Synthesis, Properties, Chemical Reactivity of 1,2,4-Triazole
Feb 14,2022
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.- Related articles
- Related Qustion
- The role of 1,2,4-triazole Jan 27, 2022Triazole is an aromatic five membered heterocyclic compound. Its unique structure is conducive to the formation of a variety of non covalent bonds and is easy to promote the binding of proteins, enzym
See also
1,2,3-Triazole is an unsaturated, aromatic, five-membered, π-excessive nitrogen heterocycle with a 6π electron ring system, comprised of three regular nitrogen and two carbon atoms with two double bonds..... Feb 14,2022Chemical Reagents
Propionic acid is a short-chain saturated fatty acid comprising ethane attached to the carbon of a carboxy group. It has a role as an antifungal drug..... Feb 14,2022Drugs
1,2,4-Triazole
288-88-0
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Mar 14, 2024
- 1H-1,2,4-Triazole
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