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

Abstract

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.

A Coherent Mechanistic Rationale for Additive Effects and Autoinductive Behaviour in Proline‐Mediated Reactions

“…11 However, our previous studies of the aldol reaction argue against this proposal. First, we showed clearly that the intrinsic kinetic effect of water is in fact to suppress, not to promote, the rate of the catalytic reaction [6]; second, our reported deuterium isotope effect of kH/kD ≈ 2 in the aldol reaction of eq 1c supports a role for the carboxyl proton in the ratedetermining enamine attack on the aldehyde 6. Further experimental studies to investigate the role of added base in the reactions of eq.…”

“…Computational studies [3] have suggested a mechanistic analogy to reactions of aldolase enzymes [4]. Our recent work provided the first kinetic support for the enamine mechanism in aldol reactions and clarified the role of water on and off the catalytic cycle [5,6].…”

“…Computational studies [3] have suggested a mechanistic analogy to reactions of aldolase enzymes [4]. Our recent work provided the first kinetic support for the enamine mechanism in aldol reactions and clarified the role of water on and off the catalytic cycle [5,6].(1a) (1b) (1c)A number of intriguing experimental observations have yet to be rationalized for these reactions. One unusual feature is a striking temporal increase in reaction rate that is observed in the α-aminoxylation [7,8] (eq 1a) and α-amination of aldehydes [9,10] (eq 1b), but is not observed in aldol reactions (eq 1c).…”

“…The intrinsic kinetic dependences of substrate concentrations for the reactions of eq.1 may be compared in the context of this mechanism. We have shown that the aldol reaction of eq 1c exhibits a positive rate dependence on the concentrations of both substrates acetone 5 and aldehyde 6 and a negative order in [H2O], implicating rate-determining attack of enamine 9 on electrophile 6 for the intermolecular aldol reaction, with the further suggestion that the enamine formation steps are in pre-equilibrium (saturation kinetics in [9]) [5,6]. The reactions of eqs 1a and 1b, by contrast, exhibit zero order kinetics in concentration of the highly active electrophiles 2a and 2b and first order dependence on the concentration of the carbonyl substrate 1 [13], dependences that hold in the presence of additives such as CH3OH and CH3COOH.…”

Synthesis of high surface area nanomaterials and their application in catalysis

“…Studies of the effect of water in the aldol condensation have been previously reported elsewhere. 38,39 They have demonstrated the role of water in the regeneration of active basic group (amines) at the expense of the inactive iminium form. This kind of observation is unlikely in our case as we don't expect to have amines in our carbons based on our investigations.…”