The apparent pK(a)’s for the base-on/base-off reaction of cobalamins have been measured as a function of temperature for cyanocobalamin (CNCbl), a series of seven alkyl-13-epicobalamins (R-13-epiCbl; R = CH3CH2, NC(CH2)3, CH3, CF3CH2, NCCH2, CF3, CN), in which the e propionamide side chain is epimerized from the lower to the upper corrin ring face, and a series of four alkyl-8-epicobalamins (R-8-epiCbl; R = CH3CH2, CF3CH2, CF3, CN), in which the d propionamide side chain is epimerized from the lower to the upper corrin ring face. These values have been used to calculate the equilibrium constant, K(Co), for the intramolecular axal nucleotide off/on equilibrium and the enthalpy and entropy change for this reaction. Taken together with previous results for a series of nine alkylcobalamins (RCbl), the data show that the free energy change and enthalpy change for this ligand substitution equilibrium are slightly sensitive to epimerization of the e and d propionamide side chains. However, the entropy change is independent of the Cbl epimer for a given R group. This suggests that changes in corrin side chain thermal motions accompanying the base-off/base-on transition do not contribute significantly to the entropy change for this reaction, which is, instead, dominated by changes in axial ligation. Since-DELTAS(Co) decreases substantially across each series of complexes as the organic ligand becomes increasingly electron withdrawing (and -DELTAG(Co) increases), it seems highly unlikely that the reaction represents the conversion of a hexacoordinate base-off aqua complex to a hexacoordinate base-on complex for all R. These results consequently provide thermodynamic evidence that the base-off RCbl’s exist as an equilibrium mixture of hexacoordinate aqua species and pentacoordinate species, the position of the equilibrium being sensitive to the nature of the organic ligand.