Organic Chemistry Chapter 9 - Reactivity Principles and Nucleophilic Acyl Substitution Reactions

Introduction

• Presenter: Iman
• Platform: YouTube
• Chapter: 9 for MCAT Organic Chemistry
• Topic: Reactivity Principles and Nucleophilic Acyl Substitution Reactions

Reactivity Principles in Nucleophilic Substitution Reactions

Reactivity Order

• The reactivity of carbonyl compounds is ranked as follows:
  1. Anhydrides (most reactive)
  2. Esters & Carboxylic acids (similar reactivity)
  3. Amides (least reactive)

Structural Explanation

• Anhydrides are most reactive due to resonance stabilization and three electron-withdrawing atoms, making them highly electrophilic.
• Esters are less reactive because they lack one electron-withdrawing carbonyl oxygen.
• Amides are the least reactive because they have an electron-donating amino group.

Factors Affecting Reactivity

1. Steric Hindrance

   • Describes when reaction is prevented due to the size of substituents.
   • Example: SN2 reactions do not occur with tertiary carbons.

2. Electronic Effects

   • Induction: Distribution of charge across sigma bonds.
     • Electrons are attracted to more electronegative atoms, generating a dipole.
     • Relatively weak but important in polarizing carbonyl groups.
   • Conjugation: Presence of alternating single and multiple bonds.
     • Delocalization of π electrons increases stability.
   • Resonance: Electrons experience resonance through unhybridized p orbitals, stabilizing the molecule.
   • Strain in Cyclic Molecules: Increased strain makes molecules more reactive (e.g., β-lactams are prone to hydrolysis).

Nucleophilic Acyl Substitution Reactions

• Focus on reactions of carboxylic acid derivatives.
• Only a few reactions are important for the MCAT.

Anhydride Cleavage

1. Using Amines

   • Nucleophile: Ammonia (NH₃) or amine
   • Products: Amide and carboxylic acid

2. Using Alcohols

   • Nucleophile: Alcohol (R-OH)
   • Products: Ester and carboxylic acid

3. Using Water

   • Nucleophile: Water (H₂O)
   • Products: Two carboxylic acid molecules

Transesterification

• Definition: Alcohols act as nucleophiles and displace the ester group on an ester.
• Result: Exchange of one esterifying group for another.
• Products: New ester depending on the alcohol used.

Hydrolysis of Amides

1. Acidic Conditions

   • Protonation of carbonyl oxygen makes it more susceptible to nucleophilic attack by water.
   • Products: Carboxylic acid and ammonia

2. Basic Conditions

   • Carbonyl oxygen is not protonated.
   • Nucleophile: Hydroxide ion (OH⁻)
   • Similar mechanism to acidic hydrolysis.

Summary & Conclusion

• Reactivity Principles: Consider steric hindrance, induction, conjugation, resonance, and strain in cyclic molecules.
• Nucleophilic Acyl Substitution Reactions: Important reactions for MCAT include anhydride cleavage, transesterification, and amide hydrolysis.
• Upcoming session: Practice problems.

Good luck with your studies!