Pivalic acid

Chemical Properties

white crystalline low melting mass

Uses

Pivalic Acid is a metabolite of oral cephem (β-lactam) antibiotics such as S-1108, containing pivaloyl moieties.

Uses

Pivalic acid can be employed:

• As a co-catalyst with palladium for the arylation of unactivated arenes and N-heterocycles.
• As an additive to facilitate the carbonylative suzuki reactions to synthesize biaryl ketones from aryl iodides and arylboronic acids by using palladium nanoparticles as catalyst.
• In the cyclization reaction of benzamides with alkynes to synthesize isoquinolones in the presence of 8-aminoquinoline ligand and cobalt catalyst.

Uses

Valuable building block offered as a solution in dichloromethane for more convenient handling.

Definition

ChEBI: Pivalic acid is a branched, short-chain fatty acid composed of propanoic acid having two methyl substituents at the 2-position. It is a branched-chain saturated fatty acid, a methyl-branched fatty acid and a short-chain fatty acid. It is a conjugate acid of a pivalate.

Preparation

Pivalic acid is prepared through the bromoform reaction on pinacolone, or from tert-butyl chloride, magnesium and carbon dioxide; a recent improvement involves the reaction of tert-butyl chloride, lithium and magnesium-2-ethoxyethanate^[1].

Synthesis Reference(s)

Journal of the American Chemical Society, 98, p. 1275, 1976 DOI: 10.1021/ja00421a046
Organic Syntheses, Coll. Vol. 1, p. 524, 1941

General Description

Pivalic acid is a colored crystalline solid of low toxicity that is soluble in water, ethyl alcohol and diethyl ether.

Air & Water Reactions

With mixing, water soluble.

Reactivity Profile

Pivalic acid is a carboxylic acid. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Carboxylic acids with six or fewer carbon atoms are freely or moderately soluble in water; those with more than six carbons are slightly soluble in water. Soluble carboxylic acid dissociate to an extent in water to yield hydrogen ions. The pH of solutions of carboxylic acids is therefore less than 7.0. Many insoluble carboxylic acids react rapidly with aqueous solutions containing a chemical base and dissolve as the neutralization generates a soluble salt. Carboxylic acids in aqueous solution and liquid or molten carboxylic acids can react with active metals to form gaseous hydrogen and a metal salt. Such reactions occur in principle for solid carboxylic acids as well, but are slow if the solid acid remains dry. Even "insoluble" carboxylic acids may absorb enough water from the air and dissolve sufficiently in Pivalic acid to corrode or dissolve iron, steel, and aluminum parts and containers. Carboxylic acids, like other acids, react with cyanide salts to generate gaseous hydrogen cyanide. The reaction is slower for dry, solid carboxylic acids. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions.

Health Hazard

CALL FOR MEDICAL AID. SOLID: Irritating to eyes and skin. Harmful if swallowed. IF IN EYES OR ON SKIN, flush with running water for at least 15 minutes; hold eyelids open if necessary. Wash skin with soap and water. Remove and isolate contaminated clothing and shoes at the site. If SWALLOWED and victim is UNCONSCIOUS OR HAVING CONVULSIONS, do nothing except keep victim warm. Because of low volatility, it is relatively harmless when inhaled at normal ambient temperature (around 20°C). It is slightly toxic by ingestion or skin absorption. The vapor is irritating at elevated temperatures. Can cause considerable discomfort by oral routes; may cause reversible or irreversible changes to exposed tissue, not permanent injury or death.

Fire Hazard

COMBUSTIBLE. Produces vapors irritating to eyes and skin. Decomposes to produce acrid smoke and fumes.

reaction suitability

reaction type: C-H Activation

Safety Profile

Moderately toxic by ingestion and skin contact. Questionable carcinogen with experimental tumorigenic data. When heated to decomposition it emits acrid smoke and irritating fumes.

Purification Methods

Fractionally distil the acid under reduced pressure, then fractionally crystallise it from its melt. Recrystallise it from *benzene. [Beilstein 2 IV 908.]

References

[1] Hamilton, G.S. and Ladd, C.L. (2015). Pivalic Acid. In Encyclopedia of Reagents for Organic Synthesis. https://doi.org/10.1002/047084289X.rp176.pub2