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 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 twodimensional (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 Eamide 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.

Molecular dynamics and NMR reveal the coexistence of H-bond-assisted and through-space JFH coupling in fluorinated amino alcohols

“…Heteronuclear nOe (nuclear Overhauser effect) was observed between H8 and fluorine atom, indicating spatial proximity between these nuclei and bringing to the discussion the possibility of a through-space transmission pathway via intramolecular H-bond ( 1h J FH8 ), instead of a solely through bond transmission pathway ( 4 J FH8 ). Recently, studies conducted by Takahashi and coworkers 48,49 and by Suryaprakash and coworkers 50–53 have also employed 1 H– 19 F HOESY experiment to confirm the presence of intramolecular H-bond. What is intriguing about these compounds is the presence of this kind of interaction in a polar solvent such as DMSO- d 6 , once it is expected that the solvent molecules would prefer to interact with the solute, thus breaking the intramolecular H-bond.…”