Difficulty: Intermediate-Advanced | Prerequisites: Carbonyl addition reactions, carbonyl reactivity order.
Carboxylic acid derivatives (acid chlorides, anhydrides, esters, amides, and nitriles) all share a carbonyl bonded to a heteroatom leaving group. Unlike aldehydes and ketones, these undergo nucleophilic acyl substitution: the nucleophile attacks the carbonyl, forms a tetrahedral intermediate, and then the leaving group departs. This chapter is about interconverting these functional groups, moving up and down the reactivity ladder, and using reductions to reach alcohols, aldehydes, or amines. You should already understand why acid chlorides are more reactive than amides (the reactivity order from the previous set of notes).
Nucleophilic acyl substitution swaps one group on a carbonyl for another through a tetrahedral intermediate. Acid chlorides are the most reactive starting point and can be converted to nearly any other derivative. Esters, amides, and nitriles can also be interconverted or reduced. The key distinction from aldehyde/ketone chemistry: here, the nucleophile replaces a leaving group rather than simply adding.
Nucleophilic acyl substitution (NAS)
The mechanism for reactions at acid chlorides, anhydrides, esters, and amides: nucleophile attacks C=O → tetrahedral intermediate forms → leaving group (Y⁻) departs → new carbonyl product. Applies when Y = Cl, OR, NR₂. Does not apply to aldehydes or ketones (they have no leaving group).
Tetrahedral intermediate
The sp³ carbon intermediate formed when a nucleophile adds to the carbonyl in NAS. It collapses by expelling the leaving group.
Acid chloride (RCOCl)
The most reactive carboxylic acid derivative. Made from a carboxylic acid using thionyl chloride (SOCl₂). Serves as the gateway to all other derivatives.
Anhydride (RCO-O-COR)
Formed by dehydration of two carboxylic acid molecules (using P₂O₅ or heat), or from an acid chloride + a carboxylate salt. Reacts similarly to acid chlorides but is slightly less reactive.
Fischer esterification
Acid-catalysed reaction of a carboxylic acid with an alcohol to form an ester + water. Equilibrium reaction, driven forward by excess alcohol or removal of water.
Saponification
Base-promoted hydrolysis of an ester to give a carboxylate salt + alcohol. Irreversible because the carboxylate anion is too stable to react further.
DIBAL (diisobutylaluminium hydride)
A selective reducing agent that reduces esters to aldehydes (stops at the aldehyde stage because the bulky aluminium intermediate is stable). A 2-electron reduction.
DCC (dicyclohexylcarbodiimide)
A coupling reagent that activates a carboxylic acid to react with an amine, forming an amide bond without needing to go through the acid chloride. Used in peptide synthesis.
Schotten-Baumann technique
A method for making amides from acid chlorides and secondary amines. Uses two equivalents of amine: one reacts, the other scavenges the HCl produced. The amine salt partitions into the aqueous layer and is recovered by basification.
Lactone
A cyclic ester. Grignard addition opens the ring and, with two equivalents, gives a diol.
Nitrile (R-C≡N)
A functional group containing a carbon-nitrogen triple bond. Can be hydrolysed to a carboxylic acid, reduced to an amine (LAH), or reacted with a Grignard to give a ketone.
Nucleophile (Nu⁻) attacks the electrophilic carbonyl carbon.
The pi bond breaks, forming a tetrahedral intermediate with four groups on carbon: R, Nu, Y (the leaving group), and O⁻.
The leaving group Y⁻ departs, and the C=O reforms.
This mechanism applies when Y = Cl, OR, or NR₂. It does not apply to aldehydes (Y = H) or ketones (Y = R), because H⁻ and R⁻ are not good leaving groups. With aldehydes and ketones, the nucleophile simply adds and stays.
Carboxylic acid + thionyl chloride (SOCl₂) → acid chloride + SO₂ + HCl.
Both byproducts are gases, driving the reaction to completion.
Acid chloride + H₂O → carboxylic acid. Water is the nucleophile.
Acid chloride + alcohol (HO-R') → ester. The alcohol attacks, Cl⁻ leaves.
Acid chloride + 2 NH₃ → amide + NH₄Cl. One equivalent of amine reacts, the second equivalent neutralises the HCl produced.
Acid chloride + LAH, then H₂O → primary alcohol. 4-electron reduction. LAH delivers hydride twice: first to the acid chloride (giving an aldehyde intermediate), then to the aldehyde.
Acid chloride + bulky hydride (e.g. Al(OC(CH₃)₃)₃H) → aldehyde. The bulky groups stop reduction at the aldehyde stage. 2-electron reduction.
Acid chloride + 2 RMgBr, then H₂O → tertiary alcohol. The Grignard adds twice (once to the acid chloride, once to the resulting ketone). 2-electron reduction overall.
Acid chloride + R₂CuLi (Gilman reagent) → ketone. The organocuprate is mild enough to add only once, stopping at the ketone. 1-electron-pair reduction.
Made from 2 equivalents of carboxylic acid + P₂O₅ (or heat), or from acid chloride + carboxylate salt.
React with amines and Grignard reagents much like acid chlorides, though slightly less vigorously.
Anhydride + 2 RNH₂ → amide + carboxylate salt.
Anhydride + 2 CH₃MgBr, then H₂O → tertiary alcohol.
From acid chloride + alcohol (in CH₂Cl₂ or similar solvent). Fast, clean. Change of functionality.
From anhydride + alcohol (in CH₂Cl₂ with CH₃OH). Also a change of functionality.
Fischer esterification: carboxylic acid + alcohol + catalytic H₃O⁺ → ester + H₂O. Equilibrium reaction. The mechanism is the reverse of acid-catalysed ester hydrolysis.
Acidic (reverse Fischer): ester + H₂O + H₃O⁺ → carboxylic acid + alcohol. Equilibrium.
Basic (saponification): ester + NaOH → carboxylate salt + alcohol. Irreversible, because the carboxylate anion is deprotonated and cannot be re-attacked.
Ester + LAH, then H₂O → primary alcohol. 4-electron reduction. Two hydride deliveries.
Ester + DIBAL, then H₃O⁺/H₂O → aldehyde. 2-electron reduction. DIBAL's bulk stops it at the aldehyde stage.
Ester + 2 CH₃MgBr, then H₂O → tertiary alcohol. 2-electron reduction. Grignard adds twice.
Lactone (cyclic ester) + 2 RMgBr, then H₂O → diol (the ring opens and both carbonyls are attacked).
Ester with an intramolecular Grignard (a Grignard tethered to the ester) → ring formation (cyclic alcohol). 2-electron reduction.
Primary alcohol → carboxylic acid: Jones oxidation (CrO₃/H₂SO₄). 4-electron oxidation.
Aldehyde → carboxylic acid: Jones oxidation. 2-electron oxidation.
Aromatic side chain → benzoic acid: KMnO₄. Works on any benzylic C-H ("aromatic systems with hydrogens"). 6-electron oxidation. The mechanism is complex.
Grignard + CO₂, then H₃O⁺ → carboxylic acid. Adds one carbon. The Grignard attacks CO₂ as a nucleophile.
Nitrile + H₂O/H₃O⁺ (heat) → carboxylic acid. Full hydrolysis. The nitrile is first hydrated to an amide, then the amide is hydrolysed to the acid.
Nitrile + H₂O/H₂O₂ or H₃O⁺ (mild) → amide. Partial hydrolysis, stopping at the amide stage.
Nitrile + RMgBr, then H₃O⁺ → ketone. 1-electron-pair reduction. The Grignard adds to the C≡N, and aqueous workup hydrolyses the resulting imine to a ketone.
Nitrile + LAH, then H₂O → primary amine. 4-electron reduction.
Primary amide + SOCl₂ → nitrile. The SOCl₂ dehydrates the amide.
Acidic: amide + H₂O/H₃O⁺ (heat) → carboxylic acid + amine (as ammonium salt).
Basic: amide + 2 KOH/H₂O (heat), then H₃O⁺ → carboxylic acid.
Amide + LAH, then H₂O → amine. 4-electron reduction.
Primary amide → primary amine.
Secondary amide → secondary amine.
Tertiary amide → tertiary amine.
Carboxylic acid + amine + DCC (in CH₂Cl₂) → amide.
DCC activates the carboxylic acid, making it a better electrophile. Used widely in peptide synthesis.
Carboxylic acid + LAH, then H₂O → primary alcohol. 4-electron reduction. LAH is powerful enough to reduce the carboxylic acid directly (NaBH₄ is not).
Acid chloride + 2 equivalents of secondary amine → amide.
The amine salt (from HCl) goes into the aqueous layer. Treatment with NaOH frees it. The amide product is in the organic layer (CH₂Cl₂).
Friedel-Crafts acylation: aromatic ring + acid chloride/AlCl₃ → aryl ketone.
Hydroboration of alkenes: anti-Markovnikov product.
Oxymercuration of alkenes: Markovnikov product.
Ozonolysis: breaks C=C into two carbonyl fragments.
Mercuration and hydroboration of alkynes: give ketones (Markovnikov) or aldehydes (anti-Markovnikov) respectively.
Students often try to run NAS on aldehydes or ketones. NAS requires a leaving group (Cl, OR, NR₂). H and R are not leaving groups.
Fischer esterification is an equilibrium. Students forget to drive it forward with excess alcohol or removal of water.
Saponification is irreversible, but students sometimes draw the reverse. The carboxylate anion is too stable to be re-attacked.
DIBAL reduces esters to aldehydes, not to alcohols. LAH reduces them all the way to primary alcohols. Mixing these up is a common exam error.
⚠️ Know the full acid chloride conversion chart: acid chloride to carboxylic acid, ester, amide, 1° alcohol, aldehyde, 3° alcohol, and ketone. This is one of the most commonly tested topics.
⚠️ Be able to propose a multi-step synthesis that uses acid chloride as the central hub.
⚠️ Fischer esterification vs saponification: know the conditions and whether the reaction is reversible.
⚠️ Nitrile transformations: hydrolysis to acid, Grignard to ketone, LAH to amine.
⚠️ The summary reaction maps (pages 77-78 in the lecture notes) are worth memorising. They connect all transformations from one functional group to another.
True or False: NaBH₄ can reduce an ester to an alcohol.
False. You need LAH.
Fill in the blank: Acid chloride + R₂CuLi → ______.
Ketone.
True or False: Saponification of an ester is reversible.
False. It is irreversible.
Fill in the blank: Nitrile + LAH, then H₂O → ______.
Primary amine.
Q: Convert benzoic acid to benzyl alcohol in two steps.
A: Step 1: Benzoic acid + SOCl₂ → benzoyl chloride. Step 2: Benzoyl chloride + LAH, then H₂O → benzyl alcohol.
Q: You need to convert an ester to an aldehyde. What reagent do you use?
A: DIBAL (at low temperature), then H₃O⁺/H₂O workup. DIBAL stops the reduction at the aldehyde stage.
Q: How would you convert a nitrile to a ketone?
A: React the nitrile with RMgBr (Grignard), then H₃O⁺ aqueous workup. The Grignard adds to C≡N, and hydrolysis gives the ketone.
NAS builds on the carbonyl reactivity order from the addition-reactions notes. It feeds directly into alpha-functionalisation chemistry, where enolates and enols react at the carbon next to a carbonyl. The acid chloride-to-amide route connects to peptide synthesis and amino acid chemistry, covered in the later notes on amines and amino acids.
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