{"title":"Origins of the substituent effects in the aldol condensation of axially chiral thiohydantoins: a computational study.","authors":"Nazli Goksel Carpa, Zekihan Ozerdem, Ilknur Dogan, Zeynep Pinar Haslak, Viktorya Aviyente","doi":"10.1039/d4ob01904k","DOIUrl":null,"url":null,"abstract":"<p><p>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 RCH<sub>3</sub>, XCF<sub>3</sub>; RCH<sub>3</sub>, XCl; RCH<sub>2</sub>Ph, XCF<sub>3</sub>; RCH(CH<sub>3</sub>)<sub>2</sub>, and XCF<sub>3</sub>. Agreement of calculations (M06-2X/6-311+G(d,p)/CPCM(THF)) with experiment suggests that the enantioselectivity is predominantly governed by thermodynamic control.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic & Biomolecular Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4ob01904k","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
引用次数: 0
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.
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.