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

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Abstract
Difluoromethylcobalamin (CF2Cbl), a vitamin B12 analogue with CHF2 replacing CN, can be synthesized in a two-step procedure from aquocobalamin and CHClF2. Its crystal structure has been determined by X-ray diffraction. The compound crystallizes in the orthorhombic space group P212121 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: R1 = 0.072 for 5675 reflections with Fo > 4 σ(Fo) and wR2 = 0.194 for all 11844 reflections. The packing motif of CF2Cbl is very similar to that described for wet vitamin B12, 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 B12 and CF2Cbl shows a significant change at the molecular level. In CF2Cbl, the c side chain of ring B takes on a conformation that brings its terminal amide group near to the CHF2 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.

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