Acetone from acetoacetic acid

Hydroxy-n-valeric acid is perhaps the most frequently observed urinary metabolite after methylcitrate and 3-hydroxypropionate, and 3-oxo-/r-valeric acid may also occur during severe ketosis. During non-ketotic periods, when propionyl-CoA accumulation still occurs, two molecules of this substrate may condense via the action of a j3-ketothiolase to form 2-methyl-3-oxovaleryl-CoA, resulting ultimately in the excretion of 2-methyl-3-hydroxyvaleric and 2-methyl-3-oxovaleric acids in the urine (Lehnert et ai, 1978 Truscott et al., 1979). The occurrence of these keto acids explains the presence of long-chain ketones in the urine, formed by decarboxylation in an analogous manner to the formation of acetone from acetoacetate (Fig. 11.6). 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

A mixture of 4.98 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 2.3 g of aminocrotonic acid methyl ester, and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100°C in an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm and height 25 cm) and then eluted with a 20 1 mixture of chloroform and acetone. The effluent containing the subject product was concentrated and checked by thin layer chromatography. The powdery product thus obtained was dissolved in acetone and after adjusting the solution with an ethanol solution saturated with hydrogen chloride to pH 1 -2, the solution was concentrated to provide 2 g of 2,6-dimethyl-4-(3 -nitrophenyl)-1,4-dihydropyridlne-3,5-dicarboxylic acid 3-methylester-5- -(N-benzyl-N-methylamino)ethyl ester hydrochloride. The product thus obtained was then crystallized from an acetone mixture, melting point 136°Cto 140°C (decomposed). 

Between 1906 and 1908 the breakdown of fatty acids to acetone was detected by Embden in perfused livers. Only fatty acids with even numbers of carbon atoms produced this effect. The acetone was postulated to have originated from acetoacetate. For the next 30 years the 6-oxidative route of fatty acid oxidation was generally unchallenged. By 1935-1936 however much more accurate determinations of the yields of acetoacetate per mole of fatty acid consumed (Deuel et al., Jowett and Quastel) indicated convincingly that more than one mole of acetoacetate might be obtained from 6C or 8C fatty acids. (Octanoic acid was often used as a model fatty acid as it is the longest fatty acid which is sufficiently soluble in water at pH 7.0 for experimental purposes.) The possibility had therefore to be entertained that 2C fragments could recondense (MacKay et al. 1942). 

Acetone cyanohydrin nitrate, a reagent prepared from the nitration of acetone cyanohydrin with acetic anhydride-nitric acid, has been used for the alkaline nitration of alkyl-substituted malonate esters. In these reactions sodium hydride is used to form the carbanions of the malonate esters, which on reaction with acetone cyanohydrin nitrate form the corresponding nitromalonates. The use of a 100 % excess of sodium hydride in these reactions causes the nitromalonates to decompose by decarboxylation to the corresponding a-nitroesters. Alkyl-substituted acetoacetic acid esters behave in a similar way and have been used to synthesize a-nitroesters. Yields of a-nitroesters from both methods average 50-55 %. 

Liver mitochondria can convert acetyl CoA derived from fatty acid oxidation into the ketone bodies, acetoacetate and (3-hydroxybutyrate. (Acetone, a nonmetabolizable ketone body, is produced spontaneously from acetoacetate in the blood.) Peripheral tissues possessing mitochondria can oxidize 3-hydroxybutyrate to acetoacetate, which can be reconverted to acetyl CoA, thus producing energy for the cell. 

In an exactly similar way acetone (B.P. 56°) can be prepared from acetoacetic ester (see p. 148) methyl propyl ketone (B.P. 102°) from monoethyl acetoacetic ester (see p. 140). The higher ketones may be purified by washing with saturated brine until alcohol is removed they are then, after drying over calcium chloride, fractionated. In all these hydrolyses dilute aqueous or alcoholic potash, or dilute sulphuric acid, may be used in place of baryta water. The yields in these preparations are all of the same order—70%. 

Precursors. Precursors for this reaction are compounds exhibiting keto-enol tau-tomerism. These compounds are usually secondary metabolites derived from the glycolysis cycle of yeast metabolism during fermentation. Pyruvic acid is one of the main precursor compounds involved in this type of reaction. During yeast fermentation it is decarboxylated to acetaldehyde and then reduced to ethanol. Acetone, ace-toin (3-hydroxybutan-2-one), oxalacetic acid, acetoacetic acid and diacetyl, among others, are also secondary metabolites likely to participate in this kind of condensation reaction with anthocyanins. 

During prolonged starvation or when carbohydrate metabolism is severely impaired, as in uncontrolled diabetes mel-iitus (see Chapter 25), the formation of acetyl-CoA exceeds the supply of oxaioacetate. The abundance of acetyl-CoA results from excessive mobilization of fatty acids from adipose tissue and excessive degradation of the fatty acids by p-oxidation in the liver. The resulting acetyl-CoA excess is diverted to an alternative pathway in the mitochondria and forms acetoacetic acid, P-hydroxybutyric acid, and acetone—three compounds known collectively as ketone bodies (Figure 26-9). The presence of ketone bodies is a frequent finding in severe, uncontrolled diabetes melUtus. 

What quantity of acetone can be produced from 125 mg of acetoacetic acid (CH3COCH2CO2H) ... 

The answer is d. (Murray, pp 190-198. Scriver, pp 1521-1552. Sack, pp 121-138. Wilson, pp 287-317.) Ketone bodies include acetoacetic acid and P-hydroxybutyrate, which are formed in the liver, and acetone, which is spontaneously formed from excess acetoacetate in the blood. Starvation results in glycogen depletion and deficiency of carbohydrates, causing increased use of lipids as energy sources. Increased oxidation of fatty acids produces acetyl coenzyme A (CoA) and acetoacetyl CoA, a precursor of ketone bodies. Although the liver synthesizes ketone bodies from excess... 

For the acetyl CoA produced by the p-oxidation of fatty acids to efficiently enter the citric acid cycle, there must be an adequate supply of oxaloacetate. If glycolysis and p-oxidation are occurring at the same rate, there will be a steady supply of pyruvate (from glycolysis) that can be converted to oxaloacetate. But what happens if the supply of oxaloacetate is too low to allow all of the acetyl CoA to enter the citric acid cycle Under these conditions, acetyl CoA is converted to the so-called ketone bodies p-hydroxybut)rrate, acetone, and acetoacetate (Figure 23.9). 

Under some conditions, fatty acid degradation occurs more rapidly than glycolysis. As a result, a large amount of acetyl CoA is produced from fatty acids, but little oxaloac-etate is generated from pyruvate. When oxaloacetate levels are too low, the excess acetyl CoA is converted to the ketone bodies acetone, acetoacetate, and (3-hydroxybutyrate. 

Apart from the symptoms we have already discussed, type 1 diabetics tend to present with another characteristic readily picked up by an alert clinician. Since sugar is not being properly handled, the tissues have to obtain more of their energy from fatty acid oxidation, but the capacity of the Krebs cycle tends also to be impaired, so that in uncontrolled type 1 diabetes there is a pile-up of ketone bodies made by the Uver. This is discussed in more detail in Topic 21. Acetoacetic acid, one of the two major ketone bodies, spontaneously breaks down to acetone, which, being very volatile, is easily lost into the air the patient breathes out. The smell of acetone on the breath is unmistakeable. This should not of course be detectable if the diabetes is well managed. 

Fatty acids undergo 3-oxidation, producing acetyl CoA, NADH and FADH2. The NADH and FADH2 are oxidised by the respiratory chain to form ATP which is used for gluconeogenesis (Chapter 34) and for urea synthesis (Chapter 44). The acetyl CoA forms the ketoacids acetoacetate and P-hydroxybutyrate, known as the ketone bodies . Acetone, formed in small amounts from acetoacetate, causes the fruity smell of the breath in ketotic patients or people on low carbohydrate diets (e.g. the Atkins diet ). NB When the ratio of NADH NAD is high, as in diabetic ketoacidosis (DKA), the equilibrium of the P-... 

The concentration of ketone bodies in the blood of healthy, well-fed humans is approximately 0.01 mM/L. However, in persons suffering from starvation or diabetes mellitus, the concentration of ketone bodies may increase to as much as 500 times normal. Under these conditions, the concentration of acetoacetic acid increases to the point where it undergoes spontaneous decarboxylation to form acetone and carbon dioxide. Acetone is not... 

Acetoacetyl Co A is built from two acetyl Co A molecules. Free acetoacetic acid is either formed from acetoacetyl CoA or from /5-hydroxybutyric acid (Fig. 50). Acetoacetic acid decarboxylates spontaneously to acetone. Reduction of acetoacetyl CoA yields j8-hydroxybutyryl CoA which may be transformed to a polymeric derivative (Fig. 50), to butyric acid, or to butanol (Fig. 51). 

The question arises as to whether acetone is a primary product of the oxidation of isovalerate or is formed secondarily by decarboxylation of acetoacetate. The experimental results of Zabin and Bloch are in accord with a reaction mechanism in which isovaleric acid is oxidized initially at the carbon 2-position to yield a 3-carbon and a 2-carbon fragment. This conclusion is based on the high absolute C concentrations found in the methyl carbons of acetone and also in comparison to that in the methyl or methylene carbons of acetoacetate. Secondly, the C C ratios were significantly greater in the acetone fractions than in the corresponding carbon atoms of acetoacetate. This finding can be explained only if acetone is formed directly from isovaleric acid, but is at variance with the assumption that acetone arose exclusively by decarboxylation of acetoacetate. The authors also point out that it is possible that the postulated 3-carbon intermediate is not acetone, but that acetone is formed in a side reaction from a more labile 3-carbon precursor. 

Ketone bodies Acetoacetate and 3-hydroxybutyrate (not chemically a ketone) formed in the liver from fatty acids in the fasting state and released into the circulation as metabolic fuels for use by other tissues. Acetone is also formed non-enzymically from acetoacetate. 

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