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Organic Chemistry 2 Unit 8: Carbonyl Condensations (Aldol, Claisen)

In condensation reactions an enolate from one carbonyl compound attacks a second carbonyl compound, forming new C–C bonds; aldol, Claisen, Michael and Robinson reactions build most of the carbon frameworks made in organic synthesis.

Covers: Aldol addition and condensation, Crossed aldol and Claisen-Schmidt reactions, Intramolecular aldol cyclizations, Claisen condensation, Crossed Claisen and Dieckmann cyclization, Michael (conjugate) addition, Robinson annulation and retrosynthesis

Study guide

In the aldol addition, an enolate of an aldehyde or ketone attacks the carbonyl carbon of a second molecule, and protonation gives a β-hydroxy aldehyde or ketone (an aldol). With base and heat, or with acid, the aldol loses water to give an α,β-unsaturated carbonyl compound; this is the aldol condensation. Base-promoted dehydration goes through an enolate that expels hydroxide (an E1cB mechanism), and it is driven by conjugation of the new C=C with the C=O. The key structural signature is that the new C–C bond joins the α-carbon of one partner to the carbonyl carbon of the other. Two propanal molecules (C₃H₆O, 58.08 g/mol) give the aldol C₆H₁₂O₂ and, after losing water, 2-methyl-2-pentenal, C₆H₁₀O (98.14 g/mol).

A crossed (mixed) aldol between two different enolizable carbonyls gives up to four products. Crossed aldols are useful when one partner has no α-hydrogens, such as benzaldehyde or formaldehyde, so it can only be the electrophile, and the other partner is added slowly or is less reactive as an electrophile. The Claisen-Schmidt reaction, benzaldehyde with a ketone in NaOH, gives conjugated enones such as benzalacetone and chalcone. Alternatively, LDA can preform one enolate completely before the second carbonyl is added. Molecules with two carbonyl groups undergo intramolecular aldol reactions, which strongly favor forming five- and six-membered rings: 2,5-hexanedione gives 3-methylcyclopent-2-enone, and 2,6-heptanedione gives 3-methylcyclohex-2-enone.

The Claisen condensation is the ester version: an ester enolate attacks a second ester molecule, the tetrahedral intermediate expels alkoxide, and the product is a β-keto ester. Two ethyl acetate molecules give ethyl acetoacetate. Because the equilibrium itself is unfavorable, the reaction is driven by deprotonating the β-keto ester (pKa about 11) with the alkoxide base, so a full equivalent of base is required and the starting ester must have two α-hydrogens. Acid workup then gives the neutral product. The base should match the ester's alkoxide (NaOEt for ethyl esters) to avoid transesterification, and hydroxide is avoided because it saponifies esters. Crossed Claisens work when one ester cannot form an enolate, such as ethyl benzoate, ethyl formate or diethyl carbonate. The Dieckmann cyclization is an intramolecular Claisen: diethyl hexanedioate gives a five-membered β-keto ester and diethyl heptanedioate a six-membered one.

α,β-Unsaturated carbonyl compounds are electrophilic at both the carbonyl carbon and the β-carbon, because resonance places δ+ on the β-carbon. Strong, hard nucleophiles such as Grignard and organolithium reagents usually add directly to the C=O (1,2-addition). Softer, stabilized nucleophiles add to the β-carbon (1,4- or conjugate addition), forming an enolate that is then protonated: this is the Michael reaction when the nucleophile is a stabilized enolate such as that of diethyl malonate or ethyl acetoacetate. Gilman reagents (R₂CuLi), amines, thiols and cyanide also add 1,4. A typical Michael acceptor is methyl vinyl ketone (MVK), CH₂=CHCOCH₃. Michael products are 1,5-dicarbonyl compounds, which are perfectly set up for a later intramolecular aldol.

The Robinson annulation combines a Michael addition with an intramolecular aldol condensation to build a new six-membered ring containing an α,β-unsaturated ketone. A ketone enolate adds to MVK to give a 1,5-diketone; then an enolate of that diketone attacks the other carbonyl, and dehydration gives a cyclohexenone. Acetone plus MVK gives 3-methylcyclohex-2-enone, and cyclohexanone plus MVK gives a bicyclic enone. For retrosynthesis, recognize the patterns: a β-hydroxy carbonyl or α,β-unsaturated carbonyl suggests an aldol (cut the C=C or the Cα–Cβ bond), a β-keto ester suggests a Claisen, a 1,5-dicarbonyl suggests a Michael addition, and a cyclohexenone fused to another ring suggests a Robinson annulation.

Key ideas

• Aldol reactions join the α-carbon of one carbonyl to the carbonyl carbon of another, giving β-hydroxy carbonyls.
• Dehydration of aldols gives conjugated α,β-unsaturated carbonyls by an E1cB mechanism.
• Crossed aldols and Claisens are clean when one partner has no α-hydrogens.
• Intramolecular aldol and Dieckmann reactions favor five- and six-membered rings.
• Claisen condensations make β-keto esters and are driven by deprotonating the product.
• Stabilized nucleophiles and cuprates add 1,4 to α,β-unsaturated carbonyls; Grignards add 1,2.
• Robinson annulation = Michael addition + intramolecular aldol condensation, forming a cyclohexenone.

Formulas and rules

Common mistakes

• Bonding the carbonyl carbon to the wrong carbon; the nucleophilic carbon is always the α-carbon.
• Running a crossed aldol between two enolizable partners and expecting one product.
• Attempting a Claisen with an ester that has only one α-hydrogen, which cannot be driven to completion.
• Using NaOH or a mismatched alkoxide with esters, causing saponification or transesterification.
• Predicting 1,2-addition for enolates and cuprates, which add 1,4 to enones.

Before the test, make sure you can

• Draw aldol addition and condensation products and mechanisms.
• Choose partners and conditions for a clean crossed aldol.
• Predict ring size and product for intramolecular aldol and Dieckmann reactions.
• Predict Claisen and crossed Claisen products and explain the role of the base.
• Distinguish 1,2- from 1,4-addition and predict Michael products.
• Draw the Robinson annulation sequence and its product.
• Work backward from a target to identify aldol, Claisen, Michael or Robinson disconnections.
• Calculate formulas, masses and yields for condensation products.

Words to know

Aldol

A β-hydroxy aldehyde or ketone formed by aldol addition.

Aldol addition

Nucleophilic addition of an enolate to an aldehyde or ketone, giving a β-hydroxy carbonyl compound.

Aldol condensation

Aldol addition followed by dehydration to an α,β-unsaturated carbonyl compound.

E1cB mechanism

Elimination through a carbanion (enolate) intermediate that then expels a leaving group such as hydroxide.

Crossed aldol

An aldol reaction between two different carbonyl compounds.

Claisen-Schmidt reaction

A crossed aldol condensation between an aromatic aldehyde and a ketone.

Claisen condensation

Condensation of two esters with alkoxide base to form a β-keto ester.

Dieckmann cyclization

An intramolecular Claisen condensation of a diester that forms a cyclic β-keto ester.

β-Keto ester

An ester with a ketone on the β-carbon, such as ethyl acetoacetate; its central C–H has pKa about 11.

α,β-Unsaturated carbonyl

A carbonyl compound with a C=C between the α- and β-carbons, electrophilic at the β-carbon.

Conjugate (1,4-) addition

Addition of a nucleophile to the β-carbon of an α,β-unsaturated carbonyl compound.

Michael reaction

Conjugate addition of a stabilized enolate to an α,β-unsaturated carbonyl compound.

Michael acceptor

An α,β-unsaturated carbonyl or nitrile, such as methyl vinyl ketone, that accepts a conjugate nucleophile.

Methyl vinyl ketone (MVK)

CH₂=CHCOCH₃, the classic Michael acceptor used in Robinson annulations.

Robinson annulation

A Michael addition followed by an intramolecular aldol condensation that forms a new cyclohexenone ring.

1,5-Dicarbonyl compound

A compound with carbonyls separated by three carbons, the product of a Michael addition.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.