Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
Molecules. 2021 Feb 21;26(4):1147. doi: 10.3390/molecules26041147.
Strategies for co-crystal synthesis tend to employ either hydrogen- or halogen-bonds between different molecules. However, when both interactions are present, the structural influence that they may exert on the resulting assembly is difficult to predict a priori. To shed some light on this supramolecular challenge, we attempted to co-crystallize ten aliphatic dicarboxylic acids (co-formers) with three groups of target molecules; -(pyridin-2-yl)picolinamides (2Pyr-), -(pyridin-2-yl)nicotinamides (3Pyr-), -(pyridin-2-yl)isonicotinamides (4Pyr-); X=Cl/ Br/ I. The structural outcomes were compared with co-crystals prepared from the non-halogenated targets. As expected, none of the reactions with 2Pyr- produced co-crystals due to the presence of a very stable intramolecular N-H···N hydrogen bond. In the 3Pyr series, all six structures obtained showed the same synthons, -COOH···N(py) and -COOH···N(py)-NH, that were found in the non-halogenated parent 3Pyr and were additionally accompanied by structure directing X···O(OH) interactions (X=Br/I). The co-crystals of the unhalogenated parent 4Pyr co-crystals assembled via intermolecular -COOH···N(py) and -COOH···N(py)-NH synthons. Three of the analogues 4Pyr-X co-crystals displayed only COOH···N(py) and -COOH···N(py)-NH interactions. The three co-crystals of 4Pyr-X with fumaric acid (for which no analogues structures with 4Pyr are known) formed -COOH···N(py)-NH and -NH···O=C hydrogen bonds and showed no structure-directing halogen bonds. In three co-crystals of 4Pyr-I in which -COOH···N(py)-NH hydrogen bond was present, a halogen-bond based -I···N(py) synthon replaced the -COOH···N(py) motif observed in the parent structures. The structural influence of the halogen atoms increased in the order of Cl < Br < I, as the size of σ-holes increased. Finally, it is noteworthy that isostructurality among structures of the homomeric targets was not translated to structural similarities between their respective co-crystals.
共晶合成策略往往采用不同分子之间的氢键或卤键。然而，当两种相互作用都存在时，它们可能对所得组装体施加的结构影响很难预先预测。为了阐明这一超分子挑战，我们试图将十种脂肪族二羧酸（共晶形成体）与三组目标分子共结晶；-（吡啶-2-基）吡啶甲酰胺（2Pyr-），-（吡啶-2-基）烟酸酰胺（3Pyr-），-（吡啶-2-基）异烟酸酰胺（4Pyr-）；X=Cl/Br/I。将结构结果与未卤化目标物制备的共晶进行比较。正如预期的那样，由于存在非常稳定的分子内 N-H···N 氢键，与 2Pyr- 的反应都没有产生共晶。在 3Pyr 系列中，获得的所有六个结构都显示了相同的连接基，-COOH···N(py) 和 -COOH···N(py)-NH，这些连接基在未卤化的母体 3Pyr 中都有发现，并且还伴随着结构导向的 X···O(OH) 相互作用（X=Br/I）。未卤化母体 4Pyr 共晶通过分子间 -COOH···N(py) 和 -COOH···N(py)-NH 连接基组装。三个 4Pyr-X 类似物共晶仅显示 COOH···N(py) 和 -COOH···N(py)-NH 相互作用。三个 4Pyr-X 与富马酸的共晶（对于没有 4Pyr 类似物结构的已知结构）形成 -COOH···N(py)-NH 和 -NH···O=C 氢键，并且没有结构导向的卤键。在三个 4Pyr-I 共晶中，存在 -COOH···N(py)-NH 氢键，卤键为基础的 -I···N(py) 连接基取代了母体结构中观察到的 -COOH···N(py) 基序。随着 σ 孔尺寸的增加，卤原子的结构影响按 Cl < Br < I 的顺序增加。最后，值得注意的是，同系物目标物之间的结构同构性并没有转化为它们各自共晶之间的结构相似性。
