Ch20: Nu acyl subs : less reactive

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 two choices.....

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.

NUCLEOPHILIC ACYL SUBSTITUTION FOR LESS REACTIVE SYSTEMS

Step 1:
An acid / base reaction. Protonation of a lone pair on the O of the carbonyl group creates a more electrophilic, cationic system.

Step 2:
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.

Step 3:
Electrons on the O are used to aid the loss of the leaving group (see note below). This reforms the p bond of the carbonyl group.

Step 4:
An acid/base reaction. Deprotonation reveals the carbonyl of the product and regenerates the acid catalyst.

acid catalysed nucleophilic acyl substitution for less reactive systems

Note: 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 mechanism:

Acid catalysed Hydrolysis of Esters or Amides