Nucleophilic Acyl Substitution Reaction

Overview

• Nucleophilic Acyl Substitution: A reaction where a nucleophile substitutes the Y group in a carboxylic acid derivative.
• Electrophilic Portion: The carbon in the carboxylic acid derivative is partially positive due to electron withdrawal by oxygen.
• Nucleophile Attack:
  • Nucleophile attacks the electrophilic carbon.
  • Electrons kick off onto oxygen.

Mechanism

1. Attack by Nucleophile:
   • Nucleophile bonds to carbonyl carbon.
   • Electrons shift, forming a negative charge on oxygen.
   • Tetrahedral intermediate is formed.
2. Reformation of Carbonyl:
   • Electrons move to reform carbonyl.
   • Leaving group is substituted.

Important Aspects

• Reactivity:

  • Influenced by substituents.
  • Acyl chlorides are very reactive.
  • Inductive vs. resonance effects are considered.

• Stearic Effects:

  • Larger R groups like tert-butyl can hinder nucleophilic attack.

• Strength of Nucleophile:

  • Strong nucleophiles are preferable for effective attack.

• Stability of Leaving Group:

  • Desirable to have a stable leaving group with a negative charge.
  • Stability matters for ease of leaving.

Example Reaction: Acetyl Chloride and Sodium Formate

• Reactive Molecules:

  • Acetyl chloride (electrophile) and sodium formate (nucleophile).
  • Acetyl chloride has a partially positive carbon.

• Intermediate Formation:

  • Nucleophile attacks, forming a tetrahedral intermediate.
  • Reformation of carbonyl leads to potential leaving groups.

Identifying the Best Leaving Group

• Leaving Group Options:

  • Chloride anion
  • Formate anion
  • Carb anion (CH3-)

• Conjugate Acid Analysis:

  • Chloride Anion: Conjugate acid is HCl (pKa ≈ -7)
  • Formate Anion: Conjugate acid is formic acid (pKa ≈ 5)
  • Carb Anion: Conjugate acid is methane (pKa ≈ 50)

• Stability and Acidity:

  • Lower pKa indicates stronger acid and more stable conjugate base.
  • Chloride anion is most stable due to the low pKa of HCl.

Final Product

• Formation of Acid Anhydride:
  • Chloride anion leaves, forming an acid anhydride (acetic formic anhydride).

Key Points

• pKa Values: Lower pKa of conjugate acid indicates a better leaving group.
• Leaving Group Effectiveness: Chloride anion > Formate anion > Carb anion.
• Mechanistic Understanding: Consider stability and pKa of conjugate acids for predicting leaving group behavior.