Chapter 21The Chemistry of Carboxylic Acid Derivatives

Carboxylic Acid Derivatives• Carboxylic acid derivative: a compound that has an acyl group

bonded to an electronegative atom or substituent that can act as a leaving group in a substitution reaction– can be hydrolyzed under acidic of basic conditions to give a

carboxylic acid

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Structures of Carboxylic Acid Derivatives

321.1 Nomenclature and Classification of Carboxylic Acid Derivatives

Reactions of Carboxylic Acid Derivatives• Chemistry dominated by nucleophilic acyl substitution rxns:

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Hydrolysis Reactions1) Hydrolysis of Esters

a) Basic Hydrolysis (Saponification)b) Acid Catalyzed Hydrolysis

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Basic Hydrolysis

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Acid Catalyzed Hydrolysis

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2) Hydrolysis of Amides

• Happens under both acidic and basic conditions• Conditions harsher than those of ester hydrolysis

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+ NH4+/NH2

-

• Basic Hydrolysis

• Acidic Hydrolysis

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3) Hydrolysis of Nitriles• Occurs in both acidic and basic environments• More extreme conditions are required compared to those of esters

and amides

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• Basic hydrolysis

1121.7 Hydrolysis of Carboxylic Acid Derivatives

• Acidic hydrolysis

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• Imidic acids can be viewed as the nitrogen-analogs of enols

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Problem• Write out the mechanism for the following rxn:

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Nucleophilic Acyl Substitution Reactions

• The conditions for hydrolysis for these derivatives can differ considerably

1521.7 Hydrolysis of Carboxylic Acid Derivatives

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Reactions of Acid Chlorides with Amines: Aminolysis

1821.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

Conversion of Acid Chlorides into Esters: Alcoholysis

1921.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

Reactions of Acid Chlorides with Carboxylate Salts: Preparation of Anydrides

2021.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

Problems

1) Give the products for the following rxns:

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2) Draw the mechanism for the following reaction:

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Reactions of Anhydrides with Nucleophiles

2321.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

Reactions of Esters with Nucleophiles

• Transesterification:

2421.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

Problems

• Give the products for the following rxns:

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Reduction Carboxylic Acid Derivatives

1) Reduction of Esters• LiAlH4 preferred over NaBH4

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-78°C, DIBAH = Diisobutyl aluminum hydride

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2) Reduction of Amides to Amines– Net effect is conversion of C=O to CH2

2821.9 Reduction of Carboxylic Acid Derivatives

Reduction of Amides to Amines

• Note how the amide reduction differs from that of ester reduction

2921.9 Reduction of Carboxylic Acid Derivatives

• Note that a protonolysis step with aqueous acid follows the LiAlH4 reduction

• This is followed by base to free the amine

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3121.9 Reduction of Carboxylic Acid Derivatives

3221.9 Reduction of Carboxylic Acid Derivatives

3) Reduction of Nitriles to Primary Amines

3321.9 Reduction of Carboxylic Acid Derivatives

• Two successive nucleophilic additions occur

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• Intermediate imine not isolated

3521.9 Reduction of Carboxylic Acid Derivatives

4) Reduction of Acid Chlorides to Aldehydes– The Rosenmund reduction:

– H2 gas over Pd on C• Poisoned with BaSO4 or quinoline

– Keeps aldehyde from further reducing to alcohol

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• Derivatives of LiAlH4 can also be used

• Can also use DIBAH

3721.9 Reduction of Carboxylic Acid Derivatives

Problems

• Draw the products for the following rxns:

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Reactions of Esters with Grignard Reagents

• Tertiary alcohol produced• Two substituents are identical

4021.10 Reactions of Carboxylic Acid Derivatives with Organometallic Reagents

Reactions of Acid Chlorides Grignard Reagents

4121.10 Reactions of Carboxylic Acid Derivatives with Organometallic Reagents

Reactions of Acid Chlorides with R2CuLi

• R2CuLi = Gilman reagent

• Dialkylcuprates are less reactive than Grignard reagents• Allow rxn to stop at ketone• Only works with acid chlorides, not with other carboxylic acid

derivatives

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Problems

• Draw the product for the following rxns:

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