Computational insights into asymmetric cross-aldol carboligation in choline chloride/ethylene glycol deep eutectic solvents

Abstract

Limited research has been conducted on the exploration of chemical reactions in deep eutectic solvents (DES) using density functional theory (DFT). In this study, a comprehensive analysis of the mechanism of a cross-aldol reaction in DES through DFT calculations at the M06-2X/6-311+G(d,p)//M06-2X/6-31G(d,p) level was carried out for the first time. The aldol reaction mechanism comprised two primary stages, namely, enolization and addition, with the former identified as the rate-determining step. In this paper, an explicit explanation of the functions of catalysts, solvents and water, with results that aligned well with experimental findings, has been provided. The theoretical analysis indicated that the –COOH group of the catalyst could enhance the stability of transition states by forming a polygonal reaction center, compared to the –OH group or water, thus favoring the reaction process. The increased susceptibility of the catalyst was attributed to the enhanced ionization of the proton in the –COOH group. Findings from the IGM analysis indicated that the stability of the system was enhanced through the formation of hydrogen bonds (HBs), resulting from the interaction between DES and the substrates. It was also noted that the number of HBs did not directly correlate with the system's stability. Notably, the most stable configuration involved the disruption of the solvent structure when DES interacted with the reactants. The introduction of water compensated for the solvent's deficiency by forming new O–H⋯Cl bonds, leading to the formation of additional hydrogen bonds and thereby enhancing the system's stability. Furthermore, the impact of substituent groups was evident through the formation of an O–H⋯O_NO bond, which was generated by the interaction between ethylene glycol and the –NO₂ group. The substituent effect played a crucial role in the reaction and elucidated the necessity of solvent disruption. The computational analysis revealed an increase in the energy barrier when the –NO₂ group was substituted with –H, –Cl and –Br. In addition, the study offered a comprehensive understanding of the influence of DES and the role of the additional third component in the reaction.