Malonic acid benzaldehyde reaction

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. 

A. tn-NUrocinnamic acid. In a 1-1. round-bottomed flask fitted with a reflux condenser are placed 151 g. (1 mole) of tw-nitro-benzaldehyde (Note 1), 115 g. (1.1 moles) of malonic acid, 250 ml. of 95% ethanol, and 25 ml. of pyridine. The mixture is heated on a steam bath under gentle reflux for 6-8 hours and cooled. The large masses of crystals are broken up with a spatula, and the reaction mixture is cooled in an ice bath. The solid is collected on a Buchner funnel, and the residue is washed with 100 ml. of cold ethanol and then with two 100-ml. portions of diethyl ether. The crude w-nitrocinnamic acid is suspended in 300 ml. of ethanol and digested on a steam plate for 2-3 hours. The mixture is cooled and filtered, and the solid is air-dried. The product, 144 155 g. (75-80%), is a light-yellow solid and melts at 200-201° (Note 2). 

The variety of educts and products of the higher MCRs is illustrated here. Product 72 (Scheme 1.18) is formed from the five functional groups of lysine, benzaldehyde, and tert-butylisocyanide. The synthesis of 73 is achieved with hydrazine, furanaldehyde, malonic acid, and the isocyano methylester of acetic acid, compound 74 results from the reaction of benzylamine, 5-methyl-2-furanaldehyde, maleic acid mono-ethylester, and benzylisocyanide. ° Zhu et al. prepared a variety of related products, such as, 75, from (9-amino-methyl cinnamate, heptanal, and a-isocyano a-benzyl acetamides. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

The so-called Doebner reaction condenses malonic acid and pyridine with an aldehyde such as benzaldehyde. Draw the product and suggest a mechanism for this reaction. 

As we learned in Section 23.3, the a hydrogens between two carbonyl groups are especially acidic, and so they are more readily removed than other a H atoms. As a result, the P-dicarbonyl compound always becomes the enolate component of the aldol reaction. Figure 24.2 shows the steps for the crossed aldol reaction between diethyl malonate and benzaldehyde. In this type of crossed aldol reaction, the initial P-hydroxy carbonyl compound always loses water to form the highly conjugated product. 

Oxalic and malonic acids, as well as a-hydroxy acids, easily react with cerium(IV) salts (Sheldon and Kochi, 1968). Simple alkanoic acids are much more resistant to attack by cerium(IV) salts. However, silver(I) salts catalyze the thermal decarboxylation of alkanoic acids by ammonium hexanitratocerate(IV) (Nagori et al., 1981). Cerium(IV) carboxylates can be decomposed by either a thermal or a photochemical reaction (Sheldon and Kochi, 1968). Alkyl radicals are released by the decarboxylation reaction, which yields alkanes, alkenes, esters and carbon dioxide. The oxidation of substituted benzilic acids by cerium(IV) salts affords the corresponding benzilic acids in quantitative yield (scheme 19) (Hanna and Sarac, 1977). Trahanovsky and coworkers reported that phenylacetic acid is decarboxylated by reaction with ammonium hexanitratocerate(IV) in aqueous acetonitrile containing nitric acid (Trahanovsky et al., 1974). The reaction products are benzyl alcohol, benzaldehyde, benzyl nitrate and carbon dioxide. The reaction is also applicable to substituted phenylacetic acids. The decarboxylation is a one-electron process and radicals are formed as intermediates. The rate-determining step is the decomposition of the phenylacetic acid/cerium(IV) complex into a benzyl radical and carbon dioxide. 

It was suggested73 that the most probable mechanism of this reaction is an initial aldol condensation of the starting ketone leading to the a,/ -unsaturated ketone 100 or to the /Miydroxyketone 101 which serve as precursors to the tertiary carbenium ions 102, which reacts in turn with nitriles by an acid-catalyzed Ritter reaction to give 103 (equation 36). This suggestion is confirmed by the results of a cross-reaction experiment of benzaldehyde and diethyl malonate with acetonitrile to give 14 (equation 37). 

A mixture of 100 g. (0.63 mole) of dry malonic ester and 70 g. (0.66 mole) of benzaldehyde is placed in a 200-ml. thick-walled vessel, and 2 g. of piperidine is added gradually. The reaction vessel is stoppered securely and allowed to stand for 2 days. The reaction mixture is then heated on a water bath for 12 hours. Ether is added, and the resulting solution is washed with dilute aqueous acid and then with water. The ethereal solution is dried over anhydrous sodium sulfate and distilled. There is obtained a 70% yield of ethyl benzalmalonate boiling at 185-186°/11 mm. and melting at 27-27.5°. 

Monomers have been prepared in benzene solvent by Knoevanagel reaction between 4-vinyl benzaldehyde and malonic derivatives at room temperature, by use of two catalysts chosen according to the nature of compounds (Table I). For carboxylic acids as malonic or cyanacetic acids piperidine can be used for esters as ethylmalo-nate or ethyl cyanacetate piperidinium benzoate is prefered. 

The catalytic activity of proton sponge in the Knoevenagel reaction has been studied227. It was shown that benzaldehyde, in the presence of 2 mol% of 1, reacts with ethyl cyanoacetate and ethyl acetoacetate (equation 22). The condensation is accelerated in polar solvents (especially in DMSO) and does not occur in the case of diethyl malonate, as its CH-acidity is too low (pK = 13.3). 

Fittig claimed that Perkin s results were due to the use of too high a temperature, and at about 100° the acid obtained corresponded with the salt used, irrespective of the anhydride. C. M. Stuart, another pupil of Fittig, found that, in presence of acetic anhydride, salts of malonic and isosuccinic acids, which do not form anhydrides, also condense with benzaldehyde. Fittig and Jayne, and Fittig and P. Ott, claimed to have obtained evidence of an addition product in the reaction ... 

A microfluidic reaction system has also been used for the production of prodrugs. A multichannel membrane microreactor was fabricated and tested for Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate to produce a-cyanocinnamic acid ethyl ester, a known intermediate for the production of an antihypertensive drug [9]. Knoevenagel condensations of carbonylic coiiqtounds and malonic esters yield several important key products such as nitriles used in anionic polymerization, and the a,p-unsaturated ester intermediates employed in the synthesis of several therapeutic drugs that include niphendip-ine and nitrendipine. Unlike most condensation reactions. 

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