Organic compounds containing the azide (N3) functional group
The azide functional group can be shown by two resonance structures.
An organic azide is an
organic compound that contains an azide (–N3 )
functional group .
[1] Because of the hazards associated with their use, few azides are used commercially although they exhibit interesting reactivity for researchers. Low
molecular weight azides are considered especially hazardous and are avoided. In the research laboratory, azides are precursors to
amines . 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 .
History
Phenyl azide ("diazoamidobenzol"), was prepared in 1864 by
Peter Griess by the reaction of ammonia and
phenyldiazonium .
[2]
[3] In the 1890s,
Theodor Curtius , who had discovered
hydrazoic acid (HN3 ), described the rearrangement of acyl azides to isocyanates subsequently named the
Curtius rearrangement .
[4]
Rolf Huisgen described the eponymous
1,3-dipolar cycloaddition .
[5]
[6]
The interest in azides among organic chemists has been relatively modest due to the reported
instability of these compounds.
[7] The situation has changed dramatically with the discovery by Sharpless et al. of Cu-catalysed (3+2)-cycloadditions between organic azides and terminal alkynes.
[8]
[9] 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 "
[10]
[11] (perhaps, the only one known to a non-specialist), and the field of organic azides exploded.
Preparation
Selected bond distances (picometers) and angles for phenyl azide.
[12]
Myriad methods exist, most often using preformed azide-containing reagent.
Alkyl azides
By halide displacement
As a
pseudohalide , azide generally displaces many leaving group, e.g. Br− , I− ,
Ts O− ,
sulfonate ,
[13]
[14] and others to give the azido compound.
[15] The azide source is most often
sodium azide (NaN3 ), although
lithium azide (LiN3 ) has been demonstrated.
From alcohols
Aliphatic alcohols give azides via a variant of the
Mitsunobu reaction , with the use of
hydrazoic acid .
[1] Hydrazines may also form azides by reaction with
sodium nitrite :
[16]
Alcohols can be converted into azides in one step using 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP)
[17] or under
Mitsunobu conditions
[18] with
diphenylphosphoryl azide (DPPA).
From epoxides and aziridines
Trimethylsilyl azide (CH3 )3 SiN3 , and
tributyltin azide (CH3 CH2 CH2 CH2 )3 SnN3 , have all been used,
[7] including
enantioselective
[19] modifications of the reaction are also known. Aminoazides are accessible by the epoxide and aziridine ring cleavage, respectively.
[20]
[21]
From amines
The azo-transfer compounds,
trifluoromethanesulfonyl azide and
imidazole-1-sulfonyl azide react with amines to give the corresponding azides. Diazo transfer onto amines using
trifluoromethanesulfonyl azide (
Tf N3 ) and
Tosyl azide (
Ts N3 ) has been reported.
[22]
Hydroazidation
Hydroazidation of
alkenes has been demonstrated
[23]
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 .
Anilines and
aromatic
hydrazines undergo
diazotization , as do
alkyl
amines and hydrazines.
[1]
PhNHNH2 +
NaNO2 →
PhN3 + NaOH + H2 O
Acyl azides
Alkyl or aryl
acyl chlorides react with
sodium azide in aqueous solution to give
acyl azides ,
[24]
[25] which give
isocyanates in the
Curtius rearrangement .
Dutt–Wormall reaction
A classic method for the synthesis of azides is the Dutt–Wormall reaction
[26] in which a
diazonium salt reacts with a
sulfonamide first to a diazoaminosulfinate and then on
hydrolysis the azide and a
sulfinic acid .
[27]
Reactions
Organic azides engage in useful
organic reactions . The terminal nitrogen is mildly nucleophilic. Generally, nucleophiles attack the azide at the terminal nitrogen Nγ , while electrophiles react at the internal atom Nα .
[28] Azides easily extrude diatomic
nitrogen , a tendency that is exploited in many reactions such as the Staudinger ligation or the
Curtius rearrangement .
[29]
Azides may be reduced to
amines by
hydrogenolysis
[30] 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 :
3 H2 + CH3 C(CH2 N3 )3 → CH3 C(CH2 NH2 )3 + 3 N2
In the
azide alkyne Huisgen cycloaddition , organic azides react as
1,3-dipoles , reacting with
alkynes to give substituted
1,2,3-triazoles .
Some azide reactions are shown in the following scheme. Probably the most famous is the reaction with
phosphines , which leads to iminophosphoranes 22; these can be hydrolysed into primary amines 23 (the
Staudinger reaction ),
[31] react with carbonyl compounds to give imines 24 (the aza-Wittig reaction),
[32]
[33]
[34] 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.
[28]
[35] Alkyl azides with low nitrogen-content ((n C + n O) / n N ≥ 3) are relatively stable and decompose only above ca. 175 °C.
[36]
Direct photochemical decomposition of alkyl azides leads almost exclusively to
imines (e.g. 25 and 26).
[28] 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.
[37]
[38] Triplet methyl nitrene is 31 kJ/mol more stable than its singlet form, and thus is most likely the ground state.
[28]
[39]
The (3+2)-cycloaddition of azides to double or triple bonds is one of the most utilised
cycloadditions in organic chemistry and affords
triazolines (e.g. 17) or
triazoles , respectively.
[40]
[41]
[42] 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.
[43]
[44] The reaction is generally free from significant solvent effects because both the reactants and the transition state (TS) are non-polar.
[45]
Another azide regular is
tosyl azide here in reaction with
norbornadiene in a nitrogen insertion reaction:
[46]
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.
Safety
Some organic azides are classified as highly explosive and toxic.
[47]
References
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This article incorporates
text by Oleksandr Zhurakovskyi available under the
CC BY 2.5 license.
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External links
Look up
azide or
azido- in Wiktionary, the free dictionary.
Salts and covalent derivatives of the
azide ion