Tetrazole

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.{{Cite journal|last1=Goddard|first1=R.|last2=Heinemann|first2=O.|last3=Krüger|first3=C.|date=1997-05-15|title=α-1H-1,2,3,4-Tetrazole|url=http://scripts.iucr.org/cgi-bin/paper?S0108270197000772|journal=Acta Crystallographica Section C|language=en|volume=53|issue=5|pages=590–592|doi=10.1107/S0108270197000772|bibcode=1997AcCrC..53..590G |issn=0108-2701|url-access=subscription}}{{Cite journal|last1=Kiselev|first1=Vitaly G.|last2=Cheblakov|first2=Pavel B.|last3=Gritsan|first3=Nina P.|date=2011-03-10|title=Tautomerism and Thermal Decomposition of Tetrazole: High-Level ab Initio Study|url=https://doi.org/10.1021/jp112374t|journal=The Journal of Physical Chemistry A|volume=115|issue=9|pages=1743–1753|doi=10.1021/jp112374t|pmid=21322546|bibcode=2011JPCA..115.1743K|issn=1089-5639|url-access=subscription}}Razynska, A.; Tempczyk, A.; Malinski, E.; Szafranek, J.; Grzonka, Z.; Hermann, P.: in J. Chem. Soc. Perkin Trans. 2 1983, 379. In the gas phase, 2H-tetrazole dominates.{{Cite journal|last1=Wong|first1=Ming Wah|last2=Leung-Toung|first2=Regis|last3=Wentrup|first3=Curt|date=1993-03-01|title=Tautomeric equilibrium and hydrogen shifts of tetrazole in the gas phase and in solution|url=https://doi.org/10.1021/ja00059a048|journal=Journal of the American Chemical Society|volume=115|issue=6|pages=2465–2472|doi=10.1021/ja00059a048|bibcode=1993JAChS.115.2465W |issn=0002-7863|url-access=subscription}}{{Cite journal|last1=Rażyńska|first1=Anna|last2=Tempczyk|first2=Anna|last3=Maliński|first3=Edmund|last4=Szafranek|first4=Janusz|last5=Grzonka|first5=Zbigniew|last6=Hermann|first6=Peter|date=1983-01-01|title=Application of mass spectrometry to the study of prototropic equilibria in 5-substituted tetrazoles in the gas phase; experimental evidence and theoretical considerations|url=https://pubs.rsc.org/en/content/articlelanding/1983/p2/p29830000379|journal=Journal of the Chemical Society, Perkin Transactions 2|language=en|issue=3|pages=379–383|doi=10.1039/P29830000379|issn=1364-5471|url-access=subscription}} These isomers can be regarded as aromatic, with 6 π-electrons, while the 5H-isomer is nonaromatic.

File:Tetrazole_Tautomerism_V.png

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.{{cite encyclopedia |title= Science of Synthesis |volume= 13: Category 2, Hetarenes and Related Ring Systems |chapter= Product Class 24: Tetraphospholes |first= S. J. |last= Collier |editor1-first= R. C. |editor1-last= Storr |editor2-first= T. L. |editor2-last= Gilchrist |publisher= Thieme |year= 2004 |doi= 10.1055/sos-SD-013-01194 |isbn= 978-3-13-112281-0 }}

Strongly inductively electron-withdrawing functional groups attached to a tetrazole may stabilize a tautomeric ring-opening equilibrium with an azidoimine form.Burke, Luke A. (25 April 1983). "Possible cause for 5-trichloromethyl­tetrazole explosion" (letter to the editor), Chemical & Engineering News. p. 2. {{doi|10.1021/cen-v061n017.p002|doi-access=free}}; but see Beck, Wolfgang and Geisenberger, Josef (5 Mar 1984). "5-Trichloromethyl­tetrazole", Ibid. p. 39. {{doi|10.1021/cen-v062n010.p002|doi-access=free}}, which indicates that the trichloromethyl derivative does not exhibit such an equilibrium.

1H-Tetrazole was first prepared by the reaction of anhydrous hydrazoic acid and hydrogen cyanide under pressure. A Pinner reaction of organic nitriles with sodium azide in the presence of a buffered strong acid (e.g. triethylammonium chloride) synthesizes 5-substituted 1H-tetrazoles cleanly.{{OrgSyn|prep=v85p0072|year=2008|volume=85|p=72|doi=10.15227/orgsyn.085.0072|title=(S)‑5‑Pyrrolidin-2‑yl-1H‑tetrazole|first1=Valentina|last1=Aureggi|first2=Vilius|last2=Franckevicius|first3=Matthew O.|last3=Kitching|first4=Steven V.|last4=Ley|author-link4=Steven Ley|first5=Deborah A.|last5=Longbottom|first6=Alexander J.|last6=Oelke|first7=Gottfried|last7=Sedelmeier}} Another method is the deamination of 5-aminotetrazole, which can be commercially obtained or prepared in turn from aminoguanidine.{{Cite journal|last1=Henry|first1=Ronald A.|last2=Finnegan|first2=William G.|date=1954-01-01|title=An Improved Procedure for the Deamination of 5-Aminotetrazole|url=https://doi.org/10.1021/ja01630a086|journal=Journal of the American Chemical Society|volume=76|issue=1|pages=290–291|doi=10.1021/ja01630a086|bibcode=1954JAChS..76..290H |issn=0002-7863|url-access=subscription}}{{Cite journal|last1=Kurzer|first1=F.|last2=Godfrey|first2=L. E. A.|date=1963|title=Syntheses of Heterocyclic Compounds from Aminoguanidine|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.196304591|journal=Angewandte Chemie International Edition in English|language=en|volume=2|issue=8|pages=459–476|doi=10.1002/anie.196304591|issn=1521-3773|url-access=subscription}}

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2-Aryl-2H-tetrazoles are synthesized by a [3+2] cycloaddition reaction between an aryl diazonium and trimethylsilyldiazomethane.{{Cite journal|last1=Patouret|first1=Remi|last2=Kamenecka|first2=Theodore M.|date=2016-04-06|title=Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction|journal=Tetrahedron Letters|volume=57|issue=14|pages=1597–1599|doi=10.1016/j.tetlet.2016.02.102|pmc=4810784|pmid=27041776}}

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.{{cite journal | journal = Nucleic Acids Res | date = Feb 11, 1989 | volume = 17 | issue = 3 | pages = 853–864 | title = Studies on the role of tetrazole in the activation of phosphoramidites |author1=S Berner |author2=K Mühlegger |author3=H Seliger |name-list-style=amp | pmc = 331708 | doi=10.1093/nar/17.3.853 | pmid=2922273}} Studies suggest VT-1161 and VT-1129 are a potential potent antifungal drugs as they disturbs fungal enzymatic function but not human enzymes.{{cite journal |last1=Warrilow |first1=A. G. S. |last2=Hull |first2=C. M. |authorlink2=Christina M. Hull|last3=Parker |first3=J. E. |last4=Garvey |first4=E. P. |last5=Hoekstra |first5=W. J. |last6=Moore |first6=W. R. |last7=Schotzinger |first7=R. J. |last8=Kelly |first8=D. E. |last9=Kelly |first9=S. L. |title=The Clinical Candidate VT-1161 Is a Highly Potent Inhibitor of Candida albicans CYP51 but Fails To Bind the Human Enzyme |journal=Antimicrobial Agents and Chemotherapy |date=December 2014 |volume=58 |issue=12 |pages=7121–7127 |doi=10.1128/AAC.03707-14|pmc=4249504 |pmid=25224009}}{{cite journal |last1=Lockhart |first1=Shawn R. |last2=Fothergill |first2=Annette W. |last3=Iqbal |first3=Naureen |last4=Bolden |first4=Carol B. |last5=Grossman |first5=Nina T. |last6=Garvey |first6=Edward P. |last7=Brand |first7=Stephen R. |last8=Hoekstra |first8=William J. |last9=Schotzinger |first9=Robert J. |last10=Ottinger |first10=Elizabeth |last11=Patterson |first11=Thomas F. |last12=Wiederhold |first12=Nathan P. |title=The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates Potent Activity against Cryptococcus neoformans and Cryptococcus gattii |journal=Antimicrobial Agents and Chemotherapy |date=April 2016 |volume=60 |issue=4 |pages=2528–2531 |doi=10.1128/AAC.02770-15|pmc=4808209 |pmid=26787697}}

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.{{cite web | url = http://www.rsc.org/chemistryworld/News/2008/October/02100801.asp | title = Greener explosives show promise | date = 2 October 2008 | publisher = Chemistry World}}{{cite journal | title = New Energetic Materials featuring Tetrazoles and Nitramines – Synthesis, Characterization and Properties | author1 = Niko Fischer|author2=Konstantin Karaghiosoff|author3=Thomas M. Klapötke|author4=Jörg Stierstorfer | journal = Zeitschrift für Anorganische und Allgemeine Chemie | volume = 636 | issue =5 | pages = 735–749 | date = April 2010 |doi = 10.1002/zaac.200900521| doi-access = }} 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,{{cite book | chapter = Energetic Tetrazole N-oxides | author = Tore Brinck, Thomas M. Klapötke and Jörg Stierstorfer | title = Energetic Tetrazole N -oxides| doi = 10.1002/9781118676448.ch06 | journal=Green Energetic Materials | pages=133–178| year = 2014 | isbn = 9781118676448 }} and have a high burn rate and relative stability,{{cite journal | title = Decomposition of Aminotetrazole Based Energetic Materials under High Heating Rate Conditions |author1=Nicholas Piekiel |author2=Michael R. Zachariah |name-list-style=amp | journal = J. Phys. Chem. A | date = 2012 | volume = 116 | issue = 6 | pages = 1519–1526 | doi = 10.1021/jp203957t|pmid=22214278 |bibcode=2012JPCA..116.1519P}} 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.{{cite journal | title = Coupling activators for the oligonucleotide synthesis via phosphoramidite approach | author = Xia Wei | journal = Tetrahedron | volume = 69 | issue = 18 | pages = 3615–3637 | date = May 6, 2013 |doi = 10.1016/j.tet.2013.03.001 }}

C,N substituted tetrazoles can undergo controlled thermal decomposition to form highly reactive nitrilimines.{{cite journal |last1=Huisgen |first1=Rolf |last2=Seidel |first2=Michael |last3=Sauer |first3=Juergen |last4=McFarland |first4=James |last5=Wallbillich |first5=Guenter |title=Communications: The Formation of Nitrile Imines in the Thermal Breakdown of 2,5-Disubstituted Tetrazoles |journal=The Journal of Organic Chemistry |date=June 1959 |volume=24 |issue=6 |pages=892–893 |doi=10.1021/jo01088a034}}{{cite journal |last1=Bertrand |first1=Guy |last2=Wentrup |first2=Curt |title=Nitrile Imines: From Matrix Characterization to Stable Compounds |journal=Angewandte Chemie International Edition in English |date=17 March 1994 |volume=33 |issue=5 |pages=527–545 |doi=10.1002/anie.199405271}} These can in turn undergo a variety of 1,3-dipolar cycloaddition reactions.{{cite journal |last1=Huisgen |first1=Rolf |title=1,3-Dipolar Cycloadditions. Past and Future |journal=Angewandte Chemie International Edition in English |date=October 1963 |volume=2 |issue=10 |pages=565–598 |doi=10.1002/anie.196305651}}

Image:Nitrilimine origin.png

• Triazoles, analogs with three nitrogen atoms
• Pentazole, the analog with five nitrogen atoms (strictly speaking, an inorganic homocycle, not a heterocycle)
• Oxatetrazole
• Thiatetrazole

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Category:Simple aromatic rings