscopic methods. The effect of ligand topology on the reactivities of nonheme iron(IV)-oxo complexes was investigated in C-H bond activation and oxygen atom-transfer reactions; cis-α-[Fe(IV)(O)(BQCN)](2+) was more reactive than cis-β-[Fe(IV)(O)(BQCN)](2+) in the oxidation reactions. The reactivity difference between the cis-α and cis-β isomers of [Fe(IV)(O)(BQCN)](2+) was rationalized with the Fe(IV/III) redox potentials of the iron(IV)-oxo complexes: the Fe(IV/III) redox potential of the cis-α isomer was 0.11 V higher than that of the cis-β isomer.

[Fe(IV)═O(TBC)(CH3CN)]2+: comparative reactivity of iron(IV)-oxo species with constrained equatorial cyclam ligation.

[Fe(IV)═O(TBC)(CH(3)CN)](2+) (TBC = 1,4,8,11-tetrabenzyl-1,4,8,11-tetraazacyclotetradecane) is characterized, and its reactivity differences relative to [Fe(IV)═O(TMC)(CH(3)CN)](2+) (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) are evaluated in hydrogen atom (H-atom) abstraction and oxo-transfer reactions. Structural differences are defined using X-ray absorption spectroscopy and correlated to reactivities using density functional theory. The S = 1 ground states are highly similar and result in large activation barriers (~25 kcal/mol) due to steric interactions between the cyclam chelate and the substrate (e.g., ethylbenzene) associated with the equatorial π-attack required by this spin state. Conversely, H-atom abstraction reactivity on an S = 2 surface allows for a σ-attack with an axial substrate approach. This results in decreased steric interactions with the cyclam and a lower barrier (~9 kcal/mol). For [Fe(IV)═O(TBC)(CH(3)CN)](2+), the S = 2 excited state in the reactant is lower in energy and therefore more accessible at the transition state due to a weaker ligand field associated with the steric interactions of the benzyl substituents with the trans-axial ligand. This study is further extended to the oxo-transfer reaction, which is a two-electron process requiring both σ- and π-electron transfer and thus a nonlinear transition state. In oxo-transfer, the S = 2 has a lower barrier due to sequential vs concerted (S = 1) two electron transfer which gives a high-spin ferric intermediate at the transition state. The [Fe(IV)═O(TBC)(CH(3)CN)](2+) complex is more distorted at the transition state, with the iron farther out of the equatorial plane due to the steric interaction of the benzyl groups with the trans-axial ligand. This allows for better orbital overlap with the substrate, a lower barrier, and an increased rate of oxo-transfer.

Redox-inactive metal ions modulate the reactivity and oxygen release of mononuclear non-haem iron( III )–peroxo complexes

Redox-inactive metal ions that function as Lewis acids play pivotal roles in modulating the reactivity of oxygen-containing metal complexes and metalloenzymes, such as the oxygen-evolving complex in photosystem II and its small-molecule mimics. Here we report the synthesis and characterization of non-haem iron(III)–peroxo complexes that bind redox-inactive metal ions, (TMC)FeIII–(μ,η2:η2-O2)–Mn+ (Mn+ = Sr2+, Ca2+, Zn2+, Lu3+, Y3+ and Sc3+; TMC, 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane). We demonstrate that the Ca2+ and Sr2+ complexes showed similar electrochemical properties and reactivities in one-electron oxidation or reduction reactions. However, the properties and reactivities of complexes formed with stronger Lewis acidities were found to be markedly different. Complexes that contain Ca2+ or Sr2+ ions were oxidized by an electron acceptor to release O2, whereas the release of O2 did not occur for complexes that bind stronger Lewis acids. We discuss these results in the light of the functional role of the Ca2+ ion in the oxidation of water to dioxygen by the oxygen-evolving complex. Non-haem iron(III)-peroxo complexes that bind redox-inactive metal ions are synthesized to investigate the role of the Ca2+ ion in the oxidation of water to dioxygen in photosystem II. The electrochemical properties and reactions of these compounds with an electron donor and an acceptor are found to be markedly dependent on the Lewis acidity of redox-inactive metal ions.

Foxp3 Expression in p53-dependent DNA Damage Responses

The forkhead transcription factor, Foxp3, is thought to act as a master regulator that controls (suppresses) expression of the breast cancer oncogenes, SKP2 and HER-2/ErbB2. However, the mechanisms that regulate Foxp3 expression and thereby modulate tumor development remain largely unexplored. Here, we demonstrate that Foxp3 up-regulation requires p53 function, showing that Foxp3 expression is directly regulated by p53 upon DNA damage responses in human breast and colon carcinoma cells. Treatment with the genotoxic agents, doxorubicin or etoposide, induced Foxp3 expression in p53-positive carcinoma cells, but not in cells lacking p53 function. Furthermore, knock down of endogenous wild-type p53 using RNA interference abrogated Foxp3 induction by genotoxic agents, and exogenous expression of p53 in cells lacking p53 restored the responsiveness of Foxp3 to DNA-damaging stresses. In addition, Foxp3 knock down blunted the p53-mediated growth inhibitory response to DNA-damaging agents. These results suggest that induction of Foxp3 in the context of tumor suppression is regulated in a p53-dependent manner and implicate Foxp3 as a key determinant of cell fate in p53-dependent DNA damage responses.

Spectroscopic Capture and Reactivity of a Low‐Spin Cobalt(IV)‐Oxo Complex Stabilized by Binding Redox‐Inactive Metal Ions

High-valent cobalt-oxo intermediates are proposed as reactive intermediates in a number of cobalt-complex-mediated oxidation reactions. Herein we report the spectroscopic capture of low-spin (S=1/2) Co(IV)-oxo species in the presence of redox-inactive metal ions, such as Sc(3+), Ce(3+), Y(3+), and Zn(2+), and the investigation of their reactivity in C-H bond activation and sulfoxidation reactions. Theoretical calculations predict that the binding of Lewis acidic metal ions to the cobalt-oxo core increases the electrophilicity of the oxygen atom, resulting in the redox tautomerism of a highly unstable [(TAML)Co(III)(O˙)](2-) species to a more stable [(TAML)Co(IV)(O)(M(n+))] core. The present report supports the proposed role of the redox-inactive metal ions in facilitating the formation of high-valent metal-oxo cores as a necessary step for oxygen evolution in chemistry and biology.

Crystallographic and spectroscopic characterization and reactivities of a mononuclear non-haem iron(III)-superoxo complex

Mononuclear non-haem iron(III)-superoxo species (Fe(III)-O2(-·)) have been implicated as key intermediates in the catalytic cycles of dioxygen activation by non-haem iron enzymes. Although non-haem iron(III)-superoxo species have been trapped and characterized spectroscopically in enzymatic and biomimetic reactions, no structural information has yet been obtained. Here we report the isolation, spectroscopic characterization and crystal structure of a mononuclear side-on (η(2)) iron(III)-superoxo complex with a tetraamido macrocyclic ligand. The non-haem iron(III)-superoxo species undergoes both electrophilic and nucleophilic oxidation reactions, as well as O2-transfer between metal complexes. In the O2-transfer reaction, the iron(III)-superoxo complex transfers the bound O2 unit to a manganese(III) analogue, resulting in the formation of a manganese(IV)-peroxo complex, which is characterized structurally and spectroscopically as a mononuclear side-on (η(2)) manganese(IV)-peroxo complex. The difference in the redox distribution between the metal ions and O2 in iron(III)-superoxo and manganese(IV)-peroxo complexes is rationalized using density functional theory calculations.

Contrasting Effects of Axial Ligands on Electron‐Transfer Versus Proton‐Coupled Electron‐Transfer Reactions of Nonheme Oxoiron(IV) Complexes

The effects of axial ligands on electron-transfer and proton-coupled electron-transfer reactions of mononuclear nonheme oxoiron(IV) complexes were investigated by using [Fe(IV)(O)(tmc)(X)](n+) (1-X) with various axial ligands, in which tmc is 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane and X is CH(3)CN (1-NCCH(3)), CF(3)COO(-) (1-OOCCF(3)), or N(3) (-) (1-N(3)), and ferrocene derivatives as electron donors. As the binding strength of the axial ligands increases, the one-electron reduction potentials of 1-X (E(red), V vs. saturated calomel electrode (SCE)) are more negatively shifted by the binding of the more electron-donating axial ligands in the order of 1-NCCH(3) (0.39) > 1-OOCCF(3) (0.13) > 1-N(3) (-0.05 V). Rate constants of electron transfer from ferrocene derivatives to 1-X were analyzed in light of the Marcus theory of electron transfer to determine reorganization energies (lambda) of electron transfer. The lambda values decrease in the order of 1-NCCH(3) (2.37) > 1-OOCCF(3) (2.12) > 1-N(3) (1.97 eV). Thus, the electron-transfer reduction becomes less favorable thermodynamically but more favorable kinetically with increasing donor ability of the axial ligands. The net effect of the axial ligands is the deceleration of the electron-transfer rate in the order of 1-NCCH(3) > 1-OOCCF(3) > 1-N(3). In sharp contrast to this, the rates of the proton-coupled electron-transfer reactions of 1-X are markedly accelerated in the presence of an acid in the opposite order: 1-NCCH(3) < 1-OOCCF(3) < 1-N(3). Such contrasting effects of the axial ligands on the electron-transfer and proton-coupled electron-transfer reactions of nonheme oxoiron(IV) complexes are discussed in light of the counterintuitive reactivity patterns observed in the oxo transfer and hydrogen-atom abstraction reactions by nonheme oxoiron(IV) complexes (Sastri et al. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 19 181-19 186).