Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

A well‐defined and stable “AB” binary system in the presence of “C” a crystalline synthon ground in a ball mill undergoes selective transformation in the solid state according to the equation AB+C→AC+B. When the amount of C is increased two times then the equation AB+2C→AC+BC is valid. The other variants are more complex. The pathway BC+A is allowed and leads to the AC and B products. The pathway AC+B is not preferred, and no transformation is observed. These non‐obvious correlations were observed for cocrystal of barbituric acid (BA):thiobarbituric acid (TBA) recently reported by Shemchuk et al. (Chem. Commun. 2016, 52, 11815–11818) in the presence of 1‐hydroxy‐4,5‐dimethyl‐imidazole 3‐oxide (HIMO). This synthon shows high affinity for the BA0.5TBA0.5 cocrystal as well for its individual components, BA and TBA. Single‐quantum, double‐quantum (SQ‐DQ) 2D 1H very fast MAS NMR with a spinning rate of 60 kHz was employed as a basic and most diagnostic tool for the study of cocrystals transformations. Analysis of the experimental data was supported by theoretical calculations, including computation of the stabilization energy, Estab, defined as the energy difference between the energy of a co‐crystal and the sum of the energies of particular components in the respective stoichiometric ratios. Two mechanisms of synthon replacement have been proposed. Pathway 1 assumes a concerted mechanism of substitution. In this approach, synthon attack is synchronized in time with the departure of one of the components of the binary system. Pathway 2 implies a non‐concerted process, with an intermediate stage in which three separate components are present. Evidence suggesting a preference for Pathway 2 is shown. In concert… or not: Monitoring the processes that occur while grinding a stable cocrystal of barbituric acid:thiobarbituric acid with an imidazol‐N‐oxide derivative in a ball mill reveals surprising synthon preferences and indicates the mechanism of synthon substitution.