Electronic structure of high-spin iron(III)-alkylperoxo complexes and its relation to low-spin analogues: reaction coordinate of O-O bond homolysis.

The spectroscopic properties of the high-spin Fe(III)-alkylperoxo model complex [Fe(6-Me(3)TPA)(OH(x))(OO(t)Bu)](x)(+) (1; TPA = tris(2-pyridylmethyl)amine, (t)Bu = tert-butyl, x = 1 or 2) are defined and related to density functional calculations of corresponding models in order to determine the electronic structure and reactivity of this system. The Raman spectra of 1 show four peaks at 876, 842, 637, and 469 cm(-1) that are assigned with the help of normal coordinate analysis, and corresponding force constants have been determined to be 3.55 mdyn/A for the O-O and 2.87 mdyn/A for the Fe-O bond. Complex 1 has a broad absorption feature around 560 nm that is assigned to a charge-transfer (CT) transition from the alkylperoxo to a t(2g) d orbital of Fe(III) with the help of resonance Raman profiles and MCD spectroscopy. An additional contribution to the Fe-O bond arises from a sigma interaction between and an e(g) d orbital of iron. The electronic structure of 1 is compared to the related low-spin model complex [Fe(TPA)(OH(x))(OO(t)Bu)](x)(+) and the reaction coordinate for O-O homolysis is explored for both the low-spin and the high-spin Fe(III)-alkylperoxo systems. Importantly, there is a barrier for homolytic cleavage of the O-O bond on the high-spin potential energy surface that is not present for the low-spin complex, which is therefore nicely set up for O-O homolysis. This is reflected by the electronic structure of the low-spin complex having a strong Fe-O and a weak O-O bond due to a strong Fe-O sigma interaction. In addition, the reaction coordinate of the Fe-O homolysis has been investigated, which is a possible decay pathway for the high-spin system, but which is thermodynamically unfavorable for the low-spin complex.     

Spectroscopic properties and electronic structure of low-spin Fe(III)-alkylperoxo complexes: homolytic cleavage of the O-O bond

The spectroscopic properties, electronic structure, and reactivity of the low-spin Fe(III)-alkylperoxo model complex [Fe(TPA)(OH(x))(OO(t)Bu)](x+) (1; TPA = tris(2-pyridylmethyl)amine, (t)Bu = tert-butyl, x = 1 or 2) are explored. The vibrational spectra of 1 show three peaks that are assigned to the O-O stretch (796 cm(-1)), the Fe-O stretch (696 cm(-)(1)), and a combined O-C-C/C-C-C bending mode (490 cm(-1)) that is mixed with upsilon(FeO). The corresponding force constants have been determined to be 2.92 mdyn/A for the O-O bond which is small and 3.53 mdyn/A for the Fe-O bond which is large. Complex 1 is characterized by a broad absorption band around 600 nm that is assigned to a charge-transfer (CT) transition from the alkylperoxo pi*(upsilon) to a t(2g) d orbital of Fe(III). This metal-ligand pi bond is probed by MCD and resonance Raman spectroscopies which show that the CT state is mixed with a ligand field state (t(2g) --> e(g)) by configuration interaction. This gives rise to two intense transitions under the broad 600 nm envelope with CT character which are manifested by a pseudo-A term in the MCD spectrum and by the shapes of the resonance Raman profiles of the 796, 696, and 490 cm(-1) vibrations. Additional contributions to the Fe-O bond arise from sigma interactions between mainly O-O bonding donor orbitals of the alkylperoxo ligand and an e(g) d orbital of Fe(III), which explains the observed O-O and Fe-O force constants. The observed homolytic cleavage of the O-O bond of 1 is explored with experimentally calibrated density functional (DFT) calculations. The O-O bond homolysis is found to be endothermic by only 15 to 20 kcal/mol due to the fact that the Fe(IV)=O species formed is highly stabilized (for spin states S = 1 and 2) by two strong pi and a strong sigma bond between Fe(IV) and the oxo ligand. This low endothermicity is compensated by the entropy gain upon splitting the O-O bond. In comparison, Cu(II)-alkylperoxo complexes studied before [Chen, P.; Fujisawa, K.; Solomon, E. I. J. Am. Chem. Soc. 2000, 122, 10177] are much less suited for O-O bond homolysis, because the resulting Cu(III)=O species is less stable. This difference in metal-oxo intermediate stability enables the O-O homolysis in the case of iron but directs the copper complex toward alternative reaction channels.     

XAS characterization of end-on and side-on peroxoiron(III) complexes of the neutral pentadentate N-donor ligand N-methyl-N,N',N'-tris(2-pyridylmethyl)ethane-1,2-diamine

Peroxo intermediates are implicated in the catalytic cycles of iron enzymes involved in dioxygen metabolism. X-ray absorption spectroscopy has been used to gain insight into the iron coordination environments of the low-spin complex [Fe(III)(Me-TPEN)(eta(1)-OOH)](2+)(1) and the high-spin complex [Fe(III)(Me-TPEN)(eta(2)-O(2))](+)(2)(the neutral pentadentate N-donor ligand Me-TPEN =N-methyl-N,N',N'-tris(2-pyridylmethyl)ethane-1,2-diamine) and obtain metrical parameters unavailable from X-ray crystallography. The complexes exhibit relatively large pre-edge peak areas of approximately 15 units, indicative of iron centers with significant distortions from centrosymmetry. These distortions result from the binding of peroxide, either end-on hydroperoxo for 1 (r(Fe-O)= 1.81A) or side-on peroxo for 2 (r(Fe-O)= 1.99 A). The XAS analyses of 1 strongly support a six-coordinate low-spin iron(III) center coordinated to five nitrogen atoms from Me-TPEN and one oxygen atom from an end-on hydroperoxide ligand. However, the XAS analyses of 2 are not conclusive: Me-TPEN can act either as a pentadentate ligand to form a seven-coordinate peroxo complex, which has precedence in the DFT geometry optimization of [Fe(III)(N4Py)(eta(2)-O(2))](+)(the neutral pentadentate N-donor ligand N4Py =N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), or as a tetradentate ligand with a dangling pyridylmethyl arm to form a six-coordinate peroxo complex, which is precedented by the crystal structure of [Fe(2)(III)(Me-TPEN)(2)(Cl)(2)(mu-O)](2+).     

End-on and side-on peroxo derivatives of non-heme iron complexes with pentadentate ligands: models for putative intermediates in biological iron/dioxygen chemistry

Mononuclear iron(III) species with end-on and side-on peroxide have been proposed or identified in the catalytic cycles of the antitumor drug bleomycin and a variety of enzymes, such as cytochrome P450 and Rieske dioxygenases. Only recently have biomimetic analogues of such reactive species been generated and characterized at low temperatures. We report the synthesis and characterization of a series of iron(II) complexes with pentadentate N5 ligands that react with H(2)O(2) to generate transient low-spin Fe(III)-OOH intermediates. These intermediates have low-spin iron(III) centers exhibiting hydroperoxo-to-iron(III) charge-transfer bands in the 500-600-nm region. Their resonance Raman frequencies, nu(O)(-)(O), near 800 cm(-)(1) are significantly lower than those observed for high-spin counterparts. The hydroperoxo-to-iron(III) charge-transfer transition blue-shifts and the nu(O)(-)(O) of the Fe-OOH unit decreases as the N5 ligand becomes more electron donating. Thus, increasing electron density at the low-spin Fe(III) center weakens the O-O bond, in accord with conclusions drawn from published DFT calculations. The parent [(N4Py)Fe(III)(eta(1)-OOH)](2+) (1a) ion in this series (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) can be converted to its conjugate base, which is demonstrated to be a high-spin iron(III) complex with a side-on peroxo ligand, [(N4Py)Fe(III)(eta(2)-O(2))](+) (1b). A detailed analysis of 1a and 1b by EPR and M?ssbauer spectroscopy provides insights into their electronic properties. The orientation of the observed (57)Fe A-tensor of 1a can be explained with the frequently employed Griffith model provided the rhombic component of the ligand field, determined by the disposition of the hydroperoxo ligand, is 45 degrees rotated relative to the octahedral field. EXAFS studies of 1a and 1b reveal the first metrical details of the iron-peroxo units in this family of complexes: [(N4Py)Fe(III)(eta(1)-OOH)](2+) has an Fe-O bond of 1.76 A, while [(N4Py)Fe(III)(eta(2)-O(2))](+) has two Fe-O bonds of 1.93 A, values which are in very good agreement with results obtained from DFT calculations.     

Stereospecific alkane hydroxylation by non-heme iron catalysts: mechanistic evidence for an Fe(V)=O active species.

High-valent iron-oxo species have frequently been invoked in the oxidation of hydrocarbons by both heme and non-heme enzymes. Although a formally Fe(V)=O species, that is, [(Por(*))Fe(IV)=O](+), has been widely accepted as the key oxidant in stereospecific alkane hydroxylation by heme systems, it is not established that such a high-valent state can be accessed by a non-heme ligand environment. Herein we report a systematic study on alkane oxidations with H(2)O(2) catalyzed by a group of non-heme iron complexes, that is, [Fe(II)(TPA)(CH(3)CN)(2)](2+) (1, TPA = tris(2-pyridylmethyl)amine) and its alpha- and beta-substituted analogues. The reactivity patterns of this family of Fe(II)(TPA) catalysts can be modulated by the electronic and steric properties of the ligand environment, which affects the spin states of a common Fe(III)-OOH intermediate. Such an Fe(III)-peroxo species is high-spin when the TPA ligand has two or three alpha-substituents and is proposed to be directly responsible for the selective C-H bond cleavage of the alkane substrate. The thus-generated alkyl radicals, however, have relatively long lifetimes and are susceptible to radical epimerization and trapping by O(2). On the other hand, 1 and the beta-substituted Fe(II)(TPA) complexes catalyze stereospecific alkane hydroxylation by a mechanism involving both a low-spin Fe(III)-OOH intermediate and an Fe(V)=O species derived from O-O bond heterolysis. We propose that the heterolysis pathway is promoted by two factors: (a) the low-spin iron(III) center which weakens the O-O bond and (b) the binding of an adjacent water ligand that can hydrogen bond to the terminal oxygen of the hydroperoxo group and facilitate the departure of the hydroxide. Evidence for the Fe(V)=O species comes from isotope-labeling studies showing incorporation of (18)O from H(2)(18)O into the alcohol products. (18)O-incorporation occurs by H(2)(18)O binding to the low-spin Fe(III)-OOH intermediate, its conversion to a cis-H(18)O-Fe(V)=O species, and then oxo-hydroxo tautomerization. The relative contributions of the two pathways of this dual-oxidant mechanism are affected by both the electron donating ability of the TPA ligand and the strength of the C-H bond to be broken. These studies thus serve as a synthetic precedent for an Fe(V)=O species in the oxygen activation mechanisms postulated for non-heme iron enzymes such as methane monooxygenase and Rieske dioxygenases.     

Electronic structure and reactivity of high-spin iron--alkyl- and--pterinperoxo complexes

The spectroscopic properties and electronic structure of the four-coordinate high-spin [FeIII(L3)(OOtBu)]+ complex (1; L3 = hydrotris(3-tert-butyl-5-isopropyl-1-pyrazolyl)borate; tBu = tert-butyl) are investigated and compared to the six-coordinated high-spin [Fe(6-Me3TPA)(OHx)(OOtBu)]x+ system (TPA = tris(2-pyridylmethyl)amine, x = 1 or 2) studied earlier [Lehnert, N.; Ho, R. Y. N.; Que, L., Jr.; Solomon, E. I. J. Am. Chem. Soc. 2001, 123, 12802-12816]. Complex 1 is characterized by Raman features at 889 and 830 cm-1 which are assigned to the O-O stretch (mixed with the symmetric C-C stretch) and a band at 625 cm-1 that corresponds to nu(Fe-O). The UV-vis spectrum shows a charge-transfer (CT) transition at 510 nm from the alkylperoxo pi v* (v = vertical to C-O-O plane) to a d orbital of Fe(III). A second CT is identified from MCD at 370 nm that is assigned to a transition from pi h* (h = horizontal to C-O-O plane) to an Fe(III) d orbital. For the TPA complex the pi v* CT is at 560 nm while the pi h* CT is to higher energy than 250 nm. These spectroscopic differences between four- and six-coordinate Fe(III)-OOR complexes are interpreted on the basis of their different ligand fields. In addition, the electronic structure of Fe-OOPtn complexes with the biologically relevant pterinperoxo ligand are investigated. Substitution of the tert-butyl group in 1 by pterin leads to the corresponding Fe(III)-OOPtn species (2), which shows a stronger electron donation from the peroxide to Fe(III) than 1. This is related to the lower ionization potential of pterin. Reduction of 2 by one electron leads to the Fe(II)-OOPtn complex (3), which is relevant as a model for potential intermediates in pterin-dependent hydroxylases. However, in the four-coordinate ligand field of 3, the additional electron is located in a nonbonding d orbital of iron. Hence, the pterinperoxo ligand is not activated for heterolytic cleavage of the O-O bond in this system. This is also evident from the calculated reaction energies that are endothermic by at least 20 kcal/mol.     

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 versus epoxidation by non-heme iron catalysts: two faces of an Fe(III)-OOH coin

The oxygenation of carbon-carbon double bonds by iron enzymes generally results in the formation of epoxides, except in the case of the Rieske dioxygenases, where cis-diols are produced. Herein we report a systematic study of olefin oxidations with H(2)O(2) catalyzed by a group of non-heme iron complexes, i.e., [Fe(II)(BPMEN)(CH(3)CN)(2)](2+) (1, BPMEN = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-1,2-diaminoethane) and [Fe(II)(TPA)(CH(3)CN)(2)](2+) (4, TPA = tris(2-pyridylmethyl)amine) and their 6- and 5-methyl-substituted derivatives. We demonstrate that olefin epoxidation and cis-dihydroxylation are different facets of the reactivity of a common Fe(III)-OOH intermediate, whose spin state can be modulated by the electronic and steric properties of the ligand environment. Highly stereoselective epoxidation is favored by catalysts with no more than one 6-methyl substituent, which give rise to low-spin Fe(III)-OOH species (category A). On the other hand, cis-dihydroxylation is favored by catalysts with more than one 6-methyl substituent, which afford high-spin Fe(III)-OOH species (category B). For catalysts in category A, both the epoxide and the cis-diol product incorporate (18)O from H(2)(18)O, results that implicate a cis-H(18)O-Fe(V)=O species derived from O-O bond heterolysis of a cis-H(2)(18)O-Fe(III)-OOH intermediate. In contrast, catalysts in category B incorporate both oxygen atoms from H(2)(18)O(2) into the dominant cis-diol product, via a putative Fe(III)-eta(2)-OOH species. Thus, a key feature of the catalysts in this family is the availability of two cis labile sites, required for peroxide activation. The olefin epoxidation and cis-dihydroxylation studies described here not only corroborate the mechanistic scheme derived from our earlier studies on alkane hydroxylation by this same family of catalysts (Chen, K.; Que, L, Jr. J. Am. Chem. Soc. 2001, 123, 6327) but also further enhance its credibility. Taken together, these reactions demonstrate the catalytic versatility of these complexes and provide a rationale for Nature's choice of ligand environments in biocatalysts that carry out olefin oxidations.     

A density functional study of O-O bond cleavage for a biomimetic non-heme iron complex demonstrating an Fe(v)-intermediate

Density functional theory using the B3LYP hybrid functional has been employed to investigate the reactivity of Fe(TPA) complexes (TPA = tris(2-pyridylmethyl)amine), which are known to catalyze stereospecific hydrocarbon oxidation when H(2)O(2) is used as oxidant. The reaction pathway leading to O-O bond heterolysis in the active catalytic species Fe(III)(TPA)-OOH has been explored, and it is shown that a high-valent iron-oxo intermediate is formed, where an Fe(V) oxidation state is attained, in agreement with previous suggestions based on experiments. In contrast to the analogous intermediate [(Por.)Fe(IV)=O](+1) in P450, the TPA ligand is not oxidized, and the electrons are extracted almost exclusively from the mononuclear iron center. The corresponding homolytic O-O bond cleavage, yielding the two oxidants Fe(IV)=O and the OH. radical, has also been considered, and it is shown that this pathway is inaccessible in the hydrocarbon oxidation reaction with Fe(TPA) and hydrogen peroxide. Investigations have also been performed for the O-O cleavage in the Fe(III)(TPA)-alkylperoxide species. In this case, the barrier for O-O homolysis is found to be slightly lower, leading to loss of stereospecificity and supporting the experimental conclusion that this is the preferred pathway for alkylperoxide oxidants. The difference between hydroperoxide and alkylperoxide as oxidant derives from the higher O-O bond strength for hydrogen peroxide (by 8.0 kcal/mol).     

Structural insights into nonheme alkylperoxoiron(III) and oxoiron(IV) intermediates by X-ray absorption spectroscopy

Transient mononuclear low-spin alkylperoxoiron(III) and oxoiron(IV) complexes that are relevant to the activation of dioxygen by nonheme iron enzymes have been generated from synthetic iron(II) complexes of neutral tetradentate (TPA) and pentadentate (N4Py, Bn-TPEN) ligands and structurally characterized by means of Fe K-edge X-ray absorption spectroscopy (XAS). Notable features obtained from fits of the EXAFS region are Fe-O bond lengths of 1.78 A for the alkylperoxoiron(III) intermediates and 1.65-1.68 A for the oxoiron(IV) intermediates, reflecting different strengths in the Fe-O pi interactions. These differences are also observed in the intensities of the 1s-to-3d transitions in the XANES region, which increase from 4 units for the nearly octahedral iron(II) precursor to 9-15 units for the alkylperoxoiron(III) intermediates to 25-29 units for the oxoiron(IV) species.     

Direct hydrogen-atom abstraction by activated bleomycin: an experimental and computational study

Bleomycin (BLM), a glycopeptide antibiotic chemotherapy agent, is capable of single- and double-strand DNA damage. Activated bleomycin (ABLM), a low-spin Fe(III)-OOH complex, is the last intermediate detected prior to DNA cleavage following hydrogen-atom abstraction from the C-4' of a deoxyribose sugar moiety. The mechanism of this C-H bond cleavage reaction and the nature of the active oxidizing species are still open issues. We have used kinetic measurements in combination with density functional calculations to study the reactivity of ABLM and the mechanism of the initial attack on DNA. Circular dichroism spectroscopy was used to directly monitor the kinetics of the ABLM reaction. These experiments yield a deuterium isotope effect, kH/kD approximately 3 for ABLM decay, indicating the involvement of a hydrogen atom in the rate-determining step. H-atom donors with relatively weak X-H bonds accelerate the reaction rate, establishing that ABLM is capable of hydrogen-atom abstraction. Density functional calculations were used to evaluate the two-dimensional potential energy surface for the direct hydrogen-atom abstraction reaction of the deoxyribose 4'-H by ABLM. The calculations confirm that ABLM is thermodynamically and kinetically competent for H-atom abstraction. The activation and reaction energies for this pathway are favored over both homolytic and heterolytic O-O bond cleavage. Direct H-atom abstraction by ABLM would generate a reactive Fe(IV)=O species, which would be capable of a second DNA strand cleavage, as observed in vivo. This study provides experimental and theoretical evidence for direct H-atom abstraction by ABLM and proposes an attractive mechanism for the role of ABLM in double-strand cleavage.     

Characterization of imidazolate-bridged dinuclear and mononuclear hydroperoxo complexes

Dinucleating ligands having two metal-binding sites bridged by an imidazolate moiety, Hbdpi, HMe(2)bdpi, and HMe(4)bdpi (Hbdpi = 4,5-bis(di(2-pyridylmethyl)aminomethyl)imidazole, HMe(2)bdpi = 4,5-bis((6-methyl-2-pyridylmethyl)(2-pyridylmethyl)aminomethyl)imidazole, HMe(4)bdpi = 4,5-bis(di(6-methyl-2-pyridylmethyl)aminomethyl)imidazole), have been designed and synthesized as model ligands for copper-zinc superoxide dismutase (Cu,Zn-SOD). The corresponding mononucleating ligands, MeIm(Py)(2), MeIm(Me)(1), and MeIm(Me)(2) (MeIm(Py)(2) = (1-methyl-4-imidazolylmethyl)bis(2-pyridylmethyl)amine, MeIm(Me)(1) = (1-methyl-4-imidazolylmethyl)(6-methyl-2-pyridylmethyl)(2-pyridylmethyl)amine, MeIm(Me)(2) = (1-methyl-4-imidazolyl-methyl)bis(6-methyl-2-pyridylmethyl)amine), have also been synthesized for comparison. The imidazolate-bridged Cu(II)-Cu(II) homodinuclear complexes represented as [Cu(2)(bdpi)(CH(3)CN)(2)](ClO(4))(3).CH(3)CN.3H(2)O (1), [Cu(2)(Me(2)bdpi)(CH(3)CN)(2)](ClO(4))(3) (2), [Cu(2)(Me(4)bdpi)(H(2)O)(2)](ClO(4))(3).4H(2)O (3), a Cu(II)-Zn(II) heterodinuclear complex of the type of [CuZn(bdpi)(CH(3)CN)(2)](ClO(4))(3).2CH(3)CN (4), Cu(II) mononuclear complexes of [Cu(MeIm(Py)(2))(CH(3)CN)](ClO(4))(2).CH(3)CN (5), [Cu(MeIm(Me)(1))(CH(3)CN)](ClO(4))(2)( )()(6), and [Cu(MeIm(Me)(2))(CH(3)CN)](ClO(4))(2)( )()(7) have been synthesized and the structures of complexes 5-7 determined by X-ray crystallography. The complexes 1-7 have a pentacoordinate structure at each metal ion with the imidazolate or 1-methylimidazole nitrogen, two pyridine nitrogens, the tertiary amine nitrogen, and a solvent (CH(3)CN or H(2)O) which can be readily replaced by a substrate. The reactions between complexes 1-7 and hydrogen peroxide (H(2)O(2)) in the presence of a base at -80 degrees C yield green solutions which exhibit intense bands at 360-380 nm, consistent with the generation of hydroperoxo Cu(II) species in all cases. The resonance Raman spectra of all hydroperoxo intermediates at -80 degrees C exhibit a strong resonance-enhanced Raman band at 834-851 cm(-1), which shifts to 788-803 cm(-1) (Deltanu = 46 cm(-1)) when (18)O-labeled H(2)O(2) was used, which are assigned to the O-O stretching frequency of a hydroperoxo ion. The resonance Raman spectra of hydroperoxo adducts of complexes 2 and 6 show two Raman bands at 848 (802) and 834 (788), 851 (805), and 835 (789) cm(-1) (in the case of H(2)(18)O(2), Deltanu = 46 cm(-1)), respectively. The ESR spectra of all hydroperoxo complexes are quite close to those of the parent Cu(II) complexes except 6. The spectrum of 6 exhibits a mixture signal of trigonal-bipyramid and square-pyramid which is consistent with the results of resonance Raman spectrum.     

EPR, 1H and 2H NMR, and reactivity studies of the iron-oxygen intermediates in bioinspired catalyst systems

Complexes [(BPMEN)Fe(II)(CH(3)CN)(2)](ClO(4))(2) (1, BPMEN = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-1,2-diaminoethane) and [(TPA)Fe(II)(CH(3)CN)(2)](ClO(4))(2) (2, TPA = tris(2-pyridylmethyl)amine) are among the best nonheme iron-based catalysts for bioinspired oxidation of hydrocarbons. Using EPR and (1)H and (2)H NMR spectroscopy, the iron-oxygen intermediates formed in the catalyst systems 1,2/H(2)O(2); 1,2/H(2)O(2)/CH(3)COOH; 1,2/CH(3)CO(3)H; 1,2/m-CPBA; 1,2/PhIO; 1,2/(t)BuOOH; and 1,2/(t)BuOOH/CH(3)COOH have been studied (m-CPBA is m-chloroperbenzoic acid). The following intermediates have been observed: [(L)Fe(III)(OOR)(S)](2+), [(L)Fe(IV)═O(S)](2+) (L = BPMEN or TPA, R = H or (t)Bu, S = CH(3)CN or H(2)O), and the iron-oxygen species 1c (L = BPMEN) and 2c (L = TPA). It has been shown that 1c and 2c directly react with cyclohexene to yield cyclohexene oxide, whereas [(L)Fe(IV)═O(S)](2+) react with cyclohexene to yield mainly products of allylic oxidation. [(L)Fe(III)(OOR)(S)](2+) are inert in this reaction. The analysis of EPR and reactivity data shows that only those catalyst systems which display EPR spectra of 1c and 2c are able to selectively epoxidize cyclohexene, thus bearing strong evidence in favor of the key role of 1c and 2c in selective epoxidation. 1c and 2c were tentatively assigned to the oxoiron(V) intermediates.     

Photocatalytic generation of a non-heme oxoiron(IV) complex with water as an oxygen source

The photocatalytic formation of a non-heme oxoiron(IV) complex, [(N4Py)Fe(IV)(O)](2+) [N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine], efficiently proceeds via electron transfer from the excited state of a ruthenium complex, [Ru(II)(bpy)(3)](2+)* (bpy = 2,2'-bipyridine) to [Co(III)(NH(3))(5)Cl](2+) and stepwise electron-transfer oxidation of [(N4Py)Fe(II)](2+) with 2 equiv of [Ru(III)(bpy)(3)](3+) and H(2)O as an oxygen source. The oxoiron(IV) complex was independently generated by both chemical oxidation of [(N4Py)Fe(II)](2+) with [Ru(III)(bpy)(3)](3+) and electrochemical oxidation of [(N4Py)Fe(II)](2+).     

Spectroscopic study of [Fe2O2(5-Et3-TPA)2]3+: nature of the Fe2O2 diamond core and its possible relevance to high-valent binuclear non-heme enzyme intermediates

The spectroscopic properties and electronic structure of an Fe(2)(III,IV) bis-mu-oxo complex, [Fe(2)O(2)(5-Et(3)-TPA)(2)](ClO(4))(3) where 5-Et(3)-TPA = tris(5-ethyl-2-pyridylmethyl)amine, are explored to determine the molecular origins of the unique electronic and geometric features of the Fe(2)O(2) diamond core. Low-temperature magnetic circular dichroism (MCD) allows the two features in the broad absorption envelope (4000-30000 cm(-)(1)) to be resolved into 13 transitions. Their C/D ratios and transition polarizations from variable temperature-variable field MCD saturation behavior indicate that these divide into three types of electronic transitions; t(2) --> t(2) involving excitations between metal-based orbitals with pi Fe-O overlap (4000-10000 cm(-)(1)), t(2)/t(2) --> e involving excitations to metal-based orbitals with sigma Fe-O overlap (12500-17000 cm(-)(1)) and LMCT (17000-30000 cm(-)(1)) and allows transition assignments and calibration of density functional calculations. Resonance Raman profiles show the C(2)(h)() geometric distortion of the Fe(2)O(2) core results in different stretching force constants for adjacent Fe-O bonds (k(str)(Fe-O(long)) = 1.66 and k(str)(Fe-O(short)) = 2.72 mdyn/A) and a small ( approximately 20%) difference in bond strength between adjacent Fe-O bonds. The three singly occupied pi-metal-based orbitals form strong superexchange pathways which lead to the valence delocalization and the S = (3)/(2) ground state. These orbitals are key to the observed reactivity of this complex as they overlap with the substrate C-H bonding orbital in the best trajectory for hydrogen atom abstraction. The electronic structure implications of these results for the high-valent enzyme intermediates X and Q are discussed.     

Catalytic oxidation with a non-heme iron complex that generates a low-spin Fe(III)OOH intermediate

The antitumor drug bleomycin (BLM) is proposed to act via a low-spin iron(III) hydroperoxide intermediate called "activated bleomycin". To gain more insight into the mechanistic aspects of catalytic oxidation by these intermediates we have studied the reactivity of [(N4Py)Fe(CH3CN)](ClO4)2 (1) (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) with excess H2O2. Under these conditions a transient purple species is generated, [(N4Py)FeOOH]2- (2), which has spectroscopic features and reactivity strongly reminiscent of activated bleomycin. The catalytic oxidation of alkanes such as cyclohexane, cyclooctane, and adamantane by 1 with H2O2 gave the corresponding alcohols and ketones in up to 31% yield. It was concluded, from the O2 sensitivity of the oxidation reactions, the formation of brominated products in the presence of methylene bromide, and the nonstereospecificity of the oxidation of cis- or trans-dimethylcyclohexane, that long-lived alkyl radicals were formed during the oxidations. Oxidation of alkenes did not afford the corresponding epoxides in good yields but resulted instead in allylic oxidation products in the case of cyclohexene, and cleavage of the double bond in the case of styrene. Addition of hydroxyl radical traps, such as benzene and acetone, led to only partial quenching of the reactivity. The kinetic isotope effects for cyclohexanol formation, ranging from 1.5 in acetonitrile to 2.7 in acetone with slow addition of H2O2, suggested the involvement of a more selective oxidizing species in addition to hydroxyl radicals. Monitoring the UV/Vis absorption of 2 during the catalytic reaction showed that 2 was the precursor for the active species. On the basis of these results it is proposed that 2 reacts through homolysis of the O-O bond to afford two reactive radical species: [(N4Py)Fe(IV)O]2+ and *OH. The comparable reactivity of 1 and Fe-BLM raises the possibility that they react through similar mechanistic pathways.     

Searching for the second oxidant in the catalytic cycle of cytochrome P450: a theoretical investigation of the iron(III)-hydroperoxo species and its epoxidation pathways

Iron(III)-hydroperoxo, [Por(CysS)Fe(III)-OOH](-), a key species in the catalytic cycle of cytochrome P450, was recently identified by EPR/ENDOR spectroscopies (Davydov, R.; Makris, T. M.; Kofman, V.; Werst, D. E.; Sligar, S. G.; Hoffman, B. M. J. Am. Chem. Soc. 2001, 123, 1403-1415). It constitutes the last station of the preparative steps of the enzyme before oxidation of an organic compound and is implicated as the second oxidant capable of olefin epoxidation (Vaz, A. D. N.; McGinnity, D. F.; Coon, M. J. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 3555-3560), in addition to the penultimate active species, Compound I (Groves, J. T.; Han, Y.-Z. In Cytochrome P450: Structure, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995; pp 3-48). In response, we present a density functional study of a model species and its ethylene epoxidation pathways. The study characterizes a variety of properties of iron(III)-hydroperoxo, such as the O-O bonding, the Fe-S bonding, Fe-O and Fe-S stretching frequencies, its electron attachment, and ionization energies. Wherever possible these properties are compared with those of Compound I. The proton affinities for protonation on the proximal and distal oxygen atoms of iron(III)-hydroperoxo, and the effect of the thiolate ligand thereof, are determined. In accordance with previous results (Harris, D. L.; Loew, G. H. J. Am. Chem. Soc. 1998, 120, 8941-8948), iron(III)-hydroperoxo is a strong base (as compared with water), and its distal protonation leads to a barrier-free formation of Compound I. The origins of this barrier-free process are discussed using a valence bond approach. It is shown that the presence of the thiolate is essential for this process, in line with the "push effect" deduced by experimentalists (Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem. Rev. 1996, 96, 2841-2887). Finally, four epoxidation pathways of iron(III)-hydroxperoxo are located, in which the species transfers oxygen to ethylene either from the proximal or from the distal sites, in both concerted and stepwise manners. The barriers for the four mechanisms are 37-53 kcal/mol, in comparison with 14 kcal/mol for epoxidation by Compound I. It is therefore concluded that iron(III)-hydroperoxo, as such, cannot be a second oxidant, in line with its significant basicity and poor electron-accepting capability. Possible versions of a second oxidant are discussed.     

Proton-shuffle mechanism of O-O activation for formation of a high-valent oxo-iron species of bleomycin

Bleomycins (BLMs) can utilize H2O2 to cleave DNA in the presence of ferric ions. DFT calculations were used to study the mechanism of O-O bond cleavage in the low-spin FeIII-hydroperoxo complex of BLM. The following alternative hypotheses were investigated using realistic structural models: (a) heterolytic cleavage of the O-O bond, generating a Compound I (Cpd I) like intermediate, formally BLM-FeV=O; (b) homolytic O-O cleavage, leading to a BLM-FeIV=O species and an OH* radical; and (c) a direct O-O cleavage/H-abstraction mechanism by ABLM. The calculations showed that (a) is a facile and viable mechanism; it involves acid-base proton reshuffle mediated by the side-chain linkers of BLM, causing thereby heterolytic cleavage of the O-O bond and generation of Cpd I. Formation of Cpd I is found to involve a barrier of 13.3 kcal/mol, which is lower than the barriers in the alternative mechanisms (b and c) that possess respective barriers of 31 and 17 kcal/mol. The so-formed Cpd I species with a radical on the side-chain linker, methylvalerate (V), adjacent to the BLM-FeIV=O complex, resembles the formation of the active species of cytochrome c peroxidase in the Poulos-Kraut proton-shuffle mechanism in heme peroxidases (Poulos, T. L.; Kraut, J. J. Biol. Chem. 1980, 255, 8199-8205). Experimental data are discussed and shown to be in accord with this proposal. It suggests that the high-valence Cpd I species of BLM participates in the DNA cleavage. This is an alternative mechanistic hypothesis to the exclusive reactivity scenario based on ABLM (FeIII-OOH).     

X-ray absorption spectroscopic studies of high-spin nonheme (alkylperoxo)iron(III) intermediates

The reactions of iron(II) complexes [Fe(T(pt-Bu,i-Pr))(OH)] (1a, Tp(t-Bu,i-Pr) = hydrotris(3-tert-butyl-5-isopropyl-1-pyrazolyl)borate), [Fe(6-Me2BPMCN)(OTf)2] (1b, 6-Me2BPMCN = N,N'-bis((2-methylpyridin-6-yl)methyl)-N,N'-dimethyl-trans-1,2-diaminocyclohexane), and [Fe(L8Py2)(OTf)](OTf) (1c, L8Py2 = 1,5-bis(pyridin-2-ylmethyl)-1,5-diazacyclooctane) with tert-BuOOH give rise to high-spin FeIII-OOR complexes. X-ray absorption spectra (XAS) of these high-spin species show characteristic features, distinct from those of low-spin Fe-OOR complexes (Rohde, J.-U.; et al. J. Am. Chem. Soc. 2004, 126, 16750-16761). These include (1) an intense 1s --> 3d preedge feature, with an area around 20 units, (2) an edge energy, ranging from 7122 to 7126 eV, that is affected by the coordination environment, and (3) a 1.86-1.96 A Fe-OOR bond, compared to the 1.78 A Fe-OOR bond in low-spin complexes. These unique features likely arise from a flexible first coordination sphere in those complexes. The difference in Fe-OOR bond length may rationalize differences in reactivity between low-spin and high-spin FeIII-OOR species.     

Syntheses, structures and properties of a series of non-heme alkoxide-Fe(III) complexes of a benzimidazolyl-rich ligand as models for lipoxygenase

The treatment of Fe(ClO(4))(2)·6H(2)O or Fe(ClO(4))(3)·9H(2)O with a benzimidazolyl-rich ligand, N,N,N',N'-tetrakis[(1-methyl-2-benzimidazolyl)methyl]-1,2-ethanediamine (medtb) in alcohol/MeCN gives a mononuclear ferrous complex, [Fe(II)(medtb)](ClO(4))(2)·?CH(3)CN·?CH(3)OH (1), and four non-heme alkoxide-iron(III) complexes, [Fe(III)(OMe)(medtb)](ClO(4))(2)·H(2)O (2, alcohol = MeOH), [Fe(III)(OEt)(Hmedtb)](ClO(4))(3)·CH(3)CN (3, alcohol = EtOH), [Fe(III)(O(n)Pr)(Hmedtb)](ClO(4))(3)·(n)PrOH·2CH(3)CN (4, alcohol = n-PrOH), and [Fe(III)(O(n)Bu)(Hmedtb)](ClO(4))(3)·3CH(3)CN·H(2)O (5, alcohol = n-BuOH), respectively. The alkoxide-iron(III) complexes all show 1) a Fe(III)-OR center (R = Me, 2; Et, 3; (n)Pr, 4; (n)Bu, 5) with the Fe-O bond distances in the range of 1.781-1.816 ?, and 2) a yellow color and an intense electronic transition around 370 nm. The alkoxide-iron(III) complexes can be reduced by organic compounds with a cis,cis-1,4-diene moiety via the hydrogen atom abstraction reaction.