PROPIONIC ACID

1

Propionic Acid

CO

2

H

[79-09-4]

C

3

H

6

O

2

(MW 74.09)

InChI = 1/C3H6O2/c1-2-3(4)5/h2H2,1H3,(H,4,5)/f/h4H
InChIKey = XBDQKXXYIPTUBI-JLSKMEETCG

(catalyst for orthoester Claisen rearrangement;

1

solvent for

malonate diester decarboxylation

13

and porphyrin synthesis

14

)

Alternate Name:

propanoic acid.

Physical Data:

clear liquid, bp 141

◦

C, 40

◦

C/10 mmHg; mp

−23

◦

C; d 0.993 g cm

−3

.

1

Solubility:

miscible with water, ethanol, ether, chloroform.

Form Supplied in:

neat liquid; commercially available.

Analysis of Reagent Purity:

by titrimetric assay; carbonyl com-

pound impurity tests are known.

15

Purification:

usually by repeated fractional distillation.

16

Handling, Storage, and Precautions:

corrosive organic acid with

an acrid odor. It is especially destructive to tissue of mucous
membranes and upper respiratory tract, eyes, and skin. Inhala-
tion is a major hazard and may be fatal. Use of a NIOSH/MSHA
approved respirator is recommended. Use gloves, eye protec-
tion, and protective clothing to avoid contact. The acid should
never be mixed with basic solvents, oxidizers, and reducing
agents. Use in a fume hood.

Orthoester Claisen Rearrangement. Propionic acid is the

classic acid catalyst for the Johnson orthoester Claisen rearrange-
ment of an allylic alcohol and trialkyl orthoester (see Triethyl
Orthoacetate). Examples have been reported for all allylic bond
substitutions, including 1,1-disubstituted (eq 1),

2

(E),

3

(Z),

4

tri-

substituted,

5

and tetrasubstituted.

6

HO

EtO

O

(1)

cat propionic acid

(EtO)

3

CMe

1 h, 138 °C

The reaction of a propargyl alcohol and triethyl orthoacetate

produces an allene ester (eq 2).

7

Allenic alcohols react in a similar

manner to give diene esters in moderate yield (eq 3).

8

(2)

OH

cat propionic acid

(EtO)

3

CMe

•

O

OEt

1 h, 100 °C

4 h, 180 °C

OH

•

O

N

O

O

O

N

O

(3)

OMe

(EtO)

3

CMe

cat propionic aci

20 h, 140 °C

The reaction of 2-butynediol with excess trimethyl orthopropi-

onate and catalytic propionic acid yields a symmetrical diene di-
ester through the novel double Claisen orthoester rearrangement
(eq 4).

9

(MeO)

3

CEt

cat propionic acid

OH

HO

(4)

MeO

OMe

O

O

3 h, 50–110 °C

distill methanol

88%

Other Variations on the Orthoester Claisen Rearrange-

ment. The condensation of a dialkyl acetal and a primary allylic
alcohol to form an unsaturated ketone has been catalyzed with pro-
pionic acid (eq 5).

10

The condensation of an allylic alcohol with

Triethyl Methanetricarboxylate yields, after decarboxylation, an
unsaturated ester (eq 6).

11

cat propionic acid

OH

MeO OMe

(5)

OMe

O

O

+

24 h, 120 °C

69%

(EtO)

3

CMe

cat propionic acid

HO

(6)

OEt

O

HC(CO

2

Et)

3

+

3 h, 140 °C

74%

Decarboxylation of Malonic Esters. The decarboxylation of

malonic ester derivatives to esters is general in propionic acid
(eq 7).

12

This reaction is complementary to the basic hydrolysis

of malonate esters to carboxylic acids.

propionic acid

CO

2

Et

CO

2

Et

CO

2

Et

(7)

48 h, reflux

85%

Synthesis of Porphyrins. The condensation of an aldehyde

and pyrrole in propionic acid leads to the formation of a tetra-
substituted porphyrin.

13

In an improved porphyrin synthesis, 2-

acylpyrroles are reduced to the corresponding alcohols and con-
verted to porphyrins by condensation and oxidation in refluxing
propionic acid (eq 8).

14

N
H

N

N

N

N

Zn

R

R

R

R

(8)

propionic acid

reflux, O

2

R

OH

0.25 equiv Zn(OAc)

2

Related Reagents. Acetic Acid; Pivalic Acid; p-Toluenesul-

fonic Acid; Trifluoroacetic Acid; 2,4,6-Trimethylbenzoic Acid.

Avoid Skin Contact with All Reagents

2

PROPIONIC ACID

1.

The Sigma–Aldrich Library of Chemical Safety Data

, 2nd ed.; Lenga, R.

E., Ed.; Sigma–Aldrich: Milwaukee, 1988; Vol. 2, p 2957.

2.

(a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li,
T.; Faulkner, D. J.; Petersen, M. R., J. Am. Chem. Soc. 1970, 92, 741.
(b) Henrick, C. A.; Schaub, F.; Siddall, J. B., J. Am. Chem. Soc. 1972,
94

, 5374.

3.

Tadano, K.; Shimada, K.; Miyake, A.; Ishihara, J.; Ogawa, S., Bull.
Chem. Soc. Jpn. 1989

, 62, 3978.

4.

Nishikimi, Y.; Iimori, T.; Sodeoka, M.; Shibasaki, M., J. Org. Chem.
1989, 54, 3354.

5.

(a) Tadano, K. I.; Idogaki, Y.; Yamada, H.; Suami, T., J. Org. Chem.
1987, 52, 1201. (b) Tadano, K. I.; Ishihara, J.; Yamada, H.; Ogawa, S.,
J. Org. Chem. 1989

, 54, 1223.

6.

Taguchi, T.; Morikawa, T.; Kitagawa, O.; Mishima, T.; Kobayashi, Y.,
Chem. Pharm. Bull. 1985

, 33, 5137.

7.

(a) Dauben, W. G.; Shapiro, G., J. Org. Chem. 1984, 49, 4252.
(b) Crandall, J. K.; Tindell, G. L., J. Chem. Soc., Chem. Commun. 1970,
1411. (c) Henderson, M. A.; Heathcock, C. H., J. Org. Chem. 1988, 53,
4736.

8.

(a) Behrens, U.; Wolff, C.; Hoppe, D., Synthesis 1991, 644. (b) Sleeman,
M. J.; Meehan, G. V., Tetrahedron Lett. 1989, 30, 3345.

9.

Ishino, Y.; Nishiguchi, I.; Kim, M.; Hirashima, T., Synthesis 1982, 9,
740.

10.

(a) Daub, G. W.; Lunt, S. R., Tetrahedron Lett. 1983, 24, 4397. (b) Daub,
G. W.; Sanchez, M. G.; Cromer, R. A.; Gibson, L. L., J. Org. Chem. 1982,
47

, 743.

11.

Kulkarni, M. G.; Sebastian, M. T., Synth. Commun. 1991, 21, 581.

12.

Brown, R. T.; Jones, M. F., J. Chem. Res. (S) 1984, 332.

13.

Datta-Gupta, N.; Malakar, D.; Jenkins, C.; Strange, C., Bull. Chem. Soc.
Jpn. 1988

, 61, 2274.

14.

Kuroda, Y.; Murase, H.; Suzuki, Y.; Ogoshi, H., Tetrahedron Lett. 1989,
30

, 2411.

15.

Reagent Chemicals: American Chemical Society Specifications

, 8th ed.;

American Chemical Society: Washington, 1993; p 606.

16.

Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals,
3rd Ed.; Pergamon: New York, 1988; p 264.

Kirk F. Eidman

Scios Nova, Baltimore, MD, USA

A list of General Abbreviations appears on the front Endpapers