Quantitative Lattice Energy Analysis of Intermolecular Interactions in Crystal Structures of Some Benzimidazole Derivatives

The benzimidazolemoiety found in a large number of biologically important drugs has not been completely realized as yet in respect of its strength and directionality of its molecular interactions. To understand the role played by the intermolecular interactions in the benzimidazole derivatives, lattice energy of a series of five important molecules has been computed and results accrued there of have been discussed. Analysis of molecular packing based on the inter molecular interaction energies suggests existence of different molecular pairs that play an important role in the stabilization of the crystal structures. Interaction energy analysis of such motifs reveals that intermolecular interactions of the type N-H…N and C-H…Nhappen to be the major contributors to the stabilization of molecular packing in the unit cell. N-H…π and C-H…π type edge-to-face stacking interactions also contribute significantly to the stabilization of crystal packing. The pairs of N-H…N intermolecular hydrogen bonds link the molecules into centrosymmetricdimers making a contribution of -14 to -18.52 kcal/mol towards stabilization, whereas C-H…N bonds link the molecules into dimers in the energy range of -2 to -5 kcal/mol. Additionally, the role of π…π interactions has also been investigated in molecular stabilization.


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. 2Substituted benzimidazole derivatives have found diverse therapeutic applications such as anti-HIV, 3 antiulcer, 4 antihypertensive,antifungal, anthelmintic, antihistaminic andcardiotonic. 5,6meprazole and mebendazole are benzimidazole derivatives available in the market as proton pump inhibitorsand 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. 6Benzimidazole 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 theseinteractions in molecular packing stability. 11he chemical structure of benzimidazole showing the numbering scheme is shown in Figure -1 and their derivatives are already reportedwith compound name, code, chemical structure are shown in Table -1.

Theoretical Calculations
Pixelc module in the CLP-PIXEL 10 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.9][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 Mercury 21 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.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.

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The pairs of N-H…N intermolecular hydrogen bonds, responsible for the formation of centrosymmetricdimmers (with an energy contribution of -14 to -18.52 kcal/mol), lend credible support to molecular packing.

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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 workreported 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 helpsdesign some new and more fascinating biologically active benzimidazolederivatives by changing the strength of donor and acceptor atoms.

Fig. 11 :
Fig. 11: Molecular packing of compound M-5 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.