Empirically Fitted Parameters for Calculating pKa Values with Small Deviations from Experiments Using a Simple Computational Strategy.

Two empirically fitted parameters have been derived for 74 levels of theory. They allow fast and reliable pKa calculations using only the Gibbs energy difference between an acid and its conjugated base in aqueous solution (ΔGs(BA)). The parameters were obtained by least-squares fits of ΔGs(BA) vs experimental pKa values for phenols, carboxylic acids, and amines using training sets of 20 molecules for each chemical family. Test sets of 10 molecules per family-completely independent from the training set-were used to verify the reliability of the fitting parameters method. It was found that, except for MP2, deviations from experiments are lower than 0.5 pKa units. Moreover, mean unsigned errors lower than 0.35 pKa units were found for the 98.6%, 98.6%, and 94.6% of the tested levels of theory for phenols, carboxylic acids and amines, respectively. The parameters estimated here are expected to facilitate computationally based estimations of pKa values of species for which this magnitude is still unknown, with uncertainties similar to the experimental ones. However, the present study deals only with molecules of modest complexity, thus the reliability of the FP method for more complex systems remains to be tested.

New free radicals to measure antiradical capacity: a theoretical study.

A new family of free radicals, that are soluble in water and stable at all pH values, were recently synthesized and used to assess the antiradical capacity of several polyphenols. In the present work, density functional calculations were used to investigate the single electron transfer reactions between these new free radicals and polyphenols in aqueous solution. The quantification of the antiradical capacity is a challenge, particularly for polyphenols, since they become unstable under experimental conditions. It was found that the electron transfer from polyphenols to the newly developed free radicals can be used to assess the efficiency of this kind of compound for preventing oxidative stress. Since one of the free radicals can be deprotonated under experimental conditions, this newly synthesized radical can help distinguish more clearly between different antiradical compounds with similar antioxidant capacity by modifying the pH in the experiments. The results reported here are in good agreement with the available experimental data and allowed making recommendations about possible experimental conditions in the design of antioxidant assays using the investigated radicals.

On the chemical behavior of C60 hosting H2O and other isoelectronic neutral molecules.

The density functional theory (DFT) was used to investigate the chemical behavior of C60 hosting neutral guest molecules (NGM). The deformed atoms in molecules (DAM) allowed identifying the regions of electron density depletion and accumulation. The studied NGM are CH4, NH3, H2O, and HF. Based on dipole moment and polarizabilities analyses it is predicted that the NGM@C60 should be more soluble in polar solvents than C60. The deformations on the surface electron density of the fullerenes explain this finding, which might be relevant for further applications of these systems. It was found that the intrinsic reactivity of studied NGM@C60 is only moderately higher than that of C60. This trend is supported by the global reactivity indexes and the frontier orbitals analyses. The free radical scavenging activity of the studied systems, via single electron transfer, was found to be strongly dependent on the chemical nature of the reacting free radical. The presence of the studied NGM inside the C60 influences only to some extent the reactivity of C60 toward free radicals. The distortion of the electron density on the C60 cage, caused by the NGM, is directly related to the electron withdrawing capacity of the later.

Influence of the environment on the protective effects of guaiacol derivatives against oxidative stress: mechanisms, kinetics, and relative antioxidant activity.

The peroxyl radical scavenging activity of five guaiacol derivatives (GD) has been studied in nonpolar and aqueous solutions, using the density functional theory. The studied GD are guaiacol, vanillin, vanillic alcohol, vanillic acid, and eugenol. It was found that the environment plays an important role in the peroxyl scavenging activity of these compounds. They were all found to react faster in aqueous solution than in nonpolar media. The order of reactivity in nonpolar environments was found to be vanillic alcohol > eugenol > guaiacol > vanillin > vanillic acid, while, in aqueous solution, at physiological pH, it becomes vanillic acid > vanillic alcohol > guaiacol ≈ eugenol > vanillin. It was also found that in aqueous solution as the pH increases so does the reactivity of GD toward peroxyl radicals. The environment also has important effects on the relative importance of the hydrogen transfer (HT) and the sequential proton electron transfer (SPET) mechanisms, which are the ones relevant to the peroxyl radical scavenging activity of GD. The HT from the phenolic OH was identified as the main scavenging process in nonpolar media, and in aqueous solution at pH ≤ 4. On the other hand, SPET is proposed to be the one contributing the most to the overall peroxyl scavenging activity of GD in aqueous solution at pH ≥ 6.

On the peroxyl scavenging activity of hydroxycinnamic acid derivatives: mechanisms, kinetics, and importance of the acid-base equilibrium.

The peroxyl radical scavenging activity of four hydroxycinnamic acid derivatives (HCAD) has been studied in non-polar and aqueous solutions, using the density functional theory. The studied HCAD are: ferulic acid (4-hydroxy-3-methoxycinnamic acid), p-coumaric acid (trans-4-hydroxycinnamic acid), caffeic acid (3,4-dihydroxycinnamic acid), and dihydrocaffeic acid (3-(3,4-dihydroxyphenyl)-2-propionic acid). It was found that the polarity of the environment plays an important role in the relative efficiency of these compounds as peroxyl scavengers. It was also found that in aqueous solution the pH is a key factor for the overall reactivity of HCAD towards peroxyl radicals, for their relative antioxidant capacity, and for the relative importance of the different mechanisms of reaction. The H transfer from the phenolic OH has been identified as the main mechanism of reaction in non-polar media and in aqueous solution at acid pHs. On the other hand, the single electron transfer mechanism from the phenoxide anion is proposed to be the one contributing the most to the overall peroxyl scavenging activity of HCAD in aqueous solution at physiological pH (7.4). This process is also predicted to be a key factor in the reactivity of these compounds towards a large variety of free radicals.

Uric and 1-methyluric acids: metabolic wastes or antiradical protectors?

The reactions of uric and 1-methyluric acids in nonpolar environments, as well as those of the corresponding urate anions in aqueous solution, with (•)OH, (•)OCH(3), (•)OOH, and (•)OOCH(3) have been studied using the density functional theory. Different mechanisms of reactions have been taken into account, and their relative importance on the antiradical activity of these compounds is analyzed. Both uric and methyluric acids are better scavengers in aqueous solution than in nonpolar media, which indicates that the urate anions are the most active species. The free radical scavenging activity of the studied compounds was found to be excellent for (•)OH, and very good for (•)OCH(3). In addition, 1-methyluric acid is predicted to moderately protect against peroxyl oxidation, while the protective effects of uric acid against these particular species are not expected to be significant. In addition, 1-methyluric acid was found to be a better radical scavenger than its precursor, caffeine, suggesting that the antiradical activity of the latter might be explained by the action of its metabolites, rather than by its direct activity.

Is caffeine a good scavenger of oxygenated free radicals?

The reactions of caffeine (CAF) with different reactive oxygen species (ROS) have been studied using density functional theory. Five mechanisms of reaction have been considered, namely, radical adduct formation (RAF), hydrogen atom transfer (HAT), single electron transfer (SET), sequential electron proton transfer (SEPT), and proton coupled electron transfer (PCET). The SET, SEPT, and PCET mechanisms have been ruled out for the reactions of CAF with (•)OH, O(2)(•-), ROO(•), and RO(•) radicals. It was found that caffeine is inefficient for directly scavenging O(2)(•-) and (•)OOCH(3) radicals and most likely other alkyl peroxyl radicals. The overall reactivity of CAF toward (•)OH was found to be diffusion-controlled, regardless of the polarity of the environment, supporting the excellent (•)OH scavenging activity of CAF. On the other hand, it is predicted to be a modest scavenger of (•)OCH(3), and probably of other alkoxyl radicals, and a poor scavenger of HOO(•). RAF has been identified as the main mechanism involved in the direct ROS scavenging activity of CAF. The excellent agreement with the available experimental data supports the reliability of the present calculations.