Claisen Condensation

Claisen condensation is an organic reaction that forms a new carbon-carbon bond, producing a β-keto ester. It involves the condensation of two esters or one ester and a carbonyl compound in the presence of a strong base, forming a β-keto ester or a β-diketone. It was discovered by German chemist Ludwig Claisen in 1887. In this article, we will look into What Claisen Condensation is, its mechanism, examples, types, etc.

What is Claisen Condensation?

Claisen condensation is an organic reaction that forms a new carbon-carbon bond, producing a β-keto ester or a β-diketone. It involves the condensation of two esters or one ester and a carbonyl compound in the presence of a strong base, forming a β-keto ester or a β-diketone.

The reaction proceeds through the deprotonation of an α-hydrogen on an ester by a strong base, creating an enolate ion, which then attacks the carbonyl carbon of a second ester or a carbonyl compound, forming a tetrahedral intermediate. The reaction requires at least one equivalent of a strong base, such as sodium alkoxide, and esters with at least two α-hydrogens to ensure the formation of an enolate ion.

Claisen Condensation Definition

Claisen condensation is a carbon-carbon bond-forming reaction between two esters or one ester and another carbonyl compound in the presence of a strong base. The reaction produces a β-keto ester or a β-diketone.

Claisen Condensation Reagents

Claisen condensation involves using esters or one ester and another carbonyl compound, such as a ketone or an aldehyde, in a strong base. Typical reagents include:

• Enolizable esters: These esters contain an α-hydrogen atom that can be deprotonated to form an enolate ion. Examples include ethyl acetate, methyl propionate, etc.
• Non-enolizable esters (for cross-Claisen condensations): These esters do not have an α-hydrogen and thus cannot form enolates themselves. They act as electrophiles in the reaction. Examples include benzoyl chloride, pivaloyl chloride, etc.
• Strong bases: Commonly used bases include sodium alkoxides like sodium ethoxide (NaOEt) or potassium tert-butoxide (t-BuOK).

Claisen Condensation Reaction

The Claisen condensation is a carbon-carbon bond-forming reaction that occurs between two esters or one ester and another carbonyl compound. The general reaction can be illustrated as follows:

R₁ COCH₂​R₂ + R₃COCH₂​R₄ → R₁COCH₂​CH₂​COR₃ + R₂COCH_2​R₄

This reaction requires at least one of the reagents to be enolizable and a solid base to facilitate the formation of an enolate ion. The product of the reaction is a β-keto ester or a β-diketone.

Mechanism of Claisen Condensation Reaction

The Claisen condensation is a carbon-carbon bond-forming reaction that involves the formation of a β-keto ester or a β-diketone. The reaction proceeds through three main steps: enolate formation, nucleophilic attack, and removal of the leaving group.

• Enolate formation: An α-proton from an ester is removed by a strong base, such as a sodium alkoxide, to form an enolate ion. The delocalization of electrons stabilizes the enolate ion. This can be represented by the general reaction:

RCOOR’ + OR^– (base) → R’-COO^– + R-OH

• Nucleophilic attack: The enolate ion acts as a nucleophile and attacks the carbonyl carbon of a second ester molecule, forming a tetrahedral alkoxide intermediate.

General reaction: R’-C(=O)O^– + R”-CO-R”’ → R’-C(=O)-O-R” + R”-C(=O)-R”‘

• Removal of the leaving group: The alkoxide ion reforms the carbonyl group, and the leaving group (usually an alkoxide) is eliminated.

General reaction: R’-C(=O)-O-R” → R’-C(=O)-R” + ROH

Claisen condensation is reversible, and the equilibrium can be driven forward by removing the acidic β-keto ester product formed during the reaction. This principle is known as Le Chatelier’s principle.

Variations of Claisen Condensation

The Claisen condensation is a carbon-carbon bond-forming reaction that involves the formation of a β-keto ester or a β-diketone. There are three main variations of the Claisen condensation: classic Claisen condensation, crossed Claisen condensation, and Dieckmann condensation.

Classic Claisen condensation

It is a self-condensation between two molecules of a compound containing an enolizable ester.

Example reaction: R₁COOR₂ + R₃COOR₄ → R₁COR₃COOR₄ + R₂O

Crossed Claisen condensation

It involves the enolate of one ester reacting as a nucleophile with a different (ideally non-enolizable) ester or ketone.

Example reaction: R₁COOR₂ + R₃COR₄ → R₁COR₃COOR₂ + R₄O

Dieckmann condensation

It is an intramolecular variant of the Claisen condensation, where a molecule featuring two ester groups undergoes an intramolecular reaction to form a cyclic β-keto ester.

Example reaction: R₁COOR₂CH₂COOR₂ → R₁COOCH₂COR₂ + R₂COO

Examples of Claisen Condensation

The Claisen condensation is a carbon–carbon bond-forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. Here are some examples of the Claisen condensation:

• Synthesis of natural products: Claisen condensation is used to synthesize various natural products, such as the formation of the A ring of the antibiotic erythromycin.
• Synthesis of pharmaceuticals: The Claisen condensation is employed in synthesizing various pharmaceuticals, such as the anticonvulsant drug phenytoin.
• Biosynthesis of fats and terpenes: Acetyl CoA, a key molecule in metabolism, undergoes a Claisen condensation, leading to the formation of complex lipids and terpenes.

Reverse Claisen Condensation

The reverse Claisen condensation is the reverse of the Claisen condensation reaction, where a β-keto ester or a β-diketone is converted back into two esters or an ester and another carbonyl compound in the presence of a strong acid or a Lewis acid. The reaction proceeds through the protonation of the carbonyl oxygen of the β-keto ester or β-diketone, followed by the cleavage of the carbon-carbon bond and the formation of two esters or an ester and another carbonyl compound.

The reverse Claisen condensation is generally less favorable than the forward reaction due to the thermodynamic stability of the β-keto ester or β-diketone product. The reaction can be helpful in synthesizing esters or carbonyl compounds from β-keto esters or β-diketones. The general reaction for the reverse Claisen condensation is:

keto ester or diketone + acid → two esters or ester and carbonyl compound

Intramolecular Claisen Condensation

The intramolecular Claisen condensation, also known as the Dieckmann condensation, is a variation of the Claisen condensation where a molecule containing two ester groups undergoes a cyclization reaction to form a cyclic β-keto ester. The reaction proceeds by forming an enolate ion from one of the ester groups, which then attacks the carbonyl carbon of the other ester group to form a cyclic intermediate.

The intermediate then undergoes protonation and dehydration to form the final product. The Dieckmann condensation is particularly useful for synthesizing five- and six-membered cyclic β-keto esters. The general reaction for the intramolecular Claisen condensation is:

keto ester with two ester groups → cyclic keto ester

Factors Affecting the Claisen Condensation

Factors affecting the Claisen condensation include:

• Nature of the Base: The choice of base is crucial, and it should be a strong base to facilitate the deprotonation and formation of the enolate ion. Typically, alkoxide bases that match the esters’ alkoxy group are used
• Solvent: The solvent used should not engage with the reagents or the base, such as ethanol or dimethyl sulfoxide (DMSO), to carry the reaction forward
• Reaction Temperature: The temperature at which the reaction is carried out can impact the rate of the reaction and the formation of the desired product
• Concentration of Reactants: The reactants’ concentration can influence the reaction’s yield and selectivity.

Claisen Condensation Applications

Claisen condensation has many applications across diverse fields, including:

• Synthesis of pharmaceuticals and agrochemicals
• Production of flavors and fragrances
• Development of biofuels using biodegradable feedstock
• Construction of polymers, such as polyesters, polyurethanes, and alkaline resins
• Preparation of advanced materials, e.g., conducting polymers and nanocomposites
• Elaboration of natural products and their analogues
• Investigation of biological systems, e.g., fatty acid and terpene biosynthesis
• Exploration of green chemistry approaches, utilizing renewable resources and environmentally friendly solvents

Claisen Condensation of Ethyl Acetate

Claisen condensation of ethyl acetate involves the formation of ethyl acetoacetate, a β-keto ester, in a strong base such as sodium ethoxide. The reaction proceeds through several steps, as outlined below:

• Step I: The ethoxide ion (-C₂​​H₅O) abstracts a proton from the α-carbon of one molecule of ethyl acetate, forming a carbanion.
• Step II: The carbanion then acts as a nucleophile, attacking the carbonyl carbon of another ethyl acetate molecule, forming a tetrahedral intermediate.
• Step III: The tetrahedral intermediate loses the ethoxide ion to produce the β-keto ester and an alkoxide ion.
• Step IV: The alkoxide ion undergoes an acid-base reaction with ethanol, forming ethoxide ion and ethanol.

The overall reaction can be summarized as follows:

C₄H₈O₂ + C₂H₅ONa → C₆H₁₀O₃ + C₂H₅OH

Difference Between Aldol and Claisen Condensation

The difference between Aldol and Claisen Condensation is as follows:

Feature	Aldol Condensation	Claisen Condensation
Reactants	Two aldehydes or ketones	Ester and carbonyl compound (ketone or aldehyde)
Products	β-hydroxyaldehyde or β-hydroxyketone	β-keto ester or β-diketone
Base	Weaker base, such as hydroxide or carbonate	Stronger base, such as sodium ethoxide or potassium tert-butoxide
Mechanism	Formation of alkoxide intermediate, which gets protonated to give β-hydroxy carbonyl compound	Formation of enolate intermediate, which expels alkoxide group, restoring C=O and producing nucleophilic acyl substituted 1,3-dicarbonyl compound
Applications	Synthesis of β-hydroxy carbonyl compounds	Synthesis of β-keto esters or β-diketones

Claisen Condensation Frequently Asked Questions

What is Claisen Condensation with example?

Claisen Condensation is a reaction where two esters or one ester and another carbonyl compound react to form β-keto esters. For example, ethyl acetate can undergo Claisen Condensation to form ethyl acetoacetate.

What is the Claisen condensation in fatty acids synthesis?

In fatty acid synthesis, Claisen Condensation is vital for elongating carbon chains. Malonyl-CoA undergoes repeated Claisen Condensations with acetyl-CoA to form longer fatty acid chains.

Who discovered the Claisen Condensation?

Claisen Condensation was discovered by German chemist Ludwig Claisen in 1887.

What are the essential requirements for the Claisen Condensation?

Critical requirements for Claisen Condensation include a strong base catalyst (such as alkoxide ions), suitable reactants (esters or carbonyl compounds), and often a polar, aprotic solvent like diethyl ether.

What is the role of the Claisen Condensation in biosynthesis?

In biosynthesis, Claisen Condensation plays a crucial role in forming complex molecules like polyketides and fatty acids, which are essential for cellular structures and functions.