Diethyl ester of malonic acid

Diethyl ester of malonic acid Sodium ethylate... 

Compounds are not always formula-indexed under their own formulas. This is a departure from the ideal, but is reasonable. The interest in a salt of a complex organic acid is likely to be mainly in the acid.. It is more valuable to have the record of the salt under the formula of the acid for the use of searchers looking up the acid. In Chemical Abstracts entries under their own formulas are made for all strictly inorganic and strictly organic compounds, both addition compounds and true reaction derivatives (esters, acetals, hydrazones, oximes, picrates, semi-carbazones, etc.) the diethyl ester of malonic acid is found under C7H]204. 

A combination of two of the reactions discussed in this chapter—alkylation of an a-carbon and decarboxylation of a j8-dicarboxylic acid—can be used to prepare carboxylic acids of any desired chain length. The procedure is called the malonic ester synthesis because the starting material for the synthesis is the diethyl ester of malonic acid. The first two carbons of the carboxylic acid come from malonic ester, and the rest of the carboxylic acid comes from the alkyl halide used in the second step of the reaction. 

The cyanoacetic acid obtained from monochloroacetic acid and sodium cyanide, is treated with hydrochloric acid and ethanol to yield the diethyl ester of malonic acid. The ester, in absolute ethanol, is reacted with the stoichiometric proportion of metallic sodium so as to replace only one active hydrogen of the methylene (CH2) group. Thereupon, a slight excess of the calculated amount of allyl bromide is added. The second replaceable hydrogen is abstracted with 1-methyl butyl bormide and the resulting product is made to react with a theoretical amount of thiourea to yield thiamylal. The free acid thus obtained is conveniently transformed into the official sodium salt by neutralization with a stoichiometric proportion of sodium hydroxide (1 1). 

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. 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

Thus the diethyl ester of succinic acid is formed from ethyl potassium malonate ... 

The Brown-Walker 1 method has been found to be of excellent service in the electrolysis of the potassium salts of the mono-esters of malonie acid. The formation of the diethyl ester of succinic acid from ethyl potassium malonate has already been mentioned fp. 103). 

A very profitable engagement of Fischer was the work on derivatives of malonic and barbituric esters. In 1902 the Professor of medicine, J. von Mering, whom Fischer had met in Strassburg, and who was working in Halle/Saale, visited Fischer in Berlin. He showed him a crystalline substance he had synthesized by the reaction of phosphorous oxichloride, urea and diethylmalonic acid. It seemed to be the diethyl ester of barbituric acid and he asked Fischer to confirm the constitution of this substance. Fischer found that the structure was different. With his nephew Alfred Dilthey he found two ways to obtain it. Mering tested diethylbarbituric acid and found that it was a very active soporific substance. Fischer himself used it successfully. Other derivatives of barbituric acid also showed hypnotic properties. Fischer and Mering published their results in January 1903.2 ... 

The barbiturates were widely used as sedative-hypnotic drugs. Barbital was introduced as a drug in 1903. The method of synthesis for thousands of its analogs has undergone little change. Urea reacts with various derivatives of malonic acid, usually a diethyl ester of a dialkyl substituted malonic acid. This is a classic example of a nucleophilic acyl substitution. A derivative of ammonia reacts with esters to form an amide, only in this case a cyclization to a strainless six-membered ring results because of the proximity of the bifunctionality. 

By interaction of malonic acid diethyl ester with sodium ethylate (molar ratio 1 1) and then with ethyl bromide (molar ratio 1 1) was prepared ethylmalonic... 

The method of synthesis for thousands of barbital analogs involves the reaction of urea with various derivatives of malonic acid, usually a diethyl ester of a dialkyl-substituted malonic acid. 

Fig. 12.9. Nitrosation of malonic acid diethyl ester. The mechanism of the acid-catalyzed enolization malonic ester malonic ester enol (E) and the mechanism of the actual nitrozation (E -> A) is shown here.

Fig. 12.11. Mechanism of the tert-butylation of malonic acid diethyl ester. From the point of view of tert-butyl chloride it is an SN1 reaction with the malonic ester enol (B) acting as the nucleophile.

It can be assumed that the small amount of piperidine in the reaction mixture is completely protonated by malonic acid because piperidine is more basic than pyridine. Hence, only the less basic pyridine is available for the formation of the malonic acid enolate D from free malonic acid and for the formation of the malonic acid dianion from the malonic acid mono-carboxylate C. The pKa value of malonic acid with regard to its C,H acidity should be close to the pKa value of malonic acid diethyl ester (p= 13.3). The pKa value of malonic acid monocarboxylate C with regard to its C,H acidity should be larger by at least a factor 10. Hence, the concentration of the malonic acid enolate D in the reaction mixture must be by many orders of magnitude higher than that of any malonic acid dianion. Due to the advantages associated with this enormous concentration D could be the actual nucleophile in Knoevenagel condensations. 

Alkylation of malonic ester with an equimolar ponion of ethylene bromide or trimethylene bromide produces ring closure to give diethyl esters of 1,1-cyclopropane- and 1,1-cyclobutane-dicarboxylic acids, respectively. Five- and six-membered rings also have been formed in this manner. ... 

The Claisen condensation of diethyl oxalate with esters of fatty acids (cf. method 211) produces a-ethoxalyl esters which are thermally de-carbonylated to alkylmalonic esters. The over-all yields range from 78% to 91% for the conversion of fatry esters up to ethyl stearate. Phenyl-malonic ester is made in 85% yield. Powdered glass is sometimes used... 

Olefinic esters may be obtained directly by the Knoevenagel reaction. Alkyl hydrogen malonates are used in place of malonic acid. Decarboxylation then gives the ester directly as in the preparation of ethyl 2-heptenoate (78%) and methyl m-nitrocinnamate (87%). Alkyl hydrogen malonates are readily available by partial hydrolysis of dialkyl malonates. The use of malonic ester in the condensation leads to olefinic diesters, namely, alkylidenemalonates such as ethyl heptylidenemalonate (68%). A small amount of organic acid is added to the amine catalyst since the salts rather than the free amines have been shown to be the catalysts in condensations of this type. Various catalysts have been studied in the preparation of diethyl methylenemalonate. Increased yields are obtained in the presence of copper salts. Trimethylacetalde-hyde and malonic ester are condensed by acetic anhydride and zinc chloride. Acetic anhydride is also used for the condensation of furfural and malonic ester to furfurylidenemalonic ester (82%). ... 

Zinc ethyl iodide and diethyl malonate yield ethyl-diethyl malon-ate and some diethyl ester of diethyl malonic acid. ... 

The reaction is equally successful when isopropylidene malonate is used in place of malonic acid or diethyl malonate.913 The isopropylidene ester contains an unusually acidic methylene group as well as an ester group that can be... 

It is prepared by the interaction of diethyl ester of ethyl malonic acid and iso-pentyl chloride in the presence of sodium metal, when ethyl is isopentyl ester of diethyl malonic acid is obtained as an intermediate compound. This on condensation with urea in the presence of sodium ethoxide results into the formation of amobarbital. 

Diethyl malonate on reaction with sodium metal gives rise to sodium malonic ester which on treatment with ethyl bromide results into the formation of diethyl ester of ethyl malonic acid with the elimination of hydrobromic acid. The resulting ester on further reaction with 2-bromopentane gives the desired eompound, i.e., diethyl ester of ethyl (1-methyl butyl) malonic acid which on subsequent treatment with thiourea forms thiopental with the elimination of two moles of ethanol. Ultimately, the enol-iorm of thiopental when reaeted with a ealeulated amoimt of sodium hydroxide, it gives thiopental sodium. 

Diethyl ester of ethyl-(1-methyl butyl) malonic acid... 

The rate of ceric oxidation of malonic add and its diethyl ester in acetic acid/sul-furic acid solutions has recently been reported by Vaidya et al. (1987). They find no evidence for precursor complex formation in either system. The reactive Ce(IV) species appear to be Ce(S04)2 ( 2) and CefSO ) " k 2). The second-order rate parameter for the oxidation of malonic add is 40 times greater than that for the ester. Oxidation of the ester is proposed to occur through the enol form yielding a malonyl radical analogous to that identified by Amjad and McAuley. Foersterling et al. (1987) find that the second-order rate constant for malonic acid oxidation by Ce(lV) in sulfuric acid is in excellent agreement with the value of Vaidya et al. They observe that Ce(III) does inhibit the reaction in sulfuric add, which they attribute to a reversible Ce(IV) malonic acid rate-controlling step. 

---