Hydrazine1

N2H4
(N2H4)

[302-01-2]  · H4N2  · Hydrazine  · (MW 32.06) (hydrate)

[10217-52-4] (monohydrate)

[7803-57-8]  · H5N2O  · Hydrazine Monohydrate  · (MW 49.07) (monohydrochloride)

[2644-70-4]  · ClH5N2  · Hydrazine Monohydrochloride  · (MW 68.52) (dihydrochloride)

[5341-61-7]  · Cl2H6N2  · Hydrazine Dihydrochloride  · (MW 104.98) (sulfate)

[10034-93-2]  · H6N2O4S  · Hydrazine Sulfate  · (MW 130.15)

(reducing agent used in the conversion of carbonyls to methylene compounds;1 reduces alkenes,9 alkynes,9 and nitro groups;14 converts a,b-epoxy ketones to allylic alcohols;32 synthesis of hydrazides;35 synthesis of dinitrogen containing heterocycles42-46)

Physical Data: mp 1.4 °C; bp 113.5 °C; d 1.021 g cm-3.

Solubility: sol water, ethanol, methanol, propyl and isobutyl alcohols.

Form Supplied in: anhydrate, colorless oil that fumes in air; hydrate and monohydrate, colorless oils; monohydrochloride, dihydrochloride, sulfate, white solids; all widely available.

Analysis of Reagent Purity: titration.1

Purification: anhydrous hydrazine can be prepared by treating hydrazine hydrate with BaO, Ba(OH)2, CaO, NaOH, or Na. Treatment with sodamide has been attempted but this yields diimide, NaOH, and ammonia. An excess of sodamide led to an explosion at 70 °C. The hydrate can be treated with boric acid to give the hydrazinium borate, which is dehydrated by heating. Further heating gives diimide.1

Handling, Storage, and Precautions: caution must be taken to avoid prolonged exposure to vapors as this can cause serious damage to the eyes and lungs. In cases of skin contact, wash the affected area immediately as burns similar to alkali contact can occur. Standard protective clothing including an ammonia gas mask are recommended. The vapors of hydrazine are flammable (ignition temperature 270 °C in presence of air). There have been reports of hydrazine, in contact with organic material such as wool or rags, burning spontaneously. Metal oxides can also initiate combustion of hydrazine. Hydrazine and its solutions should be stored in glass containers under nitrogen for extended periods. There are no significant precautions for reaction vessel type with hydrazine; however, there have been reports that stainless steel vessels must be checked for significant oxide formation prior to use. Use in a fume hood.

Reductions.

The use of hydrazine in the reduction of carbonyl compounds to their corresponding methylene groups via the Wolff-Kishner reduction has been covered extensively in the literature.1 The procedure involves the reaction of a carbonyl-containing compound with hydrazine at high temperatures in the presence of a base (usually Sodium Hydroxide or Potassium Hydroxide). The intermediate hydrazone is converted directly to the fully reduced species. A modification of the original conditions was used by Paquette in the synthesis of (±)-isocomene (eq 1).2

Unfortunately, the original procedure suffers from the drawback of high temperatures, which makes large-scale runs impractical. The Huang-Minlon modification3 of this procedure revolutionized the reaction, making it usable on large scales. This procedure involves direct reduction of the carbonyl compound with hydrazine hydrate in the presence of sodium or potassium hydroxide in diethylene glycol. The procedure is widely applicable to a variety of acid-labile substrates but caution must be taken where base-sensitive functionalities are present. This reaction has seen widespread use in the preparation of a variety of compounds. Other modifications4 have allowed widespread application of this useful transformation. Barton and co-workers further elaborated the Huang-Minlon modifications by using anhydrous hydrazine and Sodium metal to ensure totally anhydrous conditions. This protocol allowed the reduction of sterically hindered ketones, such as in the deoxygenation of 11-keto steroids (eq 2).4a Cram utilized dry DMSO and Potassium t-Butoxide in the reduction of hydrazones. This procedure is limited in that the hydrazones must be prepared and isolated prior to reduction.4b The Henbest modification4c involves the utilization of dry toluene and potassium t-butoxide. The advantage of this procedure is the low temperatures needed (110 °C) but it suffers from the drawback that, again, preformed hydrazones must be used. Utilizing modified Wolff-Kishner conditions, 2,4-dehydroadamantanone is converted to 8,9-dehydroadamantane (eq 3).5

Hindered aldehydes have been reduced using this procedure.6 This example is particularly noteworthy in that the aldehyde is sterically hindered and resistant to other methods for conversion to the methyl group.6a Note also that the acetal survives the manipulation (eq 4). The reaction is equally useful in the reduction of semicarbazones or azines.

In a similar reaction, hydrazine has been shown to desulfurize thioacetals, cyclic and acyclic, to methylene groups (eq 5). The reaction is run in diethylene glycol in the presence of potassium hydroxide, conditions similar to the Huang-Minlon protocol. Yields are generally good (60-95%). In situations where base sensitivity is a concern, the potassium hydroxide may be omitted. Higher temperatures are then required.7

Hydrazine, via in situ copper(II)-catalyzed conversion to Diimide, is a useful reagent in the reduction of carbon and nitrogen multiple bonds. The reagent is more reactive to symmetrical rather than polar multiple bonds (C=N, C=O, N=O, S=O, etc.)8 and reviews of diimide reductions are available.9 The generation of diimide from hydrazine has been well documented and a wide variety of oxidizing agents can be employed: oxygen (air),10 Hydrogen Peroxide,10 Potassium Ferricyanide,11 Mercury(II) Oxide,11 Sodium Periodate,12 and hypervalent Iodine13 have all been reported. The reductions are stereospecific, with addition occurring cis on the less sterically hindered face of the substrate.

Other functional groups have been reduced using hydrazine. Nitroarenes are converted to anilines14 in the presence of a variety of catalysts such as Raney Nickel,14a,15 platinum,14a ruthenium,14a Palladium on Carbon,16 b-iron(III) oxide,17 and iron(III) chloride with activated carbon.18 Graphite/hydrazine reduces aliphatic and aromatic nitro compounds in excellent yields.19 Halonitrobenzenes generally give excellent yields of haloanilines. In experiments where palladium catalysts are used, significant dehalogenation occurs to an extent that this can be considered a general dehalogenation method.20 Oximes have also been reduced.21

Hydrazones.

Reaction of hydrazine with aldehydes and ketones is not generally useful due to competing azine formation or competing Wolff-Kishner reduction. Exceptions have been documented. Recommended conditions for hydrazone preparation are to reflux equimolar amounts of the carbonyl component and hydrazine in n-butanol.22,23 A more useful method for simple hydrazone synthesis involves reaction of the carbonyl compound with dimethylhydrazine followed by an exchange reaction with hydrazine.24 For substrates where an azine is formed, the hydrazone can be prepared by refluxing the azine with anhydrous hydrazine.25 gem-Dibromo compounds have been converted to hydrazones by reaction with hydrazine (eq 6).26

Hydrazones are useful synthetic intermediates and have been converted to vinyl iodides27 and vinyl selenides (eq 7) (see also p-Toluenesulfonylhydrazide).28

Diazomalonates have been prepared from dialkyl mesoxylates via the Silver(I) Oxide-catalyzed decomposition of the intermediate hydrazones.29 Monohydrazones of 1,2-diketones yield ketenes after mercury(II) oxide oxidation followed by heating.30 Dihydrazones of the same compounds give alkynes under similar conditions.31

Wharton Reaction.

a,b-Epoxy ketones and aldehydes rearrange in the presence of hydrazine, via the epoxy hydrazone, to give the corresponding allylic alcohols. This reaction has been successful in the steroid field but, due to low yields, has seen limited use as a general synthetic tool. Some general reaction conditions have been set. If the intermediate epoxy hydrazone is isolable, treatment with a strong base (potassium t-butoxide or Potassium Diisopropylamide) gives good yields, whereas Triethylamine can be used with nonisolable epoxy hydrazones (eq 8).32

Some deviations from expected Wharton reaction products have been reported in the literature. Investigators found that in some specific cases, treatment of a,b-epoxy ketones under Wharton conditions gives cyclized allylic alcohols (eq 9). No mechanistic interpretation of these observations has been offered. Related compounds have given the expected products, and it therefore appears this phenomenon is case-specific.33

Cyclic a,b-epoxy ketones have been fragmented upon treatment with hydrazine to give alkynic aldehydes.34

Hydrazides.

Acyl halides,35 esters, and amides react with hydrazine to form hydrazides which are themselves useful synthetic intermediates. Treatment of the hydrazide with nitrous acid yields the acyl azide which, upon heating, gives isocyanates (Curtius rearrangement).36 Di- or trichlorides are obtained upon reaction with Phosphorus(V) Chloride.37 Crotonate and other esters have been cleaved with hydrazine to liberate the free alcohol (eq 10).38

Hydrazine deacylates amides (Gabriel amine synthesis) via the Ing-Manske protocol.39 This procedure has its limitations, as shown in the synthesis of penicillins and cephalosporins where it was observed that hydrazine reacts with the azetidinone ring. In this case, Sodium Sulfide was used.40

Heterocycle Synthesis.

The reaction of hydrazine with a,b-unsaturated ketones yields pyrazoles.41,42 Although the products can be isolated as such, they are useful intermediates in the synthesis of cyclopropanes upon pyrolysis of cyclopropyl acetates after treatment with Lead(IV) Acetate (eq 11).

3,5-Diaminopyrazoles were prepared by the addition of hydrazine (eq 12), in refluxing ethanol, to benzylmalononitriles (42-73%).43 Likewise, hydrazine reacted with 1,1-diacetylcyclopropyl ketones to give b-ethyl-1,2-azole derivatives. The reaction mixture must have a nucleophilic component (usually the solvent, i.e. methanol) to facilitate the opening of the cyclopropane ring. Without this, no identifiable products are obtained (eq 13).44

In an attempt to reduce the nitro group of nitroimidazoles, an unexpected triazole product was obtained in 66% yield. The suggested mechanism involves addition of the hydrazine to the ring, followed by fragmentation and recombination to give the observed product (eq 14).45

Finally, hydrazine dihydrochloride reacted with 2-alkoxynaphthaldehydes to give a product which resulted from an intramolecular [3+ + 2] criss-cross cycloaddition (42-87%) (eq 15).46

Peptide Synthesis.

Treatment of acyl hydrazides with nitrous acid leads to the formation of acid azides which react with amines to form amides in good yield. This procedure has been used in peptide synthesis, but is largely superseded by coupling reagents such as 1,3-Dicyclohexylcarbodiimide.47


1. (a) Todd, D. OR 1948, 4, 378. (b) Szmant, H. H. AG(E) 1968, 7, 120. (c) Reusch, W. Reduction; Dekker: New York, 1968, pp 171-185. (d) Clark, C. Hydrazine; Mathieson Chemical Corp.: Baltimore, MD, 1953.
2. Paquette, L. A.; Han, Y. K. JOC 1979, 44, 4014.
3. (a) Huang-Minlon JACS 1946, 68, 2487; 1949, 71, 3301. (b) Durham, L. J.; McLeod, D. J.; Cason, J. OSC 1963, 4, 510. (c) Hunig, S.; Lucke, E.; Brenninger, W. OS 1963, 43, 34.
4. (a) Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. JCS 1955, 2056. (b) Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. JACS 1962, 90, 7287. (c) Grundon, M. F.; Henbest, H. B.; Scott, M. D. JCS 1963, 1855. (d) Moffett, R. B.; Hunter, J. H. JACS 1951, 73, 1973. (e) Nagata, W.; Itazaki, H. CI(L) 1964, 1194.
5. Murray, R. K., Jr.; Babiak, K. A. JOC 1973, 38, 2556.
6. (a) Zalkow, L. H.; Girotra, N. N. JOC 1964, 29, 1299. (b) Aquila, H. Ann. Chim. 1968, 721, 117.
7. van Tamelen, E. E.; Dewey, R. S.; Lease, M. F.; Pirkle, W. H. JACS 1961, 83, 4302.
8. Georgian, V.; Harrisson, R.; Gubisch, N. JACS 1959, 81, 5834.
9. (a) Miller, C. E. J. Chem. Educ. 1965, 42, 254. (b) Hunig, S.; Muller, H. R.; Thier, W. AG(E) 1965, 4, 271. (c) Hammersma, J. W.; Snyder, E. I. JOC 1965, 30, 3985.
10. Buyle, R.; Van Overstraeten, A. CI(L) 1964, 839.
11. Ohno, M.; Okamoto, M. TL 1964, 2423.
12. Hoffman, J. M., Jr.; Schlessinger, R. H. CC 1971, 1245.
13. Moriarty, R. M.; Vaid, R. K.; Duncan, M. P. SC 1987, 17, 703.
14. (a) Furst, A.; Berlo, R. C.; Hooton, S. CRV 1965, 65, 51. (b) Miyata, T.; Ishino, Y.; Hirashima, T. S 1978, 834.
15. Ayynger, N. R.; Lugada, A. C.; Nikrad, P. V.; Sharma, V. K. S 1981, 640.
16. (a) Pietra, S. AC(R) 1955, 45, 850. (b) Rondestvedt, C. S., Jr.; Johnson, T. A. Chem. Eng. News 1977, 38. (c) Bavin, P. M. G. OS 1960, 40, 5.
17. Weiser, H. B.; Milligan, W. O.; Cook, E. L. Inorg. Synth. 1946, 215.
18. Hirashima, T.; Manabe, O. CL 1975, 259.
19. Han, B. H.; Shin, D. H.; Cho, S. Y. TL 1985, 26, 6233.
20. Mosby, W. L. CI(L) 1959, 1348.
21. Lloyd, D.; McDougall, R. H.; Wasson, F. I. JCS 1965, 822.
22. Schonberg, A.; Fateen, A. E. K.; Sammour, A. E. M. A. JACS 1957, 79, 6020.
23. Baltzly, R.; Mehta, N. B.; Russell, P. B.; Brooks, R. E.; Grivsky, E. M.; Steinberg, A. M. JOC 1961, 26, 3669.
24. Newkome, G. R.; Fishel, D. L. JOC 1966, 31, 677.
25. Day, A. C.; Whiting, M. C. OS 1970, 50, 3.
26. McBee, E. T.; Sienkowski, K. J. JOC 1973, 38, 1340.
27. Barton, D. H. R.; Basiardes, G.; Fourrey, J.-L. TL 1983, 24, 1605.
28. Barton, D. H. R.; Basiardes, G.; Fourrey, J.-L. TL 1984, 25, 1287.
29. Ciganek, E. JOC 1965, 30, 4366.
30. (a) Nenitzescu, C. D.; Solomonica, E. OSC 1943, 2, 496. (b) Smith, L. I.; Hoehn, H. H. OSC 1955, 3, 356.
31. Cope, A. C.; Smith, D. S.; Cotter, R. J. OSC 1963, 4, 377.
32. Dupuy, C.; Luche, J. L. T 1989, 45, 3437.
33. (a) Ohloff, G.; Unde, G. HCA 1970, 53, 531. (b) Schulte-Elte, K. N.; Rautenstrauch, V.; Ohloff, G. HCA 1971, 54, 1805. (c) Stork, G.; Williard, P. G. JACS 1977, 99, 7067.
34. (a) Felix, D.; Wintner, C.; Eschenmoser, A. OS 1976, 55, 52. (b) Felix, D.; Muller, R. K.; Joos, R.; Schreiber, J.; Eschenmoser, A. HCA 1972, 55, 1276.
35. ans Stoye, P. In The Chemistry of Amides (The Chemistry of Functional Groups); Zabicky, J., Ed.; Interscience: New York, 1970; pp 515-600.
36. (a) The Chemistry of the Azido Group; Interscience: New York, 1971. (b) Pfister, J. R.; Wymann, W. E. S 1983, 38.
37. (a) Mikhailov, Matyushecheva, Derkach, Yagupol'skii ZOR 1970, 6, 147. (b) Mikhailov, Matyushecheva, Yagupol'skii ZOR 1973, 9, 1847.
38. Arentzen, R.; Reese, C. B. CC 1977, 270.
39. Ing, H. R.; Manske, R. H. F. JCS 1926, 2348.
40. Kukolja, S.; Lammert, S. R. JACS 1975, 97, 5582 and 5583.
41. Freeman, J. P. JOC 1964, 29, 1379.
42. Reimlinger, H.; Vandewalle, J. J. M. ANY 1968, 720, 117.
43. Vequero, J. J.; Fuentes, L.; Del Castillo, J. C.; Pérez, M. I.; Garcia, J. L.; Soto, J. L. S 1987, 33.
44. Kefirov, N. S.; Kozhushkov, S. I.; Kuzetsova, T. S. T 1986, 42, 709.
45. Goldman, P.; Ramos, S. M.; Wuest, J. D. JOC 1984, 49, 932.
46. Shimizu, T.; Hayashi, Y.; Miki, M.; Teramura, K. JOC 1987, 52, 2277.
47. Bodanszky, M. The Principles of Peptide Synthesis; Springer: New York, 1984; p 16.

Brian A. Roden

Abbott Laboratories, North Chicago, IL, USA



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