Self-disproportionation of enantiomers of (R)-ethyl 3-(3,5-dinitrobenzamido)-4,4,4-trifluorobutanoate on achiral silica gel stationary phase

The very unusual phenomenon of separation of enantiomers by self-disproportionation on achiral silica gel stationary phase has been studied in detail using (R)-ethyl 3-(3,5-dinitrobenzamido)-4,4,4-trifluorobutanoate as an example. The appearance and magnitude of self-disproportionation were shown by this study to depend on the optical purity of the starting compounds and the nature (polarity) of an eluent used. Based on the results described by us and on previous literature data we conclude that it is not safe to assume that any type of chromatography is a reliable method for purification of non-racemic mixtures for determination of their enantiomeric purities. We recommend that chemists dealing with non-racemic compounds should first run an ESD-test (enantiomer self-disproportionation test) proposed herein before using chromatography for any purification. Moreover, one of the serious consequences of our finding is that all fluorine-containing chiral reagents and drugs, which are currently on the market, as well as all previously reported literature data on the stereochemical outcome of asymmetric transformations involving fluorine-containing compounds, should be carefully re-evaluated if column chromatography on silica gel was involved as a purification step.