Acetoacetic acid

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Acetoacetic acid
Acetoacetic acid.png
Acetoacetic-acid-3D-balls.png
Names
Preferred IUPAC name
3-Oxobutanoic acid[1]
Other names
Acetoacetic acid (no longer recommended[1])
Diacetic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
KEGG
Properties
C4H6O3
Molar mass 102.088 g/mol
Appearance colorless, oily liquid
Melting point 36.5 °C (97.7 °F; 309.6 K)
Boiling point Decomposes
soluble
Solubility 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).
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Infobox references

Acetoacetic acid (also diacetic acid) is the organic compound with the formula CH3COCH2COOH. It is the simplest beta-keto acid group, 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]

Biochemistry[edit]

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

Acetoacetate is produced in mitochondria of the liver from acetoacetyl coenzyme A (CoA). First another acetyl group is added from acetyl CoA to form 3-hydroxy-3-methylgluteryl CoA, and then an acetyl CoA is lost from this yielding acetoacetate. The initial acetoacetate can come from the last cycle in the beta oxidation of a fatty acid, or it can be synthesized from two acetyl CoA molecules, catalyzed by thiolase.[4]

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.[6]

Synthesis and properties[edit]

Acetoacetic acid may be prepared by the hydrolysis of diketene. Its esters are produced analogously via an reaction between diketene and alcohols,[3] and acetoacetic acid can be prepared by the hydrolysis of these species.[7] In general, acetoacetic acid is generated at 0 °C and used in situ immediately.[8] It decomposes at a moderate rate to 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.[9] It is a weak acid (like most alkyl carboxylic acids), with a pKa 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.[10]

3-Oxobutyric acid KetoEnol.svg

Applications[edit]

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 2-aminoindane:[11]

Diketene reaction Sai 2007
Pigment Yellow 16 is a typical dye containing the acetoacetyl group

Detection[edit]

Acetoacetic acid is measured in the urine of people with diabetes to test for ketoacidosis[12] and for monitoring people on a ketogenic or low-carbohydrate diet,[13][14] 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[12] and may be falsely low at diagnosis.[15]

Similar tests are used in dairy cows to test for ketosis.[16]

See also[edit]

References[edit]

  1. ^ a b 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. ^ a b c Franz Dietrich Klingler; Wolfgang Ebertz (2005). "Oxocarboxylic Acids". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a18_313. 
  4. ^ Lubert Stryer (1981). Biochemistry (2nd ed.). p. 393. 
  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. ^ Stryer 1981, p. 394.
  7. ^ Robert C. Krueger (1952). "Crystalline Acetoacetic Acid". Journal of the American Chemical Society. 74 (21): 5536–5536. doi:10.1021/ja01141a521. 
  8. ^ Reynolds, George A.; VanAllan, J. A. (1952). "Methylglyoxal-ω-Phenylhydrazone". Organic Syntheses. 32: 84. doi:10.15227/orgsyn.032.0084. ; Collective Volume, 4, p. 633 
  9. ^ Hay, R. W.; Bond, M. A. (1967). "Kinetics of decarboxilation of acetoacetic acid". Aust. J. Chem. 20 (9): 1823–8. doi:10.1071/CH9671823. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ a b 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. 
  13. ^ 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. 
  14. ^ Sumithran, Priya; Proietto, Joseph (2008). "Ketogenic diets for weight loss: A review of their principles, safety and efficacy". Obesity Research & Clinical Practice. 2: 1–13. doi:10.1016/j.orcp.2007.11.003. 
  15. ^ Misra, S; Oliver, NS (28 October 2015). "Diabetic ketoacidosis in adults" (PDF). BMJ (Clinical research ed.). 351: h5660. doi:10.1136/bmj.h5660. PMID 26510442. 
  16. ^ 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.