Synthesis, Properties, Chemical Reactivity of 1,2,4-Triazole

1,2,4-Triazole is a five-membered, π-excessive, aromatic nitrogen heterocycle, comprised of two carbon and three  nitrogen atoms present at the 1-, 2-, and 4-positions of the ring. All the atoms in 1,2,4-triazoles are sp2  hybridized  and have 6π electrons delocalized over the ring, responsible for its aromatic character. It is also known as s-triazole  (symmetrical). 1,2,4-Triazole exists in two tautomeric forms known as 1H-1,2,4-triazole and 4H-1,2,4-triazole and it is  very difficult to separate them due to their rapid interconversion.

The diverse pharmacological activities of 1,2,4-triazoles as antifungal, antiviral, herbicidal, and catalase inhibitors  induced deep interest to discover new entities for their broader applications. There are numerous 1,2,4-triazole-based  drugs in clinical use for the treatment of various diseases. Some of the important drugs available in the market are  depicted in the following scheme.

Physical Properties

Parent 1H-1,2,4-triazole is a white powder solid with an mp of 119–121°C, a bp of 260°C, a density of 1.13 g/cm3 ,  and is highly soluble in water. It is also soluble in alcohol, propanol, isopropanol, methyl acetate, and ethyl acetate.  Its ionization potential is 10.00 eV; the dipole moment in the gas phase is 2.72 D and in dioxane it is 3.27 D. 

UV (THF), λnm (ε): 216.5 (3.66). 

1 H NMR (MeOH-d4 ), δ (ppm): C3 –H, 7.92; C5 –H, 8.85. 

13C NMR (MeOH-d4 ), δ (ppm): C3 , 147.4; C5 , 147.4.

Synthesis

The parent 1H-1,2,4-triazole has been prepared by the reaction of hydrazine obtained in situ from the hydrolysis  of 1,2-di(butan-2-ylidene)hydrazine with formamide at 170°C.

Pellizzari Synthesis

Amides on reaction with hydrazides form acyl amidrazone as an intermediate, which after intramolecular cyclization delivered 1,2,4-triazoles.

Einhorn-Brunner Synthesis

Acid-catalyzed condensation of formylacetamide with alkyl hydrazines delivered 1-alkyl-5-methyl-1,2,4-triazoles.

From Amidines

Amidines are considered good precursors for the synthesis of 1,2,4-triazole on reaction with different reagents and  catalysts. 1,2,4-Triazoles have been synthesized by copper-catalyzed oxidative coupling of organic nitrile with amidine  under atmospheric air in DMSO at 120°C.

Chemical Reactivity 

Both carbon atoms in 1H-1,2,4-triazoles are π deficient because both are attached to electronegative nitrogen atoms  and the electron density (0.744) at both carbon atoms is low and susceptible to nucleophilic substitution under mild  conditions. It is a weak base and the pKa  of 2.19 is for protonated species. The NH-protons in N-unsubstituted-1,2,4- triazoles are acidic in nature. The pKa  of 1,2,4-triazoles is 10.26. The triazolium ions formed are also prone to nucleophiles. Electrophilic substitution takes place only at nitrogen atoms because of high electron density.

Electrophilic Substitution Reactions

The parent 1H-1,2,4-triazole is readily protonated at position 4 in concentrated HCl to form triazolium chloride.

Metalation

1H-1,2,4-Triazoles are easily metalated with NaOH, AgNO3 , and copper nitrate to form respective organometallic  compounds.

Alkylation

1H-1,2,4-Triazole is regioselectively alkylated at N1  when sodium ethoxide in ethanol is used as a base but alkylation in aqueous NaOH with methyl sulfate gave a mixture of 1-methyl- and 4-methyl-1,2,4-triazole. Alkylation with  ethyl chloroacetate in sodium methoxide produced N1 -substituted products.

1H-1,2, 4-Triazole on reaction with dibromomethane using aqueous NaOH as a base and n-Bu4 NBr as a phasetransfer catalyst in DCM resulted in bis(1,2,4-triazol-1-yl)methane in 31% yield.

You may like