A theoretical study of the mechanism of (S) proline-catalysed aldol reactions

Abstract

In this study, the novel, reaction energy profile-fragment attributed molecular system energy change (REP-FAMSEC) was applied in studying mechanisms of chemical reactions. The applicability of the REP-FAMSEC protocol was tested for the mechanism of proline catalysed aldol reaction whereby several possible mechanisms have been debated for the past four decades. The approach quantifies and explains energy changes for each successive step along with the reaction profile. It mainly uses interaction energies between meaningful polyatomic fragments of a molecular system and generates energy contribution made by each fragment of a molecule. The fragments or atoms driving or opposing a change can easily be discovered and the reason for their (un)reactivity can be established. The relative stability and catalytic behaviour of (S) proline conformers including the zwitterion were fully explained at an atomic and molecular level. Though the zwitterion becomes the most dominant conformer in dimethyl sulfoxide (DMSO) solvent, it is not the active catalyst in proline catalysis. It forms very weak interactions with the ketone donor and will not form the active enamine catalyst. The study shows that the first step of the catalytic reaction which was coined as the C–N bond formation using classical techniques, cannot be explained using the interaction of the N–,C+ atom pair but rather by the interaction of O-atom of acetone and the acidic H-atom of proline. Hence the first step is best described as the C–N bond formation/1st H-transfer. Based on this initial interaction the lowest energy conformer of proline is eliminated as a catalyst. When the REP is explored in the presence of an explicit solvent molecule of DMSO, FAMSEC shows that molecules of proline conformers (lowest 1a and higher energy 1b), acetone 2, and DMSO 3 are involved in strong intermolecular interactions when they form 3-molecular complexes (3-MCs). The interactions formed by the molecule of DMSO weaken interactions between 1a and 2 while strengthening those between 1b and 2, thereby eliminating 1a as an inactive catalyst. The zwitterion which becomes the most dominant in DMSO is converted to conformer 1a through a low energy barrier intramolecular proton transfer. When formed conformer 1a undergoes a puckering of the pyrrolidine ring resulting in its conversion to the catalytically active conformer 1b. The presence of a molecule of acetone, DMSO, or a combination of the two molecules facilitates the structural change of proline from conformer 1a to 1b. This shows that there is no need to adhere to a specific sequence of reagent addition in proline catalysis. During the formation of the active enamine catalyst from an initial imine, it was found that the molecule of the eliminated water acts as a medium for proton transfer relay while interaction involving the solvent molecule of DMSO is essential for decreasing the energy barrier and stabilising the resulting enamine catalyst.