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

对剑桥晶体结构数据库（Cambridge Structural Database）的分析表明，在仅含有羟基与吡啶基团且无其他氢键官能团的晶体结构中，羟基···吡啶超分子异合成子（supramolecular heterosynthon）的出现占比超过99%。在仅含有羟基与氰基基团的晶体结构中，羟基···氰基超分子异合成子的出现占比约为77%。如此高的出现频率说明，相较于与之竞争的羟基···羟基超分子同合成子（supramolecular homosynthon），这两类超分子异合成子更受偏好。然而，剑桥晶体结构数据库（CSD）所含信息不足以评估当晶体结构中仅存在羟基、吡啶与氰基三种官能团时，哪一种超分子异合成子占主导地位。

我们通过表征一组由包含羟基、吡啶与氰基官能团任意排列的共晶形成组分构成的17种共晶，探究了羟基···吡啶与羟基···氰基超分子异合成子之间的竞争关系。结构分析显示，所有共晶均由羟基···吡啶超分子异合成子支撑稳定。

关键词：剑桥晶体结构数据库；共晶；共晶多态性；药用共晶；超分子异合成子