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

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.

Interdependence of structure and physical properties in co-crystals of azopyridines

“…COOHN(py) heterosynthon (Scheme 2), which has many precedents in literature. 12 Increasing the characteristics of the individual molecules or to any systematic structural patterns that may appear in these families of compounds.…”

“…Once the appearance of co-crystals were confirmed by IR, slow 45 evaporation experiments were set up using stoichiometric amounts of the acid and base in a suitable solvent at room temperature. Since structures of 4,4'-azpy with succinic, adipic and sebacic acid were previously reported, 12,13 we analyzed the remaining five compounds using single crystal X-ray diffraction.…”

13. Crystal chemistry of the isomeric N,N'-bis(pyridin-n-ylmethyl)-ethanediamides, n = 2, 3 or 4

“…As 2 LH2 lies about a centre of inversion, there is only one unique acid molecule. The key feature of the supramolecular association is the formation of a layer whereby the pyridyl-N atoms are connected to carboxylic acids via hydroxyl-O-H…N(pyridyl) hydrogen bonds and a seven-membered {C(=O)OH...NCH} heterosynthon, being brought about a pyridyl-C-H…O(carbonyl) interaction; these are well known as being robust in co-crystal technology [12]. The amino group is pivotal in the molecular packing by donating, via amino-N-H…O(amide), and accepting, via amide-N-H…N(amino), hydrogen bonds leading to 14-membered {…NH…OC2NH}2 synthons, Fig.…”

Hydrogen bonding in 2,6-bis(4-fluorophenyl)-3,5-dimethylpiperidin-4-one methanol solvate

“…Being strong and highly directional, conventional hydrogen bonding can be exploited to rationally and reliably connect molecules into supramolecular aggregates as demonstrated, for example, in the burgeoning field of cocrystal formation [5,6]. With the above in mind, it is clearly of fundamental interest when molecules with hydrogen bonding potential crystallise without forming hydrogen bonds, as these examples might provide insight into the role of other factors that determine the ultimate crystal structure(s) adopted by molecules.…”