ABSTRACT
Aim
The aim of the present study is to synthesize novel series of substituted benzimidazole derivatives and their spectral characterization.
Materials and Methods
This study presents research on the synthesis of novel series of substituted benzimidazole derivatives using primary amine as the starting compound.
Results
All synthesized compounds were analyzed using 1 hydrogen nuclear magnetic resonance, Fourier transform infrared and mass spectrometry to validate their structures.
Conclusion
Overall, the exploration of substituted benzimidazole derivatives with varied functional groups as potential candidates for further advancement as therapeutic agents.
INTRODUCTION
Benzimidazole is indeed an interesting aromatic heterocyclic compound. It features an imidazole ring fused to a benzene ring, giving it unique properties and reactivity. N-ribosyl-dimethyl-benzimidazole is a significant derivative, particularly because it plays a critical role in the structure of vitamin B12. In vitamin B12, this compound acts as an axial ligand for the cobalt ion, which is essential for the vitamin’s biological function (Grimmett, 1997). Vitamin B12 is crucial for processes such as DNA synthesis and red blood cell formation, highlighting the importance of benzimidazole derivatives in biochemistry. Benzimidazole derivatives like mebendazole and thiabendazole play significant roles in medicine due to their anthelmintic (Abdelgawadet al., 2017) and antifungal properties. Some PPIs, which reduce stomach acid production, also contain the benzimidazole structure (Acharet al., 2010). They work by blocking the proton pump in the stomach lining, providing relief from conditions like acid reflux and ulcers. The structural features of benzimidazole allow for diverse modifications, leading to a wide range of pharmacological activities, making them valuable in drug development (Al-Hakimiet al., 2020; Khalil and Mohamed, 2022). Used as intermediates in the synthesis of various drugs, particularly those targeting parasitic infections and acid-related disorders. Benzimidazole derivatives are employed as fungicides and vermicides, helping to protect crops from pests and diseases. Used in formulations to prevent metal corrosion, extending the lifespan of materials. Acts as a hardener in epoxy resins, contributing to strong and durable materials. Enhances the performance characteristics of adhesives and plastics, improving their strength and flexibility. This wide-ranging utility highlights the importance of benzimidazole in synthetic organic chemistry and various industrial applications (Deshmukhet al., 2006; Jayachandranet al., 2003).
MATERIALS AND METHODS
All reagents used for the synthesis were of analytical grade and were employed without further purification. The melting points of the synthesized compounds were determined using an electric melting point apparatus via the open capillary method, reported in degrees Celsius and uncorrected. The progress of reactions and the purity of the synthesized compounds were monitored using silica gel-G aluminum TLC plates with various solvent combinations of differing polarities. Visualization of the spots was achieved with TLC cabinet. The FT-IR spectra of the synthesized compounds were recorded using a FT-IR spectrometer. Proton NMR (1H NMR) spectra were obtained using a Bruker AC-F 400 FT-NMR spectrometer at the Institute of Chemical Technology, Mumbai, Maharashtra, India and mass spectra at NMIMS Mumbai.
Synthetic Scheme
A: 2-(2 chloro phenyl)-1H benzimidazole.
B1-B10: Corresponding Substituted benzimidazoles.
General Method for Synthesis of Corresponding substituted benzimidazoles
Procedure for Synthesis of 2-(2 chloro phenyl)-1H benzimidazole (A) (Step I)
A solution of 2-chloro benzoic acid (0.01 mol) and 1,2-phenylenediamine (ortho-phenylenediamine) (0.01 mol) in 20 mL of glacial acetic acid was irradiated for 7 min in a synthetic microwave oven at 350 watts as shown in scheme 1. After irradiation, a precipitate was formed upon the addition of 10% NaOH while in an ice bath (Conradet al., 2000). The resulting product was then filtered, dried in a hot air oven and recrystallized from ethanol. The compounds were identified using TLC (n-Hexane: Ethanol, 3:2) and by determining their melting point described in Table 2.
Scheme 1:
Synthetic Scheme for Corresponding substituted benzimidazoles (B1-B10) from Table 1.
| Sl. No. | Compound Code | R Substitution | Corresponding Substituted Benzimidazoles |
|---|---|---|---|
| 1. | B1 | 1-Amino-4-cyclopentylPiperidine | 2- [(4-Cyclopentyl piperazin-1-yl) imino] -(2-phenyl)1H-Benzimidazole. |
| 2. | B2 | 1-Amino Piperidine | 2-[(piperidine)-imino)] -(2-phenyl)1H-Benzimidazole. |
| 3. | B3 | 1 amino 4 methyl piperazine | 2- [(4-methyl piperidin-1-yl) imino]-2-phenyl)1H-Benzimidazole. |
| 4. | B4 | Sulphanilamide | 2- [(sulphanilamido benzene) imino]-2-phenyl)1H-Benzimidazole. |
| 5. | B5 | Aniline | 2-[(phenyl imino)]-2-phenyl)1H-Benzimidazole. |
| 6. | B6 | Benzamide | 2- [(Benzene carboxamide) imino]-2-phenyl)1H-Benzimidazole. |
| 7. | B7 | Ethyl 4 amino benzoate | 2- [(ethyl benzoate) imino]-2-phenyl)1H-Benzimidazole. |
| 8. | B8 | Ortho amino phenol | 2-[(phenol)imino]-2-phenyl)1H-Benzimidazole. |
| 9. | B9 | Ortho nitroaniline | 2- [(nitro benzene) imino]-2-phenyl)1H-Benzimidazole. |
| 10. | B10 | Ortho Toluidine | 2- [(methyl benzene) imino]-2-phenyl)1H-Benzimidazole. |
| Sl. No. | Compound Code | Molecular Formula | Molecular Weight gm/mol | Melting Point (ºC) | % Yield | Rf Values | Reaction Time |
|---|---|---|---|---|---|---|---|
| 1. | A | C13H9ClN2 | 228 | 234-236 | 75 | 0.56 | 7 |
| 2. | B1 | C22H27N5 | 361 | 190-192 | 57 | 0.79 | 4 |
| 3. | B2 | C18H20N4 | 292 | 298-300 | 65 | 0.82 | 4 |
| 4. | B3 | C18H21N5 | 307 | 213-215 | 58 | 0.65 | 3 |
| 5. | B4 | C19H16N4O2S | 364 | 302-304 | 72 | 0.84 | 3 |
| 6. | B5 | C19H15N3 | 285 | 185-187 | 64 | 0.52 | 4 |
| 7. | B6 | C20H15N3O | 313 | 265-267 | 67 | 0.48 | 4 |
| 8. | B7 | C22H19N3O2 | 357 | 153-155 | 79 | 0.42 | 4 |
| 9. | B8 | C19H15N3O | 301 | 320-322 | 72 | 0.58 | 4 |
| 10. | B9 | C19H14N4O2 | 330 | 290-292 | 79 | 0.63 | 4 |
| 11. | B10 | C20H17N3 | 299 | 340-342 | 63 | 0.86 | 4 |
Procedure for Synthesis of 2-(2 chloro phenyl)-1H benzimidazole Derivatives (Corresponding substituted benzimidazoles) (B1-B10) (Step II)
To the ethanolic solution of 2-(2 chloro phenyl)-1H benzimidazole (0.005 mol), primary substituted amine 0.005 mol were added. Subsequently (Goudgaonet al., 2004), the reaction mixture was irradiated for 3 to 4 min in a synthetic microwave oven at 400 watts as shown in scheme 1. After, the resulting product hot mixture was poured in crushed ice with constant stirring. Separated solid was filtered, dried and recrystallized from ethanol, methanol. The compounds were further purified using TLC (CHCl3: Ethanol, 4:1) and characterized by determining their melting points described in Table 2.
RESULTS AND DISCUSSION
Spectral Data of Synthesized Compounds
Compound A
1H NMR spectra (δ ppm): 7.13-7.17 doublet 2H, 7.12 singlet 1H, 7.42-7.56 doublet 2H, 7.51 singlet 1H, 7.53 singlet 1H, 7.57-7.58 quartet 4H, 7.85 singlet 1H, 7.87 singlet 1H, 7.89 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1606, C-N Stretching 1328, N-H Stretching 3234, C-Cl Stretching 624.
MS: m/z: 229 [M+H] + Mol. Wt.: 228.
Compound B1
1H NMR spectra (δ ppm): 1.46 quartet 4H, 1.63 quartet 4H, 2.57-2.64 multiple 8H, 2.73 singlet 1H, 3.52 singlet 1H, 7.21-7.34 multiple 5H, 7.02 singlet 1H, 7.11 singlet 1H, 7.12 singlet 1H, 7.24 singlet 1H, 7.32 singlet 1H, 7.63-7.65 doublet 2H, 7.76 singlet 1H, 7.79 singlet 1H, 7.83 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1584, C-N Stretching 1394, C-C stretching 1462, N-H Stretching 3123.
MS: m/z: 362 [M+H] + Mol. Wt.: 361.
Compound B2
1H NMR spectra (δ ppm): 1.54 doublet 2H, 1.86 quartet 4H, 2.96 quartet 4H, 7.02-7.05 multiple 5H, 7.14 singlet 1H, 7.16 singlet 1H, 7.22 singlet 1H, 7.28 singlet 1H, 7.53 singlet 1H, 7.65-7.86 doublet 2H, 7.75 singlet 1H, 7.84 singlet 1H.
IR Spectra (cm-1): C=C Ar Stretching 1487, C-N Stretching 1397, C-C stretching 1401.
MS: m/z: 293 [M+H] + Mol. Wt.: 292.
Compound B3
1H NMR spectra (δ ppm): 2.43 triplet 3H, 2.55 quartet 4H, 2.79 quartet 4H, 7.03-7.52 multiple 5H, 7.08 singlet 1H, 7.14 singlet 1H, 7.22 singlet 1H, 7.28 singlet 1H, 7.33 singlet 1H, 7.64-7.86 doublet 2H, 7.73 singlet 1H, 7.75 singlet 1H, 7.82 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1592, C-N Stretching 1321, N-H stretching 1291, C-C stretching 1351.
MS: m/z: 308 [M+H] + Mol. Wt.: 307.
Compound B4
1H NMR spectra (δ ppm): 7.05-7.32 triplet 3H, 7.11 singlet 1H, 7.18 singlet 1H, 7.26 singlet 1H, 7.53 singlet 1H, 7.62-8.08 multiple 6H, 7.74 singlet 1H, 7.72 singlet 1H, 7.75 singlet 1H, 7.83 singlet 1H, 7.92 singlet 1H, 8.05 doublet 2H.
IR Spectra (cm-1): C=C AR Stretching 1478, C-N Stretching 1273, N-H stretching 1691, S=O stretching 1151.
MS: m/z: 365 [M+H] + Mol. Wt.: 364.
Compound B5
1H NMR spectra (δ ppm): 6.93 singlet 1H, 7.03-7.66 multiple 9H, 7.18 singlet 1H, 7.16 singlet 1H, 7.24 singlet 1H, 7.22 singlet 1H, 7.33 singlet 1H, 7.45 singlet 1H, 7.62 singlet 1H, 7.64-7.69 doublet 2H, 7.56 singlet 1H, 7.82 singlet 1H, 7.82 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1621, C-N Stretching 1196, N-H stretching 3332.
MS: m/z: 286 [M+H] + Mol. Wt.: 285.
Compound B6
1H NMR spectra (δ ppm): 7.03-7.54 multiple 7H, 7.14 singlet 1H, 7.23 singlet 1H, 7.24 singlet 1H, 7.53 singlet 1H, 7.56 singlet 1H, 7.52 singlet 1H, 7.61-7.67 triplet 3H, 7.82 singlet 1H, 7.72 singlet 1H, 7.76 singlet 1H, 7.83-8.04 triplet 3H, 7.98 singlet 1H, 8.21 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1498, C-N Stretching 1230, N-H stretching 3351, C=O stretching 1651.
MS: m/z: 314 [M+H] + Mol. Wt.: 313.
Compound B7
1H NMR spectra (δ ppm): 1.24 triplet 3H, 4.25 doublet 2H, 7.02-7.32 triplet 3H, 7.08 singlet 1H, 7.14 singlet 1H, 7.26 singlet 1H, 7.46-7.52 triplet 3H, 7.46 singlet 1H, 7.42 singlet 1H, 7.64-7.85 multiple 6H, 7.72 singlet 1H, 7.53 singlet 1H, 7.89 singlet 1H, 7.78 singlet 1H, 7.82 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1537, C-N Stretching 1283, N-H stretching 3340, C=O stretching 1561.
MS: m/z: 358 [M+H] + Mol. Wt.: 357.
Compound B8
1H NMR spectra (δ ppm): 6.82 singlet 1H, 6.81-7.32 quartet 5H, 6.87 singlet 1H, 7.32 singlet 1H, 7.12 singlet 1H, 7.22 singlet 1H, 7.24 singlet 1H, 7.33-7.87 multiple 5H, 7.52 singlet 1H, 7.66 singlet 1H, 7.84 singlet 1H, 7.73 singlet 1H, 7.72 singlet 1H, 7.82 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1523, C-N Stretching 1236, N-H stretching 3301, O-H stretching 3340.
MS: m/z: 302 [M+H] + Mol. Wt.: 301.
Compound B9
1H NMR spectra (δ ppm): 7.03-7.42 quartet 5H, 7.11 singlet 1H, 7.18 singlet 1H, 7.23 singlet 1H, 7.23 singlet 1H, 7.42 singlet 1H, 7.45-7.82 quartet 5H, 7.52 singlet 1H, 7.73 singlet 1H, 7.85 singlet 1H, 7.83 singlet 1H, 7.83 singlet 1H, 8.02-8.18 doublet 2H, 8.01 singlet 1H, 8.03 singlet 1H.
IR Spectra (cm-1): C=C Ar Stretching 1623, C-N Stretching 1470, N-H stretching 3520.
MS: m/z: 331 [M+H] + Mol. Wt.: 330.
Compound B10
1H NMR spectra (δ ppm): 2.13 triplet 3H, 6.54 singlet 1H, 6.87-7.89 multiple 10H, 6.58 singlet 1H, 7.05 singlet 1H, 7.10 singlet 1H, 7.17 singlet 1H, 7.24 singlet 1H, 7.24 singlet 1H, 7.53 singlet 1H, 7.58 singlet 1H, 7.56 singlet 1H, 7.87 singlet 1H, 7.89 singlet 1H.
IR Spectra (cm-1): C=C AR Stretching 1447, C-N Stretching 1332, N-H stretching 3447, CH3 1294.
MS: m/z: 300 [M+H] + Mol. Wt.: 299.
CONCLUSION
Corresponding Substituted benzimidazoles Derivatives was successfully synthesized. Using microwave irradiation for small-scale reactions is an effective approach to optimize the synthesis of novel benzimidazole derivatives. This method often enhances reaction rates, improves yields and can lead to more efficient processes. Synthesizing Schiff Bases of 2-(2 chloro phenyl)-1H benzimidazole derivatives using microwave irradiation is an excellent approach. The use of microwave irradiation can significantly reduce the reaction time and improve yields compared to conventional heating methods. The exploration of Schiff Bases of 2-(2 chloro phenyl)-1H benzimidazole derivatives with varied functional groups holds great potential for discovering novel pharmacological agents. This area is indeed worth pursuing, as it may lead to the development of compounds with enhanced efficacy.
Cite this article:
Jadhav BD, Narkhede SP. Synthesis and Spectral Analysis of Novel Substituted Benzimidazole Derivatives. Int. J. Pharm. Investigation. 2025;15(3):313-24.
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