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

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.