Interconversion Reactions of Esters

	esters
	acids
	amides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Esters can be converted into other esters (transesterification), the parent carboxylic acid (hydrolysis) or amides  (see above).
• Transesterification : heat with alcohol and acid catalyst
• Hydrolysis : heat with aq. acid or base (e.g. aq. H₂SO₄ or aq. NaOH) (see hydrolysis of esters for more details)
• Amide preparation :  heat with the amine, methyl  or ethyl esters are the most reactive

Hydrolysis of Esters

Summary

• Carboxylic esters hydrolyze 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 step 2).
• 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 of the ester C=O, breaking the p 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, leading to the carboxylic acid.
Step 3: An acid / base reaction. A very rapid equilibrium where the alkoxide functions as a base deprotonating the carboxylic acid (an acidic work up would allow the carboxylic acid to be obtained from the reaction).

Reaction under ACIDIC conditions:

• Note that the acid catalyzed 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 catalyzed  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.
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 in the carboxylic acid product and regenerates the acid catalyst.

Reduction of Esters
(review of Chapter 15)

Reactions usually in Et₂O or THF followed by H₃O⁺ work-ups

• Carboxylic esters are reduced give 2 alcohols, one from the alcohol portion of the ester and a 1^o alcohol from the reduction of the carboxylate portion.
• Esters are less reactive towards Nu than aldehydes or ketones.
• They can only be reduced by LiAlH₄ and NOT by the less reactive  NaBH₄
• The reaction requires that 2 hydrides (H^-) be added to the carbonyl group of the ester
• The mechanism is an example of the reactive system type.
• Note the aldehyde intermediate.

REACTION OF LiAlH4 WITH AN ESTER
Step 1: The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the ester. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 2: The tetrahedral intermediate collapses and displaces the alcohol portion of the ester as a leaving group, this produces a ketone as an intermediate.
Step 3:  Now we are reducing an aldehyde.  The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the aldehyde. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 4: This is the  work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the primary alcohol product from the intermediate complex.

  Reactions of RLi and RMgX with Esters
(review of Chapter 14)

Reaction usually in Et₂O followed by H₃O⁺ work-up

Summary:

• Carboxylic esters, R'CO₂R'', react with 2 equivalents of organolithium or Grignard reagents to give tertiary alcohols.
• The tertiary alcohol that results contains 2 identical alkyl groups (from R in the scheme)
• The reaction proceeds via a ketone intermediate which then reacts with the second equivalent of the organometallic reagent (review)
• Since the ketone is more reactive than the ester, the reaction cannot be used as a preparation of ketones.
• The mechanism is an example of the reactive system type.

REACTION OF RMgX WITH AN ESTER
Step 1: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar carbonyl group of the ester. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 2: The tetrahedral intermediate collapses and displaces the alcohol portion of the ester as a leaving group, this produces a ketone as an intermediate.
Step 3: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar carbonyl group of the ketone. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 4: This is the  work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the alcohol product from the intermediate complex.

Copyright ©2000 The McGraw-Hill Companies. All rights reserved. Any use is subject to the Terms of Use and Privacy Policy.
McGraw-Hill Higher Education is one of the many fine businesses of The McGraw-Hill Companies.
For further information about this site contact mhhe_webmaster@mcgraw-hill.com.