George’s doctoral research focused on the utilisation of the novel, reaction energy profile-fragment attributed molecular system energy change (REP-FAMSEC) quantum mechanical modelling protocol to rationalise the mechanism of the proline catalysed aldol reaction. The research highlighted the crucial and catalytic role played by the solvent DMSO, evidenced that the reaction proceeds via the highest energy conformer not the lowest energy conformer and showed that the mechanism proceeds via a proton transfer relay
A theoretical study of the mechanism of (S) proline-catalysed aldol reactions
2. Rapid 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
Ignacy Cukrowski, George Dhimba and Darren L. Riley, Molecules, 2022, 27(3), 962
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.
* Special Issue – Advances in the Theoretical and Computational Chemistry
1. A reaction energy profile and fragment attributed molecular system energy change (FAMSEC)-based protocol designed to uncover reaction mechanisms: a case study of the proline-catalysed aldol reaction
I. Cukrowski, G. Dhimba and D.L. Riley, Physical Chemistry Chemical Physics 2019, 21, 16694-16705
A REP-FAMSEC (reaction energy profile-fragment attributed molecular system energy change) protocol designed to explain each consecutive energy change along the reaction pathway is reported. It mainly explores interactions between meaningful polyatomic fragments of a molecular system and, by quantifying energetic contributions, pin-points fragments (atoms) leading to or opposing a chemical change. Its usefulness is tested, as a case study, on the proline-catalysed aldol reaction for which a number of mechanisms have been debated for over four decades. The relative stability of S-proline conformers, their catalytic (in)activity and the superior affinity of the higher energy conformer to acetone is fully explained at atomic and molecular fragment levels, but still appealing to general chemist knowledge. We found that (i) contrary to the generally accepted view, CN-bond formation cannot be explained by the Nδ−, Cδ+ atom pair, but rather by the O-atom of acetone and its strongest inter-molecular attractive interactions with the N-atom as well as the C-atom of the COO group of proline (at this initial stage the lower energy conformer of proline is eliminated) and (ii) the following ‘first’ H-transfer from N to O atoms of the proline moiety is nearly energy-free even though initially the H-atom interacts three times stronger with the N- than O-atom; a full explanation of this phenomenon is provided.