Acyl substitution reactivity: acid chloride (most reactive) > anhydride > ester > amide (least reactive). More electronegative leaving group = more reactive. This order appears on every orgo exam.
pKa ~5 for carboxylic acids vs pKa ~16 for alcohols
Carboxylic Acid Acidity
Carboxylic acids (pKa ~5) are much more acidic than alcohols (pKa ~16) because the carboxylate anion is resonance-stabilized. EWG groups lower pKa (stronger acid). EDG groups raise pKa (weaker acid).
Base-catalyzed ester hydrolysis. Unlike acid hydrolysis, saponification is irreversible because the carboxylate salt cannot be re-protonated under basic conditions. This is how soap is made (fat + NaOH).
Carboxylic acids are resistant to NaBH4. Only LiAlH4 reduces them — through the aldehyde intermediate to primary alcohol. Two equivalents of hydride are added overall.
Acyl substitution mechanism: tetrahedral intermediate with 4 groups on C
Nucleophilic Acyl Substitution Mechanism
All carboxylic acid derivative reactions go through the same mechanism: (1) Nucleophile attacks carbonyl C → tetrahedral intermediate (C now has 4 groups, no longer sp²). (2) Leaving group departs → reforms C=O. Different from SN2 (no inversion, no Walden). The leaving group ability determines rate: Cl⁻ > RCOO⁻ > RO⁻ > NR₂⁻. Adding good nucleophile or removing product drives equilibrium.
Anhydrides form by dehydration of two carboxylic acid molecules (heating, or P₂O₅). Cyclic anhydrides form readily from diacids with 1,4- or 1,5-dicarboxylic acids (succinic, maleic, phthalic). Anhydrides react like acid chlorides but more slowly: with alcohols → ester + carboxylic acid, with amines → amide + carboxylic acid. Acetic anhydride (Ac₂O) is the most common — used for acetylation (aspirin synthesis).
Decarboxylation: beta-keto acids lose CO₂ when heated — 6-membered TS
Decarboxylation Reactions
Beta-keto acids (carbonyl at beta position) readily lose CO₂ when heated. Mechanism: 6-membered cyclic transition state → CO₂ leaves, enol forms, tautomerizes to ketone. Malonic acid and beta-keto acids are classic examples: malonic ester synthesis gives carboxylic acids via decarboxylation. Requirements: carboxyl group must be beta to another carbonyl. Alpha-keto acids and gamma-keto acids do NOT decarboxylate easily.
The Hell-Volhard-Zelinsky (HVZ) reaction brominates carboxylic acids at the alpha carbon. Reagents: Br₂ + PBr₃ (or PCl₃ for chlorination). The phosphorus converts acid to acid bromide first → enol of acid bromide → bromination → hydrolysis → alpha-bromo acid. Unlike ketone halogenation (which can be mono- or poly-), HVZ gives mono-bromination. Products are precursors to alpha-amino acids (via Gabriel or azide substitution).
Malonic ester synthesis: alkylation at alpha-C then decarboxylation → substituted acetic acid
Malonic Ester Synthesis
Strategy for making substituted acetic acids (R-CH₂-COOH). Steps: (1) Diethyl malonate + strong base (NaOEt) → enolate at central C. (2) Alkylate with R-X (SN2). (3) Alkylate again if needed (disubstitution). (4) Saponify (NaOH) → dicarboxylic acid. (5) Heat → decarboxylation → monocarboxylic acid. Gives: R-CH₂-COOH or R-CR'-COOH. Classic way to make carboxylic acids with specific substituents.
Aspirin (acetylsalicylic acid) synthesis: salicylic acid (has both OH and COOH) + acetic anhydride → aspirin + acetic acid. The phenol OH is acetylated (more reactive than COOH toward anhydrides). Acid catalyst (H₃PO₄ or H₂SO₄) optional. This is an acylation of a phenol by an anhydride — a classic example of nucleophilic acyl substitution. Salicylate ion (from aspirin hydrolysis) is the active anti-inflammatory agent.
Q: What is the reactivity order of carboxylic acid derivatives?
A: From most to least reactive: acid chloride > anhydride > ester > amide. More electronegative leaving group = more reactive. Acid chlorides (Cl⁻ leaving group) react with virtually all nucleophiles. Amides are most stable — nitrogen donates electrons well, making the carbonyl less electrophilic. This order is tested on virtually every orgo exam.
Q: Why are carboxylic acids more acidic than alcohols?
A: Carboxylic acids (pKa ~5) are far more acidic than alcohols (pKa ~16) because the carboxylate anion (RCOO⁻) is stabilized by resonance — the negative charge is delocalized over both oxygens equally. The alkoxide anion from an alcohol has no comparable resonance stabilization. EWG substituents lower pKa (stronger acid); EDG substituents raise pKa (weaker acid).
Q: How does Fischer Esterification work and how do you drive it to completion?
A: RCOOH + R'OH ⇌ RCOOR' + H₂O (acid catalyst, reversible). To drive equilibrium toward ester: use excess alcohol (Le Chatelier), remove water with Dean-Stark trap or molecular sieves, or use dehydrating agents. The mechanism involves protonation of the carbonyl, nucleophilic addition of alcohol, and elimination of water through a tetrahedral intermediate.
Q: What is saponification and how does it differ from acid-catalyzed hydrolysis?
A: Saponification = base-catalyzed ester hydrolysis: RCOOR' + NaOH → RCOONa + R'OH. It is IRREVERSIBLE because the carboxylate salt cannot be re-protonated under basic conditions. Acid hydrolysis is reversible. Saponification is how soap is made (triglyceride fat + NaOH → fatty acid salts + glycerol). Base-catalyzed is faster and irreversible — preferred for complete hydrolysis.
Q: Why does NaBH₄ fail to reduce carboxylic acids while LiAlH₄ succeeds?
A: NaBH₄ is a mild reducing agent — insufficient to reduce the resonance-stabilized carboxylate. LiAlH₄ is a much stronger hydride donor and reduces carboxylic acids to primary alcohols via an aldehyde intermediate. Two equivalents of hydride are added overall. The reaction requires anhydrous conditions (LiAlH₄ reacts violently with water). NaBH₄ reduces only aldehydes and ketones selectively.
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