Decarboxylation reactions acetoacetic acid

The rate of the enzymic decarboxylation of acetoacetic acid exceeds the rate of the spontaneous reaction by perhaps a billionfold. However, simple amines of appropriate pK also catalyze the reaction, and the difference in rate between catalysis by the enzyme and catalysis by cyanomethylamine (pK 5.5) is only about 100-fold (]00). 

The roots of iminium activation can be traced back to the pioneering works of Knoevenagel [4]. The Knoevenagel condensation became the first reaction that might proceed via iminium catalysis. Next, Pollack reported that several proteins and amino acids catalyzed the decarboxylation of acetoacetic acid. The mechanism suggested by Petersen involves an imine intermediate [5]. 

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 %. 

The decarboxylation of the acetoacetic acid (227) to the hexan-2-one (228) in the presence of 180-labelled water revealed obligatory incorporation of 180 in the antibody-catalysed reaction which is consistent with the decarboxylation proceeding through an imine intermediate.203... 

Gas-phase decarboxylation of /i-ketocarboxylic acids XCOCH2COOH (X = H, OH, and CH3) has also been the subject of theoretical studies.42 Ah initio calculations reveal that decarboxylation via a six-membered (rather than four-membered) ring transition state is favoured. Activation barriers of 23.8, 23.3 and 28.5 kcal mol-1 have been calculated for decarboxylation of 3-oxopropanoic acid, acetoacetic acid, and malonic acid, respectively. Only marginal effects of solvent on the energy barriers and on the geometries of the reactants and transition structures are predicted. The activation energy predicted for reaction of malonic acid agrees well with the experimental value and rate constants have been predicted for decarboxylation of 3-oxopropanoic acid and acetoacetic acid in the gas phase. 

Aldolases such as fructose-1,6-bisphosphate aldolase (FBP-aldolase), a crucial enzyme in glycolysis, catalyze the formation of carbon-carbon bonds, a critical process for the synthesis of complex biological molecules. FBP-aldolase catalyzes the reversible condensation of dihydroxyacetone phosphate (DHAP) and glyceralde-hyde-3-phosphate (G3P) to form fructose-1,6-bisphosphate. There are two classes of aldolases the first, such as the mammalian FBP-aldolase, uses an active-site lysine to form a Schiff base, whereas the second class features an active-site zinc ion to perform the same reaction. Acetoacetate decarboxylase, an example of the second class, catalyzes the decarboxylation of /3-keto acids. A lysine residue is required for good activity of the enzyme the -amine of lysine activates the substrate carbonyl group by forming a Schiff base. 

The decarboxylation of simple /f-ketoacids, such as acetoacetic acid, is not metal promoted (Fig. 5-22) - this is in part due to formation of the chelate complex, which is in the enolate form. Mechanistic studies have indicated that the enol or enolate is inactive in the decarboxylation reaction. The mechanism indicated in Fig. 5-21 is not applicable to the metal complex. 

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. 

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

The action of the lysine-rich polymers was rather selective for OAA, in that pyruvic, malic, malonic, a-ketoglutaric, glucuronic, oxalic, or aspartic acid were not measurably decarboxylated under conditions in which OAA was 90% decarboxylated. Acetoacetic acid was decarboxylated about - 6 as fast as OAA. This selectivity is not in conflict with other reports of decarboxylation of some of these substrates, because conditions of assay have varied rather widely. The rate of decarboxylation may be essentially related to the relative stability of the substrate in question. Two reactions catalyzed separately by different types of thermal polymers describe a sequence, namely OAA pyruvate-> acetate. This sequence can be considered in the context of the beginnings of metabolism (p. 408). 

Ketone body formation, which occurs within the matrix of liver mitochondria, begins with the condensation of two acetyl-CoAs to form acetoacetyl-CoA. Then acetoacetyl-CoA condenses with another acetyl-CoA to form /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA). In the next reaction, HMG-CoA is cleaved to form acetoacetate and acetyl-CoA. Acetoacetate is then reduced to form /3-hydroxybutyrate. Acetone is formed by the spontaneous decarboxylation of acetoacetate when the latter molecule s concentration is high. (This condition, referred to as ketosis, occurs in uncontrolled diabetes, a metabolic disease discussed in Special Interest Box 16.3, and during starvation. In both of these conditions there is a heavy reliance on fat stores and /3-oxidation of fatty acids to supply energy.)... 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

The decarboxylation of y8-keto acids by both primary amines and by acetoacetate decarboxylase has been studied by the method of carbon isotope effects [90,91]. A typical isotope effect for the amine-catalyzed reaction is 1.03 for the cyanomethylamine-catalyzed decarboxylation of acetoacetate at pH 5.0. This demonstrates that the carbon-carbon bond is being cleaved in the rate-determining decarboxylation step. The comparable carbon isotope effect for the enzymatic decarboxylation is = 1.018 and is pH-independent over the range pH... 

The second classical reaction mentioned above is the acetoacetic ester synthesis. this reaction, an ester of acetoacetic acid (3-oxobutanoic acid) such as ethyl acetoacetate is treated with base under thermodynamic control conditions and alkylated, as with the malonic ester synthesis. Reaction with sodium ethoxide in ethanol (since an ethyl ester is being used) generated the enolate and quenching with benzyl bromide led to 84. Saponification and decarboxylation (as above) gave a substituted ketone (85). Although the malonic ester synthesis and the acetoacetic ester synthesis are fundamentally similar, the different substrates lead to formation of either a highly substituted acid or a ketone. The reaction is not restricted to acetoacetate derivatives, and any p-keto-ester can be used (ethyl 3-oxopentanoate for example). ... 

Hemscheidt and Spenser conducted feeding experiments and found that Lycopodium alkaloids are secondary metabolites of lysine (3) [18] (Scheme 1). The decarboxylation of lysine (3) yields cadaverine (4), which consists of five carbons, and this, in turn, is converted into A -piperideine (5). The condensation of A -piperideine (5) with 3-oxoglutaric acid (6) produces 4-(2-piperidyl)acetoacetic acid (7) and this is converted into pelletierine (8) after a decarboxylation reaction. The biosynthetic process from this point to structurally complex Lycopodium alkaloids, such as lycopodine (1) and huperzine A (2), is deduced from the structures of the isolated alkaloids. The condensation of pelletierine (8) with 4-(2-piperidyl)... 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

Protection as an ester overcomes this problem, but the resulting ester enolate is not particularly stable and its reactions can be low yielding. Addition of a second ester to the alpha carbon serves as an activating group and allows the formation of a stabilized enolate. As seen with the acetoacetic ester synthesis, this ester group can be eventually removed by a decarboxylation reaction. The malonic ester synthesis starts with commercially available diethyl malonate. Deprotonation, alkylation of the resulting enolate with an alkyl haUde, and hydrolysis followed by decarboxylation furnishes a carboxylic acid product. 

As another example, consider the decarboxylation of acetoacetate. This compound will decarboxylate under acidic conditions with heating. However, the addition of aniline catalyzes the reaction, so it occurs at less acidic pH and ambient temperature (Eq. 9.10). Formation of the imine between aniline and the p-keto acid leads to a species that is protonated and can act as a good electron sink during the decarboxylation. Hydrolysis of the enamine product gives the ketone and regenerates the catalyst, thus leading to turnover. 

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. 

Dihydroxyphenylpyruvate was not oxidized to homogentisate, thus it cannot be an intermediate in the oxidation of p-hydroxyphenyl-pyruvate. The results suggest that the hydroxylation shift of the side chain and decarboxylation of the p-hydroxyphenylpyruvate are simultaneous processes. Additional evidence that 2,5-dihydroxyphenylpyruvate is not the intermediate was obtained by experiments in which the relative rates of oxidation of this compound and of p-hydroxyphenylpyruvate were compared in homogenates of rat liver, where the reaction proceeded to formation of acetoacetic acid. Oxidation of p-hydroxyphenylpyruvate proceeded much more rapidly. Other analogs of p-hydroxyphenylpyruvate were found to be inactive as substrates. 

Groups bonded to C-2 of either acetoacetic acids or malortic adds, or to C-4 of acetoacetic acids, do not participate in the mechanism of the reaction. Both types of compounds are produced in condensation reactions of the related esters (Chapter 21). Hydrolysis of these esters yields carboxylic adds that are then heated to decarboxylate them. 

We successfully developed several amine-catalyzed decarboxylative aldol/oxa-Michael cascade reactions deploying unprotected and unactivated carbohydrates to access glycosides of acetone. Useful substrates for this transformation are acetonedi-carboxylic acid 9 or acetoacetic acid 10 (Eqs. 4 and 5 Scheme 2.1). These reactions are catalyzed by tertiary amines at room temperature. The corresponding C-glycoside 6 was isolated with good yields (60%) and selectivity (p/a 3/1) [26]. 

Racemic 3-hydroxy[3- C]butyric acid was resolved using the stereospecific 3-hydro-xybutyrate dehydrogenase enzyme (EC 1.1.1.30) which converted the undesired (R)-isomer to [3- " C]acetoacetic acid the latter was decarboxylated in situ by addition of perchloric acid and heating. Subsequent purification of the unreacted (5)-( + )-enantiomer by preparative TLC on silica gel gave a yield of 32.5% in 98% purity. This procedure was an improvement over a previous method that required the addition of acetaldehyde and alcohol dehydrogenase (EC 1.1.1.1) to the reaction mixture to force the equilibrium redox reaction to completion. ... 

---