Acetic Acid1

[64-19-7]  · C2H4O2  · Acetic Acid  · (MW 60.05)

(common organic reaction solvent; reagent for protonolysis of organometallic compounds,5,6 synthesis of aromatic methyl ketones,10 lactones,15 heterocycles13)

Alternate Name: ethanoic acid.

Physical Data: weak organic acid, pKa 4.77; d204 1.049 g cm-3; mp 14.7 °C; bp 118 °C (30 °C/31 mmHg). Forms azeotropes with many common solvents, such as benzene, pyridine, DMF, and dioxane.

Solubility: miscible with water, ethanol, acetone, benzene, ether, and carbon tetrachloride; insol CS2.

Form Supplied in: widely available as glacial acetic acid, >98% purity.

Analysis of Reagent Purity: analyzed by titration with base.2,18 High purity grades of acetic acid (>99%) are determined by the freeze-point method. Formic acid content can be determined by a redox titration based on oxidation with lead tetraacetate. Methods for analysis of trace impurities such as water, iron, or chlorine are known.

Purification: among many methods, distillation over traces of oxidants in the presence of Ac2O is effective.19

Handling, Storage, and Precautions: acetic acid is flammable with a flash point of 40 °C.3 This hazard is often overlooked by the practicing chemist and has been the source of laboratory accidents. Acetic acid is a corrosive material. Basic safety equipment including eye protection, gloves, and a chemical apron should be worn during all operations with acetic acid. Vapors will cause intense irritation to mouth, nose, eyes, skin, and upper respiratory tract. Use of an appropriate NIOSH/MSHA respirator is recommended. Use in a fume hood.

Acetic Acid as Reaction Solvent.

The most common use of acetic acid in organic synthesis is as a reaction solvent. Many types of organic compounds are highly soluble in this reagent, and the stability of acetic acid towards many reagents is good. Examples of reactions often performed in acetic acid include bromination, hydrolysis, solvolysis, reductions, and hydrogenations. A discussion of acetic acid as a reaction solvent with a given reagent will be found in the detailed treatments of individual reagents.

Protonolysis of Organometallic Compounds.

Alkylboranes are readily cleaved by protonolysis with acetic acid.4 In contrast, organoboranes are stable to water, mineral acids, and aqueous base. This reaction provides a convenient alternative to catalytic hydrogenation in cases where catalyst poisoning or selectivity would be problematic (eq 1).4 The hydroboration of alkynes followed by protonolysis with acetic acid is a selective sequence producing cis-alkenes (eq 2).5

Tetraorganoborates containing alkenyl or alkynyl groups react with acetic acid in a completely different manner, leading to the formation of new carbon-carbon bonds. The reader is referred to relevant articles dealing with organoborates for discussions of this reaction.

Acetic acid has been used to cleave organosilicon intermediates produced during the Peterson reaction (eq 3).6 The acid-catalyzed elimination is anti; this complements the base-catalyzed elimination, which is syn (eq 4).

Acetic acid promotes the stereospecific conversion of trimethylsilyl epoxides to enol acetates (eq 5).7 In all cases studied, addition of the acetate nucleophile is a to the silyl group. The stereochemistry of the overall reaction is consistent with nucleophilic addition and inversion, followed by anti b-elimination.

Cleavage of a trimethylsilylmethylcyclopropane by an acetic acid-Boron Trifluoride trifluoride complex results in formation of a terminal alkene (eq 6).8

Selective cleavage of a 1,2-disilylalkene allows synthesis of the 2-trimethylsilyl-1-alkene, which is not accessible through direct hydrosilation (eq 7).9

Acetylation of Aromatic Compounds.

Acetic acid will acetylate electron-rich aromatic compounds such as phenols or anisoles. Best results are achieved with Boron Trifluoride10 (eq 8) or Trifluoroacetic Anhydride11 (eq 9) as an acid catalyst, although other acids such as Zinc Chloride12 have been used.

Synthesis of Heterocycles.

Amino alcohols are cyclized to methyloxazolines by condensation with acetic acid (eq 10).13

A variety of other heterocyclic systems have been formed by dehydration or rearrangement in acetic acid (eqs 11 and 12).14

Formation of Lactones.

Treatment of alkenes with Manganese(III) Acetate in acetic acid leads to formation of lactones.15 The reaction is general for all alkenes and carboxylic acids, but best yields are obtained with terminal alkenes and acetic acid. Only the lactone of the g-hydroxy acid is produced. The most convenient laboratory procedure15a uses manganese(II) acetate and Potassium Permanganate to form manganese(III) acetate in situ (eq 13). The mechanism of the reaction involves addition of a carboxymethyl radical to the alkene; the carboxymethyl radicals are generated by thermolysis of the manganese(III) acetate.

Other carboxylic acids can be used in place of acetic acid. Of these, Cyanoacetic Acid is particularly reactive due to the high stability of the a-cyano radical intermediate (eq 14).15a,16 Lactones are efficiently formed by the intramolecular reaction of unsaturated acids (eq 15).17

Related Reagents.

Acetic Anhydride; Formic Acid; Glyoxylic Acid; Oxalic Acid; Propionic Acid; Trifluoroacetic Acid.

1. (a) Acetic Acid and its Derivatives; Agreda, V. H.; Zoeller, J. R., Eds.; Dekker: New York, 1993. (b) Acetic Acid; Celanese Corporation of America: New York, 1964. (c) Acetic Acid and Anhydrides; Union Carbide Chemical Company: New York, 1960.
2. Encyclopedia of Industrial Chemical Analysis; Snell, F. D.; Etter, L. S., Eds.; Interscience: New York, 1971; Vol. 4, pp 97-100.
3. Acetic Acid and its Derivatives; Agreda, V. H.; Zoeller, J. R., Eds.; Dekker: New York, 1993; pp 361-374.
4. Brown, H. C.; Murray, K. JACS 1959, 81, 4108.
5. (a) Brown, H. C.; Zweifel, G. JACS 1961, 83, 3834. (b) Zweifel, G.; Arzoumanian, H. JACS 1967, 89, 5086. (c) Plamondon, J.; Snow, J. T.; Zweifel, G. Organomet. Chem. Synth. 1971, 1, 249.
6. (a) Hudrlik, P. F.; Peterson, D. TL 1972, 1785. (b) Hudrlik, P. F.; Peterson, D. JACS 1975, 97, 1464. (c) Hudrlik, P. F.; Peterson, D.; Rona, R. J. JOC 1975, 40, 2263.
7. Hudrlik, P. F.; Hudrlik, A. M.; Rona, R. J.; Misra, R. N.; Withers, G. P. JACS 1977, 99, 1993.
8. Ochiai, M.; Sumi, K.; Fujita, E. CPB 1983, 31, 3931.
9. Hudrlik, P. F.; Schwartz, R. H.; Hogan, J. C. JOC 1979, 44, 155.
10. Da Re, P.; Cimatoribus, L. JOC 1961, 26, 3650.
11. (a) Bourne, E. J.; Stacey, M.; Tatlow, J. C.; Tedder, J. M. JCS 1951, 718.
12. Cooper, S. R. OS 1941, 21, 103; Cooper, S. R. OSC 1955, 3, 761.
13. (a) Allen, P., Jr.; Ginos, J. JOC 1963, 28, 2759. (b) Frump, J. A. CRV 1971, 71, 483.
14. (a) Stavely, H. E. JACS 1951, 73, 3450. (b) Micheel, F.; Austrup, R.; Striebeck, A. CB 1961, 94, 132.
15. (a) Heiba, E. I.; Dessau, R. M.; Rodewald, P. G. JACS 1974, 96, 7977. (b) Bush, J. B., Jr.; Finkbeiner, H. JACS 1968, 90, 5903. (c) Heiba, E. I.; Dessau, R. M.; Koehl, W. J., Jr. JACS 1968, 90, 5905.
16. Corey, E. J.; Gross, A. W. TL 1985, 26, 4291.
17. Corey, E. J.; Kang, M. JACS 1984, 106, 5384.
18. Reagent Chemicals: American Chemical Society Specifications, 8th ed.; American Chemical Society: Washington, DC, 1993; pp 98-100.
19. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: New York, 1988; p 67.

Kirk F. Eidman

Scios Nova, Baltimore, MD, USA

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