Nucleophilic acyl substitution — Schotten-Baumann
Amide synthesis from an acid chloride and amine
How the Amide synthesis from an acid chloride and amine 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: Benzoyl chloride, methylamine, aqueous NaOH. Conditions: CH₂Cl₂ / H₂O (biphasic), 0–25 °C. Bonds formed: C–N (amide); bonds broken: C–Cl; N–H. Stereochemistry: No stereocentre; planar amide. Rate and selectivity: Very fast; base neutralises HCl so the amine is not lost as its salt.
At a glance
Step 1: Amine attacks the acyl carbon
An amine's nitrogen lone pair attacks the acid chloride's electrophilic carbonyl carbon — the nitrogen analog of the acid-chloride-plus-alcohol ester synthesis covered just before this, and just as fast.
Step 2: Chloride leaves
The tetrahedral intermediate collapses, expelling chloride and reforming the C=O — the same addition-elimination mechanism used throughout nucleophilic acyl substitution chemistry.
Step 3: Base removes N–H⁺
Because the amide nitrogen ends up protonated (as an ammonium salt) after this step, a base — often aqueous NaOH, run biphasically in what's specifically called the Schotten-Baumann conditions — is included to deprotonate it and neutralize the HCl byproduct, driving the reaction to completion and preventing the amine from simply being consumed as its hydrochloride salt.
Abbreviations and terms
- DCM
- Dichloromethane. Common non-polar-ish solvent for reactions that need no nucleophilic or protic solvent.
- NaOH
- Sodium hydroxide. Strong aqueous base and nucleophile.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- HCl
- Hydrochloric acid / hydrogen chloride. Strong acid; chloride is the nucleophile in additions/substitutions.
How it compares with related reactions
| Amide synthesis from an acid chloride and amine | Acid-catalyzed amide hydrolysis | Base hydrolysis (saponification) of an ester | |
|---|---|---|---|
| Reagents | Benzoyl chloride, methylamine, aqueous NaOH | Amide, H₃O⁺ (HCl or H₂SO₄), H₂O | NaOH (aq), methyl acetate |
| Conditions | CH₂Cl₂ / H₂O (biphasic), 0–25 °C | 6 M acid, reflux (hours) | H₂O/MeOH, reflux |
| Stereochemistry | No stereocentre; planar amide | No stereocentre created; α-stereocentres retained | Retention at the acyl carbon (planar); no stereo here |
| Rate / selectivity | Very fast; base neutralises HCl so the amine is not lost as its salt | Water attack / C–N cleavage rate-limiting; far slower than ester hydrolysis | 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 Amide synthesis from an acid chloride and amine?
Benzoyl chloride, methylamine, aqueous NaOH. Conditions: CH₂Cl₂ / H₂O (biphasic), 0–25 °C.
Which bonds are formed and which are broken?
Formed: C–N (amide). Broken: C–Cl; N–H.
What is the stereochemical outcome?
No stereocentre; planar amide
What controls the rate or the selectivity?
Very fast; base neutralises HCl so the amine is not lost as its salt
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