Malonic acid halogenation

In reactions where nitriles are prepared from halogen compounds by double decomposition with alkali cyanide in alcoholic or aqueous alcoholic solution, the latter is usually added in solution or as a powder (cf. Preparations 77,78,79), otherwise the alkali halide which separates forms a coating round the cyanide and hinders further action. If the reaction is performed in aqueous solution, as in the preparation of malonic acid (p. 125), this precaution is not so necessary the alkali halide, when formed, remains in solution. 

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. 

V) The ester of malonic acid, like acetacetic ester, possesses the property in virtue of which one of the two methylene hydrogen atoms can be replaced by sodium, in consequence of the acid properties imparted by the two neighbouring carbonyl (CO) groups. When the sodium compound is treated with organic halides, like alkyl halides, halogen derivatives of add-esters, acid-chlorides, etc., the sodium is replaced by alkyl residues, add residues, etc-, just as in the case of the dosely related acetacetic ester. In the above-mentioned examples, the sodium salt of the malonic ester is first formed from sodium alcoholate and the ester ... 

The reaction of halogen-substituted 1,3,5-triazines and salts of malonic acid derivatives also affords C-C bonded compounds128-130 (see also Houben-Weyl, Vol. E16a, Parti, p 761 ff). 

It is very easy to halogenate malonic acid and its esters and alkyl or arylalkyl derivatives. Chloromalonic acid is obtained by hydrolysis of diethyl chloro-malonate, which is formed when chlorine is passed into the malonic ester at 70°.575 Cloves576 describes the preparation of 2-chlorobutyric acid by way of diethyl ethylmalonate. 

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,—... 

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-... 

The alkylation of activated halogen compounds is one of several reactions of trialkylboranes developed by Brown (see also 15-16,15-25,18-31-18-40, etc.). These compounds are extremely versatile and can be used for the preparation of many types of compounds. In this reaction, for example, an alkene (through the BR3 prepared from it) can be coupled to a ketone, a nitrile, a carboxylic ester, or a sulfonyl derivative. Note that this is still another indirect way to alkylate a ketone (see 10-105) or a carboxylic acid (see 10-106), and provides an additional alternative to the malonic ester and acetoacetic ester syntheses (10-104). 

E. Fischer has synthesised phenylalanine by the action of ammonia upon the corresponding halogen fatty acid, which he prepares from malonic ester and benzylchloride. There are six stages in the complete process, as follows —... 

Ethyl ethylenetetracarboxylate has been prepared from monochloro- and monobromomalonic ester through removal of halogen acid with sodium,1 sodium ethylate,2 potassium acetate,3 potassium carbonate,4 sodium urethane, sodium formanilide and sodium acetanilide.6 It has also been prepared by treating the disodium derivative of ethyl ethane-1,1,2,2-tetracarboxylate with bromine,7 or iodine 8 by treating dibromomalonic ester with sodium,9 or sodium ethylate 10 and by treating the disodium derivative of malonic ester with iodine.11... 

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