Synthesis and Crystal Structures of Halogen-Substituted 2-Aryl-N-phenylbenzimidazoles

Abstract

Four 2-arylbenzimidazoles (aryl = 4-Br-phenyl (1), 3-Br-phenyl (2), 4-I-phenyl (3), 3-I-phenyl (4)) were synthesized and characterized by ¹H, ¹³C{¹H} NMR, UV–Vis spectroscopy and single-crystal X-ray diffraction. Both pairs of benzimidazoles bearing the halogen atom at the same position form isostructural crystals, in which para-substituted compounds 1 and 3 are assembled by weak C–H···π and π···π interactions while their meta-isomers 2 and 4 are linked via intermolecular halogen···nitrogen and C–H···π contacts.

1. Introduction

Benzimidazoles are widespread in medicinal chemistry as building blocks for the synthesis of bioactive compounds [1,2,3,4]. In particular, 2-arylbenzimidazoles have found application as various antiviral, antihistamine, and antitumor agents, etc. [5,6,7,8]. Growing interest to benzimidazoles has motivated researchers to develop numerous high-yield synthetic routes to these compounds [9,10,11,12]. Thus, benzimidazoles with virtually unlimited sets of functional substituents and/or degrees of conjugation can now be prepared, making them very attractive for the construction of metal complexes for application in medicinal chemistry, optoelectronics and photovoltaics [13,14,15,16,17]. Recently, benzimidazole-based cyclometalated iridium(III) complexes were successfully prepared and used as emitters in organic light-emitting diodes [18,19] as well as dyes in solar cells [20,21,22]. In this work, we synthesized four 2-arylbenzimidazoles (Figure 1) bearing bromo- or iodo-substituents in para/meta positions of the phenyl ring and characterized them by ¹H, ¹³C {¹H} NMR, UV–Vis spectroscopy and single-crystal X-ray diffraction. The prepared compounds are interesting as versatile building blocks for the construction of metal complexes and, due to the presence of halogen atoms, may also be excellent starting compounds for the synthesis of various sophisticated organic substances through cross-coupling reactions [23,24,25].

2. Results and Discussion

The target compounds were prepared in high yield via condensation of N-Phenyl-o-phenylenediamine with the corresponding halogen-substituted benzaldehyde in the presence of sodium metabisulfite (Scheme 1) [26,27].

The ¹H NMR spectra of benzimidazoles 1–4 are similar and contain partially resolved as well as heavily overlapped multiplets in the range of 7.0–8.0 ppm (Figures S1, S3, S5 and S10). The signals were assigned by using 2D correlation NMR spectroscopy (for compounds 3 and 4, see Figures S7–S9 and S12–S14). In the ¹³C{¹H} NMR spectra, the number of signals corresponds to the number of magnetically nonequivalent carbon atoms, which supports the composition and structure of the obtained compounds (Figures S2, S4, S6 and S11). The structures of 1–4 were unambiguously confirmed by single-crystal X-ray diffraction (Table S1).

The prepared 2-arylbenzimidazoles are isostructural in pairs (para-bromine with para-iodine and meta-bromine with meta-iodine) and produce monoclinic crystals which do not contain solvent molecules. Compounds 1 and 3 are also isostructural to 2-(4-chlorophenyl)-1-phenyl-benzimidazole [28] and 2-(4-bromophenyl)-1-phenyl-benzimidazole whose crystal structure was reported as a CSD private communication (ref code CINTIE). Unit cell volume is slightly increased (by a factor of 1.02) upon the replacement of bromo- by iodo-substituent while the position of the substituent has a smaller effect on the cell volume (less than 1% increase, see Table S1). The molecular structures of halogenated benzimidazoles 1–4 are shown in Figure 2.

The organic molecules consist of three non-coplanar aromatic fragments: the benzimidazole and N-phenyl ring, unchanged in the series, and the variable 2-phenyl ring containing halogen substituent in positions 3 or 4. The C–Br and C–I bond lengths lie within the ranges 1.898(3)–1.8986(13) and 2.097(3)–2.1038(15) Å, which are consistent with the average values from the Cambridge Structural Database (Version 5.43, March 2022, Cambridge, UK). The dihedral angles between the benzimidazole unit and the N-phenyl ring are in the range from 66.28(11) to 67.48(11)° for 1 and 3 and varies within 54.84(6)–56.71(6)° for 2 and 4. At the same time, the interplanar angles between the 2-aryl fragment and the same benzimidazole system for the para-substituted compounds are significantly smaller (24.09(10)–24.48(10)°) than the same angles in the meta-substituted compounds (39.23(6)–41.81(5)°). The values of these angles for each pair of isostructural compounds correlate with each other, and the greater the tilting of the pendant N-phenyl substituent, the smaller the slope of the 2-aryl ring in relation to the benzimidazole system. The latter is very likely governed by intermolecular interactions, in which the halogen atom of the aryl ring seems to play a more pronounced role than the N-phenyl ring.

Indeed, the Hal···N intermolecular contacts determine the crystal packing of 2 and 4 (d(Br···N) = 3.0945(11), d(I···N) = 3.0810(13) Å) [29] assembling molecules in chains along the b direction. These chains are linked by several C–H···π contacts, forming a 3D packing of the crystal (Figures S15 and S16). In the crystals of compounds 1 and 3, weak π···π interactions between the aromatic rings C1–C6 (substituted aryl) and C14–C19 (benzimidazole) arrange molecules in centrosymmetric dimers with d(π···π)_{centroid–centroid} = 3.9974(17) Å and a shift between the centroids of 2.476(4) Å (Figure S17). These dimers are additionally stabilized by C–H···π contacts. The halogen atom is involved only in weak Hal···π interactions with d(Hal···π) = 4.1229(12)–4.1992(6) Å while several C–H···π contacts complete the 3D packing of the crystals.

3. Materials and Methods

3.1. General Comment

All commercially available reagents, except N-phenyl-o-phenylenediamine, were at least reagent grade and used without further purification. Solvents were distilled and dried according to standard procedures. Purification of N-phenyl-o-phenylenediamine was carried out according to the following method. A weighed portion of the diamine was dissolved in a minimum amount of solvent (mixture of hexane and ethyl acetate in a 3:1 volume ratio) and then passed through a chromatographic column (SiO₂, hexane/ethyl acetate 3:1 vol.). A green solution was obtained, after evaporation of which dark green crystals precipitated. They were dissolved in ethanol and used for the synthesis of 2-arylbenzimidazoles.

The ¹H, ¹³C and 2D NMR spectra were acquired at 25 °C on a Bruker Avance 400 and 600 instruments (Billerica, MA, USA) and chemical shifts were reported in ppm referenced to residual solvent signals (atom numbering for spectra assignment is presented in Figure 3). The electronic absorption spectra of 1–4 in CH₂Cl₂ (C ≈ 2 × 10⁻⁵ M) were measured on an OKB Spectr SF-2000 spectrophotometer (Saint Petersburg, Russia) (see Figure S18). Melting points of 1–4 were measured at a Linkam DSC600 optical system (Salfords, UK) equipped with an Olympus BX43 polarized light microscope (Tokyo, Japan) at a heating rate of 5 deg·min⁻¹.

3.2. Synthesis

1-Phenyl-2-(4-bromophenyl)benzimidazole (1). A solution of purified N-Phenyl-o-phenylenediamine (1.0488 g, 5.7 mmol) and p-bromobenzaldehyde (1.0550 g, 5.7 mmol) in ethanol were mixed with Na₂S₂O₅ (1.0830 g, 5.7 mmol) and refluxed under argon for 3 h. After separation of a precipitate by decantation, the filtrate was evaporated to dryness and dried in vacuo (yield 89%).

Figure 3. H and C Atom numbering in 1–4.

Figure 3. H and C Atom numbering in 1–4.

¹H NMR (400 MHz, CDCl₃, δ): 7.90–7.88 (m, 1H, m), 7.55–7.49 (m, 3H, f–h), 7.44 (s, 4H, a–d), 7.37–7.23 (m, 5H, e, i–l).

¹³C{¹H} NMR (101 MHz, CDCl₃, δ): 150.81 (7), 142.49 (19), 136.83 (14), 136.31 (8), 131.17 (2, 4), 130.45 (1, 5), 129.63 (10. 12), 128.47 (6), 128.39 (11), 126.95 (9, 13), 123.66 (3), 123.21 (16), 122.7 (17), 119.49 (18), 110.11 (15).

Mp: 166–167 °C.

UV–Vis (CH₂Cl₂): λ_max 297 nm (ε = 24,000 M⁻¹ cm⁻¹).

1-Phenyl-2-(3-bromophenyl)benzimidazole (2) was prepared as 1, yield 88%.

¹H NMR (400 MHz, CDCl₃, δ): 7.95–7.81 (m, 2H, d, m), 7.55–7.46 (m, 4H, c, f–h), 7.38–7.21 (m, 6H, a, e, i–l), 7.12 (t, J = 7.9 Hz, 1H, b).

¹³C{¹H} NMR (101 MHz, CDCl₃, δ): 150.23 (7), 142.42 (19), 136.81 (14), 136.16 (8), 132.01 (3, 5), 131.49 (6), 129.63 (10, 12), 129.29 (2), 128.48 (11), 127.34 (1), 126.95 (9, 13), 123.35 (16), 122.84 (17), 122.07 (4), 119.59 (18), 110.17 (15).

Mp: 122–123 °C.

UV–Vis (CH₂Cl₂): λ_max 298 nm (ε = 22,000 M⁻¹ cm⁻¹).

1-Phenyl-2-(4-iodophenyl)benzimidazole (3) was prepared as 1, yield 85%.

¹H NMR (400 MHz, CDCl₃, δ): 7.83 (d, J = 8.0 Hz, 1H, m), 7.62–7.57 (m, 2H, b, c), 7.55–7.48 (m, 3H, f–h),7.32–7.28 (m, 1H, l), 7.28–7.25 (m, 2H, e, i), 7.25–7.23 (m, 2H, a, d), 7.23–7.20 (m, 1H, k), 7.20–7.17 (m, 1H, j).

¹³C{¹H} NMR (101 MHz, CDCl₃, δ): 150.91 (7), 142.49 (19), 137.10 (2, 4), 136.85 (14), 136.32 (8), 130.50 (1, 5), 129.63 (10, 12), 129.03 (6), 128.40 (11), 126.95 (9, 13), 123.22 (16), 122.78 (17), 119.50 (18), 110.11 (15), 95.72 (3).

Mp: 164–165 °C.

UV–Vis (CH₂Cl₂): λ_max 304 nm (ε = 19,000 M⁻¹ cm⁻¹).

1-Phenyl-2-(3-iodophenyl)benzimidazole (4) was prepared as 1, yield 81%.

¹H NMR (600 MHz, CDCl₃, δ): 8.06–8.01 (m, 1H, d), 7.87–7.82 (m, 1H, m), 7.65–7.61 (m, 1H, c), 7.51–7.43 (m, 3H, f–h), 7.36–7.32 (m, 1H, a), 7.32–7.28 (m, 1H, l), 7.28–7.24 (m, 2H, e, i), 7.24–7.22 (m, 1H, k), 7.22–7.18 (m, 1H, j), 6.94 (t, J = 7.8 Hz, 1H, b).

¹³C{¹H} NMR (101 MHz, CDCl₃, δ): 150.07 (7), 142.43 (19), 137.92 (3), 137.87 (5), 136.79 (14), 136.18 (8), 131.47 (6), 129.61 (10, 12), 129.33 (2), 128.46 (11), 127.90 (1), 126.96 (9, 13), 123.31 (16), 122.82 (17), 119.58 (18), 110.15 (15), 93.65 (4).

Mp: 158–160 °C.

UV–Vis (CH₂Cl₂): λ_max 297 nm (ε = 18,000 M⁻¹ cm⁻¹).

3.3. Crystallography Details

Single crystals of 1–4 were grown by slow evaporation of the solution of the benzimidazoles in dichloromethane. Crystallographic data were collected on a Bruker SMART APEX II and D8 Venture diffractometers using graphite monochromatized Mo–Kα radiation (λ = 0.71073 Å) using ω-scan mode. Absorption correction based on the measurements of equivalent reflections was applied [30]. The structures were solved by direct methods and refined by full matrix least-squares on F² with anisotropic thermal parameters for all non-hydrogen atoms [31,32]. Hydrogen atoms were placed in calculated positions and refined using a riding model. The crystallographic details are presented in Table S1 and the crystal packings are plotted in Figures S15–S17. CCDC 2210233–2210236 contains the supplementary crystallographic data for 1–4. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Crystal Data for 1: C₁₉H₁₃N₂Br (M = 349.22 g/mol): monoclinic, space group P2₁/n (no. 14), a = 8.3061(15) Å, b = 9.4657(14) Å, c = 19.288(4) Å, β = 90.276(7)°, V = 1516.5(5) ų, Z = 4, T = 150(2) K, μ(MoKα) = 2.708 mm⁻¹, D_calc = 1.530 g/cm³, 15,241 reflections measured (4.22° ≤ 2Θ ≤ 50.10°), 2681 unique (R_int = 0.0548, R_sigma = 0.0377) which were used in all calculations. The final R₁ was 0.0327 (I > 2σ(I)) and wR₂ was 0.0750 (all data), max/min ΔF 0.24/−0.44 e/ų.

Crystal Data for 2: C₁₉H₁₃N₂Br (M = 349.22 g/mol): monoclinic, space group P2₁/c (no. 14), a = 8.6166(7) Å, b = 10.1262(8) Å, c = 17.6938(14) Å, β = 98.201(3)°, V = 1528.1(2) ų, Z = 4, T = 150(2) K, μ(MoKα) = 2.687 mm⁻¹, D_calc = 1.518 g/cm³, 71,674 reflections measured (4.65° ≤ 2Θ ≤ 61.81°), 4740 unique (R_int = 0.0350, R_sigma = 0.0141) which were used in all calculations. The final R₁ was 0.0271 (I > 2σ(I)) and wR₂ was 0.0724 (all data), max/min ΔF 0.56/−0.57 e/ų.

Crystal Data for 3: C₁₉H₁₃N₂I (M = 396.21 g/mol): monoclinic, space group P2₁/n (no. 14), a = 8.1539(2) Å, b = 9.6185(2) Å, c = 19.6442(5) Å, β = 91.9830(10)°, V = 1539.74(6) ų, Z = 4, T = 150(2) K, μ(MoKα) = 2.077 mm⁻¹, D_calc = 1.709 g/cm³, 19,425 reflections measured (4.15° ≤ 2Θ ≤ 63.07°), 5125 unique (R_int = 0.0255, R_sigma = 0.0246) which were used in all calculations. The final R₁ was 0.0235 (I > 2σ(I)) and wR₂ was 0.0534 (all data), max/min ΔF 0.41/−0.68 e/ų.

Crystal Data for 4: C₁₉H₁₃N₂I (M = 396.21 g/mol): monoclinic, space group P2₁/c (no. 14), a = 8.4708(5) Å, b = 10.0913(6) Å, c = 18.2452(12) Å, β = 98.622(2)°, V = 1542.00(16) ų, Z = 4, T = 100(2) K, μ(MoKα) = 2.074 mm⁻¹, D_calc = 1.707 g/cm³, 17,807 reflections measured (4.52° ≤ 2Θ ≤ 62.99°), 5060 unique (R_int = 0.0264, R_sigma = 0.0271) which were used in all calculations. The final R₁ was 0.0210 (I > 2σ(I)) and wR₂ was 0.0461 (all data), max/min ΔF 0.52/−0.46 e/ų.