A complete product and kinetic analysis has been carried out for the thermolysis of neopentyl-8-epicobalamin (Np-8-epiCbl) and neopentyl-13-epicobalamin (Np-13-epiCbl), epimers of neopentylcobalamin, NpCbl, in which the orientation of the d or e propionamide side chain has been altered by epimerization at corrin ring C8 or C13, respectively. When the organic products of the aerobic thermolysis of Np-8-epiCbl dr Np-13-epiCbl are treated with aniline in diethyl ether, the Schiffs base of pivalaldehyde is formed with a yield of approximately 50%. This observation is consistent with the disproportionation of the neopentyl peroxide radical to pivalaldehyde and neopentyl alcohol under aerobic thermolysis conditions. Anaerobic thermolysis in neutral aqueous solution in the presence of (4-hydroxy-2,2,6,6-tetramethylpiperidinyl)oxy, H-TEMPO, gives rise to quantitative yields of the O-alkylated neopentyl-H-TEMPO and 8- or 13-epicob(II)alamin. Moreover, examination of the anaerobic thermolysis of these complexes in the presence of 0.5-1.0 mM H-TEMPO showed that the rate constants for thermolysis are the same as those obtained in neutral aerobic solution, establishing that dissolved oxygen is a competent trap for the homolytically derived radicals. These results clearly reveal that the mode of thermal C-Co cleavage is homolytic as is known to be the case for NpCbl itself. Thermolysis kinetics were studied in aerobic, neutral aqueous solution spectrophotometrically and gave the following observed activation parameters : Np-8-epiCbl, Delta H double dagger(obs) = 28.7 +/- 0.1 kcal mol(-1) and Delta S double dagger(obs) 17.1 +/- 0.2 cal mol(-1) K-1; Np-13-epiCbl, Delta H double dagger(obs) = 28.2 +/- 0.1 kcal mol(-1) and Delta S double dagger(obs) = 18.4 +/- 0.3 cal mol(-1) K-1 UV-visible scanning experiments demonstrated that the base-off form of Np-8-epiCbl at pH 1.0 was at least 2 orders of magnitude less reactive than the neutral species. In addition, a complete examination ofthe pH-dependence for the thermolysis of Np-13-epiCbl demonstrated that the base-on species is about 10(3)-fold more reactive than the protonated base-off species of this epimer. Rate constants for thermal decomposition in aerobic neutral aqueous solution have been corrected for the presence of a significant amount of the base-off species by measuring the thermodynamic parameters for the intrinsic base-off/base-on equilibrium over the temperature range of interest using an NMR method.