Hydrophobic vs. Hydrophilic: Ionic Competition in Remacemide Salt Structures

Remacemide [2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide] was developed as a potential
antagonist for epilepsy, Parkinsonism, and Huntington's disease. This paper investigates hydrophilic and hydrophobic
intermolecular interactions that occur within the series of crystal structures comprising remacemide 1 and six of its
salts [2 = chloride; 3 = nitrate; 4 = acetate (C2H3O2-); 5 = hydrogenfumarate (C4H3O4-); 6 = naphthalene-2-sulfonate
(napsilate, C10H7O3S-); 7 = 1-hydroxynaphthalene-2-carboxylate (xinafoate, C11H7O3-)]. The hydrophilic interactions
are described through graph set analyses of the hydrogen bond motifs and networks. The lattice of 1 comprises
unidirectional, one-dimensional chains of molecules parallel to the c-axis. In 2, the cation−anion hydrogen bonding
imposes a well-defined hydrophilic stratum structure on the lattice. As the cation itself is amphiphilic, a natural
consequence of this is the creation of two-dimensional stacked layers with alternating hydrophilic and hydrophobic
character (lattice bilayers). This tendency to form bilayers within the lattice is also observed in structures 3−5
(polar anions) and structures 6−7 (amphiphilic anions). Relatively few well-directed intermolecular interactions
are observed between aromatic rings, either in 1 or in the hydrophobic layers of 2−7. Therefore, it is concluded that
it is the hydrophilic hydrogen bond interactions that dominate the crystal packing and drive the segregation into
lattice bilayers in the salt crystal structures.

Remacemide（2-氨基-N-(1-甲基-1,2-二苯基乙基)乙酰胺）系作为一种潜在的癫痫、帕金森病及亨廷顿病的拮抗剂而开发。本研究探讨了包含Remacemide 1及其六种盐类（2 = 氯化物；3 = 硝酸盐；4 = 醋酸盐（C2H3O2-）；5 = 富马酸氢盐（C4H3O4-）；6 = 萘-2-磺酸盐（napsilate，C10H7O3S-）；7 = 1-羟基萘-2-羧酸盐（xinafoate，C11H7O3-））系列晶体结构中存在的亲水性及疏水性分子间相互作用。亲水性相互作用通过氢键模式与网络的图集分析方法进行描述。1的晶格由平行于c轴的单向一维分子链组成。在2中，阳离子-阴离子氢键在晶格上强加了一个明确的亲水性层状结构。由于阳离子本身为两亲性，因此这一现象的自然结果是形成具有交替亲水性和疏水性的二维叠加层（晶格双层）。在3−5（极性阴离子）和6−7（两亲性阴离子）的结构中，也观察到晶格内形成双层的趋势。在1或2−7的疏水层中，芳香环之间观察到的定向分子间相互作用相对较少。因此，得出结论，亲水性氢键相互作用主导了晶体堆积，并驱动了盐晶体结构中晶格双层的分离。