Solvent‐Controlled Regioselectivity in Nucleophilic Substitution Reactions of 1‐X‐2,4‐Difluorobenzenes with Morpholine Using Deep Eutectic Solvents

Abstract Regioselectivity in aromatic nucleophilic substitution (SNAr) reactions of activated substrates is critical but challenging to control. The use of reaction media to achieve the desired regioselectivity is a promising approach, given the sensitivity of nucleophilic substitutions to solute‐solvent interactions. The present report exploits the sensitivity of SNAr reactions to medium effects by using varying compositions of deep eutectic solvents (DES) to achieve excellent regioselectivity. Substitution reactions of 2,4‐difluoroacetophenone ( 1 ), 2,4‐diflurobenzonitrile ( 3 ) and 2,4‐difluoronitrobenzene ( 5 ) with morpholine ( 2 ) were carried out in 15 DES mixtures using the “zero VOC” strategy. The regioselectivity was determined using NMR spectra and was observed to change drastically with the substrate and nature of the eutectic mixture. Substitution reaction ( 1 + 2 ) was the most sensitive to reaction medium. The regioselectivity for ( 1 + 2 ) changed from para ‐selective (85 : 15 para : ortho ratio) to ortho ‐selective (24 : 76 selectivity ratio) by merely changing the DES medium. The results demonstrate that eutectic mixtures could be effectively used as reaction media to control the desired stereochemical outcome.