Nucleophilic Acyl Substitution Reactions
In nucleophilic substitution reactions, anhydrides are more reactive than esters, which are more
reactive than amides.
Steric hindrance describes when a reaction cannot proceed (or significantly slows) because of
substituents crowding the reactive site. Protecting groups, such as acetals, can be used to
increase steric hindrance or otherwise decrease the reactivity of a particular portion of a
molecule.
Induction refers to uneven distribution of charge across a σ bond because of differences in
electronegativity. The more electronegative groups in a carbonyl-containing compound, the
greater its reactivity.
Conjugation refers to the presence of alternating single and multiple bonds, which creates
delocalized π electron clouds above and below the plane of the molecule. Electrons experience
resonance through the unhybridized p-orbitals, increasing stability. Conjugated carbonyl-
containing compounds are more reactive because they can stabilize their transition states.
Increased strain in a molecule can make it more reactive. β-lactams are prone to hydrolysis
because they have significant ring strain. Ring strain is due to torsional strain from eclipsing
interactions and angle strain from compressing bond angles below 109.5°.
All carboxylic acid derivatives can undergo nucleophilic substitution reactions. The rates at which
they do so are determined by their relative reactivities.
Anhydrides can be cleaved by the addition of a nucleophile.
Addition of ammonia or an amine results in an amide and a carboxylic acid.
Addition of an alcohol results in an ester and a carboxylic acid.
Addition of water results in two carboxylic acids.
Transesterification is the exchange of one esterifying group for another on an ester. The
attacking nucleophile is an alcohol.
Amides can be hydrolyzed to carboxylic acids under strongly acidic or basic conditions. The
attacking nucleophile is water or the hydroxide anion.
