Carboxylic Acids and Nucleophilic Acyl Substitution: every key term you need (+ practice quiz)

More Organic Chemistry II guides

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Carboxylic acid acidity

The conjugate base spreads negative charge over two equivalent oxygens, making these acids far stronger than alcohols of similar size.

Substituent effect on acidity

Electron-withdrawing groups near the carboxyl stabilize the anion and raise acidity, and the effect fades quickly as the group moves further away.

Nucleophilic acyl substitution

The characteristic reaction of acid derivatives: a nucleophile adds, then a leaving group departs, so the carbonyl is regenerated with a new group attached.

Reactivity order of acid derivatives

Acid halides react fastest, then anhydrides, then esters and acids, then amides. The order follows how well each leaving group tolerates negative charge.

Downhill rule of derivatives

Any derivative can be converted to a less reactive one directly, while going the other way requires activation of the carbonyl first.

Acid chloride

The most reactive common derivative, made from the acid with a chlorinating reagent and used as the entry point to esters, amides and ketones.

Acid anhydride

Two acyl groups sharing an oxygen. It acylates nucleophiles readily and releases one equivalent of carboxylic acid as it does so.

Fischer esterification

An acid-catalysed equilibrium between a carboxylic acid and an alcohol. It is driven forward by excess alcohol or by removing water as it forms.

Ester hydrolysis under acid

The exact reverse of the acid-catalysed synthesis, and equally reversible, so a large excess of water is needed to push it.

Saponification

Base-promoted ester hydrolysis. It is irreversible because the final step deprotonates the acid, removing it from the equilibrium.

Transesterification

Swaps one alkoxy group for another under acid or base catalysis, driven by using the new alcohol as the solvent.

Amide formation

Requires an activated derivative or a coupling agent, since simply mixing an acid with an amine gives an unreactive salt.

Amide stability

Nitrogen donates its lone pair strongly into the carbonyl, giving partial double bond character, restricted rotation and very low reactivity.

Nitrile hydrolysis

Converts a nitrile to a carboxylic acid through an amide intermediate under either acid or base, and is a standard way to lengthen a carbon chain by one.

Decarboxylation

Loss of carbon dioxide on heating, easy only when a carbonyl or other electron sink sits beta to the acid so the resulting carbanion is stabilized.

Lactone

A cyclic ester formed by intramolecular esterification. Five- and six-membered versions form readily and are stable to isolation.

Lactam

A cyclic amide. Small strained versions such as four-membered rings are unusually reactive, which underlies the chemistry of several antibiotic families.

Selective reduction of an ester

A bulky hydride reagent at low temperature stops at the aldehyde, whereas a full-strength hydride reagent drives on to the alcohol.

Amide reduction

A strong hydride reagent reduces the carbonyl to a methylene without cleaving the carbon-nitrogen bond, providing a clean route to amines.

Grignard addition to an ester

Adds twice, because the initially formed ketone is more reactive than the ester, giving a tertiary alcohol with two identical new groups.

Organocuprate with an acid chloride

Stops cleanly at the ketone stage, unlike a Grignard reagent which would add a second time.

Carboxyl activation with a coupling agent

Converts the hydroxyl of an acid into a good leaving group in one pot, allowing amide formation under mild conditions.

Thioester

A sulfur analogue of an ester that is markedly more reactive toward acyl transfer, which is why biology uses it as an activated acyl carrier.

Anhydride from a diacid

Heating a diacid whose ends can reach each other gives a cyclic anhydride, again favouring five- and six-membered rings.

Hydroxamic acid

The product of hydroxylamine acting on an ester or acid derivative, notable for chelating metal ions strongly.