Conformational preference of N-difluoromethylated amides: contributions of hydrogen-bonding, steric, and stereoelectronic effects

Abstract

Fluorine, possessing the highest electronegativity among all elements, is frequently introduced to modify the structure and properties of compounds. Among fluorine-containing substituents, the difluoromethyl group is regarded as a bioisostere of a hydroxyl or isopropyl group, but its effect on the conformation of amides has not been thoroughly investigated. This study presents a detailed analysis of the conformational preferences of N-difluoromethylated amides and the effects of the difluoromethyl group, focusing on hydrogen-bonding, steric and stereoelectronic effects. N-Difluoromethylated amides were synthesized directly from amides using TMSCF₂Br and tBuONa as a base. NMR analysis revealed that N-difluoromethylated anilides preferentially adopt cis conformation, whereas a phenylalanine derivative favors trans conformation. DFT calculations suggest that the difluoromethyl group interacts with both the carbonyl group and a phenyl group, but repulsion between the carbonyl oxygen and phenyl group and interaction play major roles in determining the conformational preferences. In addition, the trans conformer of the N-difluoromethylated phenylalanine derivative is stabilized by electron donation from fluorine, enhancing amide resonance.