Ryu Yamasaki , Ami Tashiro , Chisaki Sato , Ai Ito , Iwao Okamoto
{"title":"Conformational preference of N-difluoromethylated amides: contributions of hydrogen-bonding, steric, and stereoelectronic effects†","authors":"Ryu Yamasaki , Ami Tashiro , Chisaki Sato , Ai Ito , Iwao Okamoto","doi":"10.1039/d5qo00497g","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>N</em>-difluoromethylated amides and the effects of the difluoromethyl group, focusing on hydrogen-bonding, steric and stereoelectronic effects. <em>N</em>-Difluoromethylated amides were synthesized directly from amides using TMSCF<sub>2</sub>Br and <em>t</em>BuONa as a base. NMR analysis revealed that <em>N</em>-difluoromethylated anilides preferentially adopt <em>cis</em> conformation, whereas a phenylalanine derivative favors <em>trans</em> 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 <figure><img></figure> interaction play major roles in determining the conformational preferences. In addition, the <em>trans</em> conformer of the <em>N</em>-difluoromethylated phenylalanine derivative is stabilized by electron donation from fluorine, enhancing amide resonance.</div></div>","PeriodicalId":94379,"journal":{"name":"Organic chemistry frontiers : an international journal of organic chemistry","volume":"12 17","pages":"Pages 4834-4841"},"PeriodicalIF":0.0000,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic chemistry frontiers : an international journal of organic chemistry","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/org/science/article/pii/S2052412925003043","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.