Theoretical Study of the Spin Trapping of Hydroxyl Radical by Cyclic Nitrones: A Density Functional Theory Approach

The hydroxyl radical (•OH) is an important mediator of biological oxidative stress, and this has
stimulated interest in its detection. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) and its alkoxycarbonyl and
alkoxyphosphoryl analogues have been employed as spin traps for electron paramagnetic resonance (EPR)
spectroscopic radical detection. Energies of optimized geometries of nitrones and their corresponding •OH
adducts were calculated using density functional theory (DFT) at the B3LYP/6-31+G**//B3LYP/6-31G*
level. Calculations predict that the trans adduct formation is favored in alkoxycarbonyl nitrones, while cis
adducts with intramolecular H-bonding is favored for alkoxyphosphoryl nitrones. Addition of •OH to a
phosphoryl-substituted nitrone is more exoergic than the carbonylated nitrones. Charge and spin densities
on the nitrone spin traps were correlated with their rates of addition with •OH, and results show that the
charge density on the nitronyl C, the site of •OH addition, is more positive in phosphorylated nitrones
compared to DMPO and the alkoxycarbonyl nitrones. The dihedral angle between the β-H and nitroxyl O
bonds is smaller in phosphorylated nitrones, and that aspect appears to account for the longer half-lives
of the spin adducts compared to those in DMPO and alkoxycarbonyl nitrones. Structures of nitrones with
trifluoromethyl-, trifluoromethylcarbonyl-, methylsulfonyl-, trifluoromethylsulfonyl-, amido-, spiropentyl-, and
spiroester substituents were optimized and their energies compared. Amido and spiroester nitrones were
predicted to be the most suitable nitrones for spin trapping of •OH due to the similarity of their thermodynamic
and electronic properties to those of alkoxyphosphoryl nitrones. Moreover, dimethoxyphosphoryl substitution
at C-5 was found to be the most efficient substitution site for spin trapping of •OH, and their spin adducts
are predicted to be the most stable of all of the isomeric forms.