N -Acetyl Indole Linked to a Fused Triazolo / Thiadiazole Sca ﬀ old: Synthesis, Single Crystal X-Ray Structure, and Molecular Insight

: The designed target compound of N -acetyl indole linked to a fused triazolo / thiadiazole sca ﬀ old was synthesized via the reaction of 4-amino-5-(1 H -indol-2-yl)-1,2,4-triazol-3(2 H )-thione as the starting material with acetic anhydride under reﬂux conditions for 6 h, resulting in an excellent and pure chemical yield. The structural features of the designed compound were conﬁrmed using spectroscopic tools including single crystal X-ray di ﬀ raction analysis along with 1 H-NMR, 13 C-NMR, 2D-NMR, and high resolution mass spectrometry. Using Hirshfeld analysis, we determined the molecular packing depends on strong interactions (O ··· H and N ··· H) along with weak interactions (S ··· H, C ··· H and H ··· H). The shortest contacts corresponding to the N3 ··· H12 (2.490 Å), N2 ··· H5 (2.503 Å), and O1 ··· H2 (2.490 Å) interactions were conﬁrmed based on the Hirshfeld analysis. The calculated dipole moment was 6.6557 Debye. The atomic charge distribution, molecular electrostatic potential map, and reactivity descriptors are also discussed. The computed NMR spectra of the requisite compound correlated well with the results obtained experimentally. The UV-Vis electronic spectra of the requisite compound were simulated using the TD-DFT method and compared with the experimental data. The di ﬀ erent σ → σ *, π → π *, n → σ *, and n → π * donor–acceptor interactions and their interaction energies stabilized the studied system to 9.84, 20.65, 29.33, and 45.82 kcal / mol, respectively.


Introduction
Heterocyclic compounds are of great importance in our daily life. Almost all basic biochemical processes of living cells are mediated by biomolecules that contain these ring systems, such as enzymes, coenzymes, heme, hormones, vitamins, chlorophyll, amino acids, carbohydrates (in cyclic forms), and nucleic acids. Therefore, many synthetic heterocyclic scaffolds are designed to mimic the structure of natural metabolites, peptides, or proteins in 3D space in order to interact with the biological targets. Additionally, heterocyclic frameworks, notably those containing nitrogen and/or oxygen atoms, are considered as valuable sources for new synthetic drug candidates of high functional specialization and are targeted by drug discovery and development research programs to fight diseases. They are extensively used in agriculture as fungicides, herbicides, and insecticides. N/S-heterocycles have many industrial applications including as electron transport materials for phosphorescent organic light-emitting diodes (ETMs for PHOLEDs), as corrosion inhibitors for mild steel, and as light stabilizers of plastic materials. Moreover, many commercially significant dyestuffs contain mainly nitrogen-based heterocycles [1].
In continuation of our research program [22][23][24][25][26] to design a new scaffold that may be useful for material science, we have reported here a new motif-attributed indole synthon linked with a fused triazolo/thiadiazole scaffold at position 2 of the indole nucleus. The structural features of the designed compound were assigned based on single crystal X-ray diffraction techniques and a set of spectroscopic and spectrophotometric techniques. The molecular insight of the target molecule was also explored.

Single-Crystal X-Ray Diffraction Analysis
X-ray diffraction data of the target molecule were collected on a Bruker D8 Venture Diffractometer with the aid of Cu Kα (λ = 1.54178 Å) radiation source and CMOS Photon 100 detector 100 (2). Data integration and reduction were carried out with an APEX 3 software package (version 1, Bruker Scientific Instruments, Billerica, MA, USA) [27] followed by use of the SHELXL programs to solve and refine the final structure [28] (Table 1). Geometrical calculations and intermolecular interaction studies were performed on PLATON and Mercury 3.10.1, respectively [29,30]. An ORTEP diagram ( Figure 1) described the three-dimensional representation of the title compound. Methyl hydrogen atoms were located from difference Fourier maps or from geometrical considerations and then were refined at idealized positions riding on the carbon atoms with isotropic displacement parameters U iso (H) = 1.2U eq (C) or 1.5U eq (methyl) and C-H 0.95-0.98 Å. The Crystal Explorer 17.5 program was employed to explore the topology analyses of the requisite compound [31].

Computational Methods
"All DFT calculations were performed using the Gaussian 09 software package [32] and utilizing the B3LYP/6-31G(d,p) method. Natural bond orbital analyses were performed using the NBO 3.1 program as implemented in the Gaussian 09W package [33]. The self-consistent reaction filed (SCRF) method [34,35] was used to model the solvent (DMSO) 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) [36]. Similarly, the structure was optimized in a solution of compound using ethanol as the solvent, then the optimized molecular structure was used to calculate the electronic spectra using the time-dependent density functional theory (TD-DFT).
The structure of the target compound was elucidated based on 1 H-NMR, which showed five aromatic protons at δ 7.34, 7.36, 7.48, 7.78, and 8.10 ppm for five indole protons in addition to two methyl group signals at δ 2.52 and 2.73 ppm. 13  ¹H-¹H correlation spectroscopy (COSY) helped in assigning the positions of the indole vicinal protons, which demonstrated 3 JH,H coupling correlations between the protons at δ 7.78 and 7.36 ppm, the latter also correlated with the proton at δ 7.48 ppm, and this proton also coupled with the proton at 8.14 ppm. The 2D-HMQC NMR was used for assigning the correlation and position of each CH and CH3.
To assign the position of quaternary carbons, 2D-HMBC NMR spectroscopy was used, which displayed 2  The structure of the target compound was elucidated based on 1 H-NMR, which showed five aromatic protons at δ 7.34, 7.36, 7.48, 7.78, and 8.10 ppm for five indole protons in addition to two methyl group signals at δ 2.52 and 2.73 ppm. 13  protons, which demonstrated 3 J H,H coupling correlations between the protons at δ 7.78 and 7.36 ppm, the latter also correlated with the proton at δ 7.48 ppm, and this proton also coupled with the proton at 8.14 ppm. The 2D-HMQC NMR was used for assigning the correlation and position of each CH and CH 3 .
Crystals 2020, 10, 600 6 of 17 To assign the position of quaternary carbons, 2D-HMBC NMR spectroscopy was used, which displayed 2 J C,H coupling correlations between the methyl protons at δ 2.52 ppm and the carbon at 170.03 ppm. The methyl protons at δ 2.73 ppm displayed a 2 J C,H correlation with the carbon at δ 167.38 ppm. The proton at δ 7.34 ppm displayed a 3 J C,H coupling correlation with carbon at δ 140.47 ppm. The indole proton at δ 7.78 ppm demonstrated a 2 J C,H coupling correlation with carbon at δ 128.33 ppm. The proton at 8.14 ppm showed a 2 J C,H coupling correlation with carbon at δ 136.37 ppm (Figures 1 and 2).

Structural Features of the Target Compound
The compound crystallized in the NA-space group Cc with Z = 4, and the correct absolute structure was confirmed by the Flack parameter of 0.067 (5). Structurally, it consists of a perfectly planar fused triazolo-thiadiazole system, i.e., rings A and B attach with the perfectly planar indole moiety (rings C and D) ( Figure 3). The triazolo-thiadiazole and the substituted indole moieties are not coplanar where the angle between the mean plane passing through them is 41.82°.   Table 2). The intermolecular hydrogen bonds C5-H5···N2 and C-H12A···N3 with H···N distances of 2.62 and 2.56

Structural Features of the Target Compound
The compound crystallized in the NA-space group Cc with Z = 4, and the correct absolute structure was confirmed by the Flack parameter of 0.067 (5). Structurally, it consists of a perfectly planar fused triazolo-thiadiazole system, i.e., rings A and B attach with the perfectly planar indole moiety (rings C and D) ( Figure 3). The triazolo-thiadiazole and the substituted indole moieties are not coplanar where the angle between the mean plane passing through them is 41.82 • .

Structural Features of the Target Compound
The compound crystallized in the NA-space group Cc with Z = 4, and the correct absolute structure was confirmed by the Flack parameter of 0.067 (5). Structurally, it consists of a perfectly planar fused triazolo-thiadiazole system, i.e., rings A and B attach with the perfectly planar indole moiety (rings C and D) ( Figure 3). The triazolo-thiadiazole and the substituted indole moieties are not coplanar where the angle between the mean plane passing through them is 41.82°.   Table 2). The intermolecular hydrogen bonds C5-H5···N2 and C-H12A···N3 with H···N distances of 2.62 and 2.56   Table 2). The intermolecular hydrogen bonds C5-H5···N2 and C-H12A···N3 with H···N distances of 2.62 and 2.56 Å, respectively, as well as C2-H2···O1 with 2.59 Å link molecules stabilize the crystal packing as depicted in Figure 4. Cg···Cg contacts between ring B and ring C further enhance the crystal stability with a centroid···centroid distance of 3.769 Å, stacking the layers along the c axis.

Hirshfeld Analysis of Molecular Packing
The different contacts in the crystal structure of the target molecule based on a Hirshfeld analysis are shown in Figure 5. The packing of molecules in the crystal is mainly dependent on strong O···H and N···H contacts. The shortest N···H hydrogen bonds are N3···H12 (2.490 Å) and N2···H5 (2.503 Å) while the O1···H2 (2.490 Å) is the shortest among the O···H contacts based on the Hirshfeld analysis. The O···H and N···H hydrogen bonding interactions are manifested as spots of red color in the dnorm and intense spikes in the fingerprint plot ( Figure 6). The O···H and N···H contacts contribute 10.6 and 21.2% from the overall interactions, respectively. In addition, the S···H, C···H, and H···H contacts are weak, as indicated from the blue or white regions and less sharp spikes in the corresponding dnorm maps and fingerprint plots, respectively ( Figure S2

Optimized Geometry
The calculated geometry of the studied molecule matches very well with the X-ray one ( Figure  8). Furthermore, the calculated bond distances and angles are in good agreement (Table S1) and correlated very well with the corresponding geometric parameters obtained from the X-ray structure with correlation coefficients of 0.9938 and 0.9915 for bond distances and angles, respectively ( Figure  9). The distribution of the natural charges and the molecular electrostatic potential are shown in Figure 10. It is clear that the highest negative charges are related to the nitrogen and oxygen sites, while positive charges are related to the hydrogen and sulphur atoms. As a result of this charge distribution, the calculated dipole moment is 6.6557 Debye. The direction of the dipole moment vector is predicted towards the fused triazole ring ( Figure 10). In addition, the red (nitrogen and oxygen sites) and blue (protons) regions in the MEP map indicated the most proper regions as hydrogen bond acceptor and hydrogen bond donor, respectively.  Table 3 and is different from that in Figure 3.

Optimized Geometry
The calculated geometry of the studied molecule matches very well with the X-ray one ( Figure 8, Figure S3). Furthermore, the calculated bond distances and angles are in good agreement (Table S1) and correlated very well with the corresponding geometric parameters obtained from the X-ray structure with correlation coefficients of 0.9938 and 0.9915 for bond distances and angles, respectively ( Figure 9). The distribution of the natural charges and the molecular electrostatic potential are shown in Figure 10. It is clear that the highest negative charges are related to the nitrogen and oxygen sites, while positive charges are related to the hydrogen and sulphur atoms. As a result of this charge distribution, the calculated dipole moment is 6.6557 Debye. The direction of the dipole moment vector is predicted towards the fused triazole ring (Figure 10). In addition, the red (nitrogen and oxygen sites) and blue (protons) regions in the MEP map indicated the most proper regions as hydrogen bond acceptor and hydrogen bond donor, respectively.

Optimized Geometry
The calculated geometry of the studied molecule matches very well with the X-ray one ( Figure  8). Furthermore, the calculated bond distances and angles are in good agreement (Table S1) and correlated very well with the corresponding geometric parameters obtained from the X-ray structure with correlation coefficients of 0.9938 and 0.9915 for bond distances and angles, respectively ( Figure  9). The distribution of the natural charges and the molecular electrostatic potential are shown in Figure 10. It is clear that the highest negative charges are related to the nitrogen and oxygen sites, while positive charges are related to the hydrogen and sulphur atoms. As a result of this charge distribution, the calculated dipole moment is 6.6557 Debye. The direction of the dipole moment vector is predicted towards the fused triazole ring (Figure 10). In addition, the red (nitrogen and oxygen sites) and blue (protons) regions in the MEP map indicated the most proper regions as hydrogen bond acceptor and hydrogen bond donor, respectively.  Table 3 and is different from that in Figure 3.  Table 3 and is different from that in Figure 3. σ→σ* n→σ* BD(1)S1-C23 BD*(1)N5-C22 6.39 LP (1)
(1) Figure 9. Correlation graphs between the experimental data (bond angles and bond distance) and calculated data.
The HOMO and LUMO energies were calculated to be −5.8535 and −1.4346 eV, respectively. As a result, the ionization potential (I) and electron affinity (A) were 5.8535 and 1.4346 eV, respectively. In addition, the hardness (η = 4.4189), electrophilicity index (ω = 1.5025 eV), and chemical potential (µ = −3.6440 eV) were also computed using the frontier molecular orbitals energies. The presented descriptors have strong relation to the chemical reactivity of the compound. In addition, the HOMO is localized over the triazolo-thiadiazole moiety as a starting demand for the intramolecular charge transfer to the LUMO level ( Figure 11). The latter is disseminated over the π-system of the triazole and indole moieties. Hence, the HOMO-LUMO charge transfer is mainly π→π* excitation and the energy of this intramolecular charge transfer is 4.4189 eV.

NBO Analysis
The analysis of the different charge transfer interactions within the molecule using second order perturbation theory [44,45] within the framework of the natural bond orbital calculations shed light on the different electron delocalization processes that stabilize the molecular system. The stabilization energies (E (2) ) of the different intramolecular charge transfer interactions within the requisite molecule are listed in Table 3. The system is stabilized by different types of intramolecular charge transfer interactions such as σ→σ*, π→π*, n→σ*, and n→π* electron delocalization processes. The energies of these charge transfer interactions stabilized the studied molecule up to 9.84, 20.65, 29.33, and 45.82 kcal/mol, respectively. Table 3. The stabilization energies E (2) (kcal/mol) and the charge transfer interactions in the target compound a .

NBO Analysis
The analysis of the different charge transfer interactions within the molecule using second order perturbation theory [44,45] within the framework of the natural bond orbital calculations shed light on the different electron delocalization processes that stabilize the molecular system. The stabilization energies (E (2) ) of the different intramolecular charge transfer interactions within the requisite molecule are listed in Table 3. The system is stabilized by different types of intramolecular charge transfer interactions such as σ→σ*, π→π*, n→σ*, and n→π* electron delocalization processes. The energies of these charge transfer interactions stabilized the studied molecule up to 9.84, 20.65, 29.33, and 45.82 kcal/mol, respectively.

UV-Vis and NMR Spectra
The experimental UV-Vis charts were recorded in ethanol and showed absorption bands at 239 nm in addition to the split band at 293 and 301 nm. In order to assign the origin of these electronic transitions, a TD-DFT calculation was performed by applying the ethanol solvent model. The bands assignment is given in Table 4. The simulated and experimental electronic spectra are assigned in Figure 12. The experimentally observed bands were calculated at 245.1 nm (f = 0.1208), 283.6 nm (f = 0.0674), and 307.4 nm (f = 0.4712), respectively. The complete assignments of the molecular orbitals included in these electronic transitions are presented graphically in Figure 13. Crystals 2020, 10, x 13 of 17 The experimental UV-Vis charts were recorded in ethanol and showed absorption bands at 239 nm in addition to the split band at 293 and 301 nm. In order to assign the origin of these electronic transitions, a TD-DFT calculation was performed by applying the ethanol solvent model. The bands assignment is given in Table 4. The simulated and experimental electronic spectra are assigned in Figure 12. The experimentally observed bands were calculated at 245.1 nm (f = 0.1208), 283.6 nm (f = 0.0674), and 307.4 nm (f = 0.4712), respectively. The complete assignments of the molecular orbitals included in these electronic transitions are presented graphically in Figure 13.     Table 4.
Finally, the chemical shifts (C.S.) of 1 H and 13 C were computed and the experimental results are listed in the Supplementary data (Table S2). It is clear from Figure 14 that there is a good relation between the calculated and experimental C.S. values. The correlation coefficients are 0.9916 for 1 H-NMR and 0.9971 for 13 C-NMR.

Conclusions
We describe a new compound based on an acetylated N-indole linked with fused triazolo/thiadiazole motifs. The molecular features and chemical insight of the studied compound are outlined. The supramolecular structure of the desired molecule was analyzed by employing Hirshfeld calculations. In addition, calculated NMR spectra exhibited good harmony with the obtained experimental results. The electronic spectral bands observed experimentally were assigned using TD-DFT calculations. The different electron delocalization processes that stabilize the studied system were analyzed using NBO calculations. In addition, the electronic, and reactivity descriptors were also explored. The utility of the synthesized compound for application will be explored in the near future.
Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1. Figure S1: Hirshfeld surfaces of the studied compound; Figure S2: Atom numbering of the optimized structure; Table S1 and Table   Figure 13. Presentation of the molecular orbitals included in the electronic transitions of the studied compound in ethanol as solvent. The definitions of I, II and III refer to Table 4.
Finally, the chemical shifts (C.S.) of 1 H and 13 C were computed and the experimental results are listed in the Supplementary data (Table S2). It is clear from Figure 14 that there is a good relation between the calculated and experimental C.S. values. The correlation coefficients are 0.9916 for 1 H-NMR and 0.9971 for 13 C-NMR.  Table 4.
Finally, the chemical shifts (C.S.) of 1 H and 13 C were computed and the experimental results are listed in the Supplementary data (Table S2). It is clear from Figure 14 that there is a good relation between the calculated and experimental C.S. values. The correlation coefficients are 0.9916 for 1 H-NMR and 0.9971 for 13 C-NMR.

Conclusions
We describe a new compound based on an acetylated N-indole linked with fused triazolo/thiadiazole motifs. The molecular features and chemical insight of the studied compound are outlined. The supramolecular structure of the desired molecule was analyzed by employing Hirshfeld calculations. In addition, calculated NMR spectra exhibited good harmony with the obtained experimental results. The electronic spectral bands observed experimentally were assigned using TD-DFT calculations. The different electron delocalization processes that stabilize the studied system were analyzed using NBO calculations. In addition, the electronic, and reactivity descriptors were also explored. The utility of the synthesized compound for application will be explored in the near future.
Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1. Figure S1: Hirshfeld surfaces of the studied compound; Figure S2: Atom numbering of the optimized structure; Table S1 and Table

Conclusions
We describe a new compound based on an acetylated N-indole linked with fused triazolo/thiadiazole motifs. The molecular features and chemical insight of the studied compound are outlined. The supramolecular structure of the desired molecule was analyzed by employing Hirshfeld calculations. In addition, calculated NMR spectra exhibited good harmony with the obtained experimental results. The electronic spectral bands observed experimentally were assigned using TD-DFT calculations. The different electron delocalization processes that stabilize the studied system were analyzed using NBO calculations. In addition, the electronic, and reactivity descriptors were also explored. The utility of the synthesized compound for application will be explored in the near future.
Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4352/10/7/600/s1. Figure S1: Hirshfeld surfaces of the studied compound; Figure S2: The fingerprint and dnorm of the weak intermolecular contacts in the target compound; Figure S3: Atom numbering of the optimized structure; Table S1  and Table S2: calculated geometric parameters and the calculated and experimental chemical shifts (ppm) of the studied molecule.