Stereochemical Analysis of Tertiary Trifluoroacetamides Leveraging Both Through-Space ¹ H··· ¹⁹ F Spin–Spin Couplings and Anisotropic Solvent-Induced Shifts

In this study, the assignment of E/Z-isomers of N,N-dialkyl trifluoroacetamides (1-8) is investigated by using ¹H-nuclear magnetic resonance spectroscopy, and data pertaining to both through-space spin-spin couplings (TSCs) and aromatic solvent-induced shifts (ASISs) are utilized to develop a reliable and convenient approach for determining the stereochemistry of these isomers. Although TSCs─observed when the F from the CF₃ group is spatially close to protons─alone may be useful for determining E/Z isomers, through-bond couplings (TBCs) are also observed when the proton is five bonds apart from the F in the CF₃ group. Thus, an additional one-dimensional ¹H-¹⁹F heteronuclear Overhauser enhancement spectroscopy (HOESY) experiment is required to distinguish between the TSCs and TBCs. By contrast, the ASIS results for all compounds are consistent with the general observation that C₆D₆ preferentially shifts trans-methyl/methylene protons to the carbonyl oxygen atom over cis-methyl/methylene protons. Additionally, the ASISs with C₆F₆ of compounds 4-8 are analyzed to demonstrate the reliability of the ASIS-based method. Considering that ¹H-¹⁹F HOESY experiments are somewhat specialized and uncommon, factoring both the TSCs and ASISs during the deduction process proves highly effective for determining the stereochemical assignment of E/Z-isomers of N,N-dialkyl trifluoroacetamides.