Origins of the substituent effects in the aldol condensation of axially chiral thiohydantoins: a computational study†

IF 2.9 3区 化学 Q1 CHEMISTRY, ORGANIC
Nazli Goksel Carpa, Zekihan Ozerdem, Ilknur Dogan, Zeynep Pinar Haslak and Viktorya Aviyente
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Abstract

Aldol reactions are one of the most fundamental organic reactions involving the formation of carbon–carbon bonds that are commonly used in the synthesis of complex molecules through the condensation of an enol or enolate with a carbonyl group. The aldol reaction of thiohydantoin derivatives with benzaldehyde starts with hydrogen removal from C5 by lithium diisopropylamide (LDA) to form the enolate. Benzaldehyde adds to the enolate either at the less or more hindered site. The formed products have 3 chiral centers; thus they exist in 8 isomeric forms, RMS*/SPR*, RMR*/SPS*, SMR*/RPS*, and SMS*/RPR*, which are enantiomeric couples. Experimentally the axial chirality of the reactant is protected throughout the reaction; if the starting thiohydantoin is the M isomer, only RMS*, RMR*, SMR*, and SMS* diastereomers can be obtained. In this study, we aim to report a theoretical study of the aldol reactions between benzaldehyde and thiohydantoin derivatives conducted at the M06-2X/6-311+G(d,p) level of theory using the CPCM solvation model for THF as solvent, at 195 K. The investigation of the effect of substituents at C5 (stereocenter) and X positions on selectivity was performed by varying the substituents RCH3, XCF3; RCH3, XCl; RCH2Ph, XCF3; RCH(CH3)2, and XCF3. Agreement of calculations (M06-2X/6-311+G(d,p)/CPCM(THF)) with experiment suggests that the enantioselectivity is predominantly governed by thermodynamic control.

Abstract Image

轴向手性硫脲醛缩反应中取代基效应的起源:计算研究。
醛醇反应是最基本的有机反应之一,涉及碳-碳键的形成,通常用于通过烯醇或烯酸酯与羰基的缩合来合成复杂分子。硫代氢妥英衍生物与苯甲醛的醛醇反应首先由二异丙酰胺锂(LDA)从C5中脱氢生成烯醇酯。苯甲醛在阻碍较少或阻碍较多的位点加入到烯醇酯中。形成的产物有3个手性中心;因此它们以RMS*/SPR*、RMR*/SPS*、SMR*/RPS*和SMS*/RPR* 8种对映体对构象形式存在。实验表明,在整个反应过程中,反应物的轴向手性受到保护;如果起始硫代海因为M异构体,则只能得到RMS*、RMR*、SMR*和SMS*非对映体。在本研究中,我们的目标是在M06-2X/6-311+G(d,p)理论水平上,使用CPCM溶剂化模型,以THF为溶剂,在195 K下对苯甲醛和硫代海因衍生物之间的醛醇反应进行理论研究。通过改变取代基R ~ CH3, X ~ CF3的位置,研究了C5(立体中心)和X位置上取代基对选择性的影响;RCH3 XCl;RCH2Ph X恶;R c_ (CH3)2,和X c_ (CF3)。计算结果(M06-2X/6-311+G(d,p)/CPCM(THF))与实验结果一致,表明对映体选择性主要受热力学控制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Organic & Biomolecular Chemistry
Organic & Biomolecular Chemistry 化学-有机化学
CiteScore
5.50
自引率
9.40%
发文量
1056
审稿时长
1.3 months
期刊介绍: Organic & Biomolecular Chemistry is an international journal using integrated research in chemistry-organic chemistry. Founded in 2003 by the Royal Society of Chemistry, the journal is published in Semimonthly issues and has been indexed by SCIE, a leading international database. The journal focuses on the key research and cutting-edge progress in the field of chemistry-organic chemistry, publishes and reports the research results in this field in a timely manner, and is committed to becoming a window and platform for rapid academic exchanges among peers in this field. The journal's impact factor in 2023 is 2.9, and its CiteScore is 5.5.
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