Enzymatic Knoevenagel condensation in dual‐functionalized water‐mimicking ionic liquids and tertiary amide solvents

Abstract

BackgroundKnoevenagel condensation is an important tool for building carbon–carbon (C–C) bonds, especially when catalyzed by enzymes to enable a potentially high chemo‐, regio‐ and/or stereoselectivity. Although many Knoevenagel condensation reactions were carried out in aqueous solutions, insoluble hydrophobic substrates often lead to poor catalytic efficiencies. The use of water‐miscible organic solvents improves the substrate solubilization, but usually induces the activity suppression or inactivation of enzymes. There is a great need to develop alternative solvents for both substrate dissolution and enzyme compatibility in C–C bond formation reactions.ResultsOur group previously developed dual‐functionalized water‐mimicking ionic liquids (ILs) for the activation and stabilization of hydrolases (e.g., lipase and protease). In the present study, we evaluated the Knoevenagel condensation of 4‐chlorobenzaldehydes with acetylacetone, and found that porcine pancreas lipase (PPL) in water‐mimicking ILs carrying ammonium, imidazolium and benzimidazolium cations enabled higher reaction rates (up to 3.22 mM min–1 g–1 lipase) and better yields than tert‐butanol, glymes, and [BMIM][Tf2N]. Interestingly, tertiary amide solvents such as N‐methyl‐2‐pyrrolidone (NMP), N,N‐dimethylformamide (DMF) and N,N‐dimethylacetamide (DMAc) led to 8.2–11.1‐fold increases in the initial rate (up to 35.66 mM min–1 g–1 lipase) when compared with dual‐functionalized ILs, which is likely due to some synergistic effect of these tertiary amides with the lipase.ConclusionDual‐functionalized ILs based on ammonium, imidazolium and benzimidazolium cations improved Knoevenagel condensation reaction rates and yields when compared with tert‐butanol and glymes. Tertiary amides (NMP, DMF and DMAc) significantly increased the reaction rate.This article is protected by copyright. All rights reserved.