Cukrowski, IgnacyDhimba, GeorgeRiley, Darren Lyall2023-09-212023-09-212022-01-31Cukrowski, I.; Dhimba, G.; Riley, D.L. A Molecular-Wide and Electron Density-Based Approach in Exploring Chemical Reactivity and Explicit Dimethyl Sulfoxide (DMSO) Solvent Molecule Effects in the Proline Catalyzed Aldol Reaction. Molecules 2022, 27, 962. https://DOI.org/10.3390/molecules27030962.1420-3049 (online)10.3390/molecules27030962http://hdl.handle.net/2263/92370The Supporting Information is available free of charge as Cartesian XYZ coordinates of molecular systems and their energies; selected geometric data; net atomic charges; inter-fragment interaction energies; reaction energy profiles.DATA AVAILABILITY STATEMENT : On request, computational data are available from I.C.Modelling of the proline (1) catalyzed aldol reaction (with acetone 2) in the presence of an explicit molecule of dimethyl sulfoxide (DMSO) (3) has showed that 3 is a major player in the aldol reaction as it plays a double role. Through strong interactions with 1 and acetone 2, it leads to a significant increase of energy barriers at transition states (TS) for the lowest energy conformer 1a of proline. Just the opposite holds for the higher energy conformer 1b. Both the ‘inhibitor’ and ‘catalyst’ mode of activity of DMSO eliminates 1a as a catalyst at the very beginning of the process and promotes the chemical reactivity, hence catalytic ability of 1b. Modelling using a Molecular-Wide and Electron Density-based concept of Chemical Bonding (MOWED-CB) and the Reaction Energy Profile–Fragment Attributed Molecular System Energy Change (REP-FAMSEC) protocol has shown that, due to strong intermolecular interactions, the HN-C-COOH (of 1), CO (of 2), and SO (of 3) fragments drive a chemical change throughout the catalytic reaction. We strongly advocate exploring the pre-organization of molecules from initially formed complexes, through local minima to the best structures suited for a catalytic process. In this regard, a unique combination of MOWED-CB with REP-FAMSEC provides an invaluable insight on the potential success of a catalytic process, or reaction mechanism in general. The protocol reported herein is suitable for explaining classical reaction energy profiles computed for many synthetic processes.en© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.Proline catalyzed aldol reactionReaction mechanismExplicit solvent effectsREP-FAMSEC MethodChemical reactivityForces driving a chemical changeDimethyl sulphide (DMSO)Article