Clarification of the Role of Water in Proline-Mediated Aldol Reactions

A coherent mechanistic rationalization of the role of water in aldol reactions employing aromatic aldehydes shows that the intrinsic kinetic effect of water within the catalytic cycle is a suppression of reaction rate. The presence of water suppresses formation of key intermediates within the cycle as well as reversibly and irreversibly formed spectator species such as oxazolidinones and oxapyrrolizidines, respectively. The net effect on the observed productivity of the reaction will depend on the balance between these two effects. This work highlights the complex role that water plays both on and off the catalytic cycle and the need to separate these effects to achieve mechanistic understanding.