Directed Aldol Condensation Using Lithium Enolate

Overview

• Objective: To form a desired conjugated enone via a mixed or crossed aldol condensation using a lithium enolate.
• Challenge: Directly mixing a ketone and an aldehyde with base would yield a mixture of products.
• Solution: Use a step-wise approach known as directed aldol condensation.

Reaction Steps

Step 1: Formation of Lithium Enolate

• Reagents: Ketone, LDA (lithium diisopropylamide)
• Mechanism:
  • LDA deprotonates the ketone at the less sterically hindered alpha carbon, forming the kinetic enolate.
  • Cyclic Mechanism:
    • Electrons from LDA's nitrogen take the alpha proton.
    • Electrons form a carbon-carbon double bond, deprotonating ketone.
    • Lithium bonds with the oxygen to form the lithium enolate.
  • Result: Formation of kinetic enolate due to the bulky nature of LDA.

Step 2: Addition of Aldehyde

• Reagents: Lithium enolate, butanol (as the aldehyde)
• Mechanism:
  • Aldehyde functions as an electrophile with partially positive carbonyl carbon.
  • Cyclic Mechanism:
    • Electrons from enolate attack the carbonyl carbon.
    • Electrons form a new carbon-carbon bond, resulting in a lithium alkoxide product.
  • Result: Formation of lithium alkoxide intermediate.

Step 3: Workup to Form Aldol

• Reagents: Water
• Mechanism:
  • Aqueous workup involves protonating the alkoxide anion.
  • Result: Aldol product is formed.

Step 4: Dehydration to Form Enone

• Reagents: Tolymine sulfonic acid (proton source)
• Mechanism:
  • Protonation of oxygen to form an excellent leaving group.
  • Loss of water results in a cation.
  • A base deprotonates the alpha carbon, forming a double bond and neutralizing the cation.
  • Result: Formation of the desired enone.

Key Concepts

• Kinetic vs. Thermodynamic Enolate:
  • Kinetic enolate is formed faster and is favored by strong, bulky bases like LDA.
• Cyclic Mechanisms: Important for understanding the step-wise formation of bonds.
• Electrophile and Nucleophile Interactions: Critical in forming new carbon-carbon bonds.
• Dehydration: Essential for forming the enone from aldol through acid catalysis.

Application

• Directed aldol condensation is useful for selectively forming specific enone products in organic synthesis.