Reductive alkylation of aquacobalamin with certain alkyl halides is known to produce a mixture of diastereomeric beta-alkylcobalamins (with the organic ligand in the "upper" axial ligand position) and alpha-alkylcobalamins (with the organic ligand in the "lower" axial ligand position) when the reducing agent is zinc/acetic acid. However, reduction with sodium borohydride followed by alkylation produces only beta-alkylcobalamins. This difference has now been shown to be a pH effect, and the pH dependence of the relative proportions of alpha- and beta-diastereomers produced upon reductive alkylation of aquacobalamin with CF3CH2I, CF3I, and NCCH2Br has been studied. In each case, the fraction of the alkylcobalamin as the alpha-diastereomer increases with increasing acidity, following a typical titration curve. The apparent pK(a)'s obtained from these data (3.04 +/- 0.03, 2.69 +/- 0.02, and 2.25 +/- 0.02 for R = CF3CH2, CF3, and NCCH2, respectively) are shown to be consistent with the hypothesis that the products are under equilibrium control and that the pH dependence is due to the base-on/base-off equilibrium of the product beta-alkylcobalamin. The alternative of kinetically controlled products requires that the species being alkylated in zinc/acid reducing systems is cob(II)alamin, since cob(I)alamin is base-off at all pH's. The pK(a) for the base-on/base-off reaction of cob(II)alamin has been determined spectrophotometrically to be 3.10 +/- 0.01. However, interpretation of the apparent pK(a)'s for the pH dependence of the diastereomeric outcome of the reductive alkylation of aquacobalamin assuming kinetic control leads to relative reactivities of the base-off and base-on species of cob(II)alamin which are not consistent with the observed rates of product formation or with literature data on the reaction of cob(II)alamin with alkyl halides. Studies of the temperature dependence of the diastereomer ratio in the analogous alkylcobinamides show that the apparent equilbrium between diastereomers is entropically controlled.