Received 3 December 2012
Hydrogen-bonded sheet structures in methyl 4-(4-chloroanilino)-3-nitrobenzoate and methyl 1-benzyl-2-(4-chlorophenyl)-1H-benzimidazole-5-carboxylate
In methyl 4-(4-chloroanilino)-3-nitrobenzoate, C14H11ClN2O4, (I), there is an intramolecular N-HO hydrogen bond and the intramolecular distances provide evidence for electronic polarization of the o-quinonoid type. The molecules are linked into sheets built from N-HO, C-HO and C-H(arene) hydrogen bonds, together with an aromatic - stacking interaction. The molecules of methyl 1-benzyl-2-(4-chlorophenyl)-1H-benzimidazole-5-carboxylate, C22H17ClN2O2, (II), are also linked into sheets, this time by a combination of C-H(arene) hydrogen bonds and aromatic - stacking interactions.
We report here the molecular structures and the supramolecular assembly of the two title compounds, (I) (Fig. 1) and (II) (Fig. 2). Benzimidazoles are compounds of wide interest because of their diverse biological activities and clinical applications (Ansari & Lal, 2009). They are regarded as a promising class of bioactive heterocyclic compounds, exhibiting a wide range of biological properties such as antifungal, antiparasitic and antiviral activity. They are also active as analgesics, anticoagulants, anticonvulsants, antihistamines and anti-inflammatory agents, and they show anticancer, antihypertensive and anti-ulcer activity, as well as acting as proton-pump inhibitors (Bansal & Silakari, 2012). Consequently, substituted benzimidazoles have attracted interest, especially since it has been reported that the influence of the substitution at the 1-, 2- and 5-positions of the benzimidazole framework is important for their pharmacological effects (Kilcigil & Altanlar, 2006). We have recently reported the design of a four-step synthesis of novel 1,2,5-trisubstituted benzimidazoles bearing the 4-chlorophenyl or quinolin-2-one pharmacophores at position 2, which exhibit high activity against a range of cancer cell lines (Abonía et al., 2011). As part of our current synthetic programme aimed at the development of potential antitumour agents, we have now prepared the benzimidazole derivative, (II), using a two-step synthesis involving the in situ reduction of the nitroaniline precursor, (I), followed by cyclocondensation with 4-chlorobenzaldehyde.
Within the molecule of (I), the plane of the nitro group makes a dihedral angle of only 9.4 (2)° with that of the adjacent aryl ring, and this may be associated with the presence of an intramolecular N-HO hydrogen bond (Fig. 1 and Table 2) which gives rise to an S(6) motif (Bernstein et al., 1995). On the other hand, the two rings within the molecule make a dihedral angle of 49.8 (2)°.
The bond lengths in the molecule of (I) provide evidence for polarization of the electronic structure. Thus, the C12-C13 and C15-C16 bond lengths are significantly shorter than the other C-C bond lengths in the C11-C16 ring (Table 1); the C13-N31 bond is short for its type [mean value (Allen et al., 1987) = 1.468 Å, lower quartile value = 1.460 Å], while the C14-N41 bond is significantly shorter than the N41-C41 bond; and the N31-O31 and N31-O32 bonds are both long for their type (mean value = 1.217 Å, upper quartile value = 1.225 Å). These observations, taken as a whole, indicate that the polarized form, (Ia) (see Scheme), makes a significant contribution to the overall electronic structure, alongside the classically delocalized form, (I). Polarization of this type has been observed previously both in simple 2-nitroanilines containing unsubstituted amino groups (Cannon et al., 2001; Glidewell et al., 2001) and in N-(2-nitrophenyl)aniline (McWilliam et al., 2001).
As noted above, the molecules of (I) contain an intramolecular N-HO hydrogen bond. In addition, the molecules are linked by a combination of intermolecular N-HO, C-HO and C-H(arene) hydrogen bonds (Table 2), augmented by an aromatic - stacking interaction. The resulting rather complex sheet structure can be readily analysed in terms of two one-dimensional substructures (Ferguson et al., 1998a,b; Gregson et al., 2000).
The first substructure is built from a combination of N-HO and C-HO hydrogen bonds, which link molecules related by inversion to form a chain of rings running parallel to the  direction. Pairs of inversion-related N-HO hydrogen bonds generate R22(4) rings centred at (, n, ), where n represents an integer, and pairs of inversion-related C-HO hydrogen bonds generate R22(10) rings centred at (, n + , ), where n again represents an integer (Fig. 3).
The second substructure in (I) is built from the combination of a C-H(arene) hydrogen bond and an aromatic - stacking interaction. Aryl atom C46 in the molecule at (x, y, z) acts as hydrogen-bond donor to the C41-C46 aryl ring in the molecule at (x, -y + , z - ), so linking molecules related by the c-glide plane at y = into a chain running parallel to the  direction (Fig. 4). In addition, the plane of the trisubstituted C11-C16 ring in the molecule at (x, y, z) makes a dihedral angle of only 2.0 (2)° with the planes of the corresponding rings of the two molecules at (x, -y + , z - ) and (x, -y + , z + ). The shortest ring-centroid separation is 3.722 (2) Å and the shortest perpendicular distance between the ring planes is ca 3.34 Å, corresponding to a ring-centroid offset of ca 1.64 Å. The effect of this stacking interaction is to reinforce the chain formation along  generated by the C-H(arene) hydrogen bond (Fig. 4). The combination of the  and  chains generates a complex sheet lying parallel to (100).
The crystal structure of (I) also contains a rather short intermolecular ClO contact of 2.924 (3) Å between atom Cl44 in the molecule at (x, y, z) and atom O31 in the molecule at (x + 1, y + 1, z + 1). This contact distance is certainly shorter than the sum of the van der Waals radii (3.2 Å; Bondi, 1964), but it is unclear whether the contact is attractive, or, as seems more likely, repulsive.
In the molecule of (II) (Fig. 2), the bond lengths within the fused bicyclic system (Table 3) indicate strong bond fixation in the imidazole portion, with typical aromatic delocalization in the carbocyclic ring. The plane of the chlorinated aryl ring makes a dihedral angle of 50.2 (2)° with that of the adjacent imidazole ring, while the benzyl ring plane is almost orthogonal to that of the imidazole ring, with a dihedral angle of 81.7 (2)°.
The supramolecular assembly in (II) depends on the combination of a C-H(arene) hydrogen bond (Table 4) and an aromatic - stacking interaction, both of which involve the fused aryl ring. In the -stacking interaction, the fused rings of the molecules at (x, y, z) and (-x + 1, -y + 1, -z + 1), which are strictly parallel, have an interplanar spacing of 3.481 (2) Å and a ring-centroid separation of 3.568 (2) Å, corresponding to a ring-centroid offset of ca 0.78 Å (Fig. 5). The C-H(arene) hydrogen bond links molecules related by the 21 screw axis along (0, , z) to form a chain running parallel to the  direction (Fig. 6).
The combination of these two interactions generates a sheet structure in which, for example, the reference -stacked dimer centred at (, , ) is directly linked by C-H(arene) hydrogen bonds to the four symmetry-related dimers centred at (, 0, 0), (, 1, 0), (, 0, 1) and (, 1, 1), so forming a sheet lying parallel to (100) (Fig. 7).
The details of the supramolecular assembly in (I) and (II) provide some interesting comparisons. In each compound, the supramolecular assembly leads to the formation of a sheet parallel to (100) in the space group P21/c, and in both compounds it is the ring carrying the ester function which participates in the - stacking interaction. However, the acceptor in the C-H(arene) hydrogen bond is the chlorinated aryl ring in (I) but the fused aryl ring in (II), while the donor in this interaction forms part of the chlorinated aryl ring in (I) as opposed to the benzyl ring in (II). Finally, the ester function participates in the assembly in (I), where the ester carbonyl O atom acts as the acceptor in the C-HO hydrogen bond, while in (II) the ester function plays no part in the supramolecular assembly.
| || Figure 1 |
The molecular structure of (I), showing the atom-labelling scheme and the intramolecular N-HO hydrogen bond (dashed line). Displacement ellipsoids are drawn at the 30% probability level.
| || Figure 2 |
The molecular structure of (II), showing the atom-labelling scheme Displacement ellipsoids are drawn at the 30% probability level.
| || Figure 3 |
A stereoview of part of the crystal structure of (I), showing the formation of a chain of alternating R22(4) and R22(10) rings running parallel to the  direction. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
| || Figure 4 |
A stereoview of part of the crystal structure of (I), showing the formation of a chain running parallel to the  direction and built from C-H(arene) hydrogen bonds augmented by aromatic - stacking interactions. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
| || Figure 5 |
Part of the crystal structure of (II), showing the formation of a -stacked dimer centred at (, , ). For the sake of clarity, all H atoms have been omitted. The atom marked with an asterisk (*) is at the symmetry position (-x + 1, -y + 1, -z + 1).
| || Figure 6 |
A stereoview of part of the crystal structure of (II), showing the formation of a chain running parallel to the  direction and built from C-H(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motif shown have been omitted.
| || Figure 7 |
A stereoview of part of the crystal structure of (II), showing the formation of a sheet lying parallel to (100). For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
For the synthesis of (I), a mixture of methyl 4-fluoro-3-nitrobenzoate (0.199 g, 1 mmol) and 4-chloroaniline (1 mmol) in dimethyl sulfoxide (2 ml) was stirred at ambient temperature for 2 h. After complete disappearance of the starting materials [as monitored by thin-layer chromatography (TLC)], the solid thus formed was collected by filtration and washed with a methanol-water mixture (1:2 v/v; 3 × 2 ml) to afford (I) (yield 84%; orange crystals, m.p. 421 K). FT-IR (KBr, , cm-1): 3312 (NH), 1770 (C=O), 1718 (C=C), 1622 (C=N), 1524, 1324 (NO2). MS (70 eV) m/z (%): 308/306 (100/34) [M+], 277/275 (15/5) [M - OCH3], 243/241 (29/9), 230/228 (38/13), 201 (30), 111 (3).
For the synthesis of (II), a mixture of intermediate (A) (see Scheme) (0.306 g, 1 mmol), which had been prepared in a manner analogous to that for (I) but using benzylamine in place of 4-choloroaniline, acetic acid (2 ml) and zinc powder (5 equivalents) was stirred at ambient temperature for 15 min. After complete disappearance of starting compound (I) (as monitored by TLC), the by-product zinc acetate and excess zinc were removed by filtration. The resulting solution was then heated with 4-chlorobenzaldehyde (1.05 mmol) at 373 K for 1 h. After complete disappearance of the starting materials (as monitored by TLC), the solution was allowed to cool to ambient temperature and the excess of acetic acid was removed under reduced pressure. The solid product was washed with ethanol (2 × 1 ml) to afford (II) (yield 88%; colourless crystals, m.p. 437 K). FT-IR (KBr, , cm-1): 3028, 2951, 1719 (C=O), 1612 (C=C), 1521 (C=N), 1438, 1287 (C-O). MS (70 eV) m/z (%): 378/376 (3/12) [M+], 345 (1) [M - 28], 137 (3), 91 (28).
All H atoms were located in difference maps and subsequently treated as riding in geometrically idealized positions, with C-H = 0.95 (aromatic), 0.98 (CH3) or 0.99 Å (CH2) and N-H = 0.88 Å, and with Uiso(H) = kUeq(carrier), where k = 1.5 for the methyl groups, which were permitted to rotate but not to tilt, and 1.2 for all other H atoms.
For both compounds, data collection: COLLECT (Nonius, 1999); cell refinement: DIRAX/LSQ (Duisenberg et al., 2000); data reduction: EVALCCD (Duisenberg et al., 2003); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXL97 and PLATON.
Supplementary data for this paper are available from the IUCr electronic archives (Reference: SK3463 ). Services for accessing these data are described at the back of the journal.
The authors thank the Centro de Instrumentación Científico-Técnica of the Universidad de Jaén and the staff for the data collection. EC and RA thank COLCIENCIAS and the Universidad del Valle for financial support. JC thanks the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain) and the Universidad de Jaén for financial support.
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