Crystallographic and DFT Studies on Pyrrolo[1,2-c]imidazole Scaffolds

The crystal structures of the compounds C 15 H 14 N 4 O 2 (1) and C 16 H 16 N 4 O 4 (2) are reported and analyzed by single crystal X-ray diffraction technique. Compounds (1) and (2) crystallized in monoclinic space group P21/c and Cc with four molecules in the unit cell, respectively.The unit cell parameters for compound (1) are a = 11.4501(15) Å, b = 9.7869(11) Å, c = 12.3653(15) Å, β = 90.997(11), and Volume = 1385.5(3) Å and for compound (2) are a = 13.865(2) Å, b = 6.9538(8) Å, c = 16.841(2) Å, β = 98.602(11), and Volume = 1605.4(4) Å. In both compounds (1) and (2), the pyrrolidine ring adopts half-chair conformation. Moreover, both interand intramolecular N–H⋅ ⋅ ⋅O hydrogen bonds stabilize the crystal structure and play a crucial role in crystal packing.This intermolecular interaction alone constructs C 1 1 chain motif in both compounds. It is also supported by weak intermolecular π-π interaction which is essential for the stability of the crystal packing. Further, the Density Functional Theory (B3LYP) method with standard 6-31G basis set was used in the calculation and calculated geometrical parameter is correlated with the corresponding experimental data. The obtained HOMO and LUMO energies are in negative values indicating that the compounds are in stable state.


Introduction
The five-membered heterocyclic pyrrolidine ring system commonly occurs in many natural products and these five members are leading components of alkaloids [1]. They are essential synthetic components of HIV reverse transcriptase enzyme and inhibitors of substance P neurotransmitters [2,3]. Further, they also act as antibacterial and antiamnestic agents [4,5]. The heterocyclic imidazole derivatives are also considered to be an important synthetic precursor in drug designing and discovery process [6,7]. These imidazole derivatives have antitumor, antimicrobial, and antiinflammatory activity and they also inhibit MAP kinase p38 protein [8]. Also, the novel Py-Im derivatives have been established as powerful partial agonists of the 1A adrenoceptor (GPCR known as adrenergic receptor) and have shown better response over the 1B, 1D, and 2A receptor subtypes [9]. The fused Py-Im derivative also inhibits the JNK (c-Jun-N-terminal kinase) pathway which is the fascinating drug target for several neurodegenerative disorders. In view of the growing biological importance of Py-Im derivatives, the single crystal X-ray diffraction studies on the compounds were carried out and analyzed.

Crystallographic Data Collection and Refinement.
Colorless plate shape single crystals with dimensions of 0.3 × 0.25 × 0.1 mm (1) and 0.5 × 0.4 × 0.1 mm (2) were selected and X-ray data were collected on a Xcalibur, Eos diffractometer, using CrysAlisPro software and graphite-monochromated Mo-k ( = 0.7107Å) at 298 K. The structures were solved by direct methods using SHELXS-97 [11] and refined by SHELXL-97 [11] with the full-matrix least square procedure. For data collection, data reduction, and space group determination of compounds, CrysAlisPro [12] software was used. All of the nonhydrogen atoms were refined anisotropically while the hydrogen atoms were refined isotropically. H atoms were positioned geometrically and allowed to ride on their parent atoms, with d(N-H) = 0.86Å, d(C-H) = 0.93Å for CH and aromatic and 0.96Å for CH 3 atoms. The U iso values were constrained to be 1.5 U eq of the carrier atom for methyl H atoms and 1.2 U eq for the remaining H atoms. By using ORTEP [13] and Platon [14] programs, thermal ellipsoid and crystal packing diagrams were created. Mercury [15] program was used for analyzing the hydrogen bonding graphset motif.

Computational Details.
The molecular structures of compounds (1) and (2) were subjected to quantum chemical density functional calculation with Jaguar software package using the Becke-3Lee-Yang-Parr (B3LYP) hybrid functional with the standard 6-31G(TM) * * + (6D) basis set ( * * indicates that it places polarization functions on all atoms except for transition metals, + option places diffuse function on all atoms except H and He, and 6D represents d shells including the six Cartesian d functions d 2, d 2, d 2, d , d , and d ) used to calculate the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy distribution and HOMO-LUMO energy gap.

Results and Discussion
The crystal data and structure refinement of compounds (1) and (2) were given in Table 1. The selected geometric parameters of compounds (1) and (2) were given in Table 2.
Hydrogen bonds for the compounds (1) and (2) are listed in Table 3. The chemical structures for compounds are shown in Figure 1. The ORTEP diagram and graph-set motif of Journal of Crystallography

Molecular Orbital Analysis.
The HOMO-LUMO energy gap of a molecule will play a crucial role in deciding its bioactive properties and is a very important parameter for quantum chemistry. The HOMO energy distinguishes the capacity of electron donor, whereas LUMO energy characterizes the capacity of electron acceptor, and the gap distinguishes the chemical stability [20]. The HOMO-LUMO energy gap for the compounds (1) and (2) was calculated by 6-31G(TM) * * + (6D) basis set [20] and the values are −0.175 a.u (1) and −0.160 a.u (2). The energies of HOMO and LUMO and the HOMO-LUMO energy gap are given in Table 4 shown in Figure 5 (positives phases are mentioned in red and the negatives ones in blue). The electron density of HOMO in compounds (1) and (2) shows that the HOMO is localized on fused Py-Im ring, methyl, and carbonyl groups. In case of LUMO, the electron density is localized on benzene ring only in compound (1) while in compound (2) the electron density is fully localized in carbonyl group and partially localized in benzene ring. The HOMO to LUMO transition signifies that an electron density transfers from fused Py-Im ring to benzene ring and the HOMO-LUMO energy gap (−0.160 a.u) in compound (2) is the smallest indicator that the molecule of compound (2) is more stable compared to compound (1). The HOMO to LUMO transition indirectly explains the descriptor of electron donor and acceptor in order to understand their interacting ability with their target molecules.

Conclusions
In the present study, we presented the structural details of fused Py-Im compounds, C 15 H 15 N 4 O 2 (1) and C 16 H 16 N 4 O 4 (2), by using single crystal X-ray diffraction data. DFT calculation was performed with standard 6-31G(TM) * * + (6D) basis set to analyze the molecular geometry and compared with experimentally available X-ray crystal data of compounds (1) and (2). The calculated HOMO-LUMO energy gap in compound (2) is −0.160 a.u and this small gap value indicates that compound (2) is chemically reactive compared to compound (1). Further, the crystal structure is stabilized by both intra-and intermolecular hydrogen bonds in which intermolecular N-H⋅ ⋅ ⋅ O hydrogen bond generates C 1 1 (6) and C 1 1 (7) chain motif in compounds (1) and (2), respectively. In addition, the packing is also stabilized by intermolecular C-H⋅ ⋅ ⋅ O, N-H⋅ ⋅ ⋅ N hydrogen bonds and special type of interaction such as C-H⋅ ⋅ ⋅ , C-N⋅ ⋅ ⋅ , and -interactions.

Abbreviations
Py-Im: Pyrroloimidazole HOMO: Highest occupied molecular orbital LUMO: Lowest unoccupied molecular orbital p: P a r a .