Jin Shasha, Sanii Rana, Song Bai-Qiao, Zaworotko Michael J
Department of Chemical Sciences and Bernal Institute, University of Limerick, Co., Limerick V94 T9PX, Ireland.
Cryst Growth Des. 2022 Jul 6;22(7):4582-4591. doi: 10.1021/acs.cgd.2c00471. Epub 2022 Jun 21.
Although crystal engineering strategies are generally well explored in the context of multicomponent crystals (cocrystals) formed by neutral coformers (molecular cocrystals), cocrystals comprised of one or more salts (ionic cocrystals, ICCs) are understudied. We herein address the design, preparation, and structural characterization of ICCs formed by phenolic moieties, a common group in natural products and drug molecules. Organic and inorganic bases were reacted with the following phenolic coformers: phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol. Nine ICCs were crystallized, each of them sustained by the phenol-phenolate supramolecular heterosynthon (PhOH···PhO). Such ICCs are of potential utility, and there are numerous examples of phenolic compounds that are biologically active, some of which suffer from low aqueous solubility. The propensity to form ICCs sustained by the PhOH···PhO supramolecular heterosynthon was evaluated through a combination of Cambridge Structural Database (CSD) mining, structural characterization of nine novel ICCs, and calculation of interaction energies. Our analysis of these 9 ICCs and the 41 relevant entries archived in the CSD revealed that phenol groups can reliably form ICCs through charge-assisted PhOH···PhO interactions. This conclusion is supported by hydrogen-bond strength calculations derived from CrystalExplorer that reveal the PhOH···PhO interaction to be around 3 times stronger than the phenol-phenol hydrogen bond. The PhOH···PhO supramolecular heterosynthon could therefore enable crystal engineering studies of a large number of phenolic pharmaceutical and nutraceutical compounds with their conjugate bases.
尽管在由中性共形成物形成的多组分晶体（共晶体）（分子共晶体）的背景下，晶体工程策略通常已得到充分探索，但由一种或多种盐组成的共晶体（离子共晶体，ICCs）却研究不足。我们在此阐述了由酚类部分形成的ICCs的设计、制备和结构表征，酚类部分是天然产物和药物分子中的常见基团。有机碱和无机碱与以下酚类共形成物反应：苯酚、间苯二酚、间苯三酚、4-甲氧基苯酚和4-异丙基苯酚。九个ICCs结晶出来，它们每个都由酚-酚盐超分子异合成子（PhOH···PhO）维持。此类ICCs具有潜在用途，并且有许多酚类化合物具有生物活性的例子，其中一些存在水溶解度低的问题。通过结合剑桥结构数据库（CSD）挖掘、九个新型ICCs的结构表征以及相互作用能的计算，评估了由PhOH···PhO超分子异合成子维持形成ICCs的倾向。我们对这9个ICCs以及CSD中存档的41个相关条目进行分析后发现，酚基可通过电荷辅助的PhOH···PhO相互作用可靠地形成ICCs。这一结论得到了来自CrystalExplorer的氢键强度计算的支持，该计算表明PhOH···PhO相互作用比酚-酚氢键强约3倍。因此，PhOH···PhO超分子异合成子可用于对大量酚类药物和营养保健品及其共轭碱进行晶体工程研究。
