In recent years the interest in organocatalysis has grown substantially, with many new chemical transformations being added to the repertoire almost on a day-to-day basis. Organocatalysis describes the catalytic action of an organic molecule, and the most clear-cut example is undoubtedly the amino acid proline. Below is shown the catalytic cycle for an intermolecular, enantioselective aldol reaction in which proline acts as an efficient catalyst.1

The catalytic cycle is believed to consist of at least four steps: a) The proline catalyst interact with the ketone to form an imine, which increases the nucleophilicity towards the aldehyde. b) The carboxylic acid part of the proline organocatalyst pre-organizes the two substrates by a hydrogen-bonding interaction. c) The C-C bond formation occurs, and finally the product is released by hydrolysis (d), thus regenerating the active organocatalyst.

In this project we aim to use ReaxFF, the in-house developed reactive force-field,2 to obtain an accurate description of all events taking place during the catalytic cycle. Such a computational approach should allow facile development of new reactions within this field (new substrate types, catalysts with better selectivity, improved turnover numbers etc.).

Also in biology hydrogen-bonding in the active site of enzymes is of major importance for the the well-known fine-tuning of reactivity and selectivity for these systems. In this field, ReaxFF has the potential to give new insight into the dynamical nature of these biological transformations, as it should be capable of handling the simulation of entire enzymes or even multiple biopolymers within a reasonable time-frame.

Personnel: Peter Fristrup

1 List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000122,2395.

2 van Duin, A. C. T.; Dasgupta, S.; Lorant, F.; Goddard, W. A., III. J. Phys. Chem. A 2001105,9396.