21.2 Nucleophilic Acyl Substitution Reactions - Organic Chemistry

Introduction to Nucleophilic Acyl Substitution

• Key step in carbonyl-group reactions.
• Involves the addition of a nucleophile to a polar CO bond.
• Different paths for aldehydes/ketones vs carboxylic acid derivatives:
  • Aldehydes/ketones: forms alcohol via tetrahedral intermediate.
  • Carboxylic acid derivatives: forms new carbonyl compound via tetrahedral intermediate.

Mechanism

• Nucleophilic addition to carboxylic acid derivatives:
  • Tetrahedral intermediate expels a leaving group (Y group), resulting in nucleophilic acyl substitution.
• Similar to SN2 in final appearance but mechanistically different:
  • SN2 is a single-step, backside displacement.
  • Nucleophilic acyl substitution is a two-step process involving an intermediate.

Relative Reactivity of Carboxylic Acid Derivatives

• Reactivity depends on steric and electronic factors.
• Generally, less hindered carbonyls are more reactive.
• Electron-withdrawing groups increase reactivity by polarizing the carbonyl group.
• Reactivity order: Acid chlorides > Anhydrides > Esters > Amides.
• More reactive derivatives can be converted to less reactive ones, but not vice versa.

General Reactions of Carboxylic Acid Derivatives

• Hydrolysis: Reaction with water to yield a carboxylic acid.
• Alcoholysis: Reaction with an alcohol to yield an ester.
• Aminolysis: Reaction with ammonia or an amine to yield an amide.
• Reduction: Reaction with a hydride reducing agent to yield an aldehyde or an alcohol.
• Grignard Reaction: Reaction with organometallic reagents to yield ketones or alcohols.

Worked Example

• Predicting products of nucleophilic acyl substitution:
  • Identify the nucleophile and leaving group.
  • Replace the leaving group with the nucleophile.
• Example: Benzoyl chloride reacts with 2-propanol to form isopropyl benzoate.

Problems

• Ranking compounds by reactivity.
• Predicting products of given reactions.
• Identifying components in reaction mechanisms.

Summary

• Nucleophilic acyl substitution reactions are central to the chemistry of carboxylic acid derivatives.
• Reactivity is influenced by steric and electronic factors, and a clear understanding of these can predict reaction outcomes.
• A variety of reactions, including hydrolysis and aminolysis, are possible, providing synthetic versatility.