Synthesis, Reactions and Medicinal Uses of Thiazole

 

Synthesis, Reactions, and Medicinal Uses of Thiazole 


Thiazole is a five-membered heterocyclic compound having one Sulphur and one Nitrogen atom as heteroatoms at 1 and 3 positions respectively.
Physical properties:
Colour                :  Colourless or pale yellow
State                   :   liquid
Boiling point     :  116 - 118 oC
Melting point    :   -33 oC
Solubility           :  slightly soluble in water, soluble in organic solvents

Structure & Aromaticity:

C, N and S atoms in the thiazole ring are sp2 hybridised, so the thiazole contains a planar ring structure. the sp2 hybrid orbitals overlap with each other and with the "s" atomic orbital of the three hydrogens forming C-C, C-N, C-H, and C-S sigma bonds. all these sigma bonds lie in one plane.
Thiazole also has unhybridized p orbitals and these are perpendicular to the plane of the ring. each p orbital on carbon atom contains one electron and the p orbitals on nitrogen and sulphur contain lone pair of electrons(two electrons). the p orbitals overlap to form a delocalized pi molecular orbital. Thiazole shows aromaticity because the resulting pi molecular orbital (which contain 6 electrons) satisfies Huckel's rule (n=1 in 4n+2).

Resonance structures:

Synthesis:

1. Gabriel synthesis: Î±-Acyl amino ketones undergo cyclization in presence of phosphorous pentasulfide and strong mineral acids like hydrochloric acid or sulphuric acid followed by dehydration to give thiazole.


2. Hantzsch Thiazole synthesis:  Condensation of α-halo ketones and thioamides gives thiazole.


3. From α-aminonitrile: Condensation of α-aminonitrile and carbon disulfide to give thiazole.

4. From thiocyanate salts: halo acetones reacts with thiocyanate to give thiazole.



Electrophilic aromatic substitution reactions: 

The pi-electron density is more at C-5 and C-4.  In the presence of electron-donating groups, the electrophilic substitution takes place preferably at C-5 followed by C-4.

Suphonation: Thiazole upon sulphonation give Thiazole-5-sulphonic acid.


Halogenation: 2-amino thiazole is treated with bromine in acetic acid gives 5-substituted thiazole.


Nitration: Thiazole upon nitration gives 5-nitro and 4-nitro substituted thiazole in a 2:1 ratio.


2,5 disubstituted thiazole upon nitration gives 4-nitro substituted thiazole.


Nucleophilic substitution reactions:  

In thiazole Nucleophilic substitution reactions take place at the C-2 position.

1. Thiazole is reacted with sodamide in liquid ammonia to give 2-amino thiazole.


2. 2-chloro thiazole reacts with sodium methoxide to give 2-methoxy thiazole.


Other reactions:

Protonation: Thiazole acts as the base, when reacts with acids it abstracts the proton to form thiazolium cation.


N-alkylation: Thiazoles reacts with alkyl halides to gives N-alkyl thiazolium salts.


Reduction: Thiazole shows resistance towards many reducing agents. But Raney nickel reduces it and opens the ring.


Oxidation:  Thiazole oxidised to give thiazole-N-oxide.



Medicinal uses:


Drugs containing Thiazole ring:

1. Famotidine: Fomatidine is an H-2 receptor blocking agent used in the treatment of peptic ulcers.


2. Thiabendazole: Thiabendazole is an anthelmintic used to treat infections caused by threadworms, hookworms, pinworms and whipworms.
 

3. Sulphathiazole: Sulphathiazole is an antibiotic. it is used in combination with other sulphonamide antibiotics to treat vaginal infections.


4. Vitamine B1: Used in thiamine deficiency.


5.  Fanetizole: Fanetizole is an anti-inflammatory agent used to treat pain and inflammation.


6. Cambendazole: It is a Fungicidal agent used to treat fungal infections.


References (Latest editions):


Heterocyclic chemistry by Raj K. Bansal.
Heterocyclic chemistry by T.L. Gilchrist.
Organic chemistry by Morrison and Boyd.
A  textbook of organic chemistry - Arun Bahl. B.S. Bahl.



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