DFT/B3LYP study of tocopherols and chromans antioxidant action energetics

Gas-phase reaction enthalpies related to the individual steps of three phenolic antioxidants action mechanisms – hydrogen atom transfer (HAT), single-electron transfer–proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) for four tocopherols and seven chromans – were calculated using DFT/B3LYP method. For α-tocopherol, one of the chromans and phenol, reaction enthalpies in water were computed. In comparison to gas phase, water causes severe changes in the energetics of studied compounds antioxidant action. From the thermodynamic point of view, entering SPLET mechanism represents the most probable process in water.     

Abnormal solvent effects on hydrogen atom abstraction. 3. Novel kinetics in sequential proton loss electron transfer chemistry

[reaction: see text] A prolonged search involving several dozen phenols, each in numerous solvents, for an ArOH/2,2-diphenyl-1-picrylhydrazyl (dpph(*)) reaction that is first-order in ArOH but zero-order in dpph(*) has reached a successful conclusion. These unusual kinetics are followed by 2,2'-methylene-bis(4-methyl-6-tert-butylphenol), BIS, in five solvents (acetonitrile, benzonitrile, acetone, cyclohexanone, and DMSO). In 15 other solvents the reactions were first-order in both BIS and dpph(*) (i.e., the reactions followed "normal" kinetics). The zero-order kinetics indicate that in the five named solvents the BIS/dpph(*) reaction occurs by sequential proton loss electron transfer (SPLET). This mechanism is not uncommon for ArOH/dpph(*) reactions in solvents that support ionization, and normal kinetics have always been observed previously (see Litwinienko, G.; Ingold, K. U. J. Org. Chem. 2003, 68, 3433 and Litwinienko, G.; Ingold, K. U. J. Org. Chem. 2004, 69, 5888). The zero-order kinetics found for the BIS/dpph(*) reaction in five solvents, S, imply that BIS ionization has become the rate-determining step (rds, rate constants 0.20-3.3 s(-)(1)) in the SPLET reaction sequence: S + HOAr right harpoon over left harpoon S- HOAr SH(+) + (-)OAr SH(+) + (*)OAr + dpph(-) --> S + (*)OAr + dpph-H, where ArOH = BIS. Some properties specific to BIS that may be relevant to its relatively slow ionization in the five solvents are considered.     

Hydrogen atom transfer reactions of imido manganese(V) corrole: one reaction with two mechanistic pathways

Hydrogen atom transfer (HAT) reactions of (tpfc)MnNTs have been investigated (tpfc = 5,10,15-tris(pentafluorophenyl)corrole and Ts = p-toluenesulfonate). 9,10-Dihydroanthracene and 1,4-dihydrobenzene reduce (tpfc)MnNTs via HAT with second-order rate constants 0.16 +/- 0.03 and 0.17 +/- 0.01 M(-1) s(-1), respectively, at 22 degrees C. The products are the respective arenes, TsNH(2) and (tpfc)Mn(III). Conversion of (tpfc)MnNTs to (tpfc)Mn by reaction with dihydroanthracene exhibits isosbestic behavior, and formation of 9,9',10,10'-tetrahydrobianthracene is not observed, suggesting that the intermediate anthracene radical rebounds in a second fast step without accumulation of a Mn(IV) intermediate. The imido complex (tpfc)Mn(V)NTs abstracts a hydrogen atom from phenols as well. For example, 2,6-di-tert-butyl phenol is oxidized to the corresponding phenoxyl radical with a second-order rate constant of 0.32 +/- 0.02 M(-1) s(-1) at 22 degrees C. The other products from imido manganese(V) are TsNH(2) and the trivalent manganese corrole. Unlike reaction with dihydroarenes, when phenols are used isosbestic behavior is not observed, and formation of (tpfc)Mn(IV)(NHTs) is confirmed by EPR spectroscopy. A Hammett plot for various p-substituted 2,6-di-tert-butyl phenols yields a V-shaped dependence on sigma, with electron-donating substituents exhibiting the expected negative rho while electron-withdrawing substituents fall above the linear fit (i.e., positive rho). Similarly, a bond dissociation enthalpy (BDE) correlation places electron-withdrawing substituents above the well-defined negative slope found for the electron-donating substituents. Thus two mechanisms are established for HAT reactions in this system, namely, concerted proton-electron transfer and proton-gated electron transfer in which proton transfer is followed by electron transfer.     

Studies on electron transfer reactions: oxidation of phenol and ring-substituted phenols by heteropoly 11-tungstophosphovanadate(V) in aqueous acidic medium

The kinetics of oxidation of phenol and a few ring-substituted phenols by heteropoly 11-tungstophosphovanadate(V), [PV^VW₁₁O₄₀]⁴⁻ (HPA) have been studied spectrophotometrically in aqueous acidic medium containing perchloric acid and also in acetate buffers of several pH values at 25 °C. EPR and optical studies show that HPA is reduced to the one-electron reduced heteropoly blue (HPB) [PV^IVW₁₁O₄₀]⁵⁻. In acetate buffers, the build up and decay of the intermediate biphenoquinone show the generation of phenoxyl radical (ArO^·) in the rate-determining step. At constant pH, the reaction shows simple second-order kinetics with first-order dependence of rate on both [ArOH] and [HPA]. At constant [ArOH], the rate of the reaction increases with increase in pH. The plot of apparent second-order rate constant, k ₂, versus 1/[H⁺] is linear with finite intercept. This shows that both the undissociated phenol (ArOH) and the phenoxide ion (ArO⁻) are the reactive species. The ArO⁻–HPA reaction is the dominant pathway in acetate buffer and it proceeds through the OH⁻ ion triggered sequential proton transfer followed by electron transfer (PT-ET) mechanism. The rate constant for ArO⁻–HPA reaction, calculated using Marcus theory, agrees fairly well with the experimental value. The reactivity of substituted phenoxide ions correlates with the Hammett σ⁺ constants, and ρ value was found to be −4.8. In acidic medium, ArOH is the reactive species. Retardation of rate for the oxidation of C₆H₅OD in D₂O indicates breaking of the O–H bond in the rate-limiting step. The results of kinetic studies show that the HPA-ArOH reaction proceeds through a concerted proton-coupled electron transfer mechanism in which water acts as proton acceptor (separated-CPET).     

Studies on photoinduced H-atom and electron transfer reactions of o-naphthoquinones by laser flash photolysis

The quenching of the triplets of 1,2-naphthoquinone (NQ) and 1,2-naphthoquinone-4-sulfonic acid sodium salt (NQS) by various electron and H-atom donors was investigated by laser flash photolysis measurement in acetonitrile and benzene. The results showed that the reactivities and configurations of 3NQ* (3NQS*) are governed by solvent polarity. All the quenching rate constants (kq) measured in benzene are larger than those in acetonitrile. The SO3Na substituent at the C-4 position of NQS makes 3NQS* more reactive than 3NQ* in electron/H-atom transfer reactions. Large differences of kq values were discovered in H-atom transfer reactions for alcohols and phenols, which can be explained by different H-abstraction mechanisms. Detection of radical cations of amines/anilines in time-resolved transient absorption spectra confirms an electron transfer mechanism. Triplets are identified as precursors of formed radical anions of NQ and NQS in photoinduced reactions. The dependence of electron transfer rate constants on the free energy changes (DeltaG) was treated by using the Rehm-Weller equation. For the four anilines with different substituents on the para or meta position of amidocyanogen, good correlation between log kq values with Hammett sigma constants testifies the correctness of empirical Hammett equation. Charge density distributions, adiabatic ionization/affinity potentials and redox potentials of NQ (NQS) and some quenchers were studied by quantum chemistry calculation.     

Scavenging of dpph* radicals by vitamin E is accelerated by its partial ionization: the role of sequential proton loss electron transfer

[reaction: see text] Rate constants for reaction of alpha-tocopherol, 2,2,5,7,8-pentamethyl-6-hydroxychroman, and 2,6-di-tert-butyl-4-methylphenol with 2,2-diphenyl-1-picrylhydrazyl radical were measured in solvents of different polarity and H-bond basicity. In ionization supporting solvents besides hydrogen atom transfer (HAT), the kinetics of the process is partially governed by sequential proton loss electron transfer (SPLET). Addition of acetic acid reduces the rate by eliminating SPLET to leave only HAT, while addition of water increases the rate by enhancing phenol deprotonation.     

A DFT study on reaction of eupatilin with hydroxyl radical in solution

Antioxidants scavenge reactive oxygen species and, therefore, are vitally important in the living cells. The antioxidant properties of eupatilin have recently been reported. In this article, the reactions of eupatilin with the hydroxyl radical (OH^?) in solution are studied using density functional theory calculations and the polarizable continuum model. Three mechanisms are considered including: sequential electron proton transfer (SEPT), sequential proton loss electron transfer (SPLET), and hydrogen abstraction (HA). Three solvents with different polarities, that is, benzene, methanol, and water, are used to investigate the effect of the environment on the mechanisms. The relative Gibbs free energies and enthalpies corresponding to different mechanisms are calculated. Our results show that SEPT is thermodynamically favored in aqueous solution. Once the eupatilin anion is produced, the second step in SPLET mechanism is thermodynamically favored in methanol and water. The HA mechanism is thermodynamically favored in gas, benzene, methanol, and water. This mechanism is more energetically favorable to occur in a more polar solvent. The natural bond orbital charges and spin densities as well as the singly occupied molecular orbital are then analyzed. It is concluded that the HA process is governed by proton coupled electron transfer mechanism. The attack of the radical takes place preferentially at position 7 of eupatilin. © 2012 Wiley Periodicals, Inc.     

Repair of guanyl radicals in plasmid DNA by electron transfer is coupled to proton transfer

By using gamma-irradiation in the presence of thiocyanate ions, we have generated guanyl radicals in plasmid DNA. These can be detected by using an Escherichia coli base excision repair endonuclease to convert their stable end products to strand breaks. The yield of enzyme-sensitive sites is strongly attenuated by the presence of micromolar concentrations of one of a series of singly substituted phenols, and it is possible to derive bimolecular rate constants for the reduction of DNA guanyl radicals by these phenols. More strongly reducing phenols were found to react more rapidly. This electron-transfer reaction also involves a proton transfer. By comparing the expected energetics of the reaction with the observed rate constants, the electron transfer is found to be mechanistically coupled with the proton transfer.     

Antioxidant and spectral properties of chalcones and analogous aurones: Theoretical insights

Density functional theory (DFT) and time-dependent DFT (TD-DFT) have been employed to elucidate the radical scavenging capacity and the UV–Vis spectral property of several chalcones and analogous aurones. Three main antioxidant mechanisms, hydrogen atom transfer (HAT), electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) were investigated. The results indicate that all the studied compounds adopt a fully planar conformation in their neutral, radical, cationic as well as anionic forms. 2′-OH plays important role in the stabilization of phenolic radicals due to the formation of intramolecular hydrogen bonds (IHBs). Introduction of electron-donating substituent on B-ring is helpful for improving the activity. For the considered compounds, HAT is proposed as the thermodynamically favored mechanism in gas phase and nonpolar environment, while SPLET is preferred in polar media. The results confirmed the crucial role of hydroxyl group on A-ring, especially on position 5′/5, in terms of the radical scavenging ability. The absorption spectra of title compounds were successfully simulated and the lowest energy transitions predominantly correspond to the π-π* transitions from HOMO to LUMO with charge transfer (CT) character.     

DFT and QTAIM based investigation on the structure and antioxidant behavior of lichen substances Atranorin,Evernic acid and Diffractaic acid

In this study, the structural and antioxidant behavior of the three lichen-derived natural compounds such as atranorin (AT), evernic acid (EV) and diffractaic acid (DF) has been investigated in the gas and water phase using both B3LYP and M06-2X functional level of density functional theory (DFT) with two different basis sets 6-31+G (d, p) and 6-311++G (d, p). The intramolecular H–bonds (IHB) strength, aromaticity and noncovalent interactions (NCI) have been computed with the help of the quantum theory of atoms in molecules (QTAIM). This calculation gives major structural characteristics that indirectly influence the antioxidant behavior of the investigated compounds. The spin density (SD) delocalization of the unpaired electron is found to be the main stabilizing factor of neutral and cationic radical species. The main mechanisms, recommended in the literature, for the antioxidant action of polyphenols as radical scavengers such as hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET), were examined. The result shows that the HAT and SPLET mechanism are the most conceivable one for the antioxidant action of this class of compounds in gas and water phase respectively. Preference of SPLET over HAT in water phase is due to the significantly lower value of proton affinity (PA) compared to the bond dissociation enthalpy (BDE) value. This study reveals that O₂-H₃, O₉-H₂₆ and O₄-H₄₅ respectively are the most favored site of AT, EV and DF for homolytic as well as heterolytic OH bond breaking.     

Novel 1,3,4-thiadiazole conjugates derived from protocatechuic acid: Synthesis,antioxidant activity,and computational and electrochemical studies

A series of 15 novel 1,3,4-thiadiazole amide derivatives containing a protocatechuic acid moiety were synthesized and structurally characterized. In addition, the corresponding imino (4) and amino (5) analogues of a phenyl-substituted 1,3,4-thiadiazole amide derivative 3a were prepared to compare the effects of the structural changes on the radical-scavenging activity. The obtained compounds were examined for their antioxidative potential by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. In addition, selected compounds were studied by density functional theory (DFT) and cyclic voltammetry experiments. The tested compounds showed high potential to scavenging DPPH radical and ABTS radical cation compared with the referent antioxidants ascorbic acid and nordihydroguaiaretic acid (NDGA). On the basis of the calculated thermodynamic parameters, it can be concluded that the sequential proton loss electron transfer (SPLET) mechanism represents the most probable reaction path in a polar solvent for DPPH radical–scavenging activity. On the other hand, the single electron transfer followed by proton transfer (SET-PT) can be a likely mechanistic pathway in the case of an ABTS radical cation.     

Electron transfer reaction of oxo(salen)chromium(V) ion with anilines

The kinetics of oxidation of 16 meta-, ortho-, and para-substituted anilines with nine oxo(salen)chromium(V) ions have been studied by spectrophotometric, ESIMS, and EPR techniques. During the course of the reaction, two new peaks with lambda(max) at 470 and 730 nm appear in the absorption spectrum, and these peaks are due to the formation of emeraldine forms of oligomers of aniline supported by the ESIMS peaks with m/z values 274 and 365 (for the trimer and tetramer of aniline). The rate of the reaction is highly sensitive to the change of substituents in the aryl moiety of aniline and in the salen ligand of chromium(V) complexes. Application of the Hammett equation to analyze kinetic data yields a rho value of -3.8 for the substituent variation in aniline and +2.2 for the substituent variation in the salen ligand of the metal complex. On the basis of the spectral, kinetic, and product analysis studies, a mechanism involving an electron transfer from the nitrogen of aniline to the metal complex in the rate controlling step has been proposed. The Marcus equation has been successfully applied to this system, and the calculated values are compliant with the measured values.     

Peroxyl Radical Reactions in Water Solution: A Gym for Proton‐Coupled Electron‐Transfer Theories

The reactions of alkylperoxyl radicals with phenols have remained difficult to investigate in water. We describe herein a simple and reliable method based on the inhibited autoxidation of water/THF mixtures, which we calibrated against pulse radiolysis. With this method we measured the rate constants k_inh for the reactions of 2‐tetrahydrofuranylperoxyl radicals with reference compounds: urate, ascorbate, ferrocenes, 2,2,5,7,8‐pentamethyl‐6‐chromanol, Trolox, 6‐hydroxy‐2,5,7,8‐tetramethylchroman‐2‐acetic acid, 2,6‐di‐tert‐butyl‐4‐methoxyphenol, 4‐methoxyphenol, catechol and 3,5‐di‐tert‐butylcatechol. The role of pH was investigated: the value of k_inh for Trolox and 4‐methoxyphenol increased 11‐ and 50‐fold from pH 2.1 to 12, respectively, which indicate the occurrence of a SPLET‐like mechanism. H(D) kinetic isotope effects combined with pH and solvent effects suggest that different types of proton‐coupled electron transfer (PCET) mechanisms are involved in water: less electron‐rich phenols react at low pH by concerted electron‐proton transfer (EPT) to the peroxyl radical, whereas more electron‐rich phenols and phenoxide anions react by multi‐site EPT in which water acts as proton relay.     

Why Ortho- and Para-Hydroxy Metabolites Can Scavenge Free Radicals That the Parent Atorvastatin Cannot? Important Pharmacologic Insight from Quantum Chemistry

The pharmaceutical success of atorvastatin (ATV), a widely employed drug against the “bad” cholesterol (LDL) and cardiovascular diseases, traces back to its ability to scavenge free radicals. Unfortunately, information on its antioxidant properties is missing or unreliable. Here, we report detailed quantum chemical results for ATV and its ortho- and para-hydroxy metabolites (o-ATV, p-ATV) in the methanolic phase. They comprise global reactivity indices, bond order indices, and spin densities as well as all relevant enthalpies of reaction (bond dissociation BDE, ionization IP and electron attachment EA, proton detachment PDE and proton affinity PA, and electron transfer ETE). With these properties in hand, we can provide the first theoretical explanation of the experimental finding that, due to their free radical scavenging activity, ATV hydroxy metabolites rather than the parent ATV, have substantial inhibitory effect on LDL and the like. Surprisingly (because it is contrary to the most cases currently known), we unambiguously found that HAT (direct hydrogen atom transfer) rather than SPLET (sequential proton loss electron transfer) or SET-PT (stepwise electron transfer proton transfer) is the thermodynamically preferred pathway by which o-ATV and p-ATV in methanolic phase can scavenge DPPH• (1,1-diphenyl-2-picrylhydrazyl) radicals. From a quantum chemical perspective, the ATV’s species investigated are surprising because of the nontrivial correlations between bond dissociation energies, bond lengths, bond order indices and pertaining stretching frequencies, which do not fit the framework of naive chemical intuition.     

Calculation of the relative acidities and oxidation potentials of para-substituted phenols. A model for alpha-tocopherol in solution

Relative acidities (Delta pK(a)) of phenols and oxidation potentials (Delta E(ox)) of the phenoxide anions have been calculated for nine para-substituted phenols using density functional theory. Solvent effects were incorporated using the conductor-like polarisable continuum method. Using the calculated Delta pK(a) and Delta E(ox) values in a thermodynamic cycle, the DeltaBDE (bond dissociation enthalpy) of the phenols were also determined with all values calculated to within 1.5 kcal mol(-1) of experiment. The Delta pK(a) and Delta E(ox) values were calculated for 6-hydroxy-2,2,5,7,8-pentamethylchroman (HPMC), a model for alpha-tocopherol for which there are no known experimental values. The acidity of this compound is raised by 2.4 pK(a) units and lowered by -0.79 V relative to phenol with a calculated Delta BDE of -14.9 kcal mol(-1). There is a negative correlation (r(2) = 0.86) between the Delta pK(a) and the Delta BDE values. A stronger and positive correlation is found between the Delta E(ox) (r(2) = 0.98) and the Delta BDE values. Using these correlations it is uncovered that hydrogen abstraction of phenols, as measured by the Delta BDE, is driven by electron transfer rather than by proton transfer.     

Correlations of the physicochemical parameters of azaindoles with their reactions

Using the AM1 semiempirical quantum method the enthalpies of formation, ionization energies, electron affinities, energy differences between highest occupied and lowest unoccupied orbitals, atomic charges, bond orders, and dipole moments have been calculated for 4-, 5-, 6-, and 7-azaindoles. A correlation has been built up between the calculated physicochemical parameters and the Hammett para-substituent and inductive constants. The 1H to 7H proton transfer in 7-azaindole has been quantitatively described. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1062–1072, July, 2006.     

Kinetics and mechanism of acid catalyzed oxidation of phenol and substituted phenols by isoquinolinium bromochromate

Oxidation of phenols by isoquinolinium bromochromate (IQBC) in aqueous acetic acid leads to the formation of corresponding quinones. The reaction is first order with respect to both phenol and IQBC and catalysed by hydrogen ion. The rate of oxidation decreases with increase in dielectric constant of solvent indicating ion-dipole interaction. The rate of oxidation decreases with increase in concentration of KCl, this may be due to the formation of less reactive species by interaction of Cl⁻ and protonated IQBC. The specific rates of oxidizing phenol reaction correlate with substituents constants affording negative reaction constants. Hammett plot is found to be valid and the correlation between enthalpies and free energies of activation is reasonably linear with an isokinetic temperature of 320 K.     

Switching the redox mechanism: models for proton-coupled electron transfer from tyrosine and tryptophan

The coupling of electron and proton transfer is an important controlling factor in radical proteins, such as photosystem II, ribinucleotide reductase, cytochrome oxidases, and DNA photolyase. This was investigated in model complexes in which a tyrosine or tryptophan residue was oxidized by a laser-flash generated trisbipyridine-Ru(III) moiety in an intramolecular, proton-coupled electron transfer (PCET) reaction. The PCET was found to proceed in a competition between a stepwise reaction, in which electron transfer is followed by deprotonation of the amino acid radical (ETPT), and a concerted reaction, in which both the electron and proton are transferred in a single reaction step (CEP). Moreover, we found that we could analyze the kinetic data for PCET by Marcus' theory for electron transfer. By altering the solution pH, the strength of the Ru(III) oxidant, or the identity of the amino acid, we could induce a switch between the two mechanisms and obtain quantitative data for the parameters that control which one will dominate. The characteristic pH-dependence of the CEP rate (M. Sjodin et al. J. Am. Chem. Soc. 2000, 122, 3932) reflects the pH-dependence of the driving force caused by proton release to the bulk. For the pH-independent ETPT on the other hand, the driving force of the rate-determining ET step is pH-independent and smaller. On the other hand, temperature-dependent data showed that the reorganization energy was higher for CEP, while the pre-exponential factors showed no significant difference between the mechanisms. Thus, the opposing effect of the differences in driving force and reorganization energy determines which of the mechanisms will dominate. Our results show that a concerted mechanism is in general quite likely and provides a low-barrier reaction pathway for weakly exoergonic reactions. In addition, the kinetic isotope effect was much higher for CEP (kH/kD > 10) than for ETPT (kH/kD = 2), consistent with significant changes along the proton reaction coordinate in the rate-determining step of CEP.