The compound 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate has been prepared and characterized by IR, 1H NMR, 13C NMR and mass spectra. The crystal and molecular structure were further confirmed using single crystal X-ray diffraction. The crystal structure has been found to be stabilized by intermolecular C–H···O interaction generating bifurcated hydrogen bonds whereas the C–H···N interactions generate chain of molecules. The intramolecular N–H···N hydrogen bond forms a ring with S(7) graph-set motif

Gurubasavaraj, V.P.

Nikhath, Fathima

Noor Shahina Begum, .

ePrints@Bangalore University

Journal of Saudi Chemical Society (2014) 18, 432–436King Saud UniversityJournal of Saudi Chemical Societywww.ksu.edu.sawww.sciencedirect.comORIGINAL ARTICLESynthesis and crystal structureof 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate* Corresponding author. Address: Department of Chemistry, CentralCollege Campus, Dr. B.R. Ambedkar Street, Bangalore University,Bangalore 560 001, India. Tel.: +91 80 22961344; fax: +91 8022961331.E-mail addresses: drnoorsb@gmail.com, noorsb@rediffmail.com,drnoorsb@hotmail.com (N.S. Begum).Peer review under responsibility of King Saud University.Production and hosting by Elsevierhttp://dx.doi.org/10.1016/j.jscs.2011.09.0071319-6103 ª 2011 Production and hosting by Elsevier B.V. on behalf of King Saud University. Open access under CC BY-NC-ND license.Nikhath Fathima a, Noor Shahina Begum a,*, Gurubasavaraj V. Pujar ba Department of Studies in Chemistry, Bangalore University, Bangalore 560 001, Indiab Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS University, Mysore 570 015, IndiaReceived 2 May 2011; accepted 3 September 2011Available online 10 September 2011KEYWORDS1,2,4-Triazole derivative;Crystal structure;C–HÆÆÆN;C–HÆÆÆO/N–HÆÆÆN weakinteractionsAbstract The compound 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate has been prepared and characterized by IR, 1H NMR, 13C NMR and mass spectra.The crystal and molecular structure were further conﬁrmed using single crystal X-ray diffraction.The crystal structure has been found to be stabilized by intermolecular C–HÆÆÆO interaction gener-ating bifurcated hydrogen bonds whereas the C–HÆÆÆN interactions generate chain of molecules. Theintramolecular N–HÆÆÆN hydrogen bond forms a ring with S(7) graph-set motif.ª 2011 Production and hosting by Elsevier B.V. on behalf of King Saud University.Open access under CC BY-NC-ND license.1. Introduction1,2,4-Triazoles are among the most promising heterocycliccompounds playing an important role in medicinal, agricul-tural and industrial ﬁelds. Some of them are used as analyticalreagents for the determination of boron, cobalt and antimony.A few triazoles ﬁnd synthetic application as halogenatingagents, as activating polymeric reagents and are also used asphotographic reagents. Substituted-1,2,4-triazoles, are amongthe various heterocyclic compounds that have received consid-erable attention during the last two decades for their potentialantibacterial (Andotra et al., 1986), antifungal (Khan et al.,1987), antiviral (Somorai et al.,1986), antiHIV (Ikizler et al.,1998), anticancer (Ronghui et al., 2005), diuretic (Shah et al.,1969), antihypertensive (Emilsson et al., 1987; Kuzmierkiwiczet al., 1985), anti-inﬂammatory and analgesic (Bozo et al.,1989; Pignatellol et al., 1991; Mullican et al., 1993), hypoglyce-mic (Agarwal, 1991), anticonvulsant (Khanum et al., 2004),and antimycobacterial (Vera et al., 2004) activities. Many anti-fungal agents containing 1,2,4-triazoles are in clinical use(Frank et al., 2003; Kelly, 1997). Ribavarin, the antiviral agentis a synthetic nucleoside derivative containing 1,2,4-triazolemoiety and is active against a wide verity of RNA/DNA virus.It is used in the treatment of severe lower respiratory infectionscaused by RS virus. Guanazole, a very old compound bearingtriazole moiety, is recently found to be active against tumors.Synthesis and crystal structure of 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate 433Anastrozole is a non-steroidal aromatase inhibitor having tri-azole moiety, decreases the estrogen synthesis in the body andthereby prevents or inhibits the growth of many types of breastcancer cells that need estrogen to grow.Various 3-substituted-4-amino-5-mercapto-1,2,4-triazoleshave been reported for their wide spectrum of biological activ-ities. In recent years, the focus has been on the molecular mod-iﬁcation of the triazole moiety to obtain a lead molecule withbetter biological activity and lesser side effects. Substitutionshave been carried out primarily on the 3rd position of the1,2,4-triazole ring by substituting groups such thiol, alkylthioland alkenylthiol (Eldeen et al., 1991) in order to enhance thebiological activity.The synthesis of the compound was followed by subsequentspectroscopic analysis using IR, 1H NMR and 13CNMR tech-niques to conﬁrm the presence of the supposed ring systems, aswell as the signals for the existence of various protons. Thecompound was subjected to single crystal X-ray diffractionanalysis so that its supramolecular structure could be investi-gated in terms of possible intermolecular interactions.2. Experimental2.1. MaterialsAll chemicals were obtained from a commercial source. Sol-vents were dried and puriﬁed with known conventionalmethods.R COOH1C2H5OHH2SONHCl ClR =6RN NNSCH2COOC2H5Cl CH2CK2CO3 in CH3Scheme 1 Synthesis2.2. Analytical methods2.2.1. Physical measurementsMelting points were determined in open capillaries. IR spectrawere recorded on Nicolet FT-IR 410 spectrophotometer,NMR spectra were recorded on Bruker DRX-300 (300 MHzFT-NMR) using DMSO as solvent and TMS as internal stan-dard. Mass spectra were obtained using Shimadzu LCMS2010A. The title compound was prepared in accordance withthe scheme shown (see Scheme 1).2.3. Preparation of 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate (6)2-[2-(2,6-Dichlorophenylamino)phenyl] acetic acid (1) wasconverted to ethyl 2-[2-(2,6-dichlorophenylamino)phenyl]ace-tate (2) by treating with conc. H2SO4 and ethanol. The esterobtained was converted to 2-[2-(2,6-dichlorophenylami-no)phenyl]acetohydrazide (3) on treatment with hydrazinehydrate in absolute ethanol.1-(2-(2-(2,6-Dichlorophenylamino)phenyl)acetyl)-4-p-tolyl-thiosemicarbazide (4) was synthesized by condensing p-tolyllis-othiocyanate with 2-[2-(2,6-dichlorophenylamino)phenyl]acetohydrazide (3). The base catalyzed intramolecular dehyd-rative cyclization of 1-(2-(2-(2,6-dichlorophenylamino)phenyl)acetyl)-4-p-tolylthiosemicarbazide (4) in 2 M sodium hydrox-ide gave corresponding 5-[2-(2,6-dichlorophenylamino)benzyl]NCSRHNNH NHOSROORHNNH2O2434C2H5OH NH2NH2.H2OC2H5OH2M NaOH52M HClRNNSHOOC2H5ACETONEH3CCH3Nof compound 6.Figure 1 Ortep view of compound 6, showing 50% probabilityellipsoids and the atom numbering scheme.434 N. Fathima et al.-4-p-tolyl-4H-1,2,4-triazole-3-thiol (5). 5-[2-(2,6-Dichlorophe-nylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazole-3-thiol (5) whentreated with ethylchloroacetate, in the presence of anhydrouspotassium carbonate yields 2-{5-[2-(2,6-dichlorophenylami-no)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate (6).Yield 71% (3.65 g).2.4. Physical measurements2.4.1. 2-{5-[2-(2,6-Dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate (6)White crystalline solid (DMF), yield 71%, m.p. 158–160 C;IR (KBr) mcm1: 3250 (–NH) 2980 (CH‚), 1738 (C‚O ofester, 1583 C–N, 750 (–Cl).1H NMR (DMSO) d ppm: 1.20–1.27 (t, 3H, alk-CH3), 2.19(s, 3H, Ar–CH3), 4.01 (s, 2H, Ar–CH2), 4.05 (s, 2H, –SCH2),4.15–4.22 (q, 2H, –OCH2), 6.38 (s, Ar–NH), 6.5–7.43 (m,11H, Ar).13C NMR (DMSO) d ppm: 14.12 (alk-CH3), 21.08 (Ar–CH3), 28.77 (Ar–CH2), 34.64 (–SCH2), 62.01 (–OCH2),115.11–150.91 (C of 3Ars), 155.61 (C5 of triazole ring),160.90 (C3 of triazole ring), 168.28 (C‚O).MS m/z: (M+1) 528, the other major fragments 523, 499and 465.3. X-ray analysisSingle crystals of the compound were obtained from the solventDMF. Transparent white plate crystals were selected for X-raydiffraction analysis. The X-ray diffraction data for compound 6were collected on a Bruker Smart CCD Area Detector System,usingMoKa (0.71073 A˚) radiation for the crystal. Intensity datawere collected using a single crystal with dimensions0.40 · 0.35 · 0.30 mm up to a maximum of 28.40 in the x–ascan mode. The data were reduced using SAINTPLUS(Bruker, 1998). The structure was solved by direct methodsusing SHELXS97 (Sheldrick, 2008) and difference Fourier syn-thesis using SHELXL97 (Sheldrick, 2008). The positions andanisotropic displacement parameters of all non-hydrogen atomswere included in the full-matrix least-square reﬁnement usingFigure 2 C–HÆÆÆÆÆÆO interaction generating bifurcated bonds from tSHELXL97 (Sheldrick, 2008) and the procedure was carriedout for a few cycles until convergence was reached. A total of15,519 reﬂections were collected, out of which were 6055[R(int) = 0.0845] independent reﬂections. The number of reﬂec-tions satisfying I> 2r (I) criteria were 4013. These were treatedas observed. TheHatomswere placed at the calculated positionsin the ridingmodel approximation (C–H0.93 A˚), with their tem-perature factors set to 1.2 times those of the equivalent isotropictemperature factors of the parent atoms. All the other non-Hatoms were reﬁned anisotropically. The R factor for theobserved data ﬁnally converged to R= 0.0658. The maximumand minimum values of residual electron density were 0.566and 0.588 eA˚3. Molecular diagrams were generated usingORTEP (Farrugia, 1997). The mean plane calculation was doneusing the program PARST (Nardelli, 1983).wo donors, C4 and C24 to the same acceptor, O2 along ‘b’ axis.Figure 3 Packing of the molecules in crystal of 6 viewed along ‘a’ axis. Dotted lines indicate, C–HÆÆÆ.N intermolecular interactions.Table 1 Crystal data and structure reﬁnement.Empirical formula C25 H24 Cl2 N4 O2 SFormula weight 515.44Temperature 293(2) KWavelength 0.71073 A˚Crystal system, space group Orthorhombic, P ca21Unit cell dimensionsa (A˚) 28.792(10)b (A˚) 11.012(4)c (A˚) 7.840(3)Volume (A˚3) 2485.7(15)z 4Calculated density (Mg/m3) 1.377Absorption coeﬃcient (mm1) 0.376F(000) 1072Crystal size 0.40 · 0.35 · 0.30 mmTheta range for data collection 1.98–28.40Limiting indices 38 6 h 6 30, 13 6 k 6 14, 10 6Reﬂections collected/unique 15,519/6055 [R(int) = 0.0845]Completeness to theta 28.40 98.8%Reﬁnement method Full-matrix least-squares on F2Data/restraints/parameters 6055/1/318Goodness-of-ﬁt on F2 1.301Final R indices [I> 2r (I)] R1 = 0.0658, wR2 = 0.1284R indices (all data) R1 = 0.1165, wR2 = 0.1866Absolute structure parameter 0.82(11)Largest diﬀ. peak and hole (e A˚3) 0.566 and 0.588Table 2 Non-bonded interactions and possible hydrogenbonds (A˚, ) for compound 6. (D-donor; A-acceptor; H-hydrogen.)D–H  A D–H H  A D  A D–H  AN3–H3  N2 0.860(4) 2.256(4) 3.018(6) 147(2)C4–H4  O2i 0.930(6) 2.963(4) 3.865(7) 163(3)C24–H24  O2ii 0.930(5) 2.450(4) 3.633(6) 166(3)C18–H18B  N2iii 0.970(6) 2.688(4) 3.594(8) 155(3)Symmetry code: (0) x, y, z (i) x, +y+1, +z+1 (ii) x+1, y+2,+z+1/2 (iii) x, +y, +z1.Synthesis and crystal structure of 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate 4354. Result and discussionFig. 1 shows the ORTEP diagram of the molecule with thermalellipsoids drawn at 50% probability. Figs. 2 and 3 show hydro-gen bond interactions and crystal packing of the compound.The details of crystal data and reﬁnements are given in Table 1.Table 2 shows the respective hydrogen bond interactions forcompound 6.Compound 6 comprises 1,2,4-triazole, dichlorophenylami-no benzyl group and the p-tolyl ring. The non-coplanaritybetween triazole and p-tolyl and that between triazole anddichlorophenylamino benzyl rings is obvious from the dihedralangle values of 68.93 and 58.36 respectively. The triazole ringis essentially planar (La Keya et al., 2006; Buzykin et al., 2008),the maximum deviation of atoms from their mean statisticalplanes being 0.0161 A˚. The bond lengths and angles for the1,2,4-triazole moiety in the molecule are in good agreement,within experimental errors, with those observed in other1,2,4 triazole derivatives (La Keya et al., 2006; Buzykinet al., 2008). The N(1)–N(2) bond length in the triazole ringis shorter{1.418(6) A˚} (Gromova et al., 2002) than the distancecharacteristics of a single N–N bond (1.47 A˚). The N–C andN–N distances in the triazole ring vary from 1.30(6) to1.41(6) A˚. The orientation of thioester group is characterizedby the torsion angle N(1)–C(3)–S(1)–C(16) [22.04(4)].The molecular structure is primarily stabilized by strongintramolecular N2–H3ÆÆÆN3 hydrogen bond [N3–H3 = 0.864(4) A˚, H3ÆÆÆN2= 2.256(4) A˚, N3ÆÆÆN2= 3.018(6) A˚and the angle N3–H3ÆÆÆN2 = 147.63(2)] leading to the forma-tion of a seven-membered hydrogen bonded pattern corre-sponding to graph set S(7) (Bernstein et al., 1995), thuslocking the molecular conformation and eliminating the con-formational ﬂexibility. The crystal structure is further stabi-lized by some interesting features that compriseintermolecular interactions C–HÆÆÆO and C–HÆÆÆN. The C–HÆÆÆOl 6 10436 N. Fathima et al.interaction forms a bifurcated bond from two donors C4 andC24 to the same acceptor O2, linking the molecule in a cohe-sive manner along ‘b’ axis (Fig. 2). On the other hand the C–HÆÆÆN interaction results in one dimensional chain along ‘a’axis (Fig. 3).5. ConclusionThe synthesis of the substituted-1,2,4-triazole is described.Additionally, the X-ray analysis was carried out in order toextrapolate the results observed for structure activity correla-tions. Weak interactions and supramolecular assembly, involv-ing several hydrogen bonding interactions ofdichlorophenylamino and triazolo groups with thioester grouphave been demonstrated. The structure analysis of this com-pound provides an insight into the correlation between themolecular structures and intermolecular interactions in thecompounds for drug development. Hydrogen bonds are themain non-covalent interactions in the structure of 1,2,4 triazolederivative and have great inﬂuence on the crystal packing. Thecompound has been made with the speciﬁc aim of assessing anew donor–acceptor-type of hydrogen-bonded interactions tocontrol the architecture of organic solids for further investiga-tion of supramolecular assembly in solid-state.6. Supplementary dataCrystallographic data for the structure (6) reported in thispaper have been deposited with the Cambridge data centre.The deposition number is CCDC 795601.AcknowledgmentsNSB is thankful to the University Grants Commission, Delhifor the ﬁnancial assistance. NSB also thank the DST, for theCCD facility.ReferencesAgarwal, K., 1991. Ind. J. Pharm. Sci. 53, 192.Andotra, C.S., Langer, T.C., Sharma, S.K., Sarin, A.N., 1986. J.Pharm. Sci. 48, 192–195.Bernstein, J., Davis, R.E., Shimoni, L., Chang, N.L., 1995. Angew.Chem., Int. Ed. Engl. 34, 1555–1573.Bozo, E., Szilagyi, G., Janaky, J., 1989. Arch. Pharm. Weinhei Ger.322, 583–587.Bruker, SAINTPLUS. 1998, Program for data reduction. Bruker Axs.Inc., Madison, Wisconcin, USA.Buzykin, B.I., Mironova, E.V., Nabiullin, V.N., Azancheev, N.M.,Avvakumova, L.V., Rizvanov, I.Kh., Gubaidullin, A.T., Litvinov,I.A., Syakaev, V.V., 2008. R. J. Gen. Chem. 78, 461–479.Eldeen, Z.M., Nadir, M., Aljobory, N.R., Husseen, F., Stohs, S.J.,1991. J. Med. Chem. 26, 23.Emilsson, H., Selander, H., Gaarder, J., 1987. Acta Pharm. Suec. 24,123.Farrugia, L.J., 1997. ORTEP-3 for WINDOWS-A Version ofORTEP-111 with a Graphical User Interface (GUI). J. Appl.Cryst. 30, 565–566.Frank, C.O., Alistair, J.P.B., Neil, A.R.G., 2003. Trends Microb. 11,272–286.Gromova, S.A., Glinskaya, L.A., Barmin, M.I., Melnikov, V.V.,Klevtsova, R.F., Larionov, S.V., 2002. J. Str. Chem. 43, 180–183.Ikizler, A.A., Demirbas, A., Johanson, C.B., Celih, C., Serdar, M.,Yuksek, H., 1998. Acta Pol. Pharm. 55, 117.Kelly, S.L., 1997. J. Biol. Chem. 272, 9986–9988.Khan, R.H., Srivasstava, R.A., Rastogi, R.C., 1987. Synth. Ind. J.Pharm. Sci. 49, 48–51.Khanum, S.A., Shashikanth, S., Sudha, B.S., 2004. Ind. J. Pharm. Sci.66, 293–299.Kuzmierkiwicz, W., Foks, H., Baranowski, M., 1985. Sci. Pham. 53,133.La Keya A., Belcher, Philip J. Squattrito., 2006. J. Chem. Cryst. 36, 3.Mullican, M.D., Wilsion, M.W., Conor, D.T., Kostlan, C.R., Schrier,D.J., Dyer, R.D., 1993. J. Med. 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Synthesis and crystal structure of ethyl 2-​{5-​[2-​(2,​6-​dichlorophenylamino)​benzyl]​-​4-​p-​tolyl-​4H-​1,​2,​4-​triazol-​3-​ylthio}​acetate

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Synthesis and crystal structure of ethyl 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate

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Synthesis and crystal structure of ethyl 2-​{5-​[2-​(2,​6-​dichlorophenylamino)​benzyl]​-​4-​p-​tolyl-​4H-​1,​2,​4-​triazol-​3-​ylthio}​acetate

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Synthesis and crystal structure of ethyl 2-{5-[2-(2,6-dichlorophenylamino)benzyl]-4-p-tolyl-4H-1,2,4-triazol-3-ylthio}acetate