eduzhai > Physical Sciences > Materials Sciences >

Synthesis, crystal structure and hydrogen bond mode of rac-n-acetyl-2-thiohydantoin leucine

  • sky
  • (0) Download
  • 20211030
  • Save
https://www.eduzhai.net International Journal of M aterials and Chemistry 2013, 3(1): 1-4 DOI: 10.5923/j.ijmc.20130301.01 Synthesis, Crystal Structure and Hydrogen-bonding Patterns in Rac-N-acetyl-2-thiohydantoin-leucine Gerzon E. Delgado*, María E. Sulbaran, Asiloé J. Mora Laboratorio de Cristalografía, Departamento de Química Facultad de Ciencias, Universidad de Los Andes, M érida 5101, Venezuela Abstract In this work we present the synthesis and X-ray single crystal structural characterizat ion of the heterocyclic compound rac-N-acetyl-2-thiohydantoin-leucine. Th is material crystallize in the triclin ic system with space group P-1 (Nº2), Z=4, with two independent molecu les in the unit asymmet ric. The crystal packing is governed by N--H···O hydrogen bond-type intermo lecular interactions, forming in fin ite one-dimensional chains with graph-set motif C(6). Keywords Thiohydantoin, Crystal Structure, Hydrogen Bonding 1. Introduction Thiohydantoins and hydantoins are five-member heterocyclic system with a very reactive nucleus, which provides four possible points of diversity. Both heterocycles represent significant build ing blocks for co mb inatorial chemistry libraries[1-4]. The biolog ical activit ies of hydantoin and 2-thiohydantoin derivatives has been known for a long time, and are responsible for a wide variety of biological behaviour[5], due principally to its wide range of therapeutic properties. For instance, several applications have been reported for hydantoins: antiarrhythmic and antihypertensive[6-7], antiv iral[8], antineoplastic[9], antitumoral[10] and anticonvulsant agents[11-12]. The best knwon hydantoin, phenytoin, is the most widely used antiepileptic drug[13]. Th iohydantoins are known for their uses as hypolipidemic[14], antimutagenic[15] and anticarcinogenic agents[16]. In addit ion, both heterocyclic compounds are used as herbicides[17] and fungicides agents[18]. Recently, there has been interest in the search of new synthetic routes for the preparation of these type of compounds, via solution or solid state reactions[19-21]. We are interested in N-carbamoyl, hydantoin and thiohydantoin derivatives of α-amino acids[22-28], and report here the structure of the N-acetylthiohydantoin derivative of the α-amino acid L-leucine. 2. Experimental 2.1. Synthesis * Corresponding author: gerzon@ul a.ve (Gerzon E. Delgado) Published online at https://www.eduzhai.net Copyright © 2013 Scientific & Academic Publishing. All Rights Reserved The title co mpound was synthesized fro m L-leucine using a modified methodology previously reported[18-19]. L-leucine (1000 mg , 7.6 mmo l) and NH4SCN (580.3 mg , 7.6 mmo l) was dissolved in a 9 ml acetic anhydride - 1 ml acet ic acid mixture and transferred in a 25 ml round-bottom flask. The mixture was warmed, with agitation, to 363 K over a period of 30 min. The resulting solution was cooled in a ice/water mixture and stored in a freezer overnight. The resulting white solid was filtered o ff and washed with cool water (m.p. 404-405 K). Crystal of (I) suitable for X-ray diffraction analysis were obtained by slow evaporation of a 1:1 ethanol-methanol solution. RMN-1H (400 MHz, DMSO-d6) δ=12.66 (H3, s), 4.71 (H5, d), 2.70 (H7, s), 1.76 (H8, H9, m), 0.85 (H10, H11, d). RMN-13C (100.6 MHz, DMSO-d6) δ=182.5 (C2), 173.5 (C4), 169.7 (C6), 61.3 (C5), 38.1 (C8), 27.3 (C7), 23.7 (C9), 23.1 (C10), 21.9 (C11). S cheme 1. Synthesis of rac-N-acet yl-2-thiohydantoin-leucine 2.2. X-Ray Crystallography Colorless rectangular crystal (0.3, 0.3, 0.1 mm) was used for data collection. Diffraction data were collected at 298(2) K by ω-2θ scan technique on a Siemens P4 four-circle diffractometer[29] equipped with graphite monochromatized CuKα radiation (λ = 1.54178 Å). The data were corrected for Lorentz-polarization and absorption effects[29]. Three standard reflections were monitored every 100 reflections (intensity decay: none). The structure was solved by direct 2 Gerzon E. Delgado et al.: Synthesis, crystal structure and hydrogen-bonding patterns in rac-N-acet y l-2-t hiohy dant oin-leucine methods using the SHELXS97 p rogram[30] and refined by a full-matrix least-squares calculation on F2 using SHELXL97[30]. Table 1. Crystal data, data collection and structure refinement Chemical formula Formula weight Crystal system Space group a(Å) b(Å) c(Å) α (°) β(°) γ (°) V(Å3) Z dx (g cm-3) F(000) µ(mm-1) θ range (°) hkl range Reflect ion s Co llect ed Unique (Rint) With I > 2σ(I) Refinement method Number of parameters R(F2)[I > 2σ(I)] wR(F2)[I > 2σ(I)] Goodness of fit on F2 Max/min ∆ρ (e Å-3) C9H14N2O2S 214.28 Triclinic P-1 7.1855(4) 9.7300(4) 16.442(1) 101.13(1) 94.00(1) 90.49(1) 1125.0(1) 4 1.265 456 0.27 2.8-69.1 -1 ≤ h ≤ 8, -11 ≤ k ≤ 11, -18 ≤ l ≤ 19 4921 3991 (0.088) 3003 Full-matrix least-squares on F2 260 0.0782 0.1998 1.11 0.73/-0.71 Table 2. Select ed geometrical parameters (Å, º) Molecule A S2-C2 O4-C4 O6-C6 N1-C2 N3-C2 N3-C4 S2-C2-N1 S2-C2-N3 O4-C4-N3 O4-C4-C5 C6-N1-C2-S2 C4-N3-C2-S2 1.6340(3) 1.2050(4) 1.2130(4) 1.3860(4) 1.3770(4) 1.3700(4) 131.5(2) 122.8(2) 125.5(3) 128.2(3) 4.10(5) -174.80(2) Molecule B S21-C21 O41-C41 O61-C61 N11-C21 N31-C21 N31-C41 S21-C21-N11 S21-C21-N31 O41-C41-N31 O41-C41-C51 C61-N11-C21-S21 C41-N31-C21-S21 1.6480(3) 1.2070(4) 1.2190(4) 1.3860(4) 1.3650(4) 1.3780(4) 130.8(2) 122.6(2) 125.8(3) 127.9(3) -6.90(5) 176.50(2) Table 3. Hydrogen bonds geometry (Å, ). (D-donor; A-acceptor; H-hydrogen) D--H···A N3-- H3...O6(i) N3-H31...O61(ii) D—H 0.860(i) 0.860(ii) H···A 1.980 1.990 D···A 2.825(3) 2.834(3) D--H···A 166.6 167.7 Symmetry codes: (i) 1+x, y, z, (ii) -1+x, y, z All H ato ms were placed at calculated positions and treated using the riding model, with C-H d istances of 0.97-0.98 A, and N-H d istances of 0.86 A. The Uiso(H) parameters were fixed at 1.2Ueq(C, N) and 1.5Ueq(methyls) Crystallographic data for the structure reported here have been deposited with the Cambridge Crystallographic Data Centre (Deposition No. CCDC-860694). The data can be obtained free of charge v ia http://www.ccdc.cam.ac.uk/perl/ catreq.cgi (or fro m the CCDC, 12 Un ion Road, Camb ridge CB2 1EZ, UK; e-ma il: deposit@ccdc.cam. ac .uk). Molecular diagrams were generated using Diamond[31]. All geo metrical calculat ions were done using the program Platon[32]. Tab le 1 su mmarizes the crystal data, intensity data collection and refinement details for the title co mpound. Selected geometrical parameters are p resented in Table 2. Table 3 shows the hydrogen bonding geometry for the tit le compound. 3. Results and Discussion N-acetyl-thiohydantoin-L-leucine crystallizes with two independent mo lecules in the asymmetric unit, in a centrosymmetric space group, which imp lies that L-leucine suffered an amino acid racemization p roduced by the use of acetic acid in the synthesis[33]. Figure 1 shows the atom labeling and molecu lar conformat ion of the two independent mo lecules of the title co mpound in the asymmetric unit. All bond distances and angles are normal[34] and are in agreement with the average values found in 31 entries with 36 thiohydantoin ring frag ments, searched in the Cam b ridge Structural Database (CSD, version 5.33; Feb, 2012) with N1 and N3 unsubstituted and sp3 hybridization at C5. The thiohydantoin ring, in both molecules, is essentially p lanar with a maximu m deviat ions of 0.034 (3) Å in C4 and −0.037 (3) Å in C4, in mo lecule A and 0.039(3) Å in C41 and -0.038(3) Å in C51, for mo lecule B. The S2-C2-N1 bond angles are greater than S2-C2-N3 angles in both molecules. Th is difference is also observed in the only three 2 N-acetyl thiohydantoin compounds reported in the CSD; KOM GUO[35] with angle values 130.6° and 123.4°, NIFHIT[36] with angles 132.0° and 121.9°, and DIKWAW[28] with angles 132.2°-131.2° and 125.8°-119.0°. The average values for the same angle in the 36 frag ments searched above are 127.7° and 125.2°, respectively. The S2-C2 and S21-C21 distance values, see Table 2, agree with the average value of 1.646 Å found for the 36 frag ments search in the CSD, with min imal and maximu m reported values of 1.519 and 1.696 Å, respectively. The molecular structure and crystal packing of the title compound is stabilized by intermo lecular N3--H3···O4 (x, 1/2 − y, 1/ 2 + z) hydrogen bonds (Table 3), forming infin ite one-dimensional chains that run along[100] direction, which can be described in graph-set notation as C(6)[37] (Figure 2). International Journal of M aterials and Chemistry 2013, 3(1): 1-4 3 Fi gure 1. Asymmetric unit with anisot ropic ellipsoid represent at ions, toget her with atom labeling scheme. The ellipsoids are drawn at 25% probability level, hydrogen atoms are depicted as spheres with arbitrary radii Figure 2. Packing view of 1. Intermolecular hydrogen bonds, N--H···O and O--H···O, are indicated by dashed lines. H atoms not involved in hydrogen bonding have been omitted for clarity 4. Conclusions REFERENCES The thiohydantoin derivative rac-N-acetyl2-thiohydantoin-leucine was synthesized and characterized by NMR spectroscopy. This material crystallize in the [1] A. Boeijen, J.A. Kruijtzer, R.M . Liskamp, “Combinatorial chemistry of hydantoins”, Bioorg. M ed. Chem. Lett. 8, 2375-2380, 1998. triclin ic system with space group P-1 (Nº2), Z=4, with two [2] K.H. Park, J. Ehrler, H. Spoerri, M .J. Kurth, “Preparation of a independent mo lecules in the unit asy mmetric. In the crystal structure, the molecu les are linked by N---H···O hydrogen bonds, forming infinite one-dimensional zig zag chains, 990-member chemical compound library of hydantoin- and isoxazoline-containing heterocycles using multipin technology”, J. Comb. Chem. 3, 171-176, 2001. running along [100] direction, with C(6) graph-set motif. [3] M .J. Lin, C.M . Sun, “M icrowave-assisted traceless synthesis of thiohydantoin”, Tetrahedron Lett. 44, 8739-8742, 2003. ACKNOWLEDGEMENTS This work was supported by CDCHT-ULA (grant C-1616-08-08-A) and FONACIT (grant LA B-97000821). The authors thank H.N. de Armas and N. Blaton, Katholieke Universiteit Leuven, Belgiu m, for data collection. [4] W. Zhang, Y.M . Lu, C.H.T Chen, L. Zeng, D.B. Kassel, “Fluorous mixture synthesis of two libraries with hydantoin-, and benzodiazepinedione-fused heterocyclic scaffolds”, J. Comb. Chem. 8, 687-695, 2006. [5] E. M utschler, H. Derendorf, “Drug Actions, Basic Principles and Therapeutic Aspects”, M edpharm Scientific Publishers, Stuttgart, 1995. [6] J. Knabe, J. Baldauf, A. Ahlhem, “Racemates and 4 Gerzon E. Delgado et al.: Synthesis, crystal structure and hydrogen-bonding patterns in rac-N-acet y l-2-t hiohy dant oin-leucine enantiomers of basic substituted 5-phenylhydantoins. [21] S. Reyes, K. Burgess, “On formation of thiohydantoins from Syntheses and antiarrhythmic activity“. Pharmazie, 52, amino acids under acylation conditions”. J. Org. Chem. 71, 912-919, 1997. 2507-2509, 2006. [7] T. Dylag, M .Zygmunt, D. M aciag, J. Handzlik, M . Bednarski, [22] G.E. Delgado, A.J. M ora, J. Uzcátegui, A. Bahsas, A. Briceño, B. Filipek, K. Kiec-Kononowicz, “Synthesis and evaluation “(S)-5-benzylimidazolidine-2,4-dione monohydrate”, Acta of in vivo activity of diphenylhydantoin basic derivatives”. Cryst. C63, 448-450, 2007. Eur. J. M ed. Chem. 39, 1013-1027, 2004. [23] G.E. Delgado, L.E Seijas, A.J. M ora, T. Gonzalez, A. Briceño, [8] N. Opacic, M . Barbarić, B. Zorc, M . Cetina, A. Nagl, D. “Synthesis, crystal structure and hydrogen-bonding patterns Frkovic, M . Kralj, K. Pavelic, J. Balzarini, G. Andrei, R. in (RS)-1-carbamoyl pyrrolidine-2-carboxylic acid”. J. Chem. Snoeck, E. De Clercq, S. Raić-M alić, M . M intas, “The novel Cryst. 42, 388-393, 2012. L- and D-Amino acid derivatives of hydroxyurea and hydantoins: Synthesis, X-ray crystal structure study, and cytostatic and antiviral activity evaluations,” J. M ed. Chem. 48, 475-482, 2005. [24] G.E. Delgado, L.E Seijas, A.J. M ora, “Synthesis and crystal structure determination of hydanotin-L-proline”. J. Chem. Cryst. 2012. DOI 10.1007/s10870-012-0344-3. [9] E. Lattmann, W.O. Ayuko, D. Kinchinaton, C.A. Langley, H. Singh, L. Karimi, M .J. Tisdale, “Synthesis and evaluation of 5-ary lat ed 2(5H)-furanones and 2-ary lat ed pyridazin-3(2H)-ones as anti-cancer agents”, J. Phar. Pharmacol. 55, 1259-1265, 2003. [10] C. Carmi, A. Cavazzoni, V. Zuliani, A. Lodola, F. Bordi, P.V. Plazzi, R.R. Alfieri, P.G. Petronini, M . Mor, “5-Benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity”, Bioorg. M ed. Chem. Lett. 16, 4021-4025, 2006. [11] G. Singh, P.H. Driever, J.W. Sander, L. Sander, “Cancer risk in people with epilepsy: The role of antiepileptic drugs”, Brain 128, 7-17, 2005. [12] A.M . Kaindl, S. Asimiadou, D. M anthey, H.V.D. Hagen, V.D. Turski, C. Ikonomidou, “Antiepileptic drugs and the developing brain”, Cell. M ol. Life Sci. 63, 399-413, 2006. [13] H.H. M errit, T.J. Putnam, “A new series of anticonvulsant drugs tested by experiments on animals”, Arch. Neurol. Psychiatry 39, 1003-1015, 1938. [14] J.E. Tompkins, “5,5-diaryl-2-thiohydantoins and 5,5-diaryl N3-substituted 2-thiohydantoins as potential hypolipidemic agents”, J. M ed. Chem., 29, 855-859, 1986. [15] A. Takahashi, H. M atsuoka, K. Yamada, Y. Uda, “Characterization of antimutagenic mechanism of 3-ally l-5-subst it ut ed 2-t hiohy dant oins against 2-amino-3-methylimidazo[4,5-f]quinoline”, Food and Chem. Toxicology, 43, 521-528, 2005. [16] S. Al-M adi, A.M . Al-Obaid, H. El-Subbagh, “The in vitro antitumor assay of 5-(Z)-arylidene-4-imidazolidinones in screens of AIDS-related leukemia and lymphomas”, AntiCancer Drugs, 12, 835-839, 2001. [17] M . Shiozaki, “Syntheses of hydantocidin and C-2-thioxohydantocidin”, Carbohydr. Res. 337, 2077-2088, 2002. [18] J. M arton, J. Enisz, S. Hosztafi, T. Timar, “Preparation and fungicidal activity of 5-substituted hydantoins and their 2-thio analogs,” J. Agric. Food. Chem. 41, 148-152, 1993. [19] J. Vázquez, M . Royo, F. Albericio, “Re-evaluation of a solid-phase hydantoin synthesis”. Lett. Org. Chem. 1, 224-226, 2004. [20] Z.D. Wang, S.O. Sheikh, Y.L. Zhang, “A simple synthesis of 2-thiohydantoins”, M olecules, 11, 739-750, 2006. [25] L.E. Seijas, G. E. Delgado, A.J. M ora, A. Bahsas, J. Uzcátegui, “Síntesis y caracterización de los derivados N-carbamoilo e hidantoina de L-prolina”, Av. Quím. 1, 3-7, 2006. [26] L.E. Seijas, G. E. Delgado, A.J. M ora, A. Bahsas, A. Briceño, “(2S)-1-carbamoylpyrrolidine-2-carboxylic acid”, Acta Cryst. C63, o303-o305, 2007. [27] L.E. Seijas, A.J. M ora, G.E. Delgado, M . Brunelli, A.N. Fitch, “Study of the conversion of N-carbamoyl-L-proline to hydantoin-L-proline using powder synchrotron X-ray diffraction”, Powder Diffr. 25, 342-348, 2010. [28] M .E. Sulbaran, G.E. Delgado, A.J. M ora, A. Bahsas, H. Novoa de Armas, N. Blaton. “Hydrogen-bonding patterns in rac-1-acetyl-5-methyl-2-thioxoimidazolidine-4-one”. Acta Cryst. C63, o543-o545, 2007. [29] X-ray Single Crystal Analysis System (XSCANS), Version 2.2; Siemens Analytical X-ray Instruments Inc.: M adison, WI, USA, 1996. [30] G.M . Sheldrick, “A short history of SHELX”, Acta Cryst. A64, 112-122, 2008. [31] G. Bergerhoff, M . Berndt, K. Brandenburg, “Evaluation of Crystallographic Data with the Program DIAM OND”, J. Res. Natl. Inst. Stand. Technol. 101, 221-225, 1996. [32] A.L. Spek, “Single-crystal structure validation with the program Platon”, J. Appl. Cryst. 36, 7-13, 2003. [33] R. Yoshioka, “Racemization, optical resolution and crystallization-induced asymmetric transformation of amino acids and pharmaceutical intermediates”. Top. Curr. Chem. 269, 83-132, 2007. [34] F.H. Allen, “The cambridge structral database: a quarter of a million crystal structures and rising”, Acta Cryst. B58, 380-388, 2002. [35] M .F. M ackay, B.M. Duggan, R.L. Laslett, J.F.K. Wilshire, “Structure of a substituted 2-thiohydantoin,”. Acta Cryst. C48, 334-336, 1992. [36] J.S. Casas, A. Castañeiras, D. Couce, N. Playá, J. Sordo, J.M. Varela, “1-acetyl-2-thiohydantoin,”. Acta Cryst. C54, 427-428, 1998. [37] M .C. Etter, “Encoding and decoding hydrogen-bond patterns of organic-compounds” Acc. Chem. Res. 23, 120-126, 1990.

... pages left unread,continue reading

Document pages: 4 pages

Please select stars to rate!

         

0 comments Sign in to leave a comment.

    Data loading, please wait...
×