Difluoromethylcobalamin: Structural aspects of an old tree with a new branch

Difluoromethylcobalamin (CF(2)Cbl), a vitamin B-12 analogue with CHF2 repla cing 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 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) Angstrom, b = 21.143(3) Angstrom, and c = 15.981(3) Angstrom. The refinement model was kept as simple as possible with no restraints, and with isotropic displacement parameters for all nonhydrogen atoms except fo r Co, P, and F. The agreement factors obtained this way are: R-1 = 0.072 fo r 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 describe d for wet vitamin B-12, a distorted hexagonal close packing of the cobalami n, with channels of water running parallel to the crystallographic c axis t hrough the crystal at x = 1/4, y = 0, and x = 3/4, y = 1/2, respectively. A n analysis of interactions involving water molecules and amide groups revea led a discontinuity between oxygen-oxygen distances (which are found to be less than 2.8 Angstrom) and oxygen-nitrogen distances (which are found to b e greater than 2.8 Angstrom); this provides a useful criterion for distingu ishing between oxygen and nitrogen atoms in amide groups. A superposition o f the crystal structures of vitamin B-12 and CF(2)Cbl shows a significant c hange 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 CHS gro up. This results in both a relatively short contact (3.11 Angstrom) between F2 and O39 of the c amide and a weak C1F-H1F ... O39 interaction.