Carbonyl Condensation Reactions | Organic Chemistry 3

Carbonyl condensation reactions are studied in this chapter: aldol and retro-aldol additions, aldol condensation, crossed aldol and intramolecular aldol reactions, Claisen condensation, Dieckmann cyclization, Michael reaction, Michael acceptors and donors, Stork enamine synthesis, Enamine Alkylation, Robinson annulation.

Aldol Reactions

Aldol addition:
 


Conversion of 2 carbonyls into a β-hydroxy aldehyde or ketone called an aldol (ald- for "aldehyde" and -ol for "alcohol").

Mechanism:

  1. Deprotonation of the α position of a carbonyl to form a nucleophilic enolate.


     
  2. Nucleophilic attack of the enolate on the second aldehyde to form an alkoxide ion.
  3. Protonation of the alkoxide to form the aldol.


     

This process is a reversible equilibrium. For most aldehydes, the position of equilibrium favors the aldol product, while for most ketones, the aldol is not favored and undergoes a retro-aldol reaction.

 

Retro-aldol reaction:
 

Mechanism:

Reverse of the three-step aldol addition process.

  1. Deprotonation of the β-hydroxy group to form an alkoxide ion.
  2. Loss of the leaving group, an enolate, to re-form the carbonyl group.
  3. Protonation of the enolate.

 

Aldol condensation:
 


Conversion of 2 carbonyls into an α,β-unsaturated aldehyde or ketone. 

Mechanism: Aldol condensation is a two-step process: aldol addition followed by dehydration.

Part 1: Aldol addition

  1. Deprotonation of the α position of a carbonyl to form an enolate.
  2. Nucleophilic attack of the enolate on the second aldehyde to form an alkoxide ion.
  3. Protonation of the alkoxide to form the aldol.

Part 2: Dehydration (elimination of H2O) via an E1cb mechanism

  1. Deprotonation of the α position of the aldol to form an enolate.
  2. Loss of the leaving group, a hydroxide, to form an α,β-unsaturated aldehyde or ketone.

 

The driving force for an aldol condensation is the formation of a conjugated system.

Stereoselectivity: Formation of the trans π bond is favored over formation of the cis π bond.

Crossed Aldol Reactions

Crossed aldol (or mixed aldol) reactions:

Aldol reactions that occur between 2 different aldehydes or ketones. They result in mixtures of products from symmetrical and crossed aldol reactions.
 


In organic chemistry, mixtures of products are unless ⇒ crossed aldol reactions are only efficient if they can favor the formation of one aldol.

 

Conditions favoring one product in crossed aldol reactions:

  • If one of the aldehydes lacks α protons and has an unhindered carbonyl group ⇒ these aldehydes cannot form enolates and are more rapidly attacked by a nucleophile due to their less hindered carbonyl group.


     
  • If one of the reagents is the benzaldehyde ⇒ benzaldehyde cannot form enolate and the equilibrium shifts to the formation of the condensation product (conjugation stabilization).


     
  • When a carbonyl is added dropwise to a solution of enolate ions previously prepared with LDA. This process, called directed aldol addition, is limited by the fact that enolates can also act as bases and thus deprotonate the added carbonyl.

Intramolecular Aldol Reactions

Intramolecular aldol reactions:
 

Mechanism:

Same mechanism as aldol condensation except that the enolate and the carbonyl group are in the same molecule ⇒ intramolecular nucleophilic attack occurs.

  1. Formation of an enolate.
  2. Cyclization by intramolecular nucleophilic attack.
  3. Protonation of the alkoxide to form a cyclic β-hydroxy carbonyl compound.
  4. Dehydration to form a cyclic α,β-unsaturated carbonyl compound.


     

Highly regioselective reaction: The formation of the least strained cycloalkenones is favored (five- and six-membered rings).

Claisen Condensations

Claisen Condensation:
 

 

Conversion of 2 esters to a β-keto ester.

Mechanism:

  1. Deprotonation of the α position of an ester to form a nucleophilic ester enolate.


     
  2. Nucleophilic attack of the ester enolate on the second ester to form a tetrahedral intermediate.


     
  3. Loss of the leaving group, an alkoxide ion, to re-form the carbonyl group.
  4. Deprotonation of the α position of the β-keto ester to form a doubly stabilized enolate.


     
  5. After the reaction is complete: Acidic aqueous work-up to protonate the doubly stabilized enolate and form the desired β-keto ester.

 

  • The Claisen condensation is an equilibrium: a retro-Claisen condensation can be observed, resulting in 2 ester molecules by a mechanism that is exactly the opposite of the Claisen condensation.
  • The driving force of a Claisen condensation is the formation of a doubly stabilized enolate ⇒ the starting ester must have 2 α protons to allow a second deprotonation at the α position.
  • Hydroxide (HO-) cannot be used as a base in the Claisen condensation because it can cause hydrolysis of the starting ester resulting in the formation of a carboxylate salt ⇒ alkoxide ions with the same OR group as the starting ester are used to avoid hydrolysis and transesterification.

 

Crossed Claisen condensations:

Claisen condensations that occur between 2 different esters. As with crossed aldol reactions, crossed Claisen condensations produce a mixture of products and are only used:

  •  When one of the esters has no α protons and cannot form an enolate.


     
  • When an ester is added dropwise to a solution of ester enolate ions previously prepared with LDA (directed Claisen condensation).

The Dieckmann Cyclization

Intramolecular Claisen condensations:

Mechanism:

Same mechanism as Claisen condensation except that the ester enolate and the ester moiety are in the same molecule ⇒ intramolecular nucleophilic attack occurs.

  1. Formation of an ester enolate.
  2. Cyclization by intramolecular nucleophilic attack.
  3. Loss of an alkoxide ion to re-form the carbonyl group then deprotonation to form a doubly stabilized enolate.
  4. Acidic aqueous work-up to protonate the doubly stabilized enolate and form the desired cyclic β-keto ester.

Highly regioselective reaction: The formation of the least strained cyclic β-keto ester is favored (five- and six-membered rings).

Michael Addition

Reactivity of α,β-unsaturated carbonyl compounds:

An α,β-unsaturated aldehyde or ketone has 2 resonance structures with positive charge ⇒ it has 2 electrophilic positions: the carbon of the carbonyl group and the β position.
 


Both positions are subject to nucleophilic attack and the position depends on the nature of the nucleophile:

  • 1,2-addition: Attack on the carbonyl carbon resulting in the formation of an allylic alcohol. This is observed with Grignard reagents.
  • 1,4-addition or conjugate addition: Attack on the β carbon resulting in the formation of a carbonyl compound. This is observed with organocuprate reagents (R2CuLi).

 

Michael reaction:
 

Mechanism:

  1. Deprotonation of an α proton to form a doubly stabilized enolate.
  2. Nucleophilic attack of the enolate on the α,β-unsaturated carbonyl moiety in a 1,4-conjugate addition.
  3. Protonation of the alkoxide and tautomerization to re-form the carbonyl group.

 

Michael donors and acceptors:

  • Michael donors: doubly stabilized enolates. Regular enolates are not stable enough to function as Michael donors.


     
  • Michael acceptors: α,β-unsaturated carbonyl compounds.

Stork Enamine Synthesis

Enolate ion vs. enamine:

Similar to enolates, enamines exhibit nucleophilicity at the α position. However, enamines do not have a net negative charge, as enolates do, and are therefore less reactive ⇒ enamines are effective Michael donors and can participate in a Michael reaction.

Enolate ion:

Enamine:


 

Stork enamine synthesis:
 

Mechanism:

  1. Formation of an enamine from a ketone.


     
  2. Nucleophilic attack of the enamine (Michael donor) on the α,β-unsaturated carbonyl moiety (Michael acceptor) to form an intermediate with an iminium ion and an enolate ion.


     
  3. After the reaction is complete: Acidic aqueous work-up to hydrolyze the iminium ion into a carbonyl group, and protonate the enolate ion, which tautomerizes to form a carbonyl group.


     

The Stork enamine synthesis is particularly useful because it results in the desired product of an efficient Michael addition with regular enolates. The conversion of the ketone to an enamine allows the Michael addition and the final hydrolysis allows the reformation of the carbonyl group.

Enamine Alkylation

Enamines alkylation:
 

Mechanism:

  1. Nucleophilic attack of the enamine on the alkyl halide to form an iminium ion.
  2. Hydrolysis of the iminium ion to form a carbonyl compound.


R-X must be a primary or secondary halide (SN2 reaction).

 

Synthetic strategy: 

Advantage of alkylation of enamines over alkylation of carbonyls:

  • no polyalkylation (unlike alkylation of enolates)
  • R-X can be a secondary halide (enamines are more reactive than enolates)

Robinson Annulation

Robinson annulation:
 


Mechanism:

Two-step ring-forming process in which Michael addition is followed by intramolecular aldol condensation.

  1. Michael addition to form a 1,5-dicarbonyl compound


     
  2. Intramoleculare aldol reaction to form a β-hydroxy ketone:


     
  3. Dehydration to form the α,β-unsaturated ketone:

Check your knowledge about this Chapter

The Aldol Reaction is a fundamental carbon-carbon bond forming reaction in organic chemistry, where an enolate ion attacks another carbonyl compound, leading to the formation of a β-hydroxy aldehyde or ketone. This process involves an initial deprotonation step to generate the reactive enolate, followed by the nucleophilic addition of the enolate to the carbonyl carbon of another molecule, and finally, protonation to yield the aldol product.

The mechanism of aldol condensation involves two main steps: aldol addition and dehydration. In aldol addition, the α position of a carbonyl is deprotonated to form an enolate, which then attacks another carbonyl compound to form an aldol. In the dehydration step, the aldol undergoes deprotonation at the α position, followed by the loss of a hydroxide leaving group to form an α,β-unsaturated aldehyde or ketone.

The driving force for an aldol condensation reaction is the formation of a conjugated system, which leads to increased stability of the resulting α,β-unsaturated aldehyde or ketone.

In crossed aldol reactions, chemists typically use one of the following strategies to prevent the formation of a mixture of compounds:

  • Use a non-enolizable aldehyde or ketone.
  • Use a bulky base: A sterically hindered base, such as LDA, can selectively deprotonate the less sterically hindered and more acidic proton, usually favoring the formation of a single type of enolate.
  • Use of preformed enolates: Chemists can preform the enolate of the desired reactant before introducing the aldehyde or ketone, ensuring that only the desired enolate is present to react.

Enolates play a crucial role in Aldol Reactions as they act as the nucleophile that attacks the carbonyl carbon of another molecule. During the reaction, the α proton of a carbonyl compound is removed by a base to form the enolate ion. This reactive species then attacks an electrophilic carbonyl carbon, creating a new carbon-carbon bond and leading to the formation of a β-hydroxy carbonyl compound, which is the Aldol product.

The regioselectivity of the intramolecular aldol reaction is influenced by factors such as steric hindrance and ring strain. In general, the formation of the least strained cyclic products, such as five- and six-membered rings, is favored due to their greater stability compared to smaller or larger ring sizes.

Claisen condensation is a carbon-carbon bond formation reaction between two ester molecules in the presence of a strong base, resulting in a β-keto ester. It typically involves the nucleophilic attack of the enolate ion of one ester on the carbonyl group of the other ester.

In contrast, an aldol reaction involves the formation of a β-hydroxyaldehyde or ketone. The main difference is in the starting materials (esters in Claisen vs. aldehydes or ketones in Aldol) and the products formed (β-keto esters in Claisen vs. β-hydroxy aldehydes or ketones in Aldol).

Hydroxide (HO-) cannot be used as a base in the Claisen condensation because it can cause hydrolysis of the starting ester, resulting in the formation of a carboxylate salt. To avoid hydrolysis and transesterification, alkoxide ions with the same OR group as the starting ester are used as the base instead.

The Dieckmann Cyclization is a reaction that involves the intramolecular condensation of diesters in the presence of a strong base, forming a β-keto ester. It is a specific example of an intramolecular Claisen condensation and is typically utilized when synthesizing cyclic compounds, as it effectively creates a new carbon-carbon bond to form five- or six-membered rings.

The Michael addition is a nucleophilic addition reaction between an enolate ion (or another nucleophile, such as an enamine) and an α,β-unsaturated carbonyl compound. This reaction is significant in synthesis because it allows for the formation of carbon-carbon bonds, which is a key step in constructing complex organic molecules. Furthermore, it introduces a new functional group into the molecule, which can be further manipulated in subsequent reactions to achieve the desired target structure.

  • Michael donors refer to doubly stabilized enolates, which are able to donate a nucleophilic carbon center in the Michael addition reaction. Regular enolates are not stable enough to function as Michael donors.
  • Michael acceptors are α,β-unsaturated carbonyl compounds that undergo nucleophilic attack by the Michael donor.

The mechanism of the Stork enamine synthesis involves the formation of an enamine from a ketone, followed by nucleophilic attack of the enamine on an α,β-unsaturated carbonyl compound to form an intermediate with an iminium ion and an enolate ion. After completion of the reaction, acidic aqueous work-up is performed to hydrolyze the iminium ion and protonate the enolate ion, resulting in the desired carbonyl product.

Enamine alkylation offers an advantage over direct alkylation of carbonyl compounds primarily due to increased selectivity and reduced polyalkylation:

  • Carbonyl compounds can be prone to overreaction during direct alkylation, resulting in multiple alkyl groups attaching to the same carbon, complicating the purification process and reducing the yield of the desired monosubstituted product.
  • Enamines, which are formed by condensation of secondary amines with carbonyl compounds, are less reactive than enolates and thus reduce the risk of such overreaction. In addition, enamines are more easily deprotonated than carbonyls, allowing for more controlled reactions with alkyl halides, ultimately resulting in higher selectivity for single alkylation products.

The Stork enamine synthesis is particularly useful because it enables the efficient formation of Michael addition products using conventional enolates. By converting the ketone substrate to an enamine intermediate, the reaction facilitates Michael addition. In addition, the subsequent hydrolysis step restores the carbonyl functionality, providing access to the desired carbonyl compound. Overall, this synthetic strategy provides a versatile route to various functionalized molecules in organic synthesis.

The Robinson annulation is a synthetic organic reaction that involves the formation of a cyclic compound through a sequence of intramolecular Michael addition and aldol condensation reactions. It typically yields fused ring systems, such as cyclohexenones or cyclohexadienones, which are important intermediates in the synthesis of various natural products and pharmaceutical compounds.