16O/18O Exchange of Aldehydes and Ketones caused by H218O in the Mechanistic Investigation of Organocatalyzed Michael, Mannich, and Aldol Reactions

Organocatalyzed Michael, Mannich, and aldol reactions of aldehydes or ketones, as nucleophiles, have triggered several discussions regarding their reaction mechanism. (H2O)-O-18 has been utilized to determine if the reaction proceeds through an enamine or enol mechanism by monitoring the ratio of O-18 incorporated into the final product. In this communication, we describe the risk of (H2O)-O-18 as an evaluation tool for this mechanistic investigation. We have demonstrated that exchange of O-16/O-18 occurs in the aldehyde or ketone starting material, caused by the presence of (H2O)-O-18 and amine catalysts, before the Michael, Mannich, and aldol reactions proceed. Because the newly generated O-18 starting aldehydes or ketones and O-16 water affect the incorporation ratio of O-18 in the final product, the use of (H2O)-O-18 would not be appropriate to distinguish the mechanism of these organocatalyzed reactions.