Demonstration of the Heterolytic OO Bond Cleavage of Putative Nonheme Iron(II)OOH(R) Complexes for Fenton and Enzymatic Reactions

One‐electron reduction of mononuclear nonheme iron(III) hydroperoxo (Fe^III? OOH) and iron(III) alkylperoxo (Fe^III? OOR) complexes by ferrocene (Fc) derivatives resulted in the formation of the corresponding iron(IV) oxo complexes. The conversion rates were dependent on the concentration and oxidation potentials of the electron donors, thus indicating that the reduction of the iron(III) (hydro/alkyl)peroxo complexes to their one‐electron reduced iron(II) (hydro/alkyl)peroxo species is the rate‐determining step, followed by the heterolytic O? O bond cleavage of the putative iron(II) (hydro/alkyl)peroxo species to give the iron(IV) oxo complexes. Product analysis supported the heterolytic O? O bond‐cleavage mechanism. The present results provide the first example showing the one‐electron reduction of iron(III) (hydro/alkyl)peroxo complexes and the heterolytic O? O bond cleavage of iron(II) (hydro/alkyl)peroxo species to form iron(IV) oxo intermediates which occur in nonheme iron enzymatic and Fenton reactions.     

Demonstration of the Heterolytic O?O Bond Cleavage of Putative Nonheme Iron(II)?OOH(R) Complexes for Fenton and Enzymatic Reactions

One‐electron reduction of mononuclear nonheme iron(III) hydroperoxo (Fe^III OOH) and iron(III) alkylperoxo (Fe^III OOR) complexes by ferrocene (Fc) derivatives resulted in the formation of the corresponding iron(IV) oxo complexes. The conversion rates were dependent on the concentration and oxidation potentials of the electron donors, thus indicating that the reduction of the iron(III) (hydro/alkyl)peroxo complexes to their one‐electron reduced iron(II) (hydro/alkyl)peroxo species is the rate‐determining step, followed by the heterolytic O O bond cleavage of the putative iron(II) (hydro/alkyl)peroxo species to give the iron(IV) oxo complexes. Product analysis supported the heterolytic O O bond‐cleavage mechanism. The present results provide the first example showing the one‐electron reduction of iron(III) (hydro/alkyl)peroxo complexes and the heterolytic O O bond cleavage of iron(II) (hydro/alkyl)peroxo species to form iron(IV) oxo intermediates which occur in nonheme iron enzymatic and Fenton reactions.     

Axial Ligand and Spin‐State Influence on the Formation and Reactivity of Hydroperoxo–Iron(III) Porphyrin Complexes

The present study focuses on the formation and reactivity of hydroperoxo–iron(III) porphyrin complexes formed in the [Fe^III(tpfpp)X]/H₂O₂/HOO^? system (TPFPP=5,10,15,20‐tetrakis(pentafluorophenyl)‐21H,23H‐porphyrin; X=Cl^? or CF₃SO₃^?) in acetonitrile under basic conditions at ?15 °C. Depending on the selected reaction conditions and the active form of the catalyst, the formation of high‐spin [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] could be observed with the application of a low‐temperature rapid‐scan UV/Vis spectroscopic technique. Axial ligation and the spin state of the iron(III) center control the mode of O? O bond cleavage in the corresponding hydroperoxo porphyrin species. A mechanistic changeover from homo‐ to heterolytic O? O bond cleavage is observed for high‐ [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] complexes, respectively. In contrast to other iron(III) hydroperoxo complexes with electron‐rich porphyrin ligands, electron‐deficient [Fe^III(tpfpp)(OH)(OOH)] was stable under relatively mild conditions and could therefore be investigated directly in the oxygenation reactions of selected organic substrates. The very low reactivity of [Fe^III(tpfpp)(OH)(OOH)] towards organic substrates implied that the ferric hydroperoxo intermediate must be a very sluggish oxidant compared with the iron(IV)–oxo porphyrin π‐cation radical intermediate in the catalytic oxygenation reactions of cytochrome P450.     

Synthesis,Characterization, and Reactivity of Cobalt(III)–Oxygen Complexes Bearing a Macrocyclic N‐Tetramethylated Cyclam Ligand

Mononuclear metal–dioxygen species are key intermediates that are frequently observed in the catalytic cycles of dioxygen activation by metalloenzymes and their biomimetic compounds. In this work, a side‐on cobalt(III)–peroxo complex bearing a macrocyclic N‐tetramethylated cyclam (TMC) ligand, [Co^III(15‐TMC)(O₂)]⁺, was synthesized and characterized with various spectroscopic methods. Upon protonation, this cobalt(III)–peroxo complex was cleanly converted into an end‐on cobalt(III)–hydroperoxo complex, [Co^III(15‐TMC)(OOH)]²⁺. The cobalt(III)–hydroperoxo complex was further converted to [Co^III(15‐TMC‐CH₂‐O)]²⁺ by hydroxylation of a methyl group of the 15‐TMC ligand. Kinetic studies and ¹⁸O‐labeling experiments proposed that the aliphatic hydroxylation occurred via a Co^IV–oxo (or Co^III–oxyl) species, which was formed by O? O bond homolysis of the cobalt(III)–hydroperoxo complex. In conclusion, we have shown the synthesis, structural and spectroscopic characterization, and reactivities of mononuclear cobalt complexes with peroxo, hydroperoxo, and oxo ligands.     

Amide‐Based Nonheme Cobalt(III) Olefin Epoxidation Catalyst: Partition of Multiple Active Oxidants CoVO,CoIVO,and CoIII?OO(O)CR

A mononuclear nonheme cobalt(III) complex of a tetradentate ligand containing two deprotonated amide moieties, [Co(bpc)Cl₂][Et₄N] ( 1 ; H₂bpc=4,5‐dichloro‐1,2‐bis(2‐pyridine‐2‐carboxamido)benzene), was prepared and then characterized by elemental analysis, IR, UV/Vis, and EPR spectroscopy, and X‐ray crystallography. This nonheme Co^III complex catalyzes olefin epoxidation upon treatment with meta‐chloroperbenzoic acid. It is proposed that complex 1 shows partitioning between the heterolytic and homolytic cleavage of an O? O bond to afford Co^V?O ( 3 ) and Co^IV?O ( 4 ) intermediates, proposed to be responsible for the stereospecific olefin epoxidation and radical‐type oxidations, respectively. Moreover, under extreme conditions, in which the concentration of an active substrate is very high, the Co? OOC(O)R ( 2 ) species is a possible reactive species for epoxidation. Furthermore, partitioning between heterolysis and homolysis of the O? O bond of the intermediate 2 might be very sensitive to the nature of the solvent, and the O? O bond of the Co? OOC(O)R species might proceed predominantly by heterolytic cleavage, even in the presence of small amounts of protic solvent, to produce a discrete Co^V?O intermediate as the dominant reactive species. Evidence for these multiple active oxidants was derived from product analysis, the use of peroxyphenylacetic acid as the peracid, and EPR measurements. The results suggest that a less accessible Co^V?O moiety can form in a system in which the supporting chelate ligand comprises a mixture of neutral and anionic nitrogen donors.     

Olefin cis‐Dihydroxylation and Aliphatic CH Bond Oxygenation by a Dioxygen‐Derived Electrophilic Iron–Oxygen Oxidant

Many iron‐containing enzymes involve metal–oxygen oxidants to carry out O₂‐dependent transformation reactions. However, the selective oxidation of C? H and C?C bonds by biomimetic complexes using O₂ remains a major challenge in bioinspired catalysis. The reactivity of iron–oxygen oxidants generated from an Fe^II–benzilate complex of a facial N₃ ligand were thus investigated. The complex reacted with O₂ to form a nucleophilic oxidant, whereas an electrophilic oxidant, intercepted by external substrates, was generated in the presence of a Lewis acid. Based on the mechanistic studies, a nucleophilic Fe^II–hydroperoxo species is proposed to form from the benzilate complex, which undergoes heterolytic O? O bond cleavage in the presence of a Lewis acid to generate an Fe^IV–oxo–hydroxo oxidant. The electrophilic iron–oxygen oxidant selectively oxidizes sulfides to sulfoxides, alkenes to cis‐diols, and it hydroxylates the C? H bonds of alkanes, including that of cyclohexane.     

Spectroscopic and Kinetic Evidence for the Crucial Role of Compound 0 in the P450cam‐Catalyzed Hydroxylation of Camphor by Hydrogen Peroxide

The hydroperoxo iron(III) intermediate P450_camFe^III–OOH, being the true Compound 0 (Cpd 0) involved in the natural catalytic cycle of P450_cam, could be transiently observed in the peroxo‐shunt oxidation of the substrate‐free enzyme by hydrogen peroxide under mild basic conditions and low temperature. The prolonged lifetime of Cpd 0 enabled us to kinetically examine the formation and reactivity of P450_camFe^III–OOH species as a function of varying reaction conditions, such as pH, and concentration of H₂O₂, camphor, and potassium ions. The mechanism of hydrogen peroxide binding to the substrate‐free form of P450_cam differs completely from that observed for other heme proteins possessing the distal histidine as a general acid–base catalyst and is mainly governed by the ability of H₂O₂ to undergo deprotonation at the hydroxo ligand coordinated to the iron(III) center under conditions of pH≥p${K{{{\rm P450}\hfill \atop {\rm a}\hfill}}}$ . Notably, no spectroscopic evidence for the formation of either Cpd I or Cpd II as products of heterolytic or homolytic O?O bond cleavage, respectively, in Cpd 0 could be observed under the selected reaction conditions. The kinetic data obtained from the reactivity studies involving (1R)‐camphor, provide, for the first time, experimental evidence for the catalytic activity of the P450Fe^III–OOH intermediate in the oxidation of the natural substrate of P450_cam.     

Axial ligand and spin-state influence on the formation and reactivity of hydroperoxo-iron(III) porphyrin complexes

The present study focuses on the formation and reactivity of hydroperoxo-iron(III) porphyrin complexes formed in the [Fe(III)(tpfpp)X]/H(2)O(2)/HOO(-) system (TPFPP=5,10,15,20-tetrakis(pentafluorophenyl)-21H,23H-porphyrin; X=Cl(-) or CF(3) SO(3)(-)) in acetonitrile under basic conditions at -15 °C. Depending on the selected reaction conditions and the active form of the catalyst, the formation of high-spin [Fe(III)(tpfpp)(OOH)] and low-spin [Fe(III)(tpfpp)(OH)(OOH)] could be observed with the application of a low-temperature rapid-scan UV/Vis spectroscopic technique. Axial ligation and the spin state of the iron(III) center control the mode of O-O bond cleavage in the corresponding hydroperoxo porphyrin species. A mechanistic changeover from homo- to heterolytic O-O bond cleavage is observed for high- [Fe(III)(tpfpp)(OOH)] and low-spin [Fe(III)(tpfpp)(OH)(OOH)] complexes, respectively. In contrast to other iron(III) hydroperoxo complexes with electron-rich porphyrin ligands, electron-deficient [Fe(III)(tpfpp)(OH)(OOH)] was stable under relatively mild conditions and could therefore be investigated directly in the oxygenation reactions of selected organic substrates. The very low reactivity of [Fe(III)(tpfpp)(OH)(OOH)] towards organic substrates implied that the ferric hydroperoxo intermediate must be a very sluggish oxidant compared with the iron(IV)-oxo porphyrin π-cation radical intermediate in the catalytic oxygenation reactions of cytochrome P450.     

Olefin cis‐Dihydroxylation and Aliphatic C?H Bond Oxygenation by a Dioxygen‐Derived Electrophilic Iron–Oxygen Oxidant

Many iron‐containing enzymes involve metal–oxygen oxidants to carry out O₂‐dependent transformation reactions. However, the selective oxidation of C H and CC bonds by biomimetic complexes using O₂ remains a major challenge in bioinspired catalysis. The reactivity of iron–oxygen oxidants generated from an Fe^II–benzilate complex of a facial N₃ ligand were thus investigated. The complex reacted with O₂ to form a nucleophilic oxidant, whereas an electrophilic oxidant, intercepted by external substrates, was generated in the presence of a Lewis acid. Based on the mechanistic studies, a nucleophilic Fe^II–hydroperoxo species is proposed to form from the benzilate complex, which undergoes heterolytic O O bond cleavage in the presence of a Lewis acid to generate an Fe^IV–oxo–hydroxo oxidant. The electrophilic iron–oxygen oxidant selectively oxidizes sulfides to sulfoxides, alkenes to cis‐diols, and it hydroxylates the C H bonds of alkanes, including that of cyclohexane.     

Theoretical study of the mechanism of oxoiron(IV) formation from H2O2 and a nonheme iron(II) complex: O-O cleavage involving proton-coupled electron transfer

It has recently been shown that the nonheme oxoiron(IV) species supported by the 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane ligand (TMC) can be generated in near-quantitative yield by reacting [Fe(II)(TMC)(OTf)(2)] with a stoichiometric amount of H(2)O(2) in CH(3)CN in the presence of 2,6-lutidine (Li, F.; England, J.; Que, L., Jr. J. Am. Chem. Soc. 2010, 132, 2134-2135). This finding has major implications for O-O bond cleavage events in both Fenton chemistry and nonheme iron enzymes. To understand the mechanism of this process, especially the intimate details of the O-O bond cleavage step, a series of density functional theory (DFT) calculations and analyses have been carried out. Two distinct reaction paths (A and B) were identified. Path A consists of two principal steps: (1) coordination of H(2)O(2) to Fe(II) and (2) a combination of partial homolytic O-O bond cleavage and proton-coupled electron transfer (PCET). The latter combination renders the rate-limiting O-O cleavage effectively a heterolytic process. Path B proceeds via a simultaneous homolytic O-O bond cleavage of H(2)O(2) and Fe-O bond formation. This is followed by H abstraction from the resultant Fe(III)-OH species by an ?OH radical. Calculations suggest that path B is plausible in the absence of base. However, once 2,6-lutidine is added to the reacting system, the reaction barrier is lowered and more importantly the mechanistic path switches to path A, where 2,6-lutidine plays an essential role as an acid-base catalyst in a manner similar to how the distal histidine or glutamate residue assists in compound I formation in heme peroxidases. The reaction was found to proceed predominantly on the quintet spin state surface, and a transition to the triplet state, the experimentally known ground state for the TMC-oxoiron(IV) species, occurs in the last stage of the oxoiron(IV) formation process.     

Amide-based nonheme cobalt(III) olefin epoxidation catalyst: partition of multiple active oxidants Co(V)=O, Co(IV)=O, and Co(III)-OO(O)CR

A mononuclear nonheme cobalt(III) complex of a tetradentate ligand containing two deprotonated amide moieties, [Co(bpc)Cl(2)][Et(4)N] (1; H(2)bpc = 4,5-dichloro-1,2-bis(2-pyridine-2-carboxamido)benzene), was prepared and then characterized by elemental analysis, IR, UV/Vis, and EPR spectroscopy, and X-ray crystallography. This nonheme Co(III) complex catalyzes olefin epoxidation upon treatment with meta-chloroperbenzoic acid. It is proposed that complex 1 shows partitioning between the heterolytic and homolytic cleavage of an O-O bond to afford Co(V)=O (3) and Co(IV)=O (4) intermediates, proposed to be responsible for the stereospecific olefin epoxidation and radical-type oxidations, respectively. Moreover, under extreme conditions, in which the concentration of an active substrate is very high, the Co-OOC(O)R (2) species is a possible reactive species for epoxidation. Furthermore, partitioning between heterolysis and homolysis of the O-O bond of the intermediate 2 might be very sensitive to the nature of the solvent, and the O-O bond of the Co-OOC(O)R species might proceed predominantly by heterolytic cleavage, even in the presence of small amounts of protic solvent, to produce a discrete Co(V) ?O intermediate as the dominant reactive species. Evidence for these multiple active oxidants was derived from product analysis, the use of peroxyphenylacetic acid as the peracid, and EPR measurements. The results suggest that a less accessible Co(V)=O moiety can form in a system in which the supporting chelate ligand comprises a mixture of neutral and anionic nitrogen donors.     

A theoretical study on the reaction pathways of peroxynitrite formation and decay at nonheme iron centers

A computational study based on density functional theory was undertaken to identify possible reaction pathways for the formation and decomposition of peroxynitrite at models of the active sites of the nonheme superoxide scavenging enzymes superoxide reductase (SOR) and iron superoxide dismutase (FeSOD). Two peroxynitrite isomers and their possible protonated states were investigated, namely Fe? OONO^?, Fe? N(O)OO^?, Fe? OONOH, and Fe? N(O)OOH. Peroxynitrite formation at the active sites was assumed by either the interaction of a peroxynitrite cis/trans anion with the pentacoordinated iron active site or the interaction between a nitric oxide bound adduct and superoxide; both scenarios were found to be facile for all models investigated. The ferrous adducts of the Fe? OONO^?isomer were found to undergo instant heterolytic cleavage of the O? ONO bond to yield nitrite, whereas for the ferric adducts, the homolytic cleavage of the O? ONO bond to yield nitrogen dioxide was found to be energetically facile. For the Fe? N(O)OO^? isomer, the active site models of FeSOD and SOR were only able to accommodate the cis isomer of peroxynitrite. Ferric adducts of the cis Fe? OONO^? isomer were found to be energetically more stable than their trans counterparts and were also more stable than the cis adducts of the Fe? N(O)OO^? isomer; conversely, the protonated forms of all adducts of the Fe? OONOH isomer were found to be lower in energy than their equivalent Fe? N(O)OOH adducts. Multiple reaction pathways for the decomposition of the formed peroxynitrite adducts (whether the anions or the protonated forms) were proposed and explored. The energy requirements for the decomposition processes ranged from exothermic to highly demanding depending on the peroxynitrite isomer, the type of model (whether an SOR or FeSOD active site), and the oxidation state of iron. © 2014 Wiley Periodicals, Inc.     

Does Hydrogen‐Bonding Donation to Manganese(IV)–Oxo and Iron(IV)–Oxo Oxidants Affect the Oxygen‐Atom Transfer Ability? A Computational Study

Iron(IV)–oxo intermediates are involved in oxidations catalyzed by heme and nonheme iron enzymes, including the cytochromes P450. At the distal site of the heme in P450 Compound I (Fe^IV–oxo bound to porphyrin radical), the oxo group is involved in several hydrogen‐bonding interactions with the protein, but their role in catalysis is currently unknown. In this work, we investigate the effects of hydrogen bonding on the reactivity of high‐valent metal–oxo moiety in a nonheme iron biomimetic model complex with trigonal bipyramidal symmetry that has three hydrogen‐bond donors directed toward a metal(IV)–oxo group. We show these interactions lower the oxidative power of the oxidant in reactions with dehydroanthracene and cyclohexadiene dramatically as they decrease the strength of the O? H bond (BDE_OH) in the resulting metal(III)–hydroxo complex. Furthermore, the distal hydrogen‐bonding effects cause stereochemical repulsions with the approaching substrate and force a sideways attack rather than a more favorable attack from the top. The calculations, therefore, give important new insights into distal hydrogen bonding, and show that in biomimetic, and, by extension, enzymatic systems, the hydrogen bond may be important for proton‐relay mechanisms involved in the formation of the metal–oxo intermediates, but the enzyme pays the price for this by reduced hydrogen atom abstraction ability of the intermediate. Indeed, in nonheme iron enzymes, where no proton relay takes place, there generally is no donating hydrogen bond to the iron(IV)–oxo moiety.     

Activation of a Non‐Heme FeIII‐OOH by a Second FeIII to Hydroxylate Strong C−H Bonds: Possible Implications for Soluble Methane Monooxygenase

Non‐heme iron oxygenases contain either monoiron or diiron active sites, and the role of the second iron in the latter enzymes is a topic of particular interest, especially for soluble methane monooxygenase (sMMO). Herein we report the activation of a non‐heme Fe^III‐OOH intermediate in a synthetic monoiron system using Fe^III(OTf)₃ to form a high‐valent oxidant capable of effecting cyclohexane and benzene hydroxylation within seconds at ?40 °C. Our results show that the second iron acts as a Lewis acid to activate the iron–hydroperoxo intermediate, leading to the formation of a powerful Fe^V=O oxidant—a possible role for the second iron in sMMO.     

Heterolytic O−O Bond Cleavage Upon Single Electron Transfer to a Nonheme Fe(III)−OOH Complex

The one-electron reduction of the nonheme iron(III)-hydroperoxo complex, [Fe^III(OOH)(L₅²)]²⁺ (L₅²=N-methyl-N,N’,N’-tris(2-pyridylmethyl)ethane-1,2-diamine), carried out at −70 °C results in the release of dioxygen and in the formation of [Fe^II(OH)(L₅²)]⁺ following a bimolecular process. This reaction can be performed either with cobaltocene as chemical reductant, or electrochemically. These experimental observations are consistent with the disproportionation of the hydroperoxo group in the putative Fe^II(OOH) intermediate generated upon reduction of the Fe^III(OOH) starting complex. One plausible mechanistic scenario is that this disproportionation reaction follows an O−O heterolytic cleavage pathway via a Fe^IV-oxo species.     

Selective Formation of an FeIVO or an FeIIIOOH Intermediate From Iron(II) and H2O2: Controlled Heterolytic versus Homolytic Oxygen–Oxygen Bond Cleavage by the Second Coordination Sphere

We demonstrate that the devised incorporation of an alkylamine group into the second coordination sphere of an Fe^II complex allows to switch its reactivity with H₂O₂ from the usual formation of Fe^III species towards the selective generation of an Fe^IV‐oxo intermediate. The Fe^IV‐oxo species was characterized by UV/Vis absorption and Mössbauer spectroscopy. Variable‐temperature kinetic analyses point towards a mechanism in which the heterolytic cleavage of the O?O bond is triggered by a proton transfer from the proximal to the distal oxygen atom in the Fe^II‐H₂O₂ complex with the assistance of the pendant amine. DFT studies reveal that this heterolytic cleavage is actually initiated by an homolytic O?O cleavage immediately followed by a proton‐coupled electron transfer (PCET) that leads to the formation of the Fe^IV‐oxo and release of water through a concerted mechanism.     

Density Functional Studies on Thromboxane Biosynthesis: Mechanism and Role of the Heme‐Thiolate System

Reaction mechanisms for the isomerization of prostaglandin H₂ to thromboxane A₂, and degradation to 12‐L‐hydroxy‐5,8,10‐heptadecatrienoic acid (HHT) and malondialdehyde (MDA), catalyzed by thromboxane synthase, were investigated using the unrestricted Becke‐three‐parameter plus Lee–Yang–Parr (UB3LYP) density functional level theory. In addition to the reaction pathway through Fe^IV‐porphyrin intermediates, a new reaction pathway through Fe^III‐porphyrin π‐cation radical intermediates was found. Both reactions proceed with the homolytic cleavage of endoperoxide O? O to give an alkoxy radical. This intermediate converts into an allyl radical intermediate by a C? C homolytic cleavage, followed by the formation of thromboxane A₂ having a 6‐membered ring through a one electron transfer, or the degradation into HHT and MDA. The proposed mechanism shows that an iron(III)‐containing system having electron acceptor ability is essential for the 6‐membered ring formation leading to thromboxane A₂. Our results suggest that the step of the endoperoxide O? O homolytic bond cleavage has the highest activation energy following the binding of prostaglandin H₂ to thromboxane synthase.     

Highly Selective and Catalytic Oxygenations of C−H and C=C Bonds by a Mononuclear Nonheme High‐Spin Iron(III)‐Alkylperoxo Species

The reactivity of a mononuclear high‐spin iron(III)‐alkylperoxo intermediate [Fe^III(t‐BuL^Urea)(OOCm)(OH₂)]²⁺( 2 ), generated from [Fe^II(t‐BuL^Urea)(H₂O)(OTf)](OTf) ( 1 ) [t‐BuL^Urea=1,1′‐(((pyridin‐2‐ylmethyl)azanediyl)bis(ethane‐2,1‐diyl))bis(3‐(tert‐butyl)urea), OTf=trifluoromethanesulfonate] with cumyl hydroperoxide (CmOOH), toward the C?H and C=C bonds of hydrocarbons is reported. 2 oxygenates the strong C?H bonds of aliphatic substrates with high chemo‐ and stereoselectivity in the presence of 2,6‐lutidine. While 2 itself is a sluggish oxidant, 2,6‐lutidine assists the heterolytic O?O bond cleavage of the metal‐bound alkylperoxo, giving rise to a reactive metal‐based oxidant. The roles of the urea groups on the supporting ligand, and of the base, in directing the selective and catalytic oxygenation of hydrocarbon substrates by 2 are discussed.     

Mononuclear Nonheme High‐Spin (S=2) versus Intermediate‐Spin (S=1) Iron(IV)–Oxo Complexes in Oxidation Reactions

Mononuclear nonheme high‐spin (S=2) iron(IV)–oxo species have been identified as the key intermediates responsible for the C?H bond activation of organic substrates in nonheme iron enzymatic reactions. Herein we report that the C?H bond activation of hydrocarbons by a synthetic mononuclear nonheme high‐spin (S=2) iron(IV)–oxo complex occurs through an oxygen non‐rebound mechanism, as previously demonstrated in the C?H bond activation by nonheme intermediate (S=1) iron(IV)–oxo complexes. We also report that C?H bond activation is preferred over C=C epoxidation in the oxidation of cyclohexene by the nonheme high‐spin (HS) and intermediate‐spin (IS) iron(IV)–oxo complexes, whereas the C=C double bond epoxidation becomes a preferred pathway in the oxidation of deuterated cyclohexene by the nonheme HS and IS iron(IV)–oxo complexes. In the epoxidation of styrene derivatives, the HS and IS iron(IV) oxo complexes are found to have similar electrophilic characters.     

A single-site mutation (F429H) converts the enzyme CYP 2B4 into a heme oxygenase: a QM/MM study

The intriguing deactivation of the cytochrome P450 (CYP) 2B4 enzyme induced by mutation of a single residue, Phe429 to His, is explored by quantum mechanical/molecular mechanical calculations of the O-OH bond activation of the (Fe(3+)OOH)(-) intermediate. It is found that the F429H mutant of CYP 2B4 undergoes homolytic instead of heterolytic O-OH bond cleavage. Thus, the mutant acquires the following characteristics of a heme oxygenase enzyme: (a) donation by His429 of an additional NH---S H-bond to the cysteine ligand combined with the presence of the substrate retards the heterolytic cleavage and gives rise to homolytic O-OH cleavage, and (b) the Thr302/water cluster orients nascent OH(?) and ensures efficient meso hydroxylation.