Density functional theory (DFT) is applied to the calculation of the steric and electronic factors which might affect the Co-C-R bond activation in coenzyme B-12. The six-coordinate cobalamins (B-[Co-III(corrin)]-R, models of coenzyme Bit) include the actual corrin macroring as the equatorial ligand and imidazole (Im), dimethylbenzimidazole (DBI) or water (H2O), as the a-trans ligand (B). The beta axial ligand (R) represents a series of alkyl groups with different steric bulkiness ranging from -C dropN, -C drop CH through methyl, ethyl, isopropyl, tert-butyl to 5'-deoxy-5'-adenosyl. Each trans ligand (Im, DBI or H2O) produces a positive correlation of the Co-C-R and Co-N-B bond lengths. The increasing complexity of the R group leads to two major structural correlations: a positive correlation between the Co-C-R and Co-N-B bond lengths and an inverse correlation between the Co-C-R bond length and the flatness of the corrin ring. It is shown that stereoelectronic properties of cobalamins can only be explained on the basis of electronic considerations. Moreover, electron donation from axial ligands to the cobalt atom either by electron donating substituents or by a properly oriented external electric field caused by external electric charges is argued to be the main trigger for the activation of the Co-C-R bond.