14.24:
Amides to Amines: LiAlH4 Reduction
The reduction of amides to amines in the presence of strong reducing agents like lithium aluminum hydride proceeds through a nucleophilic acyl substitution.
Primary, secondary, and tertiary amides on reduction, yield primary, secondary, and tertiary amines, respectively.
The reaction requires two equivalents of the reducing agent, which acts as a source of hydride ions.
The mechanism begins with a nucleophilic attack by the hydride ion, a Lewis base, at the amide carbonyl carbon, forming a tetrahedral intermediate.
Next, the carbonyl oxygen reacts with aluminum hydride, now a Lewis acid, to form an oxygen–aluminum bond.
Further rearrangement of electron pairs results in the expulsion of an aluminate anion as a leaving group, giving an iminium ion intermediate.
Lastly, the iminium ion is attacked by a second hydride ion, forming amine as the final product. The net effect is converting the amide carbonyl group into a methylene group.
Notably, lactams also undergo reduction with lithium aluminum hydride to form cyclic amines.
14.24:
Amides to Amines: LiAlH4 Reduction
Amide reduction with strong reducing agents like lithium aluminum hydride proceeds through a nucleophilic acyl substitution to form amines. Primary, secondary, and tertiary amides yield primary, secondary, and tertiary amines, respectively.
Amide reduction requires two equivalents of the reducing agent, acting as a source of hydride ions. As shown in the figure, the reaction is initiated with a nucleophilic attack by the hydride ion at the carbonyl carbon to form a tetrahedral intermediate. Subsequently, the carbonyl oxygen atom reacts with aluminum hydride to form an oxygen–aluminum bond. This is followed by the rearrangement of electron pairs with the expulsion of the aluminate anion as a leaving group to give an iminium ion intermediate. A second nucleophilic attack on the iminium ion by the hydride yields amine as a final product.
Cyclic amides often called lactams, are also reduced with lithium aluminum hydride to give cyclic amines.