Acetoacetic acid

Acetoacetic acid (IUPAC name: 3-Oxobutanoic acid, also known as Acetonecarboxylic acid or Diacetic acid) is the organic compound with the formula CH₃COCH₂COOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stable, are produced on a large scale industrially as precursors to dyes. Acetoacetic acid is a weak acid.^[3]

Acetoacetic acid

Names
Preferred IUPAC name 3-Oxobutanoic acid[1]
Systematic IUPAC name 3-Oxobutyric acid
Other names Acetoacetic acid Diacetic acid Acetylacetic acid Acetonecarboxylic acid
Identifiers
CAS Number	541-50-4 Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:15344 Y
ChEMBL	ChEMBL1230762 N
ChemSpider	94 Y
DrugBank	DB01762 N
KEGG	C00164 Y
PubChem CID	96
UNII	4ZI204Y1MC Y
CompTox Dashboard (EPA)	DTXSID00202441
InChI InChI=1S/C4H6O3/c1-3(5)2-4(6)7/h2H2,1H3,(H,6,7) Y Key: WDJHALXBUFZDSR-UHFFFAOYSA-N Y InChI=1/C4H6O3/c1-3(5)2-4(6)7/h2H2,1H3,(H,6,7) Key: WDJHALXBUFZDSR-UHFFFAOYAH
SMILES O=C(C)CC(=O)O
Properties
Chemical formula	C4H6O3
Molar mass	102.089 g·mol−1
Appearance	Colorless, oily liquid
Melting point	36.5 °C (97.7 °F; 309.6 K)
Boiling point	Decomposes
Solubility in water	Soluble
Solubility in organic solvents	Soluble in ethanol, ether
Acidity (pKa)	3.58[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is YN ?) Infobox references

Biochemistry

Under typical physiological conditions, acetoacetic acid exists as its conjugate base, acetoacetate:

AcCH₂CO₂H → AcCH₂CO−2 + H⁺

Unbound acetoacetate is primarily produced by liver mitochondria from its thioester with coenzyme A (CoA):

AcCH₂C(O)−CoA + OH⁻ → AcCH₂CO−2 + H−CoA

The acetoacetate-CoA itself is formed by three routes:

• 3-hydroxy-3-methylglutaryl CoA releases acetyl CoA and acetoacetate:

  ⁻O₂CCH₂−C(Me)(OH)−CH₂C(O)−CoA → ⁻O₂CCH₂−Ac + Ac−CoA

• Acetoacetyl-CoA can come from beta oxidation of butyryl-CoA:

  Et−CH₂C(O)−CoA + 2NAD⁺ + H₂O + FAD → Ac−CH₂C(O)−CoA + 2NADH + FADH₂

• Condensation of pair of acetyl CoA molecules as catalyzed by thiolase.^[4]: 393

  2Ac−CoA → AcCH₂C(O)−CoA + H−CoA

In mammals, acetoacetate produced in the liver (along with the other two "ketone bodies") is released into the bloodstream as an energy source during periods of fasting, exercise, or as a result of type 1 diabetes mellitus.^[5] First, a CoA group is enzymatically transferred to it from succinyl CoA, converting it back to acetoacetyl CoA; this is then broken into two acetyl CoA molecules by thiolase, and these then enter the citric acid cycle. Heart muscle and renal cortex prefer acetoacetate over glucose. The brain uses acetoacetate when glucose levels are low due to fasting or diabetes.^[4]: 394

Synthesis and properties

Acetoacetic acid may be prepared by the hydrolysis of diketene. Its esters are produced analogously via reactions between diketene and alcohols,^[3] and acetoacetic acid can be prepared by the hydrolysis of these species.^[6] In general, acetoacetic acid is generated at 0 °C and used in situ immediately.^[7]

It decomposes at a moderate reaction rate into acetone and carbon dioxide:

CH₃C(O)CH₂CO₂H → CH₃C(O)CH₃ + CO₂

The acid form has a half-life of 140 minutes at 37 °C in water, whereas the basic form (the anion) has a half-life of 130 hours. That is, it reacts about 55 times more slowly.^[8] The corresponding decarboxylation of trifluoroacetoacetate is used to prepare trifluoroacetone:

CF₃C(O)CH₂CO₂H → CF₃C(O)CH₃ + CO₂

It is a weak acid (like most alkyl carboxylic acids), with a pK_a of 3.58.

Acetoacetic acid displays keto-enol tautomerisation, with the enol form being partially stabilised by extended conjugation and intramolecular H-bonding. The equilibrium is strongly solvent depended; with the keto form dominating in polar solvents (98% in water) and the enol form accounting for 25-49% of material in non-polar solvents.^[9]

Applications

Pigment Yellow 16 is a typical dye containing the acetoacetyl group

Acetoacetic esters are used for the acetoacetylation reaction, which is widely used in the production of arylide yellows and diarylide dyes.^[3] Although the esters can be used in this reaction, diketene also reacts with alcohols and amines to the corresponding acetoacetic acid derivatives in a process called acetoacetylation. An example is the reaction with 4-aminoindane:^[10]

Detection

Acetoacetic acid is measured in the urine of people with diabetes to test for ketoacidosis^[11] and for monitoring people on a ketogenic or low-carbohydrate diet.^[12][13] This is done using dipsticks coated in nitroprusside or similar reagents. Nitroprusside changes from pink to purple in the presence of acetoacetate, the conjugate base of acetoacetic acid, and the colour change is graded by eye. The test does not measure β-hydroxybutyrate, the most abundant ketone in the body; during treatment of ketoacidosis β-hydroxybutyrate is converted to acetoacetate so the test is not useful after treatment begins^[11] and may be falsely low at diagnosis.^[14]

Similar tests are used in dairy cows to test for ketosis.^[15]

See also

• 3-Hydroxybutyrate dehydrogenase
• Ethyl acetoacetate

References

1. "Front Matter". Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 748. doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4.
2. Dawson, R. M. C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959.
3. Franz Dietrich Klingler; Wolfgang Ebertz (2005). "Oxocarboxylic Acids". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a18_313. ISBN 978-3527306732.
4. Lubert Stryer (1981). Biochemistry (2nd ed.).
5. Stryer, Lubert (1995). Biochemistry (Fourth ed.). New York: W.H. Freeman and Company. pp. 510–515, 581–613, 775–778. ISBN 0-7167-2009-4.
6. Robert C. Krueger (1952). "Crystalline Acetoacetic Acid". Journal of the American Chemical Society. 74 (21): 5536. doi:10.1021/ja01141a521.
7. Reynolds, George A.; VanAllan, J. A. (1952). "Methylglyoxal-ω-Phenylhydrazone". Organic Syntheses. 32: 84. doi:10.15227/orgsyn.032.0084; Collected Volumes, vol. 4, p. 633.
8. Hay, R. W.; Bond, M. A. (1967). "Kinetics of decarboxilation of acetoacetic acid". Aust. J. Chem. 20 (9): 1823–8. doi:10.1071/CH9671823.
9. Grande, Karen D.; Rosenfeld, Stuart M. (1980). "Tautomeric equilibriums in acetoacetic acid". The Journal of Organic Chemistry. 45 (9): 1626–1628. doi:10.1021/jo01297a017. ISSN 0022-3263.
10. Kiran Kumar Solingapuram Sai; Thomas M. Gilbert; Douglas A. Klumpp (2007). "Knorr Cyclizations and Distonic Superelectrophiles". J. Org. Chem. 72 (25): 9761–9764. doi:10.1021/jo7013092. PMID 17999519.
11. Nyenwe, EA; Kitabchi, AE (April 2016). "The evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and management". Metabolism: Clinical and Experimental. 65 (4): 507–21. doi:10.1016/j.metabol.2015.12.007. PMID 26975543.
12. Hartman, AL; Vining, EP (January 2007). "Clinical aspects of the ketogenic diet". Epilepsia. 48 (1): 31–42. doi:10.1111/j.1528-1167.2007.00914.x. PMID 17241206. S2CID 21195842.
13. Sumithran, Priya; Proietto, Joseph (2008). "Ketogenic diets for weight loss: A review of their principles, safety and efficacy". Obesity Research & Clinical Practice. 2 (1): I–II. doi:10.1016/j.orcp.2007.11.003. PMID 24351673.
14. Misra, S; Oliver, NS (28 October 2015). "Diabetic ketoacidosis in adults" (PDF). BMJ (Clinical Research Ed.). 351: h5660. doi:10.1136/bmj.h5660. hdl:10044/1/41091. PMID 26510442. S2CID 2819002.
15. Tatone, EH; Gordon, JL; Hubbs, J; LeBlanc, SJ; DeVries, TJ; Duffield, TF (1 August 2016). "A systematic review and meta-analysis of the diagnostic accuracy of point-of-care tests for the detection of hyperketonemia in dairy cows". Preventive Veterinary Medicine. 130: 18–32. doi:10.1016/j.prevetmed.2016.06.002. PMID 27435643.