Enolate anions Claisen condensation

An ester enolate is formed by reaction with a strong base, and the resulting enolate anion can condense with an aldehyde, a ketone, or another ester. Ester enolates react with aldehydes or ketones to form p-hydroxy esters. Aldehyde or ketone enolate anions react with esters to form p-hydroxy esters, 1,3-diketones, or p-keto aldehydes 56,57,84,99,100,102,108,110,114,115. Enolate anions react as nucleophiles. They give nucleophilic acyl substitution reactions with acid derivatives. The condensation reaction of one ester with another is called a Claisen condensation and it generates a P-keto ester. A mixed Claisen condensation under thermodynamic conditions leads to a mixture of products, but kinetic control conditions can give a single product 52, 53, 54, 55, 59, 68, 69,98,99,101,125. 

The intra-molecular Claisen condensation is called a Dieckmann condensation, and it generates a cyclic compound 58,99,101,118. Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or add derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation 59, 60, 61, 62, 69, 99,108,110,112, 113,119,124. 

Reaction of Enolate Anions. In the presence of certain bases, eg, sodium alkoxide, an ester having a hydrogen on the a-carbon atom undergoes a wide variety of characteristic enolate reactions. Mechanistically, the base removes a proton from the a-carbon, giving an enolate that then can react with an electrophile. Depending on the final product, the base may be consumed stoichiometricaHy or may function as a catalyst. Eor example, the sodium alkoxide used in the Claisen condensation is a catalyst ... 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

As an extension of the reaction of sulphinates with organometallic compounds, the Claisen-type condensation between ketone enolate anions 101 and arenesulphinates may be considered. It was found161,162 that this reaction provides an interesting synthetic approach to a-ketosulphoxides 102 (equation 54 Table 9). 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

The Claisen reaction can now proceed smoothly, but nature introduces another little twist. The carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation. Accordingly, we now see that the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base (see Box 10.17). 

Another important reaction of esters is the Claisen condensation. In this reaction, an enolate anion is formed from the reaction between an ester and a strong base, e.g. sodium ethoxide (NaOEt in EtOH). The enolate anion reacts with another molecule of ester to produce (3-ketoester (see Section 5.5.5). 

When two molecules of ester undergo a condensation reaction, the reaction is called a Claisen condensation. Claisen condensation, like the aldol condensation, requires a strong base. However, aqueous NaOH cannot be used in Claisen condensation, because the ester can be hydrolysed by aqueous base. Therefore, most commonly used bases are nonaqueous bases, e.g. sodium ethoxide (NaOEt) in EtOH and sodium methoxide (NaOMe) in MeOH. The product of a Claisen condensation is a P-ketoester. As in the aldol condensation, one molecule of carbonyl compound is converted to an enolate anion when an a-proton is removed by a strong base, e.g. NaOEt. 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

There are certain difficulties in achieving this type of aldol reaction. First, alkali-induced ester hydrolysis would compete with addition. Second, a Claisen condensation of the ester might intervene, and third, the ester anion is a stronger base than the enolate anions of either aldehydes or ketones, which means reaction could be defeated by proton transfer of the type... 

By analogy, the chemical Claisen condensation using the enolate anion from diethyl malonate in Figure 2.10 proceeds much more favourably than that using the enolate from ethyl acetate. The same acetoacetic acid product can be formed in the malonate condensation by hydrolysis of the acylated malonate intermediate and decarboxylation of the gem-diacid. 

So far, we have seen that an enolate anion is able to act as a nucleophile in an SN2 reaction (Sections 20.3 and 20.4) and also in an addition reaction to the carbonyl group of an aldehyde in the aldol condensation (Section 20.5). It also can act as a nucleophile in a substitution reaction with the carbonyl group of an ester as the electrophile. When an ester is treated with a base such as sodium ethoxide, the enolate ion that is produced can react with another molecule of the same ester. The product has the a-carbon of one ester molecule bonded to the carbonyl carbon of a second ester molecule, replacing the alkoxy group. Examples of this reaction, called the Claisen ester condensation, are provided by the following equations ... 

A similar process is described in the Focus On box titled The Reverse Aldol Reaction in Metabolism on page 880. The Claisen ester condensation also has an equilibrium step in which an enolate anion leaves in the reverse of the step (see Figure 20.4). 

This difference affects each stage of the CLaisen ester condensation in the same way. Thiol esters are more easily converted to enolate anions, they are more easily attacked by nucleophiles, and RS is a better leaving group than RO. In each case the reaction is better (faster or equilibrium further towards product), the Claisen thiol ester condensation... 

In the synthesis, the product of the Claisen ester condensation is actually the enolate anion of the keto-aldehyde and this can be combined direcdy without isolation with cyanoacetamide to give tire pyridone in the same flask. 

The Claisen-type condensation of ketone enolate anions and arenesulfinates provides an interesting synthetic approach to diastereomeric ji-oxo sulfoxides69,70. 

Enolate anions are an important class of carbanions that appear in a variety of important reactions, including alkylation a- to a carbonyl group and the aldol (reaction 16-34) and Claisen condensation (reaction 16-85) reactions. Metal enolate anions of aldehydes, ketones, esters, and other acid derivatives exist as aggregates in ether solvents, and there is evidence that the hthium enolate of... 

When carboxylic esters containing an a hydrogen are treated with a strong base, such as sodium ethoxide, a condensation occurs to give a p-keto ester via an ester enolate anion. ° This reaction is called the Claisen condensation. When it is carried out with a mixture of two different esters, each of which possesses an a hydrogen (this reaction is called a mixed Claisen or a crossed Claisen condensation), a mixture of all four products is generally obtained and the reaction is seldom useful synthetically. However, if only one of the esters has an... 

As with ketone enolate anions (see 16-34), the use of amide bases under kinetic control conditions (strong base with a weak conjugate acid, aprotic solvents, low temperatures), allows the mixed Claisen condensation to proceed. Self-condensation of the lithium enolate with the parent ester is a problem when LDA is used as a base, ° but this is minimized with LICA (lithium isopropylcyclohexyl amide).Note that solvent-free Claisen condensation reactions have been reported. ° ... 

In the Claisen-Schmidt condensation, one of the carbonyl compounds lacks an a-hydrogen, and so cannot form an enolate anion. This reaction involves an... 

Moving to a,3-unsaturated esters, hydroxide ion and alkoxide ion (hard nucleophiles) react with ethyl acrylate 4.145 by direct attack at the carbonyl group to give ester hydrolysis and ester exchange, respectively, whereas the /3-dicarbonyl enolate ion 4.146 (a softer nucleophile) undergoes a Michael reaction.381 There is no certainty in this latter reaction that the attack of the enolate anion on the carbonyl group, in a Claisen-like condensation, is not a more rapid (and reversible) process.382... 

Work by Ashby et al. has established the intermediacy of radicals in a variety of processes previously thought to be purely ionic. The Claisen condensation of ethyl p-nitrobenzoate with the lithium enolate of pinacolone gave an EPR-active species whose rate of formation and decay indicated that it was on the pathway to the product. The postulated mechanism is shown in Scheme 3. However, this was the only example of SET observed by this group for this reaction and the intermediacy of the radical anion of the ester in this case is plausible but not proved."... 

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