Decarboxylation of Malonic Acid and Related Compounds

The loss of a molecule of carbon dioxide from a carboxylic acid is known as decarboxylation. 

Dec boxylation of simple carboxylic acids takes place with great difficulty and is rarely encountered. 

Compounds that readily nndergo thermal decarboxylation include those related to malonic acid. On being heated above its melting point, malonic acid is converted to acetic acid and carbon dioxide. 

It is important to recognize that only one carboxyl group is lost in this process. The second carboxyl gronp is retained. A mechanism recognizing the assistance that one carboxyl group gives to the departure of the other is represented by the equation 

The transition state involves the carbonyl oxygen of one carboxyl gronp—the one that stays behind—acting as a proton acceptor toward the hydroxyl gronp of the carboxyl that is lost. Carbon-carbon bond cleavage leads to the enol form of acetic acid, along with a molecule of carbon dioxide. 

The first step gives carbon dioxide and an enol, which isomerizes to acetic acid in the second step. 

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The specialized elimination reaction known as decarboxylation was introduced in Chapter 12, Section 12.6. Decarboxylation requires the presence of a carboxyl group (COOH) attached to a carbon that has another carbonyl substituent. With this structural motif, an internal acid-base reaction is possible that leads to cleavage of a C-C bond and loss of the neutral molecule carbon dioxide (CO2 = 0=C=0). Malonic acid has the requisite structural features (see 96), and when malonic acid and related compounds are heated to 200°C, they lose carbon dioxide (CO2) in other words, they undergo decarboxylation. 

Yet hands-on experience with 1 and other related compounds showed that free malonic acid groups on fullerenes are rather unstable even under physiological conditions and readily decarboxylate into side products, some of which may show toxicity under certain circumstances (Beuerle et al., 2007). To avoid these potential side effects new polar derivatives of 1 like 3, 4 and 5 have been synthesized (Beuerle et al., 2005 Witte et al., 2007). In these trisadducts the polar endgroups are attached via alkyl spacers to the fullerene core and thus no unwanted decarboxylation... 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

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