Nucleophilic Acyl Substitution Reactions of Carboxylic Acids

  • Hydroxyl group makes carboxylic acids relatively unreactive towards nucleophilic acyl substitutions.
  • The addition of a strong acid protonates the carbonyl oxygen making the carbonyl carbon more electrophilic.
  • under the specific conditions carboxylic acids can be successfully converted into acid chlorides, acid anhydrides, esters, and amides through nucleophilic acyl substitution.

 

Conversion of Carboxylic acids to Acid Chlorides

  • Carboxylic acids can be converted to acid chlorides by reaction with thionyl chloride (SOCl2).
  • During the reaction with thionyl chloride, the hydroxyl group of the carboxylic acid is converted to an acyl chlorosulfite moiety which is a better leaving group.
  • During the reaction a nucleophilic chloride anion is produced which reacts with the acyl chlorosulfite intermediate through nucleophilic acyl substitution to produce an acid halide.

General Reaction

Generic Acid Chloride Formation.svg

 

Example

Example Benzoic Acid.svg

 

Mechanism

1) Nucleophilic attack on S=O bond

Mechanism Acid Chloride Formation Step 1.svg

 

2) Removal of Cl leaving group

Mechanism Acid Chloride Formation Step 2.svg

 

3) Nucleophilic attack on the carbonyl

Mechanism Acid Chloride Formation Step 3.svg

 

4) Leaving group removal

Mechanism Acid Chloride Formation Step 4.svg

 

5) Deprotonation

Mechanism Acid Chloride Formation Step 5.svg

 

Acid Anhydride Formation

An acid anhydride is the product of condensation of two carboxylic acid molecules with the release of a water molecule eg acetic anhydride.

General Reaction

anhydride.png

 

Example

Example Anhydride formation.svg

 

Conversion of Carboxylic Acids into Esters by Alkylation

Carboxylic acids can be easily converted into their conjugate bases through deprotonation with a base, such as sodium hydroxide. The resulting carboxylate can be alkylated using by an SN2 reaction with either a methyl or primary halide. If a methyl ester is required, methyl iodide (CH3I) is a commonly used reagent.

 

Example

Mechanism Ester Formation.svg

Conversion of Carboxylic Acids to Esters

General Reaction

Generic Fischer Esterfication.svg

 

Predicting the Products of a Fischer Esterification

Predicting the Products Fischer Esterificaiton.svg

Example

Example Fischer Esterification.svg

 

Mechanism

1) Protonation of the carbonyl

Mechansim Fischer Esterification Step 1.svg

 

2) Nucleophilic attack on the carbonyl

Mechansim Fischer Esterification Step 2.svg

 

3) Proton transfer

Mechansim Fischer Esterification Step 3.svg

 

4) Removal of water as a leaving group

Mechansim Fischer Esterification Step 4.svg

 

5) Deprotonation

Mechansim Fischer Esterification Step 5.svg

 

Direct Conversion of Carboxylic Acids to Amides

General Reaction

Direct Conversion to Amide.svg

 

Conversion of Carboxylic Acids to Amides using DCC

DCC Structure.svg

  • During a DCC amide coupling, the OH of a carboxylic acid is replaced by an amine during nucleophilic acyl substitution.
  • Using DCC as a coupling reagent, 1o and 2o amines can be used to create 2o and 3o amides respectfully.

 

Basic reaction

Generic DCC Coupling.svg

 

Predicting the products of DCC Coupling

Predicting the Products of a DCC Coupling.svg

 

Example

Example DCC Coupling.svg

 

Mechanism

1) Deprotonation

Mechanism DDC Coupling Step 1.svg

 

2) Nucleophilic attack by the carboxylate

Mechanism DDC Coupling Step 2.svg

 

3) Nucleophilic attack by the amine

Mechanism DDC Coupling Step 3.svg

 

4) Proton transfer

Mechanism DDC Coupling Step 4.svg

 

5) Leaving group removal

Mechanism DDC Coupling Step 5.svg

 

Conversion of Carboxylic acids to 1o alcohols

Lithium aluminum hydride (LiAlH4)

  • Hydride nucleophiles from lithium aluminum hydride (LiAlH4) can reduce carboxylic acids to 1alcohols.
  • NaBH4 is not a strong enough reducing agent to convert carboxylic acids or esters to alcohols.

 

General reaction

Generic Hydride Coupling.svg

 

Predicting the product of a hydride reduction

Predicting the Product of a Hydride Reduction.svg

 

Example

Example Hydride Reduction.svg

 

Mechanism

1) Deprotonation

Mechanism Hydride Reduction Step 1.svg

 

2) Nucleopilic attack by a hydride anion

Mechanism Hydride Reduction Step 2.svg

 

3) Leaving group removal

Mechanism Hydride Reduction Step 3.svg

 

4) Nucleopilic attack by a hydride anion

Mechanism Hydride Reduction Step 4.svg

 

5) Alkoxide protonation

Mechanism Hydride Reduction Step 5.svg

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