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.