Synthesis, X-Ray Structure, Tautomerism Aspect, and Chemical Insight of The 3-(1H-Indol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol

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-NC-ND 4.0 https://creativecommons.org/licenses/by-nc-nd/4.0/ Synthesis, X-Ray Structure, Tautomerism Aspect, and Chemical Insight of The 3-(1HIndol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol © 2020 Elsevier B.V. All rights reserved. Published version Boraei, Ahmed T.A.; Haukka, Matti; Soliman, Saied M.; Barakat, Assem Boraei, A. T., Haukka, M., Soliman, S. M., & Barakat, A. (2021). Synthesis, X-Ray Structure, Tautomerism Aspect, and Chemical Insight of The 3-(1H-Indol-2-yl)-7H-[1,2,4]triazolo[3,4b][1,3,4]thiadiazin-6-ol. Journal of Molecular Structure, 1227, Article 129429. https://doi.org/10.1016/j.molstruc.2020.129429 2021 Journal Pre-proof Synthesis, X-Ray Structure, Tautomerism Aspect, and Chemical Insight of The 3-(1H-Indol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol Ahmed T.A. Boraei , Matti Haukka , Saied M. Soliman , Assem Barakat PII: S0022-2860(20)31744-0 DOI: https://doi.org/10.1016/j.molstruc.2020.129429 Reference: MOLSTR 129429 To appear in: Journal of Molecular Structure Received date: 22 August 2020 Revised date: 6 October 2020 Accepted date: 7 October 2020 Please cite this article as: Ahmed T.A. Boraei , Matti Haukka , Saied M. Soliman , Assem Barakat , Synthesis, X-Ray Structure, Tautomerism Aspect, and Chemical Insight of The 3-(1H-Indol2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol, Journal of Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.129429 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ©2020 Published by Elsevier B.V. Highlights  A new triazolyl-indole was synthesized and characterized.  Its low temperature X-ray single crystal structure was presented.  Analysis of intermolecular interactions was performed using Hirshfeld calculations.  DFT calculations were utilized to predict its electronic and spectroscopic aspects.  The compound exists exclusively in the enol form. Synthesis, X-Ray Structure, Tautomerism Aspect, and Chemical Insight of The 3-(1H-Indol-2-yl)-7H- [1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol Ahmed T. A. Boraei1,*, Matti Haukka 3, Saied M. Soliman 3,*, and Assem Barakat 4,* 1 Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt. 2 Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland, email: [email protected] (M.H.). 3 Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt. [email protected] & [email protected] (S.M.S). 4 Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia. * Correspondence: E-mail: [email protected]; [email protected] (A.T.A.B.); [email protected] (S.M.S); [email protected](A.B.); Tel.: +966-11467-5901(A.B.); Fax: +966-11467-5992(A.B.). Received: date; Accepted: date; Published: date Abstract: The 3-(1H-indol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol 2 was obtained exclusively in the enol configuration starting from triazolyl-indole derivative 1 and alkyl halo-esters in the presence of K2CO3. Chemical structure elucidations with the aid of physicochemical characterizations were used to predict its molecular structure while single crystal X-ray diffraction technique was used to shed the light on the supramolecular structure of 2. DFT calculations agreed very well with the reported X-ray structure where the most stable form thermodynamically is the enol form. Its optimized geometry agreed very well with the experimental structure where the correlation coefficients between the calculated and experimental geometric parameters are very close to 1. Using Hirshfeld analysis, the most significant intermolecular contacts are the N…H, H…C(π), O…H, S…H and C…C contacts. Keywords: triazolyl-indole; Tautomerism; Hirshfeld surface analysis; DFT; NBO. 1. Introduction The 1,2,4-triazole motif connected to the indole scaffold have got remarkable attention in many pharmaceutical applications with diverse pharmacological effects [1,2]. Specifically, the 1,2,4-triazole-3-thione analogues with the amino-functionality in the fourth position have gain a lot of attention due to the presence of sulfur-nitrogen donor atoms which could bind to metals leads to enhancement of the pharmaceutical activity [3]. This scaffold system also can be employed as building blocks in a lot of chemical transformation including construction of Schiff bases and fused heterocycles [4,5]. Among the fused heterocyclic molecules is the s-triazolo[3,4-b]-1,3,4-thiadiazole and thiazolidines rings. In literature, this motif has diverse of biological properties in the recent years including anti-mycobacterial, antifungal, antimicrobial, antiviral, anticonvulsant, anti-HIV, anti-inflammatory, and anticancer activities [6-25]. On other hand, keto-enol tautomerism was studied extensively in literature because it plays a crucial role particularly in the biological systems. For example, DNA consist of nucleobases which exist exclusively in the keto tautomeric forms, mutations might be occurred if a single base converted from the keto form into the enol form [26]. To design, synthesize, and separate either of the two tautomer in a pure form is a challenge. A literature survey revealed that many of the fused heterocycles based s-triazolo[3,4-b]- thiazolidines rings were found in the keto-form [27-30]. Unfortunately, most of these findings are based on routine spectroscopic techniques and no X-ray structures were reported for these examples. In this text, we have been reported the synthesis of 3-(1H-indol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol in the enol form. Additionally, the chemical insight of the synthesized compound was also investigated with the aid of different experimental and theoretical techniques. 2. Materials and Methods All general notes regarding to the equipment’s utilized in this study for structure elucidation have been provided in the Supplementary data. 2.1. Synthesis of the 3-(1H-indol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol 2 A mixture of triazolyl-indole derivative 1 (1.0 mmol) and potassium carbonate K2CO3 (1.2 mmol) dissolved in 10 mL EtOH (absolute) then allowed to stir for 1 h at rt. Subsequently, tert-butyl bromoacetate or ethyl chloroacetate (1.2 mmol) was added and the reaction mixture was refluxed for 3 h then cooled. Solvent was removed under reduced pressure, cold water has been added and the mixture was acidified with diluted HCl. The formed precipitate was filtered off, dried and recrystallized from EtOH or DMF/EtOH. Yield: 81 %, m.p. 291-292 oC; 1H NMR (DMSO-d6, 300 MHz) δ 3.92 (s, 2 H, CH2), 7.05 (dd, 1 H, J4,5 7.9, J5,6 7.3 Hz, H-5Indole), 7.16-7.21 (m, 2 H, H-3Indole, H-6Indole), 7.45 (d, 1 H, J6,7 8.1 Hz, H-7Indole), 7.64 (d, 1 H, J4,5 7.9 Hz, H-4Indole), 11.90 (br. s, 1H, NHIndole), 12.68 (br. s, 1 H, NHThiadiazine); 13C NMR (DMSO-d6, 75 MHz) δ 27.60 (CH2Thiadiazine), 102.89 (C-3Indole), 111.87 (C-7Indole), 119.76 (C-5Indole), 120.94 (C-4Indole), 122.95 (C-2Indole), 123.17 (C-6Indole), 127.47 (C-3aIndole), 136.71 (C-7aIndole), 143.30, 144.61 (C-3Triazole, C-5Triazole), 164.23 (C=O), (Figs. S1-S4, Supplementary data); HRMS (EI) calcd for C12H9N5SO (M+): 271.0552. Found: 271.0552. 2.2. Experimental method for X-Ray structure determinations The experimental method for mounting the crystal along with the software package [31-33] to solve the data have been provided in the Supplementary data. Table 1 listed the data of the solid-state structure of the studied compound. 2.3. Hirshfeld surface analysis Crystal Explorer 17.5 program employed for the topology analyses [34]. 2.4. Computational methods All software [35-39] utilized in this computational study have been provided in the Supplementary data. 3. Results 3.1. Synthesis of 2 3-(1H-Indol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol 2 was obtained in high yield from the reaction of 4-amino-5-(1H-indol-2-yl)-1,2,4-triazol-3(2H)-thione 1 with ethyl chloroacetate or tert-butyl bromoacetate in ethanol and K2CO3 as basic condition (Scheme 1). The product was found in the solid state in the enol configuration. The chemical feature of the solid compound elucidated unambiguous by single crystal x-ray diffraction technique combined with a set of spectrophotometric techniques including NMR, Uv-Vis and mass spectra. Scheme 1. Synthesis of the 3-(1H-indol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol 2 Figure 4. All intermolecular interactions summary of the studied compound 2. Figure 5. Fingerprint plots of the most important intermolecular interactions in 2. Figure 6. The dnorm maps of the most important intermolecular interactions in 2. Table 3. Summary of all short contacts and the interaction distances. Contact Distance Contact Distance O1…H6 2.075 N4…H1B 2.356 N3…H1 1.555 C9…H1A 2.684 N4…H1 2.569 C2…C11 3.164 S1...C8 3.476 3.5. DFT studies The calculated molecular structure of 2 as well as the structure match between the experimental and calculated are depicted in Fig. 7. It was observed that both structures are very close to each other. There are also good squarely interrelationship among the bond angles and bond distances of the experimental and computed study of the compound 2 (Fig. 8). The Cartesian coordinates of the optimized structure as well as the bond angles and distances compared to the acquired results experimentally are given in Table S7 (Supplementary data). Figure 7. The geometry optimized (upper) and overlay of the solid-state x-ray structure with the optimized geometry (lower) for 2. Figure 8. The straight line correlations between the calculated and experimental geometric parameters. Table 4 are summarized the natural charges acquired by NBO calculation. It is clear that the most electropositive sites are the O-H (0.5109) and N-H (0.4472) protons as well as the carbon atoms (0.6018) located between N and O as strong electronegative atoms and sulphur atom as well (0.3483). On other hand, all N (-0.2472 to -0.5555) and O (-0.6733) atomic sites have the highest negative natural charge. Presentation of the molecular electrostatic potential (MEP) mapped over electron density showing the dipole moment vector is presented in Fig. 9. There are red and blue areas representing the most electron rich and electron poor sites in 2, respectively. These atomic sites are most reactive site to be attacked by an electrophile and nuclceophile, respectively. Table 4. Natural atomic charges of 2a. Atom Charge Atom Charge Atom Charge S1 0.3483 C10 -0.2490 H19 0.2955 O2 -0.6733 H11 0.2636 H20 0.2821 H3 0.5109 C12 0.1410 C21 -0.2728 N4 -0.2472 C13 0.3426 H22 0.2357 N5 -0.2883 C14 0.6018 C23 -0.2127 N6 -0.2817 C15 0.0997 H24 0.2414 N7 -0.3873 C16 0.1666 C25 -0.2373 N8 -0.5555 C17 -0.1004 H26 0.2389 H9 0.4472 C18 -0.6884 C27 -0.2608 aAtom numbering refer to Fig. 7 Figure 9. The MEP, HOMO and LUMO of 2. To study the reactivity of the molecule, the frontier molecular orbitals (HOMO, and LUMO) were computed [41-47]. Their energies were computed and acquired to be -5.380 and -1.660 eV, respectively. Hence, the computed electron affinity (A), and ionization potential (I) are 1.6605, and 5.380 eV, respectively. Also, the electrophilicity index, and hardness are -3.262 and 3.720, 3.520 eV, respectively. The HOMO level is located over the fused triazole ring system and it represents the most favored area from which the electronic transition could occur. On other hand, the LUMO is distributed over most of the π-system. Hence, the HOMO to LUMO excitation represent mixed n-π* and π-π* transitions. The energy needed for this intermolecular charge transfer is 3.720 eV. 3.6. NBO analysis The conjugation system play a crucial role in the electron delocalization processes from occupied orbitals to antibonding empty orbitals [48, 49]. These electron delocalization processes and the corresponding stabilization energies (E(2)) are summarized in Table 5. The compound is settled by a number of σ-σ*, n→σ*, n→π*, and π→π* intramolecular charge transfer (IMCT) processes. These IMCT processes stabilized the system up to 7.73, 32.13, 12.15 and 43.34 kcal/mol, respectively. Table 5: The E(2) (kcal/mol) values for the charge transfer interactions in 2a. Donor NBO Acceptor NBO E(2) Donor NBO Acceptor NBO E(2) σ→σ* π→π* σ(O2-H3) σ*(C14 -C18) 5.46 π(N5-C12) π*(N6-C13) 11.90 σ(N4-N7) σ*(O2 -C14) 4.67 π(N6-C13) π*(N5-C12) 15.27 σ(N4-C13) σ*(S1 -C12) 4.66 π(N6-C13) π*(C10-C15) 9.45 σ(N5-N6) σ*(S1 -C12) 7.73 π(N8-C16) π*(C10-C15) 20.48 σ(N5-N6) σ*(C13 -C15) 5.55 π(N8-C16) π*(C21-C25) 5.39 σ(N8-C15) σ*(C16 -C21) 4.51 π(C10-C15) π*(N6-C13) 19.41 σ(C10-C15) σ*(C17-C23) 5.37 π(C10-C15) π*(N8-C16) 7.35 σ(C10-C17) σ*(C13-C15) 6.24 π(C21-C25) π*(N8-C16) 32.13 σ(C21-C25) σ*(N8-C16) 6.17 π(C21-C25) π*(C23-C27) 16.63 σ(C23-C27) σ*(C10-C17) 4.56 π(C23-C27) π*(C21-C25) 19.61 n→σ* n→π* n(O2) σ*(N7-C14) 6.50 n(S1) π*(N5-C12) 17.53 n(N5) σ*(N4-C12) 9.14 n(O2) π*(N7-C14) 43.34 n(N5) σ*(N6-C13) 5.60 n(N4) π*(N5-C12) 41.86 n(N5) σ*(N4-C12) 9.14 n(N4) π*(N6-C13) 40.66 n(N5) σ*(N6-C13) 5.60 n(N4) π*(N7-C14) 22.07 n(N6) σ*(N4-C13) 8.67 n(N6) σ*(N5-C12) 5.58 n(N7) σ*(O2-C14) 4.87 n(N7) σ*(N4-C12) 8.78 n(N7) σ*(N8-H 9) 4.47 n(N7) σ*(C14-C18) 12.15 aAtom numbering refer to Fig. 7 3.7. 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