Crystal Engineering of Ionic Cocrystals Sustained by the Phenol–Phenolate Supramolecular Heterosynthon

[Image: see text] Although crystal engineering strategies are generally well explored in the context of multicomponent crystals (cocrystals) formed by neutral coformers (molecular cocrystals), cocrystals comprised of one or more salts (ionic cocrystals, ICCs) are understudied. We herein address the design, preparation, and structural characterization of ICCs formed by phenolic moieties, a common group in natural products and drug molecules. Organic and inorganic bases were reacted with the following phenolic coformers: phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol. Nine ICCs were crystallized, each of them sustained by the phenol–phenolate supramolecular heterosynthon (PhOH···PhO(–)). Such ICCs are of potential utility, and there are numerous examples of phenolic compounds that are biologically active, some of which suffer from low aqueous solubility. The propensity to form ICCs sustained by the PhOH···PhO(–) supramolecular heterosynthon was evaluated through a combination of Cambridge Structural Database (CSD) mining, structural characterization of nine novel ICCs, and calculation of interaction energies. Our analysis of these 9 ICCs and the 41 relevant entries archived in the CSD revealed that phenol groups can reliably form ICCs through charge-assisted PhOH···PhO(–) interactions. This conclusion is supported by hydrogen-bond strength calculations derived from CrystalExplorer that reveal the PhOH···PhO(–) interaction to be around 3 times stronger than the phenol–phenol hydrogen bond. The PhOH···PhO(–) supramolecular heterosynthon could therefore enable crystal engineering studies of a large number of phenolic pharmaceutical and nutraceutical compounds with their conjugate bases.