Question

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with but-3-en-2-one, followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each.

Short answer

Enamines form, react with butenone, hydrolyze, then undergo aldol condensation.

Step-by-step solution

Formation of Pyrrolidine Enamine

In this step, cyclohexanone reacts with pyrrolidine to form an enamine. Pyrrolidine acts as a secondary amine, attaching to the carbonyl carbon and kicking off the oxygen as water, thus forming an enamine intermediate. This reaction is typically facilitated by mild acid catalysis in a dry solvent environment.

Michael Addition of Enamine to Butenone

The formed enamine from Step 1 acts as a nucleophile, attacking the β-carbon of the α,β-unsaturated carbonyl compound, but-3-en-2-one (a Michael acceptor). The nitrogen lone pair forms a double bond with the adjacent carbon, transferring electrons towards the double bond in the butenone, creating a new C-C bond and resulting in an enamine-ketone intermediate.

Hydrolysis of Enamine Intermediate

The enamine-ketone intermediate undergoes hydrolysis to convert the enamine back into a carbonyl group. This step involves the addition of water and a mild acid, where the nitrogen is protonated and replaced by a carbonyl group, regenerating the ketone functional group.

Intramolecular Aldol Condensation

This involves the newly produced ketone from hydrolysis undergoing an intramolecular aldol reaction. Under basic conditions, the α-hydrogen is deprotonated, forming an enolate ion. This enolate then attacks the carbonyl carbon intramolecularly, resulting in the formation of a cyclic β-hydroxy ketone. This intermediate collapses through dehydration (loss of water), forming a double bond and resulting in the cyclohexenone product.

Key concepts

Intramolecular Aldol Reaction

The intramolecular aldol reaction is a fascinating organic reaction where a molecule forms a ring by connecting different parts of itself. It is particularly useful when synthesizing cyclic compounds like cyclohexenones. Here, a molecule containing both a carbonyl group and enolate form undergoes this reaction.
The process typically starts with a base, which removes an α-hydrogen from the carbon adjacent to the carbonyl, forming an enolate ion. This highly reactive species then attacks the carbonyl carbon within the same molecule.

• The enolate ion formation is critical as it initiates the ring formation.
• The attacked carbonyl carbon forms a new bond with the enolate carbon, creating a ring structure.
• Finally, dehydration occurs, eliminating water to form a double bond, yielding the desired cyclic product.

This results in a stable six-membered ring, such as cyclohexenone, demonstrating the elegance of intramolecular reactions.

Enamine Formation

Enamine formation is a key step in many synthetic organic reactions. It involves a secondary amine reacting with a carbonyl compound - such as a ketone or aldehyde - to form an enamine. This reaction is useful because enamines are versatile intermediates that can undergo further reactions.
How does this transformation occur?

• First, the amine nitrogen attacks the carbonyl carbon, forming a tetrahedral intermediate.
• Subsequent loss of water leads to the formation of a double bond between the carbonyl carbon and the nitrogen, producing the enamine.
• This step usually requires mild acid catalysis and involves a dehydration process.

The enamine thus formed is important as it serves as a nucleophile, ready to participate in further reactions such as the Michael addition.

Mechanism of Reactions

Understanding the mechanism of reactions provides insights into how and why chemical transformations occur. Mechanisms are like a detailed roadmap, showing each step involved in turning reactants into products.
In the context of the Stork enamine reaction, several mechanisms work in concert:

• Initially, the formation of an enamine facilitates nucleophilic attack on electrophiles.
• The Michael addition follows, where the enamine attacks an unsaturated carbonyl compound, forming a new carbon-carbon bond.
• Subsequent steps involve hydrolysis and the intricate steps of intramolecular aldol reaction.

Each step involves a well-defined movement and sharing of electrons, ensuring that every atom reaches a stable state.

Michael Addition

The Michael addition is a powerful reaction in organic chemistry used to form carbon-carbon bonds. It involves the addition of a nucleophile to an α,β-unsaturated carbonyl compound, known as the Michael acceptor.
Here is how it works:

• The enamine, acting as the nucleophile, attacks the electrophilic β-carbon of the Michael acceptor.
• This nucleophilic attack leads to the formation of a new single bond between the nucleophile and the electrophile.
• As a result, the double bond electrons rearrange to accommodate the stability of the new structure.

This reaction is uniquely valuable because it forms carbon bonds with high precision, contributing significantly to building complex organic molecules.