Nitric Acid

HNO3

[7697-37-2]  · HNO3  · Nitric Acid  · (MW 63.02) (fuming)

[52583-42-3]

(nitration and oxidation of organic molecules)

Physical Data: mp -41.6 °C; bp 83 °C; d 1.50 g cm-3.1

Solubility: sol H2O.

Form Supplied in: clear colorless liquid (69-71% in H2O); fuming nitric acid is a colorless to pale yellow liquid, HNO3 content >90% widely available.

Preparative Methods: anhydrous nitric acid can be prepared by distilling fuming nitric acid from an equal volume of concentrated sulfuric acid.

Handling, Storage, and Precautions: strong acid; oxidizing agent. Colorless acid may discolor on exposure to light. Anhydrous nitric acid decomposes above the freezing point to give NO2, H2O, and O2. Emits toxic fumes of nitrogen oxides. Hygroscopic. Contact with other material may cause fire. Poison. Corrosive. Avoid contact and inhalation. May be fatal if inhaled, swallowed, or absorbed through skin. Material is extremely destructive to tissue of the mucous membranes and upper respiratory tract, eyes, and skin.2 Many of the reactions mentioned in this article require special care in order to avoid uncontrollable reactions and the possibility of explosions. Many nitrated compounds are unstable. The reader is therefore strongly urged to refer to original literature procedures.

Nitric acid holds an important place in the history of organic synthesis. It is used primarily for the nitration of organic molecules and to effect a wide variety of oxidative transformations. The advantage of nitric acid as a reagent is that it allows simple and straightforward isolation of products. However, it is not a very selective oxidant.

Nitration of Simple Aromatic Systems.3

Nitration of aromatics has been studied extensively. The mechanism by which nitration occurs is believed to involve electrophilic attack by NO2+. The concentration of the active species increases in the presence of the more acidic Sulfuric Acid. With this mixed reagent, the nitration of simple benzene derivatives4 and polyaromatic ring systems5 has been accomplished. For example, treatment of methyl benzoate with concentrated nitric acid gives methyl 3-nitrobenzoate in 81-85% yield.4a In polyaromatic ring systems, nitration usually occurs selectively on the more electron rich aromatic ring (eq 1).6 Under the reaction conditions, anilines are protonated and the aniline ring is relatively unreactive (eq 2).5e

Nitration of Aromatic Heterocycles.

Several types of aromatic heterocycles have been nitrated with nitric acid.7 For example, when thiophene is treated with nitric acid in acetic anhydride, 2-nitrothiophene is formed in 70-85% yield. In order to prepare 3-nitrothiophene, a deactivating strategy is required (eq 3). 2,4-Dinitrothiophene can be obtained by nitration of either 2-nitro- or 3-nitrothiophene.7a Nitration of the N-oxide of 2-methylpyridine allows the introduction of a nitro group at the 4 position in good yield (eq 4).7b

Nitration of Alkenes.8

Alkenes may also be nitrated by nitric acid. This reaction has been exploited in the synthesis of a number of steroid derivatives.9 Fuming nitric acid converts cholesteryl acetate to 6-nitrocholesteryl acetate in good yield (eq 5). The nitration of the more highly functionalized dienyl acetate (eq 6) provides the corresponding nitro steroid. Treatment of 1,1-dichloro-2-fluoroethylene with nitric acid in concentrated sulfuric acid provides fluoronitroacetyl chloride in 16% yield.10 2-Sulfolenes have also been nitrated.11

Nitration of Active Methylene Carbons.8,12

Active methylene carbons are nitrated by a number of reagents.12,13 With nitric acid the nitration of b-diketones can be achieved (eq 7). Nitration of diethyl malonate provides diethyl nitromalonate in 92% yield. a-Nitro ketones are obtained by nitration of ketones or enol acetates with the reagent derived from nitric acid and Acetic Anhydride in moderate to good yields (eq 8).14

Nitration of Heteroatoms.

Secondary amines and primary and secondary amides can be converted to N-nitro compounds by direct nitration with nitric acid.15,16 Although most primary amines cannot be nitrated directly, it is possible to obtain primary nitramines by nitration of the corresponding dichloroamines (eq 9).17 Treatment of pyrrolidone with nitric acid and acetic acid in the presence of copper provides N-nitroso-2-pyrrolidone in 70% yield;18 note that this transformation represents N-nitrosation.

Nitrolysis of dialkyl t-butylamines with nitric acid and sulfuric acid or acetic anhydride provides secondary nitramines (eq 10).19 More recently, Suri has shown that the reagent derived from ammonium nitrate and trifluoroacetic acid is effective for N-nitration.20

Acyl nitrates can be prepared conveniently on a laboratory scale by treatment of 90% nitric acid with a tenfold excess of the corresponding acid anhydrides.21

Oxidation of Alcohols, Aldehydes, and Esters.

Nitric acid oxidizes alcohols and aldehydes to the corresponding carboxylic acids. For example, 1-chloro-3-propanol is oxidized to 3-chloropropanoic acid in 78-79% yield.22 3-Chloropropionaldehyde affords the same product.23 Primary alcohols protected as esters are oxidized to the carboxylic acids (eq 11).24 In a two-phase solvent system (for example dimethyl ether and water), the oxidation of benzyl alcohols can be controlled so that aldehydes are obtained.25

Oxidative Cleavage.

Treatment of cyclohexanone with 33% nitric acid gives adipic acid in quantitative yield;26 oxidation of cyclohexanol affords the same product (eq 12).27 Glutaric acid is obtained in 70-75% yield by oxidative cleavage of 3,4-dihydro-2H-pyran.27

Oxidation at Benzylic Position.

Nitric acid oxidizes many aromatic alkyl substituents to the carboxylic acid group. Thus toluene is oxidized to benzoic acid in 85-90% yield.28 Oxidation of ethylbenzene with 15% nitric acid also gives benzoic acid in 80% yield. The reaction is general and has also been applied to the oxidation of pyridine derivatives. When 4-methylpyridine is treated with 10% nitric acid in phosphoric acid at elevated temperature and pressure, 4-pyridinecarboxylic acid is obtained in 93% yield.29 The reaction of p-isopropyltoluene can be controlled to give the partially oxidized product, p-methylbenzoic acid, in 56-59% yield.27 Additional examples of selective benzylic oxidations are shown in eqs 13 and 14.30,31

Oxidation to Quinones.

Nitric acid oxidizes a wide variety of hydroquinone derivatives to quinones (eq 15).32 Aminonaphthols can be converted to naphthoquinones by treatment with nitric acid (eq 16).27 Perhalogenated aromatic systems have also been oxidized to quinones (eq 17).33

Dehydrogenation and Aromatization.

Dihydropyridines can be aromatized by dilute nitric and sulfuric acid (eq 18).34 Diethyl hydrazodicarboxylate is dehydrogenated by fuming nitric acid to diethyl azodicarboxylate in 70-80% yield.35

Oxidation of Heteroatoms.

The nitroso group is oxidized efficiently to the nitro group by nitric acid.36 For example, 2,4-dinitrosoresorcinol is converted efficiently to 2,4,6-trinitroresorcinol with concentrated nitric acid (eq 19).37

Azoxycyclohexane can be obtained by oxidation of azocyclohexane.38 Dialkyl sulfides have been oxidized to the corresponding sulfones39 and sulfoxides;40 thiols provide sulfonic acids (eq 20).41 Iodoso compounds have been obtained from oxidation of aryl iodides (eq 21).42 Nitric acid converts 2-amino-6-nitrobenzonitriles to substituted 1,2,3-benzotriazin-4(3H)-one N2-oxides (eq 22).43

Other Uses.

Dichloromaleic anhydride has been obtained in 81% yield by treatment of hexachlorobutadiene with fuming nitric acid followed by concentrated sulfuric acid.25 Pyrroles react rapidly with nitric acid to give pyrrolinones (eq 23).44 Desulfurization of 1,2,4-triazole-3-thiol with nitric acid presumably involves the formation of the sulfonic acid, which is then hydrolyzed to triazole in 52-58% yield.27,45

Primary alkyl halides have also been oxidized to provide the corresponding carboxylic acids. On treatment with concentrated nitric acid, trans-2,3-bis(iodomethyl)-p-dioxane provides trans-p-dioxane-2,3-dicarboxylic acid in 73% yield.46


1. Stern, S. A.; Mullhaupt, J. T.; Kay, W. B. CRV 1960, 60, 185.
2. (a) The Merck Index, 11th ed.; Budavari, S., Ed.; Merck: Rahway, NJ, 1989; pp 6495-6497. (b) The Sigma Aldrich Library of Chemical Safety, 2nd ed.; Leng, R. E., Ed.; Sigma-Aldrich Corporation: Milwaukee, WI, 1988; pp 2546B-C.
3. (a) Hoggett, J. G.; Moodie, R. B.; Penton, J. R.; Schofield, K. Nitration and Aromatic Reactivity; Cambridge University Press: Cambridge, 1971. (b) Schofield, K. Aromatic Nitration; Cambridge University Press: Cambridge, 1980.
4. (a) Kamm, O.; Segur, J. B. OSC 1941, 1, 372. (b) Robertson, G. B. OSC 1941, 1, 396. (c) Culhane, P. J.; Woodward, G. E. OSC 1941, 1, 408. (d) Smith, L. I. OSC 1943, 2, 254. (e) Corson, B. B.; Hazen, R. K. OSC 1943, 2, 434. (f) Powell, G.; Johnson, F. R. OSC 1943, 2, 449. (g) Huntress, E. H.; Shriner, R. L. OSC 1943, 2, 459. (h) Brewster, R. Q.; Williams, B.; Phillips, R. OSC 1955, 3, 337. (i) Icke, R. N.; Redemann, C. E.; Wisegarver, B. B.; Alles, G. A. OSC 1955, 3, 644. (j) Kobe, K. A.; Doumani, T. F. OSC 1955, 3, 653. (k) Fitch, H. M. OSC 1955, 3, 658. (l) Fanta, P. E.; Tarbell, D. S. OSC 1955, 3, 661. (m) Howard, J. C. OSC 1963, 4, 42. (n) Schultz, H. P. OSC 1963, 4, 364. (o) Buckles, R. E.; Bellis, M. P. OSC 1963, 4, 722. (p) Fetscher, C. A. OSC 1963, 4, 735. (q) Boyer, J. H.; Buriks, R. S. OSC 1973, 5, 1067.
5. (a) Hartman, W. W.; Smith, L. A. OSC 1943, 2, 438. (b) Kuhn, W. E. OSC 1943, 2, 447. (c) Woolfolk, E. O.; Orchin, M. OSC 1955, 3, 837. (d) Braun, C. E.; Cook, C. D.; Merritt, C., Jr.; Rousseau, J. E. OSC 1963, 4, 711. (e) Mendenhall, G. D.; Smith, P. A. S. OSC 1975, 5, 829. (f) Newman, M. S.; Boden, H. OSC 1975, 5, 1029. (g) Vouros, P.; Petersen, B.; Dafeldecker, W. P.; Neumeyer, J. L. JOC 1977, 42, 744. (h) Keumi, T.; Tomioka, N.; Hamanaka, K.; Kakihara, H.; Fukushima, M.; Morita, T.; Kitajima, H. JOC 1991, 56, 4671.
6. (a) Grieve, W. S. M.; Hey, D. H. JCS 1932, 2245. (b) Hey, D. H. JCS 1932, 2636. (c) Hey, D. H.; Buckley Jackson, E. R. JCS 1934, 645.
7. (a) Babasnian, V. S. OSC 1943, 2, 466. (b) Taylor, E. C., Jr.; Crovetti, A. J. OSC 1963, 4, 654. (c) Fox, B. A.; Threlfall, T. L. OSC 1973, 5, 346. (d) Kolb, V. M.; Darling, S. D.; Koster, D. F.; Meyers, C. Y. JOC 1984, 49, 1636. (e) Szabo, K. J.; Hörnfeldt, A.-B.; Gronowitz, S. JOC 1991, 56, 1590. (f) Einhorn, J.; Demerseman, P.; Royer, R. CJC 1983, 61, 2287.
8. For a review on the synthesis of aliphatic and alicyclic nitro compounds, see: Kornblum, N. OR 1960, 12, 101.
9. Laron, H. O. In The Chemistry of the Nitro and Nitroso Groups; Feuer, H., Ed.; Wiley: New York, 1969; Part 1, pp. 323-324.
10. Martinov, I. V.; Kruglyak, Y. L. JGU 1965, 35, 974.
11. Titova, M. V.; Berestovitskaya, V. M.; Perekalin, V. V. JOU 1981, 17, 1172.
12. See Ref. 9; Part 1, pp 310-316.
13. Feuer, H. In The Chemistry of Amino, Nitroso and Nitro Compounds and Their Derivatives; Patai, S., Ed.; Wiley: New York, 1982; Part 2, p 805.
14. (a) Dampawan, P.; Zajac, W. W. JOC 1982, 47, 1176. (b) Stork, G.; Clark, G.; Weller, T. TL 1984, 25, 5367.
15. For a review on the formation of the nitroamine group, see: Wright, G. F. In The Chemistry of the Nitro and Nitroso Groups; Feuer, H., Ed.; Wiley: New York, 1969; Part 1, pp 613-684.
16. (a) Willer, R. L.; Atkins, R. L. JOC 1984, 49, 5147. (b) Rowlands, D. A. Synthetic Reagents; Pizey, J. S., Ed.; Wiley: New York, 1985; Vol. 6, pp 359-360.
17. Smart, G. N. R.; Wright, G. F. Can. J. Res. 1948, 26B, 284 (CA 1948, 42, 5844a).
18. McQuinn, R. L.; Cheng, Y.-C.; Digenis, G. A. SC 1979, 9, 25.
19. Cichra, D. A.; Adolph, H. G. JOC 1982, 47, 2474.
20. Suri, S. C.; Chapman, R. D. S 1988, 743.
21. Bachman, G. B.; Biermann, T. F. JOC 1970, 35, 4229.
22. Hudlicky, M. Oxidations in Organic Chemistry; American Chemical Society: Washington, 1990; p 127.
23. Haines, A. H. Methods for the Oxidation of Organic Compounds; Academic: San Diego, 1988; p 247.
24. See Ref. 22; p 224.
25. Fieser, M.; Fieser, L. F. FF 1975, 5, 474.
26. See Ref. 22; p 211.
27. Fieser, M.; Fieser, L. F. FF 1967, 1, 733.
28. See Ref. 22; pp 105-106.
29. See Ref. 22; pp 108-109.
30. Suzuki, H.; Hanafusa, T. S 1974, 432.
31. Kajimoto, T.; Tsuji, J. JOC 1983, 48, 1685.
32. For an extensive review, see: Musgrave, O. C. CRV 1969, 69, 499.
33. (a) See Ref. 22; pp 113-114. (b) Suzuki, H.; Ishizaka, K.; Maruyama, S.; Hanafusa, T. CC 1975, 51.
34. See Ref. 22; pp 52, 241.
35. See Ref. 22; p 233.
36. Iffland, D. C.; Yen, T.-F. JACS 1954, 76, 4083.
37. Fieser, M.; Fieser, L. F. FF 1972, 3, 212.
38. Langley, B. W.; Lythgoe, B.; Riggs, N. V. JCS 1951, 2309.
39. See Ref. 22; p 257.
40. Goheen, D. W.; Bennett, C. F. JOC 1961, 26, 1331.
41. See Ref. 22; p 252.
42. See Ref. 22; p 266.
43. Mitschker, A.; Wedemeyer, K. S 1988, 517.
44. Moon, M. W. JOC 1977, 42, 2219.
45. Whitehead, C. W.; Traverso, J. J. JACS 1956, 78, 5294.
46. Summerbell, R. K.; Lestina, G. J. JACS 1957, 79, 3878.

Kathlyn A. Parker & Mark W. Ledeboer

Brown University, Providence, RI, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.