Organic azide

 ( Functional Groups ) 

An organic azide is an organic compound that contains an azide (–) functional group. Because of the hazards associated with their use, few azides are used commercially although they exhibit interesting reactivity for researchers. Low molecular mass azides are considered especially hazardous and are avoided. In the research laboratory, azides are precursors to . They are also popular for their participation in the "click reaction" between an azide and an alkyne and in Staudinger ligation. These two reactions are generally quite reliable, lending themselves to combinatorial chemistry.

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History Phenyl azide ("diazoamidobenzol"), was prepared in 1864 by Peter Griess by the reaction of ammonia and phenyldiazonium. In the 1890s, Theodor Curtius, who had discovered hydrazoic acid (), described the rearrangement of acyl azides to isocyanates subsequently named the Curtius rearrangement. Rolf Huisgen described the eponymous 1,3-dipolar cycloaddition.

The interest in azides among organic chemists has been relatively modest due to the reported instability of these compounds.

The situation has changed dramatically with the discovery by Sharpless et al. of Cu-catalysed (3+2)-cycloadditions between organic azides and terminal alkynes. The azido- and the alkyne groups are "bioorthogonal", which means they do not interact with living systems, and at the same time they undergo an impressively fast and selective coupling. This type of formal 1,3-dipolar cycloaddition became the most famous example of so-called "click chemistry" (perhaps, the only one known to a non-specialist), and the field of organic azides exploded.

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Preparation Myriad methods exist, most often using preformed azide-containing reagent.

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Alkyl azides

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By halide displacement As a pseudohalide, azide generally displaces many leaving group, e.g. , , , sulfonate, and others to give the azido compound. The azide source is most often sodium azide (), although lithium azide () has been demonstrated.

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From alcohols Aliphatic alcohols give azides via a variant of the Mitsunobu reaction, with the use of hydrazoic acid. Hydrazines may also form azides by reaction with sodium nitrite: Alcohols can be converted into azides in one step using 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP) or under Mitsunobu conditions with diphenylphosphoryl azide (DPPA).

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From epoxides and aziridines

Trimethylsilyl azide , and tributyltin azide , have all been used, including enantioselective modifications of the reaction are also known. Aminoazides are accessible by the epoxide and aziridine ring cleavage, respectively.

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From amines

The diazo transfer compounds, trifluoromethanesulfonyl azide and imidazole-1-sulfonyl azide, react with amines to give the corresponding azides. Diazo transfer onto amines using trifluoromethanesulfonyl azide () and Tosyl azide () has been reported.

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Hydroazidation

Hydroazidation of has been demonstrated

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Aryl azides

Aryl azides may be prepared by displacement of the appropriate diazonium salt with sodium azide or trimethylsilyl azide. Nucleophilic aromatic substitution is also possible, even with chlorides. Aniline and aromatic hydrazines undergo diazotization, as do alkyl amines and hydrazines.

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Acyl azides

Alkyl or aryl react with sodium azide in aqueous solution to give , which give isocyanates in the Curtius rearrangement.

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Dutt–Wormall reaction

A classic method for the synthesis of azides is the Dutt–Wormall reaction in which a diazonium salt reacts with a sulfonamide first to a diazoaminosulfinate and then on hydrolysis the azide and a sulfinic acid. Name Reactions: A Collection of Detailed Reaction Mechanisms by Jie Jack Li Published 2003 Springer

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Reactions

Organic azides engage in useful . The terminal nitrogen is mildly nucleophilic. Generally, nucleophiles attack the azide at the terminal nitrogen N_γ, while electrophiles react at the internal atom N_α.

(2025). 9780470682524, John Wiley. . ISBN 9780470682524

Azides easily extrude diatomic nitrogen, a tendency that is exploited in many reactions such as the Staudinger ligation or the Curtius rearrangement.

(1971). 9780470771266 ISBN 9780470771266

Azides may be reduced to by hydrogenolysis or with a phosphine (e.g., triphenylphosphine) in the Staudinger reaction. This reaction allows azides to serve as protected -NH₂ synthons, as illustrated by the synthesis of 1,1,1-tris(aminomethyl)ethane:

In the azide alkyne Huisgen cycloaddition, organic azides react as 1,3-dipoles, reacting with to give substituted 1,2,3-triazoles.

Some azide reactions are shown in the following scheme. Probably the most famous is the reaction with , which leads to iminophosphoranes 22; these can be hydrolysed into primary amines 23 (the Staudinger reaction), react with carbonyl compounds to give imines 24 (the aza-Wittig reaction), or undergo other transformations. Thermal decomposition of azides gives nitrenes, which participate in a variety of reactions; vinyl azides 19 decompose into 2H-azirines 20. Alkyl azides with low nitrogen-content (( nC + nO) / nN ≥ 3) are relatively stable and decompose only above ca. 175 °C.

(1971). 9780470771266, Interscience Publishers. . ISBN 9780470771266

Direct photochemical decomposition of alkyl azides leads almost exclusively to (e.g. 25 and 26). It is proposed that the azide group is promoted to the singlet excited state and then undergoes concerted rearrangement without the intermediacy of nitrenes. The presence of triplet sensitisers, however, may change the reaction mechanism and result in the formation of triplet nitrenes. The latter were observed directly by ESR spectroscopy at −269 °C as well as inferred in some photolyses. Triplet methyl nitrene is 31 kJ/mol more stable than its singlet form, and thus is most likely the ground state.

The (3+2)-cycloaddition of azides to double or triple bonds is one of the most utilised in organic chemistry and affords (e.g. 17) or , respectively.

(2025). 9780471280613, Wiley. . ISBN 9780471280613

The uncatalysed reaction is a concerted pericyclic process, in which the configuration of the alkene component is transferred to the triazoline product. The Woodward–Hoffmann denomination is π4s+π2s and the reaction is symmetry-allowed. According to Sustmann, this is a Type II cycloaddition, which means the two HOMOs and the two LUMOs have comparable energies, and thus both electron-withdrawing and electron-donating substituents may lead to an increase in the reaction rate. The reaction is generally free from significant solvent effects because both the reactants and the transition state (TS) are non-polar.

Another azide regular is tosyl azide here in reaction with norbornadiene in a nitrogen insertion reaction:

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Applications Some azides are valuable as bioorthogonal chemical reporters, molecules that can be "clicked" to see the metabolic path it has taken inside a living system.

The antiviral drug zidovudine (AZT) contains an azido group.

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Additional sources

• (1971). 9780470771266, John Wiley & Sons, Ltd.. . ISBN 9780470771266
• Eric F. Scriven9780124143074, Academic Press. ISBN 9780124143074
• (2002). 9780471387268, John Wiley & Sons, Inc.. . ISBN 9780471387268
• Wolff, H. Org. React. 1946, 3, 337–349.

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External links

• Synthesis of organic azides, recent methods
• Synthesizing, Purifying, and Handling Organic Azides

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