Bromination of malonic acid

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

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).

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

The bromide ion should be regenerated and the catalyst is reduced back to its lower oxidation state. Bromomalonic acid produced in steps 3 and 8 by bromination of malonic acid is then oxidized by the cerium (IV), leading to bromide and cerium (III) and some other products... 

To illustrate the experimental determination of rate constants and mechanisms we turn to another set of reactions important in the mechanism of the Belousov-Zhabotinskii reaction. The overall reaction for the bromination of malonic acid is... 

From the following experimental data of West (1924), show that the bromination of malonic acid is rate-limited by the enolization step. Evaluate k. ... 

The bromination of malonic acid does not stop with bromomalonic acid but goes on to dibromomaIonic acid ... 

Processes A and B are fundamentally different. Process A involves ions, and the steps are two-electron transfers (oxygen-atom transfer). The dominant reaction is the reaction between bromide (Br ) and bromate (BrOJ) ions, followed by the bromination of malonic acid. Intermediates are hypobromous acid (HOBr) and bromous acid (HBr02). Process B involves radicals and one-electron transfers, whereby cerium(III) is oxidized to cerium(IV). The bromide ion concentration determines which process is dominant at a particular time. Process A occurs when the bromide concentration rises above a certain critical concentration, while... 

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. 

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. 

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). 

A malonic ester synthesis is used to form 4-methylpentanoic acid. Hell-Volhard-Zelinskii bromination of the acid, followed by reaction with ammonia, yields leucine. The last reaction is an Sn2 displacement of bromide by ammonia. 

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 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)... 

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... 

When bromine (1 mole) is added to a suspension of malonic acid in ether, the acid dissolves whilst it is converted into bromomalonic acid 575,576 use of 2 moles of bromine in formic acid leads to dibromomalonic acid, particularly rapidly if the mixture is irradiated.578 If bromine is added to a dry ethereal solution of an alkyl- or arylalkyl-malonic acid at such a rate that the mixture... 

The problem in the synthesis of malonic acid is to replace a hydrogen atom in acetic acid by the carboxyl group. This is accomplished in the same way as that by which methane is converted into acetic acid. One hydrogen atom is first replaced by a halogen atom, by treating acetic acid with chlorine or bromine. The substituted acid is then heated with potassium cyanide, and the cyanoacetic acid so formed is hydrolyzed by boiling with a solution of an alkali. The changes are indicated by the formulas,—... 

In the first step the diethyl ester of malonic acid is treated with ethyl bromide in the presence of sodium ethoxide when one of the active hydrogen atoms in the former gets eliminated with bromine atom in the later as a molecule of hydrobromic acid resulting into the formation of the corresponding diethyl ester of ethyl malonic acid. This on subsequent addition of 2-monobromopentane and in the presence of sodium ethoxide gives rise to diethyl ether of ethyl-(l-methyl butyl) malonate with the elimination of one molecule of hydrobromic acid. Urea is made to condense with the product obtained from the previous step when pentobarbital is formed with the elimination of two moles of ethanol. Finally, the pentobarbital is treated with a calculated amoimt of sodium hydroxide when the required official compoimd is formed. 

Given the importance of the BZ reaction in nonlinear chemical dynamics, it is not surprising that polymers and polymerizations would be coupled to it. Pojman et al. studied the BZ reaction to which acrylonitrile was added and showed that the polyacrylonitrile was produced periodically in phase with the oscillations (41). Given that radicals are produced periodically from the oxidation of malonic acid by ceric ion, it seemed reasonable to assume the periodic appearance of polymer was caused by periodic initiation. However, Washington et al. showed that periodic termination by bromine dioxide caused the periodic polymerization (42). 

This reaction scheme implies that an extra source for the intermediates HOBr and HBr02 appears in the BZ system. As HBr02 is the autocatalytic intermediate its production enhances the positive feedback loop, which would lead to an increase in the IP. (This is because turning off the autocatalytic HBr02 production at the end of the IP becomes more difficult.) On the other hand the inflow of HOBr would decrease the IP since HOBr brominates the malonic acid (R31, for the reactions of the unperturbed BZ system we follow the notations of the MBM model) ... 

Degn, H. (1967). "Effect of bromine derivatives of malonic acid on the oscillating reaction of malonic acid, cerium ions and bromate." Nature 213, 589-590. 

An understanding of the detailed mechanism of each step is not vital for explaining the specific features of oscillations. However, in certain suggested classroom experiments, attention has been focused on the bromination mechanism of methylene group of malonic acid, which proceeds by enolization mechanism. 

Campaigne et al. have used 3-thenyl bromide obtained by benzoyl peroxide-catalyzed, side-chain bromination of 3-methylthiophene with A -bromosuccinimide, as a starting material for 3-substituted thiophenes. - 22 3-Methylthiophene is now prepared commercially from itaconic acid. The reactive halogen in 3-thenyl bromide could be directly reacted with a variety of nucleophiles, such as cyanide, or malonate, to give more complex 3-substituted compounds. 3-Thenyl bromide was converted by the Sommelet reaction to 3-thio-phenealdehyde which, with silver oxide, was oxidized to 3-thio-... 

So do anhydrides and many compounds that enolize easily (e.g., malonic ester and aliphatic nitro compounds). The mechanism is usually regarded as proceeding through the enol as in 12-4. If chlorosulfuric acid (CISO2OH) is used as a catalyst, carboxylic acids can be ot-iodinated, as well as chlorinated or brominated. N-Bromosuccinimide in a mixture of sulfuric acid-trifluoroacetic acid can mono-brominate simple carboxylic acids. ... 

With the A-ring unit readily available, we directed our attention to the formation of the B-ring. At first, we duplicated the five step scheme reported in Sih s strigol synthesis involving 1) esterification of the acid 14, 2) allylic bromination with N-bromo 8 ucc i n imi d e (NBS) to 15, 3) condensation with the sodium salt of dimethyl malonate to 16, 4) alkylation with methyl bromoacetate to 17, and 5) acid catalyzed hydrolysis and decarboxylation to the acid 18. 

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