NITRIC ACID

1

Nitric Acid

HNO

3

[7697-37-2]

HNO

3

(MW 63.02)

(fuming)
InChI = 1/HNO3/c2-1(3)4/h(H,2,3,4)/f/h2H
InChIKey = GRYLNZFGIOXLOG-QEZKKOIZCG
[52583-42-3]
InChI = 1/HNO3/c2-1(3)4/h(H,2,3,4)/f/h2H
InChIKey = GRYLNZFGIOXLOG-QEZKKOIZCG

(nitration and oxidation of organic molecules)

Physical Data:

mp −41.6

◦

C; bp 83

◦

C; d 1.50 g cm

−

3

.

1

Solubility:

sol H

2

O.

Form Supplied in:

clear colorless liquid (69–71% in H

2

O); fum-

ing nitric acid is a colorless to pale yellow liquid, HNO

3

content

>

90% widely available.

Preparative Methods:

anhydrous nitric acid can be prepared by

distilling fuming nitric acid from an equal volume of concen-
trated sulfuric acid.

Handling, Storage, and Precautions:

strong acid; oxidizing

agent. Colorless acid may discolor on exposure to light. Anhy-
drous nitric acid decomposes above the freezing point to give
NO

2

, H

2

O, and O

2

. Emits toxic fumes of nitrogen oxides. Hy-

groscopic. 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 respi-
ratory tract, eyes, and skin.

2

Many of the reactions mentioned

in this article require special care in order to avoid uncontrol-
lable reactions and the possibility of explosions. Many nitrated
compounds are unstable. The reader is therefore strongly urged
to refer to original literature procedures.

Original Commentary

Kathlyn A. Parker & Mark W. Ledeboer
Brown University, Providence, RI, USA

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 aro-

matics has been studied extensively. The mechanism by which ni-
tration occurs is believed to involve electrophilic attack by NO

2

+

.

The concentration of the active species increases in the pres-
ence of the more acidic Sulfuric Acid. With this mixed reagent,
the nitration of simple benzene derivatives

4

and polyaromatic

ring systems

5

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 aro-
matic ring (eq 1).

6

Under the reaction conditions, anilines are

protonated and the aniline ring is relatively unreactive (eq 2).

5e

Ph

Ph

NO

2

(1)

HNO

3

AcOH

NO

2

(2)

H

2

N

HNO

3

H

2

SO

4

NH

2

56–74%

Nitration of Aromatic Heterocycles. Several types of aro-

matic heterocycles have been nitrated with nitric acid.

7

For exam-

ple, 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

S

S

SO

2

Cl

S

SO

2

Cl

O

2

N

(3)

S

O

2

N

HNO

3

ClSO

3

H

H

2

O

N

O

–

N

O

–

HNO

3

H

2

SO

4

NO

2

(4)

+

+

70–73%

Nitration of Alkenes.

8

Alkenes may also be nitrated by nitric

acid. This reaction has been exploited in the synthesis of a num-
ber 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 sul-
furic acid provides fluoronitroacetyl chloride in 16% yield.

10

2-Sulfolenes have also been nitrated.

11

AcO

O

AcO

O

HNO

3

NO

2

(5)

79%

Avoid Skin Contact with All Reagents

2

NITRIC ACID

AcO

O

O

OAc

OAc

HNO

3

O

O

NO

2

OAc

OAc

O

(6)

49%

Nitration of Active Methylene Carbons.

8

,

12

Active methy-

lene carbons are nitrated by a number of reagents.

12,13

With nitric

acid the nitration of β-diketones can be achieved (eq 7). Nitra-
tion of diethyl malonate provides diethyl nitromalonate in 92%
yield. α-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

O

O

O

O

NO

2

(7)

78%

HNO

3

O

O

H

H

O

O

O

H

H

O

O

2

N

70% HNO

3

Ac

2

O

(8)

92%

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 pri-
mary 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.

NCl

2

H
N

NO

2

1. 99% HNO

3

Ac

2

O

2. NaHSO

3

(9)

65%

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

N

N

NO

2

O

2

N

t

-Bu

t

-Bu

HNO

3

H

2

SO

4

N

N

NO

2

O

2

N

O

2

N

NO

2

(10)

85%

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 car-

boxylic acids. For example, 1-chloro-3-propanol is oxidized to
3-chloropropanoic acid in 78–79% yield.

22

3-Chloropropional-

dehyde 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

OAc

F

HNO

3

AcOH

CO

2

H

F

(11)

4

4

78–84%

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

V

2

O

5

50% HNO

3

CO

2

H

CO

2

H

OH

(12)

58–60%

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 tem-
perature 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 oxi-

dations are shown in eqs 13 and 14.

30,31

NC

CN

O

O

HNO

3

NC

(13)

76%

N

N

Et

O

O

Et

CO

2

H

CO

2

H

CO

2

H

CO

2

H

30% HNO

3

(14)

92%

Oxidation to Quinones. Nitric acid oxidizes a wide variety

of hydroquinone derivatives to quinones (eq 15).

32

Aminonaph-

thols 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

A list of General Abbreviations appears on the front Endpapers

NITRIC ACID

3

OMe

OMe

OMe

Br

HNO

3

(15)

Br

OMe

O

Br

Br

O

84%

SO

3

–

NH

4

+

O

(16)

O

HNO

3

, H

2

O

30

°C

SO

3

H

OH

NH

3

+

Cl

–

94–98%

NH

O

O

O

N

F

F

F

F

F

F

F

F

F

F

F

100% HNO

3

100

°C

(17)

92%

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

N
H

CO

2

Et

EtO

2

C

N

CO

2

Et

EtO

2

C

(18)

HNO

3

H

2

SO

4

58–65%

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-trinitro-
resorcinol with concentrated nitric acid (eq 19).

37

NO

OH

OH

NO

NO

2

OH

OH

NO

2

71% HNO

3

O

2

N

(19)

84%

Azoxycyclohexane can be obtained by oxidation of azocyclo-

hexane.

38

Dialkyl sulfides have been oxidized to the correspond-

ing sulfones

39

and sulfoxides;

40

thiols provide sulfonic acids

(eq 20).

41

Iodoso compounds have been obtained from oxida-

tion of aryl iodides (eq 21).

42

Nitric acid converts 2-amino-

6-nitrobenzonitriles to substituted 1,2,3-benzotriazin-4(3H)-one
N

2

-oxides (eq 22).

43

N

SH

N

SO

3

H

HNO

3

(20)

90%

I

O

2

N

O

2

N

CO

2

H

IO

O

2

N

O

2

N

CO

2

H

(21)

HNO

3

92%

NH

2

CN

NO

2

NH

NO

2

N

N

O

–

O

(22)

+

94%

HNO

3

H

2

SO

4

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 re-

act rapidly with nitric acid to give pyrrolinones (eq 23).

44

Desul-

furization 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

H
N

EtO

2

C

CO

2

Et

H
N

EtO

2

C

O

CO

2

Et

(23)

45%

HNO

3

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

First Update

Jeremy D. Pettigrew
The Ohio State University, Columbus, OH, USA

Oxidation

to

Dichloroquinones.

The

preparation

of

3,4-dichloroquinones can involve multistep procedures.

47

How-

ever, chlorooxidation of the corresponding hydroquinones with
nitric acid and Hydrogen Chloride allows for the preparation of
these synthetically useful compounds in a single step with ease
of product isolation (eq 24).

47

–

50

The resulting dichloroquinones

have been shown to be useful intermediates for the preparation
of substituted quinones via further nucleophilic substitution reac-
tions.

H
N

N

N

OMe

OMe

H
N

N

N

O

O

Cl

Cl

H
N

N

N

O

O

H
N

Cl

OMe

(24)

61%

HCl

HNO

3

reflux

89%

MeOC

4

H

4

NH

2

EtOH
reflux

Oxidation of Phosphorus.

In addition to the previously

mentioned heteroatom oxidations, the oxidation of trialkyl phos-
phines to the corresponding trialkylphosphine oxides has been
accomplished with nitric acid (eq 25).

51

Avoid Skin Contact with All Reagents

4

NITRIC ACID

P

Ph

Me

H

2

O

3

P

Ph

Me

P

Ph

Me

H

2

O

3

P

Ph

Me

O

HNO

3

(25)

Selective Functional Group Conversion of Phenols or

Aromatic Ethers.

The selective conversion of para-oriented

functional groups of substituted phenols and aromatic ethers to
nitro groups has been accomplished using nitric acid. For
example, 2,4,6-tribromophenol can be converted to 2,6-dibromo-
4-nitrophenol upon reaction with 1 equiv of nitric acid in ether
(eq 26).

52

The selective conversion of tert-butyl groups into

nitro groups has also been extensively developed and used in the
preparation of aromatic substrates and in calixarene chemistry
(eq 27).

53

–

57

OH

Br

Br

Br

OH

Br

Br

NO

2

(26)

HNO

3

(1 equiv)

Et

2

O, rt

74%

OH

Me

3

C

CN

CMe

3

OH

Me

3

C

CN

NO

2

(27)

81%

HNO

3

AcOH

Nitrodecarboxylation of Unsaturated Carboxylic Acids.

Nitric acid and Azobisisobutyronitrile can be used in combina-
tion to perform nitrodecarboxylations of activated styrenes and
aromatic carboxylic acids (eq 28).

58

Studies on the mechanism

of this reaction indicate that this transformation proceeds via a
radical pathway and an ionic mechanism is not involved.

MeO

CO

2

H

NO

2

(28)

HNO

3

, AIBN

MeCN, 50

°C

75%

MeO

Allylic Alcohol Isomerization. Nitric acid has been shown

to be effective for the isomerization of allylic alcohols (eq 29).

59

It is necessary to use short reaction times in order to avoid the
competing dehydration reaction. Unfortunately, mixtures of E-
and Z-double bonds are obtained.

OMe

OMe

Me

OH

Me

Me

Me

OMe

OMe

Me

HO

Me

Me

Me

(29)

HNO

3

1 min

98%

E

/Z = 56:44

Nitroxylation of Adamantoid Compounds. A direct C–H

bond activation of adamantoids has been accomplished via a
nitroxylation procedure with nitric acid. The resulting reactive
nitroxyl compounds are generally used in situ, but in some cases
these materials have been isolated (eq 30).

60

These materials can

subsequently undergo further reactions with nucleophiles to
afford amides, alcohols, or ethers (eq 31).

61

This direct C–H ac-

tivation avoids the need for a halogenation reaction to direct the
introduction of such functionality. Furthermore, the product distri-
bution with the higher order adamantoids with this direct function-
alization differs from the distribution of the halogenation reactions
and allows for access to otherwise unattainable materials.

62

ONO

2

ONO

2

(30)

HNO

3

0

°C

29%

Me

Me

Me

R

Me

(31)

1. HNO

3

, H

2

SO

4

2. H

2

NCOH or H

2

O or MeOH

R = NHCOH, 89%

R = OH, 81%

R = OMe, 33%

Oxidative Coupling of Aromatic Compounds. Nitric acid

has been used for the dimerization or trimerization of selected
aromatic systems. For example, 2,3-disubstituted-4,6-dimethoxy-
indoles that do not have electron-withdrawing substituents read-
ily undergo an oxidative dimerization upon exposure to nitric
acid to afford the corresponding 7,7

′

-biindoyls in good yields

(>80%) (eq 32).

63

It has also been shown that N-methyl-4,6-

dimethoxyindoles will dimerize to afford the corresponding 2,2

′

-

biindoyls (eq 33).

63

Also, 2,2

′

-biindanyl-1,1

′

,3,3

′

-tetraone has

been shown to undergo an oxidative cleavage followed by a trimer-
ization reaction upon exposure to nitric acid (eq 34).

64

N
H

MeO

OMe

Ph

Ph

N
H

MeO

OMe

Ph

Ph

H
N

OMe

OMe

Ph

Ph

(32)

HNO

3

, MeCN

0

°C

86%

2

A list of General Abbreviations appears on the front Endpapers

NITRIC ACID

5

Br

MeO

N

Br

OMe

OMe

Me

N

OMe

Me

N

Br

MeO

OMe

Me

(33)

HNO

3

, MeCN

0

°C

63%

2

O

O

O

O

O

O

O

O

O

O

(34)

HNO

3

, H

2

SO

4

rt

38%

Acetoxylation of 6,7-Dialkoxy-1,4-dihydroquinoxaline-2,3-

diones. The acetoxylation of 1,4-dihydroquinoxaline-2,3-diones
has been accomplished with nitric acid and Acetic Acid (eq 35).

65

Mechanistically, this reaction is thought to proceed by initial ipso
nitration, followed by solvolytic rearomatization of the resulting
intermediate. It was found that it was necessary to have the 6,7-
dialkoxy substituents for this reaction to proceed. Otherwise, stan-
dard aromatic nitration occurs.

N
H

H
N

O

O

MeO

MeO

N
H

H
N

O

O

MeO

MeO

OAc

(35)

HNO

3

, HOAc

rt

52%

Desulfonation of Mercaptoimidazoles and Mercaptotria-

zoles. Nitric acid has proven to be effective for the desulfonation
of mercaptoimidazoles.

66,67

This procedure allows for the con-

venient preparation of these small heterocycles from Potassium
Thiocyanate (eq 36) or from isothiocyanates (eq 37). Furthermore,
mercaptotriazoles can also be converted to the corresponding tri-
azoles with nitric acid (eq 38).

68

O

O

HO

OH

OH

HO

N

N

OH

Bn

HS

N

N

OH

Bn

(36)

BnNH

2

, KSCN

rt

53%

HNO

3

H

2

O

N

N

Ar

HS

N

N

Ar

H

2

N

OEt

OEt

(37)

1. ArNCS, EtOH

2. HCl

HNO

3

100

°C

58–64%

N

N

N

HS

Me

OH

N

N

N

Me

OH

(38)

73%

HNO

3

NaNO

2

Heterocycle Formation. Nitric acid has found an increasing

role in the preparation of heterocyclic compounds. Two prepara-
tions of isoxazoles using nitric acid have been reported. In one pro-
cedure, the heterocycle is prepared from 1,1-dihalocyclopropanes
(eq 39).

69

In the other procedure, the isoxazole is prepared from

terminal alkynes in the presence of a gold catalyst (eq 40).

70

Cl

Cl

O

2

N

O

2

N

O

N

Cl

(39)

81%

HNO

3

H

2

SO

4

R

H

R

O

N O

R

(40)

35–50%

2

Bu

4

N

AuCl

4

HNO

3

Nitric acid has also proven to be effective for the preparation

of furoxans. This transformation has been accomplished by ox-
idative coupling of carbonyl compounds (eq 41).

71,72

Further-

more, the oxidation of unsymmetrical bis-oximes with nitric acid
has been shown to afford a rapidly interconverting mixture of the
regioisomeric furoxans (eq 42).

73

Me

O

N

O

N

O

O

O

(41)

HNO

3

, H

2

SO

4

60

°C

2

Avoid Skin Contact with All Reagents

6

NITRIC ACID

N
H

H
N

NOH

NOH

Me

N
H

H
N

N

O

N

O

Me

N
H

H
N

N

O

N

O

Me

(42)

HNO

3

, CH

2

Cl

2

rt

51%

The synthesis of 1,2,4-triazolo[1,5-c]pyrimidin-5(6H)-ones has

also been accomplished with nitric acid (eq 43).

74,75

Mechanis-

tically, this reaction proceeds via the [4,3-c] isomers that are
unstable and undergo Dimroth rearrangements, although in sev-
eral examples these intermediates have been isolated.

75

N

N

O

Me

NH

N

Ph

N

N

N

N

Ph

O

Me

N

N

Me

O

N

N

Ph

(43)

71%

HNO

3

TFA

1.

Stern, S. A.; Mullhaupt, J. T.; Kay, W. B., Chem. Rev. 1960, 60, 185.

2.

(a) The Merck Index, 11th ed.; Budavari, S., Ed.; Merck: Rahway, NJ,
1989, p 6495. (b) The Sigma Aldrich Library of Chemical Safety, 2nd ed.;
Leng, R. E., Ed.; Sigma-Aldrich Corporation: Milwaukee, WI, 1988, p
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., Org. Synth., Coll. Vol. 1941, 1, 372. (b)
Robertson, G. B., Org. Synth., Coll. Vol. 1941, 1, 396. (c) Culhane, P.
J.; Woodward, G. E., Org. Synth., Coll. Vol. 1941, 1, 408. (d) Smith, L.
I., Org. Synth., Coll. Vol. 1943, 2, 254. (e) Corson, B. B.; Hazen, R. K.,
Org. Synth., Coll. Vol. 1943

, 2, 434. (f) Powell, G.; Johnson, F. R., Org.

Synth., Coll. Vol. 1943

, 2, 449. (g) Huntress, E. H.; Shriner, R. L., Org.

Synth., Coll. Vol. 1943

, 2, 459. (h) Brewster, R. Q.; Williams, B.; Phillips,

R., Org. Synth., Coll. Vol. 1955, 3, 337. (i) Icke, R. N.; Redemann, C.
E.; Wisegarver, B. B.; Alles, G. A., Org. Synth., Coll. Vol. 1955, 3, 644.
(j) Kobe, K. A.; Doumani, T. F., Org. Synth., Coll. Vol. 1955, 3, 653.
(k) Fitch, H. M., Org. Synth., Coll. Vol. 1955, 3, 658. (l) Fanta, P. E.;
Tarbell, D. S., Org. Synth., Coll. Vol. 1955, 3, 661. (m) Howard, J. C.,
Org. Synth., Coll. Vol. 1963

, 4, 42. (n) Schultz, H. P., Org. Synth., Coll.

Vol. 1963

, 4, 364. (o) Buckles, R. E.; Bellis, M. P., Org. Synth., Coll.

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