4-[(Benzylamino)carbonyl]-1-methylpyridinium halogenide salts: X-ray diffraction study and Hirshfeld surface analysis

The ability of 4-[(benzylamino)carbonyl]-1-methylpyridinium to form salts with halogenide anions was studied and Hirshfeld surface analysis to identify intermolecular interactions was performed.

Two salts of 4-[(benzylamino)carbonyl]-1-methylpyridinium (Am) with chloride (C 14 H 15 N 2 O + ÁCl À ) and bromide (C 14 H 15 N 2 O + ÁBr À ) anions were studied and compared with the iodide salt. AmCl crystallizes in the centrosymmetric space group P2 1 /n while AmBr and AmI form crystals in the Sohncke space group P2 1 2 1 2 1 . Crystals of AmBr are isostructural to those of AmI. The cation and anion are bound by an N-HÁ Á ÁHal hydrogen bond. Hirshfeld surface analysis was used to compare different types of intermolecular interactions in the three structures under study.

Chemical context
Organic salts are of great importance for the pharmaceutical industry (Stahl & Wermuth, 2002). Many drugs are produced in the form of salts because of their higher solubility as compared to neutral compounds. The pharmacokinetic properties may be modified by the choice of counter-ion (Guerrieri et al., 2010;He et al., 2018). Therefore, the study of the ability of an active pharmaceutical ingredient to form salts with different ions is an actual problem.
In the present work we studied salts of the 4-[(benzylamino)carbonyl]-1-methylpyridinium cation with chloride and bromide anions and compared their molecular and crystal structures with that of the iodide salt. ISSN 2056-9890

Structural commentary
Usually organic salts are obtained following hydrogen transfer within an acid-base pair. The equilibrium between the neutral acid-base pair and their cation-anion pair depends on external conditions such as temperature, concentration, nature of solvent, etc (Stahl & Nakano, 2002). As a result, organic cations formed upon protonation are not stable and can be deprotonated. The quaternization of the pyridine nitrogen atom also results in cation formation (Wei et al., 2018). However, such a cation is much more stable than its protonated analogue and can form salts with different anions.
The AmCl salt crystallizes in the centrosymmetric P2 1 /n space group while the AmBr salt crystallizes in the Sohncke space group P2 1 2 1 2 1 , similar to the AmI salt (Drebushchak et al., 2017). The cation does not contain an asymmetric atom.

Supramolecular features
Analysis of the intermolecular interactions revealed that an N-HÁ Á ÁHal intermolecular hydrogen bond is present in both of the salts under study (Tables 1 and 2 Crystal structure of 4-[(benzylamino)carbonyl]-1-methylpyridinium chloride. X-HÁ Á ÁCl hydrogen bonds are shown as dashed cyan lines.

Figure 3
Crystal structure of 4-[(benzylamino)carbonyl]-1-methylpyridinium bromide. X-HÁ Á ÁBr hydrogen bonds are shown as dashed cyan lines. is strongest in the AmCl salt as a result of the higher negativity of chloride anions as compared to bromide and iodide counter-ions. In addition, a set of C-HÁ Á ÁCl' intermolecular hydrogen bonds is found in AmCl (Fig. 2) while only two C-HÁ Á ÁHal' hydrogen bonds are present in the crystal structure of AmBr (Figs. 3 and 4; Tables 1 and 2). Generally, the presence of pyridine and benzene rings in a molecule can lead to the formation ofstacking interactions in the crystalline phase. However, no such stacking interactions were found in the AmCl and AmBr crystals.

Hirshfeld surface analysis
The formation of intermolecular interactions in the two salts under study and the AmI salt can be compared using Hirshfeld surface analysis and two-dimensional fingerprint plots [Turner et al., 2017]. The Hirshfeld surfaces were obtained for the cations using a standard high surface resolution, mapped over d norm . The red spots on the d norm surfaces correspond to contacts that are shorter than the van der Waals radii sum of the closest atoms (Fig. 4). Such red spots are observed on all the hydrogen atoms participating in the above-mentioned intermolecular hydrogen bonds (Tables 1 and 2). It should be noted that the brightness of the spot on the hydrogen atom decreases with an increase in the radius of the halogen atom, indicating a weakening of the hydrogen bond.
The hydrogen bonds and short contacts of the cations found in the structures of AmCl, AmBr and AmI are shown in the two-dimensional fingerprint plots presented in Fig. 5a    Two-dimensional fingerprint plots for the cation in the three salts under study: (a) AmCl, (b) AmBr and (c) AmI.

Table 2
Hydrogen-bond geometry (Å , ) for AmBr. Symmetry codes: (i) x À 1 2 ; Ày þ 1 cations in structures AmBr and AmI are very similar ( Fig. 5b and 5c). The main contribution to the total Hirshfeld surface (49.4% in AmCl, 50.8% in AmBr, 51.0% in AmI) is provided by HÁ Á ÁH short contacts (Fig. 6). The contribution of CÁ Á ÁH/ HÁ Á ÁC contacts is much smaller but also significant (23.9% in AmCl, 19.9% in AmBr, 20.2% in AmI). The similar contributions of HalÁ Á ÁH/HÁ Á ÁHal contacts (10.2% in AmCl, 10.5% in AmBr, 9.9% in AmI) and OÁ Á ÁH/HÁ Á ÁO contacts (9.4% in AmCl, 7.6% in AmBr, 7.9% in AmI) are slightly surprising because of the absence of X-HÁ Á ÁO intermolecular interactions in the structures under study. The presence of two aromatic rings in the cation could result in the formation of stacking interactions in the crystal, but the contribution of the CÁ Á ÁC contacts is the smallest (2.9% in AmCl, 6.7% in AmBr, 6.4% in AmI). The small contribution of the CÁ Á ÁC contacts agrees with the results of the traditional analysis of intermolecular interactions in a crystal using the shortest distances between atoms belonging to neighbouring molecules (see Supramolecular features section). It should be noted that the contribution of the CÁ Á ÁC contacts is more than twice as high in the crystals of AmBr and AmI compared to AmCl. This can be explained by a mutual orientation of the pyridine and benzene rings belonging to neighbouring molecules in the AmBr and AmI crystals. However, there are no effectiveinteraction between these rings because the distances and angles between the planar systems are too large.

Database survey
A search of the Cambridge Structural Database (Version 5.42, update of November 2020; Groom et al., 2016) revealed the structure of the AmI salt (refcode BEBFIA; Drebushchak et al., 2017). A comparison with the AmBr and AmI crystal structures showed that they are isostructural.

Synthesis and crystallization
The synthesis of salts of 4-[(benzylamino)carbonyl]-1methylpyridinium halide was carried out according to the reaction scheme below. Synthesis and crystallization of AmCl. 520 mL of acetonitrile was cooled to 273-277 K in a glass flask. Chloromethane (87.8 g, 1.739 mol) was dissolved at this temperature. Benzylamide isonicotinic acid (245.78 g, 1.16 mol) and 600 mL of cooled acetonitrile and acetonitrile solution saturated with chloromethane were loaded into an autoclave. The autoclave was closed and heated to 373 K. The mixture was incubated for 3 h at this temperature. After that, the mixture was allowed to cool to room temperature. The reaction mixture was transferred into a glass flask and cooled to 273-275 K. The reaction mixture was filtered and the precipitate was rinsed on the filter with 200 mL of cooled acetonitrile. The product was dried at 313 K for 12 h. Yield 226 g of crude 4-[(benzylamino)carbonyl]-1-methylpyridinium chloride (75%); white crystals. 226 g of crude 4-[(benzylamino)carbonyl]-1-methylpyridinium chloride were dissolved in 265 mL of 90% ethanol and 660 mL of 2-propanol, and 4.25 g activated charcoal were added. The reaction mixture was heated to boiling point, stirred at boiling for 30 min and filtered. The obtained solution was let to spontaneously cool to a temperature of 303 K, then to a temperature of 278-283 K in a cooling water bath, and stirred for 2 h at this temperature. The reaction mixture was filtrated and the precipitate rinsed on the filter with 110 mL of cold 2-propanol. The product was dried at 313 K for 12 h. Yield 180.8 g of 4-[(benzylamino)carbonyl]-1-methylpyridinium chloride (80%); white crystals; m.p. 474-477 K.
Synthesis and crystallization of AmBr. 4-[(Benzylamino)carbonyl]-1-methylpyridinium iodide (57.7 g, 0.163 mol), silver bromide (33.77 g, 0.180 mol) and 700 mL of water were loaded into a glass flask. The mixture was stirred for 72 h. The sediment was filtered off. The solvent was evaporated under reduced pressure. 300 mL of acetonitrile were added to the precipitate and the mixture was refluxed for 2 h. The reaction mixture was allowed to spontaneously cool to a temperature of 303 K. The reaction mixture was filtered and the precipitate was rinsed on the filter with 50 mL of cold acetonitrile. The product was dried at 313 K for 12 h. Yield 14 g of 4-[(benzylamino)carbonyl]-1methylpyridinium bromide (28%); white crystals; m.p. 465-468 K.
The crystals of AmCl and AmBr were grown as very small colourless and yellow parallelepipeds, respectively, in contrast to the well-grown yellow block-shaped crystals of AmI.  C NMR spectra of samples were taken in DMSO-d 6 on a 150 MHz Varian spectrometer.
The characteristic vibration frequencies of the main functional groups according to the data of FTIR spectroscopy are shown in Table 3. The full spectroscopic data are presented below and in Figs. 7 and 8. As can be seen from Table 3, the main difference in IR spectra concerns the valence vibrations of the N-H group and vibrations of C-H bonds in the pyridine ring.

Figure 7
IR spectrum of the AmCl salt.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. All of the hydrogen atoms were located in difference-Fourier maps. They were included in calculated positions and treated as riding with C-H = 0.96 Å , U iso (H) = 1.5U eq for methyl groups and with C ar -H = 0.93 Å , Csp 2 -H = 0.97 Å , U iso (H) = 1.2U eq for all other hydrogen atoms.  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.