A computational study on the relative reactivity of reductively activated 1,4-benzoquinone and its isoelectronic analogs

SummaryThe redox capacities of p-benzoquinone (I) and its analogs p-benzoquinone imine (VI) and p-benzoquinone diimine (XI) as the simplest model systems for the biochemically important quinone site of the pharmacophores of the anthracyclines has been investigated by AM1 semi-empirical and ab initio methods. The reductive activation of the parent (Q) model systems to their various redox states (quinone radical anion (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaGaaeyuamaaCa% aaleqabaGabeylayaazaaaaaaa!37BD!\[{\text{Q}}^{{\text{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } }}} \]), semiquinone (QH⋅), semiquinone anion (QH-) and hydroquinone (QH2)), the internal geometrical reorganization and the redox capacities of the redox states have been examined by using energy-partitioning analysis, reaction enthalpies/energies for electron and proton attachments, adiabatic ionization potentials (IPad) and electron affinities (EAad), adiabatic electronegativities (Xad), dipole moments, electrostatic potentials and spin-density surfaces. EAad data and results of energy-partitioning analysis suggest that the one-electron Q to % MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaGaaeyuamaaCa% aaleqabaGabeylayaazaaaaaaa!37BD!\[{\text{Q}}^{{\text{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } }}} \] reducibility of VI is diminished when compared to that of I. The data also predict that reduction to QH⋅, QH- and QH2 is more favorable in VI (cf. I). Deprotonation enthalpy/energy calculations predict that the oxidizability of the reduced forms of VI is diminished when compared to I. Overall, the calculations suggest that the redox cycling of VI should be diminished if deprotonation is the first step of the autoxidation of the reduced forms. The results suggest that the electron affinity of Q and deprotonation of the reduced forms (e.g., QH⋅) may play important roles in the redox cycling of the anthracyclines. It is further suggested that these same factors are probably responsible for the reduced toxicity of 5-iminodaunomycin, which consists of VI as part of its pharmacophore. A comparison of the AM1 results with ab initio results suggests that the AM1 method is capable of predicting trends in redox capacity, nucleophilicity, electrophilicity and electron affinity in the systems investigated.

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