Reply to the ‘Comment on “Topography of the Free Energy Landscape on the Claisen–Schmidt Condensation: Solvent and Temperature Effect in the Rate-Controlling Step”’ by N. D. Coutinho, H. G. Machado, V. H. Carvalho-Silva and W. A. da Silva, Phys. Chem. Chem. Phys., 2021, 23, 6738

Abstract

New calculations improved by explicit-implicit hybrid treatment ensure that the overall iKIE > 1 does not exclude step R4 as a limiting-step and that the debate about the infallibility of the generalization of step R5 as RCS is reasonable.

The complete mechanism of an aldol condensation in water

“…Da Silva and coworkers do not accept the principle that an overall iKIE > 1 excludes Step 4 as rate-limiting (“our calculations showed that an overall iKIE > 1 does not eliminate Step 4 as RCS”). 8 Their argument is that although the iKIE for Step 4 is 0.13 ( k 4D / k 4H = 45.955/351.513), corresponding to a typical primary KIE of 7 for H vs. D removal, the calculated overall iKIE on Step 4 is K 1D K 2D K 3D k 4D / K 1H K 2H K 3H k 4H , or 4.63, as in Table 1. This analysis depends directly on the equilibrium isotope effect for the aggregate of Steps 1, 2, and 3.…”

“…In response to those objections da Silva and coworkers re-emphasized the feature that small changes in relative free energies could shift the rate-limiting step. 8 They noted that their extreme iKIEs of 1004, 983, and 308 were for overall processes, not for individual steps. In an attempt at corroboration they cited some large observed KIEs, due to tunneling favoring H over D, but those are normal KIEs, not inverse, and never so large as these.…”