Introduction

Benzimidazole is an important class of heterocyclic aromatic organic compounds which consists of a benzene ring fused with   imidazole ring. It is present  in naturally biological active substances such as vitamin B12 and purine bases.¹  It is an important scaffold beneficial for the development of pharmaceutically as well as biologically important molecules.² Substituted benzimidazole derivatives have found diverse therapeutic applications such as anti-HIV,³ antiulcer,⁴ antihypertensive, antifungal, anthelmintic, antihistaminic and cardiotonic.^5,6 Omeprazole and mebendazole are benzimidazole derivatives available in the market as proton pump inhibitors and as anthelmintics, respectively. The structure-activity relationship (SAR) studies suggest that substitution at C-2 position of this heterocyclic aromatic system highly influences the biological activity.⁶ Benzimidazole derivatives have been paid great heed because of their high pharmacological and biological activities. Their derivatives are one of the top frequently used ring systems for small molecule drugs listed by the US FDA.⁷

As a part of our ongoing research work on the preparation of X-ray diffraction quality single crystals and their structural analysis^8,9, we have identified a series of five benzimidazole derivatives from CSD (version: 2020). The lattice and cohesive energies of all the molecular pairs were computed by using PIXEL¹⁰ software. The input CIF file required to carrying out the lattice energy calculations for each molecule was obtained from the CSD. The primary aim behind the analysis of lattice and intermolecular interaction energies is to compute and evaluate   interaction energies which are associated with the molecular pairs and to investigate the contribution of these interactions in molecular packing stability¹¹.The chemical structure of benzimidazole showing the numbering scheme is shown in Figure-1 and their derivatives are already reported with compound name, code, chemical structure are shown in Table-1.

Figure 1: Basic Structure of Benzimidazole Showing the Numbering Scheme. Click here to view Figure

Table 1: IUPAC Name and Chemical Structure of Benzimidazole Derivatives.

Code	Compound IUPAC Name and References	Chemical Structure
M-1	2-Aminobenzimidazole12
M-2	N''-1H-benzimidazol-2-ylguanidine13
M-3	1-(N-Nitrosomethylamino)- 2-methylbenzimidazole14
M-4	2-nitro-1H-benzimidazole15
M-5	2-Chlorobenzimidazole16

Theoretical Calculations

Pixelc module in the CLP-PIXEL¹⁰ package (version 3.1 may 2016 available from http://www.angelogavezzotti.it) was performed to find out the intermolecular interaction and lattice energies in the  crystal structures of benzimidazole derivatives as identified from the CSD.  Hydrogen atom positions for the interaction energy calculations were assigned  and intermolecular energies were determined based on numerical integrals over calculated electron densities of molecules  computed by using   GAUSSIAN09¹⁷ program. PIXEL allows for the total lattice energy to be divided into four main contributing terms: Coulombic, Polarization, Dispersion and Repulsion component. The sum of these four contributing terms gives the total interaction energy between the molecular pairs which assist to understand the role of intermolecular interactions in molecular packing.^18-20 The total lattice energies for molecule M-1 to M-5 and their coulombic, polarization, dispersion and repulsion contributions are presented in Table-2 while the distance between centroids, symmetry code, the individual energy components  and  total energy between the molecular pairs are presented in Table-3. The total intermolecular interaction energies between the molecular pairs  are arranged in the descending order and their pairs  were examined   using the Mercury²¹ software. The geometrical constraints put   on the selected intermolecular pairs are the sum of van der Waals radius + 0.4Å and the directionality is greater than 110º.

Table 2: Lattice Energy for M-1 to M-5 (kcal/mol)

Molecule	Coulomb Energy (ECoul)	Polarization Energy (EPol)	Dispersion Energy (EDisp)	Repulsive Energy (ERep)	Total Energy (ETot)
M-1	- 22.87	- 10.92	- 24.19	24.81	- 33.17
M-2	- 27.82	- 16.13	- 34.11	36.09	- 41.97
M-3	- 9.92	- 3.68	- 23.97	13.98	- 23.59
M-4	- 19.48	- 9.46	- 26.31	26.24	- 29.13
M-5	- 17.57	- 8.39	- 27.17	24.16	- 28.97

 

Table 3: Interaction Energies (in kcal /mol) Between Molecular Pairs.

Mot-if	Centroid Distance(Å)	ECoul	EPol	EDisp	ERep	ETot	Symmetry	Important Interactions
M-1
A	7.188	-23.59	-10.16	- 6.12	21.37	- 18.52	1-x, -y, 1-z	N2-H2A…N1
B	4.476	-7.17	-2.70	-6.43	5.74	-10.56	-½+x, ½-y, z	N3-H3…N1 N3-H3…π (C7, C8) C4-H4…π (C6, C7)
C	5.554	-2.32	-0.60	-2.99	0.96	-4.92	x, -1+y, z	C7-N3
D	7.700	-1.31	-1.67	-3.23	3.51	-2.70	½-x, -½+y, 1-z	N2-H2B…N2
M-2
A	8.065	-20.15	-10.06	-8.05	23.83	-14.46	-x, 1-y, -z	N4-H4A…N2
B	5.068	-7.41	-3.30	-7.03	9.11	-8.63	½-x, -½+y, z	C7-H7…π N3-H3…N1
C	5.241	-2.48	-1.15	-6.74	2.70	-7.67	-1+x, y, z	N5-H5A…π N5-H5B…π N5…Cg2
D	7.740	-3.03	-2.72	-5.52	5.59	-5.66	1/2 + x, 1/2 – y, -z	N4-H4A…N5 N5-H5A…N4
E	6.943	-1.46	-0.50	-1.84	0.45	-3.35	-1/2-x, -1/2+ y, z	N5-H5A…N2
F	7.622	-1.58	-0.79	-3.25	3.56	-2.05	3/2-x, -1/2+ y, z	C4-H4…π
G	8.793	-0.60	-0.48	-3.18	2.29	-1.93	-1/2+x, y,  1/2-z	C6-H6…π C5-H5…π
M-3
A	4.880	-0.21	-1.17	-10.18	5.52	-6.05	-x, 2-y, 1-z	π…π
B	7.653	-3.80	-0.74	-3.51	2.46	-5.59	-x, 2-y, 2-z	C10-H10C…N4
C	6.866	-2.08	-0.57	-2.65	1.24	-4.06	1/2-x, 1/2+y,  3/2-z	C10-H10A…π C11-H11C…N1
D	6.890	-2.41	-0.88	-3.54	2.84	-3.99	-1/2-x, 1/2+y,  3/2-z	C11-H11A…O1 C11-H11B…π
E	8.026	-1.46	-0.52	-3.39	2.01	-3.35	1/2+x, 3/2-y,  1/2+z	C6-H6…N1 C6-H6…C2 C5-H5…O1
F	6.930	-0.96	-0.84	-3.49	2.27	-2.99	1+x, y, z	C10-H10B…N4 C4-H4…N1
M-4
A	6.042	-13.77	-6.24	-6.48	13.29	-13.19	-1/4+x, 1/4-y,  -1/4+z	C4-H4…O2 N3-H3…N1 C7-H7…O1
B	3.713	-0.17	-1.05	-9.87	7.46	-3.61	x, y, -1+z	π…π N2…C2 O1…C2 O1…N2
C	9.817	-1.77	-0.45	-1.79	1.41	-2.63	1/4-x, 1/4+y, -3/4+z	C5-H5…O2 C6-H6…O1
D	7.563	-1.55	-0.36	-1.15	0.88	-2.17	1/4+x, 1/4-y, 5/4+z	C7-H7…O1
E	7.746	-0.55	-0.29	-2.22	1.27	-1.82	1/2-x, -y, -1/2+z	C6-H6…π
M-5
A	6.736	-13.24	-6.02	-6.72	12.93	-13.02	-1/2+x, 3/2-y, 1-z	C4-H4…C1 N3-H3…N1
B	5.375	-2.75	-0.81	-5.28	3.08	-5.74	1/2-x, -1/2+y, z	C2…C4 C4…N3
C	4.037	-0.86	-1.12	-8.99	5.88	-5.09	1-x, 1-y, 1-z	C6…C1 Stacking (C…C)
D	6.423	-0.67	-0.45	-3.32	2.48	-1.98	-1/2+x, y,  3/2-z	C7-H7…C5

 

Results and Discussion

M-1: 2-Aminobenzimidazole

Distinct molecular pairs of molecule M-1 (A-D) as obtained from the crystal structure   involved in the formation of intermolecular interactions are shown in Figure-2. The maximum stability to the molecular structure occurs with N2-H2A…N1 intermolecular interaction (Motif A, Figure-2). The pairs of N2-H2A…N1 interaction link the molecules into centrosymmetric dimers in the crystal, forming R²₂ (8) ring motif having interaction energy of -18.52 kcal mol^-1 with 60% contribution to the net stabilization from coulombic energy, 25% contribution from polarization energy and 15% from the dispersive energy, respectively. The next stabilized pair (Motif B, Figure 2) shows the presence of N-H…N (involving H3 and N1), N-H…π and C-H…π interactions. The C4-H4…π interaction that connects the molecules between a hydrogen atom (H4) and atom C6 and C7 of Cg1 ring (where Cg1 represents centre of gravity of benzene ring), whereas interaction N3-H3…π involving atom (H3) with atom C7 and C8 of Cg1 as shown in Figure-2 (Motif B) having interaction energy of -10.56 kcal mol^-1 with a maximum contribution of -7.17 kcal mol^-1 from coulombic component. The next stabilized motif (C) in molecule M-1 involves C…N interaction with total interaction energy of -4.92 kcal mol^-1 (40 % contribution from coulombic energy, 50% dispersion energy and 10% from polarization energy to the net stabilization). The last stabilized pair (Motif D, Figure-2) in molecule M-1 involves N-H…N (H2B and N2) weak intermolecular hydrogen interaction with total stabilization energy of -2.70 kcal mol^-1 with 52% of the maximum contribution from dispersive energy, 27% of polarization energy and 21% of coulombic energy contribution to net stabilization. The packing for M-1 shows the formation of molecular sheets in the ac plane (Figure-3).

Figure 2: Molecular Pairs (A-D) along with their Interaction Energies in M-1. Click here to view Figure

 

Figure 3: Packing of the Molecules in the Form of Molecular Sheets (ac Plane). Click here to view Figure

M-2:  N''-1H-benzimidazol-2-ylguanidine

The molecular pairs of compound M-2 and their respective interaction energies are shown in Figure-4. The contributed stabilization energy of the molecular pair (A) in compound M-2 is -14.46 kcal/mol (with 52 % major contribution from the coulombic component) is due to the presence of a N4-H4A…N2 hydrogen bond linking the molecules to form dimers (Figure-4 motif A). The motif (B), the second most stabilized pair, involves edge-to-face C-H…π interaction (involving H7 with C4 and C9 of Cg1) along with a weak intermolecular interaction (N3-H3…N1) having interaction energy -8.63 kcal/mol with 41 % maximum contribution from coulombic energy (Figure-4, Motif B). The motif (C) is the third most stabilized pair that show the presence of N5…Cg2 and N-H…π interactions (involving H5A and H5B with N1, C2, C8 and C9 respectively) contributing -7.67 kcal/mol energy towards stabilization. Motif (D) is the next most stabilized motif in the crystal packing involves N4-H4A…N5 and N5-H5A…N4 (atom N4 and N5 acts as a donor via H4A and H5A) bifurcated donor configuration having interaction energy of -5.66 kcal/mol with maximum contribution from dispersive energy. Motif (E) and (F) contributing -3.35 kcal/mol and -2.05 kcal/mol, showing the presence of N5-H5A…N2 and edge-to-face C-H…π interaction (involving H4 with C6 and C7 of Cg1 ring) with maximum contribution from dispersive energy. The molecular packing in M-2 showing the formation of sheets in the bc plane as shown in Figure-5.

Figure 4: Molecular Pairs (A-G) along with their Interaction Energies in M-2.  Click here to view Figure

 

Figure 5: Molecular Packing in M-2 Showing Formation of Sheets in the bc Plane.  Click here to view Figure

M-3: 1-(N-Nitrosomethylamino)-2-methylbenzimidazole

The molecular pairs of M-3 extracted via crystal packing carrying their respective stabilization energies are shown in Figure-6. The motif (A) shows π…π stacking with total stabilization energy of -6.05 kcal/mol (88 % contribution from coulombic energy). In   motif (B) exists  C10-H10C…N4 interaction which links the pair of molecules to form an inversion dimer having interaction energy of - 5.59 kcal/mol.  In motif (C), there exists an intermolecular interaction [C11-H11C…N1] and edge to face C-H…π stacking interaction (involving H10A interconnecting with C7 and C8 of Cg1 ring). This interaction contributes -4.06 kcal/mol energy towards stabilization. The molecular pair (D) shows the existence of C11-H11A…O1 and C-H…π interactions (involving H11B interconnecting with C4 and C5 of Cg1 ring), leading to the total interaction energy -3.99 kcal/mol with a large contribution from the dispersive energy component. Some other molecular pair (motif E) shows the existence of C5-H5…O1 and C-H…π interaction involving H6 interconnecting with C2 and N1 of Cg2 ring having total interaction energy - 3.35 kcal/mol and the stabilization largely come from a dispersive component. The least most stabilized pair (motif F) involves the existence of C-H…N type (C10-H10B…N4 & C4-H4…N1) intermolecular interactions with the total energy of -2.99 kcal/mol (dispersive energy 65% contribution). π...π interaction and C-H…N interaction link the molecules to form a molecular chain along with c- axis as shown in Figure-7.

Figure 6: Molecular Pairs (A-F) along with their Interaction Energies in M-3. Click here to view Figure

 

Figure 7: π...π and C-H…N Interactions Link the Molecules to Form Chains along c- axis. Click here to view Figure

M-4: 2-nitro-1H-benzimidazole

The molecular pairs of 2-nitro-1H-benzimidazole (M-4) extracted via crystal packing carrying their corresponding stabilization energies are shown in Figure-8. The motif (A) in the molecule M-4 is the most stabilized pair that involves  C4-H4…O2, N3-H3…N1 and C7-H7…O1 interactions having energy component of -13.19 kcal/mol ( maximum contribution from coulombic energy). The total stabilization energy (-3.61 kcal/mol) of the motif (B) is the second most stabilized pair indicating the presence of N2…C2, O1…C2, O1…N2 and π…π interactions(maximum contribution from the dispersive component).

Figure 8: Molecular Pairs (A-E) along with their Interaction Energies in M-4. Click here to view Figure

The Motif (C) has an interaction energy of -2.63 kcal/mol, indicating the presence of C-H…O intermolecular interactions (involving H5 with O2 and H6 with O1) with almost equal contribution from dispersive and coulombic component.  The Motif D & E involves C7-H7…O1 and C-H…π (involving H6 with C6 and C7 of Cg1) interactions having -2.17 kcal/mol and -1.82 kcal/mol energy component, respectively. The packing in the crystal structure of 2-nitro-1H-benzimidazole M-4 indicates the formation of molecular sheets in the ab plane (Figure-9).

Figure 9: Molecular Packing in M-4 Showing Formation of Sheets in the ab Plane. Click here to view Figure

M-5: 2-Chlorobenzimidazole

The stabilized pairs of 2-Chlorobenzimidazole (M-5)  are shown in Figure-10. The Motif (A) is involved in the formation of C4-H4…Cl and N3-H3…N1 intermolecular interactions having total interaction energy of -13.02 kcal/mol. The pairs of N2-H2A…N1 interaction connect the molecules into inversion dimers in the crystal, generating R²₂ (12) ring motif. The interaction energy component of Motif B  is - 5.74 kcal/mol, indicating the existence of C4…C2 and C4…N3 interactions (maximum contribution coming from the dispersive component).

Figure 10: Molecular Pairs (A-D) along with their Interaction Energies in M-5. Click here to view Figure

The Motif C, involved in the molecular stacking, has an interaction energy of - 5.09 kcal/mol (with 82 % contribution from dispersive energy towards the net stabilization). The last stabilized pair involves C7-H7…C5 having total interaction energy of -1.98 kcal/mol as shown in [Motif (D), Figure-12]. The molecular packing of compound M-5 is shown in Figure-11.

Figure 11: Molecular Packing of Compound M-5. Click here to view Figure

Conclusions

1. In case of all the five benzimidazole structures,  the lattice energy lies in the range -23 to -42 kcal/mol and is   separated into coulombic, polarization, dispersion and repulsion components with different energy contributions.
2. The maximum contribution comes from  the dispersion energy.
3. The stability to the molecular structure  comes from the  molecular pairs interacting via intermolecular interactions (N-H…N and C-H…N).
4. C-H…π and N-H…π type edge-to-face stacking interactions have also been found to be   contributing substantially in the stabilization of their crystal structures.
5. The pairs of N-H…N intermolecular hydrogen bonds, responsible for the formation of  centrosymmetric dimmers (with an energy contribution of  -14 to - 18.52 kcal/mol), lend credible support to molecular packing.
6. The energy of molecular pairs interacting via C-H…N interactions link the molecules into dimers (energy range being -2 to -5 kcal/mol).

Lattice energy calculation is a useful method to assess the stability of crystal structures in which Coulombic and dispersion type interactions make up an essential part of the intermolecular interactions. The work reported in this paper shows the existence of different key structural motifs that assist stabilization of molecular packing in the unit cell. The calculation of interaction energy of the molecular pairs by PIXEL help us determine the strength of each interaction and the role played by the weak intermolecular interactions in molecular structure determination also gets confirmed. The study of these interactions helps design some new and more fascinating biologically active benzimidazole derivatives by changing the strength of donor and acceptor atoms.

Acknowledgements

Rajni Kant acknowledges the Research Grants as sanctioned under RUSA 2.0 Project (Ref. No: RUSA/JU/2/2019-20/111/3588-3636).

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