Carboxylic acid malonic ester synthesis

The thermal decarboxylation of malonic acid derivatives is the last step m a multistep synthesis of carboxylic acids known as the malonic ester synthesis This synthetic method will be described m Section 21 7... 

The malonic ester synthesis is a method for the preparation of carboxylic acids and is represented by the general equation... 

Among the methods for preparing carboxylic acids carboxylation of a Grignard reagent and preparation and hydrolysis of a nitrile convert RBr to RCO2H The malonic ester synthesis converts RBr to RCH2CO2H... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Malonic ester synthesis (Section 21 7) Synthetic method for the preparation of carboxylic acids involving alkylation of the enolate of diethyl malonate... 

As noted previously, the overall effect of the malonic ester synthesis is to convert an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms. 

Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid... 

Strategy The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Malonic ester synthesis (Section 22.7) The synthesis of a carboxylic acid by alkylation of an alkyl halide, followed by-hydrolysis and decarboxylation. 

An important example of this reaction is the malonic ester synthesis, in which both Z groups are COOEt. The product can be hydrolyzed and decarboxylated (12-38) to give a carboxylic acid. An illustration is the preparation of 2-ethyl-pentanoic acid from malonic ester ... 

Compounds 137 and 138 are thus synthons for carboxylic acids this is another indirect method for the a alkylation of a carboxylic acid, representing an alternative to the malonic ester synthesis (10-104) and to 10-106 and 10-109. The method can be adapted to the preparation of optically active carboxylic acids by the use of a chiral reagent. Note that, unlike 132, 137 can be alkylated even if R is alkyl. However, the C=N bond of 137 and 138 cannot be effectively reduced, so that aldehyde synthesis is not feasible here. ... 

After the C—C bond is formed, the carboxyl group used for the activation of the position should be removed. This will be the decarboxylahon of malonic acid-type compounds, which is the same type of the famous synthehc reaction, i.e., malonic ester synthesis (Fig. 5). 

Malonic Ester Synthesis Synthesis involving a malonic ester or a related compound with a strong base such as sodium ethoxide. The ultimate product is a substituted carboxylic acid. 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0 )21497] by treatment with a strong base such as lithium diisopropylamide.1498 The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied1499 to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCHjCOOH and RR"CHCOOH.1454 This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 368), is an alternative to the malonic ester synthesis (0-94) as a means of preparing carboxylic acids and has the advantage that acids of the form RR R"CCOOH can also be prepared. In a related reaction, methylated aromatic acids can be alkylated at the methyl group by a similar procedure.1500... 

In the malonic ester synthesis this enolate ion is alkylated in the same manner as in the acetoacetic ester synthesis. Saponification of the alkylated diester produces a diacid. The carbonyl group of either of the acid groups is at the /3-position relative to the other acid group. Therefore, when the diacid is heated, carbon dioxide is lost in the same manner as in the acetoacetic ester synthesis. The difference is that the product is a carboxylic acid in the malonic ester synthesis rather than the methyl ketone that is produced in the acetoacetic ester synthesis. The loss of carbon dioxide from a substituted malonic acid to produce a monoacid is illustrated in the following equation ... 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

Decide which synthesis to use. The acetoacetic ester synthesis is used to prepare methyl ketones, and the malonic ester synthesis is used to prepare carboxylic acids. Both syntheses provide a method to add alkyl groups to the a-carbon. Therefore, next identify the group or groups that must be added to the a-carbon. Remember that the a-carbon is the nucleophile, so the groups to be attached must be the electrophile in the Sn2 reaction they must have a leaving group bonded to the carbon to which the new bond is to be formed. 

First all three ester bonds and both amide bonds are hydrolyzed to carboxylic acid groups by the aqueous acid. The mechanisms for these reactions are discussed in Section 19.5. The ester hydrolyses follow the exact reverse of the Fischer esterification mechanism shown in Figure 19.3, and the amide hydrolysis occurs by a very similar mechanism. The product of these hydrolysis steps has three carboxylic acid groups and one amino group. Two of these acid groups are attached to the same carbon so that one can be eliminated as carbon dioxide by the cyclic mechanism described in Section 20.4 for the malonic ester synthesis ... 

The product of a malonic ester synthesis is a substituted acetic acid, with the substituent being the group used to alkylate malonic ester. In effect, the second carboxyl group is temporary, allowing the ester to be easily deprotonated and alkylated. Hydrolysis and decarboxylation remove the temporary carboxyl group, leaving the substituted acetic acid. 

One of the best methods of amino acid synthesis is a combination of the Gabriel synthesis of amines (Section 19-20) with the malonic ester synthesis of carboxylic acids (Section 22-16). The conventional malonic ester synthesis involves alkylation of diethyl malonate, followed by hydrolysis and decarboxylation to give an alkylated acetic acid. 

The malonic ester synthesis converts a primary or secondary alkyl halide into a carboxylic acid with two more carbons (a substituted acetic acid). Identify the component that originates from malonic ester (the acid component). The rest of the molecule comes from the alkyl halide, which should be primary or methyl. 

Use a malonic ester synthesis if the product you want is an a-substituted carboxylic acid derivative. Use an acetoacetic acid synthesis if the product you want is an a-substituted methyl ketone. 

The malonic ester synthesis can also be used to prepare cvc/ualkane-carboxylic acids. For example, wlien 1,4-dibromobutane is treated with diethyl malonate in the presence of 2 equivalents of sodium ethoxide base, the second alkylation step occurs intnimolcailarly to yield a cyclic product. Hydrolysis and decarboxylation then give cyclopentanecarboxylic acid. I hree-, four-, five-,... 

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