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

ABSTRACT: 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 ¹H and ¹⁹F 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 ¹⁹F-decoupling experiments. One-dimensional (1D) and two-dimensional (2D) ¹H-¹⁹F 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 CF₃ (¹⁹F) and one of the CH₂-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 ¹H NMR spectra were accurately assigned using the HOESY-determined TSCs. The ¹H 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.

SUBMITTER: Li Y 

PROVIDER: S-EPMC10242751 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature