Sodium Azide1

NaN3

[26628-22-8]  · N3Na  · Sodium Azide  · (MW 65.02)

(nucleophilic azide source for organoazide preparation;2 precursor to reagents such as hydrazoic acid,3 halogen azides,4 trimethylsilyl azide,5 tosyl azide,6 and diphenyl phosphorazidate7)

Physical Data: dec ca. 300 °C; d 1.850 g cm-3.

Solubility: sol water (39 g/100 g at 0 °C, 55 g/100 g 100 °C); slightly sol alcohol; insol ether.

Form Supplied in: white solid; widely available.

Handling, Storage, and Precautions: while relatively insensitive to impact, the solid can decompose explosively above its melting point. It forms highly explosive azides with metals such as Cu, Pb, Hg, Ag, Au, their alloys and compounds, and reacts with acids to form hydrazoic acid (HN3) which is a toxic, spontaneously explosive gas. Explosive gem-diazides can be formed in CH2Cl2 or other chlorinated solvents and shock or heat sensitive metal azidothioformates in CS2. All work with NaN3 and other azides should be conducted on a very small scale behind a shield, in a fume hood. Excess NaN3 on flasks, paper, etc. can be destroyed in a fume hood by soaking with acidified Sodium Nitrite or by oxidation with Cerium(IV) Ammonium Nitrate.8

Introduction.

The reaction of NaN3 with I2 (releasing N2) is catalyzed by thiols and thiones and this has been used as a spot test for such compounds.9 NaN3 has been used to assess the interactions between charged sites in myoglobin.10

Preparation of Organic Azides.

Organic azides can be reduced readily to amines, utilized for amine, azide or diazo transfer, act as nitrene or nitrenium precursors, and undergo Curtius and Schmidt rearrangements, cycloadditions and Staudinger reactions.1b They are prepared most often by nucleophilic displacement of a leaving group by azide ion (commonly NaN3) (eq 1). Various leaving groups have been used, including halides, sulfonates (mainly OTs, OMs, or OTf, although brosylates11 and nosylates12 have been employed), sulfites,13 and anhydrides.14 Displacement of allylic acetates (and related species),15 with Tetrakis(triphenylphosphine)palladium(0) as catalyst, and groups such as nitro,16 phosphine sulfides (from thiaphosphonium species),17 and phenylseleninates18 has been reported.

Eliminative azidation to form a-azidovinyl ketones occurs on NaN3 treatment of some dibromo ketones (eq 2).19 This approach also works well for the preparation of a-azidostyrenes from styrene.20 Usually, gem-dihalo compounds react with NaN3 to give gem-diazides;21 however, an unusual nitrile formation has been reported (eq 3) under these conditions.22 An interesting, stereospecific, solvent-dependent, azide-induced ring opening reaction of a dioxaphospholane has been observed (eq 4).23

Displacements can occur at the carbon atom of alkyl (primary, or secondary; tertiary requires Zinc Chloride or Zinc Iodide catalysis24), allyl, benzyl, acyl,25 activated vinyl,26 aryl,27 or heteroaryl28 species, and aryl diazonium salts (ArN2+, from ArNH2/HNO2),29 or at the heteroatom of, amongst others, organosulfonyl, silyl and phosphoryl halides. Of the latter, p-Toluenesulfonyl Azide (PTSN3),6 Azidotrimethylsilane (TMSN3),5 and Diphenyl Phosphorazidate, (PhO)2P(O)N3 (DPPA),7 are the most common and the last two are commercially available.

Nucleophilic azide ion displacements are enhanced by polar, aprotic solvents (e.g. DMSO) with which high yield, aryl halide displacement to form even mononitrophenyl azides can occur.27 Phase-transfer catalysis30 (permitting the use of less polar solvents) or ultrasonication (for activated primary halides)31 has also been used. Under such conditions, SN2 inversion of configuration occurs and this has been observed also for alcohols under Mitsunobu conditions (Triphenylphosphine, Diethyl Azodicarboxylate, HN3).32 Retention is possible where a neighboring group is present.33

Tertiary alcohols are converted directly to azides using NaN3/Sulfuric Acid or HN3/Boron Trifluoride or Titanium(IV) Chloride (eq 5),34 and the carboxylic acid to acyl azide transformation (often en route to Curtius rearrangements to isocyanates) occurs with DPPA7,1b or via activation with DMF/Thionyl Chloride.35

NaN3 reacts with epoxides at 25-30 °C (pH 6-7) to give azido alcohols.36 Usually, inversion of stereochemistry takes place and attack at the least hindered site is preferred. The regio- and stereoselectivity of the reaction can often be enhanced by using TMSN3 with a Lewis acid.37 High selectivity was shown by NaN3 on a calcium cation-exchanged Y-type zeolite (CaY) (eq 6),38 but less so with NaN3 on silica or alumina or the NaN3/NH4Cl system. NaN3/ZnCl2 gave lower yields than TMSN3/BF3.OEt2 for the ring opening of 1,2-epoxysilanes;39a selective azide opening at the site of silyl substitution has been reported.39b With a PhSO2 group attached to the epoxide, azidation-elimination occurs to form the corresponding azidoaldehydes.40 Reaction of the epoxy ester (1) with NaN3 under more vigorous conditions gave (2) in 60% yield (eq 6).41

Hydrazoic acid (HN3; NaN3/H+) reacts with alkenes to form azidoalkanes.42 Alkenes bearing a phenyl group or two geminal alkyl groups require a Lewis acid (TiCl4 is best). Mono- or 1,2-dialkyl alkenes do not react and Michael additions occur with a,b-unsaturated alkenes.26b Enol ethers and silylenol ethers give azido ethers42 and a similar process occurs with Trifluoroacetic Acid catalysis43 or from acetals44 or aldehydes with TMSN3.43 Interestingly, TiCl4-catalyzed HN3 addition to silyl enol ethers in the presence of primary or secondary alcohols gives the azido ethers shown (eq 7).42 Recently, it has been found that (3) reacts with NaN3/CAN to form the a-azido ketone (4) (eq 8).45

Other oxidative double bond azidations have been reported. Thus an azidohydrin was formed from pregnenolone acetate and chromyl azide (NaN3, Chromium(VI) Oxide)46 and steroidal dienones reacted with TMSN3/Lead(IV) Acetate47 to give diazido compounds. Vicinal diazides also result from alkenes and FeIII,48 Manganese(III) Acetate (eq 9),49 or Iodosylbenzene and NaN3.50 Anti-Markovnikov selenoazido products were prepared from the reaction of azide ion with alkenes and (Diacetoxyiodo)benzene/Diphenyl Diselenide (eq 10);51 a-keto azides (with TMSN3) are formed without PhSeSePh.52

Azide ion (or congener) attack upon nonconjugated alkenes is aided by the use of Dimethyl(methylthio)sulfonium Tetrafluoroborate.53 Trans products are obtained and, in general, the amount of anti-Markovnikov product increases with increased azide nucleophilicity, and vice versa. Monosubstituted alkenes favor anti-Markovnikov addition, whereas the opposite occurs with trisubstitution. 1,1-Disubstituted alkenes can give either orientation.

Schmidt Reactions.54

This term is used for several transformations, general examples of which are shown in eqs 11 and 12. The former is used infrequently due to the drastic conditions required compared to the analogous Curtius and Hoffmann rearrangements and the discovery that DPPA effects the transformation under mild conditions.7,1b TMSN3 has been used frequently.

The ketone to amide transformation (eq 12) is still of considerable utility (with the provisos regarding the hazards associated with HN3) and various acids have been employed, including H2SO4 (the most common), Polyphosphoric Acid, and Methanesulfonic Acid. With an unsymmetrical ketone a mixture of amide products can result although preferential migration of an aryl group (over alkyl) has been reported. In one case, the amount of aryl migration product (6) (R = H, 75%) was greater (80%) starting from the 7-nitroketone (5) (R = NO2) and lower (70%) from the 7-amino species (5) (R = NH2) (eq 13).55 Aldehydes usually give nitriles under Schmidt conditions.56

Curtius Reaction.57

The Curtius reaction involves conversion of an acid chloride (or anhydride) to an isocyanate (eq 14). Trapping of the isocyanate is possible in the presence of a nucleophile. Some cyclic anhydrides react to give isocyanates which can cyclize subsequently.

Preparation of Heterocycles.

As mentioned, heterocycles can be obtained via Schmidt or Curtius reactions. In addition, organic azides react with alkenes to form triazolines (triazoles from alkynes), aziridines, or other heterocycles.58 In situ triazoline generation and subsequent cleavage can lead to other heterocycles (see eq 15).59 Reaction of NaN3 with other a,b-unsaturated alkenes (or alkynes) provides different heterocycles dependent on the substituents. Such reactions are too numerous to mention in detail and only selected examples are shown in eqs 16-18.60-62

A useful tetrazole preparation is the addition of NaN3 (under acidic conditions) to nitriles.63 Similar processes occur with Tri-n-butyltin Azide or TMSN3.64

Related Reagents.

Azidotrimethylsilane; N-Bromosuccinimide-Sodium Azide; Hydrazoic Acid.


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Kenneth Turnbull

Wright State University, Dayton, OH, USA



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