Quantitative Estimation of the Hydrogen-Atom-Donating Ability of 4-Substituted Hantzsch Ester Radical Cations

The purpose of this study is to investigate thermodynamic and kinetic properties on the hydrogen-atom-donating ability of 4-substituted Hantzsch ester radical cations (XRH^•+), which are excellent NADH coenzyme models. Gibbs free energy changes and activation free energies of 17 XRH^•+ releasing H^• [denoted as ΔG _HD ^o(XRH^•+) and ΔG _HD ^≠(XRH^•+)] were calculated using density functional theory (DFT) and compared with that of Hantzsch ester (HEH₂) and NADH. ΔG _HD ^o(XRH^•+) range from 19.35 to 31.25 kcal/mol, significantly lower than that of common antioxidants (such as ascorbic acid, BHT, the NADH coenzyme, and so forth). ΔG _HD ^≠(XRH^•+) range from 29.81 to 39.00 kcal/mol, indicating that XRH^•+ spontaneously releasing H^• are extremely slow unless catalysts or active intermediate radicals exist. According to the computed data, it can be inferred that the Gibbs free energies and activation free energies of the core 1,4-dihydropyridine radical cation structure (DPH^•+) releasing H^• [ΔG _HD ^o(DPH^•+) and ΔG _HD ^≠(DPH^•+)] should be 19-32 kcal/mol and 29-39 kcal/mol in acetonitrile, respectively. The correlations between the thermodynamic driving force [ΔG _HD ^o(XRH^•+)] and the activation free energy [ΔG _HD ^≠(XRH^•+)] are also explored. Gibbs free energy is the important and decisive parameter, and ΔG _HD ^≠(XRH^•+) increases in company with the increase of ΔG _HD ^o(XRH^•+), but no simple linear correlations are found. Even though all XRH^•+ are judged as excellent antioxidants from the thermodynamic view, the computed data indicate that whether XRH^•+ is an excellent antioxidant in reaction is decided by the R substituents in 4-position. XRH^•+ with nonaromatic substituents tend to release R^• instead of H^• to quench radicals. XRH^•+ with aromatic substituents tend to release H^• and be used as antioxidants, but not all aromatic substituted Hantzsch esters are excellent antioxidants.