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Organic Chemistry 2 Unit 6: Carboxylic Acids and Derivatives

Carboxylic acids and their derivatives (acid chlorides, anhydrides, esters, amides and nitriles) interconvert by nucleophilic acyl substitution, and their relative reactivity decides which conversions are possible and which reagents to use.

Covers: Acidity of carboxylic acids and substituent effects, Preparing carboxylic acids, Nucleophilic acyl substitution and relative reactivity, Acid chlorides and anhydrides, Esters: Fischer esterification, hydrolysis and lactones, Amides and nitriles, Hydride and organometallic reactions of derivatives

Study guide

Carboxylic acids, RCOOH, are much more acidic (pKa about 4 to 5) than alcohols (pKa about 16) because the carboxylate anion is stabilized by resonance that spreads the negative charge equally over two oxygens. Electron-withdrawing groups near the COOH stabilize the carboxylate further and lower the pKa: chloroacetic acid (pKa 2.87) is about 78 times stronger than acetic acid (pKa 4.76), and the effect fades quickly as the substituent moves farther from the carboxyl. On benzoic acids, electron-withdrawing para groups such as NO₂ increase acidity, while donating groups such as OCH₃ decrease it. The Henderson-Hasselbalch equation, pH = pKa + log([A⁻]/[HA]), shows that an acid is 50% ionized when pH = pKa and about 91% ionized one unit above.

Carboxylic acids are prepared by oxidizing primary alcohols or aldehydes (chromic acid, KMnO₄), by oxidizing alkylbenzene side chains, by adding a Grignard reagent to CO₂ followed by acid, and by hydrolyzing nitriles. The last two both add one carbon: RBr → RMgBr → RCOOH, and RBr → RCN (by SN2 with cyanide) → RCOOH. The derivatives all react by nucleophilic acyl substitution: a nucleophile adds to the carbonyl carbon to form a tetrahedral intermediate, which then collapses, expelling a leaving group and reforming C=O. The overall result is replacement of one group on the acyl carbon by another, in contrast to aldehydes and ketones, which simply add nucleophiles because H⁻ and R⁻ are poor leaving groups.

Reactivity follows leaving-group ability and resonance donation: acid chloride > anhydride > ester ≈ carboxylic acid > amide. Chloride is an excellent leaving group and donates little electron density to the carbonyl, while nitrogen's lone pair donates strongly by resonance, giving amides partial C=N double-bond character and making them the least reactive. A more reactive derivative can be converted into a less reactive one directly, but not the reverse. Acid chlorides, made from acids with SOCl₂, react with water to give acids, with alcohols (and pyridine to absorb HCl) to give esters, and with two equivalents of amine to give amides. Anhydrides react similarly but give a carboxylic acid as the byproduct. Fischer esterification (acid plus alcohol with an acid catalyst) is an equilibrium with K near 4, driven by excess alcohol or water removal.

Esters are hydrolyzed by aqueous acid (the reverse of Fischer esterification) or by aqueous base in saponification. Saponification is irreversible because the carboxylic acid formed is immediately deprotonated to a carboxylate, which no longer reacts with alkoxide. Cyclic esters are lactones and cyclic amides are lactams; five- and six-membered rings form easily from hydroxy acids. Amides are hydrolyzed only under vigorous acid or base with heat. Nitriles, R–C≡N, are hydrolyzed through an amide to the carboxylic acid, add one Grignard equivalent to give a ketone after aqueous acid, and are reduced by LiAlH₄ to primary amines. Labeling experiments with ¹⁸O show that Fischer esterification keeps the alcohol oxygen in the ester; the acid's OH leaves as water.

Hydride and organometallic reagents distinguish the derivatives. LiAlH₄ reduces acids, acid chlorides, anhydrides and esters to primary alcohols, and reduces amides to amines (the C=O becomes CH₂). NaBH₄ reduces acid chlorides but generally not esters, acids or amides, which allows selective ketone reductions in their presence. DIBAL-H at −78 °C reduces esters (and nitriles) to aldehydes, and LiAlH(Ot-Bu)₃ reduces acid chlorides to aldehydes. Grignard reagents add twice to esters and acid chlorides, because the ketone formed after the first addition is more reactive than the ester, giving tertiary alcohols with two identical R groups. Gilman reagents (R₂CuLi) react with acid chlorides only once, stopping cleanly at the ketone.

Key ideas

• Carboxylate resonance makes carboxylic acids far more acidic than alcohols; nearby electron-withdrawing groups strengthen them.
• Acid derivatives react by addition followed by elimination through a tetrahedral intermediate.
• Reactivity order: acid chloride > anhydride > ester ≈ acid > amide.
• Conversions run downhill in reactivity; acid chlorides are the gateway to every other derivative.
• Fischer esterification is an equilibrium, but saponification is irreversible.
• Grignard reagents add twice to esters, while Gilman reagents stop at ketones.
• LiAlH₄ reduces esters to alcohols and amides to amines; DIBAL-H stops esters at aldehydes.

Formulas and rules

Common mistakes

• Adding only one equivalent of Grignard to an ester and expecting a ketone.
• Trying to convert an amide directly into an acid chloride or ester, which runs uphill in reactivity.
• Forgetting that saponification produces a carboxylate salt, which needs acid to give the free acid.
• Expecting LiAlH₄ to reduce an amide to an alcohol instead of an amine.
• Assuming NaBH₄ reduces esters as easily as ketones.

Before the test, make sure you can

• Rank carboxylic acids by acidity and explain the substituent effects.
• Use Henderson-Hasselbalch to find the fraction of an acid ionized at a given pH.
• Draw the addition–elimination mechanism of nucleophilic acyl substitution.
• Rank derivatives by reactivity and decide which interconversions are possible.
• Predict products of Fischer esterification, saponification, lactone formation and amide hydrolysis.
• Predict products of LiAlH₄, NaBH₄, DIBAL-H, Grignard and Gilman reagents with each derivative.
• Plan syntheses of carboxylic acids that add one carbon from an alkyl halide.
• Calculate equilibrium yields for Fischer esterification.

Words to know

Carboxylate ion

RCOO⁻, the conjugate base of a carboxylic acid, with its negative charge shared by two oxygens.

Inductive effect

Electron withdrawal or donation through σ bonds that weakens with distance and changes acidity.

Nucleophilic acyl substitution

Replacement of a leaving group on an acyl carbon through a tetrahedral intermediate.

Acid chloride

RCOCl, the most reactive carboxylic acid derivative, made from an acid with SOCl₂.

Acid anhydride

(RCO)₂O, a derivative formed from two acids that acylates nucleophiles and releases a carboxylic acid.

Ester

RCOOR', a derivative of moderate reactivity made by Fischer esterification or from acid chlorides.

Amide

RCONR₂, the least reactive derivative because the nitrogen lone pair donates into the carbonyl.

Nitrile

R–C≡N, hydrolyzed to carboxylic acids and reduced to primary amines.

Fischer esterification

Acid-catalyzed equilibrium reaction of a carboxylic acid with an alcohol to form an ester and water.

Saponification

Irreversible base hydrolysis of an ester to a carboxylate salt and an alcohol.

Lactone

A cyclic ester formed by intramolecular esterification of a hydroxy acid.

Lactam

A cyclic amide, as in the β-lactam ring of penicillins.

Thionyl chloride

SOCl₂, which converts carboxylic acids into acid chlorides with SO₂ and HCl byproducts.

DIBAL-H

Diisobutylaluminum hydride, a bulky reducing agent that converts esters to aldehydes at −78 °C.

Gilman reagent

A lithium diorganocuprate, R₂CuLi, that converts acid chlorides to ketones without further addition.

Carboxylation

Reaction of a Grignard reagent with CO₂ to form a carboxylate, adding one carbon.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.