Since the first preparation of organic azides, precisely phenyl azides, by Peter Grieß almost 160 years ago, this discovery has aroused an enormous interest in the scientific community.^[1-2] A few years later, other benchmarks in azide chemistry were set with the discovery of the Curtius rearrangement in 1894^[3-4] and the first proposal of nitrenes as reaction intermediates by Tiemann in 1891.^[5] It was not until the 1950s that organic azides retrieved considerable attention again. Since then, numerous novel syntheses of organic azides and transformations of azide derivatives have been reported. Organic azides gained an increasingly strong and significant role in organic synthesis, due to their outstanding chemical properties.^[6-7]

The azide group comprises a remarkable chemical reactivity, which is ascribed to the exceptional leaving group ability of molecular nitrogen. Whether acting as electrophiles, nucleophiles or as radical acceptors, azides are a highly versatile family of compounds suitable for various reaction pathways involving highly reactive generated intermediates.^{[6, 8]}

The intriguing synthetic chemistry of organic azides has been surveyed in several reviews. Therein, either their synthesis routes and the fundamental mechanisms, their function as precursors for the formed products, their advances based on their three reactivity patterns or their applications were brought into focus.^[6-11]

Besides the above mentioned Curtius rearrangement, the most prominent reactions employing organic azides are the regioselective copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), the Staudinger reduction and ligation, the aza-Wittig reaction, the Mitsunobu reaction and the Schmidt rearrangement. This small selection already indicates the versatility of the synthetic azide chemistry, which provides a basis for a wide applicability of these energy-rich molecules. Organic azides find applications as blowing agents, as functional groups in pharmaceuticals, in natural product synthesis, in photaffinity labelling, and in the field of high-energy materials. These versatile molecules have undertaken a key role at the interface between chemistry, biology, medicine, and materials science.^[6]

Safety hazards - general remarks

Azides are an interesting class of 1,3-dipoles, which can be used to synthesize a wide range of nitrogen-containing compounds. However, azides have certain hazardous properties. Therefore, one should be familiar with the risks and several safety precautions should be made. The most important safety instructions and measures for the use of azido compouns are:^[12]

• Use a safety shield
• Keep the screen of the fumehood closed during critical operations like heating, etc.
• Work with small scales
• Keep hazardous azides in solution as long as possible, most explosives are normally desensitized in solution
• Avoid contact to metals, e.q. metal spatulas
• Keep the toxicity of azides in mind

Hydrazoic acid and Sodium Azide

Hydrazoic acid is a highly toxic, volatile liquid, which tends to spontaneous explosion. HN₃ can be released by acidifying the metal salts. Uncontrolled release should be avoided. The handling of HN₃ in lab scale should carried out in water solution or in organic solvents.^[12]

The metal salts of hydrazoic acid from lead, copper or other heavy metals are shock and pressure sensitive compounds. More stable in terms of handling are alkali metal azides, which are often not considered as explosives under the most laboratory conditions.^[12-13] However, sodium azide is thermally unstable and decomposes rapidly, when exposed to strong heat. For this reason, it is used as a detonator in airbags. The vehicle sends an electrical charge, whereby the sodium azide will be heated to high temperature, which causes the rapid release of nitrogen. However, the initiation is difficult so that the explosion hazard is unlikely in the laboratory. Nevertheless, care should be taken when working with sodium azide as it reacts violently with various common laboratory organics for example CS₂ or bromine.^[6] Furthermore, chlorinated solvents like dichloromethane or chloroform should never be used due to the formation of highly explosive azidomethanes.^[14-15]

Due to the high toxicity of sodium azide, the absorption through the skin or ingestion orally should be avoided. Azides form strong complexes with haemoglobin leading to blockage of oxygen transport in the blood. In terms of toxicity, the azide ion can be compared to the toxicity of cyanide ions.^[16-17]

Organic Azides

The stability of organic azides depends on their chemical structure. To describe the stability, rules were established that consider the number of energetic functionalities. In addition to these rules, one should keep in mind that azides with a higher molecular mass are less volatile which reduces their potential hazard. Furthermore, aliphatic azides are much more stable and less dangerous than molecules with olefinic, aromatic or carbonyl moieties next to the azide group.

1) C/N-ratio

The rule for organic azides to be manipulable or non-explosive is that the number of nitrogen atoms must not exceed that of carbon and that (N_C + N_O)/N_N ≥ 3 (N = Number of atoms). It should be noted that all nitrogen atoms, not only those of the azido group, are counted in the equation.

 A C/N-ratio between 3 and 1 indicates a high instability, such azides should be synthesized in small amounts and stored carefully below room temperature and in the dark. Furthermore, storage should be in solutions with not more than 1M and less than 5 grams.

Organic azides with C/N-ratio < 1 should never be isolated.^[6]

2) “Rule of Six”

Another method of describing the stability is the rule of six, which says that there should be no less than six carbons per energetic functional group. Six carbons (or other atoms of about the same size) per energetic functional group (azide, diazo, nitro, etc.) make the compound relatively safe to use. Having less than six carbons per functional group can result in the material being explosive.^[18]

Overview of azide handling:

Safely Scaling Up Azide Chemistry (acs.org)

Scale-up of Azide Chemistry: A Case Study | Organic Process Research & Development (acs.org)

Azide safety (ucsb.edu)

Information on Azide Compounds – Stanford Environmental Health & Safety

SafeHandlingOfSodiumAzide.pdf (wisc.edu)

Microsoft Word - 04-028 Guidelines for the Safe Handling of Azides (pitt.edu)

Lab Safety Guideline: Sodium Azide (harvard.edu)

Sodium Azide Precautions (acs.org)

News around azides

E. Liu, J. Topczewski: Enantioselective Nickel-Catalyzed Alkyne–Azide Cycloaddition by Dynamic Kinetic Resolution. J. Am. Chem. Soc. 2021, 143, 14, 5308–5313. https://doi.org/10.1021/jacs.1c01354

W. Hu, C. Qi, X. Guo, A. Pang, N. Zhou, J. Lu, G. Tang, L. Gan, J. Huang: Alkynyl-functionalization of carbon nanotubes to promote anchoring potential in glycidyl azide polymer-based binders via Huisgen reaction for solid propellant application. J. Polym. Res. 2021, 28, 126. https://doi.org/10.1007/s10965-021-02468-3

Azra Kocaarslan,Gorkem Yılmaz,Gokhan Topcu,Levent Demirel,Yusuf Yagcı: A Novel Photoinduced Ligation Approach for Cross-Linking Polymerization, Polymer Chain-End Functionalization, and Surface Modification Using Benzoyl Azides. Macromol. Rapid Commun. 2021, 42, 2100166. https://doi.org/10.1002/marc.202100166

S. Vincenzo Giofrè, M. Tiecco, A. Ferlazzo, R. Romeo, G. Ciancaleoni, R. Germani, D. Iannazzo: Base-Free Copper-Catalyzed Azide-Alkyne Click Cycloadditions (CuAAc) in Natural Deep Eutectic Solvents as Green and Catalytic Reaction Media. Eur. J. Org. Chem. 2021, 4777–4789. https://doi.org/10.1002/ejoc.202100698

Publications

D. Huang, G. Yan, Recent Advances in Reactions of Azides, Adv.Synth. Catal. 2017, 359,1600 –1619. https://doi.org/10.1002/adsc.201700103

S. Chang, S. H. Lamm, Human Health Effects of Sodium Azide Exposure: A Literature Review and Analysis. Int. J. Toxicol. 2003, 22(3), 175-186. https://doi.org/10.1080/10915810305109

V. Rostovtsev, L. Green, V. Fokin, K. Barry Sharpless, A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41, No.14. https://doi.org/10.1002/1521-3773(20020715)41:14%3C2596::AID-ANIE2596%3E3.0.CO;2-4

C. Tornøe, C. Christensen, M. Meldal, Peptidotriazoles on Solid Phase:  [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem.2002, 67, 3057-3064. https://doi.org/10.1021/jo011148j

E. Saxon, C. R. Bertozzi: Cell Surface Engineering by a Modified Staudinger Reaction. Science 2000, 287(5460), 2007–2010. https://doi.org/10.1126/science.287.5460.2007

Reviews

Bunescu, A., Abdelhamid, Y. & Gaunt, M.J. Multicomponent alkene azido-arylation by anion-mediated dual catalysis. Nature (2021). https://doi.org/10.1038/s41586-021-03980-8

From our group 

M. Schock, S. Bräse, Reactive & Efficient: Organic Azides as Cross-Linkers in Material Sciences. Molecules 2020, 25, 1009. https://doi.org/10.3390/molecules25041009

S. Bräse, M. Mende, H. H. Jobelius, H.-D. Scharf, Ullmann’s Encycl. Ind. Chem., Wiley-VCH Verlag 2015, 1–11. https://doi.org/10.1002/14356007.a13_193.pub2

D. K. Kölmel, N. Jung, S. Bräse: Azides – Diazonium ions – Triazenes: Versatile nitrogen-rich functional groups. Austr. J. Chem. 2014, 67, 328-336. https://doi.org/10.1071/CH13533

N. Jung, S. Bräse: Click reactions: Azide-Alkyne Cycloaddition. Kirk-Othmer Encycl. Chem.Tech., John Wiley & Sons 2013, 1–43. https://doi.org/10.1002/0471238961.clicjung.a01

T. Muller, S. Bräse: Azides. Kirk-Othmer Encycl. Chem.Tech., John Wiley & Sons 2012, 1–21. https://doi.org/10.1002/0471238961.azidbras.a01

N. Jung, S. Bräse, Vinyl and Alkynyl Azides: Well-Known Intermediates in the Focus of Modern Synthetic Methods. Angew. Chem. Int. Ed. 2012, 51, 12169 –12171.

C. I. Schilling, N. Jung, M. B. Biskup, U. Schepers, S. Bräse: Bioconjugation via Azide-Staudinger Ligation - An Overview. Chem. Soc. Rev. 2011, 40, 4840 – 4871. https://doi.org/10.1039/C0CS00123F

O. Plietzsch, C. I. Schilling, T. Grab, S. L. Grage, A. S. Ulrich, A. Comotti, P. Sozzani, T. Muller, S. Bräse: Click chemistry produces hyper-cross-linked polymers with tetrahedral cores. New J. Chem. 2011, 35, 1577-1581. https://doi.org/10.1039/C1NJ20370C

S. Bräse, K. Banert: Organic Azides: Syntheses and Applications. John Wiley & Sons, Ltd, 2010.

C. Schilling, N. Jung, S. Bräse: Common Synthons for Click Chemistry in Biotechnology, in Click Chemistry for Biotechnology and Materials Science, J. Lahann (Ed.), Chap. 2, John Wiley & Sons 2009, 9-28.

C. Schilling, N. Jung, S. Bräse: Synthesis and Functionalization of Biomolecules via Click Chemistry, in Click Chemistry for Biotechnology and Materials Science, J. Lahann (Ed.), Chap. 15, John Wiley & Sons 2009, 355-378.

C. Schilling, N. Jung, S. Bräse, Cycloaddition Reactions with Azides: An Overview, in Organic Azides – Syntheses and Applications, S. Bräse, K. Banert (Ed.), John Wiley & Sons 2009, 269-284.

V. Zimmermann, B. Lesch, S. Bräse: Azidoalkanes. Science of Synthesis, Thieme Verlag, Stuttgart, 2009, Vol. 41.

S. Bräse, A. Friedrich, M. Gartner, T. Grab, T. Schröder: Cycloaddition Reactions of Azides, Topics in Heterocycl., Springer Verlag 2008, 12, 45-116.

S. Bräse, D. Keck: Aryl azides, in Science of Synthesis, Chap. 31.42, Thieme Verlag, Stuttgart, 2007.

S. Bräse, C. Gil, K. Knepper, V. Zimmermann: Organic Azides: An Exploding Diversity of a Unique Class of Compounds [Organische Azide: explodierende Vielfalt bei einer einzigartigen Substanzklasse]. Angew. Chem. 2005, 117, 5320–5374, 10.1002/angew.200400657; Angew. Chem. Int. Ed. 2005, 44, 5188–5240. https://doi.org/10.1002/anie.200400657

References

[1]         P. Grieß, Philos. Trans. R. Soc. London 1864, 13, 377-377.

[2]         P. Grieß, Justus Liebig Ann. Chem. 1865, 135, 131-131.

[3]         T. Curtius, Berichte der Deutschen Chemischen Gesellschaft zu Berlin 1890, 23, 3023-3033.

[4]         T. Curtius, J. für Prakt. Chemie 1894, 50, 275-294.

[5]         F. Tiemann, Ber. Dtsch. Chem. Ges. 1891, 24, 4162-4162.

[6]         S. Bräse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem. Int. Ed. 2005, 44, 5188-5240.

[7]         E. F. V. Scriven, Azides and Nitrenes: Reactivity and Utility, Academic Press, Inc., Orlando, Florida, 1984.

[8]         D. Huang, G. Yan, Adv. Synth. Catal. 2017, 359, 1600-1619.

[9]         D. K. Kölmel, N. Jung, S. Bräse, Vol. 67, 3 ed., pp. 328-336.

[10]       M. Schock, S. Bräse, Molecules 2020, 25.

[11]       B. Hu, S. G. Dimagno, Org.Biomol. Chem. 2015, 13, 3844-3844.

[12]       K. Banert, S. Bräse, Organic azides : syntheses and applications, 1. publ. ed., Wiley, Chichester, 2010.

[13]       J. M. M.E.C. Biffin, D.B. Paul, The Chemistry of the Azido group, Interscience Publishers, New York, USA, 1971.

[14]       R. E. Conrow, W. D. Dean, Org. Process Res. Dev. 2008, 12, 1285-1286.

[15]       K. Banert, Y.-H. Joo, T. Rüffer, B. Walfort, H. Lang, Tetrahedron Lett. 2010, 51, 2880-2882.

[16]       C. L. R. Smith, R. Kruszyna, H. Kruszyna, Fundam. Appl. Toxicol. 1991, 17, 120-127.

[17]       In the MAK-Collection for Occupational Health and Safety: Natriumazid [MAK VAlue Doc. Ger. Lang. 2003], Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2012.

[18]       H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004-2021.