Sason SHAIK - Academia.edu (original) (raw)

Papers by Sason SHAIK

Research paper thumbnail of Hypercoordination in SiH5- and SiH5.bul.. An electron-count dependence

Inorganic Chemistry, 1990

Research paper thumbnail of Hypercoordinated XHn+1 radicals for first- and second-row atoms. A valence bond analysis

Journal of the American Chemical Society, 1989

A theory of hypercoordination is developed using the valence bond (VB) curve-crossing diagram mod... more A theory of hypercoordination is developed using the valence bond (VB) curve-crossing diagram model and applied to XH,,' radicals that are generated by hydrogen atom attachment to a normal-valent XH, molecule. Hypercoordinated XH,+I radicals fall into two broad classes of valence species: those that can be described by a correlation and avoided crossing of their two Lewis curves, e.g., SiH,, and those that require at least one additional curve-termed the intermediate curve-such as PH4. The Lewis curves correspond to the electron-pairing schemes of the normal-valent constituents in the exchange process H' + XH, - [XH,,,] -H,X + H'. The intermediate curve possesses an (no*) excited character and mixes into the Lewis curves, mainly at the hypercoordinated region. This mixing endows XH,+' with additional stability and a new electronic character . A third class of XH,+I radicals exists, in which the two Lewis curves are crossed by an intermediate Rydberg curve (n -R excitation) which provides an energy well to house a Rydberg XH,+I radical . The hypercoordination capability of an atom X depends on the X-H bond of the normal-valent XH, and on the presence of a lone pair on X. The weaker the X-H bond, the more stable the XH,,,, species relatice to its normal-valent constituents XH, +

Research paper thumbnail of Valence Bond Diagrams and Chemical Reactivity

Angewandte Chemie-international Edition, 1999

Research paper thumbnail of A Two-State Reactivity Rationale for Counterintuitive Axial Ligand Effects on the CH Activation Reactivity of Nonheme FeIVO Oxidants

Chemistry-a European Journal, 2008

This paper addresses the observation of counterintuitive reactivity patterns of iron–oxo reagents... more This paper addresses the observation of counterintuitive reactivity patterns of iron–oxo reagents, TMC(L)FeO2+,1+; L=CH3CN, CF3CO2−, N3−, and SR−, in O-transfer to phosphines versus H-abstraction from, for example, 1,4-cyclohexadiene. Experiments show that O-transfer reactivity correlates with the electrophilicity of the oxidant, but H-abstraction reactivity follows an opposite trend. DFT/B3 LYP calculations reveal that two-state reactivity (TSR) serves as a compelling rationale for these trends, whereby all reactions involve two adjacent spin-states of the iron(IV)–oxo species, triplet and quintet. The ground state triplet surface has high barriers, whereas the excited state quintet surface features lower ones. The barriers, on any single surface, are found to increase as the electrophilicity of TMC(L)FeO2+,1+ decreases. Thus, the counterintuitive behavior of the H-abstraction reactions cannot be explained by considering the reactivity of only a single spin state but can be rationalized by a TSR model in which the reactions proceed on the two surfaces. Two TSR models are outlined: one is traditional involving a variable transmission coefficient for crossover from triplet to quintet, followed by quintet-state reactions; the other considers the net barrier as a blend of the triplet and quintet barriers. The blending coefficient (x), which estimates the triplet participation, increases as the quintet–triplet energy gap of the TMC(L)FeO2+,1+ reagent increases, in the following order of L: CH3CN > CF3CO2− > N3− > SR−. The calculated barriers predict the dichotomic experimental trends and the counterintuitive behavior of the H-abstraction series. The TSR approaches make a variety of testable predictions.

Research paper thumbnail of Electronic Structure Makes a Difference: Cytochrome P-450 Mediated Hydroxylations of Hydrocarbons as a Two-State Reactivity Paradigm

Chemistry-a European Journal, 1998

... conditions. Electronic Structure Makes a Difference: Cytochrome P-450 Mediated Hydroxylations... more ... conditions. Electronic Structure Makes a Difference: Cytochrome P-450 Mediated Hydroxylations of Hydrocarbons as a Two-State Reactivity Paradigm Sason Shaik,* Michael Filatov, Detlef Schröder, and Helmut Schwarz* Dedicated ...

Research paper thumbnail of Two-State Reactivity in the Rebound Step of Alkane Hydroxylation by Cytochrome P-450: Origins of Free Radicals with Finite Lifetimes

Angewandte Chemie-international Edition, 2000

Alkane hydroxylation by cytochrome P-450 poses tantalizing mechanistic questions. The consensus r... more Alkane hydroxylation by cytochrome P-450 poses tantalizing mechanistic questions. The consensus rebound mechanism, Scheme 1, involves hydrogen abstraction from the Scheme 1. Schematic representation of the rebound mechanism.

Research paper thumbnail of Electronic Structures and Gas-Phase Reactivities of Cationic Late-Transition-Metal Oxides

Journal of The American Chemical Society, 1994

Electronic Structures and Gas-Phase Reactivities of Cationic ... Andreas FiedlerJ Detlef Schrtide... more Electronic Structures and Gas-Phase Reactivities of Cationic ... Andreas FiedlerJ Detlef Schrtider,+ Sason Shaik,'*$ and Helmut Schwarz*J ... Contribution from the Institut fir Organische Chemie der Technischen Universitat Berlin, Strasse des 17. Juni 135, 0-10623 Berlin, ...

Research paper thumbnail of Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P-450 revealed by theory

Current Opinion in Chemical Biology, 2002

Recent computational studies of alkane hydroxylation and alkene epoxidation by a model active spe... more Recent computational studies of alkane hydroxylation and alkene epoxidation by a model active species of the enzyme cytochrome P-450 reveal a two-state reactivity (TSR) scenario in which the information content of the product distribution is determined jointly by two states. TSR is used to reconcile the dilemma of the consensus 'rebound mechanism' of alkane hydroxylation, which emerged from experimental studies of ultra-fast radical clocks. The dilemma, stated succinctly as 'radicals are both present and absent and the rebound mechanism is both right and wrong' , is simply understood once one is cognizant that the mechanism operates by two states, one low-spin (LS) the other high-spin (HS). In both states, bond activation proceeds in a manner akin to the rebound mechanism, but the LS mechanism is effectively concerted, whereas the HS is stepwise with incursion of radical intermediates.

Research paper thumbnail of What Factors Affect the Regioselectivity of Oxidation by Cytochrome P450? A DFT Study of Allylic Hydroxylation and Double Bond Epoxidation in a Model Reaction

Journal of The American Chemical Society, 2002

Epoxidation (CdC) vis-à -vis allylic hydroxylation (C-H) reactions of propene with a model compou... more Epoxidation (CdC) vis-à -vis allylic hydroxylation (C-H) reactions of propene with a model compound I (Cpd I) of the enzyme cytochrome P450 were studied using B3LYP density functional theory. Potential energy profiles and kinetic isotope effects (KIE) were calculated. The interactions in the protein pocket were mimicked by adding two external NH---S hydrogen bonds to the thiolate ligand and by introducing a nonpolar medium (with a dielectric constant, ) 5.7) that can exert a polarization effect on the reacting species. A two-state reactivity (TSR) with high-spin (HS) and low-spin (LS) states were located for both processes (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 8977-8989. de Visser, S. P.; Ogilaro, F.; Harris, N.; Shaik, S. J. Am. Chem. Soc. 2001, 123,[3037][3038][3039][3040][3041][3042][3043][3044][3045][3046][3047]. The HS processes were found to be stepwise, whereas the LS processes were characterized as nonsynchronous but effectively concerted pathways. The computed KIE for C-H hydroxylation with and without tunneling corrections are large (>7), and they support the assignment of the corresponding transition states as hydrogen-abstraction species (Groves, J. T.; Han, Y.-Z. In Cytochrome P450: Structures, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995; Chapter 1; pp 3-48). In the gas phase, epoxidation is energetically favorable by 3.4 kcal mol -1 . Inclusion of zero-point energy reduces this difference but still predicts CdC/C-H > 1. Environmental effects were found to have major impact on the CdC/C-H ratio as well as on the stereoselectivity of the processes. Thus, two NH---S hydrogen bonds away from the reaction center reverse the regioselectivity and prefer hydroxylation, namely, CdC/C-H <1. The polarity of the medium further accentuates the trend and leads to a change by 2 orders of magnitude in the regioselectivity, CdC/C-H , 1. Furthermore, since the environmental interactions prefer the LS over the HS reactions, both hydroxylation and epoxidation processes are rendered more stereoselective, again by 2 orders of magnitude. It follows, therefore, that Cpd I is a chameleon oxidant (Ogliaro, F.; Cohen, S.; de Visser, S. P.; Shaik, S. ) that tunes its reactivity and selectivity patterns in response to the protein environment in which it is accommodated. A valence bond (VB) model, akin to "redox mesomerism" (Bernadou, J.; Fabiano, A.-S.; Robert, A.; Meunier, B. J. Am. Chem. Soc. 1994, 116, 9375-9376), is constructed and enables the description of a chameleon transition state. It shows that the good donor ability of the thiolate ligand and the acceptor ability of the iron porphyrin create mixed-valent situations that endow the transition state with a great sensitivity to external perturbations as in the protein pocket. The model is used to discuss the computed results and to relate them to experimental findings.

Research paper thumbnail of Charge-Shift Bonding—A Class of Electron-Pair Bonds That Emerges from Valence Bond Theory and Is Supported by the Electron Localization Function Approach

Chemistry-a European Journal, 2005

Research paper thumbnail of Spin−Orbit Coupling in the Oxidative Activation of H−H by FeO + . Selection Rules and Reactivity Effects

Journal of The American Chemical Society, 1997

ABSTRACT

Research paper thumbnail of Theoretical Investigation of C−H Hydroxylation by (N4Py)Fe IV O 2+ : An Oxidant More Powerful than P450

Journal of The American Chemical Society, 2005

DFT calculations of C-H hydroxylation by a synthetic nonheme oxoiron(IV) oxidant supported by a n... more 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.

Research paper thumbnail of A Different Story of π-DelocalizationThe Distortivity of π-Electrons and Its Chemical Manifestations

Research paper thumbnail of Theoretical Perspective on the Structure and Mechanism of Cytochrome P450 Enzymes

Chemical Reviews, 2005

Sason Shaik was born in 1948 in Iraq. The family immigrated to Israel in the Exodus of the Iraqi ... more Sason Shaik was born in 1948 in Iraq. The family immigrated to Israel in the Exodus of the Iraqi Jewry. He received his B.Sc. and M.Sc. degrees in Chemistry from Bar-Ilan University and Ph.D. degree from the University of Washington under Nicholaos D. Epiotis. In 1978/9 he ...

Research paper thumbnail of A Model “Rebound” Mechanism of Hydroxylation by Cytochrome P450: Stepwise and Effectively Concerted Pathways, and Their Reactivity Patterns

Journal of The American Chemical Society, 2000

A two-state rebound mechanism of alkane hydroxylation by a model active species of the enzyme cyt... more A two-state rebound mechanism of alkane hydroxylation by a model active species of the enzyme cytochrome P450 is studied using density functional theoretic calculations. Theory corroborates Groves&amp;amp;amp;amp;amp;amp;amp;#x27;s rebound mechanism (Groves, JT J. Chem. Educ. 1985, 62, 928), with a key ...

Research paper thumbnail of Why Does Benzene Possess a D6h Symmetry? A Quasiclassical State Approach for Probing .pi.Bonding and Delocalization Energies

Journal of The American Chemical Society, 1995

ABSTRACT

Research paper thumbnail of 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

Journal of The American Chemical Society, 2002

Iron(III)-hydroperoxo, [Por(CysS)Fe(III)-OOH] -, a key species in the catalytic cycle of cytochro... more 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.

Research paper thumbnail of The Elusive Oxidant Species of Cytochrome P450 Enzymes: Characterization by Combined Quantum Mechanical/Molecular Mechanical (QM/MM) Calculations

Journal of The American Chemical Society, 2002

The primary oxidant of cytochrome P450 enzymes, Compound I, is hard to detect experimentally; in ... more The primary oxidant of cytochrome P450 enzymes, Compound I, is hard to detect experimentally; in the case of cytochrome P450(cam), this intermediate does not accumulate in solution during the catalytic cycle even at temperatures as low as 200 K (ref 4). Theory can play an important role in characterizing such elusive species. We present here combined quantum mechanical/molecular mechanical (QM/MM) calculations of Compound I of cytochrome P450(cam) in the full enzyme environment as well as density functional studies of the isolated QM region. The calculations assign the ground state of the species, quantify the effect of polarization and hydrogen bonding on its properties, and show that the protein environment and its specific hydrogen bonding to the cysteinate ligand are crucial for sustaining the Fe-S bond and for preventing the full oxidation of the sulfur.

Research paper thumbnail of The“Rebound Controversy”: An Overview and Theoretical Modeling of the Rebound Step in C−H Hydroxylation by Cytochrome P450

European Journal of Inorganic Chemistry, 2004

C−H hydroxylation by the enzyme cytochrome P450 is one of Nature’s important and most ubiquitous ... more C−H hydroxylation by the enzyme cytochrome P450 is one of Nature’s important and most ubiquitous processes. There is strong evidence that the mechanism proceeds by initial hydrogen abstraction, from the alkane, by the high-valent iron−oxo species of the enzyme, followed by a rebound of the alkyl radical to form the ferric−alcohol product complex (the Groves “rebound” mechanism). Nevertheless, the “rebound” mechanism is still controversial due to the ultrashort radical lifetimes deduced from radical-clock experiments. This review describes the main elements of the controversy and its updated resolution by theory, with an emphasis on the controversial rebound step. The theoretically derived model for alkane hydroxylation is found to involve two-state reactivity (TSR). In TSR, radicals are produced on two different spin-state surfaces, and thereafter they react differently; on the low-spin surface, the rebound proceeds with no product rearrangement and the lifetime of the radicals is ultrashort (or zero), while on the high-spin surface the barrier for rebound is substantial and the lifetime of the radical is sufficiently long that rearrangement may compete with product formation by rebound. A new valence-bond model is developed to model the rebound barrier on the high-spin surface and conceptualize its dependence on the nature of the alkyl radical. The possible intermediacy of carbocationic intermediates alongside radicals is discussed. It is shown that the TSR scenario provides a satisfactory rationale for the controversial findings in the field, and makes verifiable predictions. One of the predictions of TSR is that the ratio of unrearranged to rearranged products, [U/R], will be subject to an intrinsic isotope effect that is substrate-dependent. This prediction and its possible verification by experiment are discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Research paper thumbnail of Reactivity of High-Valent Iron–Oxo Species in Enzymes and Synthetic Reagents: A Tale of Many States

Accounts of Chemical Research, 2007

Research paper thumbnail of Hypercoordination in SiH5- and SiH5.bul.. An electron-count dependence

Inorganic Chemistry, 1990

Research paper thumbnail of Hypercoordinated XHn+1 radicals for first- and second-row atoms. A valence bond analysis

Journal of the American Chemical Society, 1989

A theory of hypercoordination is developed using the valence bond (VB) curve-crossing diagram mod... more A theory of hypercoordination is developed using the valence bond (VB) curve-crossing diagram model and applied to XH,,' radicals that are generated by hydrogen atom attachment to a normal-valent XH, molecule. Hypercoordinated XH,+I radicals fall into two broad classes of valence species: those that can be described by a correlation and avoided crossing of their two Lewis curves, e.g., SiH,, and those that require at least one additional curve-termed the intermediate curve-such as PH4. The Lewis curves correspond to the electron-pairing schemes of the normal-valent constituents in the exchange process H' + XH, - [XH,,,] -H,X + H'. The intermediate curve possesses an (no*) excited character and mixes into the Lewis curves, mainly at the hypercoordinated region. This mixing endows XH,+' with additional stability and a new electronic character . A third class of XH,+I radicals exists, in which the two Lewis curves are crossed by an intermediate Rydberg curve (n -R excitation) which provides an energy well to house a Rydberg XH,+I radical . The hypercoordination capability of an atom X depends on the X-H bond of the normal-valent XH, and on the presence of a lone pair on X. The weaker the X-H bond, the more stable the XH,,,, species relatice to its normal-valent constituents XH, +

Research paper thumbnail of Valence Bond Diagrams and Chemical Reactivity

Angewandte Chemie-international Edition, 1999

Research paper thumbnail of A Two-State Reactivity Rationale for Counterintuitive Axial Ligand Effects on the CH Activation Reactivity of Nonheme FeIVO Oxidants

Chemistry-a European Journal, 2008

This paper addresses the observation of counterintuitive reactivity patterns of iron–oxo reagents... more This paper addresses the observation of counterintuitive reactivity patterns of iron–oxo reagents, TMC(L)FeO2+,1+; L=CH3CN, CF3CO2−, N3−, and SR−, in O-transfer to phosphines versus H-abstraction from, for example, 1,4-cyclohexadiene. Experiments show that O-transfer reactivity correlates with the electrophilicity of the oxidant, but H-abstraction reactivity follows an opposite trend. DFT/B3 LYP calculations reveal that two-state reactivity (TSR) serves as a compelling rationale for these trends, whereby all reactions involve two adjacent spin-states of the iron(IV)–oxo species, triplet and quintet. The ground state triplet surface has high barriers, whereas the excited state quintet surface features lower ones. The barriers, on any single surface, are found to increase as the electrophilicity of TMC(L)FeO2+,1+ decreases. Thus, the counterintuitive behavior of the H-abstraction reactions cannot be explained by considering the reactivity of only a single spin state but can be rationalized by a TSR model in which the reactions proceed on the two surfaces. Two TSR models are outlined: one is traditional involving a variable transmission coefficient for crossover from triplet to quintet, followed by quintet-state reactions; the other considers the net barrier as a blend of the triplet and quintet barriers. The blending coefficient (x), which estimates the triplet participation, increases as the quintet–triplet energy gap of the TMC(L)FeO2+,1+ reagent increases, in the following order of L: CH3CN > CF3CO2− > N3− > SR−. The calculated barriers predict the dichotomic experimental trends and the counterintuitive behavior of the H-abstraction series. The TSR approaches make a variety of testable predictions.

Research paper thumbnail of Electronic Structure Makes a Difference: Cytochrome P-450 Mediated Hydroxylations of Hydrocarbons as a Two-State Reactivity Paradigm

Chemistry-a European Journal, 1998

... conditions. Electronic Structure Makes a Difference: Cytochrome P-450 Mediated Hydroxylations... more ... conditions. Electronic Structure Makes a Difference: Cytochrome P-450 Mediated Hydroxylations of Hydrocarbons as a Two-State Reactivity Paradigm Sason Shaik,* Michael Filatov, Detlef Schröder, and Helmut Schwarz* Dedicated ...

Research paper thumbnail of Two-State Reactivity in the Rebound Step of Alkane Hydroxylation by Cytochrome P-450: Origins of Free Radicals with Finite Lifetimes

Angewandte Chemie-international Edition, 2000

Alkane hydroxylation by cytochrome P-450 poses tantalizing mechanistic questions. The consensus r... more Alkane hydroxylation by cytochrome P-450 poses tantalizing mechanistic questions. The consensus rebound mechanism, Scheme 1, involves hydrogen abstraction from the Scheme 1. Schematic representation of the rebound mechanism.

Research paper thumbnail of Electronic Structures and Gas-Phase Reactivities of Cationic Late-Transition-Metal Oxides

Journal of The American Chemical Society, 1994

Electronic Structures and Gas-Phase Reactivities of Cationic ... Andreas FiedlerJ Detlef Schrtide... more Electronic Structures and Gas-Phase Reactivities of Cationic ... Andreas FiedlerJ Detlef Schrtider,+ Sason Shaik,'*$ and Helmut Schwarz*J ... Contribution from the Institut fir Organische Chemie der Technischen Universitat Berlin, Strasse des 17. Juni 135, 0-10623 Berlin, ...

Research paper thumbnail of Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P-450 revealed by theory

Current Opinion in Chemical Biology, 2002

Recent computational studies of alkane hydroxylation and alkene epoxidation by a model active spe... more Recent computational studies of alkane hydroxylation and alkene epoxidation by a model active species of the enzyme cytochrome P-450 reveal a two-state reactivity (TSR) scenario in which the information content of the product distribution is determined jointly by two states. TSR is used to reconcile the dilemma of the consensus 'rebound mechanism' of alkane hydroxylation, which emerged from experimental studies of ultra-fast radical clocks. The dilemma, stated succinctly as 'radicals are both present and absent and the rebound mechanism is both right and wrong' , is simply understood once one is cognizant that the mechanism operates by two states, one low-spin (LS) the other high-spin (HS). In both states, bond activation proceeds in a manner akin to the rebound mechanism, but the LS mechanism is effectively concerted, whereas the HS is stepwise with incursion of radical intermediates.

Research paper thumbnail of What Factors Affect the Regioselectivity of Oxidation by Cytochrome P450? A DFT Study of Allylic Hydroxylation and Double Bond Epoxidation in a Model Reaction

Journal of The American Chemical Society, 2002

Epoxidation (CdC) vis-à -vis allylic hydroxylation (C-H) reactions of propene with a model compou... more Epoxidation (CdC) vis-à -vis allylic hydroxylation (C-H) reactions of propene with a model compound I (Cpd I) of the enzyme cytochrome P450 were studied using B3LYP density functional theory. Potential energy profiles and kinetic isotope effects (KIE) were calculated. The interactions in the protein pocket were mimicked by adding two external NH---S hydrogen bonds to the thiolate ligand and by introducing a nonpolar medium (with a dielectric constant, ) 5.7) that can exert a polarization effect on the reacting species. A two-state reactivity (TSR) with high-spin (HS) and low-spin (LS) states were located for both processes (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 8977-8989. de Visser, S. P.; Ogilaro, F.; Harris, N.; Shaik, S. J. Am. Chem. Soc. 2001, 123,[3037][3038][3039][3040][3041][3042][3043][3044][3045][3046][3047]. The HS processes were found to be stepwise, whereas the LS processes were characterized as nonsynchronous but effectively concerted pathways. The computed KIE for C-H hydroxylation with and without tunneling corrections are large (>7), and they support the assignment of the corresponding transition states as hydrogen-abstraction species (Groves, J. T.; Han, Y.-Z. In Cytochrome P450: Structures, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995; Chapter 1; pp 3-48). In the gas phase, epoxidation is energetically favorable by 3.4 kcal mol -1 . Inclusion of zero-point energy reduces this difference but still predicts CdC/C-H > 1. Environmental effects were found to have major impact on the CdC/C-H ratio as well as on the stereoselectivity of the processes. Thus, two NH---S hydrogen bonds away from the reaction center reverse the regioselectivity and prefer hydroxylation, namely, CdC/C-H <1. The polarity of the medium further accentuates the trend and leads to a change by 2 orders of magnitude in the regioselectivity, CdC/C-H , 1. Furthermore, since the environmental interactions prefer the LS over the HS reactions, both hydroxylation and epoxidation processes are rendered more stereoselective, again by 2 orders of magnitude. It follows, therefore, that Cpd I is a chameleon oxidant (Ogliaro, F.; Cohen, S.; de Visser, S. P.; Shaik, S. ) that tunes its reactivity and selectivity patterns in response to the protein environment in which it is accommodated. A valence bond (VB) model, akin to "redox mesomerism" (Bernadou, J.; Fabiano, A.-S.; Robert, A.; Meunier, B. J. Am. Chem. Soc. 1994, 116, 9375-9376), is constructed and enables the description of a chameleon transition state. It shows that the good donor ability of the thiolate ligand and the acceptor ability of the iron porphyrin create mixed-valent situations that endow the transition state with a great sensitivity to external perturbations as in the protein pocket. The model is used to discuss the computed results and to relate them to experimental findings.

Research paper thumbnail of Charge-Shift Bonding—A Class of Electron-Pair Bonds That Emerges from Valence Bond Theory and Is Supported by the Electron Localization Function Approach

Chemistry-a European Journal, 2005

Research paper thumbnail of Spin−Orbit Coupling in the Oxidative Activation of H−H by FeO + . Selection Rules and Reactivity Effects

Journal of The American Chemical Society, 1997

ABSTRACT

Research paper thumbnail of Theoretical Investigation of C−H Hydroxylation by (N4Py)Fe IV O 2+ : An Oxidant More Powerful than P450

Journal of The American Chemical Society, 2005

DFT calculations of C-H hydroxylation by a synthetic nonheme oxoiron(IV) oxidant supported by a n... more 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.

Research paper thumbnail of A Different Story of π-DelocalizationThe Distortivity of π-Electrons and Its Chemical Manifestations

Research paper thumbnail of Theoretical Perspective on the Structure and Mechanism of Cytochrome P450 Enzymes

Chemical Reviews, 2005

Sason Shaik was born in 1948 in Iraq. The family immigrated to Israel in the Exodus of the Iraqi ... more Sason Shaik was born in 1948 in Iraq. The family immigrated to Israel in the Exodus of the Iraqi Jewry. He received his B.Sc. and M.Sc. degrees in Chemistry from Bar-Ilan University and Ph.D. degree from the University of Washington under Nicholaos D. Epiotis. In 1978/9 he ...

Research paper thumbnail of A Model “Rebound” Mechanism of Hydroxylation by Cytochrome P450: Stepwise and Effectively Concerted Pathways, and Their Reactivity Patterns

Journal of The American Chemical Society, 2000

A two-state rebound mechanism of alkane hydroxylation by a model active species of the enzyme cyt... more A two-state rebound mechanism of alkane hydroxylation by a model active species of the enzyme cytochrome P450 is studied using density functional theoretic calculations. Theory corroborates Groves&amp;amp;amp;amp;amp;amp;amp;#x27;s rebound mechanism (Groves, JT J. Chem. Educ. 1985, 62, 928), with a key ...

Research paper thumbnail of Why Does Benzene Possess a D6h Symmetry? A Quasiclassical State Approach for Probing .pi.Bonding and Delocalization Energies

Journal of The American Chemical Society, 1995

ABSTRACT

Research paper thumbnail of 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

Journal of The American Chemical Society, 2002

Iron(III)-hydroperoxo, [Por(CysS)Fe(III)-OOH] -, a key species in the catalytic cycle of cytochro... more 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.

Research paper thumbnail of The Elusive Oxidant Species of Cytochrome P450 Enzymes: Characterization by Combined Quantum Mechanical/Molecular Mechanical (QM/MM) Calculations

Journal of The American Chemical Society, 2002

The primary oxidant of cytochrome P450 enzymes, Compound I, is hard to detect experimentally; in ... more The primary oxidant of cytochrome P450 enzymes, Compound I, is hard to detect experimentally; in the case of cytochrome P450(cam), this intermediate does not accumulate in solution during the catalytic cycle even at temperatures as low as 200 K (ref 4). Theory can play an important role in characterizing such elusive species. We present here combined quantum mechanical/molecular mechanical (QM/MM) calculations of Compound I of cytochrome P450(cam) in the full enzyme environment as well as density functional studies of the isolated QM region. The calculations assign the ground state of the species, quantify the effect of polarization and hydrogen bonding on its properties, and show that the protein environment and its specific hydrogen bonding to the cysteinate ligand are crucial for sustaining the Fe-S bond and for preventing the full oxidation of the sulfur.

Research paper thumbnail of The“Rebound Controversy”: An Overview and Theoretical Modeling of the Rebound Step in C−H Hydroxylation by Cytochrome P450

European Journal of Inorganic Chemistry, 2004

C−H hydroxylation by the enzyme cytochrome P450 is one of Nature’s important and most ubiquitous ... more C−H hydroxylation by the enzyme cytochrome P450 is one of Nature’s important and most ubiquitous processes. There is strong evidence that the mechanism proceeds by initial hydrogen abstraction, from the alkane, by the high-valent iron−oxo species of the enzyme, followed by a rebound of the alkyl radical to form the ferric−alcohol product complex (the Groves “rebound” mechanism). Nevertheless, the “rebound” mechanism is still controversial due to the ultrashort radical lifetimes deduced from radical-clock experiments. This review describes the main elements of the controversy and its updated resolution by theory, with an emphasis on the controversial rebound step. The theoretically derived model for alkane hydroxylation is found to involve two-state reactivity (TSR). In TSR, radicals are produced on two different spin-state surfaces, and thereafter they react differently; on the low-spin surface, the rebound proceeds with no product rearrangement and the lifetime of the radicals is ultrashort (or zero), while on the high-spin surface the barrier for rebound is substantial and the lifetime of the radical is sufficiently long that rearrangement may compete with product formation by rebound. A new valence-bond model is developed to model the rebound barrier on the high-spin surface and conceptualize its dependence on the nature of the alkyl radical. The possible intermediacy of carbocationic intermediates alongside radicals is discussed. It is shown that the TSR scenario provides a satisfactory rationale for the controversial findings in the field, and makes verifiable predictions. One of the predictions of TSR is that the ratio of unrearranged to rearranged products, [U/R], will be subject to an intrinsic isotope effect that is substrate-dependent. This prediction and its possible verification by experiment are discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Research paper thumbnail of Reactivity of High-Valent Iron–Oxo Species in Enzymes and Synthetic Reagents: A Tale of Many States

Accounts of Chemical Research, 2007