The contribution of c side chain rotational motions to the energetics of thermal carbon-cobalt bend homolysis in neopentylcobalamin (NpCbl) has been investigated by studies of NpCbl analogs including the c-monocarboxylate, and the c-N-methyl, c-N,N-dimethyl, and c-N-isopropyl derivatives. Spectrophotometric kinetic studies of the thermolysis of these NpCbl analogs in neutral aerobic aqueous solution, after correction for the measured amount of base-off species present under these conditions, showed that the enthalpy of activation was essentially constant (28.4 +/- 1.1 kcal mol(-1)) but that the entropy of activation increased with increasing size of the c-COX moiety (X = 0(-), 16.4 +/- 0.4, X = NH2 19.3 +/- 0.6, X = NHMe, 21.1 +/- 0.7, X = NMe(2), 24.8 +/- 0.6, and X = NHiPr, 24.9 +/- 0.3 cal mol(-1) K-1). Molecular mechanics calculations showed that the Co-C bond length and the Co-C-C and Co-C-H bond angles were not altered by rotation of the c side chain through 360(degrees) about the C7-C37 bond, nor were they significantly altered by the increasing steric bulk of the c side chain across the series of compounds. However, the net steric strain experienced by the compound upon rotation of the c side chain increased monotonically with the steric bulk of the c-COX moiety. Thus, the increase in the rate of thermolysis of the NpCbl analogs as the c side chain steric bulk is increased is not due to ground state enthalpic destabilization of the carbon-cobalt bond, but to increasing activation entropy, interpreted as being due to increasing restriction of c side chain rotation in the ground state which is relieved (or partially relieved) in the transition state for Co-C bond homolysis. These results may be used to estimate that approximately 30-40% of the decrease in the free energy of thermolysis of 5’-deoxyndenosylcobalamin (AdoCbl, coenzyme B-12) brought about by enzyme catalysis could possibly be due to enzymatically induced restriction of the ground state rotational freedom of the three upward projecting acetamide side chains. Thus, such a mechanism could be an important contributor to the catalysis of AdoCbl homolysis although it is almost surely not the sole mechanism employed.