Competitive and Cooperative Mechanisms in the Self-Assembly Evolution of Indole Carboxylic Acid–Bipyridine Cocrystals

Molecular self-assembly mechanisms between cocrystal components and the evolution pathways of self-assembly are crucial for the precise design of cocrystal products. To gain a deeper insight into the molecular-level formation of cocrystals, investigations of all potential synthons were conducted using indole-2-carboxylic acid, indole-3-carboxylic acid, 2,2′-bipyridine, and 4,4′-bipyridine as model compounds. Quantum chemical calculations demonstrated the competition and cooperation mechanisms during the formation of cocrystals. While energetic and topological competition exists among synthons, the synthon capable of cooperating with other synthons, favoring the cocrystal system to achieve optimal energy state and topological structure, would be preserved within the crystals. Using Process Analysis Tools and NMR spectroscopy, the self-assembly pathway of the synthons in the solution was further elucidated. It was found to include the steps of the formation of dominant synthons caused by competition, cooperative transformation with secondary synthons, and nucleation and growth of cocrystals.