21.7 Chemistry of Amides

Amide Reactions

Hydrolysis of amides

Amides are the most resistant carboxylic acid derivatives toward hydrolysis. This stability comes from resonance stabilization: the nitrogen lone pair donates into the carbonyl, which increases C–N bond order and decreases the electrophilicity of the carbonyl carbon. That means nucleophiles have a harder time attacking.

The full reactivity order for nucleophilic acyl substitution is: acid chlorides > anhydrides > esters > amides.

Acid-catalyzed hydrolysis mechanism:

1. Protonation of the carbonyl oxygen activates the amide toward nucleophilic attack.
2. Water attacks the protonated carbonyl carbon, forming a tetrahedral intermediate.
3. Proton transfers occur within the tetrahedral intermediate. The nitrogen is protonated, converting it into a good leaving group.
4. C–N bond cleavage releases the amine as an ammonium ion ($\text{RNH}_3^+$), and the product is a carboxylic acid.

Because the amine leaves as its protonated ammonium form, it's trapped and doesn't act as a nucleophile to reverse the reaction. This helps drive the equilibrium forward.

Base-promoted hydrolysis mechanism:

1. Hydroxide ion attacks the carbonyl carbon, forming a tetrahedral intermediate.
2. C–N bond cleavage expels the amine ($\text{RNH}_2$) as the leaving group.
3. The products are a carboxylate ion ($\text{RCOO}^-$) and a free amine.

This reaction is irreversible because the carboxylate product is resonance-stabilized and thermodynamically stable. Note that harsh conditions (strong acid or base, heat, long reaction times) are typically required for amide hydrolysis precisely because of that resonance stabilization.

Reduction of amides with $\text{LiAlH}_4$

This reaction is distinctive: reducing an amide with $\text{LiAlH}_4$ gives an amine, not an alcohol. Compare that to esters, acid chlorides, and anhydrides, which all reduce to primary alcohols. The difference is that in amide reduction, the C–O bond breaks rather than the C–N bond.

Mechanism:

1. Hydride ($H^-$) from $\text{LiAlH}_4$ attacks the carbonyl carbon, forming a tetrahedral alkoxide intermediate.
2. The oxygen leaves (assisted by aluminum coordination), generating an iminium ion ($\text{R}_2\text{C=NR'}$).
3. A second hydride from $\text{LiAlH}_4$ reduces the iminium ion to give the amine.

The key point is that the carbonyl oxygen is lost and the nitrogen is retained in the product. A primary amide ($\text{RCONH}_2$) gives a primary amine with one extra carbon still attached, a secondary amide gives a secondary amine, and so on.

Workup: Quench excess $\text{LiAlH}_4$ carefully with water, then add aqueous NaOH to convert aluminum salts into a filterable white solid (aluminum hydroxide). Extract the amine product with an organic solvent like diethyl ether or dichloromethane.

Methods for amide preparation

The most common route to amides is nucleophilic acyl substitution between an amine and an acid chloride. Acid chlorides are ideal because chloride is an excellent leaving group, making the reaction fast and exothermic.

Mechanism:

1. The amine nitrogen attacks the electrophilic carbonyl carbon of the acid chloride, forming a tetrahedral intermediate with chloride still attached.
2. Chloride departs as the leaving group, and a proton is lost from nitrogen, yielding the amide product and HCl.

A few practical details to keep in mind:

• The reaction is often run at 0°C or below to control the exotherm.
• A non-nucleophilic base like triethylamine ($\text{Et}_3\text{N}$) is added to scavenge the HCl byproduct. Without it, HCl would protonate unreacted amine and waste half your starting material.
• Primary and secondary amines both form amides readily. Tertiary amines cannot form amides because they lack an N–H bond needed in the final product.
• Anhydrides and esters can also react with amines to give amides, but they're less reactive than acid chlorides.

The Gabriel synthesis is a related method that uses phthalimide (a cyclic imide) as a protected nitrogen nucleophile to prepare primary amines through an amide intermediate.

Amide structural features and rearrangements

The amide bond has partial double-bond character because of nitrogen-to-carbonyl resonance. You can draw a resonance structure where nitrogen shares its lone pair with the carbonyl carbon, giving the C–N bond roughly 40% double-bond character. In proteins, this same linkage is called a peptide bond.

Because of this partial double bond, rotation around the C–N bond is restricted. The barrier to rotation is about 75–85 kJ/mol, which is high enough that amides exist as distinct cis (Z) and trans (E) rotamers that interconvert slowly on the NMR timescale. The trans rotamer is usually favored due to fewer steric interactions.

Hofmann rearrangement: Treats a primary amide ($\text{RCONH}_2$) with bromine and base ($\text{Br}_2$/NaOH) to produce a primary amine with one fewer carbon. The carbonyl carbon is lost as $\text{CO}_2$. The mechanism proceeds through an isocyanate intermediate ($\text{R{-}N{=}C{=}O}$) and involves a 1,2-shift of the R group from carbon to nitrogen.

Beckmann rearrangement: Converts an oxime ($\text{R}_2\text{C=NOH}$) to an amide under acidic conditions. The group anti to the hydroxyl migrates to nitrogen. This reaction is especially useful for making lactams (cyclic amides). A classic industrial example is the conversion of cyclohexanone oxime to caprolactam, the precursor to nylon-6.