Toward an Understanding of the Propensity for Crystalline Hydrate Formation by Molecular Compounds. Part 2

Abstract

The propensity of molecular organic compounds to form stoichiometric or nonstoichiometric crystalline hydrates remains a challenging aspect of crystal engineering and is of practical relevance to fields such as pharmaceutical science. In this work, we address the propensity for hydrate formation of a library of eight compounds comprised of 5- and 6-membered N-heterocyclic aromatics classified into three subgroups: linear dipyridyls, substituted Schiff bases, and tripodal molecules. Each molecular compound studied possesses strong hydrogen bond acceptors and is devoid of strong hydrogen bond donors. Four methods were used to screen for hydrate propensity using the anhydrate forms of the molecular compounds in our library: water slurry under ambient conditions, exposure to humidity, aqueous solvent drop grinding (SDG), and dynamic water vapor sorption (DVS). In addition, crystallization from mixed solvents was studied. Water slurry, aqueous SDG, and exposure to humidity were found to be the most effective methods for hydrate screening. Our study also involved a structural analysis using the Cambridge Structural Database, electrostatic potential (ESP) maps, full interaction maps (FIMs), and crystal packing motifs. The hydrate propensity of each compound studied was compared to a compound of the same type known to form a hydrate through a previous study of ours. Out of the eight newly studied compounds (herein numbered 4-11), three Schiff bases were observed to form hydrates. Three crystal structures (two hydrates and one anhydrate) were determined. Compound 6 crystallized as an isolated site hydrate in the monoclinic space group P2₁/a, while 7 and 10 crystallized in the monoclinic space group P2₁/c as a channel tetrahydrate and an anhydrate, respectively. Whereas we did not find any direct correlation between the number of H-bond acceptors and either hydrate propensity or the stoichiometry of the resulting hydrates, analysis of FIMs suggested that hydrates tend to form when the corresponding anhydrate structure does not facilitate intermolecular interactions.

Scheme 1. Library of N-Heterocyclic Compounds Investigated Herein for Their Propensity to Form Hydrates

REFCODEs for structures reported in the CSD of anhydrate (Anh) and hydrate (H₂O) forms, and previously unreported structures (New) are listed.

Figure 1

Electrostatic potential maps (kJ mol^–1) for 1–11.

Figure 2

Crystal structures depicting multiple intermolecular interactions (C–H···N shown in green; C–H···π and π–π shown in yellow) in the anhydrates of (a) 2 (PEXXEW), (b) 4 (RUYKIF), (c) 6 (MINWAK), (d) 8 (XAPTEO01), (e) 8 (MINVUD), (f) 9 (MINWEO), (g) 10, (h) 11 (OLEPOK) and (i) 11 (OLEPOK01).

Figure 3

Crystal structures depicting selected intermolecular interactions (O–H···N shown in green; π–π shown in yellow; O–H···O shown in purple; C–H···O shown in blue) in the hydrates of (a) 1·2H₂O (OXUHUM02), (b) 2·H₂O (HIRLUQ), (c) 2·4H₂O (OXUHIA02), (d) 3·3H₂O (OXUJAU02), (e) 5·xH₂O (MINXIT), (f) 6·H₂O, and (g) 7 4H₂O. Hydrogen atoms of water molecules were omitted for the sake of clarity.

Figure 4

Histograms showing the distribution of dihedral angles about two linked aryl rings in entries archived in the CSD. The number of structures exhibiting a torsion angle close to 0° or 180° (marked with asterisks) can also include structures with molecules on special positions for which disorder by symmetry was not taken into account.

Figure 5

Full interaction maps (FIMs) for the molecular conformers present in crystal structures of 2: (a) anhydrate (CSD refcode PEXXEW), (b) monohydrate (CSD refcode HIRLUQ), and (c) tetahydrate (CSD refcode OXUHIA02). The blue and red contours indicate regions most commonly taken by hydrogen-bond-involved water molecule and aromatic C–H moieties, respectively. The opacity of the region is positively corelated to the probability of the interaction existence. A color scale (from green, through orange, to red) was applied for hydrogen bonds to mark their relative length (green being the longest and red being the shortest). For an expanded version of the figure, see Figure S20 in the SI.

Figure 6

Interaction preferences for the molecular conformation of (a) anhydrate (MINWAK) and (b) hydrate forms of 6. For a detailed description of the color coding, see the caption for Figure 5. Possible very long contacts are marked in magenta. For an expanded version of the figure, see Figure S22 in the SI.

Figure 7

FIMs for anhydrate molecules: (a) 4 (RUYKIF), (b) 8 (MINVUD), (c) 8 (XAPTEO), (d) 9 (MINWEO), (e) 10, (f) 11 (OLEPOK), and (g) 11 (OLEPOK01). For the color coding, see the caption for Figure 5. Possible very long contacts are marked in magenta. For the expanded FIM figures showing individual compounds, see Figures S21 and S23–S26 in the SI.

Figure 8

Interaction preferences for the molecular conformation of hydrate molecules: (a) 1 (OXUHUM02), (b) 7, (c) 3 (OXUJAU02), and (d) 5. For the color coding, see the caption for Figure 5. For an expanded version of the figure, see Figure S27 in the SI.