acetoacetic acid

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

:{{chem2|AcCH2CO2H -> AcCH2CO2- + H+}}

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

:{{chem2|AcCH2C(O)\sCoA + OH- -> AcCH2CO2- + H\sCoA}}

The acetoacetate-CoA itself is formed by three routes:

• 3-hydroxy-3-methylglutaryl CoA releases acetyl CoA and acetoacetate:
• :{{chem2|-O2CCH2\sC(Me)(OH)\sCH2C(O)\sCoA -> -O2CCH2\sAc + Ac\sCoA}}
• Acetoacetyl-CoA can come from beta oxidation of butyryl-CoA:
• :{{chem2|Et\sCH2C(O)\sCoA + 2NAD+ + H2O + FAD -> Ac\sCH2C(O)\sCoA + 2NADH + FADH2}}
• Condensation of pair of acetyl CoA molecules as catalyzed by thiolase.{{cite book|author=Lubert Stryer|author-link=Lubert Stryer|title=Biochemistry|date=1981 |edition=2nd|title-link=Biochemistry (Stryer)}}{{rp|393}}
• :{{chem2|2Ac\sCoA -> AcCH2C(O)\sCoA + H\sCoA}}

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.{{cite book |last1= Stryer |first1= Lubert | title=Biochemistry. | edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 510–515, 581–613, 775–778 |isbn= 0-7167-2009-4 }} 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.{{rp|394}}

Acetoacetic acid may be prepared by the hydrolysis of diketene. Its esters are produced analogously via reactions between diketene and alcohols,{{cite book|author=Franz Dietrich Klingler|author2=Wolfgang Ebertz|chapter=Oxocarboxylic Acids|title=Ullmann's Encyclopedia of Industrial Chemistry|year=2005|publisher=Wiley-VCH|place=Weinheim|doi=10.1002/14356007.a18_313|isbn=978-3527306732}} and acetoacetic acid can be prepared by the hydrolysis of these species.{{cite journal

| author = Robert C. Krueger

| title = Crystalline Acetoacetic Acid

| journal = Journal of the American Chemical Society

| year = 1952

| volume = 74

| issue = 21

| pages = 5536

| doi = 10.1021/ja01141a521 }}

In general, acetoacetic acid is generated at 0 °C and used in situ immediately.{{OrgSynth|last1=Reynolds|first1=George A.|last2=VanAllan|first2=J. A.|title=Methylglyoxal-ω-Phenylhydrazone|journal=Organic Syntheses|year=1952|volume=32|pages=84|prep=CV4P0633|collvol=4|collvolpages=633|doi=10.15227/orgsyn.032.0084}}

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

:{{chem2|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.{{cite journal |doi= 10.1071/CH9671823 |author1=Hay, R. W. |author2=Bond, M. A. |year= 1967|title= Kinetics of decarboxilation of acetoacetic acid|journal= Aust. J. Chem.|volume = 20|issue=9|pages=1823–8}} The corresponding decarboxylation of trifluoroacetoacetate is used to prepare trifluoroacetone:

:{{chem2|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.{{cite journal|last1=Grande|first1=Karen D.|last2=Rosenfeld|first2=Stuart M.|title=Tautomeric equilibriums in acetoacetic acid|journal=The Journal of Organic Chemistry|volume=45|issue=9|year=1980|pages=1626–1628|issn=0022-3263|doi=10.1021/jo01297a017}}

center

File:YellowPig5thTry.png 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. 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:{{cite journal | title = Knorr Cyclizations and Distonic Superelectrophiles |author1=Kiran Kumar Solingapuram Sai |author2=Thomas M. Gilbert |author3=Douglas A. Klumpp | journal = J. Org. Chem. | year = 2007 | volume = 72 | pages = 9761–9764 | doi = 10.1021/jo7013092 | pmid = 17999519 | issue = 25}}

Image:DiketeneReaction.svg

Acetoacetic acid is measured in the urine of people with diabetes to test for ketoacidosis and for monitoring people on a ketogenic or low-carbohydrate diet.{{cite journal|last1=Hartman|first1=AL|last2=Vining|first2=EP|title=Clinical aspects of the ketogenic diet|journal=Epilepsia|date=January 2007|volume=48|issue=1|pages=31–42|doi=10.1111/j.1528-1167.2007.00914.x|pmid=17241206|doi-access=|s2cid=21195842 }}{{cite journal|last1=Sumithran|first1=Priya|last2=Proietto |first2=Joseph|title=Ketogenic diets for weight loss: A review of their principles, safety and efficacy|journal=Obesity Research & Clinical Practice|date=2008 |volume=2|issue=1|pages=I-II|doi=10.1016/j.orcp.2007.11.003|pmid=24351673}} 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{{cite journal|last1=Nyenwe|first1=EA|last2=Kitabchi|first2=AE|title=The evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and management|journal=Metabolism: Clinical and Experimental|date=April 2016|volume=65|issue=4|pages=507–21|pmid=26975543|doi=10.1016/j.metabol.2015.12.007}} and may be falsely low at diagnosis.{{cite journal|last1=Misra|first1=S|last2=Oliver|first2=NS|title=Diabetic ketoacidosis in adults.|journal=BMJ (Clinical Research Ed.)|date=28 October 2015|volume=351|pages=h5660|pmid=26510442|doi=10.1136/bmj.h5660|url=http://spiral.imperial.ac.uk/bitstream/10044/1/41091/2/bmj.h5660.full.pdf|hdl=10044/1/41091|s2cid=2819002|hdl-access=free}}

Similar tests are used in dairy cows to test for ketosis.{{cite journal|last1=Tatone|first1=EH|last2=Gordon|first2=JL|last3=Hubbs|first3=J|last4=LeBlanc|first4=SJ|last5=DeVries|first5=TJ|last6=Duffield|first6=TF|title=A systematic review and meta-analysis of the diagnostic accuracy of point-of-care tests for the detection of hyperketonemia in dairy cows.|journal=Preventive Veterinary Medicine|date=1 August 2016|volume=130|pages=18–32|pmid=27435643|doi=10.1016/j.prevetmed.2016.06.002}}

• 3-Hydroxybutyrate dehydrogenase
• Ethyl acetoacetate

{{Reflist}}

{{Cholesterol and steroid intermediates}}

{{HDAC inhibitors}}

Category:Histone deacetylase inhibitors

Category:Beta-keto acids