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.
