Syntheses and crystal structures of hydrated and anhydrous 1:2 cocrystals of oxyresveratrol and zwitterionic proline

The hydrated and anhydrous 1:2 cocrystals of oxyresveratrol and proline, which were prepared by crystallizations at different temperatures, show similar packing motifs.


Figure 3
Hydrogen-bond interactions between the PRO molecules viewed down [100] in (a) (I) and (b) (II).

Hirshfeld surface analysis
Hirshfeld surface analysis and two dimensional fingerprint plots are used to provide the additional insight of the weak intermolecular contacts and intermolecular interactions in the crystal packing of molecules (McKinnon et al., 2004;2007;Spackman & Jayatilaka, 2009). The blue, white and red areas in the d norm -mapped Hirshfeld surfaces indicate interatomic contacts longer, equal to and shorter than the sum of the van der Waals radii, respectively. Analysis of (I) and (II) was performed by using Crystal Explorer 17.5 (Turner et al., 2017). The Hirshfeld surfaces are plotted for individual components, to examine the interactions of the main molecules (PRO and OXY) in the cocrystals. The Hirshfeld surfaces around the PRO molecules mapped over d norm are shown in Fig. 4  In addition, the two-dimensional fingerprint plots of the PRO molecules for (I) and (II) are illustrated in Figs. 5 and 6, showing the relative contributions of the various types of contacts to the Hirshfeld surface. The overall fingerprint plot for PRO 1 is shown in Fig. 5a and 6a and those delineated into the contacts of HÁ Á ÁH, OÁ Á ÁH/HÁ Á ÁO and CÁ Á ÁH/HÁ Á ÁC interactions are displayed in Fig. 5b-d and 6b-d. Similarly, the overall fingerprint plot of PRO 2 of both cocrystals is presented in Fig. 5e and 6e and those delineated into individual contacts are shown in Fig. 5f     hydrogen bonds associated with the deep-red spots shown in Fig. 4. The asymmetric pair of wings for HÁ Á ÁC/CÁ Á ÁH interactions in both cocrystals are also found, while other types of contact make a negligible contribution. The relative percentage contributions for the PRO 1 and PRO 2 molecules in both cocrystals are summarized in Table 3.
The OXY Hirshfeld surface, including fingerprint plots for each cocrystal, is depicted in Fig. 7. The bright-red spots on the surfaces relate to the significant hydrogen bonds of the phenolic hydroxyl groups as O donors (O-HÁ Á ÁO) and acceptors (N-HÁ Á ÁO). In (I), the hydrogen-bond contacts are observed from the O atom of the water molecule linking with the OXY surface through one of the hydroxyl groups. In addition, it is found that this water molecule is connected with PRO molecule via a hydrogen-bonding interaction, as indicated in part of the PRO surfaces. The fingerprint plots for OXY are illustrated below the Hirshfeld surfaces in  Table 3. Overall, there are few differences between the Hirshfeld surfaces, fingerprint patterns and the relative percentage contributions for (I) and (II).

Database survey
Based on the SciFinder (2020)     The connecting C C bond of OXY has a trans configuration and allows the setup of a conjugated system throughout the OXY molecule. Furthermore, in the crystal, the OXY molecules are connected through O-HÁ Á ÁO hydrogen bonds between the hydroxy groups of OXY and water molecules. The anhydrous and monohydrate crystals of PRO have been reported in numerous papers (Seijas et al., 2010;Janczak & Luger, 1997;Verbist et al., 1972;Caetano et al., 2018;Koenig et al., 2018) and PRO invariably crystallizes in the zwitterionic form.
A search for cocrystal structures of PRO gave 148 hits. PRO has been used as a cocrystal former of various active pharmaceutical ingredients (Tilborg et al., 2013;Tumanova et al., 2018;Song et al., 2019). The most relevant cocrystal structure to this work is the cocrystal of RES and PRO (He et al., 2017;refcode PEBZEE). RES and PRO form O-HÁ Á ÁO hydrogen bonds in the cocrystal.

Synthesis and crystallization
OXY and PRO were purchased from Chengdu Biopurify Phytochemicals Ltd. (Sichuan, China) and Sigma Aldrich (St. Louis, MO, USA), respectively. All organic solvents used were of analytical grade and were purchased from RCI Labscan Ltd (Bangkok, Thailand). All chemicals and solvents were used as received without further purification. Solid OXY (122.10 mg, 0.50 mmol) and PRO (115.10 mg, 1.00 mmol) were added to a 20 ml transparent glass vial. To this was added a mixture of methanol and acetonitrile (1:1 v/v, 12 ml), followed by sonication until all solids were entirely dissolved. The mixture was divided into two portions, and each was covered with aluminum foil with a few small holes in it. Crystals of (I) in the form of colourless rods were obtained when the solution was placed on a hot plate at 323 K for 16 h. Single crystals of (II) (colourless blocks) were grown from a solution that was left at room temperature (303 K) for 16 h.

Refinement
Crystal data, data collection and structure refinement details for (I) and (II) are summarized in Table 4. The H atoms of PRO molecules of both cocrystals were included with calculated positions and isotropically refined with U iso (H) = 1.2U eq (N). However, two H atoms on phenolic hydroxyl groups for OXY [for (I) and (II)] and water [for (I)] were located in difference maps and isotropically refined with the distance restraint O-H = 0.82 (2)-0.89 (2) Å for OXY and O-H = 0.89 (2)-1.03 (2) Å for water. The other two H atoms of the OXY molecules were calculated and isotropically refined and the constraint with U iso (H) = 1.5U eq (O) was applied.  For both structures, data collection: APEX2 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2020); software used to prepare material for publication: WinGX (Farrugia, 2012) and publCIF (Westrip, 2010). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

4-[(E)-2-(3,5-Dihydroxyphenyl)ethenyl]benzene-1,3-diol bis[(S)-pyrrolidin-1-ium-2-carboxylate] (II)
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )