Synthesis, characterization, crystal structure and antioxidant activity of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea European Journal of Chemistry 15 (4) (2024) 320-324 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2024 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.15.4.320-324.2607 European Journal of Chemistry View Journal Online View Article Online Synthesis, characterization, crystal structure and antioxidant activity of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea Hamza Milad Ahmed Abosadiya Department of Chemistry, Faculty of Sciences, Bani Waleed University, Bani Waleed, PO Box 5338, Tripoli, Libya * Corresponding author at: Department of Chemistry, Faculty of Sciences, Bani Waleed University, Bani Waleed, PO Box 5338, Tripoli, Libya. e-mail: hamzamilad@bwu.edu.ly (H.M.A. Abosadiya). 10.5155/eurjchem.15.4.320-324.2607 Received: 16 October 2024 Received in revised form: 28 October 2024 Accepted: 8 November 2024 Published online: 31 December 2024 Printed: 31 December 2024 In the present work, a new carbonoyl thiourea derivative, N-(3-chloropropionyl)-N'-(4- methoxyphenyl)thiourea, was synthesized by the reaction of 3-chloropropionyl isothiocyanate with 4-methoxyaniline in acetone solution. The newly synthesized compound was characterized by FT-IR, 1H NMR, and 13C NMR spectroscopic techniques. X- ray crystallographic studies indicate that the compound crystallized in the triclinic crystal system with space group P-1 and unit cell dimension are a = 10.2262(6) Å, b = 11.5007(7) Å, c = 12.6116(8) Å, α = 72.253(2)°, β = 66.348(2)°, γ = 88.099(2)°, Z = 4 and V = 1287.22 (14) Å3. Strong intramolecular O-H···N hydrogen bonds are present that form a six-member pseudo-ring S(6). In the crystal structure, the molecules are linked by N-H···O, N-H···S, and C-H···O intermolecular hydrogen bonding interactions formed infinite one-dimensional chains with an R22(8) and R22(12) rings motif of molecules. The antioxidant test using the DPPH method showed that the compound exhibits a good antioxidant activity of about 80%. Synthesis DPPH method Hydrogen bond Thiourea derivative Antioxidant activity Single-crystal structure Cite this: Eur. J. Chem. 2024, 15(4), 320-324 Journal website: www.eurjchem.com 1. Introduction Thiourea and its derivatives are an important class of organosulfuric compounds with the general formula (R1R2N)(R3R4N)C=S having N- and S-donor atoms. A great deal of research has been done on the synthesis and design of new carbonoylthiourea derivatives due to their applications in numerous fields such as organic synthesis and pharmaceutical industries, as well as coordination chemistry [1-13]. N,N- Diethyl, di-n-propyl-, di-n-butyl- and diphenyl-N′-(4-chloro benzoyl)thiourea and their Pt(II) complexes have been synthesized and structurally characterized and these complexes were also evaluated for both their in- vitro antibacterial and antifungal activity [14], and the results have been reported, explained, and compared with fluconazole and ampicillin, used as reference drugs. Over the past three decades, many derivatives of thiourea derivatives containing benzoyl groups have been reported [15-17], comparable to some structures which have been reported for halogeno- carbonyl thiourea derivatives [18,19]. The presence of C- halogen bonds in the structure of halogeno-carbonoylthiourea derivatives is a useful starting material for the synthesis of other derivatives such as 2-(4-fluoroanilino)-4,5-dimethyl-1,3- thiazole and 2-anilino-4,5-dimethyl-1,3-thiazole, in the synthesis process of thiourea derivatives from 3-chloro-2- butanone, 1,3-thiazole was instead obtained [20,21]. As part of our ongoing study of thiourea derivatives, N-(3-chloro propionyl)-N'-(4-methoxyphenyl)thiourea has been synthe- sized and fully characterized by FT-IR, 1H NMR, 13C NMR spectroscopic techniques, and X-ray crystallographic studies. The antioxidant activity was also investigated using the DPPH method. 2. Experimental 2.1. Instrumentation The microelemental analysis for CHNS-O was performed using a Carlo Erba 1108 elemental analyzer (Milan, Italy). The infrared spectrum (IR) of the product (KBr pellets) was recorded using a Perkin Elmer GX spectrophotometer (Perkin Elmer, Waltham, MA, USA) in the range 400-4000 cm−1 with resolution 4 cm-1. Electronic UV/vis spectra were recorded using the 1800-PC Shimadzu spectrophotometer in the range of 200-800 nm with the highest resolution. The experiments of multinuclear (1H and 13C) NMR were performed on a Bruker 600 MHz instrument in deuterated DMSO solvent. The X-ray single crystal diffraction measurement was performed on a Bruker D-QUEST diffractometer at 296(2) K. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.15.4.320-324.2607 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.15.4.320-324.2607 mailto:hamzamilad@bwu.edu.ly http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.15.4.320-324.2607&domain=pdf&date_stamp=2024-12-31 Hamza Milad Ahmed Abosadiya / European Journal of Chemistry 15 (4) (2024) 320-324 321 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.320-324.2607 O Cl N C S H2N O N H S N H O O Cl Scheme 1. Synthesis of the title compound, N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea. The intensity data were collected using graphite monochromated with λ = 0.71073 Å. The structure was solved by direction method and refined by full matrix least-squares against F2 for all data using SHELXTL-97 program. The carbon and hydrogen atoms were positioned geometrically (C-H = 0.93-0.97 Å) and constrained to ride on their parent atoms with Uiso(H) = 1.2Ueq(C). The hydrogen atoms on the nitrogen were located in the difference Fourier map and refined freely using SHELXL [22] instruction ′DFIX 0.87 0.01. 2.2. Synthesis of N-(3-chloropropionyl)-N'-(4-methoxy phenyl)thiourea The chemical materials and solvents used in this project were available from Sigma-Aldrich and used without further purification. An acetone solution (40 mL) of p-anisidine (0.01 mol, 1.23 g) was added dropwise into a two-necked round- bottomed flask containing an equimolar amount of 3- chloropropionyl-isothiocyanate (0.01 mol, 1.49 g) which produced by the reaction of 3-chloropropionyl chloride with ammonium thiocyanate. The mixture was refluxed for approximately 3 h and filtered into a beaker and left to evaporate at room temperature. The filtrate gave a precipitate after 7 days of evaporation. The yield is 85% and the melting point of the crystal obtained by recrystallization from ethanol is 448.3-449.1 K. N-(3-Chloropropionyl)-N'-(4-methoxyphenyl)thiourea: Color: Colorless. Yield: 85%. M.p.: 175.15-175.95 °C. FT-IR (KBr, ν, cm-1): 3215 (N-H), 3150 (C-Haromatic), 2980 (C-Haliphatic), 1698 (C=O), 1348 (C-N), 828 (C=S), 657 (C-Cl). 1H NMR (600 MHz, DMSO-d6, δ, ppm): 3.86 (t, 2H, J = 6.0 Hz, ClCH2CH2), 3.77 (s, 3H, OCH3), 3.00 (t, 2H, J = 6.6 and 6.0 Hz, ClCH2CH2), 7.49 (d, 2H, J = 5.4 Hz, Ar-H), 6.95 (d, 2H, J = 4.8 Hz, Ar-H), 11.56 (s, 1H, NH), 12.22 (s, 1H, NH). 13C NMR (150 MHz, DMSO-d6, δ, ppm): 39.2 (CH2), 40.4 (CH2), 55.8 (OCH3), 114.3 (Ar-C),126.4 (Ar-C), 131.0 (Ar-C-NH), 158.0 (Ar-C-OCH3), 173.0 (C=O), 179.0 (C=S). Anal. calcd. for C11H13ClN2O2S: C, 48.44; H, 4.80; N, 10.27; S, 11.75 %. Found: C, 48.30; H, 4.11; N, 10.09; S, 11.34%. 2.3. Antioxidant activity studies The sample solution of N-(3-chloropropionyl)-N'-(4- methoxyphenyl)thiourea was prepared in dimethyl sulfoxide solvent (C = 15 mg/5 mL). The free radical stock solution of diphenylpicrylhydrazyl (DPPH, 97% purity) was also prepared daily at a concentration of 0.4 g in 1000 mL in methanol solvent and protected from light (ADPPH = 1.012). 1 mL DPPH solution was mixed with 100 μL from the stock solution of the new synthesized carbonoylthiourea compound. The mixture was shaken well and kept in the dark at room temperature for 2 hours. The absorbance of the mixture was recorded at 517 nm using a spectrophotometer (ASample = 0.191) [23,24]. The percentage reduction of the DPPH was calculated using Equation 1: DPPH Scavenging activity (%) = [(ADPPH – ASample)/(ADPPH)] ×100 (1) where ADPPH is the absorbance of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ASample is the absorbance of the mixture (DPPH and the synthesized compound). 3. Results and discussion 3.1. Synthesis The synthesis of halogenoalkoyl thiourea derivatives including functional groups of alkyl halides (C-X, where X = Cl, Br, and I) is quite important and interesting for the preparation of a variety of derivatives by catalyzed substitution and elimination reactions [25,26]. Therefore, the solution mixture of 3-chloropropionyl-isothiocyanate with 4-methoxyaniline in acetone gave a homogeneous colorless solution after refluxing for about three hours (Scheme 1). The microelemental analysis data of the precipitate are in agreement with the expected formula of N-(3-chloro propionyl)-N'-(4-methoxyphenyl)thiourea. The infrared spectrum of the compound showed the stretching frequencies of C-H (sp2 and sp3) stretching of the aromatic ring and alkyl chain at approximately 3150 and 2980 cm-1, respectively. The N-H stretching bond of the compound appeared at 3215 cm-1, this hydrogen atom of the thioamide group H-N-C=S displays an intramolecular hydrogen bond with the oxygen atom of the carbonyl group, leading to a decrease in the stretching value than that in the normal secondary amines and amides absorption (3300-3500 cm-1). The characteristic frequency of ν(C=O) stretching appeared at 1698 cm-1, this vibrational frequency is in agreement with other thiourea derivatives [1,2]. The stretching vibration at 828 cm-1 for the compound is assigned to the C=S functional group. The vibration mode observed at 657 cm-1 in the spectrum corresponding to ν(C-Cl) stretching vibration. 1H NMR spectrum shows the chemical shifts of the methylene protons (-CH2-) as a distinctive multiplet in the range of δ 3.00-3.86 ppm, these protons are more deshielded than those in alkyl-thiourea derivatives due to the electron withdrawing effect of chlorine atom [1]. The aromatic protons appeared in the normal range of δ 6.95-7.49 ppm. The chemical shifts of the amide and thiomide protons of compound are quite similar to the other thiourea derivatives [1,15,27] and appeared as a singlet at δ 12.22 and 11.56 ppm, respectively. The downfield of amide protons is mainly due to the formation of intramolecular hydrogen bonding between the amino proton N-H and the oxygen atom of the carbonyl group, as well as to the anisotropic effect. In the 13C NMR spectrum, the chemical shift of the methoxy group is found at δ 55.8 ppm, whereas the carbon chemical shifts of the methylene groups -CH2- appear at lower chemical shifts at δ 39.2 and 40.4 ppm. Similarly, the carbon chemical shifts of C=O and C=S are found at δ 173.0 and 179.0 ppm, respectively, for the compound. The aromatic carbon chemical shifts appeared in the range of δ 114.3-158.0 ppm. 3.2. X-ray structure of N-(3-chloropropionyl)- N'-(4- methoxyphenyl)thiourea The synthesized compound N-(3-chloropropionyl)-N'-(4- methoxyphenyl)thiourea has been obtained in the crystalline form by recrystallization from an ethanol solvent. X-ray single crystal investigation showed that the compound crystallized in a triclinic system with space group P-1. The crystallographic data are summarized in Table 1. 322 Hamza Milad Ahmed Abosadiya / European Journal of Chemistry 15 (4) (2024) 320-324 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.320-324.2607 Table 1. Crystal data and structure refinement of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea. Crystal parameters Data/values Empirical formula C11H13ClN2O2S Formula weight (g/mol) 272.74 Temperature (K) 296(2) Crystal system triclinic Space group P-1 a, (Å) 10.2262(6) b, (Å) 11.5007(7) c, (Å) 12.6116(8) α (°) 72.253(2) β (°) 66.348(2) γ (°) 88.099(2) Volume (Å3) 1287.22(14) Z 4 ρcalc (g/cm3) 1.407 μ (mm-1) 0.450 F(000) 568.0 Crystal size (mm3) 0.5 × 0.32 × 0.3 Radiation MoKα (λ = 0.71073) 2Θ range for data collection (°) 6.04 to 56.8 Index ranges -13 ≤ h ≤ 13, -15 ≤ k ≤ 15, -16 ≤ l ≤ 16 Reflections collected 33072 Independent reflections 6434 [Rint = 0.0360, Rsigma = 0.0275] Data/restraints/parameters 6434/4/325 Goodness-of-fit on F2 1.069 Final R indexes [I≥2σ (I)] R1 = 0.0572, wR2 = 0.1281 Final R indexes [all data] R1 = 0.0837, wR2 = 0.1508 Largest diff. peak/hole (e.Å-3) 0.46/-0.37 CCDC deposition number 2388367 Table 2. Selected bond lengths of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea. Atom Atom Length (Å) Atom Atom Length (Å) C1 Cl1 1.771(3) C12 Cl2 1.769(3) C2 C3 1.511(3) C13 C14 1.507(3) C3 N1 1.374(3) C14 N3 1.365(3) C3 O1 1.209(3) C14 O3 1.221(3) C4 N1 1.388(3) C15 N3 1.389(3) C4 N2 1.324(3) C15 N4 1.321(3) C4 S1 1.669(3) C15 S2 1.671(2) C5 N2 1.431(3) C16 N4 1.431(3) C8 O2 1.368(4) C19 O4 1.363(3) C11 O2 1.381(6) C22 O4 1.421(4) Figure 1. The molecular structure of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea with 50% probability displacement ellipsoids. The dashed line indicates an intramolecular hydrogen bond. The ORTEP diagram of the compound is shown in Figure 1 with the numbering scheme and the asymmetric unit contains two crystallographically independent molecules with different conformations. Both molecules maintain the trans-cis configuration with respect to the positions of the 3-chloro- propionyl and 4-methoxyphenyl groups, respectively, against the thiono C=S bond across their C-N bonds. The structure molecules are analogous to the previously reported N-(3-chloropropionyl)-N'-phenylthiourea [28] except that they have a methoxy group at position 4 of the phenyl ring. The carbonoyl thiourea fragments (S1/N1/N2/O1/C3/C4/C5 (A) and S2/N3/N4/O3/C13/C14/C15 (B)) and benzene rings (C5-C10 and C16-C21) in both molecules are planar with a maximum deviation of 0.057(2) Å for atom N3. In each independent molecule, the benzene rings are vertical to the thiourea fragments A and B with dihedral angles of 67.61(13) and 77.65(12)°, respectively, for the first and second molecules. A small reduction compared to the analog, N-(3-chloro- propanoyl)-N′-phenylthiourea of 82.62(10)° [28]. Bond lengths and angles (Tables 2 and 3) are in normal ranges and comparable to those found in 1-(4-bromophenyl)-3-(3- chloropropanoyl)thiourea [18]. Hamza Milad Ahmed Abosadiya / European Journal of Chemistry 15 (4) (2024) 320-324 323 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.320-324.2607 Table 3. Selected bond angles of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea. Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) C2 C1 Cl1 110.29(18) O3 C14 C13 121.6(2) C1 C2 C3 111.0(2) O3 C14 N3 122.8(2) N1 C3 C2 114.4(2) N3 C15 S2 118.78(17) O1 C3 C2 121.9(2) N4 C15 N3 116.7(2) O1 C3 N1 123.7(2) N4 C15 S2 124.56(17) N1 C4 S1 118.62(18) C17 C16 N4 120.0(2) N2 C4 N1 116.4(2) C21 C16 C17 120.3(2) N2 C4 S1 124.91(19) C21 C16 N4 119.5(2) C5 C10 C9 120.3(3) C14 N3 C15 127.5(2) N3 C14 C13 115.5(2) C19 O4 C22 118.2(3) Table 4. Geometric parameters of hydrogen bonds of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea. D-H···A D-H (Å) H···A (Å) D···A (Å) ∠ D-H···A (°) N2―H2···O1 0.87(3) 1.94(2) 2.655(3) 138(3) N4―H4···O3 0.87(3) 1.93(3) 2.627(3) 136(3) N1―H1···S2 i 0.87(2) 2.58(2) 3.439(2) 170(2) N2―H2···O3 ii 0.87(3) 2.37(3) 3.048(3) 134(2) N3―H3···S1 iii 0.87(2) 2.55(2) 3.424(2) 177(3) N4―H4···O1 iv 0.87(3) 2.42(3) 3.132(3) 139(3) C18―H18···O3 v 0.93 2.56 3.316(4) 138 Symmetry codes: i 1+x, 1+y, z; ii x, 1+y, z; iii -1+x, -1+y, z; iv x, -1+y, z; v 1-x, -y, -z. Figure 2. Molecular packing of N-(3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea, viewed down the b axis. The dashed lines denote N-H···O, N-H···S, and C- H···O hydrogen bonds. There are intramolecular hydrogen bonds between the carbonyl oxygen atom and thioamide hydrogen, N2-H2···O1 and N4-H4···O3 in both molecules (Table 4) forming pseudo- six-membered rings. In the crystal packing, the molecules are linked by N-H···O, N-H···S, and C-H···O hydrogen bonds to form infinite one-dimensional chains along the b axis and the crystal structures showing R22(8) and R22(12) rings motifs. 3.3. Antioxidant evaluation The DPPH scavenging activity of the synthesized carbonoylthiourea compound was 81.12%, which indicates good antioxidant properties compared to the scavenging activity of the 1,3-diphenyl-2-thiourea compound of approxi- mately 60% at the higher concentration of Cm = 0.80 mM [24]. The antioxidant properties are due to the acceptance of an electron or the donation of a hydrogen atom from the thioamide H-N-C=S or amide groups to the free radical diphenylpicryl- hydrazyl (DPPH) to form non-radical DPPH-H, and the color of the reaction mixture changes from purple to yellow when the DPPH radical is scavenged. 4. Conclusions The new halogenocarbonyl thiourea compound, namely, N- (3-chloropropionyl)-N'-(4-methoxyphenyl)thiourea was suc- cessfully prepared by the reaction of an equimolar amount of 3- chloropropionylisothiocyanate with 4-methoxyaniline in an acetone solution. Its structure was confirmed by FT-IR, 1H, and 13C NMR spectroscopies. The molecular structure of the compound was also determined by using an X-ray crystallography technique. The antioxidant ability of the new synthesized compound was characterized based on the measurement of the color change of 2,2-diphenyl-1- picrylhydrazyl (DPPH·) from a purple to yellow color solution when it reacts with the synthesized thiourea compound and the compound showed a good antioxidant activity of about 80%. Acknowledgements The authors would like to thank the Ministry of Higher Education of Malaysia and Universiti Kebangsaan Malaysia for the facilities and financial support. I would also like to thank the Ministry of Education of Libya and Bani Waleed University for their support to carry out this work. Supporting information CCDC-2388367 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: A sample of the compound is available from the author. http://www.ccdc.cam.ac.uk/%20data_request/cif http://www.ccdc.cam.ac.uk/%20data_request/cif mailto:data_request@ccdc.cam.ac.uk 324 Hamza Milad Ahmed Abosadiya / European Journal of Chemistry 15 (4) (2024) 320-324 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.320-324.2607 ORCID and Email Hamza Milad Ahmed Abosadiya hamza_inorg@yahoo.com hamzamilad@bwu.edu.ly https://orcid.org/0000-0003-3847-0457 References [1]. Abosadiya, H. M.; Anouar, E. H.; Hasbullah, S. A.; Yamin, B. M. Synthesis, X-ray, NMR, FT-IR, UV/vis, DFT and TD-DFT studies of N-(4- chlorobutanoyl)-N′-(2-, 3- and 4-methylphenyl)thiourea derivatives. Spectrochim. Acta. A 2015, 144, 115–124. [2]. Abosadiya, H. M.; Anouar, E. H.; Abusaadiya, S. M.; Hasbullah, S. A.; Yamin, B. M. Synthesis, characterization, crystal structures and DFT studies of some new 1,2,4-triazole and triazolidin derivatives. J. Mol. 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The full terms of this license are available at https://www.eurjchem.com/index.php/eurjchem/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (https://www.eurjchem.com/index.php/eurjchem/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). mailto:hamza_inorg@yahoo.com mailto:hamzamilad@bwu.edu.ly https://orcid.org/0000-0003-3847-0457 https://doi.org/10.1002/aoc.7107 https://doi.org/10.33640/2405-609X.3304 https://www.eurjchem.com/index.php/eurjchem/terms http://creativecommons.org/licenses/by-nc/4.0 https://www.eurjchem.com/index.php/eurjchem/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Synthesis of N-(3-chloropropionyl)-N'-(4-methoxy phenyl)thiourea 2.3. Antioxidant activity studies 3. Results and discussion 3.1. Synthesis 3.2. X-ray structure of N-(3-chloropropionyl)- N'-(4-methoxyphenyl)thiourea 3.3. Antioxidant evaluation 4. Conclusions Acknowledgements Supporting information Disclosure statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: