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Chapter: Organic Chemistry: Carboxylic acids and carboxylic acid derivatives

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Enolate reactions - Carboxylic acids and carboxylic acid derivatives

Esters contain acidic α protons which can be removed with a strong base to form enolate ions.

ENOLATE REACTIONS

Key Notes

Enolates

Esters contain acidic α protons which can be removed with a strong base to form enolate ions. A bulky base is used to prevent the possibility of nucleophilic substitution taking place. Diethyl malonate can be converted to a stable enolate ion using sodium ethoxide as base.

Alkylations

Enolate ions can be alkylated with alkyl halides. Diethyl malonate can be alkylated twice, hydrolyzed, and decarboxylated to give a disubstituted ethanoic acid.

Claisen condensation

Two esters can be condensed together to form a β-ketoester. The reaction involves the formation of an enolate ion from one molecule of ester, which then undergoes nucleophilic substitution with another ester molecule. Mixed Claisen condensations are possible with two different esters or between an ester and a ketone.

 

Enolates

Enolate ions can be formed from aldehydes and ketones containing protons on an α-carbon. Enolate ions can also be formed from esters if they have protons on an α-carbon (Fig. 1). Such protons are slightly acidic and can be removed on treatment with a powerful base such as lithium diisopropylamide (LDA). LDA acts as a base rather than as a nucleophile since it is a bulky molecule and this prevents it attacking the carbonyl group in a nucleophilic substitution reaction.


Formation of enolate ions is easier if there are two esters flanking the α−carbon since the α−proton will be more acidic. The acidic proton in diethyl malonate can be removed with a weaker base than LDA (e.g. sodium ethoxide; Fig. 2). The enolate ion is more stable since the charge can be delocalized over both carbonyl groups.


Alkylations

Enolate ions can be alkylated with alkyl halides through the SN2 nucleophilic substitution of an alkyl halide.


Although simple esters can be converted to their enolate ions and alkylated, the use of a molecule such as diethyl malonate is far more effective. This is because the α−protons of diethyl malonate (pKa 10–12) are more acidic than the α−protons of a simple ester such as ethyl acetate (pKa 25) and can be removed by a milder base. It is possible to predict the base required to carry out the deprotonation reaction by considering the pKa value of the conjugate acid for that base. If this pKa is higher than the pKa value of the ester, then the deprotonation reaction is possible. For example, the conjugate acid of the ethoxide ion is ethanol (pKa 16) and so any ester having a pKa less than 16 will be deprotonated by the ethoxide ion. Therefore, diethyl malonate is deprotonated but not ethyl acetate. A further point worth noting is that the ethoxide ion is strong enough to deprotonate the diethyl malonate quantita-tively such that all the diethyl malonate is converted to the enolate ion. This prevents the possibility of any competing Claisen reaction (see below) since that reaction requires the presence of unaltered ester. Diethyl malonate can be converted quantitatively to its enolate with ethoxide ion, alkylated with an alkyl halide, treated with another equivalent of base, then alkylated with a second different alkyl halide (Fig. 4). Subsequent hydrolysis and decarboxyla-tion of the diethyl ester results in the formation of the carboxylic acid. The decarboxylation mechanism (Fig. 5) is dependent on the presence of the other carbonyl group at the β−position.


The final product can be viewed as a disubstituted ethanoic acid. In theory, this product could also be synthesized from ethyl  ethanoate. However, the use of diethyl malonate is superior since the presence of two carbonyl groups allows easier formation of the intermediate enolate ions.

Claisen condensation

The Claisen reaction involves the condensation or linking of two ester molecules to form a β-ketoester (Fig. 6). This reaction can be viewed as the ester equivalent of the Aldol reaction. The reaction involves the formation of an enolate ion from one ester molecule, which then undergoes nucleophilic substitution with a second ester molecule (Fig. 7, Step 1). The ethoxide ion which is formed in step 2 removes anα−proton from the β−ketoester in step 3 to form a stable enolate ion and this drives the reaction to completion. The final product is isolated by protonating the enolate ion with acid. Two different esters can be used in the Claisen condensation as long as one of the esters has no α−protons and cannot form an enolate ion (Fig. 8). β−Diketones can be synthesized from the mixed Claisen condensation of a ketone with an ester (Fig. 9). Again, it is advisable to use an ester which cannot form an enolate ion to prevent competing Claisen condensations.



In both these last two examples, a very strong base is used in the form of LDA such that the enolate ion is formed quantitatively (from ethyl acetate and acetone respectively). This prevents the possibility of self-Claisen condensation and limits the reaction to the crossed Claisen condensation.


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