REDUCTIVE DEFLUORINATION OF (TRIFLUOROMETHYL)COBAMIDES

The F-19 NMR spectrum of base-on beta-(difluoromethyl)cobalamin, previously reported as a broad singlet or as a doublet, has now been shown to be a severely collapsed AB quartet of doublets. Similarly, the alpha-fluorines of a variety of perfluoroethylcobamides and of the diastereomers of difluoromethyl heptamethylcobyrinate also display AB patterns. When (trifluoromethyl)cobamides are treated with zinc reductants in a variety of media, or subjected to controlled-potential reduction in buffered aqueous media at potentials between -1.0 and -1.2 V, the (trifluoromethyl)cobamide disappears with simultaneous appearance of the appropriate (difluoromethyl)cobamide and the dealkylated cobamide. Under all of these conditions, the rates of disappearance of the starting material and the rates of appearance of the defluorinated and dealkylated products are identical. However, controlled-potential reduction in DMF/1-propanol resulted only in dealkylation. Dealkylation in these systems is shown to result from reduction of the (trifluoromethyl)cobamides, as the (difluoromethyl)cobamides are indefinitely stable to reductive dealkylation by any of these reducing agents. Similar defluorination and dealkylation of (trifluoromethyl)cobamides occur with borohydride, but the defluorination yields are lower. When (trifluoromethyl)cobalamins are treated with zinc in 10% acetic acid-d, the (difluoromethyl)cobalamin products contain a single, nonexchangeable deuterium atom in the difluoromethyl ligand as demonstrated by F-19, H-1, and H-2 NMR spectroscopy. However, reduction with NaBH4 in D2O yields the nondeuterated derivatives, while reduction with NaBD4 in H2O yields the deuterated derivatives. Controlled-potential coulometry experiments show that the net defluorination of beta-(trifuoromethyl)cobalamin results from the consumption of two electrons. These results are consistent with an ECE mechanism for reductive defluorination of (trifluoromethyl)cobamides by zinc reductants and by controlled-potential reduction, but the defluorination of these complexes by borohydride must occur by an entirely different mechanism.