The molecular and crystal structures of 2-(3-hydroxypropyl)benzimidazole and its nitrate salt

The molecular and crystal structures of 2-(3-hydroxypropyl)-1H-benzimidazole and of its nitrate salt have been studied. Hirshfeld surfaces and fingerprint plots were generated to investigate the intermolecular interactions.

2-(3-Hydroxypropyl)-1H-benzimidazole, C 10 H 12 N 2 O, which has potential biological activity, can be used as a ligand for complexation with metals. This compound is an electron donor, due to the lone pair of the nitrogen atom in the imidazole ring. This nitrogen atom also acts as a proton acceptor. In the crystalline phase, the nitrate salt, namely, 2-(3-hydroxypropyl)-1H-benzimidazol-3-ium nitrate, C 10 H 13 N 2 O + ÁNO 3 À , has been studied. The protonation of the 2-(3-hydroxypropyl)benzimidazole unit results in significant delocalization of the electron density within the imidazole ring. The salt formation leads to variations in the intermolecular interactions, which were studied by analysis of the Hirshfeld surfaces and two-dimensional fingerprint plots.
Nitrogen-containing heterocycles can be lone-pair donors, forming complex compounds with a metal; in some, the nitrogen heterocycle binds to the metal atom (Mottillo et al., 2015). The lone pair of the cyclic nitrogen atom can be protonated, forming an organic cation (Yan et al., 2009;Yu et al., 2007, Bayar et al., 2018Chen et al., 2010). It has been shown (Pilipenko & Tananaiko, 1983) that compounds containing a protonated cation are formed as a result of the combination with counter-ions. Such compounds, also called ionic associates, are intermediate compounds between simple salts and complex (coordination) compounds. They have properties similar to those of mixed-ligand complexes, although the properties of the compound as a whole depends on many factors.
In the present paper we report the molecular and crystal structures of 2-(3-hydroxypropyl)benzimidazole (BIZ) and its ISSN 2056-9890 nitrate salt (BIZHNO3), which were determined to study the influence of protonation.

Structural commentary
Analysis of the molecular structures of the title compounds revealed that the C7-N1 and C7-N2 bonds have different lengths [N1-C7 = 1.322 (4) Å and N2-C7 = 1.352 (4) Å ] in the neutral BIZ molecule ( Fig. 1) but are equal within standard uncertainties [N1-C7 = 1.329 (2) Å and N2-C7 = 1.331 (2) Å ] in its protonated form in BIZHNO3 (Fig. 2). Such a delocalization of the electron density during protonation allows the structure of protonated BIZ molecule to be described as a superposition of two resonance structures, as shown in the scheme below.
The neutral and protonated BIZ molecules differ in the conformation of the hydroxyalkyl substituent (Figs. 1 and 2).

Figure 3
Crystal packing of the neutral molecules in the BIZ structure. Projection in the [100] direction.
forming centrosymmetric dimers (Fig. 4). Stacking interactions of the head-to-tail type between the imidazole rings of BIZH + molecules are observed in the [010] direction, the distance between -systems being 3.502 (2) Å .

Hirshfeld surface analysis
Hirshfeld surface analysis (Turner et al., 2017) is one of the modern methods allowing intermolecular interactions to be studied in a more analytical way. This method appears to be effective for comparing the capability of the neutral BIZ molecule and its protonated form to participate in intermolecular interactions of different types. The Hirshfeld surfaces were calculated for the BIZ and BIZH + molecules using a standard high surface resolution, mapped over d norm (Fig. 6). Bright-red spots are observed for all the donors and acceptors of strong hydrogen bonds in the two structures under study, indicating their participation in intermolecular interactions. It should be noted that the bright-red spot on the N1 atom in the BIZ molecule indicates its capability to be protonated or participate in complexation with a metal.
The two-dimensional fingerprint plots constructed for the BIZ and BIZH + molecules show that the hydrogen bonds are stronger in the structure of the nitrate salt (see the sharp spikes in Fig. 6). To compare intermolecular interactions of different types in the structures under study, we have analysed their contributions to the total Hirshfeld surfaces (Fig. 7). As can be seen from the histogram, the protonation of the BIZ molecule and presence of the nitrate anion results in a significant increase of the contribution of OÁ Á ÁH/HÁ Á ÁO interactions associated with X-HÁ Á ÁO hydrogen bonds. In addition, the contributions of NÁ Á ÁC/CÁ Á ÁN and CÁ Á ÁC interactions indicate that stacking between imidazole rings also increases in the BIZHNO3 structure (Fig. 7). A significant decrease in the contribution of NÁ Á ÁH/HÁ Á ÁN interactions (X-HÁ Á ÁN bonding) in the BIZHNO3 structure can be explained by the protonation of the N1 atom, which participates as proton acceptor of hydrogen bonds in the BIZ structure. The different contributions of CÁ Á ÁH/HÁ Á ÁC interactions associated with X-HÁ Á ÁC () hydrogen bonds coin- Hirshfeld surfaces mapped over d norm (top) and two-dimensional fingerprint plots (bottom) of the neutral 2-(3-hydroxypropyl)benzimidazole molecule and its protonated cation in the structures of BIZ and BIZHNO3.

Figure 7
Relative contributions of the strongest intermolecular interactions (in %) to the total Hirshfeld surface of the neutral molecule and its cation in the structures of BIZ and BIZHNO3.

Figure 4
Hydrogen-bonded centrosymmetric dimer of the cations in the nitrate salt. Hydrogen bonds are shown by the cyan lines.

Figure 5
Crystal packing of the 2-(3-hydroxypropyl)benzimidazole nitrate salt in the BIZHNO3 structure. Projection in the [010] direction. Hydrogen bonds are shown by cyan lines.
cide with the presence of a C-HÁ Á ÁC() hydrogen bond in the BIZ structure (Table 1) and the absence of similar interactions in the BIZHNO3 structure ( Table 2). The nitrate anions act as bridging moieties in the BIZHNO3 structure, which results in an increase in the distances between BIZH + molecules. This fact can explain the decrease in the contribution of HÁ Á ÁH interactions in the BIZHNO3 structure (Fig. 7).  (Elmali et al., 2005) and RIYNUL (Zhao et al., 2019)]. Two of these structures (FIYXAN and FIYXER) contain protonated BIZ molecules, which form salts with PtCl 4 2À or PtCl 6 2À anions. In the RIYNUL structure, the BIZ molecule forms a coordination bond with the Cd atom.

Database survey
In addition, three structures with a close analogue of the BIZ molecule containing a carboxylic group instead of a hydroxyl group were found in the CSD [refcodes JOQROZ (Fu et al., 2016), NOVCEI (Liu et al., 2015) and TILGOL (Zeng et al., 2007)]. In all of these structures, the organic ligand forms an N-M + coordination bond with participation of the N2 atom of the imidazole ring.

Synthesis and crystallization
All chemicals were obtained from commercial sources and used directly without further purification. 1,2-Phenylenediamine (2.16 g, 0.02 mol) was dissolved in hydrochloric acid (25 mL, 4 M) at 373 K, and -hydroxybutyric acid (2.82 g, 0.02 mol) was added to the solution. The mixture was heated with reflux for 6 h at 398 K. After cooling to room temperature, the mixture was neutralized using NaOH (pH 7-9). The product was dissolved in aqueous ethanol and treated with activated carbon for purification. The 2-hydroxypropylbenzimidazole precipitate was filtered off and dried in air. Pale-beige single crystals of the title compound suitable for X-ray diffraction analysis were recrystallized from ethanol solution by slow evaporation, yield 80%, m.p. 437 K.
Synthesis of the [BIZH + ]NO 3 À salt: A weighed portion of copper nitrate (3 Â 10 À3 mol) was dissolved in a minimum amount of water and mixed with an alcoholic saturated solution of the ligand (6 Â 10 À3 mol) while heating in a water bath. The solution turned green. The solution was then acidified with nitric acid to pH 5 to prevent  the precipitation of hydroxides. The reaction was carried out for 40 minutes while heating in a water bath, after which the reaction mixture was allowed to crystallize. After three days, the precipitated light-yellow crystals were separated, washed with ethanol, and dried in air. The product yield was 62%, m.p. 371-373 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. All hydrogen atoms were located in difference-Fourier maps. All of the hydrogen atoms in the BIZ structure and H atoms participating in strong hydrogen bonds in the BIZHNO3 structure were refined using an isotropic approximation. Other hydrogen atoms in the BIZHNO3 structure were refined as riding with Csp 2 -H = 0.97 Å , U iso (H) = 1.2U eq (C) for the methylene fragments or Car-H = 0.93 Å , U iso (H) = 1.2U eq (C) for the aromatic rings. SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2016/6 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

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.

2-(3-Hydroxypropyl)-1H-benzimidazol-3-ium nitrate (BIZHNO3)
Crystal data  (11) 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.