Stereochemical Analysis of Trifluoroacetamide Derivatives Based on Through-Space(1)H–(19)F Spin–Spin Couplings

[Image: see text] In this study, the conformational properties of tertiary trifluoroacetamides in dibenzoazepine (1a and 1b) and benzodiazepine (2a and 2b) derivatives, which exist as equilibrated E- and Z-amide conformers in solution, were investigated by (1)H and (19)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 (19)F-decoupling experiments. One-dimensional (1D) and two-dimensional (2D) (1)H–(19)F heteronuclear Overhauser spectroscopy (HOESY) experiments were performed to confirm whether these couplings are attributable to through-bond spin–spin couplings (TBCs) or through-space spin–spin couplings (TSCs). HOESY cross-peaks between CF(3) ((19)F) and one of the CH(2)–N protons of the minor conformers indicate that the two nuclei are spatially close to each other, thus establishing the stereochemistry of the major (E-) and minor (Z-) conformers. The E-amide preferences of the trifluoroacetamides are consistent with the results of density functional theory calculations and X-ray crystallographic analyses. Furthermore, the otherwise incomprehensible (1)H NMR spectra were accurately assigned using the HOESY-determined TSCs. The (1)H NMR assignments of the E- and Z-methyl signals of N,N-dimethyl trifluoroacetamide, the simplest tertiary trifluoroacetamide, were revised for the first time in half a century.