Tetrazole Explained

Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen atoms and one carbon atom. The name tetrazole also refers to the parent compound with formula CH2N4, of which three isomers can be formulated.

Structure and bonding

Three isomers of the parent tetrazole exist, differing in the position of the double bonds: 1H-, 2H-, and 5H-tetrazole. The 1H- and 2H- isomers are tautomers, with the equilibrium lying on the side of 1H-tetrazole in the solid phase.[1] [2] [3] In the gas phase, 2H-tetrazole dominates.[2] [4] [5] These isomers can be regarded as aromatic, with 6 π-electrons, while the 5H-isomer is nonaromatic.

Phosphorus analogs do not have the same electronic nature, with 1H-tetraphosphole having a more pyramidal geometry of the phosphorus at position 1. Instead, it is the anionic tetraphospholides that are aromatic.[6]

Strongly inductively electron-withdrawing functional groups attached to a tetrazole may stabilize a tautomeric ring-opening equilibrium with an azidoimine form.[7]

Synthesis

1H-Tetrazole was first prepared by the reaction of anhydrous hydrazoic acid and hydrogen cyanide under pressure. Treatment of organic nitriles with sodium azide in the presence of iodine or silica-supported sodium bisulfate as a heterogeneous catalyst enables an advantageous synthesis of 5-substituted 1H-tetrazoles. Another method is the deamination of 5-aminotetrazole, which can be commercially obtained or prepared in turn from aminoguanidine.[8] [9]

2-Aryl-2H-tetrazoles are synthesized by a [3+2] cycloaddition reaction between an aryl diazonium and trimethylsilyldiazomethane.[10]

Uses

There are several pharmaceutical agents which are tetrazoles, including several cephalosporin-class antibiotics. Tetrazoles can act as bioisosteres for carboxylate groups because they have similar pKa and are deprotonated at physiological pH. Angiotensin II receptor blockers — such as losartan and candesartan, often are tetrazoles.A well-known tetrazole is dimethyl thiazolyl diphenyl tetrazolium bromide (MTT). This tetrazole is used in the MTT assay to quantify the respiratory activity of live cells culture, although it generally kills the cells in the process. Some tetrazoles can also be used in DNA assays.[11] Studies suggest VT-1161 and VT-1129 are a potential potent antifungal drugs as they disturbs fungal enzymatic function but not human enzymes.[12] [13]

Some tetrazole derivatives with high energy have been investigated as high performance explosives as a replacement for TNT and also for use in high performance solid rocket propellant formulations.[14] [15] These include the azidotetrazolate salts of nitrogen bases.

Other tetrazoles are used for their explosive or combustive properties, such as tetrazole itself and 5-aminotetrazole, which are sometimes used as a component of gas generators in automobile airbags. Tetrazole based energetic materials produce high-temperature, non-toxic reaction products such as water and nitrogen gas,[16] and have a high burn rate and relative stability,[17] all of which are desirable properties. The delocalization energy in tetrazole is 209 kJ/mol.

1H-Tetrazole and 5-(benzylthio)-1H-tetrazole (BTT) are widely used as acidic activators of the coupling reaction in oligonucleotide synthesis.[18]

2-Tetrazoles can undergo controlled thermal decomposition to form highly reactive nitrilimines.[19] [20] These can in turn undergo a variety of 1,3-dipolar cycloaddition reactions.[21]

Related heterocycles

Notes and References

  1. Goddard. R.. Heinemann. O.. Krüger. C.. 1997-05-15. α-1H-1,2,3,4-Tetrazole. Acta Crystallographica Section C. en. 53. 5. 590–592. 10.1107/S0108270197000772. 1997AcCrC..53..590G . 0108-2701.
  2. Kiselev. Vitaly G.. Cheblakov. Pavel B.. Gritsan. Nina P.. 2011-03-10. Tautomerism and Thermal Decomposition of Tetrazole: High-Level ab Initio Study. The Journal of Physical Chemistry A. 115. 9. 1743–1753. 10.1021/jp112374t. 21322546. 2011JPCA..115.1743K. 1089-5639.
  3. Razynska, A.; Tempczyk, A.; Malinski, E.; Szafranek, J.; Grzonka, Z.; Hermann, P.: in J. Chem. Soc. Perkin Trans. 2 1983, 379.
  4. Wong. Ming Wah. Leung-Toung. Regis. Wentrup. Curt. 1993-03-01. Tautomeric equilibrium and hydrogen shifts of tetrazole in the gas phase and in solution. Journal of the American Chemical Society. 115. 6. 2465–2472. 10.1021/ja00059a048. 0002-7863.
  5. Rażyńska. Anna. Tempczyk. Anna. Maliński. Edmund. Szafranek. Janusz. Grzonka. Zbigniew. Hermann. Peter. 1983-01-01. Application of mass spectrometry to the study of prototropic equilibria in 5-substituted tetrazoles in the gas phase; experimental evidence and theoretical considerations. Journal of the Chemical Society, Perkin Transactions 2. en. 3. 379–383. 10.1039/P29830000379. 1364-5471.
  6. Encyclopedia: Science of Synthesis . 13: Category 2, Hetarenes and Related Ring Systems . Product Class 24: Tetraphospholes . S. J. . Collier . R. C. . Storr . T. L. . Gilchrist . Thieme . 2004 . 10.1055/sos-SD-013-01194 . 978-3-13-112281-0 .
  7. Burke, Luke A. (25 April 1983). "Possible cause for 5‑trichloromethyl­tetrazole explosion" (letter to the editor), Chemical & Engineering News. p. 2. ; but see Beck, Wolfgang and Geisenberger, Josef (5 Mar 1984). "5‑Trichloromethyl­tetrazole", Ibid. p. 39., which indicates that the trichloromethyl derivative does not exhibit such an equilibrium.
  8. Henry. Ronald A.. Finnegan. William G.. 1954-01-01. An Improved Procedure for the Deamination of 5-Aminotetrazole. Journal of the American Chemical Society. 76. 1. 290–291. 10.1021/ja01630a086. 0002-7863.
  9. Kurzer. F.. Godfrey. L. E. A.. 1963. Syntheses of Heterocyclic Compounds from Aminoguanidine. Angewandte Chemie International Edition in English. en. 2. 8. 459–476. 10.1002/anie.196304591. 1521-3773.
  10. Patouret. Remi. Kamenecka. Theodore M.. 2016-04-06. Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction. Tetrahedron Letters. 57. 14. 1597–1599. 10.1016/j.tetlet.2016.02.102. 4810784. 27041776.
  11. Nucleic Acids Res . Feb 11, 1989 . 17 . 3 . 853–864 . Studies on the role of tetrazole in the activation of phosphoramidites . S Berner . K Mühlegger . H Seliger . amp . 331708 . 10.1093/nar/17.3.853 . 2922273.
  12. Warrilow . A. G. S. . Hull . C. M. . Christina M. Hull. Parker . J. E. . Garvey . E. P. . Hoekstra . W. J. . Moore . W. R. . Schotzinger . R. J. . Kelly . D. E. . Kelly . S. L. . The Clinical Candidate VT-1161 Is a Highly Potent Inhibitor of Candida albicans CYP51 but Fails To Bind the Human Enzyme . Antimicrobial Agents and Chemotherapy . December 2014 . 58 . 12 . 7121–7127 . 10.1128/AAC.03707-14. 4249504 . 25224009.
  13. Lockhart . Shawn R. . Fothergill . Annette W. . Iqbal . Naureen . Bolden . Carol B. . Grossman . Nina T. . Garvey . Edward P. . Brand . Stephen R. . Hoekstra . William J. . Schotzinger . Robert J. . Ottinger . Elizabeth . Patterson . Thomas F. . Wiederhold . Nathan P. . The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates Potent Activity against Cryptococcus neoformans and Cryptococcus gattii . Antimicrobial Agents and Chemotherapy . April 2016 . 60 . 4 . 2528–2531 . 10.1128/AAC.02770-15. 4808209 . 26787697.
  14. Web site: Greener explosives show promise . 2 October 2008 . Chemistry World.
  15. New Energetic Materials featuring Tetrazoles and Nitramines – Synthesis, Characterization and Properties . Niko Fischer. Konstantin Karaghiosoff. Thomas M. Klapötke. Jörg Stierstorfer . Zeitschrift für Anorganische und Allgemeine Chemie . 636 . 5 . 735–749 . April 2010 . 10.1002/zaac.200900521.
  16. Book: Energetic Tetrazole N-oxides . Tore Brinck, Thomas M. Klapötke and Jörg Stierstorfer . Energetic Tetrazole N -oxides. 10.1002/9781118676448.ch06 . Green Energetic Materials . 133–178. 2014 . 9781118676448 .
  17. Decomposition of Aminotetrazole Based Energetic Materials under High Heating Rate Conditions . Nicholas Piekiel . Michael R. Zachariah . amp . J. Phys. Chem. A . 2012 . 116 . 6 . 1519–1526 . 10.1021/jp203957t. 22214278 . 2012JPCA..116.1519P.
  18. Coupling activators for the oligonucleotide synthesis via phosphoramidite approach . Xia Wei . Tetrahedron . 69 . 18 . 3615–3637 . May 6, 2013 . 10.1016/j.tet.2013.03.001 .
  19. Huisgen . Rolf . Seidel . Michael . Sauer . Juergen . McFarland . James . Wallbillich . Guenter . Communications: The Formation of Nitrile Imines in the Thermal Breakdown of 2,5-Disubstituted Tetrazoles . The Journal of Organic Chemistry . June 1959 . 24 . 6 . 892–893 . 10.1021/jo01088a034.
  20. Bertrand . Guy . Wentrup . Curt . Nitrile Imines: From Matrix Characterization to Stable Compounds . Angewandte Chemie International Edition in English . 17 March 1994 . 33 . 5 . 527–545 . 10.1002/anie.199405271.
  21. Huisgen . Rolf . 1,3-Dipolar Cycloadditions. Past and Future . Angewandte Chemie International Edition in English . October 1963 . 2 . 10 . 565–598 . 10.1002/anie.196305651.

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