Reactions of Carboxylic Acids
High-Yield Summary
- Core mechanism: nucleophilic acyl substitution — nucleophile attacks the electrophilic carbonyl carbon → tetrahedral intermediate → OH protonated to water (good leaving group) → intermediate collapses, ejecting the leaving group.
- Amide: acid + NH₃/amine, loses H₂O ("-oic acid" → "-amide," N-alkyl groups get the "N-" prefix). Resonance (N lone pair into carbonyl) makes amides more rigid and LESS reactive than esters. Lactams (cyclic amides): β = 4-membered (penicillin core), γ = 5-membered, δ = 6-membered.
- Ester: acid + alcohol, condensation (esterification), named alkyl-group-first + "-oate" (ethyl ethanoate). Lactones (cyclic esters): α = 3-membered, β-propiolactone = 4-membered, γ-butyrolactone = 5-membered.
- Anhydride: 2 carboxylic acids condense, losing H₂O, bridged by one shared oxygen (2 acetic acid → acetic anhydride).
- LiAlH₄ reduces carboxylic acid → primary alcohol via an unisolable aldehyde intermediate (2 hydride additions) — but first wastes 1 equivalent on an acid-base step with the O-H proton, so more LiAlH₄ is needed than for a ketone/ester. NaBH₄ is too mild to do this reduction at all.
- Decarboxylation: β-keto acids lose CO₂ via a 6-membered cyclic transition state → enol → tautomerizes to the stable keto form. Saponification: fatty acid + strong base → soap (amphipathic carboxylate salt) → self-assembles into micelles in water.
Nucleophilic Acyl Substitution (Shared Mechanism)
- 1Nucleophile attacks the electrophilic carbonyl carbon; the C=O π electrons shift onto oxygen, forming a tetrahedral intermediate.
- 2Under acidic conditions, the hydroxyl group is protonated, converting it into a good leaving group (water).
- 3The tetrahedral intermediate collapses: the C=O double bond reforms, ejecting the leaving group.
- 4Net result: the original OH is replaced by the incoming nucleophile, forming a new carbonyl-containing product (amide, ester, or anhydride depending on the nucleophile).
Nucleophile → Product
| Nucleophile | Product (naming) |
|---|---|
| NH₃ / amine | Amide ("-oic acid" → "-amide"; N-alkyl substituents get "N-" prefix) |
| Alcohol | Ester ("-oic acid" → alkyl group + "-oate", e.g. ethyl ethanoate) |
| Second carboxylic acid molecule | Anhydride (two carbonyls bridged by one shared O) |
Key Terms
- Lactam
- Cyclic amide, named by ring size: β (4-membered, penicillin's core), γ (5-membered), δ (6-membered).
- Lactone
- Cyclic ester, named by ring size: α-acetolactone (3-membered), β-propiolactone (4-membered), γ-butyrolactone (5-membered).
- Decarboxylation
- Loss of a carboxyl group as CO₂, favored when the carboxyl is β to another carbonyl (β-keto acid); proceeds through a 6-membered cyclic transition state to an enol, which tautomerizes to the keto form.
- Saponification / micelle
- Fatty acid + strong base (NaOH/KOH) → soap (amphipathic carboxylate salt); in water, soap self-assembles into micelles (polar heads out, nonpolar tails in) that solubilize grease.
Common MCAT Trap
- Amides are LESS reactive than esters toward nucleophilic attack, despite both coming from the same carboxylic acid chemistry — the N lone pair's resonance donation into the carbonyl makes amides more rigid and less electrophilic.
- LiAlH₄ needs an extra equivalent to reduce a carboxylic acid vs. a ketone/ester of similar size — one equivalent is consumed by a fast acid-base reaction with the acidic O-H proton before any reduction happens.
- Decarboxylation only proceeds readily for β-keto acids (carboxyl β to another carbonyl) — the 6-membered cyclic transition state requires that specific spacing.
- Don't confuse the first deprotonation (esterification's mechanism, protonating the carbonyl O to activate it) with a simple acid-base reaction — esterification is a multi-step nucleophilic acyl substitution under acid catalysis.
Quick Recall
What two steps make up nucleophilic acyl substitution?
Why are amides less reactive toward nucleophiles than esters, despite both being carboxylic acid derivatives?
Why does reducing a carboxylic acid with LiAlH₄ require more equivalents than reducing a similarly sized ketone?
What structural feature makes a β-keto acid prone to decarboxylation?