Acetoacetic Ester Synthesis-Organic reaction

Acetoacetic Ester Synthesis

Acetoacetic ester synthesis

Acetoacetic ester synthesis is a chemical reaction where ethyl acetoacetate is alkylated at the α-carbon to both carbonyl groups and then converted into a ketone, or more specifically an α-substituted acetone. This is very similar to malonic ester synthesis.

When α-keto acetic acid is treated with one mole of a base, the methylene group which is more acidic reacts with the base. And the reaction with an alkylation reagent gives alkyl products attached to methylene. When this reaction is repeated in the next step, the other hydrogen can also react to a dialkyl product. The two alkylation agents may be the same or different (R',R'').

β-Keto esters tend to decarboxylate after hydrolysation to β-keto carboxylic acid and heating to give one or two alkyl-substituted ketones, respectively.

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Mechanism

A strong base deprotonates the dicarbonyl α-carbon. This carbon is preferred over the methyl carbon because the formed enolate is conjugated and thus resonance stabilized. The carbon then undergoes nucleophilic substitution. When heated with aqueous acid, the newly alkylated ester is hydrolyzed to a β-keto acid, which is decarboxylated to form a methyl ketone.

Deprotonates :Deprotonation is the removal of a proton (H+) from a molecule, forming the conjugate base. The proton removal decreases positive charge in the molecule and an increases negative charge. Deprotonation usually occurs from the donation of electrons or acceptance of the proton using a base, which forms its conjugate acid.

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Mechanism of Acetoacetic Ester Synthesis

Step 1

In the presence of mild base such as NaOH or NaOEt, the alpha – hydrogen of the beta-keto ester can be abstracted to produce the carbanion which can resonate to form an enolate. Since the enolate can resonate on either side of the ester and the ketone it is more stabilized and hence use of even mild bases can be made for this reaction.

Abstraction of alpha-proton yields a carbanion which is stabilized by enol formation through resonance on either side of beta keto ester

Step 2 and Step 3

The enolate carbanion thus formed is capable of attacking the alkyl halide R-X as the halide is a good leaving group. This yields the mono-alkylated beta-keto ester (i). However, reaction does not stop there. Since the base and alkyl halide are present in the same solution, step 1 and 2 can repeat in step 3 to produce the disubstituted beta-keto ester (ii).

Note - For step 2 the carbanion shown below can exist as enolates in resonance structures (as shown above) – hence it can be shown using the illustration below or using enolates but with proper arrows indicating movement of electrons.

Attack of the enolate on the alkyl halide (R-X) to yield mono- and di- alkylated beta keto ester

Step 4

Upon acidification of the solution the esters can undergo hydrolysis to yield the acid. Note – this reaction can happen with both mono (as shown) as well as di-substituted beta keto ester (not shown).

Step 5

Under acidic conditions and slight heating the beta-keto carboxylate can undergo a loss of carbon dioxide to yield either mono (as shown) or disubstituted (not shown) ketone

Under acidic conditions the carboxylic acid can loose one molecule of carbon dioxide to yield the alpha-alkyl ketone.

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References

1. Smith, Janice Gorzynski. Organic Chemistry: Second Ed. 2008. pp 905–906
2. Acetoacetic Ester Synthesis – Alkylation of Enolates | PharmaXChange.info

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Related Reactions

Knoevenagel Condensation

Malonic Ester Synthesis
Synthesis of ketones

Example