Phenyl Azide1

PhN3

[622-37-7]  · C6H5N3  · Phenyl Azide  · (MW 119.14)

(reagent for the synthesis of 4,5-dihydro-1,2,3-triazolines, 1,2,3-triazoles, aziridines, and other heterocycles via 1,3-dipolar cycloaddition with alkenes, alkynes, and other unsaturated functional groups;2 allows measurement of the degree of strain present in alkenes and alkynes by their relative rates of dipolar cycloaddition;2a,3,4 converts organoboranes into N-alkylanilines;5 in combination with Lewis or protic acids, produces nitrenium ions or their equivalent, which react as electrophiles at nitrogen or aromatic carbon to produce substituted anilines;6,7 reagent for the synthesis of 2-hetero-3H-azepines by ring expansion;7,8 related aryl azides undergo the above reactions as well as thermally or photochemically induced intramolecular C-H insertions to produce a variety of nitrogen heterocycles;7-10 substituted aryl azides are commonly used in photoaffinity labeling;11 aryl azides act as electrophiles toward carbon, nitrogen, and phosphorus nucleophiles, leading to new N-C, N-N, and N-P bonds.1,8a,b,9)

Alternate Name: azidobenzene.

Physical Data: bp 49-50 °C/5 mmHg, 66-68 °C/21 mmHg.12

Solubility: freely sol common organic solvents; insol water, aqueous acids, and aqueous alkalis.

Form Supplied in: colorless to pale yellow oil; odor resembling benzaldehyde, benzonitrile, or nitrobenzene; not available commercially.

Analysis of Reagent Purity: the concentration of toluene solutions can be determined by an iodometric titration.13

Preparative Methods: diazotization of phenylhydrazine.12,14

Handling, Storage, and Precautions: phenyl azide is explosive. A blast shield should be used during its purification by distillation, and the temperature should be controlled as recommended.12,14 The pure substance may be stored in a brown glass bottle in a cool, dark place for up to a month. It is slowly discolored by light. It is often stored and used as a solution in ether or toluene. Doering's procedure results in material that has a longer shelf-life, due to the absence of traces of phenol.14 This reagent should only be handled in a fume hood.

Cycloaddition Reactions: Formation of Triazolines, Triazoles, Imines, and Aziridines.

The 1,3-dipolar cycloaddition of phenyl azide and other aryl azides with various p-systems is well known.2 Cycloaddition with alkenes initially produces triazolines, which may be isolated in many cases. However, triazolines are thermally sensitive and are often converted to other products (e.g. triazoles, aziridines, imines, and diazo compounds) under the conditions required for cycloaddition. While simple alkenes undergo sluggish cycloadditions with phenyl azide,2 strained alkenes can be quite reactive.2a,3,4 Since the original observations by Alder and Stein,3 phenyl azide has been used frequently to trap strained and reactive alkenes and alkynes. The relative rate of reaction of aryl azides with alkenes has been used to measure their relative strain energies.2,4 The reaction of trans-cyclooctene with trinitrophenyl azide serves to illustrate the types of products observed in such cycloadditions (eq 1).4 The initially formed triazoline fragments easily to a zwiterionic intermediate, which undergoes 1,2-shifts to give imines or direct closure to produce aziridines.

Conjugated dienes are sufficiently reactive to allow useful cycloadditions.2a Simple, unstrained alkenes can be used in intramolecular 1,3-dipolar cycloadditions with aryl azides (eq 2).2,15

Electron-poor alkenes and alkynes are excellent dipolarophiles.2a Aziridines or diazo compounds may be produced from electron-poor alkenes by fragmentation of the initially formed triazoline intermediate, depending on the exact nature of the electron-withdrawing group and the presence or absence of an adjacent hydrogen on the alkene. Eq 3 illustrates the efficient formation of an aziridine.16 The triazoline was observed by NMR when the cycloaddition was run at 40 °C. In contrast, the triazoline derived from the cycloaddition of phenyl azide with Methyl Acrylate was easily transformed to the a-diazoester with base (eq 4).17 Alternatively, the triazoline could be oxidized to a triazole. Cycloadditions with electron-poor alkynes are also facile, producing triazoles directly. For example, phenyl azide reacts with Dimethyl Acetylenedicarboxylate to produce a triazole,18 which was transformed into a bis(hydroxymethyl)triazole derivative for evaluati on as an antineoplastic agent (eq 5).19

Electron-rich alkenes and alkynes are also reactive dipolarophiles toward aryl azides.2a Enol ethers and enamines are particularly useful,20a providing an excellent route to 1,2,3-triazoles after loss of the alcohol or amine from the intermediate triazoline (eq 6).20

Generation of Nitrenes: C-H Insertion and Aziridination.

The thermal or photochemical decomposition of aryl azides to nitrenes has been an active area of research.7-10 Singlet nitrenes are produced initially, which may undergo insertion reactions. Triplet nitrenes may be produced by sensitized photolysis of aryl azides or by thermolysis in the presence of certain external agents. Triplet nitrenes often participate in hydrogen atom abstraction reactions. While the thermal and photochemical decomposition of phenyl azide has been well studied, intramolecular reactions of substituted aryl azides are the most synthetically useful. For example, the thermolysis of o-azidobiphenyl is an excellent method for the formation of carbazoles (eq 7).8c,d,21 This reaction is not a direct C-H insertion, since evidence for an intermediate other than the nitrene has been obtained. A likely mechanism is an intramolecular aziridination followed by rearrangement to the carbazole.

A recent application of aryl azides to natural product synthesis illustrates the complementary chemistry of singlet and triplet nitrenes (eq 8).22 Thermolysis led to pyridocarbazole formation via a singlet nitrene. Sensitized photolysis led to benzylic C-H insertion, presumably by hydrogen atom abstraction by a triplet nitrene followed by diradical combination. This route was used to make the natural product cystodytin A.

Indoles may be produced by formal C-H insertion of o-azidostyrenes (eq 9).23 If a heteroatom is suitably tethered, reaction with a nitrene may be observed, producing a variety of heterocycles (e.g. eq 10).24 A wide variety of unsaturated groups in the ortho position lead to heterocycle formation, including imines, azo groups, azides, carbonyl groups, amides, imides, and nitro groups.8a The photolysis and thermolysis of phenyl azide itself (or of aryl azides with no ortho substituents) is complex.7-10

One useful insertion reaction is the formation of 2-hetero-3H-azepines by photolysis of aryl azides in the presence of nucleophiles such as amines and alcohols (eq 11).25 A proposed mechanism for this reaction is ring expansion of the nitrene to a dehydroazepine followed by nucleophilic addition and tautomerization. Azides are commonly used to generate nitrenes for photoaffinity labeling investigations in biological experiments.11

Reaction with Electrophiles: Nitrenium Ions and Their Equivalents.

Although azides are weak Lewis bases, they may form complexes reversibly with protic acids or Lewis acids. Complexation at the most substituted nitrogen atom is preferred, which generates an electron-deficient nitrogen species which may undergo substitution or deazoniation.6,7,8a,b,9

Complexation of trialkylboranes, dialkylchloroboranes, or alkyldichloroboranes with phenyl azide (and other azides) leads to a 1,2-shift of an alkyl group to the electron-deficient nitrogen, producing anilines after hydrolysis (eq 12).5 Complexation of phenyl azide with Aluminum Chloride generates an electrophilic reagent which may react with alkenes to produce aziridines or addition products (eq 13).26

Protonation of aryl azides with strong acids followed by loss of nitrogen produces nitrenium ions, which are potent electrophiles at both the nitrogen atom and the ortho and para positions on the arene.6 Intermolecular reactions with arenes commonly produce diarylamines (eq 14),27 but C-arylation is a competing process.6 Other nucleophiles, such as sulfides, can be used in intermolecular reactions with nitrenium ions, producing o- and p-thioanilines.28 Intramolecular reactions of nitrenium ions with arenes (eq 15)29 or other nucleophiles (eq 16)29 are more chemoselective.6

Reactions with Nucleophiles.

The terminal nitrogen of aryl azides is moderately electrophilic.1,8a,b,9 Reactions with phosphines (the Staudinger reaction, eq 17),30,31 cyanide ion (eq 18),32 organometallic reagents (eq 19),8a,b,33 and amide anions (eq 20)34 produce a variety of adducts. The phosphazenes decompose rapidly to iminophosphoranes (eq 17), which are useful for the conversion of carbonyl compounds to imines (the aza-Wittig reaction).30 The cyanotriazenes (eq 18) are easily decomposed to anilines by alkali.32 The triazenes derived from organometallic compounds (eq 19) may be converted to anilines by reduction,33 although there are other azides which better fit this purpose.8a,b Dilithiotetrazenes (eq 20) have found use as ligands for transition metals, producing metallacyclotetraazapentadienes.34 Not shown is the use of metal hydrides to reduce aryl azides.8a,b

A particularly useful type of nucleophilic addition to azides is their reaction with the anions of active methylene compounds and related nucleophilic carbon species (the Dimroth reaction), leading to 1,2,3-triazoles.8a,35 An example with phenylacetonitrile is shown in eq 21.36 Intramolecular reactions of enolates and amide anions (e.g. eq 22) have also been reported, leading to cyclization with nitrogen loss.37


1. For a general overview of the use of azides as synthetic starting materials, see: Sheradsky, T. In The Chemistry of the Azido Group; Patai, S., Ed.; Wiley: New York, 1971; pp 331-395.
2. (a) Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 559-651. (b) For reviews of intramolecular 1,3-dipolar cycloaddition reactions that include aryl azides, see: Padwa, A.; Schoffstall, A. M. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich, CT, 1990; Vol. 2, Chapter 1. (c) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 2, pp 277-406. (d) Padwa, A. AG(E) 1976, 15, 123.
3. (a) Alder, K.; Stein, G. LA 1931, 485, 211. (b) Alder, K.; Stein, G. LA 1933, 501, 1.
4. Shea, K. J.; Kim, J.-S. JACS 1992, 114, 4846 and references cited therein.
5. (a) Brown, H. C.; Midland, M. M.; Levy, A. B.; Suzuki, A.; Sono, S.; Itoh, M. T 1987, 43, 4079. (b) Brown, H. C.; Salunkhe, A. M.; Singaram, B. JOC 1991, 56, 1170 and references cited therein.
6. Abramovitch, R. A.; Jeyaraman, R. In Azides and Nitrenes: Reactivity and Utility; Scriven, E. F. V., Ed.; Academic: New York, 1984; pp 297-357.
7. Scriven, E. F. V. In Reactive Intermediates; Abramovitch, R. A., Ed.; Plenum: New York, 1982; pp 1-54.
8. (a) Smith, P. A. S. In Azides and Nitrenes: Reactivity and Utility; Scriven, E. F. V., Ed.; Academic: New York, 1984; pp 95-204. (b) Smith, P. A. S. Derivatives of Hydrazine and Other Hydronitrogens Having N-N Bonds; Benjamin Cummings: Reading, MA, 1983; pp 263-300. (c) Smith, P. A. S. In Nitrenes; Lwowski, W., Ed.; Wiley: New York, 1970; Chapter 4. (d) Wentrup, C. Adv. Heterocycl. Chem. 1981, 28, 279.
9. Abramovitch, R. A.; Kyba, E. P. In The Chemistry of the Azido Group; Patai, S., Ed.; Wiley: New York, 1971; pp 221-329.
10. (a) Reiser, A.; Wagner, H. M. In The Chemistry of the Azido Group; Patai, S., Ed.; Wiley: New York, 1971; pp 441-501. (b) Schuster, G. B.; Platz, M. S. Adv. Photochem. 1992, 17, 69. (c) Budyka, M. F.; Kantor, M. M.; Alfimov, M. V. RCR 1992, 61, 25. (d) Gritsan, N. P.; Pritchina, E. A. RCR 1992, 61, 500.
11. Bayley, H.; Staros, J. V. In Azides and Nitrenes: Reactivity and Utility; Scriven, E. F. V., Ed.; Academic: New York, 1984; pp 433-490.
12. Lindsay, R. O.; Allen, C. F. H. OSC 1955, 3, 710.
13. (a) Leffler, J. E.; Tsuno, Y. JOC 1963, 28, 190. (b) Carpenter, W. R. Anal. Chem. 1964, 36, 2352.
14. Doering, W. v. E.; Odum, R. A. T 1966, 22, 81.
15. Fusco, R.; Garanti, L.; Zecchi, G. JOC 1975, 40, 1906.
16. Vebrel, J.; Carrié, R. T 1983, 39, 4163.
17. Huisgen, R.; Szeimies, G.; Möbius, L. CB 1966, 99, 475.
18. Dimroth, O. CB 1902, 35, 1036.
19. (a) Anderson, W. K.; Jones, A. N. JMC 1984, 27, 1559. (b) Lalezari, I.; Gomez, L. A.; Khorshidi, M. JHC 1990, 27, 687. (c) For related compounds derived from aliphatic azides, see: Pearson, W. H.; Bergmeier, S. C.; Chytra, J. A. S 1990, 156.
20. (a) Huisgen, R.; Möbius, L.; Szeimies, G. CB 1965, 98, 1138. (b) Olsen, C. E. ACS 1974, B28, 425.
21. Smith, P. A. S.; Brown, B. B. JACS 1951, 73, 2438.
22. Ciufolini, M. A.; Byrne, N. E. JACS 1991, 113, 8016.
23. Smith, P. A. S.; Rowe, C. D.; Hansen, D. W., Jr. TL 1983, 24, 5169.
24. Sakai, K.; Anselme, J.-P. JOC 1972, 37, 2351.
25. Doering, W. v. E.; Odum, R. A. T 1966, 22, 81.
26. Takeuchi, H.; Shiobara, Y.; Kawamoto, H.; Koyama, K. JCS(P1) 1990, 321.
27. Takeuchi, H.; Takano, K. CC 1983, 447.
28. Takeuchi, H.; Hirayama, S.; Mitani, M.; Koyama, K. JCS(P1) 1988, 521.
29. Abramovitch, R. A.; Cooper, M.; Iyer, S.; Jeyaraman, R.; Rodriguez, J. A. R. JOC 1982, 47, 4819.
30. (a) Kukhar, V. P.; Gilyarov, V. A. PAC 1980, 52, 891. (b) Barluenga, J. OPP 1991, 23, 1.
31. (a) Staudinger, H.; Hauser, E. HCA 1921, 4, 861. (b) Horner, L.; Gross, A. LA 1955, 591, 117. (c) Brass, K.; Albrecht, F. CB 1928, 61, 983. (d) Leffler, J. E.; Honsberg, V.; Tsuno, Y.; Forsblad, I. JOC 1961, 26, 4810.
32. (a) Bretschneider, H.; Rager, H. M 1950, 81, 970, 981. (b) Wolff, L.; Grau, G. K. LA 1912, 394, 68. (c) Tanno, M.; Sueyoshi, S.; Kamiya, S. CPB 1982, 30, 3125.
33. de Nanteuil, G.; Ahond, A.; Poupat, C.; Thoison, O.; Potier, P. BSF(2) 1986, 813.
34. (a) Lee, S. W.; Miller, G. A.; Campana, C. F.; Maciejewski, M. L.; Trogler, W. C. JACS 1987, 109, 5050. (b) Trogler, W. C. ACR 1990, 23, 426.
35. (a) Wamhoff, H. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; p 669. (b) Gilchrist, T. L.; Gymer, G. E. Adv. Heterocycl. Chem. 1974, 16, 33.
36. Lieber, E.; Chao, T.-S.; Rao, C. N. R. OS 1957, 37, 26.
37. Ardakani, M. A.; Smalley, R. K. TL 1979, 4765, 4769.

William H. Pearson & P. Sivaramakrishnan Ramamoorthy

University of Michigan, Ann Arbor, MI, USA



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