X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives

*Aravazhi Amalan Thiruvalluvar, Gopalsamy Vasuki, Jayaraman Jayabharathi and Sivaraman Rosepriya*

#### **Abstract**

This chapter describes the X-ray crystal structure analysis of selected benzimidazole derivatives, viz. BIP: 2-(1H-benzimidazol-2-yl)phenol, MBMPBI: 1-(4-methylbenzyl)-2-(4-methylphenyl)-1H-benzimidazole, DPBI: 1,2-diphenyl-1H-benzimidazole, PBIP: 2-(1-phenyl-1H-benzimidazol-2-yl)phenol, FPPBI: 2-(4-fluorophenyl)-1-phenyl-1H-benzimidazole and NPBIBHS: 2-(naphthalen-1-yl)- 1-phenyl-1H-benzimidazole benzene hemisolvate. The BIP molecule is planar, and in the crystal, it is arranged in parallel planes, stabilised by π-π interactions and the hydrogen bonds. In MBMPBI, benzimidazole cores of the two independent (A and B) molecules are planar. Two C▬H…N hydrogen bonds link B molecules only, forming centrosymmetric dimers with R2 2(8) ring motifs. In the DPBI molecule, the benzimidazole core is planar: one hydrogen-bond interaction (C▬H…N) and C▬H…π (three) interaction leading to the three-dimensional arrangement. In the PBIP molecule, the benzimidazole is nearly planar. The hydrogen bonds and a π-π stacking interaction are present in the crystal. In the FPPBI molecule, the benzimidazole unit is almost planar. The C▬H…F hydrogen bonds and weak C▬H…π interactions lead to a three-dimensional architecture in the crystal. In NPBIBHS, the naphthalene fragment lies out of the plane about the benzimidazole core unit. The C▬H…N hydrogen bonds and C▬H…π interactions lead to a three-dimensional architecture in the crystal.

**Keywords:** X-ray, single crystal, synthesis, structural analysis, inter and intramolecular hydrogen bonds, C▬H…π and π…π interactions

#### **1. Introduction**

The X-ray diffraction technique is the most powerful technique of determining the relative atomic positions in a molecular structure. Furthermore, it is distinctively capable of providing precise evidence concerning bond lengths, bond angles, torsion angles and molecular dimensions. It is a well-known fact that hydrogen bonding is one of the crucial factors that contribute to the stability of a structure. Thus, it forms a part of the molecular conformation in that the symmetry and the subsequent packing of the molecules should yield the formation of as many hydrogen bonds as possible. This present chapter depicts the work carried out by the authors, on the crystal structure determination of selected biologically important new benzimidazole derivatives.

Literature survey shows that the benzimidazole is an aromatic ring system where an imidazole ring is fused to the 4 and 5 positions with a benzene ring. Benzimidazole derivatives in OLEDs are of current interest because of their thermal stability [1]. Benzimidazole derivatives are a part of vitamin B12 [2] and commercialised as anthelmintic and antihistaminic agents [3].

#### **2. Synthetic approaches of benzimidazole compounds**

Due to their possible biological and pharmacological activities, benzimidazoles synthesis has become a vital target in recent years [4]. Since our group is researching organic light emitting devices (OLEDs), we are concerned in using the MBMPBI [5] and DPBI [6] compounds as a ligand in the preparation of Ir(III) complexes and exploring further their electroluminescence (EL) properties. Furthermore, we are interested in using the PBIP [7], FPPBI [8] and NPBIBHS [9] compound as a ligand to study excited state intramolecular proton transfer (ESIPT) processes.

#### **2.1 Synthesis of 2-(1H-benzimidazol-2-yl)phenol (C13H10N2O): BIP**

To 15 mmol of o-phenylenediamine in minimum 10 ml ethanol, a mixture of 15 mmol of o-hydroxybenzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C for 2 days. The reaction mixture was cooled and extracted with dichloromethane. The TLC monitored the completion of the reaction. The separated solid was purified by column chromatography (benzene: ethyl acetate (9:1)), after solvent evaporation, and the yield was 60% (**Figure 1**). Furthermore, a suitable single crystal is subjected to collect the X-ray diffraction data [4].

#### **2.2 Synthesis of 1-(4-methylbenzyl)-2-(4-methylphenyl)-1H-benzimidazole (C22H20N2): MBMPBI**

To 15 mmol of o-phenylenediamine in minimum 10 ml ethanol, a mixture of 15 mmol of p-methylbenzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (48 h). Purification of MBMPBI was made by following the procedure as that of BIP (column chromatography: benzene: ethyl acetate (9:1)), and the yield was 40% (**Figure 1**). Furthermore, a suitable single crystal is subjected to collect the X-ray diffraction data [5].

#### **2.3 Synthesis of 1,2-diphenyl-1H-benzimidazole (C19H14N2): DPBI**

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of 17 mmol of benzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (4 h). Purification of DPBI was made by following the procedure as that of BIP (column chromatography: benzene: ethyl acetate (9:1)), and the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal is subjected to collect the X-ray diffraction data [6].

#### **2.4 Synthesis of 2-(1-phenyl-1H-benzimidazol-2-yl)phenol (C19H14N2O): PBIP**

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of 17 mmol of o-hydroxybenzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (4 h). Purification of PBIP was made by following

**33**

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

the procedure as that of BIP (column chromatography-petroleum ether (60–80°C)), and the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal is subjected

*Chemical structures of the studied compounds: BIP, MBMPBI, DPBI, PBIP, FPPBI and NPBIBHS.*

**2.5 Synthesis of 2-(4-fluorophenyl)-1-phenyl-1H-benzimidazole (C19H13FN2):** 

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of p-fluorobenzaldehyde (17 mmol) and 60 mmol of ammonium acetate was added and refluxed at 90°C (4 h). Purification of FPPBI was made by following the procedure as that of BIP (column chromatography-petroleum ether: ethyl acetate (9:1)), the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal

**2.6 Synthesis of 2-(naphthalen-1-yl)-1-phenyl-1H-benzimidazole benzene** 

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of 17 mmol of 1-naphthaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (48 h). Purification of NPBIBHS was made by following

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

to collect the X-ray diffraction data [7].

is subjected to collect the X-ray diffraction data [8].

**hemisolvate (C23H16N2. 0.5C6H6): NPBIBHS**

**FPPBI**

**Figure 1.**

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

**Figure 1.**

*Chemistry and Applications of Benzimidazole and its Derivatives*

cialised as anthelmintic and antihistaminic agents [3].

(ESIPT) processes.

data [4].

**(C22H20N2): MBMPBI**

jected to collect the X-ray diffraction data [5].

to collect the X-ray diffraction data [6].

**2. Synthetic approaches of benzimidazole compounds**

**2.1 Synthesis of 2-(1H-benzimidazol-2-yl)phenol (C13H10N2O): BIP**

Literature survey shows that the benzimidazole is an aromatic ring system where an imidazole ring is fused to the 4 and 5 positions with a benzene ring. Benzimidazole derivatives in OLEDs are of current interest because of their thermal stability [1]. Benzimidazole derivatives are a part of vitamin B12 [2] and commer-

Due to their possible biological and pharmacological activities, benzimidazoles synthesis has become a vital target in recent years [4]. Since our group is researching organic light emitting devices (OLEDs), we are concerned in using the MBMPBI [5] and DPBI [6] compounds as a ligand in the preparation of Ir(III) complexes and exploring further their electroluminescence (EL) properties. Furthermore, we are interested in using the PBIP [7], FPPBI [8] and NPBIBHS [9] compound as a ligand to study excited state intramolecular proton transfer

To 15 mmol of o-phenylenediamine in minimum 10 ml ethanol, a mixture of 15 mmol of o-hydroxybenzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C for 2 days. The reaction mixture was cooled and extracted with dichloromethane. The TLC monitored the completion of the reaction. The separated solid was purified by column chromatography (benzene: ethyl acetate (9:1)), after solvent evaporation, and the yield was 60% (**Figure 1**). Furthermore, a suitable single crystal is subjected to collect the X-ray diffraction

**2.2 Synthesis of 1-(4-methylbenzyl)-2-(4-methylphenyl)-1H-benzimidazole** 

To 15 mmol of o-phenylenediamine in minimum 10 ml ethanol, a mixture of 15 mmol of p-methylbenzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (48 h). Purification of MBMPBI was made by following the procedure as that of BIP (column chromatography: benzene: ethyl acetate (9:1)), and the yield was 40% (**Figure 1**). Furthermore, a suitable single crystal is sub-

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of 17 mmol of benzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (4 h). Purification of DPBI was made by following the procedure as that of BIP (column chromatography: benzene: ethyl acetate (9:1)), and the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal is subjected

**2.4 Synthesis of 2-(1-phenyl-1H-benzimidazol-2-yl)phenol (C19H14N2O): PBIP**

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of 17 mmol of o-hydroxybenzaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (4 h). Purification of PBIP was made by following

**2.3 Synthesis of 1,2-diphenyl-1H-benzimidazole (C19H14N2): DPBI**

**32**

*Chemical structures of the studied compounds: BIP, MBMPBI, DPBI, PBIP, FPPBI and NPBIBHS.*

the procedure as that of BIP (column chromatography-petroleum ether (60–80°C)), and the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal is subjected to collect the X-ray diffraction data [7].

#### **2.5 Synthesis of 2-(4-fluorophenyl)-1-phenyl-1H-benzimidazole (C19H13FN2): FPPBI**

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of p-fluorobenzaldehyde (17 mmol) and 60 mmol of ammonium acetate was added and refluxed at 90°C (4 h). Purification of FPPBI was made by following the procedure as that of BIP (column chromatography-petroleum ether: ethyl acetate (9:1)), the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal is subjected to collect the X-ray diffraction data [8].

#### **2.6 Synthesis of 2-(naphthalen-1-yl)-1-phenyl-1H-benzimidazole benzene hemisolvate (C23H16N2. 0.5C6H6): NPBIBHS**

To 17 mmol of N-phenyl-o-phenylenediamine in minimum 10 ml ethanol, a mixture of 17 mmol of 1-naphthaldehyde and 60 mmol of ammonium acetate was added and refluxed at 90°C (48 h). Purification of NPBIBHS was made by following the procedure as that of BIP (column chromatography-benzene as the eluent), and the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal is subjected to collect the X-ray diffraction data [9].

#### **3. Structural analysis of six benzimidazole compounds**

#### **3.1 Structural analysis of 2-(1H-benzimidazol-2-yl)phenol (BIP)**

This section describes the determination of the crystal structure and molecular structure of BIP [4]. The direct method program SIR2011 [10] is used in solving the crystal structure. The SHELXL2013/4 [11] program was used to refine the structure.

This compound crystallises in the monoclinic system in the space group P21/c. Molecular formula: C13H10N2O; molecular weight: 210.23; Z = 4; crystal data: a = 16.864(4) Å; b = 4.7431(8) Å; c = 12.952(2) Å; β = 102.34(2)°; V = 1012.1(3) Å3 ; Dcal = 1.380 Mg m<sup>−</sup><sup>3</sup> ; F000 = 440; final R[F2 > 2σ(F2 )] = 0.067 and wR(F2 ) = 0.131 for 1184 reflections observed with I > 2σ(I).

From a difference Fourier map, H1 attached to N1 was located and freely refined with (N1▬H1 = 0.91(2) Å). The outstanding H atoms were placed geometrically and permitted to ride on their parental atoms, with O▬H = 0.82 and C▬H = 0.93 Å for Csp2 hydrogens; Uiso(H) = kUeq(C), where k = 1.5 for methyl and 1.2 for all other C-bonded H atoms.

This molecule is planar [maximum deviation = 0.016(2) Å]. The dihedral angle between the five-membered imidazole ring and the attached six-membered benzene ring is 0.37(13)°. An S(6) ring motif [12] is generated by the O▬H…N hydrogen bond. The hydrogen bond involves the hydroxyl substituent (O26) as the proton donor and the nitrogen (N3) atom as the acceptor, which forms a six-membered ring. The N▬H…O hydrogen bonds link the molecules, by making chains spreading in [001]. Four π-π assembling contacts concerning the five-membered ring, fused six-membered benzene ring and attached benzene ring system [The Cg-Cg distances increase from 3.6106(17) to 3.6668(17) Å].

The thermal displacement ellipsoid plot (**Figure 2**) at the 50% probability level was drawn using the program ORTEP-3 for Windows [13]. **Figure 3** presents the π-π interactions detected in the crystal structure, brought using the program PLATON [14]. The crystal structure packing view is shown in **Figure 4** [14].

**35**

**Figure 4.**

**Figure 3.**

*(ii): x, 1 + y, z.*

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

**3.2 Structural analysis of 1-(4-methylbenzyl)-2-(4-methylphenyl)-1H-**

*The partial crystal packing with hydrogen bonds [14], viewed along the b axis.*

This section describes the determination of the crystal and molecular structure of MBMPBI [5]. The direct method program SIR2002 [15] is used in solving the crystal structure. The SHELXL97 [11] program was used to refine the structure. This compound crystallises in the triclinic system in the space group P¯

*The crystal structure, partially showing the formation of π-π interactions. Symmetry codes (i): x, −1 + y, z and* 

formula: C22H20N2; molecular weight: 312.40; Z = 4; crystal data: a = 9.6610(2) Å;

1. Molecular

**benzimidazole (MBMPBI)**

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

**Figure 2.** *The thermal displacement ellipsoid plot (at the 50% probability level).*

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

#### **Figure 3.**

;

) = 0.131 for

*Chemistry and Applications of Benzimidazole and its Derivatives*

**3. Structural analysis of six benzimidazole compounds**

; F000 = 440; final R[F2

**3.1 Structural analysis of 2-(1H-benzimidazol-2-yl)phenol (BIP)**

collect the X-ray diffraction data [9].

1184 reflections observed with I > 2σ(I).

increase from 3.6106(17) to 3.6668(17) Å].

Dcal = 1.380 Mg m<sup>−</sup><sup>3</sup>

C-bonded H atoms.

Csp2

the procedure as that of BIP (column chromatography-benzene as the eluent), and the yield was 50% (**Figure 1**). Furthermore, a suitable single crystal is subjected to

This section describes the determination of the crystal structure and molecular structure of BIP [4]. The direct method program SIR2011 [10] is used in solving the crystal structure. The SHELXL2013/4 [11] program was used to refine the structure. This compound crystallises in the monoclinic system in the space group P21/c.

> 2σ(F2

From a difference Fourier map, H1 attached to N1 was located and freely refined with (N1▬H1 = 0.91(2) Å). The outstanding H atoms were placed geometrically and permitted to ride on their parental atoms, with O▬H = 0.82 and C▬H = 0.93 Å for

hydrogens; Uiso(H) = kUeq(C), where k = 1.5 for methyl and 1.2 for all other

This molecule is planar [maximum deviation = 0.016(2) Å]. The dihedral angle between the five-membered imidazole ring and the attached six-membered benzene ring is 0.37(13)°. An S(6) ring motif [12] is generated by the O▬H…N hydrogen bond. The hydrogen bond involves the hydroxyl substituent (O26) as the proton donor and the nitrogen (N3) atom as the acceptor, which forms a six-membered ring. The N▬H…O hydrogen bonds link the molecules, by making chains spreading in [001]. Four π-π assembling contacts concerning the five-membered ring, fused six-membered benzene ring and attached benzene ring system [The Cg-Cg distances

The thermal displacement ellipsoid plot (**Figure 2**) at the 50% probability level was drawn using the program ORTEP-3 for Windows [13]. **Figure 3** presents the π-π interactions detected in the crystal structure, brought using the program PLATON

[14]. The crystal structure packing view is shown in **Figure 4** [14].

)] = 0.067 and wR(F2

Molecular formula: C13H10N2O; molecular weight: 210.23; Z = 4; crystal data: a = 16.864(4) Å; b = 4.7431(8) Å; c = 12.952(2) Å; β = 102.34(2)°; V = 1012.1(3) Å3

**34**

**Figure 2.**

*The thermal displacement ellipsoid plot (at the 50% probability level).*

*The crystal structure, partially showing the formation of π-π interactions. Symmetry codes (i): x, −1 + y, z and (ii): x, 1 + y, z.*

**Figure 4.** *The partial crystal packing with hydrogen bonds [14], viewed along the b axis.*

#### **3.2 Structural analysis of 1-(4-methylbenzyl)-2-(4-methylphenyl)-1Hbenzimidazole (MBMPBI)**

This section describes the determination of the crystal and molecular structure of MBMPBI [5]. The direct method program SIR2002 [15] is used in solving the crystal structure. The SHELXL97 [11] program was used to refine the structure.

This compound crystallises in the triclinic system in the space group P¯ 1. Molecular formula: C22H20N2; molecular weight: 312.40; Z = 4; crystal data: a = 9.6610(2) Å;

b = 10.2900(2) Å; c = 17.7271(3) Å; α = 84.437(2)°; β = 81.536(2)°; γ = 76.165(2)°; V = 1689.02(6) Å3 ; Dcal = 1.229 Mg m<sup>−</sup><sup>3</sup> ; F000 = 664; final R[F2 > 2σ(F2 )] = 0.039 and wR(F2 ) = 0.104 for 6452 observed reflections with I > 2σ(I).

All the H atoms were placed geometrically and allowed to trip on their parental atoms, with C▬H = 0.93 (Csp2 ), 0.96 (methyl) and 0.97 Å (methylene) hydrogen atoms. Uiso(H) = kUeq(C), with k = 1.5 (▬CH3 H atoms) and 1.2 (for carbon-attached H atoms). The ▬CH3 groups are disordered over two positions. So, they are refined as idealised disordered methyl groups with identical occupancy of the two locations.

Two crystallographically independent molecules A (first) and B (second) of this compound make the asymmetric unit. The planar [maximum deviations = 0.0161(8) Å for A (first) and 0.0276(8) Å for B (second)] benzimidazole least-squares plane and the benzene least-squares planes of the 4-methylbenzyl and 4-methylphenyl groups make dihedral angles of 76.64(3) and 46.87(4)° in A (first). The similar values in B (second) are 86.31(2) and 39.14(4)°. The two benzene rings make the dihedral angle of 73.73(3)° in A (first) and 80.69(4)° in B (second). The variation in the dihedral angles may be due to the H▬H repulsions. The centrosymmetric dimers with R<sup>2</sup> 2(8) ring motifs [12] are formed by the two C4B▬H4B…N3B hydrogen bonds in B (second). The pattern contains a total of eight atoms in which two of them are donors, and two are acceptors, hence designated as R<sup>2</sup> 2(8). There are no corresponding interactions involving the A molecules.

The thermal displacement ellipsoid plot (for molecule A (first) only) (**Figure 5**) at the 30% probability level was drawn using the program ORTEP-3 for Windows [13]. The crystal structure packing view is shown in **Figure 6** [14].

#### **3.3 Structural analysis of 1,2-diphenyl-1H-benzimidazole (DPBI)**

This section describes the determination of the crystal structure and molecular structure of DPBI [6]. The direct method program SHELXS97 [11] is used in solving the crystal structure. The SHELXL97 [11] program was used to refine the structure.

This compound crystallises in the monoclinic system in the space group C2/c. Molecular formula: C19H14N2; molecular weight: 270.32; Z = 8; crystal

**37**

structure.

V = 2848.13(14) Å3

tal atoms, with C▬H = 0.93 Å (Csp2

dimensional architecture in the crystal.

▬CH3 H atoms and 1.2 for all other H atoms.

and wR(F<sup>2</sup>

**Figure 6.**

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

data: a = 10.1878(3) Å; b = 16.6399(4) Å; c = 17.4959(5) Å; β = 106.205(3)°;

All the H atoms were placed geometrically and permitted to trip on their paren-

The thermal displacement ellipsoid plot (**Figure 7**) at the 50% probability level was drawn using the program ORTEP-3 for Windows [13]. **Figure 8** presents the C▬H…π interactions in the crystal structure brought using the program PLATON

This section describes the determination of the crystal structure and molecular structure of PBIP [7]. The direct method program SHELXS86 [11] is used in solving the crystal structure. The SHELXL97 [11] program was used to refine the

**3.4 Structural analysis of 2-(1-phenyl-1H-benzimidazol-2-yl)phenol (PBIP)**

The benzimidazole unit is planar [maximum deviation = 0.0102(6) Å]. The least-squares planes of the phenyl rings at N1 and C2 make angles of 55.80(2) and 40.67(3)° with the least-squares plane of the benzimidazole part. The least-squares planes of the phenyl rings at N1 and C2 make a dihedral angle of 62.37(3)°. One C▬H…N hydrogen bond and three C▬H…π interactions concerning the fused benzene ring and the five-membered imidazole rings are observed, forming a three-

) = 0.137 for 5803 reflections observed [I > 2σ(I)].

[14]. The crystal structure packing view is shown in **Figure 9** [14].

; F000 = 1136; final R[F2

) and Uiso(H) = kUeq(C), where k = 1.5 for

> 2σ(F2

)] = 0.052

; Dcal = 1.261 Mg m<sup>−</sup><sup>3</sup>

*The crystal packing with hydrogen bonds [14], viewed along the a axis.*

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

**Figure 5.** *The thermal displacement ellipsoid plot (at the 30% probability level).*

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

*Chemistry and Applications of Benzimidazole and its Derivatives*

; Dcal = 1.229 Mg m<sup>−</sup><sup>3</sup>

) = 0.104 for 6452 observed reflections with I > 2σ(I).

disordered methyl groups with identical occupancy of the two locations.

two of them are donors, and two are acceptors, hence designated as R<sup>2</sup>

[13]. The crystal structure packing view is shown in **Figure 6** [14].

**3.3 Structural analysis of 1,2-diphenyl-1H-benzimidazole (DPBI)**

are no corresponding interactions involving the A molecules.

V = 1689.02(6) Å3

atoms, with C▬H = 0.93 (Csp2

metric dimers with R<sup>2</sup>

wR(F2

b = 10.2900(2) Å; c = 17.7271(3) Å; α = 84.437(2)°; β = 81.536(2)°; γ = 76.165(2)°;

All the H atoms were placed geometrically and allowed to trip on their parental

Two crystallographically independent molecules A (first) and B (second) of this compound make the asymmetric unit. The planar [maximum deviations = 0.0161(8) Å for A (first) and 0.0276(8) Å for B (second)] benzimidazole least-squares plane and the benzene least-squares planes of the 4-methylbenzyl and 4-methylphenyl groups make dihedral angles of 76.64(3) and 46.87(4)° in A (first). The similar values in B (second) are 86.31(2) and 39.14(4)°. The two benzene rings make the dihedral angle of 73.73(3)° in A (first) and 80.69(4)° in B (second). The variation in the dihedral angles may be due to the H▬H repulsions. The centrosym-

hydrogen bonds in B (second). The pattern contains a total of eight atoms in which

The thermal displacement ellipsoid plot (for molecule A (first) only) (**Figure 5**) at the 30% probability level was drawn using the program ORTEP-3 for Windows

This section describes the determination of the crystal structure and molecular structure of DPBI [6]. The direct method program SHELXS97 [11] is used in solving the crystal structure. The SHELXL97 [11] program was used to refine the structure. This compound crystallises in the monoclinic system in the space group C2/c. Molecular formula: C19H14N2; molecular weight: 270.32; Z = 8; crystal

Uiso(H) = kUeq(C), with k = 1.5 (▬CH3 H atoms) and 1.2 (for carbon-attached H atoms). The ▬CH3 groups are disordered over two positions. So, they are refined as idealised

; F000 = 664; final R[F2

2(8) ring motifs [12] are formed by the two C4B▬H4B…N3B

> 2σ(F2

), 0.96 (methyl) and 0.97 Å (methylene) hydrogen atoms.

)] = 0.039 and

2(8). There

**36**

**Figure 5.**

*The thermal displacement ellipsoid plot (at the 30% probability level).*

**Figure 6.** *The crystal packing with hydrogen bonds [14], viewed along the a axis.*

data: a = 10.1878(3) Å; b = 16.6399(4) Å; c = 17.4959(5) Å; β = 106.205(3)°; V = 2848.13(14) Å3 ; Dcal = 1.261 Mg m<sup>−</sup><sup>3</sup> ; F000 = 1136; final R[F2 > 2σ(F2 )] = 0.052 and wR(F<sup>2</sup> ) = 0.137 for 5803 reflections observed [I > 2σ(I)].

All the H atoms were placed geometrically and permitted to trip on their parental atoms, with C▬H = 0.93 Å (Csp2 ) and Uiso(H) = kUeq(C), where k = 1.5 for ▬CH3 H atoms and 1.2 for all other H atoms.

The benzimidazole unit is planar [maximum deviation = 0.0102(6) Å]. The least-squares planes of the phenyl rings at N1 and C2 make angles of 55.80(2) and 40.67(3)° with the least-squares plane of the benzimidazole part. The least-squares planes of the phenyl rings at N1 and C2 make a dihedral angle of 62.37(3)°. One C▬H…N hydrogen bond and three C▬H…π interactions concerning the fused benzene ring and the five-membered imidazole rings are observed, forming a threedimensional architecture in the crystal.

The thermal displacement ellipsoid plot (**Figure 7**) at the 50% probability level was drawn using the program ORTEP-3 for Windows [13]. **Figure 8** presents the C▬H…π interactions in the crystal structure brought using the program PLATON [14]. The crystal structure packing view is shown in **Figure 9** [14].

#### **3.4 Structural analysis of 2-(1-phenyl-1H-benzimidazol-2-yl)phenol (PBIP)**

This section describes the determination of the crystal structure and molecular structure of PBIP [7]. The direct method program SHELXS86 [11] is used in solving the crystal structure. The SHELXL97 [11] program was used to refine the structure.

#### **Figure 8.**

*The crystal structure, partially showing the formation of C▬H…π interactions. Symmetry codes are (ii): −x, y, −z + 1/2 and (iii): −x, −y + 1, −z.*

This compound crystallises in the triclinic system in the space group P¯ 1 Molecular formula: C19H14N2O; molecular weight: 286.32; Z = 2; crystal data: a = 8.1941(6) Å; b = 9.5983(14) Å; c = 10.3193(18) Å; α = 64.637(16)°; β = 80.356(10)°; γ = 83.610(9)°; V = 722.3(2) Å3 ; Dcal = 1.316 Mg m<sup>−</sup><sup>3</sup> ; F000 = 300; final R[F2 > 2σ(F2 )] = 0.059 and wR(F2 ) = 0.171 for 2420 observed reflections with I > 2σ(I).

**39**

**(FPPBI)**

**Figure 9.**

program SHELXL97 [11].

V = 1463.75(11) Å3

and wR(F<sup>2</sup>

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

A difference Fourier map was used to locate the H atom attached to O atom and refined freely with O26▬H26 = 0.97(3) Å. The outstanding H atoms were placed geometrically and permitted to trip on their parental atoms, with C▬H = 0.95 Å, and

The phenyl mean plane at N1 and the benzene mean plane at C2 makes angles of 68.98(6) and 20.38(7)°, respectively, with benzimidazole planar unit [maximum deviation = 0.0253(11) Å]. The phenyl and the adjacent benzene mean planes makes an angle of 64.30(7)°. An intramolecular S(6) ring motif [12] is generated by O▬H…N hydrogen bond. The hydrogen bond involving has the hydroxyl substituent (O26) as the proton donor and the nitrogen (N3) atom as the acceptor, which forms a six-membered ring (N3, C2, C21, C26, O26 and H26). The C▬H…N and C▬H…O hydrogen bonds links the molecules. There is a π-π assembling contact,

The ORTEP-3 for Windows [13] was used to draw the thermal displacement ellipsoid plot (**Figure 10**) at the 50% probability level. **Figure 11** presents the π-π interactions observed in the crystal structure brought using the program PLATON

The dashed lines indicate the intramolecular O▬H…N hydrogen bond.

**3.5 Structural analysis of 2-(4-fluorophenyl)-1-phenyl-1H-benzimidazole** 

This compound crystallises in the Monoclinic system in the space group P21/n. Molecular formula: C19H13FN2; Molecular weight: 288.31; Z = 4; crystal data: a = 8.7527(4) Å; b = 10.1342(4) Å; c = 17.0211(6) Å; β = 104.187(4)°;

) = 0.160 for 5352 observed reflections with (I > 2σ(I)).

This section describes the determination of the crystal structure and molecular structure of FPPBI [8]. The crystal structure of FPPBI was solved by direct methods, using the program SIR2004 [16]. The crystal structure is refined by the

; F000 = 600; final R[F2

> 2σ(F2

)] = 0.063

[14]. The crystal structure packing view is shown in **Figure 12** [14].

; Dcal = 1.308 Mg m<sup>−</sup><sup>3</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

with Uiso(H) = 1.2Ueq(parental atom).

with a centroid-centroid distance of 3.8428(12) Å.

*The crystal packing with hydrogen bonds [14], viewed along the a axis.*

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

#### **Figure 9.**

*Chemistry and Applications of Benzimidazole and its Derivatives*

*The thermal displacement ellipsoid plot (at the 50% probability level).*

This compound crystallises in the triclinic system in the space group P¯

; Dcal = 1.316 Mg m<sup>−</sup><sup>3</sup>

) = 0.171 for 2420 observed reflections with I > 2σ(I).

formula: C19H14N2O; molecular weight: 286.32; Z = 2; crystal data: a = 8.1941(6) Å; b = 9.5983(14) Å; c = 10.3193(18) Å; α = 64.637(16)°; β = 80.356(10)°; γ = 83.610(9)°;

*The crystal structure, partially showing the formation of C▬H…π interactions. Symmetry codes are (ii): −x, y,* 

; F000 = 300; final R[F2

> 2σ(F2

1 Molecular

)] = 0.059 and

**38**

wR(F2

**Figure 8.**

**Figure 7.**

V = 722.3(2) Å3

*−z + 1/2 and (iii): −x, −y + 1, −z.*

*The crystal packing with hydrogen bonds [14], viewed along the a axis.*

A difference Fourier map was used to locate the H atom attached to O atom and refined freely with O26▬H26 = 0.97(3) Å. The outstanding H atoms were placed geometrically and permitted to trip on their parental atoms, with C▬H = 0.95 Å, and with Uiso(H) = 1.2Ueq(parental atom).

The phenyl mean plane at N1 and the benzene mean plane at C2 makes angles of 68.98(6) and 20.38(7)°, respectively, with benzimidazole planar unit [maximum deviation = 0.0253(11) Å]. The phenyl and the adjacent benzene mean planes makes an angle of 64.30(7)°. An intramolecular S(6) ring motif [12] is generated by O▬H…N hydrogen bond. The hydrogen bond involving has the hydroxyl substituent (O26) as the proton donor and the nitrogen (N3) atom as the acceptor, which forms a six-membered ring (N3, C2, C21, C26, O26 and H26). The C▬H…N and C▬H…O hydrogen bonds links the molecules. There is a π-π assembling contact, with a centroid-centroid distance of 3.8428(12) Å.

The ORTEP-3 for Windows [13] was used to draw the thermal displacement ellipsoid plot (**Figure 10**) at the 50% probability level. **Figure 11** presents the π-π interactions observed in the crystal structure brought using the program PLATON [14]. The crystal structure packing view is shown in **Figure 12** [14].

The dashed lines indicate the intramolecular O▬H…N hydrogen bond.

#### **3.5 Structural analysis of 2-(4-fluorophenyl)-1-phenyl-1H-benzimidazole (FPPBI)**

This section describes the determination of the crystal structure and molecular structure of FPPBI [8]. The crystal structure of FPPBI was solved by direct methods, using the program SIR2004 [16]. The crystal structure is refined by the program SHELXL97 [11].

This compound crystallises in the Monoclinic system in the space group P21/n. Molecular formula: C19H13FN2; Molecular weight: 288.31; Z = 4; crystal data: a = 8.7527(4) Å; b = 10.1342(4) Å; c = 17.0211(6) Å; β = 104.187(4)°; V = 1463.75(11) Å3 ; Dcal = 1.308 Mg m<sup>−</sup><sup>3</sup> ; F000 = 600; final R[F2 > 2σ(F2 )] = 0.063 and wR(F<sup>2</sup> ) = 0.160 for 5352 observed reflections with (I > 2σ(I)).

#### **Figure 11.**

*The crystal structure, partially showing the formation of π-π stacking interactions. Symmetry code (i): 2 − x, −y, −z.*

All the H atoms were placed geometrically and allowed to trip on their parental atoms, with C▬H = 0.93 Å (Csp2 ). Uiso(H) = kUeq(C), where k = 1.5 (CH3H) and 1.2 (for all other carbon-attached H atoms).

The benzimidazole group is nearly planar [maximum deviation = 0.0342(9) Å]. The mean planes of the phenyl at N1 and fluorobenzene at C2 make dihedral angles of 58.94(3) and 51.43(3)°, respectively, with the benzimidazole least-squares plane. The phenyl and fluorobenzene mean planes make an angle of 60.17(6)°. Finally, three C▬H…F hydrogen bonds and two weak C▬H…π contacts connecting the fused benzene ring lead to a three-dimensional construction.

**41**

**Figure 13.**

**Figure 12.**

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

*The crystal packing with hydrogen bonds [14], viewed along the c axis.*

*The thermal displacement ellipsoid plot (at the 50% probability level).*

The ORTEP-3 for Windows [13] was used to draw the thermal displacement ellipsoid plot (**Figure 13**) at the 50% probability level. **Figure 14** presents the C▬H…π interactions observed in the crystal structure, brought using the program PLATON [14]. The crystal structure packing view is shown in **Figure 15** [14].

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

*Chemistry and Applications of Benzimidazole and its Derivatives*

*The thermal displacement ellipsoid plot (at the 50% probability level).*

All the H atoms were placed geometrically and allowed to trip on their parental

*The crystal structure, partially showing the formation of π-π stacking interactions. Symmetry code (i): 2 − x, −y, −z.*

The benzimidazole group is nearly planar [maximum deviation = 0.0342(9) Å]. The mean planes of the phenyl at N1 and fluorobenzene at C2 make dihedral angles of 58.94(3) and 51.43(3)°, respectively, with the benzimidazole least-squares plane. The phenyl and fluorobenzene mean planes make an angle of 60.17(6)°. Finally, three C▬H…F hydrogen bonds and two weak C▬H…π contacts connecting the

). Uiso(H) = kUeq(C), where k = 1.5 (CH3H) and 1.2

**40**

**Figure 11.**

**Figure 10.**

atoms, with C▬H = 0.93 Å (Csp2

(for all other carbon-attached H atoms).

fused benzene ring lead to a three-dimensional construction.

The ORTEP-3 for Windows [13] was used to draw the thermal displacement ellipsoid plot (**Figure 13**) at the 50% probability level. **Figure 14** presents the C▬H…π interactions observed in the crystal structure, brought using the program PLATON [14]. The crystal structure packing view is shown in **Figure 15** [14].

**Figure 12.** *The crystal packing with hydrogen bonds [14], viewed along the c axis.*

**Figure 13.** *The thermal displacement ellipsoid plot (at the 50% probability level).*

#### **3.6 Structural analysis of 2-(naphthalen-1-yl)-1-phenyl-1H-benzimidazole benzene hemisolvate (NPBIBHS)**

This section describes the determination of the crystal structure and molecular structure of NPBIBHS [9]. The direct method program SHELXS2013 [11] was used to solve the crystal structure. SHELXL2013 [11] program is used to refine the crystal structure. This compound crystallises in the triclinic system in the space group P¯ 1 Molecular formula: C23H16N2.0.5C6H6; molecular weight: 359.43; Z = 2; crystal data: a = 8.5529(3) Å; b = 9.4517(3) Å; c = 11.8936(3) Å; α = 86.334(2)°;

#### **Figure 14.**

*The crystal structure, partially showing the formation of C▬H…π interactions. Symmetry codes are (iv): −x, −y + 1, −z and (v): −x + 1, −y + 1, −z.*

**43**

**Figure 17.**

**Figure 16.**

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

*The thermal displacement ellipsoid plot (at the 50% probability level).*

*The crystal structure, showing the formation of complex C*▬*H…π interactions.*

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

**Figure 15.** *The crystal packing with hydrogen bonds [14], viewed along the b axis.*

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

*Chemistry and Applications of Benzimidazole and its Derivatives*

**benzene hemisolvate (NPBIBHS)**

group P¯

**3.6 Structural analysis of 2-(naphthalen-1-yl)-1-phenyl-1H-benzimidazole** 

structure of NPBIBHS [9]. The direct method program SHELXS2013 [11] was used to solve the crystal structure. SHELXL2013 [11] program is used to refine the crystal structure. This compound crystallises in the triclinic system in the space

crystal data: a = 8.5529(3) Å; b = 9.4517(3) Å; c = 11.8936(3) Å; α = 86.334(2)°;

This section describes the determination of the crystal structure and molecular

1 Molecular formula: C23H16N2.0.5C6H6; molecular weight: 359.43; Z = 2;

*The crystal structure, partially showing the formation of C▬H…π interactions. Symmetry codes are (iv): −x,* 

**42**

**Figure 15.**

**Figure 14.**

*−y + 1, −z and (v): −x + 1, −y + 1, −z.*

*The crystal packing with hydrogen bonds [14], viewed along the b axis.*

**Figure 16.** *The thermal displacement ellipsoid plot (at the 50% probability level).*

**Figure 17.** *The crystal structure, showing the formation of complex C*▬*H…π interactions.*

**Figure 18.** *The crystal packing with hydrogen bonds [14], viewed along the a axis.*

β = 89.838(2)°; γ = 75.051(3)°; V = 926.94(5) Å3 ; Dcal = 1.288 Mg m<sup>−</sup><sup>3</sup> ; F000 = 378; final R[F2 > 2σ(F2 )] = 0.057 and wR(F2 ) = 0.160 for 9086 observed reflections with I > 2σ(I).

All the H atoms were placed geometrically and permitted to trip on their parental atoms, with C▬H = 0.95 Å (Csp2 ) and Uiso(H) = kUeq(C), where k = 1.5 (▬CH3 H) and 1.2 (for all other H).

The benzimidazole least-squares plane [maximum deviation = 0.0258(6) Å] and the naphthalene least-squares plane [maximum deviation = 0.0254(6) Å] make dihedral angle of 61.955(17)°. The least-squares planes of the imidazole ring and the phenyl ring make a dihedral angle of 61.73(4)°. An intramolecular S(6) ring motif [12] is generated by the C▬H…N hydrogen bond. The hydrogen bond involving has the carbon atom (C28) as the proton donor and the nitrogen atom (N3) as the acceptor, which forms a six-membered ring. Seven weak C▬H…π links concerning the attached ring system, the benzene solvent molecule, the imidazole and the phenyl rings are detected, to a three-dimensional architecture.

The thermal displacement ellipsoid plot (**Figure 16**) at the 50% probability level was drawn using the program ORTEP-3 for Windows [13]. **Figure 17** presents the C▬H…π interactions observed in the crystal structure brought using the program PLATON [14]. The crystal structure packing view is shown in **Figure 18** [14].

#### **4. Comparative study on the structural aspects of the six benzimidazole derivatives**

Section 3 presents the X-ray crystal structure analyses of six closely related organic benzimidazole compounds. The MBMPBI compound is similar to 2-(1H-benzimidazol-2-yl)phenol (BIP) except for the presence of methylbenzyl at the first position of the benzimidazole unit, a methyl at the fourth position of the phenyl group and the absence of hydroxyl group. The DPBI compound is similar to 2-(1H-benzimidazol-2-yl)phenol (BIP) except for the presence of a phenyl group at

**45**

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

C▬H…F; (2) interactions C▬H…π and (3) stacking interactions π-π.

A type of hydrogen bond operational among a soft acid CH and a soft base π-system is known as a C▬H…π interaction. The most striking contacts are (1) the connections among the aliphatic C▬H donors and the aromatic π-acceptors and (2) the connections among the aromatic C▬H donors and aromatic π-acceptors. The non-covalent contacts that encompass the π systems in chemistry are the π-effects

Related crystal structures: 1293 articles match the search term 'Benzimidazole' on IUCr Journals Crystallography Journals Online (https://journals.iucr.org/) as on February 10, 2019. The search (IUCr Journals' paper reference codes are: bh2413: 2-(4-chlorophenyl)-1-phenyl-1H-benzimidazole, bi2334: 1-benzyl-2-phenyl-1H-benzimidazole, bv2218: 1-phenyl-2-[4-(trifluoromethyl)phenyl]-1H-benzimidazole, bx2457: 1-(4-bromobenzyl)-2-(4-bromophenyl)-1H-benzimidazole, ci2926: 1-benzyl-1H-benzimidazole, fy2081: 1-phenyl-2-p-tolyl-1H-benzimidazole, go2077: 2-(4-methoxyphenyl)-1-phenyl-1H-benzimidazole, hk2704: 2-p-tolyl-1-ptolylmethyl-1H-benzimidazole, lh5659: 2-(3,4-difluorophenyl)-1H-benzimidazole and lh5706: 2-[4-(trifluoromethyl)phenyl]-1H-benzimidazole)) confirms that the geometry of the benzimidazole cores is similar in all the reported structures.

This chapter described the research work carried out by the authors on the crystal structure determination of some selected biologically important new benzimidazole derivatives by using X-rays. The detailed structural analyses on the bond lengths, bond angles, torsion angles and dihedral angles between the least-squares planes of these six benzimidazole derivatives indicate that in the compounds BIP, MBMPBI, DPBI, PBIP, FPPBI and NPBIBHS, the benzimidazole unit is essentially planar as expected and as revealed by the latest literature survey (https://journals.iucr.org/). The present X-ray study confirms that the benzimidazole skeleton has an imidazole planer five-membered heterocyclic ring fused with the benzene ring. The basic geometrical examination (bond lengths and bond angles) of the benzimidazole core in the BIP molecule are in good agreement with those observed in other closely related benzimidazole derivatives. All the substituents are in the expected positions around the benzimidazole units. The X-ray study confirms the molecular structure and atom connectivity of the above-studied compounds as shown in **Figures 2**, **5**, **7**, **10**, **13** and **16**. The O▬H…N, N▬H…O, C▬H…N, C▬H…O, C▬H…F hydrogen bonds, C▬H…π and the π-π interactions are effective in the stabilisation of the crystal structure. We are interested in studying the biological and photophysical properties of BIP, MBMPBI, DPBI, PBIP, FPPBI and NPBIBHS compounds. The benzimidazole derivatives are a sensitive fluorescent sensor for TiO2 (P25), Fe2O3, WO3, Al2O3,

the first position of the benzimidazole unit and the absence of an ▬OH group. The PBIP compound is similar to that of 2-(1H-benzimidazole-2-yl)phenol (BIP) except for the presence of a phenyl group at the first position of the benzimidazole unit and the absence of the ▬H atom. The FPPBI compound is like that of 1,2-diphenyl-1H-benzimidazole (DPBI) except for the presence of a fluorine atom at the fourth position of the phenyl group in the second location of the benzimidazole core. All the six structures have the benzimidazole core essentially as the basic skeleton, with different groups (▬H, ▬C6H4▬OH, ▬CH2▬C6H4▬CH3, ▬C6H4▬CH3, ▬C6H5, ▬C6H5, ▬C6H5, ▬C6H4▬OH, ▬C6H5, ▬C6H4-F, ▬C6H5, and ▬C10H7) as substituents. The structural determinations of the compounds have revealed several features, such as (1) the hydrogen bonds: O▬H…N, N▬H…O, C▬H…N, C▬H…O,

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

or the π-interactions.

**5. Conclusions**

#### *X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

the first position of the benzimidazole unit and the absence of an ▬OH group. The PBIP compound is similar to that of 2-(1H-benzimidazole-2-yl)phenol (BIP) except for the presence of a phenyl group at the first position of the benzimidazole unit and the absence of the ▬H atom. The FPPBI compound is like that of 1,2-diphenyl-1H-benzimidazole (DPBI) except for the presence of a fluorine atom at the fourth position of the phenyl group in the second location of the benzimidazole core.

All the six structures have the benzimidazole core essentially as the basic skeleton, with different groups (▬H, ▬C6H4▬OH, ▬CH2▬C6H4▬CH3, ▬C6H4▬CH3, ▬C6H5, ▬C6H5, ▬C6H5, ▬C6H4▬OH, ▬C6H5, ▬C6H4-F, ▬C6H5, and ▬C10H7) as substituents. The structural determinations of the compounds have revealed several features, such as (1) the hydrogen bonds: O▬H…N, N▬H…O, C▬H…N, C▬H…O, C▬H…F; (2) interactions C▬H…π and (3) stacking interactions π-π.

A type of hydrogen bond operational among a soft acid CH and a soft base π-system is known as a C▬H…π interaction. The most striking contacts are (1) the connections among the aliphatic C▬H donors and the aromatic π-acceptors and (2) the connections among the aromatic C▬H donors and aromatic π-acceptors. The non-covalent contacts that encompass the π systems in chemistry are the π-effects or the π-interactions.

Related crystal structures: 1293 articles match the search term 'Benzimidazole' on IUCr Journals Crystallography Journals Online (https://journals.iucr.org/) as on February 10, 2019. The search (IUCr Journals' paper reference codes are: bh2413: 2-(4-chlorophenyl)-1-phenyl-1H-benzimidazole, bi2334: 1-benzyl-2-phenyl-1H-benzimidazole, bv2218: 1-phenyl-2-[4-(trifluoromethyl)phenyl]-1H-benzimidazole, bx2457: 1-(4-bromobenzyl)-2-(4-bromophenyl)-1H-benzimidazole, ci2926: 1-benzyl-1H-benzimidazole, fy2081: 1-phenyl-2-p-tolyl-1H-benzimidazole, go2077: 2-(4-methoxyphenyl)-1-phenyl-1H-benzimidazole, hk2704: 2-p-tolyl-1-ptolylmethyl-1H-benzimidazole, lh5659: 2-(3,4-difluorophenyl)-1H-benzimidazole and lh5706: 2-[4-(trifluoromethyl)phenyl]-1H-benzimidazole)) confirms that the geometry of the benzimidazole cores is similar in all the reported structures.

#### **5. Conclusions**

*Chemistry and Applications of Benzimidazole and its Derivatives*

β = 89.838(2)°; γ = 75.051(3)°; V = 926.94(5) Å3

*The crystal packing with hydrogen bonds [14], viewed along the a axis.*

)] = 0.057 and wR(F2

parental atoms, with C▬H = 0.95 Å (Csp2

rings are detected, to a three-dimensional architecture.

(▬CH3 H) and 1.2 (for all other H).

; Dcal = 1.288 Mg m<sup>−</sup><sup>3</sup>

All the H atoms were placed geometrically and permitted to trip on their

The benzimidazole least-squares plane [maximum deviation = 0.0258(6) Å] and the naphthalene least-squares plane [maximum deviation = 0.0254(6) Å] make dihedral angle of 61.955(17)°. The least-squares planes of the imidazole ring and the phenyl ring make a dihedral angle of 61.73(4)°. An intramolecular S(6) ring motif [12] is generated by the C▬H…N hydrogen bond. The hydrogen bond involving has the carbon atom (C28) as the proton donor and the nitrogen atom (N3) as the acceptor, which forms a six-membered ring. Seven weak C▬H…π links concerning the attached ring system, the benzene solvent molecule, the imidazole and the phenyl

The thermal displacement ellipsoid plot (**Figure 16**) at the 50% probability level was drawn using the program ORTEP-3 for Windows [13]. **Figure 17** presents the C▬H…π interactions observed in the crystal structure brought using the program PLATON [14]. The crystal structure packing view is shown in **Figure 18** [14].

**4. Comparative study on the structural aspects of the six benzimidazole** 

Section 3 presents the X-ray crystal structure analyses of six closely related

2-(1H-benzimidazol-2-yl)phenol (BIP) except for the presence of methylbenzyl at the first position of the benzimidazole unit, a methyl at the fourth position of the phenyl group and the absence of hydroxyl group. The DPBI compound is similar to 2-(1H-benzimidazol-2-yl)phenol (BIP) except for the presence of a phenyl group at

organic benzimidazole compounds. The MBMPBI compound is similar to

) = 0.160 for 9086 observed reflections with I > 2σ(I).

) and Uiso(H) = kUeq(C), where k = 1.5

; F000 = 378; final

**44**

R[F2

**Figure 18.**

> 2σ(F2

**derivatives**

This chapter described the research work carried out by the authors on the crystal structure determination of some selected biologically important new benzimidazole derivatives by using X-rays. The detailed structural analyses on the bond lengths, bond angles, torsion angles and dihedral angles between the least-squares planes of these six benzimidazole derivatives indicate that in the compounds BIP, MBMPBI, DPBI, PBIP, FPPBI and NPBIBHS, the benzimidazole unit is essentially planar as expected and as revealed by the latest literature survey (https://journals.iucr.org/). The present X-ray study confirms that the benzimidazole skeleton has an imidazole planer five-membered heterocyclic ring fused with the benzene ring. The basic geometrical examination (bond lengths and bond angles) of the benzimidazole core in the BIP molecule are in good agreement with those observed in other closely related benzimidazole derivatives. All the substituents are in the expected positions around the benzimidazole units. The X-ray study confirms the molecular structure and atom connectivity of the above-studied compounds as shown in **Figures 2**, **5**, **7**, **10**, **13** and **16**. The O▬H…N, N▬H…O, C▬H…N, C▬H…O, C▬H…F hydrogen bonds, C▬H…π and the π-π interactions are effective in the stabilisation of the crystal structure. We are interested in studying the biological and photophysical properties of BIP, MBMPBI, DPBI, PBIP, FPPBI and NPBIBHS compounds. The benzimidazole derivatives are a sensitive fluorescent sensor for TiO2 (P25), Fe2O3, WO3, Al2O3,

CuO, TiO2 (H), ZnO, Cu-ZnO, Ag-ZnO, TiO2 (R) and TiO2 (A) nanoparticles. The benzimidazole-based iridium(III) complexes show green emission with maximum electroluminescent efficiencies at low voltage.

## **Acknowledgements**

We acknowledge Dr. Anthony Linden and Professor R. J. Butcher for their help in collecting the single-crystal X-ray diffraction data.

## **Conflict of interest**

There is no conflict of interest in writing this chapter.

#### **Thanks**

Aravazhi Amalan Thiruvalluvar thanks his wife Lilly for all her emotional support and help at various stages of this chapter writing and his son Uthaya Raj and daughter Manju Princy for their loving support.

#### **List of abbreviations (a partial crystallographic information file (CIF) for the compound BIB only as an example)**

**47**

**Author details**

Tamil Nadu, India

Aravazhi Amalan Thiruvalluvar1

and Sivaraman Rosepriya3

Thanjavur, Tamil Nadu, India

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*, Gopalsamy Vasuki1

1 Department of Physics, Kunthavai Naacchiyaar Government Arts College for

3 Department of Physics, Rajah Serfoji Government College (Autonomous),

2 Department of Chemistry, Annamalai University, Chidambaram,

Women (Autonomous), Thanjavur, Tamil Nadu, India

\*Address all correspondence to: thiruvalluvar.a@gmail.com

, Jayaraman Jayabharathi2

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

*DOI: http://dx.doi.org/10.5772/intechopen.85291*


*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

#### **Author details**

*Chemistry and Applications of Benzimidazole and its Derivatives*

maximum electroluminescent efficiencies at low voltage.

in collecting the single-crystal X-ray diffraction data.

daughter Manju Princy for their loving support.

**for the compound BIB only as an example)**

\_space\_group\_crystal\_system monoclinic \_space\_group\_name\_H-M\_alt P 21/c

\_chemical\_formula\_weight 210.23 \_cell\_formula\_units\_Z 4

\_cell\_length\_a 16.864(4) \_cell\_length\_b 4.7431(8) \_cell\_length\_c 12.952(2) \_cell\_angle\_alpha 90 \_cell\_angle\_beta 102.34(2) \_cell\_angle\_gamma 90 \_cell\_volume 1012.1(3) \_exptl\_crystal\_density\_diffrn 1.380 \_exptl\_crystal\_F\_000 440 \_reflns\_threshold\_expression I > 2(I) \_refine\_ls\_R\_factor\_gt 0.067 \_refine\_ls\_wR\_factor\_gt 0.131 \_reflns\_number\_gt 1184

\_chemical\_formula\_moiety C13 H10 N2 O

There is no conflict of interest in writing this chapter.

**Acknowledgements**

**Conflict of interest**

**Thanks**

CuO, TiO2 (H), ZnO, Cu-ZnO, Ag-ZnO, TiO2 (R) and TiO2 (A) nanoparticles. The benzimidazole-based iridium(III) complexes show green emission with

We acknowledge Dr. Anthony Linden and Professor R. J. Butcher for their help

Aravazhi Amalan Thiruvalluvar thanks his wife Lilly for all her emotional support and help at various stages of this chapter writing and his son Uthaya Raj and

**List of abbreviations (a partial crystallographic information file (CIF)** 

**46**

Aravazhi Amalan Thiruvalluvar1 \*, Gopalsamy Vasuki1 , Jayaraman Jayabharathi2 and Sivaraman Rosepriya3

1 Department of Physics, Kunthavai Naacchiyaar Government Arts College for Women (Autonomous), Thanjavur, Tamil Nadu, India

2 Department of Chemistry, Annamalai University, Chidambaram, Tamil Nadu, India

3 Department of Physics, Rajah Serfoji Government College (Autonomous), Thanjavur, Tamil Nadu, India

\*Address all correspondence to: thiruvalluvar.a@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Cross EM, White KM, Moshrefzadeh RS, Francis CV. Azobenzimidazole compounds and polymers for nonlinear optics. Macromolecules. 1995;**28**(7):2526-2532. DOI: 10.1021/ ma00111a055

[2] Brown KL. Chemistry and enzymology of vitamin B12. Chemical Reviews. 2005;**105**(6):2075-2150. DOI: 10.1021/cr030720z

[3] Spasov AA, Yozhitsa IN, Bugaeva LI, Anisimova VA. Benzimidazole derivatives: Spectrum of pharmacological activity and toxicological properties (a review). Pharmaceutical Chemistry Journal. 1999;**33**(5):232-243. DOI: 10.1007/ BF02510042

[4] Prakash SM, Thiruvalluvar A, Rosepriya S, Srinivasan N. 2-(1H-Benzimidazol-2-yl)phenol. Acta Crystallographica Section E: Crystallographic Communications. 2014;**E70**:o184. DOI: 10.1107/ S1600536814001366

[5] Rosepriya S, Thiruvalluvar A, Jayamoorthy K, Jayabharathi J, Linden A. 1-(4-Methylbenzyl)-2-(4 methylphenyl)-1H-benzimidazole. Acta Crystallographica Section E: Crystallographic Communications. 2011;**E67**:o3519. DOI: 10.1107/ S160053681105077X

[6] Rosepriya S, Thiruvalluvar A, Jayamoorthy K, Jayabharathi J, Öztürk Yildirim S, Butcher RJ. 1,2-Diphenyl-1Hbenzimidazole. Acta Crystallographica Section E: Crystallographic Communications. 2012;**E68**:o3283. DOI: 10.1107/S1600536812044960

[7] Thiruvalluvar A, Rosepriya S, Jayamoorthy K, Jayabharathi J, Öztürk Yildirim S, Butcher RJ. 2-(1-Phenyl-1H-benzimidazol-2-yl)phenol. Acta Crystallographica Section E:

Crystallographic Communications. 2013;**E69**:o62. DOI: 10.1107/ S1600536812049859

[8] Jayamoorthy K, Rosepriya S, Thiruvalluvar A, Jayabharathi J, Butcher RJ. 2-(4-Fluorophenyl)-1-phenyl-1Hbenzimidazole. Acta Crystallographica Section E: Crystallographic Communications. 2012;**E68**:o2708. DOI: 10.1107/ S1600536812035155

[9] Srinivasan N, Thiruvalluvar A, Rosepriya S, Prakash SM, Butcher RJ. 2-(Naphthalen-1-yl)-1-phenyl-1Hbenzimidazole benzene hemisolvate. Acta Crystallographica Section E: Crystallographic Communications. 2014;**E70**:o55-o56. DOI: 10.1107/ S160053681303331X

[10] Burla MC, Caliandro R, Camalli M, Carrozzini B, Cascarano GL, Giacovazzo C, et al. SIR2011: A new package for crystal structure determination and refinement. Journal of Applied Crystallography. 2012;**45**:357-361. DOI: 10.1107/ S0021889812001124

[11] Sheldrick GM. A short history of SHELX. Acta Crystallographica Section A: Foundations and Advances. 2008;**A64**:112-122. DOI: 10.1107/ S0108767307043930

[12] Bernstein J, Davis RE, Shimoni L, Chang N-L. Patterns in hydrogen bonding: Functionality and graph set analysis in crystals. Angewandte Chemie International Edition in English. 1995;**34**:1555-1573. DOI: 10.1002/ anie.199515551

[13] Farrugia LJ. WinGX and ORTEP for windows: An update. Journal of Applied Crystallography. 2012;**45**:849-854. DOI: 10.1107/S0021889812029111

**49**

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives*

*DOI: http://dx.doi.org/10.5772/intechopen.85291*

Crystallographica Section D: Structural Biology. 2009;**D65**:148-155. DOI: 10.1107/S090744490804362X

[15] Burla MC, Camalli M, Carrozzini B, Cascarano GL, Giacovazzo C,

[16] Burla MC, Caliandro R, Camalli M, Carrozzini B, Cascarano GL, De Caro L, et al. SIR2004: An improved tool for crystal structure determination and refinement. Journal of Applied Crystallography. 2005;**38**:381-388. DOI:

2003;**36**:1103. DOI: 10.1107/

10.1107/S002188980403225X

S0021889803012585

Polidori G, et al. SIR2002: The program. Journal of Applied Crystallography.

[14] Spek AL. Structure validation in chemical crystallography. Acta

*X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.85291*

Crystallographica Section D: Structural Biology. 2009;**D65**:148-155. DOI: 10.1107/S090744490804362X

[15] Burla MC, Camalli M, Carrozzini B, Cascarano GL, Giacovazzo C, Polidori G, et al. SIR2002: The program. Journal of Applied Crystallography. 2003;**36**:1103. DOI: 10.1107/ S0021889803012585

[16] Burla MC, Caliandro R, Camalli M, Carrozzini B, Cascarano GL, De Caro L, et al. SIR2004: An improved tool for crystal structure determination and refinement. Journal of Applied Crystallography. 2005;**38**:381-388. DOI: 10.1107/S002188980403225X

**48**

*Chemistry and Applications of Benzimidazole and its Derivatives*

Crystallographic Communications. 2013;**E69**:o62. DOI: 10.1107/

[8] Jayamoorthy K, Rosepriya S,

[9] Srinivasan N, Thiruvalluvar A, Rosepriya S, Prakash SM, Butcher RJ. 2-(Naphthalen-1-yl)-1-phenyl-1Hbenzimidazole benzene hemisolvate. Acta Crystallographica Section E: Crystallographic Communications. 2014;**E70**:o55-o56. DOI: 10.1107/

[10] Burla MC, Caliandro R, Camalli M, Carrozzini B, Cascarano GL, Giacovazzo C, et al. SIR2011: A new package for crystal structure determination and refinement. Journal of Applied Crystallography. 2012;**45**:357-361. DOI: 10.1107/

[11] Sheldrick GM. A short history of SHELX. Acta Crystallographica Section A: Foundations and Advances. 2008;**A64**:112-122. DOI: 10.1107/

[12] Bernstein J, Davis RE, Shimoni L, Chang N-L. Patterns in hydrogen bonding: Functionality and graph set analysis in crystals. Angewandte Chemie International Edition in English.

1995;**34**:1555-1573. DOI: 10.1002/

10.1107/S0021889812029111

[14] Spek AL. Structure validation in chemical crystallography. Acta

[13] Farrugia LJ. WinGX and ORTEP for windows: An update. Journal of Applied Crystallography. 2012;**45**:849-854. DOI:

Thiruvalluvar A, Jayabharathi J, Butcher RJ. 2-(4-Fluorophenyl)-1-phenyl-1Hbenzimidazole. Acta Crystallographica Section E: Crystallographic Communications. 2012;**E68**:o2708. DOI: 10.1107/

S1600536812049859

S1600536812035155

S160053681303331X

S0021889812001124

S0108767307043930

anie.199515551

[1] Cross EM, White KM, Moshrefzadeh RS, Francis CV. Azobenzimidazole compounds and polymers for nonlinear optics. Macromolecules. 1995;**28**(7):2526-2532. DOI: 10.1021/

[2] Brown KL. Chemistry and

enzymology of vitamin B12. Chemical Reviews. 2005;**105**(6):2075-2150. DOI:

[3] Spasov AA, Yozhitsa IN, Bugaeva LI, Anisimova VA. Benzimidazole

**References**

ma00111a055

10.1021/cr030720z

BF02510042

derivatives: Spectrum of pharmacological activity and toxicological properties (a review). Pharmaceutical Chemistry Journal. 1999;**33**(5):232-243. DOI: 10.1007/

[4] Prakash SM, Thiruvalluvar A, Rosepriya S, Srinivasan N. 2-(1H-Benzimidazol-2-yl)phenol. Acta Crystallographica Section E: Crystallographic Communications. 2014;**E70**:o184. DOI: 10.1107/

[5] Rosepriya S, Thiruvalluvar A, Jayamoorthy K, Jayabharathi J, Linden A. 1-(4-Methylbenzyl)-2-(4 methylphenyl)-1H-benzimidazole. Acta Crystallographica Section E: Crystallographic Communications. 2011;**E67**:o3519. DOI: 10.1107/

[6] Rosepriya S, Thiruvalluvar A, Jayamoorthy K, Jayabharathi J, Öztürk Yildirim S, Butcher RJ. 1,2-Diphenyl-1Hbenzimidazole. Acta Crystallographica

Communications. 2012;**E68**:o3283. DOI:

Section E: Crystallographic

10.1107/S1600536812044960

[7] Thiruvalluvar A, Rosepriya S, Jayamoorthy K, Jayabharathi J, Öztürk Yildirim S, Butcher RJ. 2-(1-Phenyl-1H-benzimidazol-2-yl)phenol. Acta Crystallographica Section E:

S1600536814001366

S160053681105077X

**51**

**Chapter 4**

**Abstract**

**1. Introduction**

*Kantharaju Kamanna*

Synthesis and Pharmacological

Benzimidazoles are a class of heterocyclic, aromatic compounds which share a fundamental structural characteristic of six-membered benzene fused to fivemembered imidazole moiety. Molecules having benzimidazole motifs showed promising application in biological and clinical studies. Nowadays it is a moiety of choice which possesses many pharmacological properties extensively explored with a potent inhibitor of various enzymes involved in a wide range of therapeutic uses which are antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, and antihistamine, as well as used in cardiovascular disease, neurology, endocrinology, ophthalmology, and more. The increased interest for benzimidazole compounds has been due to their excellent properties, like increased stability, bioavailability, and significant biological activity. This book chapter mainly discussed recent synthetic methods developed for the benzimidazole derivatives and their

The biological application of benzimidazole nucleus is discovered way back 1944, when Woolley speculated that benzimidazoles resemble purine-like structure and elicit some biological application [1]. Hence benzimidazole structure found isosters of naturally occurring nucleotides, which allows them to contact easily with the biopolymers of the living system. Later, Brink discovered 5,6-dimethylbenzimidazole as a degradation product of vitamin B12 and subsequently found some of its analogs having vitamin B12-like activity [2, 3]. These initial study reports emerged to explore various decorated benzimidazole motif discoveries by the medicinal chemist. Over the few decades of active research, benzimidazole has evolved as an important heterocyclic nucleus due to its wide range of pharmacological applications. Hence, it's worth to understand the basic chemistry and structure of such a wonderful molecule. Benzimidazole is formed by the fusion of benzene and imidazole moiety, and numbering system according to the IUPAC is depicted in **Figure 1**. Historically, the first benzimidazole was prepared in 1872 by Hoebrecker, who obtained 2,5 (or 2,6)-dimethylbenzimidazole by the reduction of 2-nitro-4-methylacetanilide [4]. Benzimidazoles which contain a hydrogen atom attached to nitrogen in the 1-position readily tautomerize, and this may be depicted in **Figure 1**. This basic "6 + 5" heterocyclic structure is shared by another class of chemical compounds existing in nature shown in **Figure 2**.

Profile of Benzimidazoles

pharmacological properties exemplified on several derivatives.

**Keywords:** benzimidazole, heterocycle, medicinal chemistry,

structure activity relationship, biological activity

#### **Chapter 4**

## Synthesis and Pharmacological Profile of Benzimidazoles

*Kantharaju Kamanna*

#### **Abstract**

Benzimidazoles are a class of heterocyclic, aromatic compounds which share a fundamental structural characteristic of six-membered benzene fused to fivemembered imidazole moiety. Molecules having benzimidazole motifs showed promising application in biological and clinical studies. Nowadays it is a moiety of choice which possesses many pharmacological properties extensively explored with a potent inhibitor of various enzymes involved in a wide range of therapeutic uses which are antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, and antihistamine, as well as used in cardiovascular disease, neurology, endocrinology, ophthalmology, and more. The increased interest for benzimidazole compounds has been due to their excellent properties, like increased stability, bioavailability, and significant biological activity. This book chapter mainly discussed recent synthetic methods developed for the benzimidazole derivatives and their pharmacological properties exemplified on several derivatives.

**Keywords:** benzimidazole, heterocycle, medicinal chemistry, structure activity relationship, biological activity

#### **1. Introduction**

The biological application of benzimidazole nucleus is discovered way back 1944, when Woolley speculated that benzimidazoles resemble purine-like structure and elicit some biological application [1]. Hence benzimidazole structure found isosters of naturally occurring nucleotides, which allows them to contact easily with the biopolymers of the living system. Later, Brink discovered 5,6-dimethylbenzimidazole as a degradation product of vitamin B12 and subsequently found some of its analogs having vitamin B12-like activity [2, 3]. These initial study reports emerged to explore various decorated benzimidazole motif discoveries by the medicinal chemist. Over the few decades of active research, benzimidazole has evolved as an important heterocyclic nucleus due to its wide range of pharmacological applications. Hence, it's worth to understand the basic chemistry and structure of such a wonderful molecule. Benzimidazole is formed by the fusion of benzene and imidazole moiety, and numbering system according to the IUPAC is depicted in **Figure 1**. Historically, the first benzimidazole was prepared in 1872 by Hoebrecker, who obtained 2,5 (or 2,6)-dimethylbenzimidazole by the reduction of 2-nitro-4-methylacetanilide [4]. Benzimidazoles which contain a hydrogen atom attached to nitrogen in the 1-position readily tautomerize, and this may be depicted in **Figure 1**. This basic "6 + 5" heterocyclic structure is shared by another class of chemical compounds existing in nature shown in **Figure 2**.

#### **Figure 1.**

*Tautomeric forms of benzimidazole.*

#### **Figure 2.** *Common biomolecules with a "6 + 5" heterocyclic structure.*

**Figure 3.** *Benzimidazole-based drugs.*

Among the members of this group of molecules are well-known building blocks for biopolymers, such as adenine and guanine, two of the five nucleic acid bases, uric acid, and caffeine. From this basic structural similarity, it is not too surprising that benzimidazole nucleus has emerged biologically as an important pharmacophore with a privileged structure in medicinal chemistry. Nowadays it is a moiety of choice which possesses many pharmacological properties. The most prominent benzimidazole compound in nature is *N*-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. The pharmacological application of benzimidazole analogs found potent inhibitors of various enzymes involved and therapeutic uses including as antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, antihistamine, and also neurological, endocrinological, and ophthalmological drugs [5–13].

The use of benzimidazole started many years back in 1990 onward, a vast number of benzimidazole analogs synthesis were reported, which resulted in increased stability, bioavailability, and significant biological activity. Some of the well-known active drugs with benzimidazole ring are mentioned in **Figure 3**, omeprazole, bendamustine,

**53**

**Figure 5.**

**Figure 4.**

*Synthesis and Pharmacological Profile of Benzimidazoles DOI: http://dx.doi.org/10.5772/intechopen.85229*

**2. Overview of benzimidazole synthesis**

 **with OPD**

used for the benzimidazole motif synthesis reviewed.

albendazole, and mebendazole. This chapter is mainly focused on the chemistry of the benzimidazoles and on the recently reported synthesis and mechanisms, structural aspects, and pharmacological applications with biological and clinical studies.

Experimentally the simple method for the synthesis of benzimidazole derivatives begin with benzene containing nitrogen functions at *ortho*-position to each other *o*-phenylenediamine (OPD) is well documented. In this section several synthetic methodologies are grouped according to the starting material which is

The reaction of OPD with aromatic/aliphatic aldehyde under suitable condition for the synthesis of 2-substituted benzimidazoles is well-known. Since the reaction involved oxidation, it required oxidative condition. The oxidation reaction may be carried out in the presence of air or more conveniently by oxidizing agent such as cupric acetate first introduced by Weidenhagen [14–16]. This method reported the reaction of OPD with aldehyde in the presence of water or alcoholic solution in the presence of cupric acetate. The formed cuprous salt of benzimidazole is decomposed with hydrogen sulfide which gave free benzimidazole after filtration. This method isolated excellent yields of 2-substituted benzimidazoles of alkyl, aryl, and heterocyclic substituted moiety. Further Wright's group reported the synthesis of *N*-alkylated benzimidazoles using *N*-alkylated-*o*-phenylenediamine with aldehydes gave good yields of 1-substituted benzimidazole. The mechanism found the initial formation of a Schiff intermediate by the reaction of aldehyde with one of the amines of OPD, followed by cyclization to form the product (**Figure 4**). The researcher observed that, the reaction between OPD and aldehyde in the absence of a specific oxidizing agent results to either 2-substituted benzimidazoles or aldimines (**Figure 5**) product formation in some cases aldimines major and some cases 2-substituted benzimidazoles are the major or both form exists in equal amounts. Rao and Smith et al. independently reviewed the reaction between OPD and Aldehydes (**Figure 6**) as a simple and efficient method to synthesize benzimidazoles [17, 18]. Numerous methods

**2.1 Synthesis of benzimidazoles by the reaction of substituted aldehyde**

*Mechanism of formation of benzimidazole catalyzed by oxidizing agent [PhI (OAc)2 ].*

*Synthesis of benzimidazoles via aldiminic intermediates in the absence of catalyst.*

*Chemistry and Applications of Benzimidazole and its Derivatives*

**52**

**Figure 3.**

**Figure 2.**

**Figure 1.**

*Tautomeric forms of benzimidazole.*

*Benzimidazole-based drugs.*

*Common biomolecules with a "6 + 5" heterocyclic structure.*

ophthalmological drugs [5–13].

Among the members of this group of molecules are well-known building blocks for biopolymers, such as adenine and guanine, two of the five nucleic acid bases, uric acid, and caffeine. From this basic structural similarity, it is not too surprising that benzimidazole nucleus has emerged biologically as an important pharmacophore with a privileged structure in medicinal chemistry. Nowadays it is a moiety of choice which possesses many pharmacological properties. The most prominent benzimidazole compound in nature is *N*-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. The pharmacological application of benzimidazole analogs found potent inhibitors of various enzymes involved and therapeutic uses including as antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, antihistamine, and also neurological, endocrinological, and

The use of benzimidazole started many years back in 1990 onward, a vast number of benzimidazole analogs synthesis were reported, which resulted in increased stability, bioavailability, and significant biological activity. Some of the well-known active drugs with benzimidazole ring are mentioned in **Figure 3**, omeprazole, bendamustine, albendazole, and mebendazole. This chapter is mainly focused on the chemistry of the benzimidazoles and on the recently reported synthesis and mechanisms, structural aspects, and pharmacological applications with biological and clinical studies.

#### **2. Overview of benzimidazole synthesis**

Experimentally the simple method for the synthesis of benzimidazole derivatives begin with benzene containing nitrogen functions at *ortho*-position to each other *o*-phenylenediamine (OPD) is well documented. In this section several synthetic methodologies are grouped according to the starting material which is used for the benzimidazole motif synthesis reviewed.

#### **2.1 Synthesis of benzimidazoles by the reaction of substituted aldehyde with OPD**

The reaction of OPD with aromatic/aliphatic aldehyde under suitable condition for the synthesis of 2-substituted benzimidazoles is well-known. Since the reaction involved oxidation, it required oxidative condition. The oxidation reaction may be carried out in the presence of air or more conveniently by oxidizing agent such as cupric acetate first introduced by Weidenhagen [14–16]. This method reported the reaction of OPD with aldehyde in the presence of water or alcoholic solution in the presence of cupric acetate. The formed cuprous salt of benzimidazole is decomposed with hydrogen sulfide which gave free benzimidazole after filtration. This method isolated excellent yields of 2-substituted benzimidazoles of alkyl, aryl, and heterocyclic substituted moiety. Further Wright's group reported the synthesis of *N*-alkylated benzimidazoles using *N*-alkylated-*o*-phenylenediamine with aldehydes gave good yields of 1-substituted benzimidazole. The mechanism found the initial formation of a Schiff intermediate by the reaction of aldehyde with one of the amines of OPD, followed by cyclization to form the product (**Figure 4**). The researcher observed that, the reaction between OPD and aldehyde in the absence of a specific oxidizing agent results to either 2-substituted benzimidazoles or aldimines (**Figure 5**) product formation in some cases aldimines major and some cases 2-substituted benzimidazoles are the major or both form exists in equal amounts. Rao and Smith et al. independently reviewed the reaction between OPD and Aldehydes (**Figure 6**) as a simple and efficient method to synthesize benzimidazoles [17, 18]. Numerous methods

**Figure 4.** *Mechanism of formation of benzimidazole catalyzed by oxidizing agent [PhI (OAc)2 ].*

**Figure 5.** *Synthesis of benzimidazoles via aldiminic intermediates in the absence of catalyst.*

**Figure 6.** *Synthesis of benzimidazole derivatives from OPD and aldehydes.*

are reported for the condensation of substituted OPD with aryl/alkyl/heterocyclic aldehydes catalyzed by different oxidizing agents or metal triflate such as Sc (OTf)3 or Yb (OTf)3 [19], sulfamic acid [20], H2O2-HCl [21], FeBr3 [22], PhI (OAc)2 [23], LaCl3 [24], H5IO6-SiO2 [25], Ce (NO3)3.6H2O [26], NaHSO4-SiO2 [27], mercuric oxide [28], chloranil [29], manganese dioxide [30], and I2/TBHP [31] and more methods [32–34]. This method isolated excellent yields of 2-substituted benzimidazoles with alkyl, aryl, and heterocyclic substituted moiety (**Figure 6**).

#### **2.2 Synthesis of benzimidazoles by the reaction of aryl/alkyl/heterocyclic acid chloride with OPD**

Other synthetic routes involved carboxylic acid with an OPD-required harsh condition in the presence of a strong acid at elevated temperatures with poor yield reported for the benzimidazole. Alternatively, a two-step synthesis is reported, wherein the OPD is treated with one equivalent of an acid chloride derivative and the resulting mono-acylated product is subjected to cyclodehydration under various conditions such as heating in aqueous acids/solvents or by greener methods such as glycerol [35], ionic liquid [Hbim] BF4 [36], agro-waste extract WEPBA [37], heteropolyacid [38], BF3.Et2O [39], zeolite [40], KF-Al2O3 [41], and more (**Figure 7**).

#### **2.3 Synthesis of benzimidazoles by the reaction of substituted alcohol or amines with** *o***-nitroarylamines**

Researcher demonstrated alternative substrate *o*-nitroarylamine reaction with substituted alcohol or amines by using various reducing/redox agents (FeCl3) for the synthesis of benzimidazole in a single step. This procedure has got commercial importance due to reasonable yield isolation (**Figure 8**) [42–44].

#### **Figure 7.** *Synthesis of benzimidazole starting OPD with acyl chloride derivatives.*

**55**

**Figure 10.**

**Figure 9.**

*Synthesis and Pharmacological Profile of Benzimidazoles DOI: http://dx.doi.org/10.5772/intechopen.85229*

*o***-substituted arylamines**

**2.4 Synthesis of benzimidazoles by the reaction of aldehyde or EAA with** 

methoxy linked on benzene rings which were tolerated (**Figure 9**) [47].

moderate to very good yields (**Figure 10**) [49].

*Synthesis of benzimidazoles using N-substituted amidines.*

*One-pot three-component reaction for the synthesis of benzimidazole.*

**2.5 Synthesis of benzimidazoles by** *C-H* **amination of** *N***-substituted amidines**

Researcher demonstrated oxidative C-H amination of *N*"-aryl-N'-tosyl/N' methylsulfonylamidines and *N*,*N*'-*bis*(aryl)amidines using iodobenzene as a catalyst to obtain 1,2-disubstituted benzimidazoles in the presence of *m*-CPBA which gave target product moderate to high yields (**5a**) [48]. Alternatively, other research group reported intramolecular *N*-arylations of amidines mediated by KOH in DMSO at 120°C (**5b**). The method allows diversely substituted products in

One-pot three-component reaction of 2-haloanilines, aldehydes, and NaN3 is also reported for the synthesis of benzimidazole [45]. The reaction catalyzed CuCl (5 mol%), and 5 mol% of TMEDA was reacted in DMSO at 120°C which gave the product good yields (**4a**). The reaction showed tolerance toward aliphatic, heterocyclic aldehydes, and functional groups such as ester, nitro, and chloro on aromatic afforded the desired products in moderate yields. Bahrami et al. reported useful synthetic methodology for the synthesis of benzimidazoles using catalytic redox cycling based on (Ce(IV)/Ce(III))/H2O2 redox-mediated oxidation of the Schiff intermediate derived from differently substituted aromatic 1,2-phenylendiamines/2-thiol with a variety of aromatic aldehydes which resulted in isolation of the product in good yield (**4b**) [46]. Further, Bao et al. found Brønsted acid-catalyzed (TsOH) cyclization reactions of 2-amino anilines with ethylacetoaceate (EAA) under oxidant-, metal-, and radiation-free conditions (**4c**). In this method various 2-substituted benzimidazoles are obtained with different groups such as methyl, chloro, nitro, and

**Figure 8.** *Synthesis of benzimidazoles starting o-nitroarylamines.* *Chemistry and Applications of Benzimidazole and its Derivatives*

*Synthesis of benzimidazole derivatives from OPD and aldehydes.*

alkyl, aryl, and heterocyclic substituted moiety (**Figure 6**).

**chloride with OPD**

**Figure 6.**

**with** *o***-nitroarylamines**

are reported for the condensation of substituted OPD with aryl/alkyl/heterocyclic aldehydes catalyzed by different oxidizing agents or metal triflate such as Sc (OTf)3 or Yb (OTf)3 [19], sulfamic acid [20], H2O2-HCl [21], FeBr3 [22], PhI (OAc)2 [23], LaCl3 [24], H5IO6-SiO2 [25], Ce (NO3)3.6H2O [26], NaHSO4-SiO2 [27], mercuric oxide [28], chloranil [29], manganese dioxide [30], and I2/TBHP [31] and more methods [32–34]. This method isolated excellent yields of 2-substituted benzimidazoles with

**2.2 Synthesis of benzimidazoles by the reaction of aryl/alkyl/heterocyclic acid** 

Other synthetic routes involved carboxylic acid with an OPD-required harsh condition in the presence of a strong acid at elevated temperatures with poor yield reported for the benzimidazole. Alternatively, a two-step synthesis is reported, wherein the OPD is treated with one equivalent of an acid chloride derivative and the resulting mono-acylated product is subjected to cyclodehydration under various conditions such as heating in aqueous acids/solvents or by greener methods such as glycerol [35], ionic liquid [Hbim] BF4 [36], agro-waste extract WEPBA [37], heteropolyacid [38], BF3.Et2O [39], zeolite [40], KF-Al2O3 [41], and more (**Figure 7**).

**2.3 Synthesis of benzimidazoles by the reaction of substituted alcohol or amines** 

Researcher demonstrated alternative substrate *o*-nitroarylamine reaction with substituted alcohol or amines by using various reducing/redox agents (FeCl3) for the synthesis of benzimidazole in a single step. This procedure has got commercial

**54**

**Figure 8.**

**Figure 7.**

*Synthesis of benzimidazole starting OPD with acyl chloride derivatives.*

importance due to reasonable yield isolation (**Figure 8**) [42–44].

*Synthesis of benzimidazoles starting o-nitroarylamines.*

#### **2.4 Synthesis of benzimidazoles by the reaction of aldehyde or EAA with**  *o***-substituted arylamines**

One-pot three-component reaction of 2-haloanilines, aldehydes, and NaN3 is also reported for the synthesis of benzimidazole [45]. The reaction catalyzed CuCl (5 mol%), and 5 mol% of TMEDA was reacted in DMSO at 120°C which gave the product good yields (**4a**). The reaction showed tolerance toward aliphatic, heterocyclic aldehydes, and functional groups such as ester, nitro, and chloro on aromatic afforded the desired products in moderate yields. Bahrami et al. reported useful synthetic methodology for the synthesis of benzimidazoles using catalytic redox cycling based on (Ce(IV)/Ce(III))/H2O2 redox-mediated oxidation of the Schiff intermediate derived from differently substituted aromatic 1,2-phenylendiamines/2-thiol with a variety of aromatic aldehydes which resulted in isolation of the product in good yield (**4b**) [46]. Further, Bao et al. found Brønsted acid-catalyzed (TsOH) cyclization reactions of 2-amino anilines with ethylacetoaceate (EAA) under oxidant-, metal-, and radiation-free conditions (**4c**). In this method various 2-substituted benzimidazoles are obtained with different groups such as methyl, chloro, nitro, and methoxy linked on benzene rings which were tolerated (**Figure 9**) [47].

#### **2.5 Synthesis of benzimidazoles by** *C-H* **amination of** *N***-substituted amidines**

Researcher demonstrated oxidative C-H amination of *N*"-aryl-N'-tosyl/N' methylsulfonylamidines and *N*,*N*'-*bis*(aryl)amidines using iodobenzene as a catalyst to obtain 1,2-disubstituted benzimidazoles in the presence of *m*-CPBA which gave target product moderate to high yields (**5a**) [48]. Alternatively, other research group reported intramolecular *N*-arylations of amidines mediated by KOH in DMSO at 120°C (**5b**). The method allows diversely substituted products in moderate to very good yields (**Figure 10**) [49].

#### **Figure 9.** *One-pot three-component reaction for the synthesis of benzimidazole.*

**Figure 10.** *Synthesis of benzimidazoles using N-substituted amidines.*

#### **2.6 Functionalization of benzimidazole to 2-substituted (hetero)aryl benzimidazole**

Shao et al. recently reported the synthesis of benzimidazoles via direct C−H bond arylation in the presence of a NHC-Pd(II)-Im complex. The method is tolerable to various activated and deactivated (hetero)aryl chlorides to get 2-(hetero) aryl benzimidazoles in high yields. It is a facile and an alternative methodology for the direct C−H bond arylation of (*benz*)imidazoles (**Figure 11**) [50].

#### **2.7 Synthesis by the reaction of** *N***-substituted formamides with OPD derivatives**

Bhanage et al. demonstrated efficient and convenient one-pot protocol synthesis of a benzimidazole derivative using various OPD derivatives and *N*-substituted formamides (C1 sources) in a zinc acetate-catalyzed cyclization in the presence of poly(methylhydrosiloxane) to afford corresponding products in good yields (**Figure 12**) [51].

**Figure 11.** *Synthesis of 2-substituted (hetero)aryl benzimidazoles.*

**Figure 12.**

*N-Substituted formamides as C1 sources for the synthesis of benzimidazole.*

**Figure 13.** *One-pot three-component reaction.*

**57**

**3.1 Anticancer activity**

*Synthesis and Pharmacological Profile of Benzimidazoles DOI: http://dx.doi.org/10.5772/intechopen.85229*

**2.8 Synthesis by one-pot three-component reaction**

**2.9 Synthesis of 1,2-disubstituted benzimidazole**

1,2-disubstituted benzimidazoles (**Figure 14**) [54].

Punniyamurthy's group reported copper-catalyzed one-pot, three-component reaction of *N*-aryl imines, in which imine acts as a directing group by chelating to the metal center, which affords a potential route for the transformation of the commercial aryl amines, aldehydes, and azides into valuable benzimidazole with vast substrate scope and diversity (**8a**). Further, the same group is reported in copper(II)-catalyzed oxidative cross-coupling of anilines, primary alkyl amines, and sodium azide in the presence of TBHP at moderate temperature (**8b**). This one-pot protocol involves a domino C-H functionalization, transamination, *ortho-*selective amination, and cyclization sequence. The method is found tolerable to broad functional group and

Chang et al. demonstrated intramolecular C−H amidation using molecular iodine under basic conditions. The imine substrates required were readily prepared by condensation of aldehydes with OPD derivatives. The reaction is carried out in the absence of metal-free cyclization, works well with crude imines, and allows synthesis of series of *N*-substituted benzimidazoles. This method is tolerable to a

Benzimidazole moiety came in scenic after discovery of it as an integral part of the structure of the vitamin B12 in the 1950s. In the early 1960s, it was developed as plant fungicides and later as veterinary anthelminthic. Further, a variety of veterinary anthelmintics were developed and marketed, including parbendazole, fenbendazole, oxfendazole, and cambendazole. In 1962 the first benzimidazole developed and licensed for human use was thiabendazole, and present more derivatives of benzimidazole that have been clinically approved are albendazole, mebendazole, and flubendazole as anthelmintic; omeprazole, lansoprazole, and pantoprazole as proton pump inhibitors; astemizole as antihistaminic; enviradine as antiviral; and candesartan cilexetil and telmisartan as antihypertensives. In literature various substituted derivatives of benzimidazole demonstrated various therapeutic agents such as anticancer, antiproliferative, antimicrobials, antivirals, antiparasites, anthelmintic activity, anticonvulsant, antioxidants, anti-inflammatory, antihypertensive, immunomodulators, proton pump inhibitors, anticoagulants, hormone modulators, and CNS stimulants as well as antidepressants, antidiabetics, anti-HIV, lipid level modulators, etc. and have made an important scaffold

variety of aromatic, aliphatic, and cinnamic aldehydes to produce diverse

for the development of new therapeutic agents (**Figure 15**) [10, 12, 13, 55–79].

Yang et al. optimized the solubility problem of lead benzimidazole (**1)** through introducing *N*-methylpiperazine groups at the 2-position showing preliminary in vitro anticancer activities [80]. Raghavan et al. demonstrated synthesis and evaluation of 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives (**2**). Caused maximum cell death in leukemic cells with a micromolar concentration [81]. Omar et al. demonstrated synthesis and docking studies of new series benzimidazole-pyrrole and tetracycline conjugates (**3**) tested against lung cancer cell line A549 and breast cancer cell line MCF-7 and found these molecules exhibited

**3. Pharmacological profile of benzimidazole derivatives**

can be extended to the coupling of benzyl alcohols (**Figure 13**) [52, 53].

**Figure 14.** *Synthesis of 1,2-disubstituted benzimidazole.*

*Chemistry and Applications of Benzimidazole and its Derivatives*

**benzimidazole**

good yields (**Figure 12**) [51].

**2.6 Functionalization of benzimidazole to 2-substituted (hetero)aryl** 

the direct C−H bond arylation of (*benz*)imidazoles (**Figure 11**) [50].

Shao et al. recently reported the synthesis of benzimidazoles via direct C−H bond arylation in the presence of a NHC-Pd(II)-Im complex. The method is tolerable to various activated and deactivated (hetero)aryl chlorides to get 2-(hetero) aryl benzimidazoles in high yields. It is a facile and an alternative methodology for

**2.7 Synthesis by the reaction of** *N***-substituted formamides with OPD derivatives**

Bhanage et al. demonstrated efficient and convenient one-pot protocol synthesis of a benzimidazole derivative using various OPD derivatives and *N*-substituted formamides (C1 sources) in a zinc acetate-catalyzed cyclization in the presence of poly(methylhydrosiloxane) to afford corresponding products in

**56**

**Figure 14.**

*Synthesis of 1,2-disubstituted benzimidazole.*

*One-pot three-component reaction.*

**Figure 11.**

**Figure 12.**

**Figure 13.**

*Synthesis of 2-substituted (hetero)aryl benzimidazoles.*

*N-Substituted formamides as C1 sources for the synthesis of benzimidazole.*

#### **2.8 Synthesis by one-pot three-component reaction**

Punniyamurthy's group reported copper-catalyzed one-pot, three-component reaction of *N*-aryl imines, in which imine acts as a directing group by chelating to the metal center, which affords a potential route for the transformation of the commercial aryl amines, aldehydes, and azides into valuable benzimidazole with vast substrate scope and diversity (**8a**). Further, the same group is reported in copper(II)-catalyzed oxidative cross-coupling of anilines, primary alkyl amines, and sodium azide in the presence of TBHP at moderate temperature (**8b**). This one-pot protocol involves a domino C-H functionalization, transamination, *ortho-*selective amination, and cyclization sequence. The method is found tolerable to broad functional group and can be extended to the coupling of benzyl alcohols (**Figure 13**) [52, 53].

#### **2.9 Synthesis of 1,2-disubstituted benzimidazole**

Chang et al. demonstrated intramolecular C−H amidation using molecular iodine under basic conditions. The imine substrates required were readily prepared by condensation of aldehydes with OPD derivatives. The reaction is carried out in the absence of metal-free cyclization, works well with crude imines, and allows synthesis of series of *N*-substituted benzimidazoles. This method is tolerable to a variety of aromatic, aliphatic, and cinnamic aldehydes to produce diverse 1,2-disubstituted benzimidazoles (**Figure 14**) [54].

#### **3. Pharmacological profile of benzimidazole derivatives**

Benzimidazole moiety came in scenic after discovery of it as an integral part of the structure of the vitamin B12 in the 1950s. In the early 1960s, it was developed as plant fungicides and later as veterinary anthelminthic. Further, a variety of veterinary anthelmintics were developed and marketed, including parbendazole, fenbendazole, oxfendazole, and cambendazole. In 1962 the first benzimidazole developed and licensed for human use was thiabendazole, and present more derivatives of benzimidazole that have been clinically approved are albendazole, mebendazole, and flubendazole as anthelmintic; omeprazole, lansoprazole, and pantoprazole as proton pump inhibitors; astemizole as antihistaminic; enviradine as antiviral; and candesartan cilexetil and telmisartan as antihypertensives. In literature various substituted derivatives of benzimidazole demonstrated various therapeutic agents such as anticancer, antiproliferative, antimicrobials, antivirals, antiparasites, anthelmintic activity, anticonvulsant, antioxidants, anti-inflammatory, antihypertensive, immunomodulators, proton pump inhibitors, anticoagulants, hormone modulators, and CNS stimulants as well as antidepressants, antidiabetics, anti-HIV, lipid level modulators, etc. and have made an important scaffold for the development of new therapeutic agents (**Figure 15**) [10, 12, 13, 55–79].

#### **3.1 Anticancer activity**

Yang et al. optimized the solubility problem of lead benzimidazole (**1)** through introducing *N*-methylpiperazine groups at the 2-position showing preliminary in vitro anticancer activities [80]. Raghavan et al. demonstrated synthesis and evaluation of 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives (**2**). Caused maximum cell death in leukemic cells with a micromolar concentration [81]. Omar et al. demonstrated synthesis and docking studies of new series benzimidazole-pyrrole and tetracycline conjugates (**3**) tested against lung cancer cell line A549 and breast cancer cell line MCF-7 and found these molecules exhibited

**Figure 15.** *Pharmacological profile of benzimidazole nucleus.*

**Figure 16.** *Benzimidazole derivatives with anticancer effect.*

remarkable higher activity than standard [82]. Karthikeyan et al. discovered derivatives of benzimidazoles 2-(phenyl)-3*H*-benzo[d]imidazole-5-carboxylic acids (**4**) and its methyl esters for anti-breast cancer agents [83]. Yoon et al. demonstrated novel benzimidazole derivatives (**5**) in sirtuin inhibitors (SIRT1 and SIRT2) with antitumor activities [84]. El-Nassan's group showed novel 1,2,3,4-tetrahydro[1,2,4] triazino[4,5-*a*]benzimidazole (**6**) analogs of aryl and heteroaryl groups showing antitumor activity in human breast adenocarcinoma cell line (MCF-7) [85]. Singh and Tandon demonstrated 2-aryl-substituted 2-*bis*-1*H*-benzimidazoles (**7**) evaluated as a topoisomerase-I inhibitor, and more benzimidazole derivatives are in line for the development of drug candidates (**Figure 16**) [86, 87].

#### **3.2 Antiviral activity**

Benzimidazole and its derivatives showed antiviral activity via contact with different virus particles such as human cytomegalovirus (HCMV), human herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and hepatitis-B and hepatitis-C virus (HBV and HCV). Luo et al. demonstrated the hepatitis-B virus inhibition by

**59**

*Synthesis and Pharmacological Profile of Benzimidazoles DOI: http://dx.doi.org/10.5772/intechopen.85229*

*Benzimidazole derivatives with antiviral activity.*

concentration with low cytotoxicity (**Figure 17**) [94].

**4. Conclusions**

**Figure 17.**

**Acknowledgements**

novel benzimidazole derivatives (**8**) in HepG2.2.15 cell line [88]. Gudmundsson et al. discovered alkyl and cyclic alkyl amine substituted *N*-(1*H*-benzimidazol-2-ylmethyl)- 5,6,7,8-tetrahydro-8-quinolinamines (**9**) and screened them for anti-HIV-1 activity as CXCR4 antagonists [89]. Miller et al. demonstrated stereochemically defined *N*-substituted benzimidazoles containing cyclic alkyl amine side chains (**10**), and its SAR analogs showed CXCR4 antagonist activity as anti-HIV agents [90]. Beaulieu et al. demonstrated few benzimidazole-based allosteric inhibitors (**11**) that bind to thumb pocket I of the HCV NS5B polymerase inhibition to HCV NS5B [91]. In another work, Wubulikasimu et al. evaluated a series of benzimidazoles bearing a heterocyclic ring as oxadiazole, thiadiazole, and triazole (**12**) for their inhibition against *Coxsackieviruses* B3 and B6 in Vero cells [92]. Monforte et al. reported N-1-aryl-benzimidazole 2-substituted analogs (**13**) inhibit HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) [93]. Some of these analogs inhibited the replication of HIV at nanomolar

The modern drug discovery more emphasizes on benzimidazole nucleus containing pharmacophore extensively applied in the biological and clinical studies. In this book chapter reviewed, recent optimized synthetic methods reported by various research groups for the synthesis of benzimidazole derivatives are exemplified. Further, the therapeutic use of benzimidazole in important areas such as antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, antihistamine, and more is discussed. In spite of the active, exhaustive, and target-based research on the development of many drug-like molecule development, the number of molecules that made its way to the market and clinic is not measurable. It can be probably due to lack of a comprehensive compilation of various research reports in each activity capable of giving an insight into the SAR of the compounds. The biological profiles of these new generations of benzimidazole would represent a

I would like to thank my PhD students for contributing to this book chapter in experimental and literature collection. The authors thank the University Grants Commission and DST-FIST, New Delhi, India, VGST-GoK, for the financial support

fruitful matrix for further development of better medicinal agents.

*Synthesis and Pharmacological Profile of Benzimidazoles DOI: http://dx.doi.org/10.5772/intechopen.85229*

*Chemistry and Applications of Benzimidazole and its Derivatives*

**58**

**3.2 Antiviral activity**

**Figure 15.**

**Figure 16.**

*Pharmacological profile of benzimidazole nucleus.*

*Benzimidazole derivatives with anticancer effect.*

development of drug candidates (**Figure 16**) [86, 87].

remarkable higher activity than standard [82]. Karthikeyan et al. discovered derivatives of benzimidazoles 2-(phenyl)-3*H*-benzo[d]imidazole-5-carboxylic acids (**4**) and its methyl esters for anti-breast cancer agents [83]. Yoon et al. demonstrated novel benzimidazole derivatives (**5**) in sirtuin inhibitors (SIRT1 and SIRT2) with antitumor activities [84]. El-Nassan's group showed novel 1,2,3,4-tetrahydro[1,2,4] triazino[4,5-*a*]benzimidazole (**6**) analogs of aryl and heteroaryl groups showing antitumor activity in human breast adenocarcinoma cell line (MCF-7) [85]. Singh and Tandon demonstrated 2-aryl-substituted 2-*bis*-1*H*-benzimidazoles (**7**) evaluated as a topoisomerase-I inhibitor, and more benzimidazole derivatives are in line for the

Benzimidazole and its derivatives showed antiviral activity via contact with different virus particles such as human cytomegalovirus (HCMV), human herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and hepatitis-B and hepatitis-C virus (HBV and HCV). Luo et al. demonstrated the hepatitis-B virus inhibition by

**Figure 17.** *Benzimidazole derivatives with antiviral activity.*

novel benzimidazole derivatives (**8**) in HepG2.2.15 cell line [88]. Gudmundsson et al. discovered alkyl and cyclic alkyl amine substituted *N*-(1*H*-benzimidazol-2-ylmethyl)- 5,6,7,8-tetrahydro-8-quinolinamines (**9**) and screened them for anti-HIV-1 activity as CXCR4 antagonists [89]. Miller et al. demonstrated stereochemically defined *N*-substituted benzimidazoles containing cyclic alkyl amine side chains (**10**), and its SAR analogs showed CXCR4 antagonist activity as anti-HIV agents [90]. Beaulieu et al. demonstrated few benzimidazole-based allosteric inhibitors (**11**) that bind to thumb pocket I of the HCV NS5B polymerase inhibition to HCV NS5B [91]. In another work, Wubulikasimu et al. evaluated a series of benzimidazoles bearing a heterocyclic ring as oxadiazole, thiadiazole, and triazole (**12**) for their inhibition against *Coxsackieviruses* B3 and B6 in Vero cells [92]. Monforte et al. reported N-1-aryl-benzimidazole 2-substituted analogs (**13**) inhibit HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) [93]. Some of these analogs inhibited the replication of HIV at nanomolar concentration with low cytotoxicity (**Figure 17**) [94].

#### **4. Conclusions**

The modern drug discovery more emphasizes on benzimidazole nucleus containing pharmacophore extensively applied in the biological and clinical studies. In this book chapter reviewed, recent optimized synthetic methods reported by various research groups for the synthesis of benzimidazole derivatives are exemplified. Further, the therapeutic use of benzimidazole in important areas such as antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, antihistamine, and more is discussed. In spite of the active, exhaustive, and target-based research on the development of many drug-like molecule development, the number of molecules that made its way to the market and clinic is not measurable. It can be probably due to lack of a comprehensive compilation of various research reports in each activity capable of giving an insight into the SAR of the compounds. The biological profiles of these new generations of benzimidazole would represent a fruitful matrix for further development of better medicinal agents.

#### **Acknowledgements**

I would like to thank my PhD students for contributing to this book chapter in experimental and literature collection. The authors thank the University Grants Commission and DST-FIST, New Delhi, India, VGST-GoK, for the financial support to establish research laboratory and instrumental facility. Author is also grateful to the host university, RCUB, for financial and infrastructure support.

## **Conflict of interest**

The authors confirm that this book chapter content has no conflicts of interest.

#### **Abbreviations**


**61**

**Author details**

Kantharaju Kamanna

provided the original work is properly cited.

Rani Channamma University, Belagavi, Karnataka, India

\*Address all correspondence to: kk@rcub.ac.in

*Synthesis and Pharmacological Profile of Benzimidazoles DOI: http://dx.doi.org/10.5772/intechopen.85229*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Chemistry, Peptide and Medicinal Chemistry Research Laboratory,

*Synthesis and Pharmacological Profile of Benzimidazoles DOI: http://dx.doi.org/10.5772/intechopen.85229*

*Chemistry and Applications of Benzimidazole and its Derivatives*

**Conflict of interest**

**Abbreviations**

2-PrOH 2-propanol AcOH acetic acid

CH3CN acetonitrile Cu(OAc)2 cupric acetate CuCl copper chloride CuI copper iodide DCM dichloromethane

EtOH ethanol

I2 iodine

EAA ethyl acetoacetate H2O2 hydrogen peroxide

HCl hydrochloric acid HCOOH formic acid

KOH potassium hydroxide KOtBu potassium tertiary butoxide *m*-CPBA *m*-chloroperoxybenzoic acid

PMHS poly(methylhydrosiloxane)

SAR structure activity relationship TBHP *tert*-butyl hydroperoxide

WEPBA water extract of papaya bark ash

TMEDA *N,N,N*'*,N*'-tetramethylethylenediamine

NaN3 sodium azide NH4Cl ammonium chloride OPD *o*-phenylenediamine PhI(OAc)2 benzene (diacetoxyiodo)

PhI iodobenzene

r.t room temperature

TMSN3 trimethylsilyl azide TsOH *p*-toluene sulfonic acid

Zn(OAc)2 zinc acetate

CAN ceric ammonium nitrate

DMF *N,N*-dimethylformamide DMSO dimethyl sulfoxide

DPPH 2,2-diphenyl-1-picrylhydrazyl

H5IO6-SiO2 silica-supported periodic acid

HFIP 1,1,1,3,3,3-hexafluoro-2-propanol

to establish research laboratory and instrumental facility. Author is also grateful to

The authors confirm that this book chapter content has no conflicts of interest.

the host university, RCUB, for financial and infrastructure support.

ABTS 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)

**60**

#### **Author details**

Kantharaju Kamanna

Department of Chemistry, Peptide and Medicinal Chemistry Research Laboratory, Rani Channamma University, Belagavi, Karnataka, India

\*Address all correspondence to: kk@rcub.ac.in

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[20] Heravi MM, Derikvand F, Ranjbar L. Sulfamic acid-catalyzed, three-component, one-pot synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone derivatives. Synthetic Communications. 2010;**40**:677-685. DOI: 10.1080/00397910903009489

[21] Bahrami K, Khodaei MM, Kavianinia I. H2O2/HCl as a new and efficient system for synthesis of 2-substituted benzimidazoles. Journal of Chemical Research. 2006;**12**:783-784. DOI: 10.3184/030823406780199730

[22] Ma H, Han X, Wang Y, Wang J. A simple and efficient method for synthesis of benzimidazoles using FeBr3 or Fe(NO3)3·9H2O as catalyst. ChemInform. 2007;**38**:49. DOI: 10.1002/ chin.200749146

[23] Du L-H, Wang Y-G. A rapid and efficient synthesis of benzimidazoles using hypervalent iodine as oxidant. Synthesis. 2007;**5**:675-678. DOI: 10.1055/s-2007-965922

[24] Venkateswarlu Y, Kumar SR, Leelavathi P. Facile and efficient onepot synthesis of benzimidazoles using lanthanum chloride. Organic and Medicinal Chemistry Letters. 2013;**3**:7. DOI: 10.1186/2191-2858-3-7

[25] Sontakke VA, Ghosh S, Lawande PP, Chopade BA, Shinde VS. A simple,

efficient synthesis of 2-aryl benzimidazoles using silica supported periodic acid catalyst and evaluation of anticancer activity. ISRN Organic Chemistry. 2013:1-7. DOI: 10.1155/2013/453682

[26] Martins GM, Puccinelli T, Gariani RA, Xavier FR, Silveira CC, Mendes SR. Facile and efficient aerobic one-pot synthesis of benzimidazoles using Ce(NO3)3·6H2O as promoter. Tetrahedron Letters. 2017;**58**:1969-1972. DOI: 10.1016/j.tetlet.2017.04.020

[27] Kumar KR, Satyanarayana PVV, Reddy BS. NaHSO4-SiO2 promoted synthesis of benzimidazole derivatives. Archives of Applied Science Research. 2012;**4**:1517-1521

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10.1016/j.arabjc.2013.07.003

DOI: 10.1016/j.bmc.2013.12.029

bmcl.2009.06.103

2012.10.010

**71**

Section 3

The Therapeutic Potential

of Benzimidazoles

Section 3
