Isotope Effects Reveal the Mechanism of Enamine Formation in l-Proline-Catalyzed α-Amination of Aldehydes

Abstract

The mechanism of l-proline-catalyzed α-amination of 3-phenylpropionaldehyde was studied using a combination of experimental kinetic isotope effects (KIEs) and theoretical calculations. Observation of a significant carbonyl (13)C KIE and a large primary α-deuterium KIE support rate-determining enamine formation. Theoretical predictions of KIEs exclude the widely accepted mechanism of enamine formation via intramolecular deprotonation of an iminium carboxylate intermediate. An E2 elimination mechanism catalyzed by a bifunctional base that directly forms an N-protonated enamine species from an oxazolidinone intermediate accounts for the experimental KIEs. These findings provide the first experimental picture of the transition-state geometry of enamine formation and clarify the role of oxazolidinones as nonparasitic intermediates in proline catalysis.

Water in asymmetric organocatalytic systems: a global perspective

“…Thus, going back to the original proposal of Seebach and Eschenmoser, 29 it has been very recently proposed that they are indeed key oncycle intermediates in the enamine formation mechanism, at least for the α-amination reaction where base catalyzed elimination (likely coming from proline-product adducts) accounts for the observed kinetic isotopic effects. 31…”

Reaction Mechanism of Organocatalytic Michael Addition of Nitromethane to Cinnamaldehyde: A Case Study on Catalyst Regeneration and Solvent Effects

“…In the case where proline was used as the catalyst, the corresponding iminium intermediate can lead to the formation of an off-target parasitic species that can also be reversed by including water in the reaction. 18 − 20 On the other hand, water also disfavors the formation of the iminium intermediate, shifting the equilibrium toward the free catalyst. 3 It is also believed that the reaction cycle eventually leads to the formation of the second iminium intermediate, which upon hydrolysis yields the product and catalyst.…”

Mechanism and rate constant of proline-catalysed asymmetric aldol reaction of acetone and p-nitrobenzaldehyde in solution medium: Density-functional theory computation

“…Table 2 presents the results of the rate constants of the various elementary steps calculated at 298.15 K from the Eyring equation (Eq. (2) ), in which is the entropy of activation [40] , [41] , [42] . The equation is applicable to only solution-phase bimolecular reactions [42] .…”

“…(2) ), in which is the entropy of activation [40] , [41] , [42] . The equation is applicable to only solution-phase bimolecular reactions [42] . …”