Probing the cytochrome P450-like reactivity of high-valent oxo iron intermediates in the gas phase

Electrospray ionization in combination with Fourier transform ion cyclotron resonance spectrometry is used to prepare and characterize at a molecular level high-valent oxoiron intermediates formed in the reaction of [(TPFPP)Fe(III)]Cl (TPFPP= meso-tetrakis(pentafluorophenyl)porphinato dianion) (1-Cl) with H(2)O(2) in methanol. The intrinsic reactivity in the gas phase of the iron(IV) oxo porphyrin cation radical complex, [(TPFPP)(.+)Fe(IV)=O](+), has been probed toward selected substrates (S), chosen among naturally occurring and model compounds. Whereas CO and cyclohexane proved to be unreactive, olefins, sulfides, amines, and phosphites all undergo oxygen atom transfer in the gas phase yielding the reduction product 1 and/or an adduct ion ([1-S](+)). The reaction efficiencies show a qualitative correlation with the oxophilic character of the active site of S. A notable exception is nitric oxide, which displays a remarkably high reactivity, in line with the important role of NO reactions with iron porphyrin complexes. Furthermore, subsidiary information on the neat association reaction of 1 with selected ligands (L) has been obtained by a kinetic study showing that both the efficiency and the extent of ligation toward the naked ion 1 depend on the electron-donating ability of L.     

Axial ligand substituted nonheme FeIV=O complexes: observation of near-UV LMCT bands and Fe=O Raman vibrations

Axial ligand substitution of a mononuclear nonheme oxoiron(IV) complex, [FeIV(O)(TMC)(NCCH3)]2+ (1) (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), leads to the formation of new FeIV=O species with relatively intense electronic absorption features in the near-UV region. The presence of these near-UV features allowed us to make the first observation of Fe=O vibrations of S = 1 mononuclear nonheme oxoiron(IV) complexes by resonance Raman spectroscopy. We have also demonstrated that the reactivity of nonheme oxoiron(IV) intermediates is markedly influenced by the axial ligands.     

Fast catalytic hydroxylation of hydrocarbons with ruthenium porphyrins

Ruthenium porphyrin complexes such as carbonylruthenium(II) tetrakispentafluorophenylporphyrin [Ru(II)(TPFPP)(CO)] were found to be efficient catalysts for the hydroxylation of alkanes in the presence of 2,6-dichloropyridine N-oxide as the oxidant under mild, nonacidic conditions. Up to 14 800 turnovers (TO) and rates of 800 TO/min were obtained for the hydroxylation of adamantane. The hydroxylation of cis-decalin afforded cis-9-decalol and cis-decalin-9,10-diol, exclusively, thus, excluding a long-lived radicals mechanism. The kinetics of product evolution in a typical catalytic oxygenation showed an initial induction period followed by a fast, apparently zero-order phase with maximum rates and high efficiencies. Deuterium isotope effects (kH/kD) in the range of 4.2-6.4 were found for the hydroxylation of alkanes. A Hammett treatment of the data for the oxidation of para-substituted toluene derivatives showed a linear correlation with a highly negative rho+ value of -2.0. On the basis of kinetic and spectroscopic evidence, Ru(VI)(TPFPP)(O)2, Ru(II)(TPFPP)(CO), and Ru(IV)(TPFPP)Cl2 observed during catalysis were ruled out as candidates for the active catalyst responsible for the high efficiencies and turnover rates in the oxidation reactions. The fastest rates of adamantane hydroxylation with 2,6-dichloropyridine N-oxide were achieved by the reductive activation of Ru(IV)(TPFPP)Cl2 with a zinc amalgam. This redox activation is consistent with the formation of an active Ru(III) intermediate in situ by a one-electron reduction of the Ru(IV) porphyrin. EPR spectra characteristic of Ru(III) have been observed upon the reduction of Ru(IV)(TPFPP)Cl2 with a zinc amalgam. In the adamantane oxidation mediated with Ru(III)(TPFPP)(OEt), it was found that, during this process, the Ru(III) porphyrin was gradually converted to a dioxoRu(VI) porphyrin. Concomitant with this conversion, the reaction rates decreased. Catalyst activation was also stimulated by autoxidation of the solvent CH2Cl2. On the basis of these data, a mechanism is proposed that incorporates a "fast" cycle involving metastable Ru(III) and oxoRu(V) intermediates and a "slow" oxidation cycle, mediated by oxoRu(IV) and trans-dioxoRu(VI) porphyrin complexes.     

Laser flash photolysis generation and kinetic studies of porphyrin-manganese-oxo intermediates. Rate constants for oxidations effected by porphyrin-Mn(V)-oxo species and apparent disproportionation equilibrium constants for porphyrin-Mn(IV)-oxo species

Porphyrin-manganese(V)-oxo and porphyrin-manganese(IV)-oxo species were produced in organic solvents by laser flash photolysis (LFP) of the corresponding porphyrin-manganese(III) perchlorate and chlorate complexes, respectively, permitting direct kinetic studies. The porphyrin systems studied were 5,10,15,20-tetraphenylporphyrin (TPP), 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPFPP), and 5,10,15,20-tetrakis(4-methylpyridinium)porphyrin (TMPyP). The order of reactivity for (porphyrin)Mn(V)(O) derivatives in self-decay reactions in acetonitrile and in oxidations of substrates was (TPFPP) > (TMPyP) > (TPP). Representative rate constants for reaction of (TPFPP)Mn(V)(O) in acetonitrile are k = 6.1 x 10(5) M(-1) s(-1) for cis-stilbene and k = 1.4 x 10(5) M(-1) s(-1) for diphenylmethane, and the kinetic isotope effect in oxidation of ethylbenzene and ethylbenzene-d(10) is k(H)/k(D) = 2.3. Competitive oxidation reactions conducted under catalytic conditions display approximately the same relative rate constants as were found in the LFP studies of (porphyrin)Mn(V)(O) derivatives. The apparent rate constants for reactions of (porphyrin)Mn(IV)(O) species show inverted reactivity order with (TPFPP) < (TMPyP) < (TPP) in reactions with cis-stilbene, triphenylamine, and triphenylphosphine. The inverted reactivity results because (porphyrin)Mn(IV)(O) disproportionates to (porphyrin)Mn(III)X and (porphyrin)Mn(V)(O), which is the primary oxidant, and the equilibrium constants for disproportionation of (porphyrin)Mn(IV)(O) are in the order (TPFPP) < (TMPyP) < (TPP). The fast comproportionation reaction of (TPFPP)Mn(V)(O) with (TPFPP)Mn(III)Cl to give (TPFPP)Mn(IV)(O) (k = 5 x 10(8) M(-1) s(-1)) and disproportionation reaction of (TPP)Mn(IV)(O) to give (TPP)Mn(V)(O) and (TPP)Mn(III)X (k approximately 2.5 x 10(9) M(-1) s(-1)) were observed. The relative populations of (porphyrin)Mn(V)(O) and (porphyrin)Mn(IV)(O) were determined from the ratios of observed rate constants for self-decay reactions in acetonitrile and oxidation reactions of cis-stilbene by the two oxo derivatives, and apparent disproportionation equilibrium constants for the three systems in acetonitrile were estimated. A model for oxidations under catalytic conditions is presented.     

Redox potentials of oxoiron(IV) porphyrin π-cation radical complexes: participation of electron transfer process in oxygenation reactions

The oxoiron(IV) porphyrin π-cation radical complex (compound I) has been identified as the key reactive intermediate of several heme enzymes and synthetic heme complexes. The redox properties of this reactive species are not yet well understood. Here, we report the results of a systematic study of the electrochemistry of oxoiron(IV) porphyrin π-cation radical complexes with various porphyrin structures and axial ligands in organic solvents at low temperatures. The cyclic voltammogram of (TMP)Fe(IV)O, (TMP = 5,10,15,20-tetramesitylporphyrinate), exhibits two quasi-reversible redox waves at E(1/2) = 0.88 and 1.18 V vs SCE in dichloromethane at -60 °C. Absorption spectral measurements for electrochemical oxidation at controlled potential clearly indicated that the first redox wave results from the (TMP)Fe(IV)O/[(TMP(+?))Fe(IV)O](+) couple. The redox potential for the (TMP)Fe(IV)O/[(TMP(+?))Fe(IV)O](+) couple undergoes a positive shift upon coordination of an anionic axial ligand but a negative shift upon coordination of a neutral axial ligand (imidazole). The negative shifts of the redox potential for the imidazole complexes are contrary to their high oxygenation activity. On the other hand, the electron-withdrawing effect of the meso-substituent shifts the redox potential in a positive direction. Comparison of the measured redox potentials and reaction rate constants for epoxidation of cyclooctene and demethylation of N,N-dimethylanilines enable us to discuss the details of the electron transfer process from substrates to the oxoiron(IV) porphyrin π-cation radical complex in the oxygenation mechanisms.     

Anionic ligand effect on the nature of epoxidizing intermediates in iron porphyrin complex-catalyzed epoxidation reactions

We have studied an anionic ligand effect in iron porphyrin complex-catalyzed competitive epoxidations of cis- and trans-stilbenes by various terminal oxidants and found that the ratios of cis- to trans-stilbene oxide products formed in competitive epoxidations were markedly dependent on the ligating nature of the anionic ligands. The ratios of cis- to trans-stilbene oxides obtained in the reactions of Fe(TPP)X (TPP = meso-tetraphenylporphinato dianion and X(-) = anionic ligand) and iodosylbenzene (PhIO) were 14 and 0.9 when the X(-) of Fe(TPP)X was Cl(-) and CF(3)SO(3)(-), respectively. An anionic ligand effect was also observed in the reactions of an electron-deficient iron(III) porphyrin complex containing a number of different anionic ligands, Fe(TPFPP)X [TPFPP = meso-tetrakis(pentafluorophenyl)porphinato dianion and X(-) = anionic ligand], and various terminal oxidants such as PhIO, m-chloroperoxybenzoic acid (m-CPBA), tetrabutylammonium oxone (TBAO), and H(2)O(2). While high ratios of cis- to trans-stilbene oxides were obtained in the reactions of iron porphyrin catalysts containing ligating anionic ligands such as Cl(-) and OAc(-), the ratios of cis- to trans-stilbene oxide were low in the reactions of iron porphyrin complexes containing nonligating or weakly ligating anionic ligands such as SbF(6)(-), CF(3)SO(3)(-), and ClO(4)(-). When the anionic ligand was NO(3)(-), the product ratios were found to depend on terminal oxidants and olefin concentrations. We suggest that the dependence of the product ratios on the anionic ligands of iron(III) porphyrin catalysts is due to the involvement of different reactive species in olefin epoxidation reactions. That is, high-valent iron(IV) oxo porphyrin cation radicals are generated as a reactive species in the reactions of iron porphyrin catalysts containing nonligating or weakly ligating anionic ligands such as SbF(6)(-), CF(3)SO(3)(-), and ClO(4)(-), whereas oxidant-iron(III) porphyrin complexes are the reactive intermediates in the reactions of iron porphyrin catalysts containing ligating anionic ligands such as Cl(-) and OAc(-).     

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)Fe^IV(O)(CH₃CN)]²⁺ ( 2 ; cyclam=1,4,8,11‐tetraazacyclotetradecane), is reported in the reactions of [(cyclam)Fe^II]²⁺ with aqueous hydrogen peroxide (H₂O₂) 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)Fe^II]²⁺ and H₂O₂. 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.     

What factors influence the ratio of C-H hydroxylation versus C=C epoxidation by a nonheme cytochrome P450 biomimetic?

Density functional calculations on a nonheme biomimetic (Fe=O(TMCS+) have been performed and its catalytic properties versus propene investigated. Our studies show that this catalyst is able to chemoselectively hydroxylate C=H bonds even in the presence of C=C double bonds. This phenomenon has been analyzed and found to occur due to Pauli repusions between protons on the TMCS ligand with protons attached to the approaching substrate. The geometries of the rate determining transition states indicate that the steric hindrance is larger in the epoxidation transition states than in the hydroxylation ones with much shorter distances; hence the hydroxylation pathway is favored over the epoxidation. Although, the reactant experiences close lying triplet and quintet spin states, the dominant reaction mechanism takes place on the quintet spin state surface; i.e., Fe=O(TMCS)+ reacts via single-state reactivity. Our calculations show that this spin state selectivity is the result of geometric orientation of the transition state structures, whereby the triplet ones are destabilized by electrostatic repulsions between the substrate and the ligand while the quintet spin transition states are aligned along the ideal axis. The reactivity patterns and geometries are compared with oxoiron species of dioxygenase and monoxygenase enzymes. Thus, Fe=O(TMCS)+ shows some similarities with P450 enzyme reactivity: it chemoselectively hydroxylates C=H bonds even in the presence of a C=C double bond and therefore is an acceptable P450 biomimetic. However, the absolute barriers of substrate oxidation by Fe=O(TMCS)+ are higher than the ones obtained with heme enzymes, but the chemoselectivity is lesser affected by external perturbations such as hydrogen bonding of a methanol molecule toward the thiolate sulfur or a dielectric constant. This is the first oxoiron complex whereby we calculated a chemoselective hydroxylation over epoxidation in the gas phase.     

Substitution effects on olefin epoxidation catalyzed by Oxoiron(IV) porphyrin π-cation radical complexes: A dft study

The effects of peripheral fluorine atoms on epoxidation reactions of ethylene by oxoiron(IV) porphyrin cation radical complex in the quartet and sextet spin multiplicities are systematically investigated using the DFT method. The overall reaction routes are determined using a model system of ethylene and Fe(IV)OCl-porphyrin with substituted fluorine atoms. By obtaining the energy diagrams and electron- and spin-density difference contour maps of the transition states and intermediate compounds, we confirm that the electron-withdrawing by peripheral fluorine atoms enhances the reactivity as the number of fluorine atoms increases, as is observed experimentally. The intersystem crossing between the quartet and sextet spin multiplicities is discussed by means of the intrinsic reaction coordinate method. We conclude that the rate-determining step is located at the first transition state (TS1) for the activation of CC and FeO bonds, and the ground electronic state changes from quartet to sextet around the TS1. © 2019 Wiley Periodicals, Inc.     

Factors affecting the catalytic epoxidation of olefins by iron porphyrin complexes and H2O2 in protic solvents

The catalytic epoxidation of cyclohexene by iron(III) porphyrin complexes and H2O2 has been investigated in alcohol solvents to understand factors affecting the catalyst activity in protic solvents. The yields of cyclohexene oxide and the Fe(III/II) reduction potentials of iron porphyrin complexes were significantly affected by the protic solvents, and there was a close correlation between the product yields and the reduction potentials of the iron porphyrin catalysts. The role of alcohol solvents was proposed to control the electronic nature of iron porphyrin complexes that determines the catalyst activity in the epoxidation of olefins by H2O2. We have also demonstrated that an electron-deficient iron porphyrin complex can catalyze the epoxidation of olefins by H2O2 under conditions of limiting substrate with high conversion efficiency in a solvent mixture of CH3OH and CH2Cl2.     

Catalysts for monooxygenations made from polyoxometalate: an iron(V)-oxo derivative of the Lindqvist anion

This work uses density functional calculations to design a new high-valent Fe(V)=O catalyst [Mo5O18Fe=O]3-, which is based on the Lindqvist polyoxometalate (Mo6O19(2-)). Because the parent species is stable to oxidative conditions, one may assume that the newly proposed iron-oxo species will be stable, too. The calculated M?ssbauer spectroscopic data may be helpful toward an eventual identification of the species. The calculations of C-H hydroxylation and C=C epoxidation of propene show that, if made, [Mo5O18Fe=O]3- should be a potent oxidant that will be subject to strong solvent effect. Moreover, the Lindqvist catalyst leads to an intriguing result; the reaction that starts along an epoxidation pathway with C=C activation ends with a C-H hydroxylation product ((4)6) due to rearrangement on the catalyst. The origins of this result are analyzed in terms of the structure of the catalyst and the electronic requirements for conversion of an epoxidation intermediate to a hydroxylation product. Thus, if made, the [Mo5O18Fe=O]3 will be a selective C-H hydroxylation reagent.     

Nonheme FeIVO complexes that can oxidize the C-H bonds of cyclohexane at room temperature

Nonheme oxoiron(IV) complexes of two pentadentate ligands, N4Py (N,N-bis(2-pyridylmethyl)-bis(2-pyridyl)methylamine) and Bn-tpen (N-benzyl-N,N',N'-tris(2-pyridylmethyl)-1,2-diaminoethane), have been generated and found to have spectroscopic properties similar to the closely related tetradentate TPA (tris(2-pyridylmethyl)amine) complex reported earlier. However, unlike the TPA complex, the pentadentate complexes have a considerable lifetime at room temperature. This greater thermal stability has allowed the hydroxylation of alkanes with C-H bonds as strong as 99.3 kcal/mol to be observed at room temperature. Furthermore, a large deuterium KIE value is found in the oxidation of ethylbenzene. These observations lend strong credence to postulated mechanisms of mononuclear nonheme iron enzymes that invoke the intermediacy of oxoiron(IV) species.     

Probing the Compound I-like reactivity of a bare high-valent oxo iron porphyrin complex: the oxidation of tertiary amines

The mechanisms of oxidative N-dealkylation of amines by heme enzymes including peroxidases and cytochromes P450 and by functional models for the active Compound I species have long been studied. A debated issue has concerned in particular the character of the primary step initiating the oxidation sequence, either a hydrogen atom transfer (HAT) or an electron transfer (ET) event, facing problems such as the possible contribution of multiple oxidants and complex environmental effects. In the present study, an oxo iron(IV) porphyrin radical cation intermediate 1, [(TPFPP)*+ Fe(IV)=O]+ (TPFPP = meso-tetrakis (pentafluorophenyl)porphinato dianion), functional model of Compound I, has been produced as a bare species. The gas-phase reaction with amines (A) studied by ESI-FT-ICR mass spectrometry has revealed for the first time the elementary steps and the ionic intermediates involved in the oxidative activation. Ionic products are formed involving ET (A*+, the amine radical cation), formal hydride transfer (HT) from the amine ([A(-H)]+, an iminium ion), and oxygen atom transfer (OAT) to the amine (A(O), likely a carbinolamine product), whereas an ionic product involving a net initial HAT event is never observed. The reaction appears to be initiated by an ET event for the majority of the tested amines which included tertiary aliphatic and aromatic amines as well as a cyclic and a secondary amine. For a series of N,N-dimethylanilines the reaction efficiency for the ET activated pathways was found to correlate with the ionization energy of the amine. A stepwise pathway accounts for the C-H bond activation resulting in the formal HT product, namely a primary ET process forming A*+, which is deprotonated at the alpha-C-H bond forming an N-methyl-N-arylaminomethyl radical, A(-H)*, readily oxidized to the iminium ion, [A(-H)]+. The kinetic isotope effect (KIE) for proton transfer (PT) increases as the acidity of the amine radical cation increases and the PT reaction to the base, the ferryl group of (TPFPP)Fe(IV)=O, approaches thermoneutrality. The ET reaction displayed by 1 with gaseous N,N-dimethylaniline finds a counterpart in the ET reactivity of FeO+, reportedly a potent oxidant in the gas phase, and with the barrierless ET process for a model (P)*+ Fe(IV)=O species (where P is the porphine dianion) as found by theoretical calculations. Finally, the remarkable OAT reactivity of 1 with C6F5N(CH3)2 may hint to a mechanism along a route of diverse spin multiplicity.     

Does substrate oxidation determine the regioselectivity of cyclohexene and propene oxidation by cytochrome p450?

DFT and QM/MM computations of allylic C-H hydroxylation versus C=C epoxidation in cyclohexene and propene by Compound I of P450cam demonstrate that the relative barriers for the oxidative processes themselves are not good predictors of the observed selectivity. However, a kinetic expression previously developed (Kozuch, S.; Shaik, S. J. Am. Chem. Soc. 2006, 128, 3355) for catalytic cycles under steady-state conditions, predicts, in accord with experiment, that propene will undergo exclusive C=C epoxidation, while cyclohexene will undergo both reactions with a small preference for epoxidation. The model expression for the effective barrier of the cycle forms a general basis for understanding and predicting the selectivity of P450 isozymes.     

Theoretical investigation of C--H hydroxylation by (N4Py)Fe(IV)=O(2+): an oxidant more powerful than P450?

DFT calculations of C-H hydroxylation by a synthetic nonheme oxoiron(IV) oxidant supported by a neutral pentadentate N5 ligand show that this reagent is intrinsically more reactive than compound I of P450. This nonheme iron oxidant is predicted to exhibit stereoselective reactions, strong solvent effect, and involve multistate reactivity with spin-state crossing.     

Predictable stereoselective and chemoselective hydroxylations and epoxidations with P450 3A4

Enantioselective hydroxylation of one specific methylene in the presence of many similar groups is debatably the most challenging chemical transformation. Although chemists have recently made progress toward the hydroxylation of inactivated C-H bonds, enzymes such as P450s (CYPs) remain unsurpassed in specificity and scope. The substrate promiscuity of many P450s is desirable for synthetic applications; however, the inability to predict the products of these enzymatic reactions is impeding advancement. We demonstrate here the utility of a chemical auxiliary to control the selectivity of CYP3A4 reactions. When linked to substrates, inexpensive, achiral theobromine directs the reaction to produce hydroxylation or epoxidation at the fourth carbon from the auxiliary with pro-R facial selectivity. This strategy provides a versatile yet controllable system for regio-, chemo-, and stereoselective oxidations at inactivated C-H bonds and demonstrates the utility of chemical auxiliaries to mediate the activity of highly promiscuous enzymes.     

Remarkably stable iron porphyrins bearing nonheteroatom-stabilized carbene or (alkoxycarbonyl)carbenes: isolation,X-ray crystal structures,and carbon atom transfer reactions with hydrocarbons

Reactions of [Fe(TPFPP)] (TPFPP = meso-tetrakis(pentafluorophenyl)porphyrinato dianion) with diazo compounds N(2)C(Ph)R (R = Ph, CO(2)Et, CO(2)CH(2)CH=CH(2)) afforded [Fe(TPFPP)(C(Ph)R)] (R = Ph (1), CO(2)Et (2), CO(2)CH(2)CH=CH(2) (3)) in 65-70% yields. Treatment of 1 with N-methylimidazole (MeIm) gave the adduct [Fe(TPFPP)(CPh(2))(MeIm)] (4) in 65% yield. These new iron porphyrin carbene complexes were characterized by NMR and UV-vis spectroscopy, mass spectrometry, and elemental analyses. X-ray crystal structure determinations of 1.0.5C(6)H(6).0.5CH(2)Cl(2) and 4 reveal Fe=CPh(2) bond lengths of 1.767(3) (1) and 1.827(5) A (4), together with large ruffling distortions of the TPFPP macrocycle. Complexes 2 and 4 are reactive toward styrene, affording the corresponding cyclopropanes in 82 and 53% yields, respectively. Complex 1 is an active catalyst for both intermolecular cyclopropanation of styrenes with ethyl diazoacetate and intramolecular cyclopropanation of allylic diazoacetates. Reactions of 2 and 4 with cyclohexene or cumene produced allylic or benzylic C-H insertion products in up to 83% yield.     

Epoxidation and 1,2-dihydroxylation of alkenes by a nonheme iron model system - DFT supports the mechanism proposed by experiment

The FeII complexes of two isomeric pentadentate bispidine ligands in the presence of H2O2 are catalytically active for the epoxidation and 1,2-dihydroxylation of cyclooctene (bispidine = 3,7-diazabicyclo[3.3.1]nonane; the two isomeric pentadentate bispidine ligands discussed here have two tertiary amine and three pyridine donors). The published spectroscopic and mechanistic data, which include an extensive set of 18O labeling experiments, suggest that the FeIV=O complex is the catalytically active species, which produces epoxide as well as cis- and trans-1,2-dihydroxylated products. Several observations from the published experimental study are addressed with hybrid density functional methods and, in general, the calculations support the proposed, for nonheme iron model systems novel mechanism, where the formation of a radical intermediate emerges from the reaction of the FeIV=O oxidant and cyclooctene. The calculations suggest that the S = 1 ground state of the FeIV=O complex reacts with cyclooctene in a stepwise reaction, leading to the formation of a carbon-based radical intermediate. This radical is captured by O2 from air to produce the majority of the epoxide products in an aerobic atmosphere. Under anaerobic conditions, the produced epoxide product is due to the cyclization of the radical intermediate. Several possible spin states (ST = 3, 2, 1, 0) of the radical intermediate are close in energy. As a result of the substantial energy barrier, calculated for the ST = 3 spin ground state, a spin-crossover during the cyclization step is assumed, and a possible two-state scenario is found, where the S = 2 state of the FeIV=O complex participates in the catalytic mechanism. The 1,2-dihydroxylation proceeds, as suggested by experiment, via an unprecedented pathway, where the radical intermediate is captured by a hydroxyl radical, the source of which is FeIII-OOH, and this reaction is barrierless. The calculations suggest that dihydroxylation can also occur by a direct oxidation pathway from FeIII-OOH. The strikingly different reactivities observed with the two isomeric bispidine FeII complexes are rationalized on the basis of structural and electronic differences.     

Spectroscopic and Mechanistic Studies on Oxidation Reactions Catalyzed by the Functional Model SR Complex for Cytochrome P450: Influence of Oxidant,Substrate, and Solvent

Kinetic and mechanistic studies on the formation of an oxoiron(IV) porphyrin cation radical bearing a thiolate group as proximal ligand are reported. The SR complex, a functional enzyme mimic of P450, was oxidized in peroxo‐shunt reactions under different experimental conditions with variation of solvent, temperature, and identity and excess of oxidant in the presence of different organic substrates. Through the application of a low‐temperature rapid‐scan stopped‐flow technique, the reactive intermediates in the SR catalytic cycle, such as the initially formed SR acylperoxoiron(III) complex and the SR high‐valent iron(IV) porphyrin cation radical complex [( SR ^.+)Fe^IV?O], were successfully identified and kinetically characterized. The oxidation of the SR complex under catalytic conditions provided direct spectroscopic information on the reactivity of [( SR ^.+)Fe^IV?O] towards the oxidation of selected organic substrates. Because the catalytically active species is a synthetic oxoiron(IV) porphyrin cation radical bearing a thiolate proximal group, the effect of the strong electron donor ligand on the formation and reactivity/stability of the SR high‐valent iron species is addressed and discussed in the light of the reactivity pattern observed in substrate oxygenation reactions catalyzed by native P450 enzyme systems.