|| Chapter 20: Carboxylic
Acid Derivatives. Nucleophilic Acyl Substitution
Nucleophilic Acyl Substitution
: Less Reactive Systems
- If the reaction components are
less reactive, for example neutral nucleophiles (e.g.
H2O or ROH etc.) or the electrophile is a less reactive carboxylic
acid derivative (e.g. esters or amides), then the reaction will be
very slow unless the reaction is promoted.
- To promote the reaction, we have
- Activating the Nucleophile
If a base is used, then this can activate the nucleophile by
deprotonating it, creating the more nucleophilic anion (e.g.
H2O to HO-, or ROH to RO-). In this
case we see the mechanism discussed previously.
- Activating the Electrophile
If an acid is used then this can activate the electrophile by protonating
the carbonyl thus making it more electrophilic. In this case
we see the mechanism shown below.
- This is similar to what we have
talked about previously for the reactions epoxides (Chapter
16) and aldehydes / ketones (Chapter 17)
with weaker nucleophiles.
ACYL SUBSTITUTION FOR LESS REACTIVE SYSTEMS
An acid / base reaction. Protonation of a lone pair on the O of
the carbonyl group creates a more electrophilic, cationic system.
The nucleophile attacks the electrophilic C of the carbonyl group
causing the p bond in the C=O to break and allows for neutralisation
of the positive charge. This converts the sp2 C=O
into the sp3 tetrahedral intermediate.
Electrons on the O are used to aid the loss of the leaving group
(see note below). This reforms the p bond of the
An acid/base reaction. Deprotonation reveals the carbonyl of the product
and regenerates the acid catalyst.
In some cases (especially esters and amides) the leaving group must
also be activated prior to being lost. This can also be achieved by protonation.
This adds a step to the process shown above.
Examples Reactions that follow this