Proton-Coupled Electron Transfer and Hydrogen Tunneling in Olive Oil Phenol Reactions.

Olive oil phenols are recognized as molecules with numerous positive health effects, many of which rely on their antioxidative activity, i.e., the ability to transfer hydrogen to radicals. Proton-coupled electron transfer reactions and hydrogen tunneling are ubiquitous in biological systems. Reactions of olive oil phenols, hydroxytyrosol, tyrosol, oleuropein, oleacein, oleocanthal, homovanillyl alcohol, vanillin, and a few phenolic acids with a DPPH• (2,2-diphenyl-1-picrylhydrazyl) radical in a 1,4-dioxane:water = 95:5 or 99:1 v/v solvent mixture were studied through an experimental kinetic analysis and computational chemistry calculations. The highest rate constants corresponding to the highest antioxidative activity are obtained for the ortho-diphenols hydroxytyrosol, oleuropein, and oleacein. The experimentally determined kinetic isotope effects (KIEs) for hydroxytyrosol, homovanillyl alcohol, and caffeic acid reactions are 16.0, 15.4, and 16.7, respectively. Based on these KIEs, thermodynamic activation parameters, and an intrinsic bond orbital (IBO) analysis along the IRC path calculations, we propose a proton-coupled electron transfer mechanism. The average local ionization energy and electron donor Fukui function obtained for the phenolic compounds show that the most reactive electron-donating sites are associated with π electrons above and below the aromatic ring, in support of the IBO analysis and proposed PCET reaction mechanism. Large KIEs and isotopic values of Arrhenius pre-exponential factor AH/AD determined for the hydroxytyrosol, homovanillyl alcohol, and caffeic acid reactions of 0.6, 1.3, and 0.3, respectively, reveal the involvement of hydrogen tunneling in the process.

Intriguing Chloride: Involvement of Chloride Ions in Proton Transfers.

The proton transfer from carbon to a chloride ion and the proton transfer to a molecule of water promoted by chloride ions in the acid-catalyzed formation of hydroxamic acids from aldehydes and substituted nitrosobenzenes in mixed solvents have been proposed based on experimental and theoretical investigations. The formation of uncommon contact ion pairs consisting of the nitrosocarbinolic cation intermediate and a chloride anion, followed by the proton transfer from a C-H moiety of the cation intermediate, has been proposed. The influence of chloride on the proton transfer to a water molecule of the solvent-separated nitrosocarbinolic-cation-chloride ion pair was investigated too. The insights are based on the obtained kinetic and other evidence with regard to (1) influences of chloride anions on the observed reaction rates and primary kinetic isotope effects (PKIE) in the reaction; (2) the observed variation of the PKIE-s and rates of the reaction when perchlorate anions are present along with the chloride ions; and (3) the consideration of a model of the nitrosocarbinolic-cation-intermediate-chloride ion pair and transition structure for the proposed proton transfers based on the ab initio calculations.

Kinetic Isotope Effects and Hydrogen Tunnelling in PCET Oxidations of Ascorbate: New Insights into Aqueous Chemistry?

Recent experimental studies of kinetic isotope effects (KIE-s) and hydrogen tunnelling comprising three proton-coupled electron transfer (PCET) oxidations of ascorbate monoanion, (a) in aqueous reaction solutions, (b) in the mixed water-organic cosolvent systems, (c) in aqueous solutions of various salts and (d) in fairly diluted aqueous solutions of the various partial hydrophobes are reviewed. A number of new insights into the wealth of the kinetic isotope phenomena in the PCET reactions have been obtained. The modulation of KIE-s and hydrogen tunnelling observed when partially hydrophobic solutes are added into water reaction solution, in the case of fairly diluted solutions is revealed as the strong linear correlation of the isotopic ratios of the Arrhenius prefactors Ah/Ad and the isotopic differences in activation energies ΔEa (D,H). The observation has been proposed to be a signature of the involvement of the collective intermolecular excitonic vibrational dynamics of water in activation processes and aqueous chemistry.

Hydrogen Tunnelling as a Probe of the Involvement of Water Vibrational Dynamics in Aqueous Chemistry?

Our study of tunnelling in proton-coupled electron transfer (PCET) oxidation of ascorbate with hexacyanoferrate(III) follows the insights obtained from ultrafast 2D IR spectroscopy and theoretical studies of the vibrational water dynamics that led to the proposal of the involvement of collective intermolecular excitonic vibrational water dynamics in aqueous chemistry. To test the proposal, the hydrogen tunnelling modulation observed in the PCET reaction studied in the presence of low concentrations of various partial hydrophobic solutes in the water reaction system has been analyzed in terms of the proposed involvement of the collective intermolecular vibrational water dynamics in activation process in the case. The strongly linear correlation between common tunnelling signatures, isotopic values of Arrhenius prefactor ratios ln AH/AD and isotopic differences in activation enthalpies ΔΔH‡ (H,D) observed in the process in fairly diluted water solutions containing various partial hydrophobic solutes (such as dioxane, acetonitrile, ethanol, and quaternary ammonium ions) points to the common physical origin of the phenomenon in all the cases. It is suggested that the phenomenon can be rooted in an interplay of delocalized collective intermolecular vibrational dynamics of water correlated with vibrations of the coupled transition configuration, where the donor-acceptor oscillations, the motions being to some degree along the reaction coordinate, lead to modulation of hydrogen tunnelling in the reaction.

Zn(II) halide coordination compounds with imidazole and 2-methylimidazole. Structural and computational characterization of intermolecular interactions and disorder.

Novel zinc(II) coordination compounds with imidazole (Im) and 2-methylimidazole (2-MeIm) were prepared and characterized: [ZnX2(Im)2] (X = Cl (1a), Br (1b), I (1c)) and [ZnX2(2-MeIm)2] (X = Cl (2a), Br (2b), I (2c)). Coordination compounds 1a-c were prepared mechanochemically by neat grinding while 2a-c were prepared by solution synthesis. The complexes were characterized by FT-IR and NMR spectroscopy and by powder X-ray diffraction. Crystal and molecular structures were determined by the single crystal X-ray diffraction. The characteristic of all structures is a distorted tetrahedral coordination of zinc consisting of two halide atoms and two nitrogen atoms from the imidazole (or 2-methylimidazole) ligand. Molecules in 1a-c are interconnected by hydrogen bonds into 3D structures. Structures of 1b and 1c were found to have similar unit cells and similar crystal packing and hydrogen bonding. Introduction of the 2-methylimidazole substituent introduced disorder in the crystal structures of 2a-c. Because of the very small size of the crystals data were collected by synchrotron radiation. For the disordered 2a , 2b and 2c fixed geometry was used in refining of the structures. Crystal structures of 2a-c are characterized by chains of molecules connected by hydrogen bonds of the type N-H⋅⋅⋅X, with weak π⋅⋅⋅π and van der Waals interactions between the chains. The QTAIM, RDG and NCI computational analysis of 1a and 2a-c confirmed the presence of weak attractive intermolecular interactions that can be attributed to weak N-H⋅⋅⋅X and van der Waals interactions.

Solvent dependence of the kinetic isotope effect in the reaction of ascorbate with the 2,2,6,6-tetramethylpiperidine-1-oxyl radical: tunnelling in a small molecule reaction.

The oxidation of ascorbate with the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical in water and water-dioxane mixed solvent has been demonstrated to be a proton-coupled electron transfer (PCET) process, involving hydrogen tunnelling at room temperature. The magnitude of the kinetic isotope effect (KIE) k(H)/k(D) in the reaction increases with decrease of the solvent polarity. The evidence comprise: (a) the spectroscopic and kinetic evidence for the interaction of ascorbate and TEMPO; (b) the observation of KIEs k(H)/k(D) of 24.2(0.6) in water and 31.1(1.1) in 1:1 v/v water-diox. (diox = dioxane), at 298 K; (c) the observation of isotope effect on the Arrhenius prefactor, A(H)/A(D) of 0.6(0.2) in the reaction in water and 1.2(0.2) in 1:1 v/v water-diox solvent; (d) the observation of isotope differences in the enthalpies of activation in water and D(2)O, Delta(r)H(double dagger) (in H(2)O) = 31.0(0.4) kJ/mol, Delta(r)H(double dagger) (in D(2)O) = 40.0 (0.5) kJ/mol; in 1:1 v/v water-diox and 1:1 v/v D(2)O-diox, Delta(r)H(double dagger) (in H(2)O/diox) = 23.9(0.2) kJ/mol, Delta(r)H(double dagger) (in D(2)O/diox) = 32.1(0.3) kJ/mol; (e) the temperature dependence of the KIEs in water and 1:1 v/v water-dioxane; these KIEs range from 27.3 at 285.4 K to 19.1 at 317.4 K in water and from 34.3 to 24.6 at the corresponding temperatures in 1:1 v/v water-diox, respectively; (f) the observation of an increase of the KIE in 10-40% v/v dioxane-water solvents relative to the KIE in water alone. There is a weak solvent dependence of the rate constant on going from water to 1:1 v/v water-diox. solvent, from 2.20(0.03) mol(-1) dm(3) s(-1) to 5.50(0.14) mol(-1) dm(3) s(-1), respectively, which originates from the mutual compensation of the enthalpy and entropy of activation.

Structural and computational analysis of intermolecular interactions in a new 2-thiouracil polymorph.

The crystallization and characterization of a new polymorph of 2-thiouracil by single-crystal X-ray diffraction, Hirshfeld surface analysis and periodic density functional theory (DFT) calculations are described. The previously published polymorph (A) crystallizes in the triclinic space group P\overline{1}, while that described herein (B) crystallizes in the monoclinic space group P21/c. Periodic DFT calculations showed that the energies of polymorphs A and B, compared to the gas-phase geometry, were -108.8 and -29.4 kJ mol-1, respectively. The two polymorphs have different intermolecular contacts that were analyzed and are discussed in detail. Significant differences in the molecular structure were found only in the bond lengths and angles involving heteroatoms that are involved in hydrogen bonds. Decomposition of the Hirshfeld fingerprint plots revealed that O...H and S...H contacts cover over 50% of the noncovalent contacts in both of the polymorphs; however, they are quite different in strength. Hydrogen bonds of the N-H...O and N-H...S types were found in polymorph A, whereas in polymorph B, only those of the N-H...O type are present, resulting in a different packing in the unit cell. QTAIM (quantum theory of atoms in molecules) computational analysis showed that the interaction energies for these weak-to-medium strength hydrogen bonds with a noncovalent or mixed interaction character were estimated to fall within the ranges 5.4-10.2 and 4.9-9.2 kJ mol-1 for polymorphs A and B, respectively. Also, the NCI (noncovalent interaction) plots revealed weak stacking interactions. The interaction energies for these interactions were in the ranges 3.5-4.1 and 3.1-5.5 kJ mol-1 for polymorphs A and B, respectively, as shown by QTAIM analysis.

Synthesis, X-ray crystal structure study, and cytostatic and antiviral evaluation of the novel cycloalkyl-N-aryl-hydroxamic acids.

In vitro evaluation of the novel cycloalkyl-N-(4-chlorophenyl)-hydroxamic acids (2a-g) demonstrated that 2b,d,e exhibited rather marked inhibitory activity (IC50 = 7-10 microM) against pancreatic carcinoma, 2b-d against colon carcinoma, 2d against laryngeal carcinoma, and 2b,d against breast carcinoma. 2e showed the most pronounced anti-cytomegalovirus activity (EC50 = 1.5 and 0.8 microg mL(-1)) only at > or = 5-fold lower than the cytotoxic concentration. 2d and 2f showed modest, albeit selective, activity against cytomegalovirus (2d, EC50 = 7.3-8.9 microg mL(-1), selectivity index 7-10; 2f, EC50 = 7-13 microg mL(-1), selectivity index 10).

The DFT local reactivity descriptors of α-tocopherol.

The calculations of local reactivity descriptors, the electron donor Fukui function f(-)(r), the average local ionization energy I(r), the Fukui function dual descriptor f((2))(r), and the electron acceptor Fukui function f(+)(r) for α-tocopherol, the main biologically active form of vitamin E for antioxidant reactions in phospholipid membranes, is presented. The calculations are performed at B3LYP/6-311++G** level of theory in the gas-phase. The obtained results indicate that the most preferred sites for donating electron in a reaction with radical or oxidizing molecule are associated mostly with π electrons above and below the aromatic part of the α-tocopherol chromanol ring. The most reactive sites for accepting electrons are associated with the leaving H(9) atom in the extension of the phenolic OH bond on the α-tocopherol chromanol ring plane, in the place where the formation of H-bond of the precursor complex between approaching reactive oxygen radical and phenolic OH group of α-tocopherol could be expected. The separated reactive sites in α-tocopherol suggest that the proton and electron, along with the hydrogen atom transfer (HAT) process, could also be transferred to different proton and electron acceptors as in bidirectional proton coupled electron transfer (PCET) reactions. The results presented in this paper suggest that large charge redistribution and significant π-π interactions may be expected in antioxidant reactions of α-tocopherol.