Topography of the free energy landscape of Claisen-Schmidt condensation: solvent and temperature effects on the rate-controlling step

Recent studies have found that hydroxide elimination and the C = C bond formation step in base-promoted aldol condensation have a strong influence on the overall rate of the reaction, in contrast to the well-accepted first enolization or C-C bond formation step. Here, applying theoretical models to the prototypical reaction of chalcone formation, the complete free energy profile of Claisen-Schmidt condensation is assessed, revealing how a protic solvent and a slight increase in temperature can induce the second enolization as the rate-controlling step (RCS). It is also observed: i) the nonexistence of a step with a much higher energetic barrier than the others, making the concept of RCS debatable; and ii) that the overall inverse kinetic isotopic effect does not exclude second enolization as a RCS in protic continuum medium. We expect that these results can expand the understanding of the decisive role of physicochemical factors on the choose of the RCS in the aldol condensation.

Automated summary

Recent studies have shown that hydroxide elimination and C = C bond formation in base-promoted aldol condensation significantly impact the overall reaction rate, contrary to the widely accepted first enolization or C-C bond formation steps. By applying theoretical models to the prototypical reaction of chalcone formation, researchers have revealed how a protic solvent and a slight increase in temperature can induce the second enolization as the rate-controlling step. Additionally, observations suggest that there may not be a single step with a notably higher energy barrier than others, challenging the concept of a specific rate-controlling step.