The thermodynamics of the spin trapping of various cyclic nitrones with biologically relevant radicals such as methyl, mercapto, hydroperoxy, superoxide anion, and nitric oxide was investigated using computational methods. A density functional theory (DFT) approach was employed in this study at the B3LYP/6-31+G(d,p)// B3LYP/6-31G(d) level. The order of increasing favorability for DeltaG(rxn) (kcal/mol) of the radical reaction with various nitrones, in general, follows a trend similar to their respective experimental reduction potentials as well as their experimental second-order rate constants in aqueous solution: NO (14.57) < O-2(.-) (-7.51) < (O2H)-O-. (-13.92) < (SH)-S-. (-16.55) < (CH3)-C-. (-32.17) < (OH)-O-. (-43.66). The same qualitative trend is predicted upon considering the effect of solvation using the polarizable continuum model (PCM): i.e., NO (14.12) < O-2(.-) (9.95) < (O2H)-O-. (-6.95) < (SH)-S-. (-13.57) < (CH3)-C-. (-32.88) < (OH)-O-. (-38.91). All radical reactions with these nitrones are exoergic, except for NO (and O-2(.-) in the aqueous phase), which is endoergic, and the free energy of activation (DeltaG(double dagger)) for the NO additions ranges from 17.7 to 20.3 kcal/mol. This study also predicts the favorable formation of certain adducts that exhibit intramolecular H-bonding interactions, nucleophilic addition, or H-atom transfer reactions. The spin density on the nitronyl N of the superoxide adducts reveals conformational dependences. The failure of nitrones to trap NO at normal conditions was theoretically rationalized due to the endoergic reaction parameters.