Synthesis, Physical Properties, Chemical Reactivity of Benzotriazole

Benzotriazole is a bicyclic nitrogen heterocycle formed by the fusion of the benzene ring with the 4,5-positions or  the “d” site of 1H-1,2,3-triazole. It is also known as 1H-benzo[d]-1,2,3-triazole and exists in two tautomeric 1H- and  2H- forms in which the 1H- form predominates (99.9%) over the 2H- form at room temperature in both gas and solution phases.

Benzotriazole is a very weak base with a pKa  of 8.2, but NH is more acidic than indazole, benzimidazole, and  1,2,3-triazoles. It is quite a stable molecule because the fused benzene ring gives additional strength to the stability  of the conjugate base. 

There are numerous benzotriazole-based clinically used drugs in the market for the treatment of various diseases.  Some of the anticancer, antifungal, and antibacterial drugs are depicted in the following scheme. 

Synthesis

There are numerous methods for the synthesis of benzotriazole but only the important and general routes of this  ring system are depicted here.

o-Phenylenediamine on treatment with NaNO2  in acetic acid undergoes intramolecular cyclization to yield  benzotriazoles.

Dehydrobenzene (benzyne) generated in situ by a slow addition of anthranilic acid to an alkyl nitrite followed  by addition of alkyl, aryl, and acyl or sulfonyl azides afforded benzotriazoles.

1-Chloro-2-nitrobenzene or 1,2-dinitrobenzene on reaction with hydrazine produced benzotriazol-1-ol via  2-nitrophenylhydrazine.

The reaction of 1,3-dihydrobenzimidazol-2-one with sodium nitrite and water under high temperature (190– 300°C) and pressure afforded 1-sodium benzotriazole, which on acid treatment gave 1H-benzotriazole in high  yields.

An alternative way to prepare N-aryl benzotriazole has been reported by treating a diazotized solution derived  from 2-chloroaniline with aryl amine followed by intramolecular cyclization in the presence of CuI and CsCO3.

Physical Properties

It is a white sold with an mp of 100°C, a bp of 350°C, a density 1.36 g/cm3 , and is soluble in water. 

UV (EtOH), λnm (ε): 259 (3.75), 275 (3.71).    

1 H NMR (DMSO-d6 ), δ (ppm): C4 –H, 8.00; C5 –H, 7.44; C6–H, 7.44; C7 –H, 8.0. 

13C NMR (DMSO-d6 ), δ (ppm): C4 , 130.3; C5 , 130.3; C6 , 130.3; C7 , 130.3.

Chemical Reactivity

Electrophilic substitution reactions in benzotriazoles are facile at the N1 - and N2 -positions as well as at position 4  of the benzene ring.

Alkylation 

Reaction of 1H-benzotriazole with different methylating agents such as methyl sulfate, diazomethane, and methyl  halide gave a mixture of 1-methyl- and 2-methylbenzotriazole in the ratio of 5:17. Alkylation of 1H-benzotriazole with  alkyl halide using NaOH or NaOEt as a base gave 1-alkylbenzotriazole as a major product and 2-alkylbenzotriazole  and 1,3-dialkylbenzotriazolium salts as minor products.

Sulfonation

1H-Benzotriazole on reaction with trifluoromethanesulfonic anhydride in dry DCM and dry pyridine at −78°C  afforded 1-(trifluoromethyl)sulfonyl-1H-benzotriazole in 87% yields.

N-Amination

Treatment of 1H-benzotriazole with hydroxylamine-O-sulfonic acid in hot aqueous potassium hydroxide at 70– 75°C gave a mixture of 1H-benzotriazol-1-amine and 2H-bezotriazol-2-amine in a 3:1 ratio.

Nitration

1H-Benzotriazole has been nitrated with a mixture of concentrated nitric acid and sulfuric acid at room temperature to give 4-nitro-1H-benzotriazole in 50% yields.

Applications

It is used as a corrosion inhibitor for copper and copper alloys from atmospheric as well as immersed conditions.  Diverse pharmacological properties are associated with benzotriazole-based compounds. For the pharmaceutical  industry this structural motif is highly useful for new drug discovery.

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