Stereochemical Analysis of Trifluoroacetamide Derivatives Based on Through- HF Spin-Spin Couplings.

In this study, the conformational properties of tertiary trifluoroacetamides in dibenzoazepine ( and ) and benzodiazepine ( and ) derivatives, which exist as equilibrated - and amide conformers in solution, were investigated by H and F NMR spectroscopy. In all cases, one of the methylene protons neighboring the nitrogen atom of the minor conformer showed a finely split pattern due to coupling with the trifluoromethyl fluorine atoms, as confirmed by F-decoupling experiments. One-dimensional (1D) and two-dimensional (2D) H-F heteronuclear Overhauser spectroscopy (HOESY) experiments were performed to confirm whether these couplings are attributable to through- spin-spin couplings (TBCs) or through- spin-spin couplings (TSCs). HOESY cross-peaks between CF (F) and one of the CH-N protons of the minor conformers indicate that the two nuclei are spatially close to each other, thus establishing the stereochemistry of the major () and minor () conformers. The -amide preferences of the trifluoroacetamides are consistent with the results of density functional theory calculations and X-ray crystallographic analyses. Furthermore, the otherwise incomprehensible H NMR spectra were accurately assigned using the HOESY-determined TSCs. The H NMR assignments of the - and -methyl signals of ,-dimethyl trifluoroacetamide, the simplest tertiary trifluoroacetamide, were revised for the first time in half a century.