Trans and cis effects of axial fluoroalkyl ligands in Vitamin B12 analogues: relationship between alkyl and fluoroalkyl-cobalamins

CF3CH2Cbl, CF2HCbl and CF3Cbl have been synthesised and characterised in solution by 1H NMR and UV-vis spectroscopy and their X-ray crystal structures have been determined using synchrotron radiation. The structure of CF3CH2Cbl is reported for the first time, while those of CF2HCbl and CF3Cbl are re-examined to obtain more precise structural data. Comparison of the structural data obtained with the alkylcobalamin analogues, MeCbl and EtCbl, indicates that Co-C and Co-NB3 bond lengths are both shorter in the fluoroalkylcobalamins. The structural data of the fluoroalkylcobalamins, previously reported in the literature had been conflicting in this regard. Thus, much less dramatic shortening of the two axial bonds was found for CF3Cbl, while in the case of CF2HCbl, the Co-NB3 bond length is shorter than in MeCbl. Direct comparison of the structures of CF3CH2Cbl and EtCbl indicated a large distortion of the axial fragment in the former case which can be attributed to steric effects. A number of previously reported correlations of the effect of the β-ligand on the structure and properties of cobalamins are re-examined in the light of the present results. Particular emphasis is placed on the axial fragment. This analysis substantially confirms and, with the new data reported here, adjusts and expands the dataset for correlations between trans and cis influences of the β-ligand cobalamins on the structure (Co-X and Co-NB3 distances, corrin fold angle) and properties (UV-visible spectra, NMR spectra, pKbase-off).