title: Rate constants of hydroperoxyl radical addition to cyclic nitrones: a DFT study.
abstract: 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.
authors.affiliation: Department of Pharmacology, Center for Biomedical EPR Spectroscopy and Imaging, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Villamena
authors.forename: John K
authors.initials: JK
authors.lastname: Merle
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hadad
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D002627:Chemistry, Physical / Q000379:methods*; D003497:Cyclic N-Oxides / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D006878:Hydroxides / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009589:Nitrogen Oxides / Q000737:chemistry*; D010070:Oxalates / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D010545:Peroxides; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D003497:Cyclic N-Oxides; D006878:Hydroxides; D009589:Nitrogen Oxides; D010070:Oxalates; D010545:Peroxides; C015388:nitrones; D014867:Water; C041020:bis(2,4,5-trichloro-6-carbopentoxyphenyl)oxalate; C049375:perhydroxyl radical; C069977:2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxy; D006859:Hydrogen; D010100:Oxygen