Directed Condensations: Videos & Practice Problems

The aldol condensation is a crucial reaction in organic chemistry, particularly when dealing with asymmetrical ketones. In such cases, the formation of enolates can lead to two possible pathways, complicating the reaction process. To navigate this, chemists employ directed reactions, which help in selecting the desired enolate for the reaction with the electrophile.

When considering enolate formation, it is essential to distinguish between thermodynamic and kinetic control. The thermodynamic enolate is the more substituted form, which is favored by small bases such as sodium hydroxide (NaOH). This enolate is more stable due to greater substitution, making it the preferred choice when the goal is to achieve a more stable product. Conversely, the kinetic enolate is the less substituted form, which is easier to form and is favored by bulky bases. These bulky bases, like lithium diisopropylamide (LDA) or tert-butoxide, facilitate the formation of the less stable enolate, allowing for selective reactions on the less substituted side of the ketone.

For instance, if the objective is to direct the reaction to the more substituted side of the ketone, a small base would be employed. In contrast, to target the less substituted side, a bulky base would be necessary. LDA is particularly favored in these scenarios due to its non-nucleophilic nature, ensuring that it only abstracts a proton without participating in further reactions.

Understanding these principles allows for better prediction of reaction outcomes in aldol condensations involving asymmetrical ketones. By carefully selecting the base and considering the stability of the enolates, chemists can effectively control the direction of the reaction and the resulting products.

Lithium diisopropylamide (LDA) is a strong base commonly used in organic chemistry to generate enolates from carbonyl compounds, such as ketones and aldehydes. In the context of aldol reactions, the formation of an enolate occurs when LDA interacts with a ketone, leading to the generation of a negatively charged nitrogen species and the corresponding enolate. This enolate can then react with itself, as there is no other electrophile present, which is a key characteristic of aldol reactions.

To visualize the mechanism, consider the enolate formation: the less substituted side of the ketone is typically where the enolate forms, following the directed reaction principle. When drawing the mechanism, it is essential to orient the enolate so that the negatively charged oxygen is positioned to attack the carbonyl carbon of the ketone. This results in the formation of a tetrahedral intermediate, where the enolate attacks the carbonyl oxygen, leading to the creation of a new carbon-carbon bond.

Following this step, the tetrahedral intermediate can undergo protonation, typically facilitated by the conjugate acid of LDA, resulting in a beta-hydroxycarbonyl compound. This compound is a crucial intermediate in the aldol reaction pathway. However, it is important to note that the aldol reaction is reversible, allowing the beta-hydroxycarbonyl to revert back to the starting materials under certain conditions.

Nonetheless, the reaction can progress to an irreversible dehydration step, where water is eliminated between the alpha and beta positions of the carbon chain. This dehydration leads to the formation of an alpha, beta-unsaturated carbonyl compound, also known as an enone. The stability of this product is enhanced due to conjugation, and because dehydration is an irreversible step, the reaction tends to favor the formation of the enone over time. As the reaction proceeds, the continuous removal of the dehydration product from the solution drives the equilibrium towards the formation of the stable enone, ultimately resulting in a higher yield of this final product.