Synthesis of Enaminones-Based Benzo[d]imidazole Scaffold: Characterization and Molecular Insight Structure

(E)-1-(1H-Benzo[d]imidazol-2-yl)-3-(dimethylamino)prop-2-en-1-one 2 was synthesized by one-pot synthesis protocol of 2-acetyl benzo[d]imidazole with dimethylformamide dimethylacetal (DMF-DMA) in xylene at 140 ◦C for 8 h. Reaction of enaminone derivative 1 with acetylacetone in the presence of AcOH/NH4OAc under reflux afforded the cyclized pyridino-benzo[d]imidazole derivative 3. The latter compound was converted into the corresponding β-enaminone 4 with DMF-DMA. The single crystal X-ray diffraction technique eventually confirmed the assigned chemical structure of the N-alkyl-β-enaminone 2 and pyridino-benzo[d]imidazole derivative 3. N-alkyl-β-enaminone 2 crystallized in the monoclinic space group P21/n with unit cell parameters of a = 9.8953(3) Å, b = 5.7545(2) Å, c = 21.7891(7) Å, and β =100.627(2)◦, and with one molecule per asymmetric unit. On the other hand, compound 3 crystallized in the orthorhombic crystal system and space group P212121 with unit cell parameters of a = 6.82950(10) Å, b = 8.00540(10) Å, c = 22.4779(2) Å, and also with one molecule per asymmetric unit. Based on Hirshfeld analysis, the H...H (51.3%), O...H (10.0%), N...H (10.3%), and C...H (27.6%) contacts in 2 and the H...H (46.8%), O...H (9.9%), N...H (13.0%), and C...H (21.6%) in addition to the C . . . C (6.7%) interactions in 3 are the most important towards crystal stability via molecular packing. The main difference is the presence of π–π interaction among the molecular units of 3 but not in 2. The calculated 1H and 13C NMR chemical shifts showed good agreements with experimental data. Electronic properties and reactivity parameters of both compounds are also calculated and compared.

Polydentate enaminone reagents have gained more attention in the last decade due to their utilization as synthons in organic synthesis transformation [14][15][16]. These building blocks have dual electronic attitude and can be employed as electrophilic enones or act as nucleophilic enones in many chemical transformations for the construction of many cyclic compounds with interesting biological activities as antibacterial, antitumor, anti-convulsant, and anti-glycating agents, as well as enzyme inhibitors [17][18][19][20][21][22]. The structural features of the pharmacophore play a crucial role for the biological activity of the compound. Combining two pharmacophores in one hybrid is a challenge.
Pyridine scaffold is a very important skeleton of the heterocyclic family which exists as core structure in many divergent natural products such as alkaloids, coenzymes, and vitamins. Furthermore, it is used in a large scale in industrial chemistry for the synthesis of many products such as herbicide, bactericide, and insecticide. Additionally, in biological sciences, it has been approved to have a high pharmacological importance [23,24].
The molecular structure of the synthesized β-enaminones was elucidated by spectrophotometric tools including NMR spectra. The structural features of β-enaminone 2 and 3 were assigned eventually by X-ray single crystal analysis combined with density functional theory (DFT) calculations and Hirshfeld analysis.

Materials and Methods
General: The 1 H-and 13 C-NMR spectra of both β-enaminones were recorded on a JEOL 400MHz spectrometer (JEOL, Ltd., Tokyo, Japan) at ambient temperature. The solvent used was DMSO-d 6 ; the chemical shifts (δ) are given in ppm. The topology analyses were performed using the Crystal Explorer 17.5 program [31]. All DFT calculations were performed using the Gaussian 09 software package [32,33] utilizing the B3LYP/6-31G(d,p) method. Natural population analysis was performed using the NBO 3.1 program as implemented in the Gaussian 09W package [34]. The self-consistent reaction filed (SCRF) method [35,36] was used to model the solvent effects when calculating the optimized geometries in solution. Then, the NMR chemical shifts for the protons and carbons were computed using the GIAO method in the same solvent (DMSO) [37].
The reaction mixture of 2-acetyl benzimidazole (1.60 g, 10 mmol) and DMF-DMA (1.19 g, 10 mmol) in xylene (40 mL) was refluxed for 3 h, then the reaction mixture was allowed to cool at room temperature. The precipitated solid product was isolated by simple filtration and subsequently washed with petroleum ether to afford compound 2 in a pure form as yellowish brown crystals.

(E)-3-(Dimethylamino
The reaction mixture of 2-acetyl benzimidazole (1.60 g, 10 mmol) and DMF-DMA (1.55 g, 13 mmol) in xylene (40 mL) was refluxed at 140 • C for 8 h. The reaction mixture was cooled down to room temperature and left for a period of time to give product 2 in a pure form as yellowish brown crystals.
Yield 71%, mp 228-230 • C. 1 A mixture of 1 (0.432 g, 2 mmol), acetylacetone (0.20 g, 2 mmol), and ammonium acetate (0.385 g, 5 mmol) in 15 mL of acetic acid was refluxed for 4-6 h. The progress of the reaction was monitored by using thin layer chromatography (TLC). After completion, 50 mL ice-cold water was added to the reaction mixture and neutralized with a solution of NaHCO 3 leading to a pale brown precipitate of 3 which was filtered and dried. Pale

Synthesis of β-enaminones
The synthesis of β-enaminones-based benzo[d]imidazole 1 and 2 have been reported before [38][39][40][41][42], but a direct method to reach the final β-enaminone 2 from the starting material 2-acetyl benzo[d]imidazole has not been reported to the best of our knowledge. The synthesis of N-alkyl-βenaminone-based benzo[d]imidazole scaffold 2 was achieved by a reaction of 2-acetyl benzo[d]imidazole with DMF-DMA as outlined in Scheme 1. The formation of compound 1 was obtained at 125 • C but was unprecedented. The N-methyl-β-enaminone 2 was obtained by restarting the reaction at higher temperature of 140 • C. The plausible mechanism for N-alkylation transformation of 1 to 2 via deprotonation of the NH of the imidazole ring to generate the more powerful nuclophile subsequently attack the electrophilic center of the (methoxymethylene)dimethyl-azonium ion to form the final compound 2. The chemical structure of the N-alkyl-β-enaminone-based benzo[d]imidazole scaffold 2, eventually confirmed by X-ray single crystal analysis, is consistent with the one reported before [38][39][40][41][42].
Further, the β-enaminones-based benzo[d]imidazole 1 was cyclized with the acetylacetone, and ammonium acetate in acetic acid, and refluxed for 4-6 h to afford the substituted pyridine-βenaminones-based benzo[d]imidazole 3. Luckily, suitable single crystals were obtained for compounds 2 and 3, which support the 1 H and 13 C-NMR spectral analyses, and confirmed the chemical features of these compounds. Finally, compound 3 was converted into substituted pyridine-β-enaminones-based benzo[d]imidazole 4.

X-ray Structure
The β-enaminone 2 crystallized in the monoclinic space group P21/n with Z = 4 ( Table 1). A list of bond distances and angles are provided in Table S1 (Supplementary Materials). The asymmetric unit comprised one perfectly planar molecule ( Figure 1, upper part). Even the side chain and the benzo[d]imidazole moiety are also coplanar with a maximum deviation of 0.335 Å of C13 from the benzo[d]imidazole mean plane. The molecules are connected to form a three-dimensional network by C-H…O and C-H…π interactions shown in Figure 2 (upper left part). Each two molecules are interconnected by C12-H12…O1 with a donor-acceptor distance of 3.347(3) Å, then the resulting dimeric units are further connected by weak C-H…π interactions leading to the three-dimensional packing structure shown in Figure 2 (lower left part).

Hirshfeld Analysis
All Hirshfeld surfaces are given in Figures       is the presence of π-π interaction among the molecular units of 3. The shortest C…C distance is C4…C8 (3.410 Å).

DFT Studies
The calculated geometries of the studied compounds match the experimental structures very well ( Figure 6). Furthermore, the calculated bond distances and angles (Tables S3 and S4) correlated very well with the corresponding geometric parameters obtained from the X-ray structure with correlation coefficients of 0.9696-0.9951 and 0.9866-0.9931, respectively (Figure 7). The distribution of the natural charges and the molecular electrostatic potential mapped over electron density are shown in Figure 8. It is clear that the carbonyl oxygen and carbon atoms have the highest negative and positive charge in both molecules, respectively. As a result of this charge distribution, the calculated dipole moment values are 3.1956 and 0.3833 Debye for 2 and 3, respectively. It is possible to suggest that the low dipole moment of 3 could be attributed to the presence of almost similar electronegative atoms at both sides of the molecule connected by the C-C bond. Such an almost symmetrical situation could be a main reason for the low polarity of 3. The direction of the dipole moment vector is from the dimethylamine group towards the imidazole moiety in 2 while it is almost passing through at the middle of the C-C bond in 3. Figure 6. Overlay of the optimized and calculated structures for the studied organic compounds.

DFT Studies
The calculated geometries of the studied compounds match the experimental structures very well ( Figure 6). Furthermore, the calculated bond distances and angles (Tables S3 and S4) correlated very well with the corresponding geometric parameters obtained from the X-ray structure with correlation coefficients of 0.9696-0.9951 and 0.9866-0.9931, respectively (Figure 7). The distribution of the natural charges and the molecular electrostatic potential mapped over electron density are shown in Figure 8. It is clear that the carbonyl oxygen and carbon atoms have the highest negative and positive charge in both molecules, respectively. As a result of this charge distribution, the calculated dipole moment values are 3.1956 and 0.3833 Debye for 2 and 3, respectively. It is possible to suggest that the low dipole moment of 3 could be attributed to the presence of almost similar electronegative atoms at both sides of the molecule connected by the C-C bond. Such an almost symmetrical situation could be a main reason for the low polarity of 3. The direction of the dipole moment vector is from the dimethylamine group towards the imidazole moiety in 2 while it is almost passing through at the middle of the C-C bond in 3. is the presence of π-π interaction among the molecular units of 3. The shortest C…C distance is C4…C8 (3.410 Å).

DFT Studies
The calculated geometries of the studied compounds match the experimental structures very well ( Figure 6). Furthermore, the calculated bond distances and angles (Tables S3 and S4) correlated very well with the corresponding geometric parameters obtained from the X-ray structure with correlation coefficients of 0.9696-0.9951 and 0.9866-0.9931, respectively (Figure 7). The distribution of the natural charges and the molecular electrostatic potential mapped over electron density are shown in Figure 8. It is clear that the carbonyl oxygen and carbon atoms have the highest negative and positive charge in both molecules, respectively. As a result of this charge distribution, the calculated dipole moment values are 3.1956 and 0.3833 Debye for 2 and 3, respectively. It is possible to suggest that the low dipole moment of 3 could be attributed to the presence of almost similar electronegative atoms at both sides of the molecule connected by the C-C bond. Such an almost symmetrical situation could be a main reason for the low polarity of 3. The direction of the dipole moment vector is from the dimethylamine group towards the imidazole moiety in 2 while it is almost passing through at the middle of the C-C bond in 3. Figure 6. Overlay of the optimized and calculated structures for the studied organic compounds. Figure 6. Overlay of the optimized and calculated structures for the studied organic compounds.

Reactivity Studies
The reactivity indices based on the frontier molecular orbital energies for the studied compounds are calculated and compared [43][44][45][46][47][48][49]. The highest occupied (HOMO) and lowest unoccupied molecular orbital (LUMO) energies are calculated to be −5.7022 and −1.6409 eV, respectively, for 2, while they are generally lower (−6.2162 and −2.4090 eV, respectively) in 3. The reason could be related to the presence of a more conjugated system in 3 compared to 2. As a result, electron affinity (A) and ionization potential (I) are 1.6409 and 5.7022 eV, respectively. The hardness (η = 4.0613), electrophilicity index (ω = 1.6596 eV), and chemical potential (µ = -3.6715 eV) were also computed using the frontier molecular orbitals energies. On the other hand, the corresponding values in 3 are 2.4090, 6.2162, 3.8072, 2.4426, and -4.3126 eV, respectively. It is clear that the intramolecular charge transfer represented by HOMO → LUMO excitation is easier in 3 than 2. It is clear that both MOs are delocalized over the π-system indicating π-π* charge transfer-based transition ( Figure 9). Moreover, compound 3 has a higher electrophilicity index indicating a higher ability to gain electron than 2 which agree very well with the low energy of LUMO in the former compared to the latter. In contrast, 2 is a better electron donor than 3. The presented descriptors have a strong relation to the chemical reactivity of compounds.

Reactivity Studies
The reactivity indices based on the frontier molecular orbital energies for the studied compounds are calculated and compared [42][43][44][45][46][47][48]. The highest occupied (HOMO) and lowest unoccupied molecular orbital (LUMO) energies are calculated to be −5.7022 and −1.6409 eV, respectively, for 2, while they are generally lower (-6.2162 and -2.4090 eV, respectively) in 3. The reason could be related to the presence of a more conjugated system in 3 compared to 2. As a result, electron affinity (A) and ionization potential (I) are 1.6409 and 5.7022 eV, respectively. The hardness (η = 4.0613), electrophilicity index (ω = 1.6596 eV), and chemical potential (μ = -3.6715 eV) were also computed using the frontier molecular orbitals energies. On the other hand, the corresponding values in 3 are 2.4090, 6.2162, 3.8072, 2.4426, and -4.3126 eV, respectively. It is clear that the intramolecular charge transfer represented by HOMO → LUMO excitation is easier in 3 than 2. It is clear that both MOs are delocalized over the π-system indicating π-π* charge transfer-based transition ( Figure 9). Moreover, compound 3 has a higher electrophilicity index indicating a higher ability to gain electron than 2 which agree very well with the low energy of LUMO in the former compared to the latter. In contrast, 2 is a better electron donor than 3. The presented descriptors have a strong relation to the chemical reactivity of compounds.

NMR Spectra
The chemical shifts (C.S) of 1 H and 13 C were computed and the results are summarized in Tables S5-S6 (SI) in comparison with the results obtained experimentally. It is clear from Figure 10

NMR Spectra
The chemical shifts (C.S) of 1 H and 13 C were computed and the results are summarized in Tables S5-S6 (SI) in comparison with the results obtained experimentally. It is clear from Figure 10

Conclusions
The N-alkyl-β-enaminone-based benzo[d]imidazole scaffold 2 was obtained with a 72% yield at higher temperature (140 °C), but with a lower temperature of 125 °C, the reaction afforded 1. Further, the cyclized pyridine-based benzo [d]imidazole and the corresponding β-enaminone were successfully achieved. The supramolecular structures of 2 and 3 were analyzed using Hirshfeld calculations. DFT calculations were used to compute the electronic properties of both systems. Some reactivity descriptors were also calculated based on the energies of the frontier molecular orbitals and then compared. Moreover, calculated NMR spectra are in good agreement with the experimental data.

Conclusions
The N-alkyl-β-enaminone-based benzo[d]imidazole scaffold 2 was obtained with a 72% yield at higher temperature (140 • C), but with a lower temperature of 125 • C, the reaction afforded 1. Further, the cyclized pyridine-based benzo [d]imidazole and the corresponding β-enaminone were successfully achieved. The supramolecular structures of 2 and 3 were analyzed using Hirshfeld calculations. DFT calculations were used to compute the electronic properties of both systems. Some reactivity descriptors were also calculated based on the energies of the frontier molecular orbitals and then compared. Moreover, calculated NMR spectra are in good agreement with the experimental data.