Lecture Notes: Carboxylic Acids, Ammonia, and Amide Formation

Introduction to Reaction with Ammonia

• Adding ammonia to carboxylic acid at room temperature:
  • Ammonia acts as a base, not as a nucleophile.
  • Resulting in the formation of a carboxylate anion.
  • Ammonia forms ammonium salt (NH4+).
• Heating the salt can sometimes form amide, but it’s not efficient.

Efficient Amide Formation: Using DCC

• DCC stands for Dicyclohexylcarbodiimide.
• DCC allows amine to function as a nucleophile.
• Mechanism Overview:
  1. DCC acts as a base, deprotonating carboxylic acid to form carboxylate anion.
  2. Carboxylate anion acts as nucleophile, attacking the electrophilic carbon of DCC.
  3. Amine acts as nucleophile in subsequent steps.
  4. Formation of dicyclohexylurea as a byproduct.
• DCC provides a good leaving group, facilitating the reaction.

Applications of DCC

• Peptide Synthesis:
  • Used to react amino acids to form peptides.
  • Requires protecting groups for carboxylic acids and amines.
  • DCC acts as a dehydrating agent.
  • Developed by Dr. Sheehan’s group in the 1950s at MIT.

Historical Significance

• Dr. Sheehan’s Work:
  • Contribution to total synthesis of penicillin in 1957.
  • DCC used to join components of penicillin, forming a beta-lactam.
  • Beta-lactam formation (four-membered ring) was challenging.
  • DCC enabled synthesis under normal conditions, groundbreaking in penicillin synthesis.
• DCC and beta-lactam synthesis played a crucial role during WWII.

Key Takeaways

• DCC is crucial for amide formation, specifically in peptide and penicillin synthesis.
• Carboxylic acids react differently with ammonia at room temperature, requiring DCC for effective amide formation.
• The chemistry facilitated by DCC was pivotal in historical antibiotic development.