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

Ryu Yamasaki , Ami Tashiro , Chisaki Sato , Ai Ito , Iwao Okamoto
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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.

Abstract Image

n-二氟甲基化酰胺的构象偏好:氢键、立体电子和立体电子效应的贡献
氟在所有元素中具有最高的电负性,经常被引入来修饰化合物的结构和性质。在含氟取代基中,二氟甲基被认为是羟基或异丙基的生物同分异构体,但其对酰胺构象的影响尚未得到充分研究。本研究详细分析了n-二氟甲基化酰胺的构象偏好和二氟甲基的影响,重点研究了氢键、立体电子和立体电子效应。以TMSCF2Br为原料,以丁腈丁酸为底物,由酰胺直接合成n -二氟甲基化酰胺。核磁共振分析表明,n -二氟甲基化苯胺倾向于顺式构象,而苯丙氨酸衍生物倾向于反式构象。DFT计算表明,二氟甲基与羰基和苯基相互作用,但羰基氧与苯基之间的斥力和n(O)→π*C=O相互作用是决定构象偏好的主要因素。此外,n -二氟甲基化苯丙氨酸衍生物的反式构象被氟给电子稳定,增强酰胺共振。
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CiteScore
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