Hierarchy of Supramolecular Synthons: Persistent Carboxylic Acid···Pyridine Hydrogen Bonds in Cocrystals That also Contain a Hydroxyl Moiety

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Abstract

A Cambridge Structural Database (CSD) analysis was conducted in order to evaluate the hierarchy of supramolecular heterosynthons that involve two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids and alcohols, in competitive environments. The study revealed that 34% of the 5690 molecular carboxylic acid entries and 26% of the 25 035 molecular alcohol entries form supramolecular homosynthons, whereas the remaining entries form supramolecular heterosynthons with other functional groups, in particular Narom, CONH2, C−O−C, C═O, and chloride anions. Further refinement of this raw data revealed the following: 98% occurrence of the COOH···Narom supramolecular heterosynthon in the 126 crystal structures that contain acid and pyridine moieties in the absence of other hydrogen bond donors or acceptors; and 78% occurrence of the OH···Narom supramolecular heterosynthon in 228 crystal structures that contain hydroxyl and pyridine moieties (excluding intramolecular hydrogen bonding). Such high frequencies indicate that these supramolecular heterosynthons are strongly favored over their respective COOH···COOH and OH···OH supramolecular homosynthons. However, the CSD does not contain enough information to evaluate the predictability of even common supramolecular heterosynthons in the presence of competing hydrogen bonding moieties; for example, there are only 15 entries when -COOH, -OH, and Narom moieties are present exclusively (no other hydrogen bond donors and acceptors groups) in a molecule. We have addressed the competition between the COOH···Narom and the OH···Narom supramolecular heterosynthons by analyzing these 15 entries in CSD and characterizing 15 new compounds (cocrystals 1−13; salts 14 and 15) that are composed of cocrystal formers which contain a permutation of -COOH, -OH and Narom functional groups. Analysis of this group of compounds reveals that supramolecular heterosynthons are favored over the respective supramolecular homosynthons. We also address the methodologies that can be used to prepare 1−15 in the context of solvent evaporation, solvent-drop grinding, and slurrying.

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