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DOI:10.29013/AJT-24-3.4-12-16
REACTIONS OF N-CHLORACETYLATION OF TOLUIDINE ISOMERS
Bobonazarova Sarvinoz Habibullaevna 1, Abdushukurov Anvar Kabirovich 1, Yusufov Mukhriddin Saidovich 1, Islamova Yulduz Oralovna 1, Azimova Gulmira Zainuddinovna 1, Abdujabborova Obida Orifovna 1
1 National University of Uzbekistan, Tashkent
Cite: Bobonazarova S. H, Abdushukurov A. K, Yusufov M. S, Islamova Y. O., Azimova G. Z., Abdujabborova O. O. (2024). Reactions of N-Chloracetylation of Toluidine Isomers. Austrian Journal of Technical and Natural Sciences 2024, No 3 -4. https://doi.org/10.29013/AJT-24-3.4-12-16
Abstract
The results of the study of reactions of N-chloroacetylation of toluidine isomers are presented in the article. Methods for purification of reaction products have been developed. Structure of the obtained compounds has been confirmed by means of 1H and 13C NMR spectroscopy. Keyword: N-chloroacetylation, chloroacetyl chloride, o-, m-, p-toluidine, 2-chloro-N-tolyl acetamide, acetonitrile, acetone, ethylacetates
Introduction
Many biologically active substances have been synthesized on the basis of chloracetyl-ation reactions of amino compounds and are widely used in medicine today. Currently, the study of the structure of amide bonds between amino acids reveals new methods for the synthesis of new peptides and proteins, which are an integral part of biology and medicine. It is known that more than 50% of all medicinal substances contain amide bonds. Amide bonds are formed by N-acylation reactions. Acid chloride anhydrides are one of the most widely used N-acylating agents for the formation of amide bonds and are used industrially throughout the world. When chloroacetyl chloride is used as an acylating agent, the reactions proceed under mild conditions and allow obtaining chloroacetyl products in high yields. Because, on the one hand, most of the com-
pounds containing chloroacetyl group have high biological activity, on the other hand, chloroacetyl chloride is a strong acylating agent. The reason is that due to the negative inductive effect of the chlorine atom in chlo-roacetyl chloride, the carbon atom in the car-bonyl group has an additional positive charge and facilitates the progress of the nucleophilic substitution reaction. N-aryl 2-chloroacet-amides are used as herbicides, antimicrobials, antifungals, disinfectants (Manuri Brah-mayyaa, Shing-Yi Suena, Shenghong A. Dai, 2017. P. 1-2). In addition, carbonic acid amides and their derivatives are used in medicine as antidepressants. Currently, paracetamol, phenacetin and filament are widely used in modern medicine. The main active fragment of these drugs is acrylamides of aromatic car-boxylic acids. Expanding research work, new amides, including p-toluidine glycolate and
2-hydroxy-N-(4-methyl) phenylacetamide, are synthesized based on N-hydroxyacetyla-tion of p-toluidine (Joris Hulsbosch, Laurens Claes, Dirk E. D eVos. 2018. P. 1646-1650; Koula, D.O.U.K.A.N.I., Nacera, G.A.C.E. M. and Hayat, B.E.N.L.A.R.B.I.. 2014. P. 1-16). It is known from the literature that acylation reactions of aromatic amines with halogen anhydrides are carried out at low temperatures, otherwise, due to the release of a large amount of heat in the reaction mixture, the mixture of oxidation and polymerization products sinks to the bottom of the vessel in the form of resin, the reason for which is explained by the easy access of the amino group to acylation reactions. Therefore, reagents for N-chloroace-tylation reactions of aniline were obtained in the same molar ratio and carried out at a temperature below -20 C (Yusufov M. S., Abdu-shukurov A. K., 2020. P. 74-75; Yusufov M. S., Abdushukurov A. K., Akhmedova N. B., Yazi-lova G. M., 2018. P. 159-161). Currently, ben-zimidazole and benzoxazole derivatives are of great interest to pharmaceutical experts, since they are inhibitors of fructose-1,6-bisphos-phatases in the condensation reactions of ben-zoxazoles with benzenesulfonamide, in which they have good pharmacokinetic activity (Lai C., Rebecca J., Daly M., Fry E., Hutchins C.,
CH3
O,
cOC-
CH2
-Cl
Abad-Zapatero C., P. 1807-1810), and they are also inhibitors of amyloxygenases is considered (Neochoritis C., Zarganes-Tzitzikas T., Tsoleridis C., Stephanidou-Stephanatou J., Kontogiorgis C., Hadjipavlou-Litina D., Cho-li-Papadopoulou T., P. 297-306). In addition, many member derivatives of benzimidazole exhibit antibacterial and antimicrobial activity. Their use as a substrate of diazonium salts, a derivative of aminophenylbenzoxazole, increases the anti-inflammatory properties of the drugs (Carella A., Centore R., Sirigu A., Tuzi A., Quatela A., Schutzmann S., Casalboni M. 2004. P. 1948-1954). Experiments carried out in this field in our country and abroad show that it is possible to recommend synthesis of new organic substances and intermediate compounds with high biological activity based on reactions of chloroacetylation of aromatic hydrocarbons, as well as for use in the national economy and medicine.
Results and discussion:
To achieve these goals, chloroacetylation reactions of toluidine isomers were studied. In the literature, it was found that N-acyl products are formed when there are 1:1 molar ratios of reagents (Yusufov M. S., Abdushukurov A. K., 2020. P. 236-237).
O
5'?H5hN
[(C2H5)3NH+]Cl-
H3C
CH2-Cl
The results of the reactions are presented in the table below.
Table 1. Effect of solvent and time on reactions of chloroacetyl chloride with toluidine isomers to obtain 2-chloro-N-o-, m-, p-tolylacetamides:
Name of reagents Mole Tem-ratios of pera-reagents ture, °C Duration of reaction, hours Solvent Yeild, % Product T(liquid) Rf
Chloro acetyl Acetonitrile 83
chloride: o-tolui- 1:1:1 2-5 6 106 0.65
dine: TEA Benzene 78
Chloroacetyl Acetonitrile 85
chloride: m-tolu- 1:1:1 -2-5 6 183 0.62
idine: TEA Benzene 79
Chloroacetyl Acetonitrile 88
chloride: p-tolui- 1:1:1 -2-5 6 175 0,73
dine: TEA Benzene 79
+
Toluidine isomers are more nucleophil-ic than aniline because the presence of an electron-donating (CH3) substituent on the aromatic ring increases the nucleophilicity of the amino group on the aromatic ring and the chloroacetylation reaction proceeds bet-
Name of reagents
Chloro acetyl chloride: o-tolui-dine: TEA
Chloroacetyl chloride: m-tolu-idine: TEA
Chloroacetyl chloride: p-tolui-dine: TEA
Polar and non-polar solvents were used for the reaction, and in order to reduce the duration of the reaction, it was carried out in an ultrasonic device and optimal conditions were selected.
Experimental part: 0.0214 g (0.0001 mol) of o-toluidine and 0.0338 ml (0.0001 mol) of triethylamine were placed in a round bottomed flask and dissolved in 10 ml of acetonitrile. In the second bowl, 0.02712 g (0.0001 mol) of chloroacetyl chloride was also dissolved in 5 ml of acetonitrile. Then, the reaction mixture in the first bowl was added dropwise to the reaction mixture in the second bowl while cooling (-2-5 °C) and stirring. Cooling stopped. The reaction was stirred at room temperature for 6 h. The formation of new substance in the reaction was monitored by chromatography every hour. A hexane: ethyl acetate ratio of 10:1 was used for this purpose. The solvent was evaporated in a rotary evaporator and the resulting reaction mixture was recrys-tallized from an organic solvent.
In order to reduce the duration of the reaction and increase the yield of the reaction, without changing the mole ratio, the solutions were added dropwise while stirring at -2-5 °C and carried out in an ultrasonic
ter. In order to synthesize biologically active substances, N-chloroacetylation reactions of toluidine isomers were carried out under different conditions, and this reaction proceeds as follows.
device at room temperature. The reaction product was monitored every 15 minutes by thin layer chromatography (TLC) for the formation of the N-acyl product. The duration of the reaction was 1 hour. Reactions carried out in an ultrasonic device were chosen as optimal conditions. Acetonitrile and benzene were chosen as solvents for the reactions.
The advantage of this method over the above method is the difference in time, and it is possible to obtain a product with a high yield in a short period of time.
I. Synthesis of 2-Chloro-N-(o-tolyl)-acetamide: The obtained 2-chloro-N-o-toly-lacetamide amide melting point and Rf values were determined. Yield 3.07 g (85%). mp 105-1060C., Rf=0,65 1H and 13C NMR were recorded on a JNM-ECZ400R spectrometer (JEOL, Japan) at an operating frequency of 400 MHz for 1H in CD3OD solutions.d 2.24 (s, 3H, CH3), 4.17 (s, 2H, CH2), 6.95 (d, 2H, H-Ar), 6.85 (d, 2H, H-Ar), 9.9 (s, 1H, NH); 13C NMR spektrum (CD3OD) 400 MHz 163.86, 135.1, 134.2, 129.7, 120.3, 42.66, 21.0; IR spectra were recorded on an FT-IR/ NIR Spectrum 3 spectrometer (Perkin Elmer, Switzerland) using an ATR system. (KBr) v/cm-1, 3254- (NH), 3134, 3089 (CHAr.),
Table 2. Results obtained under ultrasonic conditions of chloroacetyl chloride with toluidine isomers:
Mole Tem- Dura tion Yeild ProduCt
ratios of pera- of reaction, Solvent % ' T(li id) Rf reagents ture,°C hours q
1:1:1 -2-5
1:1:1 -2-5
1:1:1 -2-5
Acetonitrile 88
Benzene 86
Acetonitrile 90
Benzene 85
Acetonitrile 91
Benzene 87
106 0,65
183 0,62
175 0,73
1
1
1
2953 (CH2Alip.), 1671 (C=O), 1552 (C=CAr.), 1253 (C-C1), 864 (CHAr.), 505 (C-CAr.),
II. Synthesis of 2-Chloro-N-(m-tolyl)-acetamide: The obtained 2-chloro-N-m-tolylacetamide amide melting point and Rf values were determined. mp 183-185 °C, Yield 2.88 g. (83%). Rf=0,62. 1H and 13C NMR were recorded on a JNM-EC-Z400R spectrometer (JEOL, Japan) at an operating frequency of 400 MHz for 1H in CD3OD solutions.d 2.19 (s, 3H, CH3), 6.35 (s, 2H, CH2), 6.68 (d, 2H, H-Ar), 10.41 (s, 1H, NH); 13C NMR spektrum (CD3OD) 400 MHz 162.84, 135.1, 134.2, 129.7, 120.3, 42.66, 21.0; IR spectra were recorded on an FT-IR/NIR Spectrum 3 spectrometer (Perkin Elmer, Switzerland) using an ATR system. (KBr) v/cm-1, 3253 (NH), 3134, 3091 (CHAr.), 2853 (CHAlip.), 1674 (C=O), 1616 (C=CAr.), 1252 (C-Cl), 864 (CHAr.), 505 (C-CAr.).
III. Synthesis of2-chloro-N-(p-tolyl)-acetamide. The obtained 2-chloro-N-p-toly-lacetamide amide melting point and Rf values were determined. mp 174-175 °C; Yield -3.17 g (88%) Rf=0,73 1H and 13C NMR
were recorded on a JNM-ECZ400R spectrometer (JEOL, Japan) at an operating frequency of 400 MHz for 1H in CD3OD solutions.d 2.33 (s, 3H, CH3), 4.17 (s, 2H, CH2), 7.15 (d, 2H, H-Ar), 7.42 (d, 2H, H-Ar), 8.21 (s, 1H, NH); 13C NMR (50 MHz), 163.86, 135.1, 134.2, 129.7, 120.3, 42.66, 21.0; IR spectra were recorded on an FT-IR/NIR Spectrum 3 spectrometer (Perkin Elmer, Switzerland) using an ATR system. (KBr) v/cm-1 3307, 3203 (NH), 3134, 3089 (CHAr.), 2953 (CHAlip.), 1674 (C=O), 1552 (C=CAr.), 1292, 1252 (C--Cl), 748 (NH), 505 (C-CAr.).
Conclusion
2-chloro-N-(o-tolyl)-acetamide, 2-chloro-N-(m-tolyl)-acetamide, 2-chloro-N-(p-tolyl)-acetamide synthesized from tolu-idine isomers as chloroacetylation products. The effect of solvent and time on the reaction yield was investigated and the optimum conditions were found. Methods of purification of the obtained substances were determined. The structure of the substances was confirmed by IR and PMR sectors.
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submitted 12.04.2024;
accepted for publication 30.04.2024;
published 23.05.2024
© Bobonazarova S. H., Abdushukurov A. K., Yusufov M. S., Islamova Y. O., Azimova G. Z., Abdujabborova O. O.
Contact: Bobnazarovasarvinoz7 @gmail.com
