Synthesis, Characterization of New1,3,4-thiadiazole Derivatives with Studying their Biological Activity

 

Shetha. F. Al-Zubiady, Zainab. H. Kadhim Al-Khafaji, Iman. M. Mohamed

Department of Chemistry, Collage of Science for women, Baghdad University, Iraq.

 

ABSTRACT:

In this work, thiadiazole derivatives were prepared by taking advantage of active sites in (2-amino-5-mercapto-1,3,4-thiadiazole) as base. The main hetrocyclic compounds (1,3,4-thiadiazole, oxazole) etc. 2-amino-5-mercapto-1,3,4-thiadiazole  compound [1] was prepared by cyclic closure of thiosemicarbazide compound with anhydrous sodium carbonate and carbon disulfide. Oxidation of [1] via hydrogen peroxide, to have [2] which was treat with chloro acetyl chloride to get [3]. Preparation of oxazole ring [4] obtained from reacting of [3] with urea. Schiff bases [5 – 7] prepared by reacting [3] with different benzyl aldehyde. And Preparation of derivative [8 – 11], from reaction [3] with of hydrazine derivatives. Full characterization of the synthesized compounds was done by using of spectroscopic analysis such as FT-IR, ¹H-NMR and C.H.N.S,

 

 

INTRODUCTION:

Thiadiazole is a 5-membered ring system having hydrogen-binding domain, Sulphur atom, and two- electron donor nitrogen system (–N=C–S) that show a widespread diversity of biotic activity. In the nature, they occur in four isomeric structures., 1, 2, 3-thiadiazole, 1, 2, 5-thiadiazole, 1,2,4-thiadiazole, 1, 3, 4- thiadiazole.⁽¹⁾ 1, 3, 4-Thiadiazole was first defined in 1882 by Fischer and further advanced by Busch and his coworkers.⁽²⁾

 

Works study exposed that many thiadiazoles have resulted in many possible medications and are known to display a broad range of pharmacological properties. The specific pharmacological activities including Antitumor ⁽³⁾ Antiviral, Antibacterial, Amoebicidal, Anti-inflammatory, Anti tubercular, Antipyretic, Anticancer, Antischistosomal ⁽⁴⁾

 

Herbicidal, Insecticidal, Pesticidal and Hypoglycemic.⁽¹⁾ Oxazoles are a form of five-membered ring, heteroaromatic compounds have an oxygen atom and a pyridine-type nitrogen atom at the 1 and 3 locations of the ring, and, like pyridines, oxazoles are feebly basic substances ⁽⁵⁾. The first oxazole was prepared in 1840 by Zinin, who obtained the compound he called Azobenzil from the reaction of benzil with alcoholic ammonia.⁽⁶⁾

 

The "Schiff base" term was established on organic chemical compounds that have Imine group (C = N) or (Azomethine), which is composed of the bond of a carbon atom with a double bond with nitrogen. In the 19th century, Hugo Schiff (1864) reported the first preparation of Imines.⁽⁷⁾ It is generally shaped by condensation of an aldehyde or ketone with primary amine.^{(7) (8)}

 

MATERIALS AND METHODS:

All chemicals were supplied from different companies such as Thomas baker, Merck, BDH, GCC and Scharlau and used without further purification. Melting points are determined on an electro thermal melting point apparatus (Stuart, Germany), and they are uncorrected. Completion of reaction and purity of all compounds are checked on aluminum coated TLC plates 60 F245 (E. Merck) using Methanol and Ethanol as the mobile phase and visualized under iodine vapor. Determinations of infrared spectra were done and recorded as a KBr disks in the range of (400 -4000 cm-1) using FTIR Shimadzu (Japan).

 

The proton 1H-NMR spectra were recorded for the synthesized compounds using Bruker DMX-500 spectrophotometer (500 MHZ, solvent DMSO-d6). Moreover, elemental analysis (C.H.N.S) was approved for compounds (3) and (10).

 

Synthesis of 2-amino-5-mercapto-1, 3, 4-thiadiazole compound [1] ^{(9) (10)}:

(0.05 mole, 4.56 gm) of Thiosemicarbazide has been dissolved in 15 ml of absolute ethanol in 50 ml round bottom flask, then (0.005 mole, 2.84 gm) of anhydrous sodium carbonate added (after drying for 30 minute in 40 C°) with continues stirring, (12 ml) of CS2 added and the mixture refluxed in sand bath at temperature 50 C° for 1 hour then increase the temperature to (120 – 130) C° for 7 hours, the mixture cooled at room temperature, the precipitate filtered and washed by hot distilled water, then (drop by drop ) of Concentrated HCl added to the filtered until precipitate shown, the precipitate washed by cold dist. water to remove acid presence. To indicate the presence of the acid, used a solution of AgNO3 (0.01N), the clarity of the filtered mean that the acid has been removed. The precipitate purified by recrystallization from distilled Water then dried.

 

Synthesis of 5,5'-disulfanediylbis(1,3,4-thiadiazol-2-amine) compound [2]^{(11) (12)}

(0.03 mole, 3.99 gm) of compound (1) was added to absolute Ethanol (20 ml) in (50 ml) beaker, then few drops hydrogen peroxide (50%) to the mixture with continuous stirring for 3 hours at room temperature. The precipitate filtered and wash with distil Water and dried overnight, recrystallization with ethanol/water (1:2) and the product dried overnight. Collected as yellow powder.

 

Synthesis of N,N'-(5,5'-disulfanediylbis(1,3,4-thiadiazole-5,2-diyl))bis(2-chloroacetamide) compound [3]⁽¹³⁾

In beaker, added (20 ml) Pyridine to (0.012 mole, 3 gm) of compound [2] in ice bath (0 - 3) C°, after 15 min. drops of Chloro acetyl chloride gradually added with magnetic stirring for 4 hours. The mixture poured in ice water and the solid precipitate separated by filtration and dried, recrystallized from ethanol.

 

Synthesis of N5,N5'-(5,5'-disulfanediylbis(1,3,4-thiadiazole-5,2-diyl))dioxazole-2,5-diamine compound [4]⁽¹⁴⁾

(0.008 mole, 0.3 gm) from Compound [3] with urea, (0.003 mole, 0.2 gm) fused for 1 hour at (160) C°, then cooled at room temperature, washed several times by distil water, the precipitate filtered and recrystallized from absolute ethanol.

 

Synthesis of Schiff base compound [5 – 7]⁽¹⁵⁾:

Different aromatic benzyl aldehyde (0.0006 mole, 0.12 gm) dissolved in absolute ethanol, added drops of glacial acetic acid, then added compounds [4] (0.0003 mole, 0.15 gm), reflexed for 8 hours. The mixture lifted to cool at room temperature and collected by filtration, recrystallized from absolute ethanol.

 

Synthesis of N,N'-(5,5'-disulfanediylbis(1,3,4-thiadiazole-5,2-diyl))bis(2-(hydrazine: derivatives)acetamide) compound [8 – 11]^{(16) (17)}

(0.0004 mole, 0.1 gm) from compound [3] dissolved in (20 ml) of absolute ethanol, (0.0008 mole, 0.05 gm) of hydrazine derivatives add to the mixture. Then reflexed for 10 hours and lifted overnight to evaporate the excess solvent, filtered the precipitate and recrystallized from absolute ethanol.

 

Antibacterial activity test:

The antibacterial activity of compound [3], [5] and [10]. Each sample was tested against Gram +ve bacteria (Staphylococcus aureus), Gram –ve bacteria (E.coli) and yeast (Candida albicans).The samples were dissolved using dimethylsulfoxide (DMSO) as a solvent and cultured in Muller Hinton agar for 24 h at 37°C.

 

RESULTS AND DISCUSSION:

The overall reaction was summarized in Scheme (1)

 

 

Compound [1] was prepared by the reacting of thiosemicarbazide with carbon disulphide in the presence of anhydrase Sodium carbonate in ethanol followed by concentrated hydrochloric acid ⁽¹⁸⁾. Since the bond energy for (SH) group in thiol is (80 Kcal/mole) it's very little comparison the bond energy for (OH) group in alcohols, thus thiol possess the ability to couple oxidation when it reacted with oxidizing agent to give disulfide. Oxidation of compound [1] through hydrogen peroxide H₂O₂ (percent 30%) gives disulfide compound [2]. ⁽¹⁹⁾ Compound [3] was preparation from reacting of compound [2] with chloroacetyl chloride (1:2) in the presence of dry pyridine. Mechanism includes nucleophilic aggression on the positive carbon atom in chloroacetyl chloride by the lone pair on the amine group in the compound [2], flowed via liberate of two HCl molecules. The suggested mechanism steps are shown in Scheme (2)⁽²⁰⁾

 

 

Compound [4] has been prepared from fusing compound [3] with urea (1:2). The reaction occurred as a result of adding nucleophile to the carbonyl group in compound[3], then elimination of the H₂O molecule.⁽¹³⁾ Scheme (3) shown the mechanism steps of this reaction

 

 

 

Schiff bases were prepared by condensing compound [4] with various benzylaldehyde in alcoholic environ ment in the presence of glacial acetic acid for 8 hours at temperature 220 – 250 C°. The amine group possesses electron pair that gave strong nucleophilic character. It will reactive the reaction by forming hydrogen bonding of the solvent with oxygen atom in carbonyl group, which increases the positive character of the carbon atom in carbonyl aldehyde group which facilitates the nucleophilic attack , thus forming an unstable intermediate compound followed by proton transfer and loses water molecules. Scheme (4) exhibit the mechanism steps of this reaction. ⁽²¹⁾

 

 

Compounds [8 – 11] were synthesized from reaction between compound [3] with (hydrazine 80%, phenyl hydrazine, thiosmicarbazide, and hydroxylamine hydrochloride) in absolute ethanol were refluxed 10 hours. The suggested mechanism occurs by nucleophilic aggression to liberate two HCl molecules, the mechanism steps for reaction shown in Scheme (5)⁽²²⁾

 

 

 

 

The characterization and the purity of the intermediates and the targets (melting points, and yielded percentages) were summarized in Table (1) The FT-IR spectra of the synthesized compounds showed a characteristic bands of absorption, which were in consistence with the proposed structure of the compounds. The values of the characteristics bands of these spectra were discussed according to the literature survey of similar compounds and references. The functional groups of the starting materials and the synthesized compounds were identified using FT-IR spectroscopy as shown in Table (2).The chemical structures were confirmed using elemental microanalysis (C.H.N.S) as presented in Table (3), the results were found agree with the corresponding calculated values. Tables (4)summarized the suggested fragmentation with the abundance and formula for each fragment. The 1H-NMR analysis was used to identify the synthesized compounds. The spectra were recorded using DMSO-d₆ solvent the values of the characteristics of the chemical shift were discussed according to the literature survey of similar compounds and references. Table (5) exhibit the biological activity of compounds [3], [5] and [10]

Table (1): Physical Properties of Synthesized Compounds [1-11]

 

Table (2): FT-IR Spectral data for the synthesized compounds (cm^-1, KBr disk)

Compound [1]			Compound [2]
3367-3263	ʋ (NH2) asymmetric and symmetric stretching vibration		3309-3250		ʋ (NH2) asymmetrical and symmetrical stretching vibration of primary amine groups
3178	ʋ (NH) tautomeric from stretching vibration		1508		ʋ (NH2) bending vibration of primary amine groups
2615	ʋ (SH) stretching vibration		1635		ʋ (C=N) stretching vibration of azomethine group
1165	ʋ (C=S) stretching vibration		682		ʋ (C-S-C) stretching vibration
1315	ʋ (C-N) stretching vibration		528		ʋ (S-S) stretching vibration
1531	ʋ (N-N) stretching vibration		1453		ʋ (S-S) stretching vibration
648	ʋ (C-S) stretching vibration		1453		ʋ (N-N) stretching vibration
1500-1535	ʋ (N-C=S) stretching vibration
Compound [3]			Compound [4]
3259	ʋ (NH) stretching vibration of amid group		3305-3271		ʋ (NH2) asymmetrical and symmetrical stretching vibration
2935-2920	ʋ (C-H) aliphatic stretching vibration		3193		ʋ (N-H)) stretching vibration
1635	ʋ (C=O) stretching vibration of amid group		3066		ʋ (C-H) aromatic stretching vibration
1670	ʋ(C=N) stretching vibration of azomethine group		1690		ʋ (C=N) stretching vibration of azomethine group
1319	ʋ (C-N) stretching vibration		1303		ʋ (C-N) stretching vibration
1496	ʋ (N-N) stretching vibration		1635		ʋ (N-N) stretching vibration
748	ʋ (C-Cl) stretching vibration		1546		ʋ (C=C) stretching vibration
671	ʋ (C-S-C) stretching vibration		682		ʋ (C-S-C) stretching vibration
574	ʋ (S-S) stretching vibration		1500		ʋ (N-H) bending vibration
1554	ʋ (N-H) bending vibration
Compound [5]			Compound [6]
3267	ʋ (N-H) stretching vibration		3271		ʋ (N-H) stretching vibration
3074	ʋ (C-H) aromatic stretching vibration		3074		ʋ (C-H) aromatic stretching vibration
1642,1620	ʋ (C=N) stretching vibration of imine group		1649,1631		ʋ (C=N) stretching vibration of imine group
1388	ʋ (C-N) stretching vibration		1388		ʋ (C-N) stretching vibration
1504	ʋ(C=C) aromatic stretching vibration		1580		ʋ(C=C) aromatic stretching vibration
1504	ʋ (N-N) stretching vibration		1504		ʋ (N-N) stretching vibration
1249	ʋ (C-O-C) stretching vibration		1269		ʋ (C-O-C) stretching vibration
2954	ʋ (C-H) Aliphatic stretching vibration		2958		ʋ (C-H) Aliphatic stretching vibration
Compound [7]			Compound [8]
3170	ʋ (N-H) stretching vibration		3136	ʋ (N-H) stretching vibration
3028	ʋ (C-H) aromatic stretching vibration		2924	ʋ (C-H) aliphatic stretching vibration
1670,1600	ʋ (C=N) stretching vibration of imine group		1651	ʋ (C=O) stretching vibration of amide group
1381	ʋ (C-N) stretching vibration		1608	ʋ (C=N) stretching vibration of azomethine group
1526	ʋ(C=C) aromatic stretching vibration		1330	ʋ(C-N) stretching vibration
1512	ʋ (N-N) stretching vibration		1500	ʋ (N-N) stretching vibration
1288	ʋ (O-H) stretching vibration of hydroxyl group		3340-3255	ʋ (NH2) asymmetric and symmetric stretching vibration
2900	ʋ (C-H) Aliphatic stretching vibration		675	ʋ (C-S) stretching vibration
3452	ʋ (C-O-C) stretching vibration
Compound [9]			Compound [10]
3302-3109	ʋ (N-H) stretching vibration		3093	ʋ (N-H) stretching vibration
2924	ʋ (C-H) aliphatic stretching vibration		2920	ʋ (C-H) aliphatic stretching vibration
1662	ʋ (C=O) stretching vibration of amide group		1643	ʋ (C=O) stretching vibration of amide group
1631	ʋ (C=N) stretching vibration of azomethine group		1604	ʋ (C=N) stretching vibration of azomethine group
1330	ʋ(C-N) stretching vibration		1321	ʋ(C-N) stretching vibration
1600	ʋ (N-N) stretching vibration		1531	ʋ (N-N) stretching vibration
3055	ʋ (C-H) aromatic stretching vibration		3371-3263	ʋ (NH2) asymmetric and symmetric stretching vibration
621	ʋ (C-S) stretching vibration		648	ʋ (C-S) stretching vibration
1554	ʋ(C=C) stretching vibration		1165	ʋ(C=S) stretching vibration
Compound [11]
3039		ʋ (N-H) stretching vibration
2719		ʋ (C-H) aliphatic stretching vibration
1664		ʋ (C=O) stretching vibration of amide group
1627		ʋ (C=N) stretching vibration of azomethine group
1315		ʋ(C-N) stretching vibration
1581		ʋ (N-N) stretching vibration
3537		ʋ (O-H) stretching vibration
609		ʋ (C-S) stretching vibration

 

Table (3): Elemental microanalysis data (%) of the synthesized compounds (C.H.N.S.)

 

Table (4): ¹H-NMR data and their interpretation for the synthesized compounds

 

 

 

Table (5) biological activity for some synthesized compounds.

 

 

Figure 1 : FT-IR spectrum of compound [3

 

Figure 2: FT-IR spectrum of compound [4]

Figure 3:FT-IR spectrum of compound [5

 

Figure 4:FT-IR spectrum of compound [6]

 

Figure 5:FT-IR spectrum of compound [7]

 

 

Figure 6:FT-IR spectrum of compound [8]

 

 

Figure 7FT-IR spectrum of compound [9]

 

 

Figure 8:¹H-NMR spectrum of compound [3]

 

 

Figure 9:¹H-NMR spectrum of compound [4]

 

Figure 10:¹H-NMR spectrum of compound [5]

 

Figure 11:¹H-NMR spectrum of compound [8]

 

 

Figure 12:¹H-NMR spectrum of compound [10]

 

CONCLUSION:

During the preparation of the new derivatives from the basic compound (2-amino-5-mercapto-1,3,4-thiadiazole) we noticed high stability of new synthesized hetero cyclic compounds and fused rings have very biological activity, analytical and spectral data (FT-IR,1H-NMR,C.H.N.S) proved the proposed structures.

 

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Received on 12.12.2017             Modified on 24.12.2017

Accepted on 20.01.2018           © RJPT All right reserved