Carboxylic Acids and Derivatives

Carboxylic acids and their derivatives — esters, amides, anhydrides, and acid halides — share the acyl group and interconvert through nucleophilic acyl substitution.

Definition

This topic addresses carboxylic acids and the family of acyl derivatives that arise by replacing the hydroxyl group, unified by the nucleophilic acyl substitution mechanism.

Scope

This topic covers the acidity of carboxylic acids and the effect of substituents, the relative reactivity of acyl derivatives, esterification and hydrolysis, amide formation, the chemistry of acid chlorides and anhydrides, and decarboxylation.

Core questions

• Why are carboxylic acids more acidic than alcohols?
• What ordering of reactivity governs the interconversion of acyl derivatives?
• How do esterification and hydrolysis proceed, and how are they driven in each direction?

Key theories

Resonance stabilization of the carboxylate

Loss of the acidic proton gives a carboxylate anion whose negative charge is delocalized equally over two oxygens, accounting for the relatively high acidity of carboxylic acids.

Nucleophilic acyl substitution reactivity ladder

Acyl derivatives interconvert through a tetrahedral intermediate; more reactive species (acid chlorides, anhydrides) are readily converted to less reactive ones (esters, amides), but not easily the reverse.

Mechanisms

Nucleophilic acyl substitution proceeds by addition of a nucleophile to the carbonyl to form a tetrahedral intermediate, followed by expulsion of the leaving group. Acid-catalyzed Fischer esterification is an equilibrium driven by removing water or using excess reagent, while amide and ester hydrolysis can be acid- or base-promoted, the latter (saponification) being irreversible.

Clinical relevance

The amide bond is the linkage of proteins and of countless drugs; ester groups are exploited in prodrugs that hydrolyze to release the active agent. Carboxylic acid groups confer acidity and solubility on many pharmaceuticals, including aspirin and the nonsteroidal anti-inflammatory drugs.

History

Fischer's late nineteenth-century work on esterification, together with the systematic study of acyl substitution, established the reactivity relationships among acid derivatives that remain foundational to synthesis and biochemistry.

Key figures

• Emil Fischer
• Rainer Ludwig Claisen

Seminal works

• careysundberg2007b

Frequently asked questions

Why can an acid chloride make an ester but not the reverse easily?

Reactivity in acyl substitution runs from acid chlorides down to amides; a more reactive derivative readily converts to a less reactive one because it has the better leaving group, while the reverse requires special activation.

What is saponification?

Saponification is the base-promoted hydrolysis of an ester to give a carboxylate salt and an alcohol; because the carboxylate is stable and unreactive, the reaction is effectively irreversible.