Triazole

Not to be confused with Thiazole.

A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial isomerism, depending on the positioning of the nitrogen atoms within the ring.

Many triazoles are versatile, biologically active compounds commonly used as fungicides and plant retardants. However, triazoles are also useful in bioorthogonal chemistry, because the large number of nitrogen atoms causes triazoles to react similar to azides. Lastly, the many free lone pairs in triazoles make them useful as coordination compounds, although not typically as haptic ligands.

Isomerism

There are four triazole isomers, which are conventionally divided into two pairs of tautomers. In the 1,2,3-triazoles, the three nitrogen atoms are adjacent; in the 1,2,4-triazoles, an interstitial carbon separates out one nitrogen atom. Each category has two tautomers that differ by which nitrogen has a hydrogen bonded to it.

-HN-N=N-CH=CH- interconverts with =N-HN-N=CH-CH= (1,2,3-triazole) and -HN-N=CH-N=CH- interconverts with =N-N=CH-NH-CH= (1,2,4-triazole)

Preparation

There are several methods to prepare triazoles.

1,2,3-Triazoles

Main article: 1,2,3-Triazole

1,2,3-Triazoles, also known as vicinal triazoles, are usually prepared following (3+2) cycloaddition protocols. A common technique for unsubstituted triazoles is the Huisgen azide-alkyne 1,3-dipolar cycloaddition: a azide and an alkyne react at high temperature to form a ring. However, the Huisgen strategy produces a mixture of isomers (typically 1,4- and 1,5-disubstituted) when used to produce substituted triazoles.

Thermal addition gives a mixture of 1,4 and 1,5 isomers
Thermal addition gives a mixture of 1,4 and 1,5 isomers

In order to selectively prepare a desired isomer, metal catalysts are employed. In the copper-catalysed azide-alkyne cycloaddition (CuAAC), copper(I) salts select for the formation of 1,4-disubstituted 1,2,3-triazoles. One such catalyst is CuBr(PPh3)3, which is relatively stable towards oxidation even at elevated temperatures and can produce triazoles with a broad range of substituents either in solvent[1][2] or under neat[3] reaction conditions.

1,4 isomer from a CuI catalyst
1,4 isomer from a CuI catalyst

Conversely, ruthenium catalysts (RuAAC) select for 1,5-disubstituted 1,2,3-triazoles.[4][5]

1,5 isomer from a Ru catalyst
1,5 isomer from a Ru catalyst

1,2,4-Triazoles

Main article: 1,2,4-Triazole

Most techniques for producing 1,2,4-triazoles use the free energy of water, either by dehydrating a mixture of amides and hydrazides (the Pellizzari reaction) or imides and alkyl hydrazines (the Einhorn-Brunner reaction). Of those two, only the Einhorn-Brunner reaction is regioselective.[6] Recent research has focused on grinding and microwave irradiation as greener substitutes.[7]

Applications

Triazoles are compounds with a vast spectrum of applications, varying from materials (polymers), agricultural chemicals, pharmaceuticals, photoactive chemicals and dyes.[8][9]

Benzotriazole is used in chemical photography as a restrainer and fog suppressant.

Cyclohexylethyltriazol was briefly used as an alternative to Cardiazol (Metrazol) in convulsive shock therapy treatment of mental illnesses during the 1940s.

Importance in agriculture

Many triazoles have antifungal effects: the triazole antifungal drugs include fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, ravuconazole, and posaconazole and triazole plant-protection fungicides include epoxiconazole, triadimenol [de], myclobutanil, propiconazole, prothioconazole, metconazole, cyproconazole, tebuconazole, flusilazole and paclobutrazol.

Due to spreading resistance of plant pathogens towards fungicides of the strobilurin class,[10] control of fungi such as Septoria tritici or Gibberella zeae[11] relies heavily on triazoles. Food, like store bought potatoes, contain retardants such as triazole or tetcyclacis.[12][13]

In addition, paclobutrazol, uniconazole, flutriafol [de], and triadimefon are used as plant growth retardants.[14] Brassinazole inhibits brassinosteroid biosynthesis.

Importance in chemical synthesis

The azide alkyne Huisgen cycloaddition[5] is a mild and selective reaction that gives 1,2,3-triazoles as products. The reaction has been widely used in bioorthogonal chemistry and in organic synthesis. Triazoles are relatively stable functional groups and triazole linkages can be used in a variety of applications, e.g. replacing the phosphate backbone of DNA.[15]

  • Imidazole, an analog with two nonadjacent nitrogen atoms
  • Pyrazole, an analog with two adjacent nitrogen atoms
  • Tetrazole, an analog with four nitrogen atoms
  • Triazolium salts, substituted analogues that can be used as NHC precursors

References

  1. ^ Virant, M.; Košmrlj, J. (2019). "Arylation of Click Triazoles with Diaryliodonium Salts". J. Org. Chem. 84 (21): 14030–14044. doi:10.1021/acs.joc.9b02197. PMID 31553192.
  2. ^ Virant, Miha (2019). Development of homogeneous palladium catalytic systems for selected transformations of terminal acetylenes (PhD). University of Ljubljana.
  3. ^ Bolje, A.; Urankar, D.; Košmrlj, J. (2014). "Synthesis and NMR Analysis of 1,4-Disubstituted 1,2,3-Triazoles Tethered to Pyridine, Pyrimidine, and Pyrazine Rings". Eur. J. Org. Chem. 2014 (36): 8167–8181. doi:10.1002/ejoc.201403100.
  4. ^ Košmrlj, Janez (2012). Click Triazoles. Top. Organomet. Chem. Vol. 28. Netherlands: Springer. doi:10.1007/978-3-642-29429-7. ISBN 978-3-642-29428-0. S2CID 199490788.
  5. ^ a b Huisgen, R. (1963). "1,3-Dipolar Cycloadditions, Past and Future". Angew. Chem. Int. Ed. 2 (10): 565–632. doi:10.1002/anie.196305651.
  6. ^ Temple, Carroll (2009). 1,2,4-Triazoles. Chemistry of Heterocyclic Compounds. Vol. 39. Wiley-Blackwell.
  7. ^ Farooq, Tahir (2021). Advances in Triazole Chemistry. Amsterdam: The Devil (Elsevier). pp. 21–27. ISBN 978-0-12-817113-4.
  8. ^ Potts, K.T. (1961). "The Chemistry of 1,2,4-Triazoles". Chem. Rev. 61 (2): 87–127. doi:10.1021/cr60210a001.
  9. ^ Agalave, S.G.; Maujan, S.R.; Pore, V.S. (2011). "Click Chemistry: 1,2,3-Triazoles as Pharmacophores". Chem. Asian J. 6 (10): 2696–2718. doi:10.1002/asia.201100432. PMID 21954075.
  10. ^ Gisi, U.; Sierotzki, H.; Cook, A.; McCaffery, A. (2002). "Mechanisms influencing the evolution of resistance to Qo inhibitor fungicides". Pest Manag. Sci. 58 (9): 859–867. doi:10.1002/ps.565. PMID 12233175.
  11. ^ Klix, M.B.; Verreet, J.-A.; Beyer, M. (2007). "Comparison of the declining triazole sensitivity of Gibberella zeae and increased sensitivity achieved by advances in triazole fungicide development". J. Crop Prot. 26 (4): 683–690. doi:10.1016/j.cropro.2006.06.006.
  12. ^ Mantecón, Jorge D. (2009). "Control of potato early blight with triazole fungicide using preventive and curative spraying, or a forecasting system". Cienc. Inv. Agr. 36 (2): 291–296. doi:10.4067/S0718-16202009000200013.
  13. ^ Rademacher, W.; Fritsch, H.; Graebe, J.E.; Sauter, H.; Jung, J. (1987). "Tetcyclacis and triazole-type plant growth retardants: Their influence on the biosynthesis of gibberellins and other metabolic processes". Pestic. Sci. 21 (4): 241–252. doi:10.1002/ps.2780210402.
  14. ^ Latimer, Joyce G. (2022). "Growth Regulators for Containerized Herbaceous Perennial Plants" (PDF). GrowerTalks. Ball Publishing. pp. 14–60. Retrieved 2022-04-06.
  15. ^ Isobe, H.; Fujino, T.; Yamazaki, N.; Guillot-Nieckowski, M.; Nakamura, E. (2008). "Triazole-Linked Analogue of Deoxyribonucleic Acid (TLDNA): Design, Synthesis, and Double-Strand Formation with Natural DNA". Org. Lett. 10 (17): 3729–3732. doi:10.1021/ol801230k. PMID 18656947.