Polymorphism in N -(5-methylisoxazol-3-yl)malonamide: understanding the supramolecular structure and the crystallization mechanism

The supramolecular architectures of amide-containing compounds are highly dependent on the side-chain substituents, although the potential impact of isoxazole substituents on polymorph formation has not been thoroughly explored. Hence, three distinct forms of N 1 , N 3 -bis(5-methylisoxazol-3-yl)malonamide (1) were obtained and characterized: two polymorphic forms and one solvate. An in-depth analysis of the interactions and energy content of the crystals based on supramolecular clusters allowed us to propose crystallization mechanisms (crystal retrosynthesis). Specifically, the energy similarities between the interaction of the first sites NH amide ⋯OC amide (form 1I) and the symmetric sites NH amide ⋯N isox (form 1II) were found to contribute to their formation. Nonetheless, the presence of DMSO resulted in the formation of form 1III, where the solvent molecule disrupted amide-amide interactions. The first nuclei are more stable than forms 1I and 1II. The compound of N 1 , N 2 -bis(5-methylisoxazol-3-yl)oxalamide (2) was used as a comparison, and through the absence of polymorphs, revealed that the central carbon in molecule 1 allows a flexible adaptation that leads to the three forms. These findings suggest that variations in solvents, flexibility, and the presence/absence of amide–amide interactions can modulate the competition between amide-containing isoxazole compounds.