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Amides are unique among carboxylic acid derivatives, resisting hydrolysis due to resonance stabilization. Their reactions, from acid and base-catalyzed hydrolysis to reduction with LiAlH4, showcase their distinct reactivity compared to esters, anhydrides, and acid chlorides.

Amide preparation often involves nucleophilic acyl substitution between amines and acid chlorides. The amide bond's partial double bond character leads to interesting structural features and rearrangements, like the Hofmann and Beckmann rearrangements, crucial in organic synthesis.

Amide Reactions

Hydrolysis of amides

  • Amides are more resistant to hydrolysis compared to other carboxylic acid derivatives (esters, anhydrides, acid chlorides) due to resonance stabilization
    • Resonance structures involve donation of the nitrogen lone pair into the carbonyl, increasing the C-N bond order and decreasing the carbonyl electrophilicity
  • Acid-catalyzed hydrolysis mechanism:
    1. Protonation of the carbonyl oxygen activates the amide
    2. Water attacks the protonated carbonyl forming a tetrahedral intermediate
    3. Proton transfer from the oxonium ion to the nitrogen followed by C-N bond cleavage yields a carboxylic acid and an ammonium ion
  • Base-promoted hydrolysis mechanism:
    1. Hydroxide attacks the carbonyl forming a tetrahedral intermediate
    2. Proton transfer from the nitrogen to the alkoxide followed by C-N bond cleavage yields a carboxylate and an amine
  • Reactivity order of carboxylic acid derivatives towards nucleophilic acyl substitution: acid chlorides > anhydrides > esters > amides

Reduction of amides with LiAlH4

  • Amide reduction with LiAlH4 yields primary amines while reduction of other carboxylic acid derivatives (esters, acid chlorides, anhydrides) yields primary alcohols
  • Mechanism:
    1. Hydride ($H^-$) from LiAlH4 attacks the carbonyl carbon forming a tetrahedral intermediate
    2. Proton transfer from the nitrogen to the alkoxide yields an aldehyde intermediate and an aluminum-coordinated amide
    3. The aldehyde is further reduced by LiAlH4 to yield a primary amine
  • Workup involves quenching excess LiAlH4 with water, adding aqueous NaOH to convert aluminum salts to a white gelatinous solid, and extracting the primary amine product with ether or dichloromethane

Methods for amide preparation

  • Nucleophilic acyl substitution reaction between an amine and an acid chloride
    • Amine acts as a nucleophile attacking the electrophilic carbonyl carbon of the acid chloride with chloride as the leaving group
    • Reaction is rapid and exothermic, often performed at 0°C or below with a non-nucleophilic base (triethylamine) to neutralize the HCl byproduct
  • Mechanism:
    1. Nucleophilic addition of the amine to the carbonyl carbon forms a tetrahedral intermediate
    2. Proton transfer from the ammonium ion to the chloride yields the amide product and HCl
  • Primary and secondary amines readily form amides while tertiary amines cannot due to the absence of an N-H bond
  • Acid chlorides are highly reactive due to the excellent leaving group ability of chloride, but anhydrides and esters can also be used to prepare amides with lower reactivity
  • Gabriel synthesis is a method for preparing primary amines via an amide intermediate

Amide structural features and rearrangements

  • Amide bond (peptide bond when part of a protein) exhibits partial double bond character due to resonance
  • Amide bond rotation is restricted due to this partial double bond character, leading to cis/trans isomerism
  • Hofmann rearrangement: conversion of primary amides to primary amines with one fewer carbon
  • Beckmann rearrangement: conversion of oximes to amides, often used in the synthesis of lactams