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Abstract
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.
Highlights
Organocatalysts have historically been utilized to catalyze a range of non-asymmetrical organic transformations, most notably Knoevenagel condensations, esterifications, Baylis-Hillman reactions and Stetter reactions [1,2]
We decided to pay special attention to two aspects in our preliminary investigations, namely: 1. The minimum number of explicit dimethyl sulfoxide (DMSO) solvent molecules needed to strike a balance between the computational cost and insights derived knowing that the computational time and a number of intermolecular interactions increase exponentially with a number of atoms in a molecular system
We decided to limit the number of DMSO solvent molecules to three at most and use a smaller basis set in our preliminary studies, namely 6-31+G(d,p), rather than 6-311++G(d,p) employed in this work
Summary
Organocatalysts have historically been utilized to catalyze a range of non-asymmetrical organic transformations, most notably Knoevenagel condensations, esterifications, Baylis-Hillman reactions and Stetter reactions [1,2]. Attempts to develop organocatalyzed asymmetrical transformations led to the development of the Hajos-Parrish-Eder-SauerWiechert reaction in the 1970s [3,4]. Following this breakthrough, the development in the field remained largely limited until the late 1990s [2]. In the past two decades, the increasing demand for pure and optically active compounds in chemical industries and academia and a growing drive for greener metal-free catalytic processes has prompted a renaissance in the field of asymmetric organocatalysis [2,5,6,7]. The use of proline and related analogues in asymmetric synthesis has continued to see development, becoming one of the most widely utilized classes of organocatalysts [8,9,10,11]
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