Each is an acyl group (R–C=O) bonded to a different atom: two acyloxy oxygens (anhydride), one alkoxy oxygen (ester), or a nitrogen (amide).
The three common carboxylic acid derivatives — structures drawn live.
1. All three are made and cleaved by nucleophilic acyl substitution
A nucleophile adds to the carbonyl to give a tetrahedral intermediate, which collapses and ejects the best leaving group — net substitution, since there is always a leaving group to depart.
2. Reactivity runs anhydride > ester > amide, and amides are the most stable
Reactivity tracks leaving-group quality and how strongly the attached atom donates into the carbonyl; nitrogen donates most and –NR2 is the worst leaving group, so a more reactive derivative can always be made into a less reactive one but never the reverse.
3. Esters form by Fischer esterification, which is reversible
Fischer esterification couples a carboxylic acid and alcohol under acid catalysis; every step is reversible, so drive it forward with excess alcohol or by removing water (and reverse it for acidic hydrolysis).
Fischer esterification: acetic acid + methanol give methyl acetate (reversible).
4. Saponification cleaves an ester irreversibly to a carboxylate
Aqueous NaOH hydrolyzes the ester and immediately deprotonates the product to a carboxylate salt — an irreversible step that drives it to completion (the reaction that turns fats into soap).
Saponification: ethyl acetate + NaOH give acetate (plus ethanol), irreversibly.
5. Esters reduce to alcohols or aldehydes, and swap groups by transesterification
LiAlH4 reduces esters fully to a primary alcohol; bulky DIBAL at −78 °C delivers one hydride and stops at the aldehyde.
LiAlH4 reduces methyl acetate fully to ethanol (a primary alcohol).
Transesterification swaps one –OR for another with a different alcohol and a trace of acid or base — reversible, like Fischer. The DIBAL product is the aldehyde .
6. Amides form from acid chlorides or anhydrides plus an amine, and resist hydrolysis
An acid plus an amine only forms an unreactive ammonium salt, so react a more reactive derivative (acid chloride or anhydride) with the amine; hydrolyzing an amide back needs hot strong acid or base, while LiAlH4 reduces it to an amine.
Acetyl chloride + methylamine give N-methylacetamide.
7. Anhydrides are reactive acylating agents
One acyl half becomes the product while the other leaves as a carboxylate, making acetic anhydride a cheap acetylating reagent — it converts alcohols to esters, amines to amides, and salicylic acid to aspirin.
Acetic anhydride acylates methanol to methyl acetate.
8. Summary
One addition–elimination mechanism · ladder anhydride > ester > amide · build down the ladder from acid chlorides/anhydrides · esters hydrolyze by acid (reversible) or NaOH (saponification) · amides need hot acid/base · LiAlH4 → alcohols/amines, DIBAL stops at the aldehyde.
Quiz yourself
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Anhydride > ester > amide. The amide is least reactive because nitrogen donates its lone pair strongly into the carbonyl (large resonance stabilization) and –NR2 is a very poor leaving group.
Saponification ends by deprotonating the product carboxylic acid to a carboxylate salt — an effectively irreversible step — so the reaction is pulled all the way forward. Fischer esterification has no such trap; every step is reversible, so it settles at equilibrium and must be driven with excess alcohol or by removing water.
Use DIBAL at −78 °C. It is bulky and delivers only one hydride, so the tetrahedral intermediate survives until workup and gives the aldehyde. LiAlH4 would add a second hydride and over-reduce all the way to the primary alcohol.
The amine is basic, so it simply deprotonates the acid to form an unreactive ammonium carboxylate salt instead of substituting at the carbonyl. Make the amide from a more reactive derivative — an acid chloride or anhydride — plus the amine, with a base to absorb the byproduct.
Draw this on the whiteboard
Open the OChem Board whiteboard — benzene rings, curved arrows, wedge/dash bonds and a clickable periodic table built in. No account needed.