Hierarchy of Supramolecular Synthons: Persistent Hydroxyl···Pyridine Hydrogen Bonds in Cocrystals That Contain a Cyano Acceptor

An analysis of the Cambridge Structural Database reveals >99% occurrence of the
hydroxyl···pyridine supramolecular heterosynthon in crystal structures that contain hydroxyl and
pyridine moieties in the absence of other hydrogen-bonding moieties. The occurrence of the
hydroxyl···cyano supramolecular heterosynthon in crystal structures that contain hydroxyl and
cyano moieties is ca. 77%. Such high frequencies indicate that these heterosynthons are strongly
favored over the competing hydroxyl···hydroxyl supramolecular homosynthon. However, the
CSD does not contain enough information to evaluate which supramolecular heterosynthon
prevails when only OH, pyridine, and CN moieties are present in a crystal structure. We have
addressed the competition between the hydroxyl···pyridine and the hydroxyl···cyano supramolecular heterosynthons by characterizing a series of 17 cocrystals that are composed of cocrystal
formers which contain a permutation of OH, pyridine, and CN functional groups. Structural
analysis reveals that all cocrystals are sustained by the hydroxyl···pyridine heterosynthon.
Keywords: Cambridge Structural Database; cocrystal; polymorphism in cocrystals; pharmaceutical
cocrystal; supramolecular heterosynthon