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 3 -buten- 2 -one, followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each.

Short answer

The reaction sequence involves enamine formation, Michael addition, enamine hydrolysis, intramolecular aldol reaction, and dehydration.

Step-by-step solution

Formation of Enamine

The first step involves the reaction between cyclohexanone and pyrrolidine to form the enamine. Pyrrolidine, a secondary amine, reacts with cyclohexanone to form an iminium ion intermediate. This is followed by deprotonation to create the enamine, enabling nucleophilic characteristics at the alpha-position of the carbonyl group. This allows further reactions with electrophiles.

Michael Addition

The enamine formed in Step 1 undergoes a Michael addition with 3-buten-2-one. In this reaction, the nucleophilic carbon (alpha to the nitrogen) in the enamine attacks the electrophilic beta-carbon in the conjugated ketone (3-buten-2-one), forming a new carbon-carbon bond. This creates an intermediate product, which leads to the formation of a stabilized enolate.

Enamine Hydrolysis

The next step involves hydrolysis of the enamine back to the ketone. This is achieved by acidic hydrolysis, where the nitrogen is protonated, making it a better leaving group. Water then attacks the iminium ion, eventually resulting in the regeneration of the carbonyl group and the release of pyrrolidine.

Intramolecular Aldol Reaction

With the carbonyl group restored, an intramolecular aldol reaction occurs. A base deprotonates the alpha position to form an enolate ion, which then attacks the carbonyl group, forming a new carbon-carbon bond. This closes the ring, leading to the formation of a cyclohexanone structure.

Dehydration to Form Cyclohexenone

Finally, dehydration occurs by elimination of a water molecule, which results in the formation of a double bond. This is facilitated by the presence of a base, leading to the final product: cyclohexenone. This step converts the cyclohexanone structure into the desired cyclohexenone.

Key concepts

Stork Enamine Reaction

The Stork Enamine Reaction is a crucial process in organic synthesis for forming carbon-carbon bonds. It starts with the formation of an enamine from a carbonyl compound, like cyclohexanone, and a secondary amine, such as pyrrolidine. This process begins with the nucleophilic attack of the amine on the carbonyl carbon, creating an iminium ion intermediate. Subsequently, a hydrogen atom is removed from the iminium ion to form an enamine. Enamines are valuable because they have nucleophilic properties at the alpha-carbon, making them excellent candidates for further reactions, particularly with electrophiles. This nucleophilicity is key for the successive Michael Addition step.

Intramolecular Aldol Reaction

The Intramolecular Aldol Reaction is a fascinating transformation where an enolate ion formed from a molecule reacts with a carbonyl group within the same molecule, resulting in the formation of a ring. In the context of cyclohexenone synthesis, once the carbonyl group is restored — usually after enamine hydrolysis — a base can deprotonate the alpha-carbon adjacent to the carbonyl to form an enolate ion. This enolate acts as a nucleophile, attacking another carbonyl group within the molecule and forming a new carbon-carbon bond. This intramolecular reaction is intrinsic in synthesizing cyclic compounds, such as the cyclohexanone, which provides the scaffold for the final product.

Michael Addition

Michael Addition is an important conjugate addition reaction where an enamine reacts with an alpha, beta-unsaturated carbonyl compound, like 3-buten-2-one. This reaction is powerful for forming carbon-carbon bonds. In this specific reaction, the nucleophilic carbon atom of the enamine performs a 1,4-addition to the beta-carbon of the electrophilic compound, resulting in a newly formed carbon-carbon bond. The product of this process is an enolate, which is a key intermediate enabling further transformation steps. The Michael Addition establishes the carbon framework necessary for further intramolecular cyclizations seen in cyclohexenone synthesis.

Enamine Hydrolysis

Enamine Hydrolysis involves converting an enamine back to its original carbonyl compound, which is critical for further transformations. When hydrolysis occurs, the nitrogen in the enamine is first protonated, making it a suitable leaving group. This is followed by a nucleophilic attack by water, leading to the formation of an iminium ion which rapidly converts back to the original carbonyl compound. This step is significant in regeneration of the ketone, setting the stage for the succeeding aldol reaction and eventual cyclohexenone formation. The process effectively eliminates the reversible enamine and reinstates the carbonyl functionality needed for intramolecular cyclization.

Cyclohexenone Synthesis

Cyclohexenone Synthesis is the culmination of several key stepwise reactions, resulting in the formation of a cyclic compound with both a carbonyl and an alkene group. Following the intramolecular aldol reaction, the newly formed ring undergoes dehydration, a crucial step in introducing a double bond, converting the cyclohexanone nucleus into cyclohexenone. This dehydration typically involves the elimination of a water molecule facilitated by a base, creating the characteristic double bond within the ring. Cyclohexenone synthesis showcases the power of sequential reactive mechanisms to build complex organic molecules from simpler substrates through well-organized chemical transformations.