The Schotten–Baumann reaction is an acylation reaction in which an amine or a phenol reacts with an acyl chloride under basic, usually aqueous, conditions. Amines react to form amides, whereas alcohols react to form esters. ^[1–4]

The reaction is named after Carl Schotten and Eugen Baumann, who studied benzoylation reactions in the late nineteenth century.

General Reaction

The Schotten–Baumann reaction commonly involves an acyl chloride as the acylating agent. The reaction is carried out in the presence of a base, commonly aqueous NaOH, which neutralizes the acid produced during the acylation. ^[1]

Reaction with Amines

A primary amine reacts with an acyl chloride to form a secondary amide:

R¹COCl + R²NH₂ –[aq. NaOH]→ R¹CONHR²

A secondary amine forms a tertiary amide:

R¹COCl + R²R³NH –[aq. NaOH]→ R¹CONR²R³

Reaction with Phenol

Under Schotten–Baumann conditions, a phenol can react with an acyl chloride to form an ester:

R¹COCl + ArOH –[aq. NaOH]→ R¹COOAr

Examples

The following examples show the formation of amides and an ester under Schotten–Baumann conditions. ^[2]

Mechanism

The Schotten–Baumann reaction proceeds through nucleophilic acyl substitution. The following mechanism shows the reaction of an acyl chloride with an amine to form an amide. ^[1]

Step 1: Nucleophilic Attack

The carbonyl carbon of the acyl chloride is electrophilic–the lone pair on the nitrogen atom of the amine attacks this carbon. At the same time, the π electrons of the C=O bond move onto the oxygen atom, forming a tetrahedral intermediate.

Step 2: Collapse and Chloride Departure

The negatively charged oxygen reforms the carbonyl group. As the C=O bond reforms, the C–Cl bond breaks and a chloride ion ( Cl^–) leaves. This produces a positively charged amide intermediate because the nitrogen is still protonated.

Step 3: Deprotonation

The base removes a proton from nitrogen, producing the neutral amide.

Applications

The Schotten–Baumann reaction is widely used in organic synthesis, particularly for preparing amides and esters from acid chlorides. ^[4]

One important industrial application is in the manufacture of flutamide, a pharmaceutical drug. During its synthesis, a Schotten–Baumann-type acylation is used to form an amide bond.

The same type of acylation has also been used in peptide synthesis. In the Fischer peptide synthesis, an acid chloride derivative reacts with an amino acid derivative to form an amide bond. Repeating this type of reaction allows the peptide chain to be extended.