FORMIC ACID 1
reaction is autocatalytic due to the high acidity of formic acid. The
equilibrium position of this reaction is closer to completion than
for other carboxylic acids.
Formic Acid1
Ac
OH
O
HCO2H
98% formic acid
H benzene
85%
[64-18-6] CH2O2 (MW 46.03) H H
Ac
OH
O
InChI = 1/CH2O2/c2-1-3/h1H,(H,2,3)/f/h2H
HO
H
InChIKey = BDAGIHXWWSANSR-QEZKKOIZCL
(1)
O
H H
(formation of formate esters,3 amides;7 reductions;10 transfer
H O
hydrogenation;12 rearrangements22)
Alternate Name: methanoic acid. Formate esters can also be produced during acid-catalyzed
Physical Data: strongest of the simple organic acids; pKa 3.77 rearrangements (eq 2),4 by addition to alkenes (eq 3),5 or by 1,3-
ć% ć%
(4.77 for acetic acid). Pure acid, mp 8.4 C; bp 100.7 C, Dicyclohexylcarbodiimide coupling (eq 4).6
ć% ć%
50 C/120 mmHg, 25 C/40 mmHg. Formic acid and water
ć%
form an uncommon maximum boiling azeotrope, bp 107.3 C,
petroleum
H
containing 77.5% acid. The dielectric constant of formic acid
ether
(2)
is 10 times greater than acetic acid.
HO formic acid, 22 °C O O
93%
Solubility: misc water in all proportions; misc EtOH, ether; mod
sol C6H6.
Form Supplied in: commercially available as 85 95% aqueous
solutions and as glacial formic acid, containing 2% water.
Analysis of Reagent Purity: formic acid is determined by titra- 98% formic acid
H
(3)
O
tion with base. If other acids are present, formic acid content
reflux
O
90%
can be determined by a redox titration based on oxidation with
H
potassium permanganate. Methods for analysis of trace organic
and inorganic materials are presented.2,23
Purification: fractional distillation in vacuo; dehydration over
1. DCC, cat CuCl
(4)
CuSO4 or boric anhydride.24
2. formic acid
O
Handling, Storage, and Precautions: the strongly acidic nature
toluene, reflux
HO O
of formic acid is the primary safety concern. Contact with the
H
skin will cause immediate blistering. Immediately treat affected
areas with copious amounts of water. Do not use dilute base
solutions as a first treatment. Formic acid has a large heat of
Formation of Amides. Most amines react with formic acid to
solution; the combined heat of neutralization and dilution will
produce the expected amide in high yield.7 Reaction with diamines
lead to thermal burns. Eye protection, gloves, and a chemi-
is an important reaction for the formation of heterocyclic com-
cal apron should be worn during all operations with concen-
pounds, including benzimidazoles (eq 5)8 and triazoles (eq 6).9
trated formic acid. Volatile; vapors will cause intense irritation
to mouth, nose, eyes, skin, and upper respiratory tract. Use of
NH2
an appropriate NIOSH/MSHA respirator is recommended. Use N
formic acid
(5)
in a fume hood.
reflux
N
NH2
During storage, glacial formic acid decomposes to form
H
water and carbon monoxide. Pressure can develop in sealed
containers and may result in rupture of the vessel. Ventilation
NH2
NH2
should be provided to prevent the buildup of carbon monoxide
N
formic acid
ć%
HN NH
(6)
in storage areas. Storage temperatures above 30 C should be
N
cat H2SO4
N
avoided.
NH2
H
Formic acid is incompatible with strong oxidizing reagents,
bases, and finely powdered metals, furfuryl alcohol, and
thallium nitrate. Contact with conc sulfuric acid will produce
Reductions with Formic Acid. Formic acid is unique among
carbon monoxide from decomposition.
the simple organic acids in its ability to react as a reducing
agent. Ketones are reduced and converted to primary amines by
reaction with ammonia and formic acid (see Ammonium For-
mate) (eq 7).10 Ketones or aldehydes will react with formic acid
Formation of Formate Esters. Formic acid will esterify and primary or secondary amines to produce secondary or tertiary
primary, secondary, and tertiary alcohols in high yield (eq 1).3 The amines (eq 8).10a,11
Avoid Skin Contact with All Reagents
2 FORMIC ACID
O
(eq 13).21 The reaction has been reviewed.22 Formic acid is the
CO2H
most common catalyst employed.
O HN
H
formic acid
(7)
HO HO
NH3, 100 °C
formic acid
CO2H
87% (13)
OH 62%
CO2H O
N N
Bn
Bn
Related Reagents. For uses of other carboxylic acids in
O HN
NH2
synthesis, see Acetic Acid, Acrylic Acid, Glyoxylic Acid, Oxalic
Ph
H2N NH
(8) Acid, Methanesulfonic Acid and Trifluoroacetic Acid.
formic acid
O
Ph
ethanol
O O
75%
1. Gibson, H. W., Chem. Rev. 1969, 69, 673.
2. Encyclopedia of Industrial Chemical Analysis; Snell, F. D.; Etter, L. S.,
Catalytic Transfer Hydrogenation.12 Catalytic transfer
Eds.; Interscience: New York, 1971; Vol. 13, p 125.
hydrogenation uses a metal catalyst and an organic hydro-
3. Hilscher, J.-C., Chem. Ber. 1981, 114, 389.
gen donor as a stoichiometric reducing agent. This is a useful
4. Kozar, L. G.; Clark, R. D.; Heathcock, C. H., J. Org. Chem. 1977, 42,
laboratory alternative to normal catalytic reduction, as the use 1386.
5. Kleinfelter, D. C.; Schleyer, P. v. R., Org. Synth. 1962, 42, 79; Org.
of flammable hydrogen gas is avoided. Formic acid and amine
Synth., Coll. Vol. 1973, 5, 852.
formates are common hydrogen donors. Formic acid has been used
6. Kaulen, J., Angew. Chem., Int. Ed. Engl. 1987, 26, 773.
to reduce Ä…,²-unsaturated aldehydes and acids13 to the saturated
7. Fieser, L. F.; Jones, J. E., Org. Synth., Coll. Vol. 1955, 3, 590.
compounds (eq 9). Benzyl ethers (eq 10)14 and benzyl amines
8. (a) Wagner, E. C.; Millett, W. H., Org. Synth., Coll. Vol. 1943, 2, 65.
(eq 11)15 are cleaved by transfer hydrogenation with formic acid.
(b) Mathias, L. J.; Overberger, C. G., Synth. Commun. 1975, 5, 461.
A variety of nitrogen functions are reduced including the nitro
9. Elion, G. B.; Lange, W. H.; Hitchings, G. H., J. Am. Chem. Soc. 1956,
group,16 azo group,17 hydrazines,18 and enamines.19 The result-
78, 2858.
ing amines will be formylated under the reaction conditions; use of
10. (a) Moore, M. L., Org. React. 1949, 5, 301. (b) Stoll, A. P.; Niklaus, P.;
water or alcohol as solvent will limit formylation. If the reduction
Troxler, F., Helv. Chim. Acta 1971, 54, 1988.
results in a suitable diamine, formylation will lead to heterocycle
11. Mosher, W. A.; Piesch, S., J. Org. Chem. 1970, 35, 1026.
formation (eq 12).16a Aromatic halides are reduced to the aromatic
12. (a) Johnstone, R. A. W.; Wilby, A. H., Chem. Rev. 1985, 85, 129.
hydrocarbon.20 See also Palladium Triethylamine Formic Acid. (b) Brieger, G.; Nestrick, T. J., Chem. Rev. 1974, 74, 567.
13. (a) Elamin, B.; Park, J.-W.; Means, G. E., Tetrahedron Lett. 1988, 29,
5599. (b) Cortese, N. A.; Heck, R. F., J. Org. Chem. 1978, 43, 3985.
CO2H formic acid CO2H
(9)
14. (a) Araki, Y.; Mokubo, E.; Kobayashi, N.; Nagasawa, J., Tetrahedron
Pd0
Lett. 1989, 30, 1115. (b) Rao, V. S.; Perlin, A. S., Carbohydr. Res. 1980,
100%
83, 175.
15. (a) Roush, W. R.; Walts, A. E., J. Am. Chem. Soc. 1984, 106, 721.
(b) Wang, C.-L. J.; Ripka, W. C.; Confalone, P. N., Tetrahedron Lett.
OBn
HO
1984, 25, 4613. (c) El Amin, B.; Anantharamaiah, G. M.; Royer, G. P.;
Pd0/C
O OH
Means, G. E., J. Org. Chem. 1979, 44, 3442.
formic acid
(10)
16. (a) Leonard, N. J.; Morrice, A. G.; Sprecker, M. A., J. Org. Chem. 1975,
MeOH, 22 °C
BnO HO
40, 356. (b) Morrice, A. G.; Sprecker, M. A.; Leonard, N. J., J. Org.
O O
Chem. 1975, 40, 363. (c) Entwistle, I. D.; Jackson, A. E.; Johnstone,
R. A. W.; Telford, R. P., J. Chem. Soc., Perkin Trans. 1 1977, 443.
17. (a) Taylor, E. C.; Barton, J. W.; Osdene, T. S., J. Am. Chem. Soc. 1958,
O O
BnHN H H2N H
80, 421. (b) Moore, J. A.; Marascia, F. J., J. Am. Chem. Soc. 1959, 81,
Pd0
formic acid
6049.
(11)
MeOH 18. Schneller, S. W.; Christ, W. J., J. Org. Chem. 1981, 46, 1699.
95%
19. Kikugawa, Y.; Kashimura, M., Synthesis 1982, 785.
20. Pandey, P. N.; Purkayastha, M. L., Synthesis 1982, 876.
21. (a) Newman, M. S.; Goble, P. H., J. Am. Chem. Soc. 1960, 82, 4098.
O
(b) Takeshima, T., J. Am. Chem. Soc. 1953, 75, 3309.
O
22. Swaminathan, S.; Narayanan, K. V., Chem. Rev. 1971, 71, 429.
10% Pd0/C
H
formic acid H
O2N 23. Reagent Chemicals: American Chemical Society Specifications, 8th ed.;
(12)
N
American Chemical Society: Washington, 1993; p 348.
H H reflux
H H
76 94%
24. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals,
H2N
N
3rd ed.; Pergamon: New York, 1988; p 185.
H
Kirk F. Eidman
Scios Nova, Baltimore, MD, USA
The Rupe Rearrangement. Tertiary propargyl alcohols
isomerize to Ä…,²-unsaturated ketones in the Rupe rearrangement
A list of General Abbreviations appears on the front Endpapers