How the addition of a polar aprotic solvent alters aldol-addition kinetics: exploring the role of solvent molecules and their dynamics†

This paper investigates how solvent composition, and dynamics influence the aldol-addition reaction, which is an important reaction in acid-catalyzed biomass transformations. The reaction between 5-hydroxymethylfurfural (5-HMF) and 5,6-enol is used as a case-study since this is also a key step in the formation of humins (undesired carbonaceous polymers) in the condensed phase biomass transformation. Using first principles based molecular simulations performed at experimental conditions, with finite temperature effects, reaction dynamics and quantum mechanically treated explicit solvent molecules, we show that polar, aprotic cosolvents like DMSO can alter reaction pathways, conformations of reacting species, and energetics of the aldol addition reaction. Open-chain conformations of 5,6-enol are stable in water due to hydrogen bonding, while the presence of DMSO promotes quasi-cyclic structures. In both pure water and water–DMSO mixtures, the aldol addition reaction can proceed via both, concerted and stepwise pathways. Analysis of the reaction free energy landscape reveals that the aldol addition reaction is kinetically more favorable in water compared to water–DMSO mixtures, for both the concerted and stepwise pathways. Dynamic solvent reorganization during the reaction has a higher free energy penalty in DMSO than in pure water, highlighting the role of DMSO in increasing the activation free energy for aldol-addition. This investigation advances our understanding of explicit and dynamic solvent effects in condensed phase biomass transformation and particularly on the key aldol-addition reaction.