These are compounds in which an amino (NH2) group and a carboxyl group are attached to the same carbon atom (alpha-amino acids):

general structure of an amide

Such compounds contain a chiral carbon atom (unless R = H, which is glycine). Proteins can be considered to consist of amino acid residues joined by amide (or peptide) links. These peptide links consist of exactly the same structural units that we find in N‑substituted primary amides.

21.7 peptide links.svg

21.7 peptide types.svg

 

 

Preparation of Amides

  1. Amides are most commonly prepared though the reaction of an acid chloride with ammonia, a 1o amine, or 2o amine.
  2. an amide can be prepared through the reaction of a carboxylic acid and an amine using a coupling agent such as DCC.
  3. Simple amides can be prepared by reacting an acid anhydride with an amine.
  4. Amides can be formed through the direct reaction of a carboxylic acid and an amine.

 

 

Reactions of Amides

Amides are relatively unreactive towards nucleophilic acyl substitutions due to the poor leaving group ability of its nitrogen containing Y group. Despite this, amides can:

  1. react with water under acidic or basic conditions to create a carboxylic acid through nucleophilic acyl substitution.
  2. Reaction of primary amides with thionyl chloride (SOCl2) creates nitriles.
  3. Hydride reduction using LiAlH4 causes the carbonyl oxygen of the amide to eliminate as a leaving group creating the corresponding amine.

 

 

Conversion of Amides to Carboxylic Acids: Hydrolysis

Amides can be hydrolyzed into a carboxylic acid and ammonia or an amine by heating in an acidic or basic aqueous solution. In both cases, acid-base reactions occurring with the products make the overall reaction irreversible.

  1. Under acidic conditions the amine produced by the reaction is protonated to form a non-nucleophilic ammonium compound.
  2. Under basic conditions the carboxylic acid produced by the reaction is deprotonated to a non-electrophilic carboxylate.

 

General Reaction

 

Examples

 

 

Mechanism Under Acidic Conditions

1) Protonation of the carbonyl

Protonation of the amide increases the electrophilicity of the carbonyl carbon allowing water to add causing formation of a tetrahedral oxonium intermediate.

 

 

2) Nucleophilic attack by water

 

 

3) Proton transfer

a proton is transferred to the amide nitrogen giving it a positive charge and increasing its ability to act as a leaving group. Reforming the carbonyl double bond causes the elimination of an amine as a leaving group, creating a protonated carboxylic acid.

 

 

4) Leaving group removal

 

 

5) Deprotonation

The produced amine acts as a base, removing a hydrogen, to form a carboxylic acid and an ammonium compound.

 

 

 

Mechanism Under Basic Conditions

1) Nucleophilic attack by hydroxide

Nucleophilic addition of a hydroxide ion at the carbonyl carbon creating a tetrahedral alkoxide intermediate.

 

2) Leaving group removal

The carbonyl bond is reformed along with the elimination of an amide ion (-NHR) leaving group (note this is a different use of the word amide meaning an amine anion), forming a carboxylic acid.

 

 

3) Deprotonation

The amide ion deprotonates the carboxylic acid to form a carboxylate salt and an amine as products.

 

 

Conversion of 1o Amides to Nitriles

Dehydration

1o Amides can be converted into a nitrile through reaction with thionyl chloride (SOCl2). Sulfurdioxide (SO2) and hydrochloric acid are produced as byproducts.

 

General Reaction

 

clipboard_e65d10255a9a3ef7bce17f280727353af.png

 

 

Mechanism for the Conversion of a 1o Amide to a Nitrile

 

1) Nucleophilic attach on thionyl chloride

The amide acts as a nucleophile and attacks the electrophilic sulfur of thionyl chloride, pushing the pi electrons of the S=O bond onto oxygen.

 

 

2) Leaving group removal

Removal of a chloride anion as a leaving group allows the sulfoxide S=O bond to reform creating a protonated imine chlorosulfite.

 

 

3) Deprotonation

Deprotonation forms an imine chlorosulfite intermediate.

 

 

4) Leaving group removal

A second deprotonation eliminates the chlorosulfite leaving group as sulfur dioxide and a chloride anion and forms the C-N triple bond of the nitrile product.

 

 

Conversion of Amides to 1o, 2o or 3o Amines:

Amides are reduced to amines by treatment with LiAlH4, and this one of the most general methods for preparing of amines (1º, 2º & 3º).

 

General Reaction

 

 

 

Predicting the Products of a Hydride Reduction

During this reaction, there are two major changes in bonding:

1) The C=O carbonyl is removed from the starting material.

2) Two hydride nucleophiles are added to what was the carbonyl carbon of the amide.

 

 

 

 

Example 1.

 

 

Alkyl groups attached to the nitrogen do not affect the reaction.

 

 

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