Can we predict specific numbers of catalytically important molecules of water in H/D exchange in aromatic systems? A combined NMR and DFT study

Abstract

Base-catalyzed H/D exchange reactions through keto–enol tautomeric equilibrium are a textbook example in mechanistic organic chemistry. The pH effect of H₂O catalysis, however, is largely unknown. We report, herein, variable temperature and pD ¹H NMR studies of the experimental activation enthalpy , entropy , and Gibbs free energy of H/D exchange reactions of the H-6 and H-8 protons belonging to ring A of the natural product taxifolin. The experimental values range from ∼25 to 23 kcal mol⁻¹ for pD values of 6.1 to 9.6 and a buffer concentration in the range of 25 to 1000 mM. Differences in values of neutral and anionic taxifolin and phloroglucinol were found to be very small (≤1.5 kcal mol⁻¹). The experimental data of taxifolin and phloroglucinol were compared with DFT calculations with two up to four H₂O molecules explicitly present, which demonstrate a unique catalytic role of H₂O of over 35 kcal mol⁻¹. Excellent agreement between and DFT calculated Gibbs free activation energies, , was obtained with the use of three molecules of H₂O for the neutral state of phloroglucinol (with the “in–in” configuration of the phenol OH groups) and taxifolin. In the ionic form of phloroglucinol, the mechanistic pathway with two molecules of H₂O in the transition state (one of which involves the CO moiety) showed very good agreement with the experimental data. For the anionic form of taxifolin, the mechanistic pathway with three molecules of H₂O in the transition state showed excellent agreement with the experimental values. Among the various functionals used, the APFD/6-31+G(d) and B3LYP/6-31+G(d)/GD3BJ resulted in optimum agreement with . The enthalpic term is considerably larger than the entropic term , in agreement with the experimental data. This indicates a dissociative mechanism of the loosely bound activated complex. The present results demonstrate the unique catalytic role of two and/or three molecules of H₂O, through keto–enol tautomerization, with minor contribution of base-catalysis, in H/D exchange reactions in aromatic systems.