Nucleophilic acyl substitution — harder case
Acid-catalyzed amide hydrolysis
How the Acid-catalyzed amide hydrolysis works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Amide, H₃O⁺ (HCl or H₂SO₄), H₂O. Conditions: 6 M acid, reflux (hours). Bonds formed: C–O (acid); N–H (ammonium); bonds broken: C–N amide; π C=O (temporarily). Stereochemistry: No stereocentre created; α-stereocentres retained. Rate and selectivity: Water attack / C–N cleavage rate-limiting; far slower than ester hydrolysis.
At a glance
Step 1: Protonation of the carbonyl O
Acid protonates the amide's carbonyl oxygen, activating the carbonyl carbon toward attack — amides are far less electrophilic than esters, since nitrogen donates electron density into the carbonyl more strongly than oxygen does.
Step 2: Water adds; N is protonated
Water attacks the activated carbonyl carbon, forming a tetrahedral intermediate; proton transfers convert the amine into a much better leaving group (a protonated amine, R–NH₃⁺-like) before it departs.
Step 3: Expulsion of the ammonium
Collapse of the intermediate expels the ammonium leaving group and reforms the C=O, giving a carboxylic acid — this step requires much harsher conditions than ester hydrolysis specifically because amide nitrogen is such a poor leaving group.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- M
- Metal. A generic metal centre.
- Me
- Methyl. –CH₃.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- H2SO4
- Sulfuric acid. Strong acid and dehydrating agent.
- HCl
- Hydrochloric acid / hydrogen chloride. Strong acid; chloride is the nucleophile in additions/substitutions.
How it compares with related reactions
| Acid-catalyzed amide hydrolysis | Amide synthesis from an acid chloride and amine | Base hydrolysis (saponification) of an ester | |
|---|---|---|---|
| Reagents | Amide, H₃O⁺ (HCl or H₂SO₄), H₂O | Benzoyl chloride, methylamine, aqueous NaOH | NaOH (aq), methyl acetate |
| Conditions | 6 M acid, reflux (hours) | CH₂Cl₂ / H₂O (biphasic), 0–25 °C | H₂O/MeOH, reflux |
| Stereochemistry | No stereocentre created; α-stereocentres retained | No stereocentre; planar amide | Retention at the acyl carbon (planar); no stereo here |
| Rate / selectivity | Water attack / C–N cleavage rate-limiting; far slower than ester hydrolysis | Very fast; base neutralises HCl so the amine is not lost as its salt | Rate = k[ester][HO⁻]; irreversible because the acid is deprotonated |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Acid-catalyzed amide hydrolysis?
Amide, H₃O⁺ (HCl or H₂SO₄), H₂O. Conditions: 6 M acid, reflux (hours).
Which bonds are formed and which are broken?
Formed: C–O (acid); N–H (ammonium). Broken: C–N amide; π C=O (temporarily).
What is the stereochemical outcome?
No stereocentre created; α-stereocentres retained
What controls the rate or the selectivity?
Water attack / C–N cleavage rate-limiting; far slower than ester hydrolysis
Study guides that help with this reaction
- Carbonyl chemistry: addition, acyl substitution and enolates
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go
Related mechanisms
- Amide synthesis from an acid chloride and amine
- Base hydrolysis (saponification) of an ester
- Base-catalyzed transesterification
- Ester synthesis from an acid chloride and alcohol
- Fischer esterification
- In-line phosphoryl transfer (SN2 at phosphorus)
- Weinreb amide addition
- Hydride adds to acetaldehyde's carbonyl