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

Abstract

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.

A New Model for Proposing Crystallization Mechanisms at the Molecular Level Based on Energetic and Topological Data of Supramolecular Interactions: An Application to Halogenated Anilines

“…This theory is also defined as the crystalline nucleus appearing within pre-existing metastable clusters by self-organization, i.e., the formation of a droplet of a dense liquid followed by the nucleation of a periodic crystal within the droplet . There are also other more recent theories proposed for molecular mechanisms of crystal nucleation from solutions described in the literature as the theory of prenucleation clusters, crystallization by particle bonding and other nucleation pathways proposed in recent years with remarkable results . These studies have paid more attention to the aspect of physical transformation than to the process of self-assembly or self-organization at the molecular level. , However, Davey et al reviewed the nucleation process of organic crystals from a molecular perspective and subsequently gave a detailed summary of the transition states, rate-determining steps, and complexity of crystal nucleation from solutions .…”

Frontiers of molecular crystal structure prediction for pharmaceuticals and functional organic materials

“…There are multiple reasons for this over-prediction of structures, 51 but crystallization kinetics are one major reason that more candidate polymorphs are not found experimentally. While there have been important advances in modeling organic crystal polymorph nucleation and growth in recent years, [52][53][54][55] the statistical mechanical sampling challenges and the need for accurate but computationally inexpensive potentials represent on-going hurdles to reliable prediction of crystallization kinetics. Moreover, CSP routinely focuses on innite crystals, ignoring the surface energy contributions that depend on the size and shape of the nite crystallite.…”

On the Continuous Mechanics First and Second-Order Formulations for Nonequilibrium Nucleation: Derivation and Applications

“…Classical nucleation theory, known as CNT, has its origins in Fahrenheit's work on the supercooling of water, later receiving thermodynamic support in studies of droplet formation on a supersaturated vapor. Volmer and Weber, among others, formulated the kinetics of vapor condensation, later extended by Turnbull and Fisher to the case of nucleation of condensed phases [6]. The basic mechanism underpinning CNT consists of a change in the free energy of the system during homogeneous nucleation of a spherical nucleus.…”