Navigating Molecular\nAggregation in Isonicotinamide\nBased Cocrystals: Cl···O and C–H···O\nTip the Balance towards Metastable Synthon in the Solid State

We report on an investigation aimed at selectively isolating\ncocrystalline\nphases through solution crystallization. Isonicotinamide was used\nas the model compound, and six isomeric dichlorophenols served as\ncoformers. Out of the possible combinations, five novel cocrystals\nwere identified (excluding 2,4-dichlorophenol-isonicotinamide). These\nsolid phases were characterized by using single crystal X-ray diffraction\n(SC-XRD), powder X-ray diffraction (PXRD), and differential scanning\ncalorimetry (DSC). This study highlights that dichloro substitution\non the phenolic moiety significantly influences the hydroxyl group’s\nbehavior in the solid state. For instance, in cocrystals <b>4</b> and <b>5</b> secondary Cl···O and C–H···O\ninteractions disrupt the typical hierarchy of synthons, allowing the\nless favored synthons <b>III</b> and <b>IV</b> to form,\nsuggesting that the composition of less favored interactions might\nsometimes be more effective than favored ones.