Molecular Mechanism of Organic Crystal Nucleation: A Perspective of Solution Chemistry and Polymorphism

Crystal nucleation determining the formation and assembly pathway of first organic materials is the central science of various scientific disciplines such as chemical, geochemical, biological, and synthetic materials. However, our current understanding of the molecular mechanisms of nucleation remains limited. Over the past decades, the advancements of new experimental and computational techniques have renewed numerous interests in detailed molecular mechanisms of crystal nucleation, especially structure evolution and solution chemistry. These efforts bifurcate into two categories: (modified) classical nucleation theory (CNT) and non-classical nucleation mechanisms. In this review, we briefly introduce the two nucleation mechanisms and summarize current molecular understandings of crystal nucleation that are specifically applied in polymorphic crystallization systems of small organic molecules. Many important aspects of crystal nucleation including molecular association, solvation, aromatic interactions, and hierarchy in intermolecular interactions were examined and discussed for a series of organic molecular systems. The new understandings relating to molecular self-assembly in nucleating systems have suggested more complex multiple nucleation pathways that are associated with the formation and evolution of molecular aggregates in solution