Lecture Notes: Alkylation Reactions of Ketones

Overview

• Cyclopentanone Alkylation:
  • React cyclopentanone with LDA, then methyl bromide.
  • Major product: Alkylated ketone.

Key Concepts

LDA (Lithium Diisopropylamide)

• Strong base used to deprotonate alpha hydrogens in ketones.
• Composed of lithium (Li) and diisopropyl amide, with a negative charge on nitrogen.

Reaction Mechanism

1. Deprotonation:

   • LDA removes an acidic alpha hydrogen from cyclopentanone.
   • Forms a resonance-stabilized enolate ion.

2. Alkylation:

   • Enolate ion reacts with methyl bromide.
   • Pi bond reforms, allowing for nucleophilic attack and expulsion of bromide ion.
   • Result: Adds a methyl group to alpha carbon.

Practice Problem

• Ketone + LDA + Ethyl bromide: Replace alpha hydrogen with ethyl group for major product.

Kinetic vs. Thermodynamic Products

• Unsymmetrical Ketones:

  • Kinetic Product: Uses LDA at low temperature to add methyl group selectively.
  • Thermodynamic Product: Uses sodium hydride at room temperature.

• Base Selection:

  • Sodium Hydride: Not sterically hindered, can remove multiple hydrogen types.
  • LDA: Sterically hindered, favors removal of accessible secondary hydrogens.

Enamine Alkylation

• Enamines:

  • Formed by reacting ketones with secondary amines.
  • Allow alkylation without strong bases.

• Reaction with Alkyl Halides:

  • Nitrogen's lone pair forms double bond, attacking methyl group.
  • Enamine hydrolysis back to ketone using H₂O⁺.

Other Reactions with Enamines

• React with:
  • Alpha-beta Unsaturated Aldehydes: Attacks beta carbon.
  • Acid Chlorides: Forms diketones.

Summary

• LDA is used to form enolate ions for alkylation.
• Enamines offer alternative pathways for monoalkylation.
• Different bases and conditions lead to kinetic vs. thermodynamic products.
• Various electrophiles can react with enamine intermediates.