The "somersault" mechanism for the p-450 hydroxylation of hydrocarbons. The intervention of transient inverted metastable hydroperoxides

A series of model theoretical calculations are described that suggest a new mechanism for the oxidation step in enzymatic cytochrome P450 hydroxylation of saturated hydrocarbons. A new class of metastable metal hydroperoxides is described that involves the rearrangement of the ground-state metal hydroperoxide to its inverted isomeric form with a hydroxyl radical hydrogen bonded to the metal oxide (MO-OH --> MO....HO). The activation energy for this somersault motion of the FeO-OH group is 20.3 kcal/mol for the P450 model porphyrin iron(III) hydroperoxide [Por(SH)Fe(III)-OOH(-)] to produce the isomeric ferryl oxygen hydrogen bonded to an *OH radical [Por(SH)Fe(III)-O....HO(-)]. This isomeric metastable hydroperoxide, the proposed primary oxidant in the P450 hydroxylation reaction, is calculated to be 17.8 kcal/mol higher in energy than the ground-state iron(III) hydroperoxide Cpd 0. The first step of the proposed mechanism for isobutane oxidation is abstraction of a hydrogen atom from the C-H bond of isobutane by the hydrogen-bonded hydroxyl radical to produce a water molecule strongly hydrogen bonded to anionic Cpd II. The hydroxylation step involves a concerted but nonsynchronous transfer of a hydrogen atom from this newly formed, bound, water molecule to the ferryl oxygen with a concomitant rebound of the incipient *OH radical to the carbon radical of isobutane to produce the C-O bond of the final product, tert-butyl alcohol. The TS for the oxygen rebound step is 2 kcal/mol lower in energy than the hydrogen abstraction TS (DeltaE() = 19.5 kcal/mol). The overall proposed new mechanism is consistent with a lot of the ancillary experimental data for this enzymatic hydroxylation reaction.     

Theory favors a stepwise mechanism of porphyrin degradation by a ferric hydroperoxide model of the active species of heme oxygenase

The report uses density functional theory to address the mechanism of heme degradation by the enzyme heme oxygenase (HO) using a model ferric hydroperoxide complex. HO is known to trap heme molecules and degrade them to maintain iron homeostasis in the biosystem. The degradation is initiated by complexation of the heme, then formation of the iron-hydroperoxo species, which subsequently oxidizes the meso position of the porphyrin by hydroxylation, thereby enabling eventually the cleavage of the porphyrin ring. Kinetic isotope effect studies indicate that the mechanism is assisted by general acid catalysis, via a chain of water molecules, and that all the events occur in concert. However, previous theoretical treatments indicated that the concerted mechanism has a high barrier, much higher than an alternative mechanism that is initiated by O-O bond homolysis of iron-hydroperoxide. The present contribution studies the stepwise and concerted acid-catalyzed mechanisms using H(3)O(+)(H(2)O)(n)(), n = 0-2. The effect of the acid strength is tested using the H(4)N(+)(H(2)O)(2) cluster and a fully protonated ferric hydroperoxide. All the calculations show that a stepwise mechanism that involves proton relay and O-O homolysis, in the rate-determining step, has a much lower barrier (>10 kcal/mol) than the corresponding fully concerted mechanism. The best fit of the calculated solvent kinetic isotope effect, to the experimental data, is obtained for the H(3)O(+)(H(2)O)(2) cluster. The calculated alpha-deuterium secondary kinetic isotope effect is inverse (0.95-0.98), but much less so than the experimental value (0.7). Possible reasons for this quantitative difference are discussed. Some probes are suggested that may enable experiment to distinguish the stepwise from the concerted mechanism.     

Reactivity of alkyl versus silyl peroxides. The consequences of 1, 2-silicon bridging on the epoxidation of alkenes with silyl hydroperoxides and bis(trialkylsilyl)peroxides

The bond dissociation energies for a series of silyl peroxides have been calculated at the G2 and CBS-Q levels of theory. A comparison is made with the O-O BDE of the corresponding dialkyl peroxides, and the effect of the O-O bond strength on the activation barrier for oxygen atom transfer is discussed. The O-O bond dissociation enthalpies (DeltaH(298)) for bis (trimethylsilyl) peroxide (1) and trimethylsilyl hydroperoxide (2) are 54.8 and 53.1 kcal/mol, respectively at the G2 (MP2) and CBS-Q levels of theory. The O-O bond dissociation energies computed at G2 and G2(MP2) levels for bis(tert-butyl) peroxide and tert-butyl hydroperoxide are 45.2 and 48.3 kcal/mol, respectively. The barrier height for 1,2-methyl migration from silicon to oxygen in trimethylsilyl hydroperoxide is 47.9 kcal/mol (MP4//MP2/6-31G). The activation energy for the oxidation of trimethylamine to its N-oxide by bis(trimethylsilyl) peroxide is 28.2 kcal/mol (B3LYP/6-311+G(3df,2p)// B3LYP/6-31G(d)). 1,2-Silicon bridging in the transition state for oxygen atom transfer to a nucleophilic amine results in a significant reduction in the barrier height. The barrier for the epoxidation of E-2-butene with bis(dimethyl(trifluoromethyl))silyl peroxide is 25.8 kcal/mol; a reduction of 7.5 kcal/mol relative to epoxidation with 1. The activation energy calculated for the epoxidation of E-2-butene with F(3)SiOOSiF(3) is reduced to only 2.2 kcal/mol reflecting the inductive effect of the electronegative fluorine atoms.     

Quantum mechanical/molecular mechanical study on the mechanisms of compound I formation in the catalytic cycle of chloroperoxidase: an overview on heme enzymes

The formation of Compound I (Cpd I), the active species of the enzyme chloroperoxidase (CPO), was studied using QM/MM calculation. Starting from the substrate complex with hydrogen peroxide, FeIII-HOOH, we examined two alternative mechanisms on the three lowest spin-state surfaces. The calculations showed that the preferred pathway involves heterolytic O-O cleavage that proceeds via the iron hydroperoxide species, i.e., Compound 0 (Cpd 0), on the doublet-state surface. This process is effectively concerted, with a barrier of 12.4 kcal/mol, and is catalyzed by protonation of the distal OH group of Cpd 0. By comparison, the path that involves a direct O-O cleavage from FeIII-HOOH is less favored. A proton coupled electron transfer (PCET) feature was found to play an important role in the mechanism nascent from Cpd 0. Initially, the O-O cleavage progresses in a homolytic sense, but as soon as the proton is transferred to the distal OH, it triggers an electron transfer from the heme-oxo moiety to form water and Cpd I. This study enables us to generalize the mechanisms of O-O activation, elucidated so far by QM/MM calculations, for other heme enzymes, e.g., cytochrome P450cam, horseradish peroxidase (HRP), nitric oxide synthase (NOS), and heme oxygenase (HO). Much like for CPO, in the cases of P450 and HRP, the PCET lowers the barrier below the purely homolytic cleavage alternative (in our case, the homolytic mechanism is calculated directly from FeIII-HOOH). By contrast, the absence of PCET in HO, along with the robust water cluster, prefers a homolytic cleavage mechanism.     

Formation of a Criegee intermediate in the low-temperature oxidation of dimethyl sulfoxide

Dimethyl sulfoxide (DMSO) is the major sulfur-containing constituent of the Marine Boundary Layer. It is a significant source of H2SO4 aerosol/particles and methane sulfonic acid via atmospheric oxidation processes, where the mechanism is not established. In this study, several new, low-temperature pathways are revealed in the oxidation of DMSO using CBS-QB3 and G3MP2 multilevel and B3LYP hybrid density functional quantum chemical methods. Unlike analogous hydrocarbon peroxy radicals the chemically activated DMSO peroxy radical, [CH3S(=O)CH2OO*]*, predominantly undergoes simple dissociation to a methylsulfinyl radical CH3S*(=O) and a Criegee intermediate, CH2OO, with the barrier to dissociation 11.3 kcal mol(-1) below the energy of the CH3S(=O)CH2* + O2 reactants. The well depth for addition of O2 to the CH3S(=O)CH2 precursor radical is 29.6 kcal mol(-1) at the CBS-QB3 level of theory. We believe that this reaction may serve an important role in atmospheric photochemical and irradiated biological (oxygen-rich) media where formation of initial radicals is facilitated even at lower temperatures. The Criegee intermediate (carbonyl oxide, peroxymethylene) and sulfinyl radical can further decompose, resulting in additional chain branching. A second reaction channel important for oxidation processes includes formation (via intramolecular H atom transfer) and further decomposition of hydroperoxide methylsulfoxide radical, *CH2S(=O)CH2OOH over a low barrier of activation. The initial H-transfer reaction is similar and common in analogous hydrocarbon radical + O2 reactions; but the subsequent very low (3-6 kcal mol(-1)) barrier (14 kcal mol(-1) below the initial reagents) to beta-scission products is not common in HC systems. The low energy reaction of the hydroperoxide radical is a beta-scission elimination of *CH2S(=O)CH2OOH into the CH2=S=O + CH2O + *OH product set. This beta-scission barrier is low, because of the delocalization of the *CH2 radical center through the -S(=O) group, to the -CH2OOH fragment in the transition state structure. The hydroperoxide methylsulfoxide radical can also decompose via a second reaction channel of intramolecular OH migration, yielding formaldehyde and a sulfur-centered hydroxymethylsulfinyl radical HOCH2S*(=O). The barrier of activation relative to initial reagents is 4.2 kcal mol(-1). Heats of formation for DMSO, DMSO carbon-centered radical and Criegee intermediate are evaluated at 298 K as -35.97 +/- 0.05, 13.0 +/- 0.2 and 25.3 +/- 0.7 kcal mol(-1) respectively using isodesmic reaction analysis. The [CH3S*(=O) + CH2OO] product set is shown to form a van der Waals complex that results in O-atom transfer reaction and the formation of new products CH3SO2* radical and CH2O. Proper orientation of the Criegee intermediate and methylsulfinyl radical, as a pre-stabilized pre-reaction complex, assist the process. The DMSO radical reaction is also compared to that of acetonyl radical.     

Conformation-dependent state selectivity in O-O cleavage of ONOONO: an "inorganic cope rearrangement" helps explain the observed negative activation energy in the oxidation of nitric oxide by dioxygen

ONOONO has been proposed as an intermediate in the oxidation of nitric oxide by dioxygen to yield nitrogen dioxide. The O-O bond breaking reactions of this unusual peroxide, and subsequent rearrangements, were evaluated using CBS-QB3 and B3LYP/6-311G hybrid density functional theory. The three stable conformers (cis,cis-, cis,trans-, and trans,trans-ONOONO, based on the O-N-O-O dihedral angles of either approximately 0 degrees or approximately 180 degrees ) are predicted to have very different O-O cleavage barriers: 2.4, 13.0, and 29.8 kcal/mol, respectively. These large differences arise because bond breaking leads to correlation of the nascent NO(2) fragments with either the ground (2)A(1) state or the excited (2)B(2) state of NO(2), depending on the starting ONOONO conformation. A cis-oriented NO(2) fragment correlates with the (2)A(1) state, whereas a trans-oriented NO(2) fragment correlates with the (2)B(2) state. Each NO(2) fragment that correlates with (2)A(1) lowers the O-O homolysis energy by approximately 15 kcal/mol, similar to the approximately 17-25 kcal/mol (2)A(1) --> (2)B(2) energy difference in NO(2). Hence, this provides an unusual example of conformation-dependent electronic state selectivity. The O-O bond homolysis of cis,cis-ONOONO is particularly interesting because it has a very low barrier and arises from the most stable ONOONO conformer, and also due to obvious similarities to the well-known [3,3]-sigmatropic shift of 1,5-hexadiene, i.e., the Cope rearrangement. As an additional proof of our state selectivity postulate, a comparison is also made to breakage of the O-O bond of cis,cis-formyl peroxide, where no significant stabilization of the transition state is available because the (2)A(1) and (2)B(2) states of formyloxy radical are near-degenerate in energy. In the case of trans,trans-ONOONO, the O-O bond breaking transition state is a concerted rearrangement yielding O(2)NNO(2), whereas for cis,cis- and cis,trans-ONOONO, the initially formed NO(2) radical pairs can undergo further rearrangement to yield ONONO(2). It is proposed that previous spectroscopic observations of certain N=O stretching frequencies in argon-matrix-isolated products from the reaction of NO with O(2) (or (18)O(2)) are likely from ONONO(2), not the OONO radical as reported.     

McLafferty rearrangement of the radical cations of butanal and 3-fluorobutanal: a theoretical investigation of the concerted and stepwise mechanisms

The stepwise and concerted pathways for the McLafferty rearrangement of the radical cations of butanal (Bu(+)) and 3-fluorobutanal (3F-Bu(+)) are investigated with density functional theory (DFT) and ab initio methods in conjunction with the 6-311+G(d,p) basis set. A concerted transition structure (TS) for Bu(+), (H), is located with a Gibbs barrier height of 37.7 kcal/mol as computed with CCSD(T)//BHandHLYP. Three pathways for the stepwise rearrangement of Bu(+) have been located, which are all found to involve different complexes. The barrier height for the H(gamma) transfer is found to be 2.2 kcal/mol, while the two most favorable TSs for the C(alpha)-C(beta) cleavage are located 8.9 and 9.2 kcal/mol higher. The energies of the 3F-Bu(+) system have been calculated with the promising hybrid meta-GGA MPWKCIS1K functional of DFT. Interestingly, the fluorine substitution yields a barrier height of only 20.5 kcal/mol for the concerted TS, (3F-H). A smaller computed dipole moment, 12.1 D, for (3F-H) compared with 103.2 D for (H) might explain the stabilization of the substituted TS. The H(gamma) transfer, with a barrier height of 4.9 kcal/mol, is found to be rate-determining for the stepwise McLafferty rearrangement of 3F-Bu(+), in contrast to the unsubstituted case. By inspection of the spin and charge distributions of the stationary points, it is noted that the bond cleavages in the concerted rearrangements are mainly of heterolytic nature, while those in the stepwise channels are found to be homolytic.     

Model studies on p-hydroxybenzoate hydroxylase. The catalytic role of Arg-214 and Tyr-201 in the hydroxylation step

A model C-(4a)-flavinhydroperoxide (FlHOOH) is described that contains the tricyclic isoalloxazine moiety, the C-4a-hydroperoxide functionality, and a beta-hydroxyethyl group to model the effect of the 2'-OH group of the ribityl side chain of native FADHOOH. The electronic structures of this reduced flavin (H(3)()Fl(red)()), its N1 anion (H(2)()Fl(red)()(-)()), oxidized flavin (HFl(ox)()), and FlHOOH have been fully optimized at the B3LYP/ 6-31+G(d,p) level of theory. This model C-4a-flavinhydroperoxide is used to describe the transition state for the key step in the paradigm aromatic hydroxylase, p-hydroxybenzoate hydroxylase (PHBH): the oxidation of p-hydroxybenzoate (p-OHB). The Tyrosine-201 residue in PHBH is modeled by phenol, and Arginine-214 is modeled by guanidine. Electrophilic aromatic substitution proceeds by an S(N)2-like attack of the aromatic sextet of p-OHB phenolate anion on the distal oxygen of FlHOOH 3. The transition structure for oxygen atom transfer is fully optimized [B3LYP/6-31+G(d,p)] and has a classical activation barrier of 24.9 kcal/mol. These data suggest that the role of the Tyr-201 is to orient the p-OHB substrate and to properly align it for the oxygen transfer step. Although the negatively charged phenolate oxygen does activate the C-3 carbon of p-OHB phenolate anion toward oxidation relative to ortho oxidation of the carboxylate anion, it appears that H-bonding the Tyr-201 residue to this phenolic oxygen stabilizes both the ground state (GS) and the transition state (TS) approximately equally and therefore plays only a minor role, if any, in lowering the activation barrier. Complexation of p-OHB with guanidine has only a modest effect upon the oxidation barriers. When the complex is in the form of a salt-bridge (10a), the barrier is only slightly reduced. When the TSs are placed in THF solvent (COSMO) with full geometry optimization, salt-bridge TS-A is slightly favored (DeltaDeltaE() = 2.3 kcal/mol).     

Quantum chemical study of low temperature oxidation mechanism of dibenzofuran

A density functional theory (DFT) study of the reaction of dibenzofuranyl radical with oxygen molecule has been made. The geometries, energies, and vibrational frequencies of the reactant, transition states, intermediates, and products have been calculated at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31G(d) level of theory. The initial reaction of dibenzofuran (DBF) with molecular oxygen results in the formation of the 1-dibenzofuranylperoxy radical. The stability of this adduct toward decomposition at low to intermediate temperatures results in it undergoing several possible rearrangements. The lowest energy pathway with a barrier of 24.2 kcal/mol involves a rearrangement to the 1,1-dioxadibenzofuran radical. The next lowest energy pathway involves fission of the O-O linkage whose reaction energy was found to be 37.6 kcal/mol. Transition state theory (TST) calculations indicate that the lowest energy pathway should predominate at temperatures up to about 1200 K. Two other unimolecular reaction pathways with barriers of 45.5 and 91.1 kcal/mol have also been discovered. The latter pathway leads to the formation of a para-quinone (dibenzofuran quinone) which has been detected experimentally in the low-temperature oxidation of DBF [Marquaire, P. M.; Worner, R.; Rambaud, P.; Baronnet, F. Organohalogen Compd. 1999, 40, 519]. Our quantum calculations, however, do not support this latter pathway to quinone formation. Instead, the quinone is most probably formed as a consequence of recombination of the 1-dibenzofuranyloxy radical (produced by peroxy fission) with an O atom in the para position. Each of the unimolecular reaction pathways have been subjected to detailed quantum chemical investigation and transition states and intermediates leading to the final products (principally CO, CO2, and C2H2 with traces of benzofuran and benzene) have been identified. For certain stable intermediates, their possible reactions with molecular oxygen have been further investigated quantum chemically. The present work therefore presents a detailed quantum chemical investigation of the reaction pathways in the low-temperature oxidation mechanism of DBF. Since the dibenzofuran moiety is present in the polychlorinated DBFs, our conclusions should be generally applicable to this family of compounds.     

Ab Initio Kinetics for Thermal Decomposition of CH(3)N(•)NH(2), cis-CH(3)NHN(•)H, trans-CH(3)NHN(•)H, and C(•)H(2)NNH(2) Radicals

The thermal decomposition of the CH(3)N(?)NH(2), cis-CH(3)NHN(?)H, trans-CH(3)NHN(?)H, and C(?)H(2)NNH(2) radicals, which are the four radical products from the H-abstraction reactions of monomethylhydrazine, were theoretically studied by using ab initio Rice-Ramsperger-Kassel-Marcus (RRKM) transition-state theory and master equation analysis. Various decomposition pathways were identified by using either the QCISD(T)/cc-pV∞Z//CASPT2/aug-cc-pVTZ or the QCISD(T)/cc-pV∞Z//B3LYP/6-311++G(d,p) quantum chemistry methods. The results reveal that the β-scission of NH(2) to form methyleneimine is the predominant channel for the decomposition of the C(?)H(2)NNH(2) radical due to its small energy barrier of 13.8 kcal mol(-1). The high pressure limit rate coefficient for the reaction is fitted by 3.88 × 10(19)T(-1.672) exp(-9665.13/T) s(-1). In addition, the pressure dependent rate coefficients exhibit slight temperature dependence at temperatures of 1000-2500 K. The cis-CH(3)NHN(?)H and trans-CH(3)NHN(?)H radicals are the two distinct spatial isomers with an energy barrier of 26 kcal mol(-1) for their isomerization. The β-scission of CH(3) from the cis-CH(3)NHN(?)H radical to form trans-diazene has an energy barrier of 35.2 kcal mol(-1), and the β-scission of CH(3) from the trans-CH(3)NHN(?)H radical to form cis-diazene has an energy barrier of 39.8 kcal mol(-1). The CH(3)N(?)NH(2) radical undergoes the β-scission of methyl hydrogen and amine hydrogen to form CH(2)═NNH(2), trans-CH(3)N═NH, and cis-CH(3)N═NH products, with the energy barriers of 42.8, 46.0, and 50.2 kcal mol(-1), respectively. The dissociation and isomerization rate coefficients for the reactions were calculated via the E/J resolved RRKM theory and multiple-well master equation analysis at temperatures of 300-2500 K and pressures of 0.01-100 atm. The calculated rate coefficients associated with updated thermochemical property data are essential components in the development of kinetic mechanisms for the pyrolysis and oxidation of MMH and its derivatives.     

Quantum mechanical/molecular mechanical study of mechanisms of heme degradation by the enzyme heme oxygenase: the strategic function of the water cluster

Heme degradation by heme oxygenase (HO) enzymes is important in maintaining iron homeostasis and prevention of oxidative stress, etc. In response to mechanistic uncertainties, we performed quantum mechanical/molecular mechanical investigations of the heme hydroxylation by HO, in the native route and with the oxygen surrogate donor H2O2. It is demonstrated that H2O2 cannot be deprotonated to yield Fe(III)OOH, and hence the surrogate reaction starts from the FeHOOH complex. The calculations show that, when starting from either Fe(III)OOH or Fe(III)HOOH, the fully concerted mechanism involving O-O bond breakage and O-C(meso) bond formation is highly disfavored. The low-energy mechanism involves a nonsynchronous, effectively concerted pathway, in which the active species undergoes first O-O bond homolysis followed by a barrier-free (small with Fe(III)HOOH) hydroxyl radical attack on the meso position of the porphyrin. During the reaction of Fe(III)HOOH, formation of the Por+*FeIV=O species, compound I, competes with heme hydroxylation, thereby reducing the efficiency of the surrogate route. All these conclusions are in accord with experimental findings (Chu, G. C.; Katakura, K.; Zhang, X.; Yoshida, T.; Ikeda-Saito, M. J. Biol. Chem. 1999, 274, 21319). The study highlights the role of the water cluster in the distal pocket in creating "function" for the enzyme; this cluster affects the O-O cleavage and the O-Cmeso formation, but more so it is responsible for the orientation of the hydroxyl radical and for the observed alpha-meso regioselectivity of hydroxylation (Ortiz de Montellano, P. R. Acc. Chem. Res. 1998, 31, 543). Differences/similarities with P450 and HRP are discussed.     

The 1deltag dioxygen ene reaction with propene: a density functional and multireference perturbation theory mechanistic study

This study aims to determine whether a balance between concerted and non-concerted pathways exists, and in particular to ascertain the possible role of diradical/zwitterion or peroxirane intermediates. Three non-concerted pathways, via 1) diradical or 2) peroxirane intermediates, and 3) by means of hydrogen-abstraction/radical recoupling, plus one concerted pathway (4), are explored. The intermediates and transition structures (TS) are optimized at the DFT(MPW1K), DFT(B3LYP) and CASSCF levels of theory. The latter optimizations are followed by multireference perturbative CASPT2 energy calculations. (1) The polar diradical forms from the separate reactants by surmounting a barrier (deltaE(++)(MPW1K)=12, deltaE++(B3LYP)=14, and deltaE(++)(CASPT2)=16 kcal mol(-1) and can back-dissociate through the same TS, with barriers of 11 (MPW1K) and 8 kcal mol(-1) (B3LYP and CASPT2). The diradical to hydroperoxide transformation is easy at all levels (deltaE(++)(MPW1K)<4, deltaE(++)(B3LYP)=1 and deltaE(++)(CASPT2)=1 kcal mol(-1)). (2) Peroxirane is attainable only by passing through the diradical intermediate, and not directly, due to the nature of the critical points involved. It is located higher in energy than the diradical by 12 kcal mol(-1), at all theory levels. The energy barrier for the diradical to cis-peroxirane transformation (deltaE(++)=14-16 kcal mol(-1)) is much higher than that for the diradical transformation to the hydroperoxide. In addition, peroxirane can very easily back-transform to the diradical (deltaE(++)<3 kcal mol(-1)). Not only the energetics, but also the qualitative features of the energy hypersurface, prevent a pathway connecting the peroxirane to the hydroperoxide at all levels of theory. (3) The last two-step pathway (hydrogen-abstraction by (1)O(2), followed by HOO-allyl radical coupling) is not competitive with the diradical mechanism. (4) A concerted pathway is carefully investigated, and deemed an artifact of restricted DFT calculations. Finally, the possible ene/[pi2+pi2] competition is discussed.     

Double proton transfer and one-electron oxidation behavior in double H-bonded glycinamide-glycine complex in the gas phase

The behaviors of double proton transfer (DPT) occurring in a representative glycinamide-glycine complex have been investigated employing the B3LYP/6-311++G** level of theory. Thermodynamic and especially kinetic parameters, such as tautomerization energy, equilibrium constant, and barrier heights have been discussed, respectively. The relevant quantities involved in the DPT process including geometrical changes, interaction energies, and deformation energies have also been studied. Analogous to that of tautomeric process assisted with a formic acid molecule, the participation of a glycine molecule favors the proceeding of the proton transfer (PT) for glycinamide compared with that without mediator-assisted case. The DPT process proceeds with a concerted mechanism rather than a stepwise one because no zwitterionic complexes have been located during the DPT process. The barrier heights are 12.14 and 0.83 kcal/mol for the forward and reverse directions, respectively. However, both of them have been reduced by 3.10 and 2.66 kcal/mol to 9.04 and -1.83 kcal/mol with further inclusion of zero-point vibrational energy (ZPVE) corrections, where the disappearance of the reverse barrier height implies that the reverse reaction should proceed with barrierless spontaneously, analogous to those of DPTs occurring between glycinamide and formic acid (or formamide). Additionally, the oxidation process for the double H-bonded glycinamide-glycine complex has also been investigated. The oxidated product is characterized by a distonic radical cation due to the fact that one-electron oxidation takes place on glycine fragment and a proton has been transferred from glycine to glycinamide fragment spontaneously. As a result, the vertical and adiabatic ionization potentials for the neutral complex have been determined to be about 8.71 and 7.85 eV, respectively, where both of them have been reduced by about 0.54 (1.11) and 0.75 (1.13) eV relative to those of isolated glycinamide (glycine) due to the formation of the intermolecular H-bond.     

Beyond the Roger Brown rearrangement: long-range atom topomerization in conjugated polyynes

Long-range carbon atom topomerization in a 1,3-diyne has been demonstrated for the first time. 1-Phenyl-4-p-tolyl-1,3-butadiyne, (13)C-enriched at C-1, was synthesized and subjected to flash vacuum pyrolysis. At 800 degrees C and 0.01 Torr, this resulted in nearly complete (13)C label equilibration between C-1 and C-2, as seen by NMR analysis. Pyrolysis at 900 degrees C further led to ca. 35% of the label migrating about equally to C-3 and C-4. These results demonstrate that both intrabond and interbond atom exchange processes are operative, with the former having a lower activation barrier. DFT and Moller-Plesset calculations support a mechanism that passes through Brown rearrangement (1,2-shift), closure to trialene (bicyclo[1.1.0]-1,3-butadiene), bond-shift isomerization to exchange C-2 and C-3, and ring opening. The resulting vinylidene can rearrange to a butadiyne with the isotopic label at C-3 or C-4. Consistent with earlier calculations, trialene is predicted to have alternating peripheral bonds, with a weak central sigma bond and significant diradical character. Trialene is predicted [(B3LYP/6-311+G(2d,p)] to lie 64.6 kcal/mol above butadiyne, with barriers of 2.2 and 4.4 kcal/mol, respectively, for ring opening or bond-shift isomerization. Other potential rearrangement mechanisms which pass through tetrahedrene (E(rel) = 167.2 kcal/mol) or 1,2,3-cyclobutatriene (E(rel) = 161.1 kcal/mol) lie at much higher energies.     

Revisiting the mechanism of P450 enzymes with the radical clocks norcarane and spiro[2,5]octane

Norcarane (1) and spiro[2.5]octane (2) yield different product distributions depending on whether they are oxidized via concerted, radical, or cationic mechanisms. For this reason, these two probes were used to investigate the mechanisms of hydrocarbon hydroxylation by two mammalian and two bacterial cytochrome P450 enzymes. Products indicative of a radical intermediate with a lifetime ranging from 16 to 52 ps were detected during the oxidation of norcarane by P450(cam) (CYP101), P450(BM3) (CYP102), CYP2B1, and CYP2E1. Trace amounts of the cation rearrangement product were observed with norcarane for all but CYP2E1, while no cation or radical rearrangement products were observed for spiro[2.5]octane. The results for the oxidation of norcarane with a radical rearrangement rate of 2 x 10(8) s(-1) are consistent with the involvement of a two-state radical rebound mechanism, while for the slower (5 x 10(7) s(-1)) spiro[2,5]oct-4-yl radical rearrangement products were beyond detection. Taken together with earlier data for the hydroxylation of bicyclo[2.1.0]pentane, which also suggested a 50 ps radical lifetime, these three structurally similar and functionally simple substrates show a consistent pattern of rearrangement that supports a radical rebound mechanism for this set of cytochrome P450 enzymes.     

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).     

The carbon-skeleton rearrangement in tropane alkaloid biosynthesis

High-level quantum chemistry calculations have been performed to examine the carbon-skeleton rearrangement of the tropane alkaloid littorine to hyoscyamine. Two pathways involving radical and carbocation intermediates have been investigated in this regard, namely, stepwise (or fragmentation-recombination) and concerted. The fragmentation products are calculated to be of high energy for both the radical- and carbocation-based mechanisms (136.3 and 170.9 kJ mol(-1), respectively). Similarly, the rearrangement barrier for the radical-based concerted pathway is calculated to be quite high (135.6 kJ mol(-1)). In contrast, the carbocation-based concerted pathway is found to be associated with a relatively low barrier (47.4 kJ mol(-1)). The ionization energy of the substrate-derived radical 3a is calculated to be 7.01 eV, suggesting that its oxidation to generate the substrate-derived carbocation 3b ought to be facile. In an attempt to investigate how an enzyme might modulate the rearrangement barriers, the separate and combined influences of partially protonating the migrating group and partially deprotonating the spectator OH group of the substrate were investigated. Such interactions can lead to significant reductions in the rearrangement barrier for both the radical- and carbocation-based concerted pathways, although the carbocation pathway continues to have significantly lower energy requirements. Also, the relatively high (gas-phase) acidity of the OH group of the product-related carbocation 4b indicates that the direct formation of hyoscyamine aldehyde (6) is a highly exothermic process. Although we would not wish to rule out alternative possibilities, our calculations suggest that a concerted rearrangement mechanism involving carbocations constitutes a viable low-energy pathway for the carbon-skeleton rearrangement in tropane alkaloid biosynthesis.     

On the mechanisms of oxidation of organic sulfides by H2O2 in aqueous solutions

The mechanism of oxidation of organic sulfides in aqueous solutions by hydrogen peroxide was investigated via ab initio calculations. Specifically, two reactions, hydrogen transfer of hydrogen peroxide to form water oxide and the oxidation of dimethyl sulfide (DMS) by hydrogen peroxide to form dimethyl sulfoxide, were studied as models of these processes in general. Solvent effects are included both via including explicitly water molecules and via the polarizable continuum model. The former was found to have a much more significant effect than the latter. When explicit water molecules are included, a mechanism different from those proposed in the literature was found. Specific interactions including hydrogen bonding with 2-3 water molecules can provide enough stabilization for the charge separation of the activation complex. The energy barrier of the oxidation of DMS by hydrogen peroxide was estimated to be 12.7 kcal/mol, within the experimental range of the oxidation of analogous compounds (10-20 kcal/mol). The major reaction coordinates of the reaction are the breaking of the O-O bond of H2O2 and the formation of the S-O bond, the transfer of hydrogen to the distal oxygen of hydrogen peroxide occurring after the system has passed the transition state. Reaction barriers of the hydrogen transfer of H2O2 are an average of 10 kcal/mol or higher than the reaction barriers of the oxidation of DMS. Therefore, a two-step oxidation mechanism in which, first, the transfer of a hydrogen atom occurs to form water oxide and, second, the transfer of oxygen to the substrate occurs is unlikely to be correct. Our proposed oxidation mechanism does not suggest a pH dependence of oxidation rate within a moderate range around neutral pH (i.e., under conditions in which hydronium and hydroxide ions do not participate directly in the reaction), and it agrees with experimental observations over moderate pH values. Also, without including a protonated solvent molecule, it has activation energies that correspond to measured activation energies.     

Theoretical studies on reactions of the stabilized H2COO with HO2 and the HO2···H2O complex

The reactions of H(2)COO with HO(2) and the HO(2)···H(2)O complex are studied by employing the high-level quantum chemical calculations with B3LYP and CCSD(T) theoretical methods, the conventional transition-state theory (CTST), and the Rice-Ramsperger-Kassel-Marcus (RRKM) with Eckart tunneling correction. The calculated results show that the proton transfer plus the addition reaction channel (TS1A) is preferable for the reaction of H(2)COO with HO(2) because the barriers are -10.8 and 1.6 kcal/mol relative to the free reactants and the prereactive complex, respectively, at the CCSD(T)/6-311++G(3df,2p)//B3LYP/6-311++G(d,p) level of theory. Furthermore, the rate constant via TS1A (2.23 × 10(-10) cm(3) molecule(-1) s(-1)) combined with the concentrations of the species in the atmosphere demonstrates that the HO(2) radical would be the dominant sink of H(2)COO in some areas, where the concentration of water is less than 10(17) molecules cm(-3). In addition, although the single water molecule would lower the activated barrier of TS1A from 1.0 to 0.1 kcal/mol with respect to the respective complexes, the rate constant is lower than that of the reaction of HO(2) with H(2)COO.     

Integration of catalysis and analysis is the key: rapid and precise investigation of the catalytic asymmetric Gosteli-Claisen rearrangement

The kinetics of the Cu(II)(bisoxazoline)-catalyzed diastereo- and enantioselective Gosteli-Claisen rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers has been investigated by enantioselective on-column reaction gas chromatography (ocRGC). Enantioselective ocRGC integrates (stereoselective) catalysis and enantioselective chromatography in a single microcapillary, which is installed in a GC-MS for direct analysis of conversion and selectivity. Thus, this technique allows direct differentiation of thermal and stereoselectively catalyzed reaction pathways and determination of activation parameters and selectivities of the individual reaction pathways starting from stereoisomeric reactants with high precision. Two modes of operation of enantioselective ocRGC are presented to investigate noncatalyzed, i.e., conversion of isopropyl-2-(allyloxy)but-2Z-enoate 1 to isopropyl-3R,S-methyl-2-oxy-hex-5-enoate (±)-2 and the [Cu{(R,R)-Ph-box}](SbF(6))(2)-catalyzed Gosteli-Claisen rearrangement, i.e., conversion of isopropyl-2-(but-2'E-en-1-yloxy)but-2Z-enoate (E,Z)-3 to isopropyl-3S,4S-dimethyl-2-oxy-hex-5-enoate 4b. Eyring activation parameters have been determined by temperature-dependent measurements: Uncatalyzed rearrangement of 1 to (±)-2 gives ΔG(?) (298 K) = 114.1 ± 0.2 kJ·mol(-1), ΔH(?) = 101.1 ± 1.9 kJ·mol(-1), and ΔS(?) = -44 ± 5 J·(K·mol)(-1), and catalyzed rearrangement of (E,Z)-3 to 4b gives ΔG(?)(298 K) = 101.1 ± 0.3 kJ·mol(-1), ΔH(?) = 106.1 ± 6.6 kJ·mol(-1), and ΔS(?) = 17 ± 19 J·(K·mol)(-1).