Crystallization mechanism of organic compounds: the supramolecular cluster – a demarcation tool

Abstract

The formation of a crystal structure from molecules that self-assemble in solution until the final crystal formation constitutes the construction of a supramolecular structure. In this process, molecules interact to form a complex system. These self-organized systems, characterized as open, can organize spontaneously when exposed to a given gradient. Because this gradient is information-neutral, the organization emerges from within the system, resulting in “emergent” properties that are unpredictable and irreducible. This highlight review provides a concise guide to understanding the fundamentals of a holistic approach, where the emergent properties of the crystal system are considered in the study. It emphasizes that interactions between molecules result from the interaction of their surfaces with complementary electrostatic potentials; regions of high negative electrostatic potential on one molecule interact with regions of high positive electrostatic potential on another. According to the non-classical theory of nucleation, these complementary interactions between molecules lead to the formation of the “first building blocks” while still in solution. As the process progresses, interactions among the more robust and cooperative building blocks self-organize to form the three-dimensional supramolecular structure. Understanding the complexity inherent in the formation of supramolecular structures poses a major challenge, beginning with the difficulty of delimiting a portion of the supramolecular system that represents all the interactions existing in the crystal. This study considers a demarcation based on the “supramolecular cluster” formed by a central molecule (M1) and its neighbors (MN) in the first coordination sphere. Thus, the supramolecular cluster is conceptualized as the smallest portion of the crystal that contains all the intermolecular interactions present in the system. Through the concept of retrocrystallization, it is possible to identify the main building blocks of the crystal. Utilizing the energetic and topological data of the intermolecular interactions, we developed proposals for crystallization mechanisms. Some steps in these mechanisms are confirmed by ¹H NMR and mass spectrometry, which identify initial nucleation blocks still in solution. In this highlight review, we present proposed crystallization mechanisms for more than 200 organic compounds with diverse molecular structures, identifying at least nine main crystallization mechanisms.