The Claisen condensation is a chemical reaction that occurs between an ester and a compound containing an active methylene group (-CH2-). It is a condensation reaction in which water is formed as a byproduct. This is the acyl substitution reaction between esters and a carbonyl compound in the presence of a strong base. In this reaction, the enolate of one molecule is added to the carbonyl of another and forms β-keto esters and alcohols.
This reaction was named after German chemist Rainer Ludwig Claisen. He was famous for his work in the field of carbonyl condensation and sigmatropic rearrangements. In 1887, he published his work on this reaction.
It is an important synthetic tool in organic chemistry for the synthesis of β-ketoesters or β-diketones and is widely used for the synthesis of various chemicals, including pharmaceuticals, flavorings, and fragrances.
Claisen condensation vs. Aldol condensation
Claisen condensation is often confused with aldol condensation due to similar types of reactants and products. The key differences are given in the table below:
| Aldol codensation | Claisen condensation |
| In this reaction, the main reactants are aldehydes or ketones | The reactants are esters or ketones |
| β-hydroxy aldehydes or ketones are the final products | β-ketoesters or β-diketones are the final products |
| It requires a strong base | It requires a base that can not undergoes nucleophilic substitution reaction |
| Water is the only byproduct | Alcohol and water are the byproducts |
| Types: Acid-catalyzed, Base catalyzed | Types: Self claisen condensation, Cross claisen condensation, Intramolecuar claisen condensation, Stobe condensation |
Example of Claisen condensation
A common example of Claisen condensation is the formation of ethyl acetoacetate or acetoacetic ester. It is also named 3-oxobutanoate.
Mechanism of Claisen condensation
The reaction mechanism consists of five steps:
- Formation of the enolate ion
- Nucleophilic addition (Attack of enolate ion)
- Nucleophilic elimination (Removal of an alkoxide)
- Deprotonation
- Acidification (quenching)
Formation of the enolate ion
In the first step of Claisen condensation, base attacks at α-hydrogen of ester and result in the formation of enolate ion. This enolate anion stabilized itself by resonance (delocalization of negative charge).
Nucleophilic addition
In this step, the enolate anion attacks the carbonyl carbon of the ester and forms a tetrahedral intermediate.
Nucleophilic elimination
In this step, an alkoxide is removed by the dissociation of a tetrahedral intermediate. Here alkoxide act as leaving group.
Deprotonation
In this step, the alkoxide ion removes α-hydrogen from the newly formed condensed product. This results in the formation of resonance-stabilized structures (tautomers). Alcohol formed as a by-product during the reaction which can be separated out through distillation.
Acidification
The reaction mixture is acidified to quench the reaction. This is performed to isolate the products in their neutral form. Note that, this step is also known as protonation.
Types of Claisen condensation
There are four types of Claisen condensation reactions based on the reaction conditions:
- Cross condensation reaction
- Intramolecular condensation reaction
- Stobe condensation
- Self-Claisen condensation reaction
Cross Claisen condensation reaction
This reaction is also known as a mixed condensation reaction. In the cross-condensation reaction, one of the reagents is an ester that is enolizable whereas the other reagent is a ketone or non-enolizable ester. They don’t have α-hydrogens so they can not undergo enolization or self-condensation. For example,
Unsymmetrical ketones can give cross Clasien condensation reactions without using a specific enol equivalent. The reaction occurs on the less substituted side.
Intramolecular condensation reaction
The intramolecular condensation reaction is also known as Dieckmann condensation. This is a very useful method for the production of cyclic β-ketoesters at a large scale. In this reaction, two ester groups react intramolecularly and form cyclic β-ketoesters.
Stobe condensation
Stobe condensation is a modified form of the claisen condensation reaction. In this reaction diethyl ester of succinic acid reacts with benzophenone in the presence of weaker bases.
Self-condensation reaction
In this type, two esters groups are condensed in the presence of a strong base to form β-ketoesters. By using alkoxide bases, ester undergoes self-condensation. The main product of self-condensation is β-ketoesters whereas alcohol is formed as a by-product.
Key Takeaways
- Claisen condensation is one of the important reactions for the synthesis of β-ketoesters.
- β-ketoesters are essential reagents in synthetic organic chemistry.
- β-ketoesters are useful starting materials for the preparation of ketones. They are also used as intermediates for the synthesis of different drug molecules.
- Transesterification of β-ketoesters has wide applications in the field of agrochemicals.
- These reactions are also used in the synthesis of biodiesel.
Related resources:
- Aldol Condensation
- Step-by-Step Mechanism of Fischer Esterification
- Transesterification: Mechanism and Applications
- Hydrolysis of Esters: Mechanism and Conditions
Concepts Berg
What is meant by condensation reaction?
It is the type of chemical reaction in which two molecules combine to form a single molecule with the elimination of smaller molecules as a by-product. Smaller molecules are usually water molecules.
Why are small member rings not favorable?
Smaller member rings are not favorable due to angle strain.
What are the products of Claisen condensation?
The product of claisen condensation are β-ketoesters or β-diketones.
What intermediate formed during Claisen condensation?
A tetrahedral intermediate is formed during Claisen condensation.
References
- 10th edition of Organic Chemistry by T.W Graham Solomons and Craig B. Fryhle.
- 2nd edition of Organic Chemistry by Jonathan Clayden, Nick Greeves, and Stuart Warren.
