Lecture Notes: Organic Chemistry - Alkylation of Ketones

Key Reactions and Concepts

Cyclopentanone Reaction Sequence
- Step 1: React with Lithium Diisopropylamide (LDA)
  - LDA (Lithium diisopropylamide) is a strong base used to deprotonate alpha hydrogens.
  - Formation of a resonance-stabilized enolate ion.
- Step 2: React with Methyl Bromide
  - Enolate ion attacks methyl bromide, resulting in alkylation.
  - Adds a methyl group to the alpha carbon of a ketone.
Alkylation Practice Problems
- Example: Ketone, LDA, and Ethyl Bromide
  - Replace alpha hydrogen with ethyl group.
Unsymmetrical Ketone Alkylation
- Kinetic vs Thermodynamic Products:
  - Kinetic Product: Use LDA at low temperatures, followed by methyl bromide.
  - Thermodynamic Product: Use a non-sterically hindered base like sodium hydride at room temperature, followed by methyl bromide.

Removing Alpha Hydrogens
- Sodium hydride can remove alpha hydrogen atoms due to its strong base nature.
- Higher temperatures favor the formation of the more stable, substituted enolate ion.
Base Choice for Different Products
- Sterically Hindered Base (LDA): Favors kinetic product by attacking more accessible hydrogen atoms.
- Non-Hindered Base (Sodium Hydride): Favors thermodynamic product by attacking more substituted positions.

Enamine Intermediate Formation
- React ketone with a secondary amine to form an enamine.
- Alkyl Halide Reaction: Reacts with methyl bromide resulting in alkylation without using a strong base.
- Restoration to Ketone: Accomplished using H2O plus (water and HCl).
Reactivity with Other Electrophiles
- Alpha Beta Unsaturated Aldehydes
  - Enamine attacks beta carbon, forming a new double bond and eventually returning to aldehyde state.
- Acid Chlorides
  - Enamine forms diketone upon reacting with acid chloride.

Enamines offer a versatile route for ketone alkylation, allowing reactions with various electrophiles and avoiding the necessity of strong bases like LDA.
Understanding base choice and reaction conditions is key to directing desired product formation (kinetic vs thermodynamic).