Quantum-chemical investigation of the structure and the antioxidant properties of α-lipoic acid and its metabolites

Quantum-chemical computations were used to investigate the structure–antioxidant parameter relationships of α-lipoic acid and its natural metabolites bisnorlipoic acid and tetranorlipoic acid in their oxidized and reduced forms. The enantiomers of lipoic and dihydrolipoic acid were optimized using the B3LYP/6-311+G(3df,2p), B3LYP/aug-cc-pVDZ and MP2(full)/6-31+G(d,p) levels of theory as isolated molecules and in the presence of water. The geometries of the metabolites and the values of their antioxidant parameters (proton affinity, bond dissociation enthalpy, adiabatic ionization potential, spin density, and the highest occupied molecular orbital energy) were calculated at the B3LYP/6-311+G(3df,2p) level of theory. The results obtained reveal similarities between these structures: a pentatomic, nonaromatic ring is present in the oxidized forms, while an unbranched aliphatic chain (as found in saturated fatty acids) is present in both the oxidized and the reduced forms. Analysis of the spin density and the highest occupied molecular orbital energy revealed that the SH groups exhibited the greatest electron-donating activities. The values obtained for the proton affinity, bond dissociation enthalpy and adiabatic ionization potential indicate that the preferred antioxidant mechanisms for α-lipoic acid and its metabolites are sequential proton loss electron transfer in polar media and hydrogen atom transfer in vacuum

Abnormal solvent effects on hydrogen atom abstraction. 2. Resolution of the curcumin antioxidant controversy. The role of sequential proton loss electron transfer

The rates of reaction of 1,1-diphenyl-2-picrylhydrazyl (dpph.) radicals with curcumin (CU, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3, 5-dione), dehydrozingerone (DHZ, "half-curcumin"), and isoeugenol (IE) have been measured in methanol and ethanol and in two non-hydroxylic solvents, dioxane and ethyl acetate, which have about the same hydrogen-bond-accepting abilities as the alcohols. The reactions of all three substrates are orders of magnitude faster in the alcohols, but these high rates can be suppressed to values essentially equal to those in the two non-hydroxylic solvents by the addition of acetic acid. The fast reactions in alcohols are attributed to the reaction of dpph. with the CU, DHZ, and IE anions (see J. Org. Chem. 2003, 68, 3433), a process which we herein name sequential proton loss electron transfer (SPLET). The most acidic group in CU is the central keto-enol moiety. Following CU's ionization to a monoanion, ET from the [-(O)CCHC(O)-]- moiety to dpph. yields the neutral [-(O)CCHC(O)-]. radical moiety which will be strongly electron withdrawing. Consequently, a phenolic proton is quickly lost into the alcohol solvent. The phenoxide anion so formed undergoes charge migration to produce a neutral phenoxyl radical and the keto-enol anion, i.e., the same product as would be formed by a hydrogen atom transfer (HAT) from the phenolic group of the CU monoanion. The SPLET process cannot occur in a nonionizing solvent. The controversy as to whether the central keto-enol moiety or the peripheral phenolic hydroxyl groups of CU are involved in its radical trapping (antioxidant) activity is therefore resolved. In ionizing solvents, electron-deficient radicals will react with CU by a rapid SPLET process but in nonionizing solvents, or in the presence of acid, they will react by a slower HAT process involving one of the phenolic hydroxyl groups.Peer reviewed: YesNRC publication: Ye

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

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\u2032-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 \u21cc S- HOAr \u2192rds SH+ + -OAr \u2192dpph. SH+ + .OAr + dpph- \u2192 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. \ua9 2005 American Chemical Society.Peer reviewed: YesNRC publication: Ye

Intramolecular and intermolecular hydrogen bond formation by some ortho-substituted phenols: Some surprising results from an experimental and theoretical investigation

The effects produced by addition of various concentrations of the strong hydrogen bond (HB) acceptor, dimethyl sulfoxide (DMSO), on the OH fundamental stretching region of the IR spectra of several o-methoxy, o-nitro, and o-carbonyl phenols in CCI4 are reported. In most of these phenols the intramolecular HB is not broken by the DMSO. Instead, the DMSO acts as a HB acceptor to the intramolecular HB forming a bifurcated intra/intermolecular HB. For o-methoxyphenols the bifurcated HBs are observed as new IR bands at much lower wavenumbers (\u394v(OH) 3c -300 cm-1) than the band due to their intramolecular HB. The formation of bifurcated HBs and the large frequency shift of their OH bands in o-methoxyphenols are well reproduced by theoretical modeling. In contrast to the o-methoxyphenols DMSO has little effect (other than causing some broadening) on the intramolecular HB OH bands of o-nitro and o-carbonyl phenols, with the single exception of 2,4-dinitrophenol. In this case, but not for 2,4-diformylphenol, the intramolecular HB OH band decreases as the DMSO concentration increases and a new absorption grows in at lower wavenumbers, indicating that DMSO can break this intra-HB and form an inter-HB, a result well reproduced by theory. Although DMSO has little effect on the O-H stretching band of 2-nitrophenol, theory indicates extensive formation (90%) of bifurcated HBs with OH stretching bands at slightly higher wavenumbers (\u394v(OH) 3c +20 cm-1) than that for the intramolecular HB OH group and 10% of a "simple" intermolecular HB in which the intramolecular HB has been broken. Theory also indicates that, with DMSO, 2-formylphenol also forms a bifurcated HB (\u394v(OH) 3c +150 cm -1), whereas 2,4-diformylphenol forms both intermolecular HBs (\u394v(OH) 3c -130 cm-1) and bifurcated HBs (\u394v(OH) 3c +165 cm-1). The IR spectrum of 2-methoxy-methylphenol shows that although an intramolecular HB conformer is dominant there is a small percentage of a "free" OH, non-HB conformer (2.1% in CCl4, 1.5% in cyclohexane). These results are quantitatively reproduced by theory. We conclude that theory can provide important insights into the formation and structure of inter, intra, and bifurcated HBs, and into their OH stretching frequencies, that are not always revealed by IR studies alone. \ua9 2009 American Chemical Society.Peer reviewed: YesNRC publication: Ye

Kinetic Solvent Effects on the Reaction of an Aromatic Ketone p,p* Triplet with Phenol. Rate-Retarding and Rate-Accelerating Effects of Hydrogen-Bond Acceptor Solvents

Quenching of the 2-benzoylthiophene \u3c0,\u3c0* triplet, 3BT*, by phenol yields the corresponding ketyl and phenoxyl radicals. Reaction rates were measured in 10 solvents having a range of hydrogen-bond acceptor strengths (\u3b22H values). There appear to be two mechanisms:\u2009 (i) a bimolecular reaction of 3BT* with \u201cfree\u201d (i.e., not H-bonded) phenol in which the 3BT* accepts both a proton and an electron from the phenol, the rate decreasing as \u3b22H increases; (ii) a trimolecular reaction of 3BT* with phenol that is H-bonded to a solvent molecule, PhO 12H\ub7\ub7\ub7S, in which the proton goes to the S and the electron to the 3BT*, the rate increasing as \u3b22H increases.NRC publication: Ye