Malonic acid bromination

Tribromoacetic acid [75-96-7] (Br CCOOH), mol wt 296.74, C2HBr302, mp 135°C bp 245°C (decomposition), is soluble in water, ethyl alcohol, and diethyl ether. This acid is relatively unstable to hydrolytic conditions and can be decomposed to bromoform in boiling water. Tribromoacetic acid can be prepared by the oxidation of bromal [115-17-3] or perbromoethene [79-28-7] with fuming nitric acid and by treating an aqueous solution of malonic acid with bromine. 

One such compound, bropirimine (112), is described as an agent which has both antineo-plastic and antiviral activity. The first step in the preparation involves formation of the dianion 108 from the half ester of malonic acid by treatment with butyllithium. Acylation of the anion with benzoyl chloride proceeds at the more nucleophilic carbon anion to give 109. This tricarbonyl compound decarboxylates on acidification to give the beta ketoester 110. Condensation with guanidine leads to the pyrimidone 111. Bromination with N-bromosuccinimide gives bropirimine (112) [24]. 

In the case of malonic acid, CH2(COOH)2 propane, CH2Me2 or any other molecule of the form CH2Y2, if we replace either of the CH2 hydrogens by a group Z, the identical compound results. The two hydrogens are thus equivalent. Equivalent atoms and groups need not, of course, be located on the same carbon atom. For example, all the chlorine atoms of hexachlorobenzene are equivalent as are the two bromine atoms of 1,3-dibromopropane. 

When solution contains sufficient amount of Br", reduction of BrOj and bromination of malonic acid (HMa) take place by HOBr or Br2 as follows ... 

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. 

When it is required to prepare an a-bromo acid from a carboxylic acid which is not particularly readily available commercially, but which can be synthesised by the malonic acid route (Section 5.11.6, p. 680), advantage may be taken of the ease of bromination in the a-position of the intermediate alkylmalonic acid. The substituted bromomalonic acid undergoes ready decarboxylation on heating to yield the a-bromo acid (e.g. 2-bromo-3-methylpentanoic acid, Expt 5.166). 

The uncatalysed Belousov-Zhabotinsky (B-Z) reaction between malonic acid and acid bromate proceeds by two parallel mechanisms. In one reaction channel the first molecular products are glyoxalic acid and carbon dioxide, whereas in the other channel mesoxalic acid is the first molecular intermediate. The initial reaction for both pathways, for which mechanisms have been suggested, showed first-order dependence on malonic acid and bromate ion.166 The dependence of the maximal rate of the oxidation of hemin with acid bromate has the form v = [hemin]0-8 [Br03 ] [H+]12. Bromate radical, Br02, rather than elemental bromine, is said to play the crucial role. A mechanism has been suggested taking into account the bromate chemistry in B-Z reactions and appropriate steps for hemin. Based on the proposed mechanism, model calculations have been carried out. The results of computation agree with the main experimental features of the reaction.167... 

The heart of the preparation of capsaicin is a malonic ester synthesis. The first step is bromination of the primary alcohol by phosphorous tribromide. The resulting primary alkyl bromide is used to alkylate the sodium salt of diethyl malonate. A substituted malonic acid derivative is obtained following basic hydrolysis of the ester groups. 

If the enolization has enough time to proceed, the transformation in Figure 12.4 completely leads to a brominated /J-ketoester. Basically, the same method can be employed to also a-brominate ketones (Figure 12.5), alkylated malonic acids (Figure 12.6), acid bromides (Figure 12.7,12.8) and acid chlorides (not shown). The mechanistic details are detailed in the cited figures. Look at how similar they are. 

According to Figure 12.6, the bromination of alkylated malonic acids A initially furnishes oc-brominated alkyl malonic acids B. Upon heating they decarboxylate to form the a-bromo-carboxylic acids C. This two-step approach to C can be managed without using the expensive phosphorus tribromide, which would be required in the alternative single-step Hell-Volhard-Zelinsky synthesis of this compound (Figures 12.7, 12.8). 

Fig. 12.6. Bromination of malonic acids or alkylated mal-onic acids. The figure shows the mechanisms of the acid-catalyzed enolization (alkyl) malonic acid enol of (alkyl) malonic acid (E) and the actual bromination (E —> B).

On the other heuid,if this were the correct forr..ula the con.pound should readily add bromine and reduce potassium penuangante the first reaction it gave only in the sunlight,the other not at all. These facts,its stability towards reduction with sodium aiualgam, the value of its magnetic rotation and the fact that it behaved like a disubstituted malonic acid settled the dispute in favor of Perkin. 

Malonic acid, ethyl malonate, and their monoalkyl derivatives can be readily halogenated in ether solution subsequent decarboxylation leads to the corresponding a-halogenated acetic acid in 55-80% yield. The reaction of the potassium salts of monoethyl alkylmalonates with bromine provides the a-bromo esters directly, although the yields ate relatively low. ... 

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. 

Synthesis from Ethylene Bromide.—Such an acid is known as a commonly occurring substance in nature and is called succinic acid. It has the composition C4H6O4 and is plainly isomeric with methyl malonic acid. Its constitution as given above is, however, proven by the following syntheses Ethylene bromide, or symmetrical di-brom ethane, which is made by the addition of bromine to ethylene gas, yields by treatment with potassium cyanide a symmetrical di-... 

The Belousov-Zhabotinsky reaction demonstrated here is set in train by the reduction of potassium bromate to elemental bromine by malonic acid and manganese(II) sulfate this is shown by the orange coloration. The reaction of the bromine with malonic acid to give mono or dibromomalonic acid leads to decolorisation. At the same time more bromine is formed in the initial redox process, and this again replaces one or two hydrogen atoms of the malonic acid. The process is repeated many times the start reaction is inhibited by complexa-tion of the brominated malonic acid by Mn(ll) ions, so that the oscillation slowly comes to an end. ... 

Then, bromine reacts with malonic acids to yield bromomalonic acid as (= Bromi-nation of malonic acid by bromine)... 

Subsequently hypobromous acid reacts with malonic acid to yield bromomalonic acid (= Bromination of malonic acid by hypobromous acid)... 

III C) 1967 Degn, H. Effect of Bromine Derivatives of Malonic Acid on the Oscillating Reaction of Malonic Acid, Cerium Ions and Bromate, Nature, vol. 213, 589-590... 

The presence of Br2 in solution cannot be detected, since bromine rapidly reacts with malonic acid... 

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