Difluoromethylcobalamin: Structural Aspects of an Old Tree with a New Branch

Difluoromethylcobalamin (CF(2)Cbl), a vitamin B(12) analogue with CHF(2) replacing CN, can be synthesized in a two-step procedure from aquocobalamin and CHClF(2). Its crystal structure has been determined by X-ray diffraction. The compound crystallizes in the orthorhombic space group P2(1)2(1)2(1) with Z = 4 and 17 water molecules per formula unit. The unit cell dimensions are a = 24.08(1) Å, b = 21.143(3) Å, and c = 15.981(3) Å. The refinement model was kept as simple as possible with no restraints, and with isotropic displacement parameters for all non-hydrogen atoms except for Co, P, and F. The agreement factors obtained this way are: R(1) = 0.072 for 5675 reflections with F(o) > 4 sigma(F(o)) and wR(2) = 0.194 for all 11844 reflections. The packing motif of CF(2)Cbl is very similar to that described for wet vitamin B(12), a distorted hexagonal close packing of the cobalamin, with channels of water running parallel to the crystallographic c axis through the crystal at x = (1)/(4), y = 0, and x = (3)/(4), y = (1)/(2), respectively. An analysis of interactions involving water molecules and amide groups revealed a discontinuity between oxygen-oxygen distances (which are found to be less than 2.8 Å) and oxygen-nitrogen distances (which are found to be greater than 2.8 Å); this provides a useful criterion for distinguishing between oxygen and nitrogen atoms in amide groups. A superposition of the crystal structures of vitamin B(12) and CF(2)Cbl shows a significant change at the molecular level. In CF(2)Cbl, the c side chain of ring B takes on a conformation that brings its terminal amide group near to the CHF(2) group. This results in both a relatively short contact (3.11 Å) between F2 and O39 of the c amide and a weak C1F-H1F.O39 interaction.