Why Do Hydrates (Solvates) Form in Small Neu tral Organic Molecules? Exploring the Crystal Form Landscapes of the Alkaloids Brucine and Strychnine

摘要

Computational methods were used to generate and explore the crystal structure landscapes of the 2 alkaloids strychnine and brucine. The computed structures were analyzed and rationalized by correlating the modeling results to a rich pool of available experimental data. Despite their structural similarity, the 2 compounds show marked differences in the formation of solid forms. For strychnine, only 1 anhydrous form is reported in the literature and 2 new solvates from 1,4-dioxane were detected in the course of this work. In contrast, 22 solid forms are known so far to exist for brucine, comprising 2 anhydrates, 4 hydrates (HyA - HyC and a 5.25-hydrate), 12 solvates (alcohols and acetone), and 4 heterosolvates (mixed solvates with water and alcohols). For strychnine, it is hard to produce any solid form other than the stable anhydrate, while the formation of specific solid state forms of brucine is governed by a complex interplay between temperature and relative humidity/water activity and it is rather a challenge to avoid hydrate formation. Differences in crystal packing and the high tendency for brucine to form hydrates are not intuitive from the molecular structure alone, as both molecules have hydrogen bond acceptor groups but lack hydrogen bond donor groups. Only the evaluation of the crystal energy landscapes, in particular, the close-packed crystal structures and high-energy open frameworks containing voids of molecular (water) dimensions, allowed us to unravel the diverse solid state behavior of the 2 alkaloids at a molecular level. In this study we demonstrate that expanding the analysis of anhydrate crystal energy landscapes to higher energy structures and calculating the solvent-accessible volume can be used to estimate non-stoichiometric or channel hydrate (solvate) formation, without explicitly computing the hydrate/solvate crystal energy landscapes.