The standard molar enthalpies and heat capacities of dissolution of pharmacologically promising trimethylethylglycoluril (TriMEGU) and triethylmethylglycoluril (TriEMGU) in ordinary (H2O) and heavy (D2O) water were determined calorimetrically at T = (288.15, 298.15, 308.15, 313.15, and 318.15) K and ambient pressure. The corresponding solvent D2O–H2O isotope effects (IEs) in these quantities were estimated. The enthalpic effects of TriMEGU dissolution (○) in the aqueous medium experience a negative-to-positive sign inversion at (296.15–297.15) K. The same goes for the IE in ○, with the only difference being that such an inversion occurs at ca. 308.15 K. In turn, for TriEMGU, both the ○ values in water H/D isotopologues and the corresponding IEs were found to be negative up to ∼315.15 K. The hydration behavior of each of bicyclic solutes under study was discussed in comparison with that for the related chiral dimethyldiethylglycoluril (trans-DMDEGU, being the tranquilizer albicar) using the results of previously performed calorimetric experiments. It is established that the temperature-dependent balance of hydrophilic and hydrophobic forces in the process of a solute hydration is determined not only by the number of bulkier alkyl substituents in the molecule of the racemic tetraalkylated glycoluril-derivative, but also by the stereochemical peculiarities of their N-locations.
