From intermolecular forces to physical properties via crystal engineering

Abstract

Acetylated 2-aminopyridine derivatives tend to form two distinct types of homomeric interactions in the solid state. To elucidate why these specific assemblies form, we examined the structural landscape of two families of acetylated 2-aminpyridines; 5-NO₂ and 3-Cl, 5-CF₃. In the NO₂ series, increasing steric demands induce a switch from N-H···C=O chains to N-H···N(pyridine) dimers. In contrast, the 3-Cl, 5-CF₃ series consistently formed infinite N-H···O=C chains, indicating that electrostatics governs the assembly. In addition, we also noted that IR spectroscopy may be used to predict the type of interaction formed. To verify this observation, two more series were examined using IR spectroscopy and crystallography. It was found that chain-forming compounds exhibited C=O stretching modes at 1655-1688 cm⁻¹, whereas the dimers appeared at 1697-1709cm⁻¹. 20 of 22 compounds (91%) fit this behavior, confirming that IR spectroscopy can serve as a useful diagnostic structural tool when suitable single crystals are unavailable. The effect of chain vs dimer motifs on cocrystallization was then studied using extensive cocrystallization experiments (~500 grindings), and results revealed that dimer-forming targets formed significantly more cocrystals (66%) than chain-forming targets (10%), likely due to weaker interactions, an explanation which was validated through interaction energy calculations. A study on acetylated 2-aminopyrimidine derivatives introduced an additional acceptor site relative to the pyridine system, enhancing the structural complexity. Across 22 crystal structures, variations in alkyl chain length and halogen-atom substitution did not alter primary hydrogen-bonding motifs. Notably, strong hydrogen bonds can be replaced by halogen bonds without disrupting the overall crystal assembly, and halogen bonds exhibit greater directionality, highlighting their potential as reliable alternatives in crystal engineering. Stoichiometric control in cocrystals was examined using mechanochemical and solution methods. Varying coformer ratios during grinding enabled the selective cocrystal formation with distinct stoichiometries. However, solution crystallizations were strongly influenced by solubility, solvation, nucleation, and coformer strength. These findings emphasize the interplay between thermodynamic stability and kinetic accessibility in determining crystallization outcomes. A structure-property study of 2-aminopyrazine derivatives examined the odd-even effect on bulk properties. The results demonstrate that the odd-even effect clearly influences thermal stability but does not affect hygroscopicity; subtle variations in molecular structure can significantly affect macroscopic thermal and hygroscopic properties. A structure-property analysis of an iodo analogue of the antiviral drug favipiravir, showed an increased crystal form diversity and produced cocrystals with generally higher thermal stability than those of favipiravir. Finally, nine cocrystals of N-(5-nitropyridin-2-yl) amide derivatives with two different coformers were synthesized and characterized. Coformer changes exhibited notable color differences during grindings, supported by UV-visible spectroscopy and photoluminescence studies. The photophysical properties can be rationalized and predicted using calculated HOMO-LUMO gaps, demonstrating a strategy for controlled bottom-up design of functional cocrystals.