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

In this study, theconformational properties of tertiary trifluoroacetamidesin dibenzoazepine (1a and 1b) and benzodiazepine(2a and 2b) derivatives, which exist asequilibrated E- and Z-amide conformersin solution, were investigated by H-1 and (FNMR)-F-19 spectroscopy. In all cases, one of the methylene protons neighboringthe nitrogen atom of the minor conformer showed a finely split patterndue to coupling with the trifluoromethyl fluorine atoms, as confirmedby F-19-decoupling experiments. One-dimensional (1D) andtwo-dimensional (2D) H-1-F-19 heteronuclearOverhauser spectroscopy (HOESY) experiments were performed to confirmwhether these couplings are attributable to through-bond spin-spin couplings (TBCs) or through-space spin-spin couplings (TSCs). HOESY cross-peaks between CF3 (F-19) and one of the CH2-N protonsof the minor conformers indicate that the two nuclei are spatiallyclose to each other, thus establishing the stereochemistry of themajor (E-) and minor (Z-) conformers.The E-amide preferences of the trifluoroacetamidesare consistent with the results of density functional theory calculationsand X-ray crystallographic analyses. Furthermore, the otherwise incomprehensible H-1 NMR spectra were accurately assigned using the HOESY-determinedTSCs. The H-1 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.