3.5.2. Bilastine Chloroform Solvates

As it has been mentioned, the solvated phase S3CHCl3-H2O has resulted to be unstable, the crystals losing solvent rapidly after removal from the mother liquor and generally rendering manipulation of the material and accurate analysis of its composition impossible. The first visible signs of desolvation, such as opacification of the crystals, were observed only after seconds at r.t. However, its crystal structure has been successfully determined at 100K resulting in an orthorhombic *Pna*21 cell with Z = 4. In S3CHCl3-H2O BL molecules are linked by hydrogen bonds involving the carboxylate oxygen of one BL molecule and the piperidinium nitrogen of another BL in an alternated mode similar to form I, forming corrugated layer structures (Figure 17).

**Figure 17.** Carboxylate/piperidinium H-bond interactions between BL molecules observed in the crystal structure of S3CHCl3-H2O. Water molecules represented by red balls. Hydrogens have been omitted for clarity.

Water and chloroform molecules occupy voids inside the crystal structure as it is shown in Figure 18.

**Figure 18.** Packing diagram of form S3CHCl3-H2O viewed parallel to [100]. Water molecules represented by red balls. Hydrogens have been omitted for clarity.

The X-ray structural analysis reveals the presence of one hydrogen-bonded water molecule as well as three hydrogen- and halogen-bonded chloroform molecules and one BL in its asymmetric unit. As shown in Figure 19, the water molecule acts as hydrogen bond donor in a DD environment, its hydrogens showing H-bonding with the nitrogen of the benzimidazol of one BL, on one hand (distance: 2.077 Å), and with an oxygen of the carboxylate of another BL molecule, on the other hand (distance: 2.133 Å). This carboxylate oxygen is also involved in an asymmetric three-center (or bifurcated) hydrogen bond system (distances: 1.887 Å and 2.452 Å) with the piperidinium of the first BL (being the structure zwitterionic), forming altogether R2 <sup>3</sup> (11) and R2 1(4) supramolecular heterosynthons. Moreover, one chloroform molecule interacts via halogen bond with the other oxygen of the carboxylate, being 3.139 Å its Cl2HC-Cl···O=C distance, shorter than the sum of the van der Waals radii of the involved atoms. Moreover, this chloroform molecule is involved in a Cl3C-H···O=C (distance: 2.142 Å) hydrogen bond with the carboxylate and in a Cl2HC-Cl···Cl-CHCl2 (distance: 3.366 Å) halogen bond with a second chloroform molecule which in turn interacts with the third chloroform forming also a Cl2HC-Cl···Cl-CHCl2 (distance: 3.322 Å) halogen bond. The second chloroform is involved also in a Cl3C-H···π (distance Ph-center: 2.354 Å) interaction with the phenyl ring of another BL and the third chloroform in turn interacts also with the water molecule via Cl3C-H···O-H2 (distance: 2.011 Å) hydrogen bond.

As stated, it was not possible to grow single crystals of SCHCl3-H2O as once its precursor solvate was obtained, the crystals were not stable and two chloroform molecules were rapidly lost after removal from the mother liquor, leaving a darkened crystal. Therefore, its powder diffraction pattern was indexed to an orthorhombic cell and the space group perfectly determined to be *Pna*21 from the systematic absences. The crystal structure was solved with the direct-space strategy TALP, and its refinement was performed by the Rietveld method. Figure 20 depicts the final Rietveld plot.

The X-ray structural analysis of the structure of SCHCl3-H2O solved from PXRD reveals the presence of one hydrogen-bonded water molecule, one hydrogen-bonded chloroform molecule and one BL in its asymmetric unit. BL molecules are also linked by hydrogen bonds involving the carboxylate oxygen of one BL molecule and the piperidinium nitrogen of another BL in an asymmetric three-center hydrogen bond system (distances: 1.731 Å and 2.253 Å), with the same R<sup>2</sup> 1(4) heterosynthon, forming corrugated layer structures as in S3CHCl3-H2O. In this case, an interlayer interaction is accomplished by π···π parallel displaced phenyl stacking of the alternated BL (observed lateral offset stack: 4.66 Å,

centroid to centroid distance d(π··· π): 5.19 Å, interplanar distance: 2.29 Å). Moreover, the water molecule acts as hydrogen bond donor in a D environment as only one hydrogen is involved in hydrogen-bonding (distance: 1.942 Å) with the nitrogen of the benzimidazol of one BL. Finally, the chloroform molecule is involved in a Cl3C-H···O=C (distance: 2.337 Å) hydrogen bond with the carboxylate (Figure 21).

Unlike solvate S3CHCl3-H2O, the water molecule cannot form another H-bond with an oxygen of the carboxylate of another BL molecule as the carboxylate is not pointing towards it as it has rotated some degrees being in this case too far. The conformations of the BL molecules in both heterosolvates are compared in Figure 22, differing particularly with respect to the orientation of the carboxylate fragment.

**Figure 19.** Intermolecular interactions (distances in Å) observed in the crystal structure of S3CHCl3-H2O.

**Figure 20.** Final Rietveld plot for the crystal structure refinement of form SCHCl3-H2O. Agreement factor: Rwp = 2.3%. The plot shows the experimental powder XRD profile (red+marks), the calculated powder XRD profile (black solid line) and the difference profile (blue, lower line). Tick marks indicate peak positions.

**Figure 21.** Intermolecular interactions (distances in Å) observed in the crystal structure of SCHCl3-H2O.

**Figure 22.** Overlay of BL molecules of form S3CHCl3-H2O (yellow) and SCHCl3-H2O (green) showing that the water molecule (represented by red balls) is too far (distances in Å) from the carboxylate of SCHCl3-H2O. Hydrogen atoms are omitted for clarity.

The channeled crystal structure of solvate SCHCl3-H2O is shown in Figure 23 where chloroform and water molecules occupy different channels.

**Figure 23.** Crystal packing of form SCHCl3-H2O viewed parallel to [100]. Water molecules represented by red balls. Hydrogens have been omitted for clarity.

Finally, single crystals of SCHCl3 were grown in anhydrous chloroform. This solvate crystallizes in the monoclinic space group *P*21 with two molecules of BL and two molecules of chloroform in the asymmetric unit. Again, BL molecules are linked by hydrogen bonds (distance: 1.583 Å) involving one oxygen of the carboxylate and the piperidinium NH, forming cascade layers as in Form III (Figure 24).

**Figure 24.** Hydrogen bonds between BL molecules observed in form SCHCl3.

There are two different chloroform molecules in this solvate: 1-CHCl3 which is involved in a Cl3C-H···O=C (distance: 2.008 Å) hydrogen bond with the carboxylate of one BL and 2-CHCl3 which forms the same H-bond (distance: 2.013 Å) with the carboxylate of the other BL (Figure 25). This chloroform participates also in a Cl···π interaction with the benzene ring of another BL (Cl-centroid distance: 3.683 Å, C-Cl-centroid angle: 159.51◦). Figure 26 shows the crystal packing of SCHCl3.

The crystal data of all the crystal structures solved for BL are summarized in Table S15 (from SCXRD) and Table S16 (from PXRD) of the Supplementary Material.

The three anhydrous polymorphs of BL crystallize in the same space group *P*21/*c* and Form II shows a unit cell similar to Form III except for the parameter "a" which is approximately twice as much as in Form III. This results in a cell for Form II with double volume than forms I and III and with Z = 8.

On the other hand, both heterosolvates S3CHCl3-H2O and SCHCl3-H2O crystallize in the same orthorhombic space group *Pna*21 showing similar unit cell parameters, while the monosolvate SCHCl3 crystallizes in *P*21, the three solvates with Z = 4.

BL is a molecule which shows an imbalance between hydrogen bond donors and acceptor groups, having only one N-H donor group. All the structures solved are zwitterionic and BL molecules are linked by hydrogen bonds involving the carboxylate oxygen and the piperidinium nitrogen. The incorporation of water and chloroform molecules in the solvates of BL can be attributed to the imbalance in the ratio of donors and acceptors groups. Water molecules act as hydrogen bond donors in both heterosolvates, interacting with the nitrogen of the benzimidazol of BL. Instead, chloroform molecules form hydrogen bonds with the carboxylate in all solvates. Some halogen bonds are also observed in these structures, confirming that halogen bonding is one of the stabilizing interactions in chloroform solvates. However, as it has been stated [30], halogen bonding does not seem to be sufficiently strong to retain the solvent in the crystals on its own as other short contacts are also present. In fact, the two chloroform molecules in S3CHCl3-H2O which are not linked by hydrogen bonds to the carboxylate, are lost when this solvate is removed from the solution. On the other hand, a water molecule captured from the air is incorporated in the crystal structure of SCHCl3 when taking it out from the solution, probably to further stabilize its structure. In fact, SCHCl3 can be considered a hygroscopic solid form as it has the ability

to take up and retain water vapor. This is also true for many other compounds such as 1,10-phenanthroline [27].

**Figure 25.** Intermolecular interactions (distances in Å) observed in solvate SCHCl3.

**Figure 26.** Crystal packing of SCHCl3 along the b axis. Green color for 1-CHCl3 and purple color for 2-CHCl3.
