Author: Prasenjit Bera & Dr. Koomkoom Khawas
DOI Link: https://doi.org/10.70798/Bijmrd/04080022
Abstract: Nucleophilic aromatic substitution (SNAr) is an important synthetic approach for constructing carbon–sulfur bonds in electron-deficient aromatic systems. This critical review explores the mechanistic pathways, substrate scope, reactivity, selectivity, and practical limitations of sulfur-mediated SNAr reactions, with particular emphasis on ethyl 3-mercaptopropionate (HS–CH₂–CH₂–CO₂Et). Key factors influencing reaction efficiency, including electron-withdrawing substituents, leaving-group identity, solvent polarity, base strength, and temperature, are critically examined. Classical addition–elimination mechanisms involving Meisenheimer intermediates are compared with concerted SNAr pathways. Literature-based kinetic and computational findings are discussed alongside applications in aromatic functionalization and heterocyclic chemistry. Potential challenges, including thiol oxidation, incomplete deprotonation, ester hydrolysis, and product selectivity, are highlighted. The review identifies existing research gaps and proposes integrated kinetic, spectroscopic, and computational approaches to improve mechanistic understanding and reaction reproducibility. Overall, this analysis provides valuable insights into the development of efficient and selective sulfur-based SNAr methodologies.
Keywords: Nucleophilic aromatic substitution (SNAr); Ethyl 3-mercaptopropionate; Sulfur nucleophiles; Thiolate ions; Aryl–sulfur bond formation; Meisenheimer intermediate; Reaction kinetics; Density functional theory; Structure–reactivity relationships; Porphyrinoids.
Page No: 179-201