Rate constants of hydroperoxyl radical addition to cyclic nitrones: a DFT study.

Nitrones are potential synthetic antioxidants against the reduction of radical-mediated oxidative damage in cells and as analytical reagents for the identification of HO2* and other such transient species. In this work, the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) and PCM/mPW1K/6-31+G(d,p) density functional theory (DFT) methods were employed to predict the reactivity of HO2* with various functionalized nitrones as spin traps. The calculated second-order rate constants and free energies of reaction at both levels of theory were in the range of 100-103 M-1 s-1 and 1 to -12 kcal mol-1, respectively, and the rate constants for some nitrones are on the same order of magnitude as those observed experimentally. The trend in HO2* reactivity to nitrones could not be explained solely on the basis of the relationship of the theoretical positive charge densities on the nitronyl-C, with their respective ionization potentials, electron affinities, rate constants, or free energies of reaction. However, various modes of intramolecular H-bonding interaction were observed at the transition state (TS) structures of HO2* addition to nitrones. The presence of intramolecular H-bonding interactions in the transition states were predicted and may play a significant role toward a facile addition of HO2* to nitrones. In general, HO2* addition to ethoxycarbonyl- and spirolactam-substituted nitrones, as well as those nitrones without electron-withdrawing substituents, such as 5,5-dimethyl-pyrroline N-oxide (DMPO) and 5-spirocyclopentyl-pyrroline N-oxide (CPPO), are most preferred compared to the methylcarbamoyl-substituted nitrones. This study suggests that the use of specific spin traps for efficient trapping of HO2* could pave the way toward improved radical detection and antioxidant protection.