Hamza M Abosadiya Siti Aishah Hasbullah Bohari M Yamin

?

Synthesis, Characterization and X-ray Structure of-(4-bromobutanoyl-?-(2-3-and 4-methylphenyl)thiourea①

Hamza M Abosadiya Siti Aishah Hasbullah②Bohari M Yamin

()

-4-(bromobutanoyl)-?-(-,- and-tolyl)thioureas 3a, 3b and 3crespectively, were synthesized by the reaction of 4-bromobutanoylisothiocyanate with-,- and-toludine. The products were characterized by IR, and NMR spectroscopic techniques. The two carbonoylthiourea isomers-(4-bromobutanoyl)-?-(3-methylphenyl)thiourea (3b) and-(4-bromobutanoyl)--(4-methylphenyl)thiourea (3c) were obtained in crystalline form by recrystallization from DMSO. X-ray crystallographic studies showed that both compounds 3b and 3c crystallizein triclinic system with space group of. The molecules adoptconfiguration with respect to the positions of 4-bromobutanoyl and tolyl groups respectively, against the thiono C=S bond across their C–N bonds. The configuration is attributed by the intrahydrogen bond between the carbonyl oxygen and amide hydrogen atoms. Both crystal structures are stabilized by N–H···S intermolecular hydrogen bonds to form dimers and arranged along theaxis.

4-bromobutyryl chloride, thiourea derivatives, X-ray structural study;

1 INTRODUCTION

The progress on the synthesis of carbonoylthio-urea derivatives has been quite rapid for the last eight years not only because of their relatively easier reaction but also of their potential in biological activities[1-4]. The nucleophilic nature of thiourea moiety together with suitable molecular design could lead to complexation with metals[5, 6]and interactions that can be applied for the development of devices such as sensor or receptor[7,8]. It is well established that ipso-halogenocarbonyl compounds undergo substitution through nitrogen atom of the thiocyanate anion to produce isothio- cyanatocar- bonyl as intermediate, the source for the formation of thiourea moiety. On the other hand, the-chlorocarbonyl will facilitate attack by sulfur atom to produce-thiocynatocarbonyl followed by cyclization when reacting with the amine com-pounds to form thiazole derivatives[9, 10]. In some cases,-isothiocyanatocarbonyl reacting with certain amines could also give an unexpected pro-duct depending on the type of amine compound and solvent used in the reaction. For example,-(2-methylbenzoyl)--(6-methylpyridine-2-yl)thione was obtained from the reaction of-methylbenzo- ylisothiocyanate with 2-amino-6-methylpyridine[11]. On the other hand,-substituted carbonoy-lisothiocyanate always gives thiourea product. It is a fact that at-position the distance of halogen from the carbonyl has less influence on the stability and reaction of the carbonoylisothiocyanate inter-mediate with the amine. This is demonstrated in the present work where 4-bromobutanoyl chloride was reacted with ammonium thiocyanate to form 4-bromobutanoylisothiocyanate followed by-,- and-toludine to form-(4-bromobutanoyl)-N?-(2-methylphenyl)thiourea 3a,-(4-bromobutanoyl)-N?-(3-methyl phenyl)thiourea 3b and-(4-bromobuta-noyl)--(4-methylphenyl)thiourea 3c,respectively (Scheme 1). The synthesis, characterization and X-ray structures of the isomers are presented.

Scheme 1. Reaction scheme for the synthesis of-(4-bromobutanoyl)--(2-, 3- and 4-methyl phenyl)thiourea 3a, 3b and 3c

2 EXPERIMENTAL

2.1 Materials and physical measurements

All the compounds utilized in this work were commercially available from Acros Organics (Geel, Belgium) and Sigma-Aldrich (St Louis, MO, USA) and were used without further purification. All solvents were distilled before use. The microele- mental analysis for CHNS-O was carried out using a Carlo Erba 1108 Elemental Analyzer (Milan, Italy). The infrared spectrum (IR) of the product (KBr pellets) was recorded using a Perkin Elmer Spectrum GX spectrophotometer (Perkin Elmer, Waltham, MA, USA) in the range of 400～4,000 cm?1. Nuclear Magnetic Resonance (1H and13C) experi-ments were performed on a Bruker 600 MHz instrument using DMSO-d6as the solvent. ESI-MS spectra were obtained on a Micro Tof Q (Bruker, AXS Inc., Madison, WI, USA). Single-crystal X-ray experiments were performed on a Bruker D-QUEST diffractometer (Bruker, AXS Inc., Madison, WI, USA) using graphite-monochromated Mo-radia- tion (= 0.71073 ?). Intensity data were measured at room temperature by the-scan. Accurate cell parameters and orientation matrix were determined by the full-matrix least-squares fit of 25 reflections. Intensity data were collected for Lorentz and pola-rization effects. Empirical absorption correction was carried out using multi-scan. The structure was solved by direct methods and least-squares refine-ment of the structure was performed by the SHELXL-2007 program[12]. All the non-hydrogen atoms were refined anisotropically. The hydrogen atoms were placed in the calculated positions except those of the terminal nitrogen atoms of thiourea moieties located from Fourier maps and refined isotropically.

2. 2 Syntheses of-(4-bromobutanoyl)--(2, 3 and 4-methylphenyl)thiourea 3a, 3b and 3c

An acetone solution (30mL) of-,- ortolui-dine (0.01mol, 1.071 gmwas added dropwise into a two-necked round-bottomed flask containing an equimolar amount of 4-bromobutanoyl-isothiocya- nate 1 (0.01mol). The mixture was refluxed for about 4h and filtered into a beaker and left to eva-porate at room temperature. The yellow precipitates formed were washed with cold ethanol and dried under vacuum. Crystals suitable for X-ray study were obtained by recrystallization from DMSO.

2.2.1-(4-bromobutanoyl)--(2-methylphenyl)thiourea, 3a

The title compound was obtained as yellow preci-pitate in 71% yield. IR (KBr pellets)/cm-1: 3169.72 (N-H), 1704.89 (C=O), 1376.28 (C-N), 733.08 (C=S), 521.88 (C-Br).1H NMR (600 MHz; DMSO-d6)H 2.09 (2H, pen, J = 6.6, BrCH2CH2CH2), 2.11 (3H, s, C3), 2.64 (2H, t, J= 6.6, BrCH2CH2CH2), 3.57 (2H, t, J= 6.6, BrCH2), 7.20～7.29 (3H, m, C64), 7.56 (1H, d, J= 7.2, C64), 11.55 (1H, s, NH), 12.08 (1H, s, NH).13C NMR (150 MHz; DMSO) δC18.1 (CH3), 27.7 (CH2), 34.6 (CH2), 34.7 (CH2), 126.6 (CHAr), 126.9 (CHAr), 127.5 (CHAr), 130.9 (CHAr), 133.7 (NHCAr), 137.2 (CAr), 174.7 (C=O), 180.1 (C=S). ESI-MS m/z 316.0323 [MH+]. Anal. (C12H15BrN2OS) (%): C calcd 45.72, found 45.41; H calcd 4.80. found 4.76; N calcd 8.89, found 8.56; S calcd 10.17, found 10.03.

2.2.2-(4-bromobutanoyl)--(3-methylphenyl)thiourea, 3b

The title compound was obtained as colourless crystal in 63% yield after recrystallization. m.p: 381～383 K. IR (KBr pellets)/cm-1: 3186.61 (N-H), 1698.1 (C=O), 1378.92 (C-N), 755.32 (C=S), 505.14 (C-Br). 1H NMR (600 MHz; DMSO-d6)H 2.09 (2H, pen, J = 6.6 BrCH2CH2CH2), 2.62 (2H, t. J= 6.6, BrCH2CH2CH2), 3.55 (2H, t, J = 6.6 and 13.8, BrCHCH2CH2), 3.83 (3H, s, C), 6.97 (1H, m, C64), 7.09 (1H, m, C64), 7.20 (1H, m, C64), 7.38 (1H, m, C64), 11.47 (1H, s, NH), 12.71(1H, s, NH13C NMR (150 MHz; DMSO) δC27.7 (CH3), 27.9 (CH2), 34.6 (CH2), 34.7 (CH2), 111.3 (CHAr), 113.0 (CHAr), 121.1 (CHAr), 123.5 (CHAr), 127.0(NHCAr), 130.3 (CAr), 174.6 (C=O), 178.0 (C=S). Anal. (C12H15BrN2OS) (%): C calcd 45.72, found 45.21; H calcd 4.80. found 4.32; N calcd 8.89, found 8.63; S calcd 10.17, found 9.84.

2.2.3-(4-bromoobutanoyl)--(4-methylphenyl)thiourea, 3c

The title compound was obtained as colorless crystalline in 74% yield after recrystallization. m.p: 384～386 K. IR (KBr pellets)/cm-1: 3189.47 (N-H), 1698.07 (C=O), 1376.05 (C-N), 753.45 (C=S), 507.74 (C-Br).1H NMR (600 MHz; DMSO-d6)H 2.11 (2H, pen, J = 8.4, BrCH2CH2CH2), 2.31 (3H, s, C3), 2.63 (2H, t, 8.4, BrCH2CH2CH2), 3.58 (2H, t, J = 8.4 and 9.6, BrCH2), 7.20 (2H, d, J = 8.4, C64), 7.49 (2H, d, J = 9.6, C64), 11.48 (1H, s, NH), 12.36 (1H, s, NH).13C NMR (150 MHz; DMSO) δC21.1 (CH3), 27.8 (CH2), 34.5 (CH2), 34.8 (CH2),124.5 (CHAr), 129.5 (CHAr), 135.7 (NHCAr), 136.1 (CAr), 174.7 (C=O), 179.1 (C=S). Anal. (C12H15BrN2OS) C, H, N, S: C calcd 45.72, found 45.43; H calcd 4.80. found 4.72; N calcd 8.89, found 8.76; S calcd 10.17, found 10.11.

3 RESULTS AND DISCUSSION

3.1 Spectroscopic data

The infrared spectra of isomeric compounds 3a, 3b and 3cshowed the N?H stretching frequencies at 3169.72, 3186.61 and 3189.47 cm-1, respectively. The characteristic frequencies of(C=O) stretching are at 1704.89, 1698.11 and 1698.07 cm-1. The frequencies of 733.08, 755.32 and 753.45 cm-1in the spectra of the isomers are assigned for(C=S) stretching vibration. The lower stretching vibration of(C=S) in the isomers than the normal value of 1050～1200 cm-1is due to the presence of intramo-lecular hydrogen bond between the hydrogen atom of thioamide group H?N?C=S and the oxygen atom of carbonyl group. The bands observed at 491.04, 505.14 and 507.74 cm-1in the spectra correspondto(C?Br) stretching vibrations for compounds 3a, 3b and 3c. The1H NMR studies show that the chemical shifts of the amide and thiomide protons for the three isomers are quite similar and appear as a singlet at 12.0 and 11.0 ppm, respectively. The aromatic protons for the three compounds 3a, 3b and 3c appeared in the range of 7.20～7.55 ppm. The chemical shifts of the methylene protons (-CH2-) as distinctive multiplet are observedfrom 2.08 to 3.82 ppm. The methyl protons chemical shifts are at 2.20 ppm. In the13C NMR spectra, the carbon chemical shifts of C=O and C=S are found at 174.0 and 179.0 ppm, respectively for the three isomers. The aromatic carbon chemical shifts of the isomers occurred in the range of 124.5～136.0 ppm. The multiplet signals in the range of 21.1～43.8 ppm suggested theattribution of aliphatic carbon chemical shifts.

3.2 X-ray crystallographic studies of the-(4-chlorobutanoyl)-?-(3-methylphenyl) thiourea 3b and-(4-bromobutanoyl)--(4-methylphenyl)thiourea 3c

Both compounds 3b and 3ccrystallized in triclinic system with space group of.The crystallographic data are summarized in Table 1.

Fig. 1 shows the molecular structures with num-bering scheme of compounds 3b and 3c isomers. Unlike 3b, the asymmetric unit of 3c consists of two independent molecules.The molecules maintain theconfiguration with respect to the positions of 4-bromobutanoyl and tolyl groups, respectively, against the thiono C=S bond across their correspon- ding C–N bonds.

3b

3c

Fig.1. ORTEP diagrams of the-(4-chlorobutanoyl)-?-(3-methylphenyl)thiourea 3b and-(4-bromobutanoyl)--(4-methylphenyl)thiourea 3c drawn at 50% probability displacement ellipsoids. The dashed line indicates the intramolecular hydrogen bond

Table 1. Crystal Data and Structure Refinement for Compounds 3b and 3c

The molecules are not planar. In 3b the propionyl-thiourea fragment, S(1)/O(1)/N(1)/N(2)/(C(2)～C(6)),and benzene ring (C(6)～C(11)) are planar with maximum deviation of 0.037(4)? for the C(6) atom from the least-squares plane of the thiourea fragment. The two planes are perpendicular with dihedral angle of 78.8(2)°. There are two indepen-dent mole-cules in the asymmetric unit of compound 3c. The benzene rings (C(6)～C(11)) and (C(18)～C(23)) are understandably planar. Although the propionyl-thiourea, S(1)/O(1)/N(1)/N(2)/(C(2)～C(6)), in the first molecule is planar with maximum deviation of 0.028(4) for the O(1) atom, and the second molecule shows good planarity for ethanoyl-thiourea fragment, S(2)/O(2)/N(3)/N(4)/(C(15)～C(17)), with maxi-mum deviation of 0.044(4) ? for O(2) atom. Both thiourea fragments are also perpen-dicular to the corresponding benzene ring but at smaller angles of 12.5(2)° and 34.9(2)°, respectively. On the other hand, similar dihedral angles in its analogue of-(4-bromobutanoyl)-?-phenyl thiourea (triclinic and two molecules in asymmetric unit) are 72.98(12) and 81.47(14)°, respectively[13]. The conformation about C(1)–C(2) in 3b is gauche although quite close to stagger with torsion angle of C(3)–C(2)–C(1)–H(1B)to be 171°. The conforma-tions about C(1)–C(2) and C(13)–C(14) in 3c are gauche with torsion angles C(3)–C(2)–C(1)–H(1B) and C(15)–C(14)–C(13)–H(13B) of –51 and 51°, respectively.

The bond lengths and bond angles are in normal ranges and comparable to those in-(4-bromobu-tanoyl)-?-phenylthiourea (Table 2).

Table 2. Selected Bond Lengths (?) and Bond Angles (°) for Compounds 3b and 3c

Like in most carbonoylthiourea derivatives, the molecules possess intramolecular hydrogen bond between the carbonyl oxygen and thioamide hy-drogen atoms, N(2)–H(2)···O(1). As a result, a pseudo-six membered ring N(2)···H(2)/O(1)/C(4)/N(1)/C(5)is formed. In addition, there isC(7)–H(7)···S(1) intramolecular hydrogen bond in the first molecule of 3c isomer. Weak C(1)–H(1A)···O(1) and C(23)–H(23)···S(2) intramolecular hydrogen bonds are also observed in 3b and 3c isomers, respectively. In the crystal structure, the molecules are linked by N–H···S (Table 3) intermolecular hydrogen bonds to form dimers along theaxis (Fig.2).

3b ????????????????3c

Fig. 2. Molecular packing of 3b and 3c viewed down theaxis. The dashed lines denote the N–H…S hydrogen bonds

Table 3. Hydrogen Bond Lengths (?) and Bond Angles (°) for Compounds 3b and 3c

(1) Zhang, Y. M.; Wei, T. B.; Gao, L. M. Synthesis and biological activity of-aroyl-?-substituted thiourea derivatives..2001, 31, 3099–3105.

(2) Si-Jia, Y. L. X. Crystal structure and biological activities of-(5-(4-chloro-2-(trifluoromethyl) phenyl) furan-2-carbonyl)-?-(4,6-dimethylpyrimidin-2-yl)thiourea. 2008, 27, 543–546.

(3) Lv, P. C.; Li, H. Q.; Sun, J.; Zhou, Y.; Zhu, H. L. Synthesis and biological evaluation of pyrazole derivatives containing thiourea skeleton as anticancer agents.2010, 18, 4606–4614.

(4) Mahdavi, M.; Shirazi, M. S.; Taherkhani, R.; Saeedi, M.; Alipour, E.; Moghadam, F. H.; Foroumadi, A. Synthesis, biological evaluation and docking study of 3-aroyl-1-(4-sulfamoylphenyl)thiourea derivatives as 15-lipoxygenase inhibitors.2014, 82, 308–313.

(5) Arslan, H.; Külcü, N.; Fl?rke, U. Synthesis and characterization of copper(II), nickel(II) and cobalt(II) complexes with novel thiourea derivatives.2003,28, 816–819.

(6) Yusof, M. S. M.; Yamin, B. M.; Kassim, M. B. Bis(-chlorophenylbenzoyl thiourea-S)diiodomercury(II).2003,60, m98–m99.

(7) Ghanei-Motlagh, M.; Fayazi, M.; Taher, M. A. On the potentiometric response of mercury(II) membrane sensors based on symmetrical thiourea derivatives experimental and theoretical approaches.2014, 199, 133–141.

(8) Kormos, A.; Móczár, I.; Pál, D.; Baranyai, P.; Kupai, J.; Tóth, K.; Huszthy, P. Synthesis and enantiomeric recognition studies of a novel 5,5-dioxophenothiazine-1,9-bis(thiourea) containing glucopyranosyl groups.2013,24, 62–65.

(9) Yamin, B. M.; Kasim, N. A.; Akhiar, E. 5-Acetyl-4-methyl-2-(o-toluidinyl)-1,3-thiazole.2005,61, o1478–o1479.

(10) Jumal, J.; Yamin, B. M. 2-Anilino-4,5-dimethyl-1,3-thiazole.2006,62, o2893–o2894.

(11) Jusoh, R. H.; Khairul, W. M.; Yusof, M. S. M.; Kadir, M. A.; Yamin, B. M. Structural and spectroscopic studies of novel methylbenzoyl thiourea derivatives.2011,15, 170–180.

(12) Sheldrick, G.M.. University of Gottingen: Gottingen, Germany1997.

(13) Yamin, B. M.; Othman, N. E. A.-(4-Bromobutanoyl)-?-phenylthiourea.2011,67, o1629–o1629.

15 September 2014; accepted 6 January 2015

①The authors thank the Ministry of Higher Education of Malaysia and Universiti Kebangsaan Malaysia for the research grant DIP-2014-016 and FRGS/1/2013/ST01/UKM/03/4. One of us HAMZA would like to thank the Ministry of Higher Education of Libya for the scholarship

. E-mail: aishah80@ukm.edu.my

10.14102/j.cnki.0254-5861.2011-0509