Chapter 20: Carboxylic Acid Derivatives. NucleophilicAcyl Substitution

Hydrolysis of Esters

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Carboxylic esters hydrolyse to the parent carboxylic acid and an alcohol.
• Reagents : aqueous acid (e.g. H₂SO₄) / heat,or aqueous NaOH / heat (known as "saponification").
• These mechanisms are among some of the most studied in organic chemistry.
• Both are based on the formation of a tetrahedral intermediate which then dissociates.
• In both cases it is the C-O bond between the acyl group and the oxygen that is cleaved.

• Fischer esterification
• Hydrolysis of Amides

• The mechanism shown below leads to acyl-oxygen cleavage (see step2).
• The mechanism is supported by experiments using ¹⁸O labeled compounds and esters of chiral alcohols.
• This reaction is known as "saponification" because it is the basis of making soap from glycerol triesters in fats.
• The mechanism is an example of the reactive system type.

MECHANISM OF THE BASE HYDROLYSIS OF ESTERS
Step 1: The hydroxide nucleophiles attacks at the electrophilic C ofthe ester C=O, breaking the π bond and creating the tetrahedral intermediate.
Step 2: The intermediate collapses, reforming the C=O results in the loss of the leaving group the alkoxide, RO-, leading to the carboxylic acid.
Step 3: An acid / base reaction. A very rapid equilibrium where the alkoxide,RO- functions as a base deprotonating the carboxylic acid, RCO2H, (an acidic work up would allow the carboxylic acid to be obtained from the reaction).

Reaction under ACIDIC conditions:

• Note that the acid catalysed mechanism is the reverse of the Fischer esterification.
• The mechanism shown below also leads to acyl-oxygen cleavage (see step 5).
• The mechanism is an example of the less reactive system type.

MECHANISM OF THE ACID CATALYSED  HYDROLYSIS OF ESTERS
Step 1: An acid/base reaction. Since we only have a weak nucleophile and a poor electrophile we need to activate the ester. Protonation of the ester carbonyl makes it more electrophilic.
Step 2: The water O functions as the nucleophile attacking the electrophilic C in the C=O, with the electrons moving towards the oxonium ion, creating the tetrahedral intermediate.
Step 3: An acid/base reaction. Deprotonate the oxygen that came from the water molecule to neutralise the charge.
Step 4: An acid/base reaction. Need to make the -OCH3 leave, but need to convert it into a good leaving group first by protonation.
Step 5: Use the electrons of an adjacent oxygen to help "push out" the leaving group, a neutral methanol molecule.
Step 6: An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl C=O in the carboxylic acid product and regenerates the acid catalyst.

© Dr. Ian Hunt, Department of Chemistry