Persistence of N-H•••O=C Interactions in the Crystallization Mechanisms of Trisubstituted Bis-Ureas with Bulky Substituents

Bis-ureas are generally associated with strongly bifurcated hydrogen bonds (N-H center dot center dot center dot O.C interactions). For this reason, a series of trisubstituted bis-ureas (TBU) with bulk substituents were designed and used as a study model to gain a better understanding of the persistence of N-H center dot center dot center dot O.C interactions as driving interactions of the crystallization process. The TBU molecules possess different substituents (isopropyl, benzyl, and 4-nitro-benzyl) and variations in the methylene spacer. The TBU self-assembly, through crystallization mechanism proposals, is discussed related to the role of intermolecular interactions that drive and participate in the crystallization process. The intermolecular interactions present in the proposed first nuclei of crystallization were studied by concentration-dependent H-1 NMR experiments and QTAIM analysis. Our findings showed that even with bulky substituents, the N-H center dot center dot center dot O.C interactions in most compounds played an important role in stabilizing the first nuclei formed during the crystallization process. However, in one case the molecular topology prevented the formation of N-H center dot center dot center dot O.C as the driving interaction in the first crystallization nuclei. In this case, the crystallization was mainly governed by a set of weaker interactions, showing that a subtle molecular change in the methylene spacer favored H center dot center dot center dot H interactions over directional N-H center dot center dot center dot O interactions. For some of the compounds studied, we propose both when the symmetry-independent molecules observed in the crystal lattice could be formed and when the water molecules are probably trapped during the crystallization to form the hydrate crystalline phases. This study contributes to the better understanding of issues related to modulating N-H center dot center dot center dot O.C hydrogen bonds using bulky substituents in the self-assembly of flexible TBU molecules.

Automated summary

The study investigated the persistence of N-H···O.C interactions as driving interactions in the crystallization process using trisubstituted bis-ureas. The findings demonstrated the importance of N-H···O.C interactions in stabilizing the first crystallization nuclei, even with bulky substituents.