PHOSPHORIC ACID

1

Phosphoric Acid

H

3

PO

4

[7664-38-2]

H

3

O

4

P

(MW 98.00)

InChI = 1/H3O4P/c1-5(2,3)4/h(H3,1,2,3,4)/f/h1-3H
InChIKey = NBIIXXVUZAFLBC-UGMYVIKVCK

(acid catalyst; dehydrating agent; phosphorylating agent

1

)

Physical Data:

mp 41

◦

C; bp 158

◦

C.

Solubility:

sol water, formic acid, acetic acid.

Form Supplied in:

commercially available; low melting white

solid or colorless liquid.

Analysis of Reagent Purity:

titration.

Preparative Method:

anhydrous H

3

PO

4

can be prepared by dis-

solving P

2

O

5

in 85% H

3

PO

4

.

Purification:

dry at 150

◦

C. At temperatures above 200

◦

C, mono-

meric H

3

PO

4

changes to oligomeric metaphosphoric acid.

Handling, Storage, and Precautions:

corrosive.

Introduction. Phosphoric acid is a strong, nonoxidizing acid

that is available in a number of different forms. Anhydrous, mono-
meric H

3

PO

4

(orthophosphoric acid) is a low melting solid

that can be purchased commercially or prepared by adding
P

2

O

5

to commercial 85% aqueous H

3

PO

4

. This combination has

been used to iodinate alcohols, cleave ethers, and hydroiodinate
alkenes, in addition to a variety of uses listed below.

2

Metaphos-

phoric acid [37267-86-0] is an oligomeric form, also commer-
cially available.

3

Hydrolysis of Imines, Amides, and Nitriles. The hydrolysis

of imines,

4

amides, and nitriles to carboxylic acids (eq 1) using

H

3

PO

4

is a time-honored technique.

5

There are numerous meth-

ods for accomplishing this transformation.

6

Ph CN

Ph CO

2

H

100% H

3

PO

4

155 °C, 4 h

(1)

70–90%

Preparation of Phosphates.

1

Phosphate mono- and dialkyl

esters have been prepared from phosphoric acid (see also Phos-
phorus Oxychloride). Treatment of (1) with H

3

PO

4

at rt provides

the corresponding phosphate in good yield (eq 2).

7

At high tem-

peratures, diesterification can occur (eq 3).

8

N
HCl

HO

NH

2

•HCl

OH

N
HCl

HO

NH

2

•HCl

O

P

OH

O

OH

100% H

3

PO

4

25 °C

(2)

(1)

70%

H

3

PO

4

, K

2

CO

3

xylene, 195 °C

HO

O

P

O

HO

(3)

2

76%

An effective, large-scale synthesis of diammonium acetylphos-

phate has been developed, and involves direct acylation of H

3

PO

4

.

Either ketene

9

or acetic anhydride

10

(eq 4) can be used in this

process.

O

O

O

O

P

O

O

ONH

4

ONH

4

1. H

3

PO

4

, EtOAc, 0 °C

2. NH

3

, MeOH, –30 °C

(4)

86%

Acid Cyclization Catalyst. A common use for H

3

PO

4

, as

a solution in water, a liquid acid, or in anhydrous form, is as
an acid cyclization catalyst. Cyclization of cross-conjugated ke-
tones in H

3

PO

4

/formic acid leads to 2,3-dialkylcyclopentenones

(eq 5) rather than the 3,4-dialkyl products expected of the Nazarov
cyclization.

11

This result is obtained when either the ketone or the

corresponding ethylene acetal is used as starting material. Similar
results are obtained using HBr/HOAc, although, in these exam-
ples, some of the 3,4-dialkyl products are obtained as well.

O

Et

Et

O

Et

Et

H

3

PO

4

, HCO

2

H

90 °C, 3 h

(5)

77%

An intermolecular example of an alkene-cation addition reac-

tion provides access to chromenes through isoprenylation of a
phenol (eq 6).

12

HO

OH

OH

O

O

OH

OH

O

H

3

PO

4

, xylene

78%

(6)

Cyclization of (2) in phosphoric acid results in an azabicy-

clononane (eq 7).

13

85% H

3

PO

4

(7)

N

N

(2)

73%

Phosphoric acid-mediated condensation of indole derivatives

with ketones provides access to 3-substituted indoles (eq 8).

14

N
H

MeO

N

O

Me

N
H

MeO

N

Me

(8)

88%

2N H

3

PO

4

Cyclization of enol acetates (eq 9), δ,ε-unsaturated aldehydes,

15

and ketene dithioacetals (eq 10) can also be accomplished by
heating in H

3

PO

4

. The cyclization of (3) results in dithiopy-

ridines by way of an intramolecular Ritter reaction followed by a
1,3-methylthio shift. Lewis acids, Boron Trifluoride Etherate in
particular, lead to simple dehydration.

16

Avoid Skin Contact with All Reagents

2

PHOSPHORIC ACID

(9)

OAc

H

H

O

85% aq. H

3

PO

4

toluene

100 °C

trans

:cis = 8:1

80%

N

Ph

SMe

SMe

SMe

CN

OH

Ph

SMe

88% H

3

PO

4

130 °C, 3 h

(10)

(3)

82%

Debenzylation. Treatment of (4), an N-benzyl derivative of

biotin, with anhydrous H

3

PO

4

and phenol at elevated temperature

leads to debenzylation (eq 11).

17

This reaction provides a nonre-

ductive route to deprotection of the urea while not attacking the
unsaturated ester.

N

N

Ph

Ph

O

S

H

H

CO

2

Et

NH

HN

O

S

H

H

H

3

PO

4

, phenol

150 °C, 3 h

(11)

CO

2

Et

(4)

53%

Related Reagents. Phosphorus(V) Oxide–Phosphoric Acid;

Phosphorus Oxychloride; Polyphosphoric Acid; Sulfuric Acid.

1.

Methoden Org. Chem. (Houben-Weyl) 1982

, E2, 491.

2.

Fieser & Fieser 1967

, 1, 872.

3.

Kirk-Othmer Encyclopedia of Chemical Technology

; Wiley: New York,

1978; Vol. 17, pp 428, 448.

4.

Mislow, K.; McGinn, F. A., J. Am. Chem. Soc. 1958, 80, 6036.

5.

Berger, G.; Olivier, S. C. J., Recl. Trav. Chim. Pays-Bas 1927, 46, 600.

6.

Haslam, E., Tetrahedron 1980, 36, 2409.

7.

Wilson, A. N.; Harris, S. A., J. Am. Chem. Soc. 1951, 73, 4693.

8.

Inamoto, Y.; Aigami, K.; Kadono, T.; Nakayama, H.; Takatsuki, A.;
Tamura, G., J. Med. Chem. 1977, 20, 1371.

9.

Whitesides, G. M.; Siegel, M.; Garrett, P., J. Org. Chem. 1975, 40, 2516.

10.

Lewis, J. M.; Haynie, S. L.; Whitesides, G. M., J. Org. Chem. 1979, 44,
864.

11.

Hirano, S.; Hiyama, T.; Nozaki, H., Tetrahedron Lett. 1974, 1429.

12.

Ahluwalia, V. K.; Arora, K. K., Tetrahedron 1981, 37, 1437.

13.

Beretta, M. G.; Rindone, B.; Scolastico, C., Synthesis 1975, 440.

14.

Freter, K., J. Org. Chem. 1975, 40, 2525.

15.

Saucy, G.; Ireland, R. E.; Bordner, J.; Dickerson, R. E., J. Org. Chem.
1971, 36, 1195.

16.

Gupta, A. K.; Ila, H.; Junjappa, H., Tetrahedron Lett. 1988, 29, 6633.

17.

Field, G. F.; Zally, W. J.; Sternbach, L. H.; Blount, J. F., J. Org. Chem.
1976, 41, 3853.

Mark S. Meier

University of Kentucky, Lexington, KY, USA

A list of General Abbreviations appears on the front Endpapers