Decarboxylation reactions malonic acid

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

A typical chemical system is the oxidative decarboxylation of malonic acid catalyzed by cerium ions and bromine, the so-called Zhabotinsky reaction this reaction in a given domain leads to the evolution of sustained oscillations and chemical waves. Furthermore, these states have been observed in a number of enzyme systems. The simplest case is the reaction catalyzed by the enzyme peroxidase. The reaction kinetics display either steady states, bistability, or oscillations. A more complex system is the ubiquitous process of glycolysis catalyzed by a sequence of coordinated enzyme reactions. In a given domain the process readily exhibits continuous oscillations of chemical concentrations and fluxes, which can be recorded by spectroscopic and electrometric techniques. The source of the periodicity is the enzyme phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate by ATP, resulting in the formation of fructose-1,6 biphosphate and ADP. The overall activity of the octameric enzyme is described by an allosteric model with fructose-6-phosphate, ATP, and AMP as controlling ligands. 

SAMPLE SOLUTION (a) By analogy to the thermal decarboxylation of malonic acid, we represent the corresponding reaction of benzoylacetic acid as... 

Previous work on this reaction has included the use of triethanolamine as catalyst, as well as triethylamine as catalyst and solvent. [21-24] The use of elevated temperatures (>75°C) can lead to uncontrolled decarboxylation of malonic acid before condensation, giving acetic acid, which is then too weak a carbon acid to condense. This difficulty means that often up to 3 equivalents of the malonic acid need to be used to achieve good conversion. Our aim in this work was therefore to find a catalyst which would cause the condensation to occur efficiently, but at low enough temperatures to avoid decomposition of the malonic acid. Using THF as solvent and a 1 1 ratio of malonic acid to aldehyde, with 15g of catalyst per mole of reagent, we obtained high levels of conversion of aldehyde in a reasonable time (Table 3). 

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. 

Bronsted LFERs also apply to reactions of metal ions (Lewis acids). Dissociation rates of Ni(II) complexes are correlated with corresponding dissociation equilibrium constants. This suggests that the reactions occur by dissociative interchange, in which breakage of the Ni(II)-ligand bond predominates over formation of the Ni(II)-water bond in the rate-determining step (Hoffmann, 1981). In addition, rates of metal-catalyzed decarboxylation of malonic acid are correlated with the stability constants for the metal-malonate complexes (Prue, 1952). 

The key feature in the decarboxylation of malonic acid derivatives is that they are 1,3-dicarbonyl compounds with the acidic proton of the acid in close proximity to a carbonyl oxygen that is two carbon atoms away from the carboxyl unit. The proximity of these units is essential, which is why decarboxylation occurs with 1,3-dicarbonyl compormds and 7 o with 1,4-dicarbonyl compounds. This is a form of an elimination reaction (see Chapter 12). Going back to the expected product, 97 from 96, it is clear that this is a 1,3-dicarbonyl compound capable of decarboxylation upon heating. That is precisely what occurs, so the product is 98 rather than 97. Decarboxylation of malonic acid derivatives gives functionalized carboxylic acids. 

Consider two examples—a decarboxylation and an Sn2 reaction. The primary kinetic isotope effects (PKIE, ku ku for C relative to the natural abundance C, which is mostly C) at the methylene and carboxyl carbons in the decarboxylation of malonic acid are 1.076 and 1.065, respectively (Eq. 8.19). The values are very close. Indicating that a bond to each of these carbons breaks in the rate-determining step. The isotope effect (Icjs/in the displacement of chloride from benzyl chloride by cyanide is 1.0057, indicating that the bond to chlorine breaks in the rate-determining step (Eq. 8.20). 

Enthalpies and entropies of activation for the decarboxylation of oxalic, malonic, and acetic acids are listed in Table 1 and are shown separately on the isokinetic plots in Fig. 8. Linear trends are observed for (1) aqueous acetic acid and sodium acetate in the presence of various catalysts (2) aqueous oxalic acid at several pH values (3) oxalic acid in different solvents and (4) malonic acid in different solvents and in aqueous solutions having a different pH. Note that the isokinetic trend for the decarboxylation of malonic acid in aqueous solutions at various pH is identical to that for the reaction in nonaqueous solvents, i.e., there is one isokinetic trend for malonic acid. Moreover, the effect of pH on the activation parameters for the decarboxylation of malonic acid in aqueous solution is minimal. On the other hand, the activation data for the decarboxylation of oxalic acid in aqueous solutions determined by Crossey (1991) do not follow the same isokinetic trend as do the corresponding data for this reaction in other solvents. By contrast, activation data calculated from the rate constants determined by Dinglinger and Schroer (1937) for oxalic acid in water (pH 0.5) fall on the isokinetic trend set by the decarboxylation of oxalic acid in nonaqueous solvents, as well as the rate data determined by Lapidus et al. (1964) in the vapor phase. The cause of the disparity between the isokinetic relationships determined by Crossey (1991) and the remainder of the oxalic acid results requires further investigation. The reaction could have been surface-catalyzed, but this is doubtful because some of the oxalic acid... 

The role of the base is apparently primarily that of a proton remover from the reactive methylene group thus if B represents the base, reaction (i) gives the carbanion, which then combines with the positive carbon of the carbonyl group (reaction ii) the product regains a proton from the piperidinium ion, and then by loss of water followed by mono-decarboxylation of the malonic acid residue gives the final acid. 

The physical properties of cyanoacetic acid [372-09-8] and two of its ester derivatives are Hsted ia Table 11 (82). The parent acid is a strong organic acid with a dissociation constant at 25°C of 3.36 x 10. It is prepared by the reaction of chloroacetic acid with sodium cyanide. It is hygroscopic and highly soluble ia alcohols and diethyl ether but iasoluble ia both aromatic and aUphatic hydrocarbons. It undergoes typical nitrile and acid reactions but the presence of the nitrile and the carboxyUc acid on the same carbon cause the hydrogens on C-2 to be readily replaced. The resulting malonic acid derivative decarboxylates to a substituted acrylonitrile ... 

Reactions. Heating an aqueous solution of malonic acid above 70°C results in its decomposition to acetic acid and carbon dioxide. Malonic acid is a useful tool for synthesizing a-unsaturated carboxyUc acids because of its abiUty to undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic acids are formed from the reaction of malonic acid and benzaldehyde derivatives (1). If aUphatic aldehydes are used acryhc acids result (2). Similarly this facile decarboxylation combined with the condensation with an activated double bond yields a-substituted acetic acid derivatives. For example, 4-thiazohdine acetic acids (2) are readily prepared from 2,5-dihydro-l,3-thiazoles (3). A further feature of malonic acid is that it does not form an anhydride when heated with phosphorous pentoxide [1314-56-3] but rather carbon suboxide [504-64-3] [0=C=C=0], a toxic gas that reacts with water to reform malonic acid. 

With active methylene compounds, the carbanion substitutes for the hydroxyl group of aHyl alcohol (17,20). Reaction of aHyl alcohol with acetylacetone at 85°C for 3 h yields 70% monoaHyl compound and 26% diaHyl compound. Malonic acid ester in which the hydrogen atom of its active methylene is substituted by A/-acetyl, undergoes the same substitution reaction with aHyl alcohol and subsequendy yields a-amino acid by decarboxylation (21). 

In contrast to other acids, anhydrous hydrogen fluoride does not cause hydroly SIS and decarboxylation of the malonic acid residues in these reactions [5]. It is a good reagent for the cyclization of a-benzamidoacetophenones to 2,5 diphenyl-oxazoles [6] (equation 7) The same reaction with concentrated sulfuric acid gives cyclic product with only a 12% yield [6]... 

Decarboxylation is not a general reaction of carboxylic acids. Rather, it is unique to compounds that have a second carbonyl group two atoms away from the —COoH. That is, only substituted malonic acids and /3-keto acids undergo loss of CC>2 on heating. The decarboxylation reaction occurs by a cyclic mechanism and involves initial formation of an enol, thereby accounting for the need to have a second carbonyl group appropriately positioned. 

Although heating benzene-1,2-diamine with malonic acid in aqueous hydrochloric acid affords the parent dione 26 (R = H) in 62% yield,277 the method cannot be extended to substituted malonic acids because decarboxylation intervenes however, the reaction of benzene-1,2-diamines with diethyl malonate and its derivatives constitutes a general procedure for the synthesis of l,5-benzodiazepine-2,4-diones 26 selected examples are given.278... 

The predominant gaseous products of the decomposition [1108] of copper maleate at 443—613 K and copper fumarate at 443—653 K were C02 and ethylene. The very rapid temperature rise resulting from laser heating [1108] is thought to result in simultaneous decarboxylation to form acetylene via the intermediate —CH=CH—. Preliminary isothermal measurements [487] for both these solid reactants (and including also copper malonate) found the occurrence of an initial acceleratory process, ascribed to a nucleation and growth reaction. Thereafter, there was a discontinuous diminution in rate (a 0.4), ascribed to the deposition of carbon at the active surfaces of growing copper nuclei. Bassi and Kalsi [1282] report that the isothermal decomposition of copper(II) adipate at 483—503 K obeyed the Prout—Tompkins equation [eqn. (9)] with E = 191 kJ mole-1. Studies of the isothermal decompositions of the copper(II) salts of benzoic, salicylic and malonic acids are also cited in this article. 

Malonic acid and its derivatives, which would give four-membered cyclic anhydrides, do not give this reaction when heated but undergo decarboxylation (12-38) instead. 

In this chapter, decarboxylation of disubstituted malonic acid derivatives and application of the transketolases in organic syntheses are summarized. Although decarboxylation may be seen as a simple C-C bond breaking reaction, it can be regarded as a carbaniongenerating reaction. As the future directions of this field, expansion of some unique decarboxylation reactions is proposed. In relation of carbanion chemistry, promiscuity of enolase superfamily is discussed. 

Thus, decarboxylase of disubstituted malonic acid could be easily converted to racemase of the corresponding monobasic acid, in spite of the fact that decarboxylation and racemization are quite different from each other. The key for the success is the mechanistic consideration focusing on the fact that the intermediate of both reactions is the same type of enolate of monobasic carboxylic acid. 

Although the reaction mechanism of this type of reactions is not fully elucidated, it is easily anticipated that no intramolecular special stabilization effect for the carbanion generated from decarboxylation is expected, different from the case of malonic acid-type compounds. Moreover, cinnamic acid derivatives that have both the electron-donating and withdrawing substituents have been reported to undergo this reaction. This fact suggests that the enzyme itself stabilizes the transition state without the aid of mesomeric and inductive effects of the other part of the substrate molecule itself. If such unknown mechanism also works for other... 

In a similar way, carbocycles having a quaternary center could be obtained from acyclic unsaturated 1,3-dicarbonyl compounds [206]. Other combinations are the domino hydroformylation/Wittig olefmation/hydrogenation described by Breit and coworkers [207]. The same group also developed the useful domino hydroformyla-tion/Knoevenagel/hydrogenation/decarboxylation process (Scheme 6/2.14) [208] a typical example is the reaction of 6/2-66 in the presence of a monoester of malonic acid to give 6/2-67 in 41 % yield in a syn anti-ratio of 96 4. Compounds 6/2-68 and 6/2-69 can be assumed as intermediates. 

Synthesis of Compound I. As shown in Scheme II, 3-(thiophene-3-yl)propyl bromide can be prepared by a two-carbon homologation(2 ) of 3-thenyl bromide via reaction with diethyl malonate to form diethyl 3-thenylmalonate. This is followed by saponification, decarboxylation, reduction of acid to alcohol, (2 ) and replacement of the hydroxyl group with bromide by reacting with PBr3.(22) Compound 2 is synthesized by mono-quaternization of an excess of 4,4 -bipyridine with 3-(thiophene-3-yl)propyl bromide followed by N-methylation with CH3I. All the intermediates in Scheme II have been identified by NMR spectroscopy. 2 has been characterized by NMR and high resolution mass spectroscopy and by electrochemistry. 

While much attention has been paid to the chemistry of cyclodextrin complexes in solution, there have been relatively few studies of their solid-state reactions. One such reaction is the decarboxylation of phenylethylmalonic acid, 155. In solution this is catalyzed by fj-cyclodextrin, and yields racemic 2-phenylbutyric acid, 156 (230). The malonic acid forms a crystalline 1 1 complex with p-cyclodextrin in which decarboxylation occurs at a much lower temperature than in the crystalline diacid. Interestingly, the product formed in the clathrate reaction is nonracemic, the optical yield being 7%. 

At the start of this project, we chose a-arylpropionic acids as the target molecules, because their S-isomers are well established anti-inflammatory agents. When one plans to prepare this class of compounds via an asymmetric decarboxylation reaction, taking advantage of the hydrophobic reaction site of an enzyme, the starting material should be a disubstituted malonic acid having an aryl group on its a-position. 

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