Hydroxylamine1

HONH2
(HONH2)

[7803-49-8]  · H3NO  · Hydroxylamine  · (MW 33.04) (HONH2.HCl)

[5470-11-1]  · ClH4NO  · Hydroxylamine Hydrochloride  · (MW 69.50) ((HONH2)3.H3PO4)

[20845-01-6]  · H12N3O7P  · Hydroxylamine phosphate  · (MW 197.12) ((HONH2)2.H2SO4)

[10039-54-0]  · H8N2O6S  · Hydroxylamine Sulfate  · (MW 164.17)

(nucleophile in aromatic substitution,63 oxime-,36 hydroxamic acid-,30 pyridine-61 and isoxazole-forming56 reactions; reducing agent;66 in combination with dehydrating agents, used for the conversion of aldehydes to nitriles43)

Physical Data: HONH2: hydroscopic white needles or flakes; decomposes rapidly at rt; mp 32.05 °C; bp 56.5 °C/22 mmHg, 70 °C/60 mmHg, 110 °C/760 mmHg. HONH2.HCl: white crystals; mp 151 °C; d 1.67 g cm-3; pKa1 5.97; pKa2 13.7.10 (HONH2)3.H3PO4: mp 169-171 °C. (HONH2)2.H2SO4: mp 170 °C (dec).

Solubility: HONH2: decomposes in hot water; sol cold water, methanol; sparingly sol ether, benzene, chloroform, carbon disulfide.2 HONH2.HCl: 83 g/100 mL in cold water; very sol hot water; 4.43 g/100 mL in EtOH; 16.4 g/100 mL in MeOH; insol ether.

Form Supplied in: hydroxylamine hydrochloride is widely available and is the most commonly used hydroxylamine salt. Each of the other salts listed above is also commercially available, as are HONH2.HCl-d4 and HONH2.HCl-15N.6

Preparative Methods: hydroxylamine base has been prepared by the action of sodium butoxide on the hydrochloride in butanol.3 The free base can be isolated as a white solid at -30 °C and is stable to storage for several days at -20 °C.4 It can be prepared just prior to use or, more typically, in situ from one of the salts by treatment with hydroxide, alkoxide, carbonate, or amine base (see below). The preparation of hydroxylamine via the electrochemical reduction of nitric acid has been reported.5

Handling, Storage, and Precautions: all of the salts of hydroxylamine are corrosive and hygroscopic. Specific precautions in the literature indicate that the free base is a much more hazardous substance to work with than are the salts.7 HONH2: a moderately toxic, corrosive irritant to the eye, skin, and mucous membranes. Explodes at 130 °C. Explodes in air when heated above 70 °C. May ignite spontaneously in air, or in contact with PCl3 or PCl5. Calcium reacts to give the heat-sensitive explosive bis(hydroxylamide). In the event of a spill, cover with sodium bisulfite and sprinkle with water. HONH2.HCl: harmful if inhaled or swallowed (oral LD50 400-420 mg kg-1; mouse). Not compatible with oxidizing agents. May explode if heated above 115 °C; do not store above 65 °C. A comprehensive review of the biological activity of hydroxylamine and its salts has appeared.2

Introduction.

Hydroxylamine, usually as one of its more stable salts, has been used as a nucleophile in a wide variety of reactions and only the most common uses of this versatile reagent are described here. The name hydroxylamine is used throughout this review as a interchangable designator for either the free base or one of its salts. Where appropriate, the specific derivative will be named.

General Reactivity with Simple Electrophiles.

Hydroxylamine and its derivatives undergo reaction with many simple electrophiles such as alkylating, acylating, phosphinylating, and silylating agents, aldehydes and ketones, and Michael acceptors. The potent nucleophilic reactivity of hydroxylamine evident in these transformations is thought to arise as a consequence of what has been labeled the a-effect, an effect observed in a variety of nucleophiles which possess a heteroatom in the position a to the attacking nucleophilic atom.8 Hydroxylamine reacts with simple electrophiles typically at both nitrogen and oxygen, with multiple reactions often giving rise to undesired side-products. Many derivatives of hydroxylamine have been prepared in an effort to circumvent this potential problem of ambident reactivity (see below).9

Reactions with Alkylating Agents: N vs. O Selectivity.

The products obtained in the reaction of simple alkylating agents with hydroxylamine are exemplary of the ambident reactivity discussed above. In a study directed toward the preparation of O-alkylated hydroxylamines, it was found that several benzylic and one alkyl halide react preferentially at oxygen in t-butoxide/t-butanol solution (eq 1).10 Results similar to those obtained with benzyl bromide were found for five other benzylic halides.

Selective N-alkylation has been accomplished in a wide variety of cases using the hydroxylamine derivative t-butyl N-benzyloxycarbamate.11 The preparation of N-octylhydroxylamine.HCl is illustrative of this process (eq 2). Ethyl 3-methylhydroxy-4-isoxazolecarboxylate12 is another versatile reagent which has been developed for this purpose. O-Trimethylsilyl- and O-(t-butyldiphenylsilyl)hydroxylamine13 have also seen use in the preparation of N-alkylhydroxylamine derivatives, although these reagents have not been shown to be as generally useful in this regard as the previously mentioned two. N-Allylation has recently been accomplished via the Pd0-mediated reaction of N,O-bis(Boc)hydroxylamine with allylic carbonates, chlorides, and acetates.14 A similar study showed that the use of HONH2.HCl in the same reaction leads to N,N-diallylated products.15 N,O-Dimethylhydroxylamine.HCl has been prepared on a large scale by dimethylation (Dimethyl Sulfate) of ethyl hydroxycarbamate at pH 11-12 followed by acidolysis.16

Reactions with Silylating Agents.

O-Mono-, N,O-bis-,17 and N,N,O-tris(trimethylsilylated)18 derivatives of hydroxylamine have been prepared. One distinct advantage of these silylated hydroxylamine reagents is their solubility in nonpolar solvents in which hydroxylamine and its salts show poor solubility. N,O-Bis(trimethylsilyl)hydroxylamine undergoes facile O,N-silyl transfer upon treatment with n-Butyllithium in ether, allowing the generation the lithium salt of N,N-bis(trimethylsilyl)hydroxylamine in situ.19 This species plays an important role in the preparation of O-arenesulfonyl- and O-arenecarbonylhydroxylamines.20

Reactions with a-Halo or a-Hydroxy Esters: Preparation of N-Hydroxy-a-amino Acids.

Hydroxylamine and its derivatives have been reacted with both a-halo and a-hydroxy esters as a method to prepare N-hydroxy-a-amino acid derivatives.21 While hydroxylamine has seen some utility along these lines with t-butyl esters (eqs 3 and 4),22,23 the use of derivatives such as N-[(trichloroethoxy)carbonyl]-O-benzylhydroxylamine24 and O-Benzylhydroxylamine Hydrochloride25 appear to offer some advantages. The latter reagent has been used in the displacement of the triflates of (R)- or (S)-a-hydroxy esters, leading to N-hydroxy-a-amino methyl esters with both excellent chemical yield and optical purity.26

Reactions with Michael Acceptors.

The reaction of hydroxylamine hydrochloride with Michael acceptors offers a convenient synthesis of b-amino acids and esters. The preparation of (±)-b-aminophenylpropionic acid has been reported wherein the reduction of the hydroxyamine is effected with a second equiv of HONH2.HCl (eq 5).27 In a more comprehensive investigation of this reaction, it was found that catalytic reduction of the intermediate hydroxylamine leads to better yields (70% in the case shown in eq 5) of the amino acid.28

Tandem Michael additions are also known, the reaction of phorone with hydroxylamine giving a highly congested, cyclic hydroxylamine derivative (eq 6).29

Reaction with Acid Derivatives: Preparation of Hydroxamic Acids.

Hydroxylamine and its derivatives have been reacted with esters and acid halides to prepare hydroxamic acids. The reaction of HONH2.HCl with esters is particularly useful along these lines because overacylation is not a problem (eq 7).30,31

Reaction of hydroxylamine with acid halides can result in the formation of di- and triacylated products in addition to the desired hydroxamic acid. As is the case with alkylation, several hydroxylamine derivatives have been developed to address this problem. O-benzyl-,32 N,N,O-tris(trimethylsilyl)- (eq 8),33 N-Boc-O-TBDMS-, and N-Boc-O-THP-hydroxylamine (eq 9)34 have all proven to be useful for the synthesis of protected hydroxamic acids.

The reaction of succinic anhydride with hydroxylamine (prepared from NaOMe and H2NOH.HCl in MeOH) leads to N-hydroxysuccinimide.35

Reaction with Aldehydes and Ketones: Oxime Formation.

Reaction of hydroxylamine with an aldehyde or ketone under basic or acidic conditions leads to the formation of the corresponding oxime. For example, the (E) and (Z) isomers of 4-acetylpyridine oxime have been prepared via the reaction of 4-acetylpyridine with HONH2.HCl (eq 10).36

Other examples of this reaction include the preparation of the oxime of methyl glyoxylate (eq 11)23 and the oximes of some difluoromethylene-containing chiral aldehydes (eq 12).37

Both hydrazones (eq 13)38 and enol esters (eq 14)39 are efficient carbonyl surrogates in this transformation.

A solid-phase reagent which binds carbonyl compounds as their corresponding oximes has been developed and employed in the isolation of steroidal ketones.40 a-Halo ketones produce a-hydroxylamino oximes on treatment with hydroxylamine.41 The mechanism of this nucleophilic addition-dehydration process has been studied by a number of groups.42

Reaction with Aldehydes: Nitrile Formation.

Nitriles can be effectively prepared directly from aldehydes by a wide variety of methods involving hydroxylamine. Two convenient methods employ HONH2.HCl and either refluxing formic acid43 or pyridine with azeotropic removal of water with refluxing toluene (eq 15).44 The former reaction has been used to convert a 4-formyl b-lactam into its corresponding nitrile derivative.45

Two hydroxylamine-derived reagents, O-(2-aminobenzoyl)hydroxylamine46 and Hydroxylamine-O-sulfonic Acid,47 have also been used to effect this transformation, although in a more limited number of cases. Several methods exist which do not rely on hydroxylamine, including NH4Cl/Cu0/py/O2,48 EtNO2/NaOAc/AcOH,49 and N,N-dimethylhydrazine/MeOH/MMPP.6H2O50 (MMPP = magnesium monoperoxyphthalate).

Reaction with Phosphinylating Agents.

Both N- and O-phosphinylated hydroxylamine are available via reaction of the appropriate hydroxylamine derivative with diphenylphosphinyl chloride. Use of hydroxylamine base results in the formation of O-(Diphenylphosphinyl)hydroxylamine,4 while employment of TMSONH2 followed by hydrolysis gives N-diphenylphosphinylhydroxylamine (eq 16).51

Reaction with Miscellaneous Electrophiles.

Hydroxylamine reacts with nitriles to yield amide oximes (eq 17).52,53 The reaction of hydroxylamine with uracil and cytosine has been applied in the Chemical Cleavage of Mismatch (CCM) technique for identifying DNA mutants.54

Preparation of Isoxazoles and Isoxazolines.

Isoxazoles are conveniently prepared via the reaction of HONH2.HCl with 1,3-dicarbonyl compounds or their equivalents.55 In some cases, the regiochemistry of the reaction can be controlled. For example, the regiochemistry of the reaction of hydroxylamine with acylketene dithioacetals depends on reaction conditions (eqs 18 and 19).56

In like fashion, reaction conditions are important in the preparation of 3-amino-5-t-butylisoxazole from 4,4-dimethyl-3-oxopentanenitrile (eqs 20 and 21).57

Functionalized 4,5-dihydroisoxazoles58 have been prepared by the reaction of a,b-epoxy ketones with HONH2.HCl (eq 22)59 and also by the cycloaddition reaction between styrene and aryl nitrile oxides prepared in situ from trichloromethylarenes and hydroxylamine.60

Preparation of Substituted Pyridines.

Two novel approaches to the synthesis of substituted pyridines have appeared. Treatment of dihydropyran acetals61 with HONH2.HCl (eq 23) or bicyclic acetals62 with HONH2.HCl and Aluminum Chloride (eq 24) leads to good yields of pyridines. The first process appears to be the more general of the two, though it is limited somewhat by the availability of starting materials.

Aromatic Substitution Reactions.

In certain cases, hydroxylamine can act as a nucleophile in aromatic substitution reactions. This has shown to be the case in the reactions with 6-nitroquinoxalines (eq 25)63 and N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine (eq 26).64 Other examples are known.65

Use as a Reducing Agent.

The combination of hydroxylamine and ethyl acetate in DMF represents a useful in situ preparation of Diimide and this procedure has been reported to reduce a variety of unsaturated compounds (eq 27).66,67 Diimide formation from hydroxylamine has been used to explain the reductive cyclization of some o-nitroazobenzenes.68

Use in Peptide Chemistry.

Hydroxylamine has been used as a reagent to cleave the acetoacetyl amino acid protecting group69 and has also been employed to cleave the asparaginyl-glycyl peptide bond.70


1. Several excellent reviews have appeared covering the preparation and reactivity of hydroxylamine and its derivatives. (a) Andree, R.; Neuth, J. F.; Wroblowsky, Hs.-J. MOC 1990, E16a, 1. (b) Askani, R.; Taber, D. F. COS 1991, 6, 103. (c) Roberts, J. S. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 2, p 185. Several references to the use of hydroxylamine are presented in FF: 1, 478, 565, 903, 939; 2, 217; 5, 206; 6, 400, 533, 538; 7, 176, 225; 9, 245, 409; 10, 206; 11, 257; 12, 67, 251; 15, 170.
2. Gross, P. CRC Crit. Rev. Toxicol. 1985, 14, 87.
3. Hurd, C. Inorg. Synth., 1939, 1, 87.
4. Klotzer, W.; Stadlwieser, J.; Raneburger, J. OSC, 1990, 7, 8.
5. Fioshin, M. Ya.; Avrutskaya, I. A.; Surov, I. I.; Novikov, V. T. CCC 1987, 52, 182.
6. Chem Sources 1993; Chemical Sources International; Fernandina Beach, FL, 1993.
7. Information in this section was compiled from several sources: (a) Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens; Noyes: Park Ridge, NJ, 1991; pp 918-919. (b) The Merck Index, 11th ed.; Merck & Co.: Rahway, NJ, 1991. (c) Bretherick, L. Bretherick's Handbook of Reactive Chemical Hazards, 4th ed.; Butterworths: Boston, 1990; pp 1233-1234. (d) Toxic and Hazardous Industrial Chemicals Safety Manual; The International Technical Information Institute; Japan, 1985; pp 281-282. (e) Lewis, R. J. Sax's Dangerous Properties of Industrial Materials, 8th ed.; Van Nostrand Reinhold: New York, 1992; p 1936.
8. March, J. Advanced Organic Chemistry; Wiley: New York, 1992.
9. Lee, B. H.; Miller, M. J. JOC 1983, 48, 24.
10. Kashima, C.; Yoshiwara, N.; Omote, Y. TL 1982, 23, 2955.
11. Sulsky, R.; Demers, J. P. TL 1989, 30, 31.
12. Doleschall, G. TL 1987, 28, 2993.
13. (a) Stewart, A. O.; Martin, J. G. JOC 1989, 54, 1221. (b) For a similar reaction with HONH2.HCl see: Lamanec, T. R.; Bender, D. R.; DeMarco, A. M.; Karady, S.; Reamer, R. A.; Weinstock, L. M. JOC 1988, 53, 1768.
14. Genet, J.-P.; Thorimbert, S.; Touzin, A. M. TL 1993, 34, 1159.
15. Murahashi, S.-I.; Imada, Y.; Taniguchi, Y.; Kodera, Y. TL 1988, 29, 2973.
16. Goel, O. P.; Krolls, U. OPP 1987, 19, 75.
17. Bottaro, J. C.; Bedford, C. D.; Dodge, A. SC 1985, 15, 1333. Other bis-silylated hydroxylamines are also known: West, R.; Boudjouk, P. JACS 1973, 95, 3983.
18. Ando, W.; Tsumaki, H. SC 1983, 13, 1053.
19. West, R.; Boudjouk, P. JACS 1973, 95, 3987.
20. King, F. D.; Walton, D. R. M. S 1975, 788.
21. For an excellent review of the preparation and reactions of these compounds, see: Ottenheijm, H. C. J.; Herscheid, J. D. M. CRV 1986, 86, 697.
22. Shin, C.-g.; Nanjo, K.; Ando, E.; Yoshimura, J. BCJ 1974, 47, 3109.
23. Huang, N. Z.; Miller, M. J.; Fowler, F. W. H 1988, 27, 1821.
24. Kolasa, T.; Miller, M. J. JOC 1987, 52, 4978.
25. Akiyama, M.; Iesaki, K.; Katoh, A.; Shimizu, K. JCS(P1) 1986, 851.
26. Feenstra, R. W.; Stokkingreef, E. H. M.; Nivard, R. J. F.; Ottenheijm, H. C. J. T 1988, 44, 5583.
27. Steiger, R. E. OSC 1963, 3, 91.
28. Basheeruddin, K.; Siddiqui, A. A.; Khan, N. H.; Saleha, S. SC 1979, 9, 705.
29. Rozantzev, E. G.; Neiman, M. B. T 1964, 20, 131.
30. Hauser, C. R.; Renfrow, W. B., Jr. OSC 1943, 2, 67.
31. Brown, D.; Ismail, S. ICA 1990, 171, 41.
32. Lee, B. H.; Miller, M. J. JOC 1983, 48, 24.
33. Ando, W.; Tsumaki, H. SC 1983, 13, 1053.
34. Altenburger, J. M.; Mioskowski, C.; d'Orchymont, H.; Schirlin, D.; Schalk, C.; Tarnus, C. TL 1992, 33, 5055.
35. Wang, K.-T.; Brattesani, D. N.; Weinstein, B. JHC 1966, 3, 98.
36. LaMattina, J. L.; Suleske, R. T. OSC 1990, 7, 149.
37. Bravo, P.; Pregnolato, M.; Resnati, G. JOC 1992, 57, 2726.
38. Fox, M. E.; Holmes, A. B.; Forbes, I. T.; Thompson, M.; Ziller, J. W. TL 1992, 33, 7425.
39. Lichtenthaler, F. W.; Jarglis, P. TL 1980, 21, 1425.
40. Prasad, V. V. K.; Warne, P. A.; Lieberman, S. J. Steroid Biochem. 1983, 18, 257.
41. Volodarsky, L. B.; Tikhonov, A. Ya. S 1986, 704.
42. Brighente, I. M. C.; Vottero, L. R.; Terezani, A. J.; Yunes, R. A. JPOC 1991, 4, 107. Lamaty, G.; Roque, J. P.; Natat, A.; Silou, T. T 1986, 42, 2667. Agami, C.; Rizk, T.; Durand, R.; Geneste, P. CJC 1982, 60, 2355.
43. Olah, G.; Keumi, T. S 1979, 112.
44. Saednya, A. S 1982, 190.
45. Alcaide, B.; Gomez, A.; Plumet, J.; Rodriguez-Lopez, J. T 1989, 45, 2751.
46. Reddy, P. S. N.; Reddy, P. P. SC 1988, 18, 2179.
47. Streith, J.; Fizet, C.; Fritz, H. HCA 1976, 59, 2786.
48. Capdevielle, P.; Lavigne, A.; Maumy, M. S 1989, 451.
49. Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S. S 1985, 510.
50. Fernandez, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M.; Vazquez, J. TL 1993, 34, 141.
51. (a) Harger, M. J. P. JCS(P1) 1983, 2699. (b) Harger, M. J. P. JCS(P1) 1981, 3284.
52. Piskunova, I. P.; Eremeev, A. V.; Mishnev, A. F.; Vosekalna, I. A. T 1993, 49, 4671.
53. Showell, G. A.; Gibbons, T. L.; Kneen, C. O.; MacLeod, A. M.; Merchant, K.; Saunders, J.; Freedman, S. B.; Patel, S.; Baker, R. JMC 1991, 34, 1086.
54. Smooker, P. M.; Cotton, R. G. H. Mutat. Res. 1993, 288, 65.
55. For other isoxazole syntheses see: (a) Tronchet, J. M. J.; Massoud, M. A. M. Mansour J. Pharm. Sci. 1988, 2, 99. (b) Cherton, J.-C.; Lanson, M.; Ladjama, D.; Guichon, Y.; Basselier, J.-J. CJC 1990, 68, 1271.
56. Purkayastha, M. L.; Ila, H.; Junjappa, H. S 1989, 20.
57. Takase, A.; Murabayashi, A.; Sumimoto, S.; Ueda, S.; Makisumi, Y. H 1991, 32, 1153.
58. For other syntheses of 4,5-dihydroisoxazoles, see: (a) Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer, P. S 1991, 483. (b) Curzu, M. M.; Pinna, G. A.; Cignarella, G.; Barlocco, D.; Demontis, M. P. CCC 1991, 56, 2494.
59. Ito, S.; Sato, M. BCJ 1990, 63, 2739.
60. Brokhovetskii, D. B.; Belen'kii, L. I.; Krayushkin, M. M. IZV 1990, 1692 (CA 1991, 115, 279 557).
61. Ciufolini, M. A.; Byrne, N. E. CC 1988, 1230.
62. Jun, J.-G.; Shin, H. S.; Kim, S. H. JCS(P1) 1993, 1815.
63. Nasielski-Hinkens, R.; Kotel, J.; Lecloux, T.; Nasielski, J. SC 1989, 19, 511.
64. Hojo, M.; Masuda, R.; Okada, E. S 1990, 481.
65. Reaction with (a) halobenzonitriles: Wrubel, J.; Mayer, R. ZC 1984, 24, 254 (CA 1985, 102, 45 820h). (b) Nitroimidazoles: Suwinski, J.; Swierczek, K.; Glowiak, T. T 1993, 49, 5339.
66. Wade, P. A.; Amin, N. V. SC 1982, 12, 287.
67. Gangadhar, A.; Rao, T. C.; Subbarao, R.; Lakshminarayana, G. J. Am. Oil Chem. Soc. 1989, 66, 1507 (CA 1990, 112, 22 677j).
68. Wilshire, J. F. K. AJC 1988, 41, 617.
69. Di Bello, C.; Filira, F.; Giormani, V.; D'Angeli, F. JCS(C) 1969, 350.
70. Bornstein, P.; Balian, G. Methods Enzymol. 1977, 47, 132.

Michael A. Walters & Andrew B. Hoem

Dartmouth College, Hanover, NH, USA



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