Complexos de inclusão de ciclodextrina na engenharia de cristais: avaliação dos mecanismos de cristalização

Abstract

Cyclodextrins (CDs) are considered one of the most important potential host molecules, capable of forming host–guest complexes through intermolecular interactions. This supramolecular structure, known as an inclusion complex, is relevant because it might enhance properties of guest molecules, including water solubility and photostability, as well as enable the encapsulation of volatile compounds. Understanding the crystalline solid state of these structures contributes to crystal engineering, enabling the development of reliable synthetic routes for obtaining functional molecular solids. Regarding these molecular complexes, host–guest interactions and crystallization pathways are still not fully understood. In this context, the present study aims to investigate the crystallization mechanisms of cyclodextrin inclusion complexes and to evaluate how guest molecules influence nucleation and crystal growth using a supramolecular cluster and retrocrystallization approach, allowing the reconstruction of sequential stages of the crystallization process and comparison of formation pathways. To achieve these objectives, supramolecular clusters were identified for a series of nine inclusion complexes, including a novel structure composed of hydrated β-CD/2-thenoyltrifluoroacetone (TTA-H). Contact area data (using the Voronoi–Dirichlet polyhedron) and stabilization energies (calculated via DFT at the ωB97x-D/cc-pVDZ level) between the dimers forming each supramolecular cluster were also analyzed. QTAIM analysis and molecular electrostatic potential (MEP) analysis were employed to characterize intermolecular interactions and identify nucleation pathways. Based on these data, crystallization mechanisms were proposed using a nonclassical nucleation approach, considering the first coordination sphere in defining supramolecular clusters, thereby allowing the elucidation of crystal formation steps from the already determined structure. The results indicate that non-classical hydrogen bonds of the CH•••X type (X=S, O, π carbons) and cumulative CH•••HC interactions contribute significantly to the stabilization of the inclusion complexes. The supramolecular cluster data reveal distinct crystallization mechanisms governed by the balance between stabilization energy arising from intermolecular interactions and topology (contact area). Depending on the guest molecule, three behaviors were observed for β-CD complexes: preservation of the native β-CD crystallization pathway, subtle modulation of early nuclei, or guest-driven nucleation. In contrast, methyl-β-CD inclusion complexes do not present clearly defined early nuclei, suggesting crystallization through competing pathways. Overall, these results provide insight into how host–guest interactions influence crystallization modes in cyclodextrin systems and advance the understanding of their solid-state behavior.