Kinetic and mechanistic studies of proline-mediated direct intermolecular aldol reactions

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

“…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.…”

Mechanistic Complexity in Organo–SOMO Activation

“…Utilization of RPKA in conjunction with spectroscopic studies allowed for the detailed determination of the kinetic properties of a reaction containing organocatalysis, phase transfer, singleelectron oxidation, and free-radical chemistry. Additionally, this work, in concert with the studies of the groups of Blackmond and Armstrong on the proline-catalyzed aldol reaction [10] and the recent work of Wennemers et al on organocatalytic conjugate additions, [14] shows that a thorough understanding of the role of H 2 O is necessary for all organocatalytic processes that proceed through an enamine intermediate, regardless of the catalyst structure and the nature of the major bond-forming event. We are currently examining the mechanism of other SOMO-activated processes to further understand the effect of solvent and H 2 O on the phase-transfer process that controls the homogenous concentration of the oxidant.…”

“…[7] The groups of Ward [8] and Pihko [9] observed that the presence of at least one equivalent [10] Additionally, the groups of Armstrong and Blackmond showed that while the active concentration of the catalyst is maintained by H 2 O, it in fact suppresses the rate of the aldol reaction, possessing a reaction order of À0.7. [10] To further elucidate the role of H 2 O in organo-SOMO activation, its impact on enamine formation was examined outside the reaction conditions. When 1 and 3 were combined in dry, deuterated acetone, no enamine was observed by 1 H NMR spectroscopy over the course of 7 h (see the Supporting Information).…”