Synthesis, Characterization and Single Crystal X-ray Diffraction Analysis of Fused Triazolo/Thiadiazole Clubbed with Indole Scaffold

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ Synthesis, Characterization and Single Crystal X-ray Diffraction Analysis of Fused Triazolo/Thiadiazole Clubbed with Indole Scaffold © 2023 by the authors. Licensee MDPI, Basel, Switzerland Published version Altowyan, Mezna Saleh; Haukka, Matti; Soliman, Saied M.; Barakat, Assem; Alaswad, Saleh O.; Boraei, Ahmed T. A.; Gad, Emad M.; Youssef, Mohamed F. Altowyan, M. S., Haukka, M., Soliman, S. M., Barakat, A., Alaswad, S. O., Boraei, A. T. A., Gad, E. M., & Youssef, M. F. (2023). Synthesis, Characterization and Single Crystal X-ray Diffraction Analysis of Fused Triazolo/Thiadiazole Clubbed with Indole Scaffold. Crystals, 13(3), Article 423. https://doi.org/10.3390/cryst13030423 2023 Citation: Altowyan, M.S.; Haukka, M.; Soliman, S.M.; Barakat, A.; Alaswad, S.O.; Boraei, A.T.A.; Gad, E.M.; Youssef, M.F. Synthesis, Characterization and Single Crystal X-ray Diffraction Analysis of Fused Triazolo/Thiadiazole Clubbed with Indole Scaffold. Crystals 2023,13, 423. https://doi.org/10.3390/ cryst13030423 Academic Editor: Volodymyr Bon Received: 4 February 2023 Revised: 19 February 2023 Accepted: 23 February 2023 Published: 1 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). crystals Article Synthesis, Characterization and Single Crystal X-ray Diffraction Analysis of Fused Triazolo/Thiadiazole Clubbed with Indole Scaffold Mezna Saleh Altowyan 1, Matti Haukka 2, Saied M. Soliman 3, Assem Barakat 4,* , Saleh O. Alaswad 5, Ahmed T. A. Boraei 6,*, Emad M. Gad 6and Mohamed F. Youssef 6,* 1 Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia 2Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland 3Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt 4Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia 5Nuclear Science Research Institute (NSRI), King Abdulaziz City for Science and Technology (KACST), P.O. Box 6086, Riyadh 11442, Saudi Arabia 6Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt *Correspondence: [email protected] (A.B.); [email protected] or [email protected] (A.T.A.B.); [email protected] (M.F.Y.); Tel.: +966-11467-5901 (A.B.); Fax: +966-11467-5992 (A.B.) Abstract: The present synthetic strategy involves the synthesis of indolyl-triazolo-thiadiazole heterocyclic ring systems 8 – 13 from the condensation of 4-amino-5-(1H-indol-2-yl)-3H-1,2,4-triazole3-thione 1 with the aromatic carboxylic acid derivatives 2 – 7 in presence of POCl 3 for 1 h. All compounds were obtained in very good yields and have been well-characterized using spectroscopic techniques. Exclusively, good quality crystals from the target organic hybrid 8-(1H-indol-2-yl)-5- (p-tolyl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 9 were obtained and found suitable for X-ray single crystal diffraction measurement, which is used to confirm and analyze the molecular and supramolecular structure aspects of 9 . The solid-state structure of the synthesized molecule 9 agrees very well with other characterizations. The packing of 9 is dominated by the N . . . H, S . . . H, C . . . C and S . . . C non-covalent interactions, which agree with the Hirshfeld surface analysis. The percentages of these contacts are calculated to be 20.3%, 5.4%, 9.4% and 4.3%, respectively. Keywords: fused heterocycle; triazole; thiadiazole; computational study 1. Introduction Indole chemistry is a wonderful area of research and has gained a lot of attention from researchers for centuries. This fused heterocycle pharmacophore ring exists in many biological hits, which makes this unit a privileged molecule [ 1 ]. The indole core structure is found in alkaloid polycyclic compounds and has shown broad-spectrum actions in many pharmacological applications. Among their biological activities, these compounds have been applied as targeting enzyme inhibitors in cancer research, specifically PARP-1 and EGFR inhibitors [ 2 – 4 ], α -glucosidase inhibitor [ 5 ] and anti-HIV (anti-human immunodeficiency virus) [ 6 ], and have also exhibited other activities, including anti-microbial [ 7 ], anti-inflammation [ 8 ], anti-vascular [ 9 ], ischemia/reperfusion injury [ 10 ], and anti-malarial potential [11]. On the other hand, the 4-amino-1,2,4-triazole-3-thione motif is an interesting scaffold that can be utilized for the synthesis of heterocyclic compounds via annulation or Schiff base formation because it has good functionality. This pharmacophore showed interesting biological patterns, including anti-tumor [ 12 ], anti-malarial [ 13 ], anti-microbial [ 14 ], anticonvulsant [ 15 ], and anti-proliferative behaviors [ 16 ]. Additionally, it has been used as an Crystals 2023,13, 423. https://doi.org/10.3390/cryst13030423 https://www.mdpi.com/journal/crystals Crystals 2023,13, 423 2 of 10 enzyme inhibitor, such as for protein tyrosine phosphatase 1B [ 17 ], AChE enzyme [ 18 ], urease enzymes [ 19 ] and dizinc metalloβ -lactamase [ 20 ]. L. Gavara et al. have designed and synthesized a new Schiff base derived from the 4-amino-1,2,4-triazole-3-thione core structure, which showed high efficacy and more selectivity against metalloβ -lactamases (MBLs) [ 21 ]. Recently, Boraei et al. [ 22 ] utilized this synthon combined with indole moiety for annulation, and yielded a new triazolo/thiadiazole heterocycle with a confirmed molecular structure, which makes this scaffold interesting and will lead to further research. Triazole and fused rings have shown great biological importance in the medical chemistry and drug discovery research fields [23–27]. The chemical insights yielded by the newly synthesized molecules have attracted the attention of many researchers. One of the most powerful tools that can provide insights into the intermolecular interactions in molecular crystals is Hirshfeld surface analysis. The shapeand size-based Hirshfeld surface analysis approach allows the quantitative and qualitative exploration and visualization of the intermolecular contacts in crystalline molecules. In this context, based on the findings mentioned above and in continuation of our research program focused on heterocyclic chemistry [ 28 – 30 ], we have synthesized new fused triazolo/thiadiazole heterocycles combined with an indole scaffold. The molecular structures of the desired molecules are fully characterized based on spectrophotometric tools, in addition to single-crystal X-ray diffraction (SCXRD) analysis. Hirshfeld surface analysis has also been performed. 2. Materials and Methods 2.1. General Melting points were measured via a melting point apparatus (SMP10) with open capillaries and are inclded uncorrected. Nuclear magnetic resonance (1H-NMR and 13C-NMR) spectra were determined using DMSO-d 6 on Bruker AC 300 and 400 MHz spectrometers, respectively, in the presence of tetramethylsilane as an internal standard. Chemical shifts are described in δ (ppm) and coupling constants are given in Hz. Elemental analysis was performed on a Flash EA-1112 instrument. A Finnigan MAT 95XP was used to record the mass spectra of HREI experiments. A Jeol JMS HX110 mass spectrometer was used to capture the FAB-MS data. 2.2. General Procedures A mixture of 3.0 mmol of appropriate aromatic carboxylic acid derivative 2 – 7 (3.0 mmol) was refluxed in 10 mL phosphorus oxychloride for 1 h, then left to cool to room temperature, before being poured over ice water. The formed precipitates were collected by filtration, dried and recrystallized from DMF to produce the pure compounds 8 – 13 . Only 8-(1Hindol-2-yl)-5-(p-tolyl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 9 was obtained in a sufficient crystal form for SCXRD measurement. 8-(1H-Indol-2-yl)-5-phenyl-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 8 Yield: 87%, m.p. > 300 ◦ C; 1 H NMR (DMSO-d 6 , 300 MHz) δ 7.09 (dd, J= 7.8, J= 7.2 Hz, 1H), 7.22 (dd, J= 7.2, J= 7.8 Hz, 1H), 7.47–7.72 (m, 6H), 8.13 (d, J= 6.6 Hz, 2H), 12.13 (br.s, 1H); 13 C NMR (DMSO-d 6 , 75 MHz) δ 102.67, 111.97, 119.88, 121.00, 122.27, 123.27, 127.30, 127.58, 128.95, 129.63, 132.95, 137.15, 141.13, 153.45, 167.01; HRMS (EI) calcd for C 17 H 11 N 5 S (M+): 317.0715. Found: 317.0726. 8-(1H-Indol-2-yl)-5-(p-tolyl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 9 Yield: 83%, m.p. > 300 ◦ C; 1 H NMR (DMSO-d 6 , 400 MHz) δ 2.42 (s, 3H), 7.08 (dd, J= 8.0 ,J= 7.5 Hz, 1H), 7.22 (dd, J= 7.5, J= 8.4 Hz, 1H), 7.45–7.51 (m, 4H), 7.71 (d, J= 8.0 Hz , 1H), 7.99 (d, J= 8.0 Hz, 2H), 12.08 (br.s, 1H); 13 C NMR (DMSO-d 6 , 100 MHz) δ 21.19, 102.69, 112.04, 119.95, 121.09, 122.94, 123.33, 126.31, 127.29, 127.66, 130.24, 137.21, 143.52, 167.13; HRMS (FAB +ve) calcd for C18H14N5S (M + 1): 332.0970. Found: 332.0955. 3-(1H-Indol-2-yl)-6-(4-methoxyphenyl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 10 Yield: 82%, m.p. > 300 ◦ C; 1 H NMR (DMSO-d 6 , 400 MHz) δ 3.91 (s, 3H), 7.11 (t, J= 7.5 Hz , 1H), 7.18–7.31 (m, 3H), 7.40–7.58 (m, 2H), 7.73 (d, J= 7.9 Hz, 1H), 8.10 (d, Crystals 2023,13, 423 3 of 10 J= 8.8 Hz , 2H), 12.14 (s, 1H); 13 C NMR (DMSO-d 6 , 100 MHz) δ 56.19, 103.15, 112.51, 115.57, 120.45, 121.56, 123.40, 123.53, 128.10, 129.70, 137.62, 141.51, 162.90, 163.40; elemental analysis calculated for [C 18 H 13 N 5 OS]: C, 62.23; H, 3.77; N, 20.16; S, 9.23. Found: C, 62.34; H, 3.86; N, 20.08; S, 9.35. 8-(1H-Indol-2-yl)-5-(4-chlorophenyl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 11 Yield: 92%, m.p. >300 ◦ C; 1 H NMR (DMSO-d 6 , 300 MHz) δ 7.09 (dd, J= 8.1, J= 7.2 Hz , 1H), 7.22 (dd, J= 7.2, J= 8.4 Hz, 1H), 7.46 (s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.69–7.76 (m, 4H), 8.16 (d, J= 8.4 Hz, 2H), 12.13 (br.s, 1H); 13 C NMR (DMSO-d 6 , 75 MHz) δ 102.74, 111.96, 119.96, 121.06, 122.81, 123.36, 127.61, 127.88, 129.12, 129.77, 137.20, 137.66, 141.18, 153.60, 165.97; HRMS (FAB +ve) calcd for C17H11N5SCl (M+1): 352.0424. Found: 352.0441. 6-(2-Bromophenyl)-3-(1H-indol-2-yl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 12 Yield: 73%, m.p. 296–297 ◦ C; 1 H NMR (400 MHz, DMSO) δ 7.11 (d, J= 7.2 Hz, 1H), 7.24 (d, J= 8.1 Hz, 1H), 7.43 (d, J= 1.4 Hz, 1H), 7.52 (d, J= 8.3 Hz, 1H), 7.84–7.62 (m, 4H), 8.25 (dd, J= 7.7, 1.7 Hz, 1H), 12.18 (s, 1H); 13 C NMR (DMSO-d 6 , 100 MHz) δ 103.30, 112.53, 120.47, 121.61, 121.88, 123.20, 123.93, 128.08, 129.09, 129.88, 132.87, 134.27, 134.71, 137.70, 141.60, 150.53, 165.88; elemental analysis calculated for [C 17 H 10 BrN 5 S]: C, 51.53; H, 2.54; Br, 20.16; N, 17.67; S, 8.09. Found: C, 51.70; H, 2.55; Br, 20.18; N, 17.61; S, 8.13. 3-(1H-indol-2-yl)-6-(pyridin-3-yl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 13 Yield: 77%, m.p. >300 ◦ C; 1 H NMR (DMSO-d 6 , 400 MHz) δ 7.19 (m, 2H), 7.52 (s, 2H), 7.73 (d. J= 7.5 Hz, 2H), 8.55 (s, 1H), 8.90 (s, 1H), 9.35 (s, 1H), 12.16 (s, 1H); 13 C NMR (DMSO-d 6 , 100 MHz) δ 103.50, 112.56, 120.48, 121.58, 123.24, 123.89, 124.95, 128.17, 135.59, 137.78, 148.31, 153.76, 162.82, 165.17; elemental analysis calculated for [C 16 H 10 N 6 S]: C, 60.36; H, 3.17; N, 26.40; S, 10.07. Found: C, 60.41; H, 3.13; N, 26.32; S, 10.11. 2.3. X-ray Structure Determinations The technical procedure for the chemical structural elucidation of compound 9 via Xray single-crystal diffraction analysis is given in the Supplementary Materials (The protocol and refinement crystal data Tables S1–S6). Crystal data were refined using the software from [31–34]. Table 1lists the data regarding the synthesized crystals of compound 9. Table 1. Crystal data for 9. 9 CCDC 2239222 empirical formula C18H13N5S fw 331.39 temp. (K) 120(2) K λ(Å) 0.71073 Å cryst syst Monoclinic space group P21/n a(Å) a= 7.8707(2) Å b(Å) b= 15.9681(4) Å c(Å) c= 11.9798(4) Å β(deg) 100.283(3)◦ V(Å3) 1481.44(7) Å3 Z 4 ρcalc (Mg/m3) 1.486 Mg/m3 µ(Mo Kα) (mm−1) 0.228 mm−1 No. reflns. 7305 Unique reflns. 3997 Completeness to θ= 25.242◦100% GOOF (F2)1.031 Rint 0.0213 R1a(I≥2σ) 0.0454 wR2b(I≥2σ)0.1095 aR1=Σ||Fo|−|Fc||/Σ|Fo|. bwR2= {Σ[w(Fo2−Fc2)2]/Σ[w(Fo2)2]}1/2. Crystals 2023,13, 423 4 of 10 2.4. Hirshfeld Surface Analysis The Crystal Explorer 17.5 program was used to perform the topology analysis of studied compound 9[35]. 3. Results and Discussion 3.1. Chemistry and Characterizations 4-Amino-5-(1H-indol-2-yl)-3H-1,2,4-triazole-3-thione 1 was mixed separately with benzoic acid, p-toluic acid, anisic acid, p-chlorobenzoic acid, o-bromobenzoic acid and nicotinic acid 2 – 7 in POCl 3 for 1 h; this afforded the indolyl-triazolo-thiadiazoles 8 – 13 , respectively, in excellent yields (Scheme 1). 1Hand 13C-NMR exhibited the characteristic signals of aromatic protons, between 7.08 ppm and 8.28 ppm, whereas the aromatic carbons were found at 102.0–167.0 ppm. In addition, the NMR study of compound 9 showed the proton for the methyl group at 2.42 ppm, and the carbon of the methyl group at 21.19 ppm. Moreover, the NMR of compound 10 revealed methoxy protons at 3.91 ppm and methoxy carbon at 56.19 ppm. Crystals suitable for the X-ray single-crystal analysis of compound 9 were obtained via recrystallization from DMF. Crystals 2023, 13, x FOR PEER REVIEW 4 of 10 μ(Mo Kα) (mm−1) 0.228 mm−1 No. reflns. 7305 Unique reflns. 3997 Completeness to θ = 25.242° 100% GOOF (F2) 1.031 Rint 0.0213 R1 a (I ≥ 2σ) 0.0454 wR2 b (I ≥ 2σ) 0.1095 a R1 = ||Fo| − |Fc||/|Fo|. b wR2 = {[w(Fo2 − Fc2)2]/[w(Fo2)2]}1/2. 2.4. Hirshfeld Surface Analysis The Crystal Explorer 17.5 program was used to perform the topology analysis of studied compound 9 [35]. 3. Results and Discussion 3.1. Chemistry and Characterizations 4-Amino-5-(1H-indol-2-yl)-3H-1,2,4-triazole-3-thione 1 was mixed separately with benzoic acid, p-toluic acid, anisic acid, p-chlorobenzoic acid, o-bromobenzoic acid and nicotinic acid 2–7 in POCl3 for 1 h; this afforded the indolyl-triazolo-thiadiazoles 8–13, respectively, in excellent yields (Scheme 1). 1Hand 13C-NMR exhibited the characteristic signals of aromatic protons, between 7.08 ppm and 8.28 ppm, whereas the aromatic carbons were found at 102.0–167.0 ppm. In addition, the NMR study of compound 9 showed the proton for the methyl group at 2.42 ppm, and the carbon of the methyl group at 21.19 ppm. Moreover, the NMR of compound 10 revealed methoxy protons at 3.91 ppm and methoxy carbon at 56.19 ppm. Crystals suitable for the X-ray single-crystal analysis of compound 9 were obtained via recrystallization from DMF. Scheme 1. Synthesis of the target fused heterocycles. 3.2. Crystal Structure Description Figure 1 shows the molecular structure of compound 9, obtained by single-crystal Xray diffraction analysis. Table 1 lists some of the selected bon angles and bond distances of the desired compound. The monoclinic system was observed in the crystallized compound and centrosymmetric P21/n space group, with lattice parameters a = 7.8707(2) Å, b = 15.9681(4) Å, c = 11.9798(4) and β = 100.283(3)°. The asymmetric unit contained one Scheme 1. Synthesis of the target fused heterocycles. 3.2. Crystal Structure Description Figure 1shows the molecular structure of compound 9 , obtained by single-crystal X-ray diffraction analysis. Table 1lists some of the selected bon angles and bond distances of the desired compound. The monoclinic system was observed in the crystallized compound and centrosymmetric P2 1 /n space group, with lattice parameters a= 7.8707(2) Å, b= 15.9681(4) Å, c= 11.9798(4) and β = 100.283(3) ◦ . The asymmetric unit contained one molecule, while the unit cell comprised four molecules. The crystal density was 1.486 Mg/m 3 and the unit cell volume was 1481.44(7) Å 3 . The molecule comprised a number of aromatic ring systems, which were perfectly planar but showed some twists. The phenyl group of the aryl moiety was twisted from the mean plane of the fused aromatic ring system ( A ) by only 2.85 ◦ . The two fused ring systems A and C were nearly coplanar with one another. The twist angle between the mean plane of the two fused ring systems was only 0.60 ◦ . Selected bond lengths and angles are depicted in Table 2. Crystals 2023,13, 423 5 of 10 Crystals 2023, 13, x FOR PEER REVIEW 5 of 10 molecule, while the unit cell comprised four molecules. The crystal density was 1.486 Mg/m3 and the unit cell volume was 1481.44(7) Å3. The molecule comprised a number of aromatic ring systems, which were perfectly planar but showed some twists. The phenyl group of the aryl moiety was twisted from the mean plane of the fused aromatic ring system (A) by only 2.85°. The two fused ring systems A and C were nearly coplanar with one another. The twist angle between the mean plane of the two fused ring systems was only 0.60°. Selected bond lengths and angles are depicted in Table 2. Figure 1. ORETP of crystalized compound 9. Table 2. Bond lengths (Å) and angles (°) of 9. Bond Length/Å Bond Length/Å S(1)-C(10) 1.7275(18) N(3)-C(10) 1.306(2) S(1)-C(11) 1.7734(17) N(4)-C(10) 1.360(2) N(1)-C(7) 1.376(2) N(4)-C(9) 1.370(2) N(1)-C(8) 1.381(2) N(4)-N(5) 1.3747(19) N(2)-C(9) 1.324(2) N(5)-C(11) 1.304(2) N(2)-N(3) 1.402(2) Bonds Angle/° Bonds Angle/° C(10)-S(1)-C(11) 87.61(8) N(1)-C(7)-C(6) 130.16(16) C(7)-N(1)-C(8) 108.31(14) N(1)-C(7)-C(2) 107.94(15) C(9)-N(2)-N(3) 109.54(14) N(1)-C(8)-C(9) 120.90(15) C(10)-N(3)-N(2) 104.79(14) N(2)-C(9)-N(4) 107.75(14) C(10)-N(4)-C(9) 105.87(14) N(2)-C(9)-C(8) 127.46(16) C(10)-N(4)-N(5) 118.88(14) N(4)-C(9)-C(8) 124.79(15) C(9)-N(4)-N(5) 135.17(14) N(3)-C(10)-N(4) 112.04(15) C(11)-N(5)-N(4) 107.48(14) N(3)-C(10)-S(1) 138.55(14) N(5)-C(11)-S(1) 116.67(13) N(4)-C(10)-S(1) 109.37(12) C(1)-C(8)-N(1) 109.98(15) N(5)-C(11)-C(12) 123.27(15) The molecular units of this compound are controlled by a range of weak non-covalent interactions, including the N…H, S…H and C…C interactions. The molecules are connected to each other by N1-H1...N2, N1-H1...N3 and C14-H14...S1 interactions (Table 3). The different N…H and S…H contacts are shown in Figure 2A, while the resulting packing scheme is presented in Figure 2B. Additionally, the packing of 9 is controlled by different levels of C…C interactions, which are kinds of π–π stacking interactions (Figure 2C). The shortest C…C interactions are depicted in Table 4. Figure 1. ORETP of crystalized compound 9. Table 2. Bond lengths (Å) and angles (◦) of 9. Bond Length/Å Bond Length/Å S(1)-C(10) 1.7275(18) N(3)-C(10) 1.306(2) S(1)-C(11) 1.7734(17) N(4)-C(10) 1.360(2) N(1)-C(7) 1.376(2) N(4)-C(9) 1.370(2) N(1)-C(8) 1.381(2) N(4)-N(5) 1.3747(19) N(2)-C(9) 1.324(2) N(5)-C(11) 1.304(2) N(2)-N(3) 1.402(2) Bonds Angle/◦Bonds Angle/◦ C(10)-S(1)-C(11) 87.61(8) N(1)-C(7)-C(6) 130.16(16) C(7)-N(1)-C(8) 108.31(14) N(1)-C(7)-C(2) 107.94(15) C(9)-N(2)-N(3) 109.54(14) N(1)-C(8)-C(9) 120.90(15) C(10)-N(3)-N(2) 104.79(14) N(2)-C(9)-N(4) 107.75(14) C(10)-N(4)-C(9) 105.87(14) N(2)-C(9)-C(8) 127.46(16) C(10)-N(4)-N(5) 118.88(14) N(4)-C(9)-C(8) 124.79(15) C(9)-N(4)-N(5) 135.17(14) N(3)-C(10)-N(4) 112.04(15) C(11)-N(5)-N(4) 107.48(14) N(3)-C(10)-S(1) 138.55(14) N(5)-C(11)-S(1) 116.67(13) N(4)-C(10)-S(1) 109.37(12) C(1)-C(8)-N(1) 109.98(15) N(5)-C(11)-C(12) 123.27(15) The molecular units of this compound are controlled by a range of weak non-covalent interactions, including the N . . . H, S . . . H and C . . . C interactions. The molecules are connected to each other by N1-H1 . . . N2, N1-H1 . . . N3 and C14-H14 . . . S1 interactions (Table 3). The different N . . . H and S . . . H contacts are shown in Figure 2A, while the resulting packing scheme is presented in Figure 2B. Additionally, the packing of 9 is controlled by different levels of C . . . C interactions, which are kinds of π – π stacking interactions (Figure 2C). The shortest C . . . C interactions are depicted in Table 4. Table 3. Hydrogen bonds for 9(Å and ◦). D-H . . . A d(D-H) d(H . . . A) d(D . . . A) <(DHA) N1-H1 . . . N2#1 0.85(2) 2.12(2) 2.959(2) 169(2) N1-H1 . . . N3#1 0.85(2) 2.60(2) 3.292(2) 139(2) C14-H14 . . . S1#2 0.95 2.905 2.905 179.35 Symm. codes: #1 −x + 1, −y + 1, −z and #2 −1/2 + x, 1.5−y, −1/2 + z. Crystals 2023,13, 423 6 of 10 Crystals 2023, 13, x FOR PEER REVIEW 6 of 10 Figure 2. The N…H/S…H contacts (A), molecular packing view via N…H/S…H contacts (B) and π– π stacking interactions (C) for 9. Table 3. Hydrogen bonds for 9 (Å and °). D-H...A d(D-H) d(H...A) d(D...A) <(DHA) N1-H1...N2#1 0.85(2) 2.12(2) 2.959(2) 169(2) N1-H1...N3#1 0.85(2) 2.60(2) 3.292(2) 139(2) C14-H14...S1#2 0.95 2.905 2.905 179.35 Symm. codes: #1 −x + 1, −y + 1, −z and #2 −1/2 + x, 1.5−y, −1/2 + z. Table 4. The shortest C…C for π–π stacking interactions. Contact Distance Symmetry Code C1…C18 3.371 1 − x,1 − y,1 − z C3…C13 3.342 1 − x,1 − y,1 − z C9…C15 3.288 2 − x,1 − y,1 − z C10…C17 3.349 2 − x,1 − y,1 − z 3.3. Hirshfeld Surface Analysis The stability of crystalline materials is controlled by different intermolecular interactions that occur among the adjacent molecules [36,37]. The types, strengths and weights of the intermolecular interactions in the crystal structure could be simply analyzed using Hirshfeld calculations. There are three important maps, which are the dnorm, shape index and curvedness maps. A view of these surfaces is shown in Figure 3. In the dnorm map, the presence of red regions indicates short contacts, which are considered of great importance to crystal stability. Figure 2. The N . . . H/S . . . H contacts ( A ), molecular packing view via N . . . H/S . . . H contacts ( B ) and π–πstacking interactions (C) for 9. Table 4. The shortest C . . . C for π–πstacking interactions. Contact Distance Symmetry Code C1 . . . C18 3.371 1 −x,1 −y,1 −z C3 . . . C13 3.342 1 −x,1 −y,1 −z C9 . . . C15 3.288 2 −x,1 −y,1 −z C10 . . . C17 3.349 2 −x,1 −y,1 −z 3.3. Hirshfeld Surface Analysis The stability of crystalline materials is controlled by different intermolecular interactions that occur among the adjacent molecules [ 36 , 37 ]. The types, strengths and weights of the intermolecular interactions in the crystal structure could be simply analyzed using Hirshfeld calculations. There are three important maps, which are the d norm , shape index and curvedness maps. A view of these surfaces is shown in Figure 3. In the d norm map, the presence of red regions indicates short contacts, which are considered of great importance to crystal stability. The decomposition of the fingerprint plot gives the weight of each contact in the crystal structure, and also sheds light on the strength of each contact. The percentages of all contacts contributing to molecular packing are presented in Figure 4. The most important short contacts are the N . . . H, S . . . H, C . . . C and S . . . C interactions. Their percentages are calculated to be 20.3%, 5.4%, 9.4% and 4.3%, respectively. Decomposed fingerprint plots of these short contacts are shown in Figure 5. The majority of these interactions appeared in the fingerprint plots as sharp spikes, which confirms that that these interactions are important. A list of the short N . . . H, S . . . H, C . . . C and S . . . C contacts and their corresponding interaction distances is presented in Table 5. Other contacts contributed to a large extent in the molecular packing, including H . . . H and H . . . C interactions. The percentages of these interactions are 38.3% and 18.3%, respectively. Crystals 2023,13, 423 7 of 10 Crystals 2023, 13, x FOR PEER REVIEW 7 of 10 Figure 3. Hirshfeld surfaces of 9 showing the most important interactions: N…H (A), S…H (B), C…C (C) and C…S (D). The decomposition of the fingerprint plot gives the weight of each contact in the crystal structure, and also sheds light on the strength of each contact. The percentages of all contacts contributing to molecular packing are presented in Figure 4. The most important short contacts are the N...H, S...H, C...C and S...C interactions. Their percentages are calculated to be 20.3%, 5.4%, 9.4% and 4.3%, respectively. Decomposed fingerprint plots of these short contacts are shown in Figure 5. The majority of these interactions appeared in the fingerprint plots as sharp spikes, which confirms that that these interactions are important. A list of the short N...H, S...H, C...C and S...C contacts and their corresponding interaction distances is presented in Table 5. Other contacts contributed to a large extent in the molecular packing, including H...H and H...C interactions. The percentages of these interactions are 38.3% and 18.3%, respectively. Table 5. Short contacts and the corresponding interaction distances. Contact Distance Contact Distance N2…H1 1.963 C9…C15 3.288 N3…H1 2.483 C10…C17 3.349 N3…H6 2.512 C6…S1 3.469 S1…H14 2.772 C7…S1 3.42 Figure 3. Hirshfeld surfaces of 9 showing the most important interactions: N . . . H ( A ), S . . . H ( B ), C . . . C (C) and C . . . S (D). Crystals 2023, 13, x FOR PEER REVIEW 8 of 10 Figure 4. Intermolecular contacts and their percentages in 9. Figure 5. Decomposed fingerprint plots for the short contacts in 6. Another important feature of molecular packing is the π–π stacking interactions. The presence of these types of intermolecular contact is indicated by the presence of short C9…C15 (3.288 Å) and C10…C17 (3.349 Å) interactions. Additionally, the presence of π– π stacking interactions is clearly implied by the presence of red/blue triangles and a flat green area in the shape index and curvedness maps, respectively (Figure 3). 4. Conclusions New heterocyclic systems including indole, triazole amd thiadiazole rings 8–13 were synthesized from the reaction of 4-amino-5-(1H-indol-2-yl)-3H-1,2,4-triazole-3-thione and benzoic acid derivatives in POCl3. The success of our strategy to design target compounds is proven by our obtaining of the hybrid heterocycle 9 in a good crystalline form. Its structure was revealed by measuring its X-ray single-crystal structure. The resulting X-ray structure was used to analyze the molecular packing of the newly synthesized compound 9. Additionally, the type, strength and weight of the intermolecular interactions in the crystal structure were analyzed using Hirshfeld calculations. It was found that the N...H Figure 4. Intermolecular contacts and their percentages in 9. Crystals 2023,13, 423 8 of 10 Crystals 2023, 13, x FOR PEER REVIEW 8 of 10 Figure 4. Intermolecular contacts and their percentages in 9. Figure 5. Decomposed fingerprint plots for the short contacts in 6. Another important feature of molecular packing is the π–π stacking interactions. The presence of these types of intermolecular contact is indicated by the presence of short C9…C15 (3.288 Å) and C10…C17 (3.349 Å) interactions. Additionally, the presence of π– π stacking interactions is clearly implied by the presence of red/blue triangles and a flat green area in the shape index and curvedness maps, respectively (Figure 3). 4. Conclusions New heterocyclic systems including indole, triazole amd thiadiazole rings 8–13 were synthesized from the reaction of 4-amino-5-(1H-indol-2-yl)-3H-1,2,4-triazole-3-thione and benzoic acid derivatives in POCl3. The success of our strategy to design target compounds is proven by our obtaining of the hybrid heterocycle 9 in a good crystalline form. Its structure was revealed by measuring its X-ray single-crystal structure. The resulting X-ray structure was used to analyze the molecular packing of the newly synthesized compound 9. Additionally, the type, strength and weight of the intermolecular interactions in the crystal structure were analyzed using Hirshfeld calculations. It was found that the N...H Figure 5. Decomposed fingerprint plots for the short contacts in 6. Table 5. Short contacts and the corresponding interaction distances. Contact Distance Contact Distance N2 . . . H1 1.963 C9 . . . C15 3.288 N3 . . . H1 2.483 C10 . . . C17 3.349 N3 . . . H6 2.512 C6 . . . S1 3.469 S1 . . . H14 2.772 C7 . . . S1 3.42 Another important feature of molecular packing is the π – π stacking interactions. The presence of these types of intermolecular contact is indicated by the presence of short C9 . . . C15 (3.288 Å) and C10 . . . C17 (3.349 Å) interactions. Additionally, the presence of π – π stacking interactions is clearly implied by the presence of red/blue triangles and a flat green area in the shape index and curvedness maps, respectively (Figure 3). 4. Conclusions New heterocyclic systems including indole, triazole amd thiadiazole rings 8 – 13 were synthesized from the reaction of 4-amino-5-(1H-indol-2-yl)-3H-1,2,4-triazole-3-thione and benzoic acid derivatives in POCl 3 . The success of our strategy to design target compounds is proven by our obtaining of the hybrid heterocycle 9 in a good crystalline form. Its structure was revealed by measuring its X-ray single-crystal structure. The resulting X-ray structure was used to analyze the molecular packing of the newly synthesized compound 9 . Additionally, the type, strength and weight of the intermolecular interactions in the crystal structure were analyzed using Hirshfeld calculations. It was found that the N . . . H (20.3%), S . . . H (5.4%), C . . . C (9.4%) and S . . . C (4.3%) non-covalent interactions were the most important. Supplementary Materials: The following supporting information can be downloaded at: https://www. mdpi.com/article/10.3390/cryst13030423/s1, X-ray determination protocol for compound 9 [ 31 , 33 , 34 ]. Table S1: Atomic coordinates ( × 10 4 ) and equivalent isotropic displacement parameters (Å2 × 10 3 ) for 9 . U(eq) is defined as one third of the trace of the orthogonalized Uij tensor; Table S2: Selected bond lengths [Å] and angles [ ◦ ] for 9 ; Table S3: Bond lengths [Å] and angles [ ◦ ] for 9 ; Table S4: Anisotropic