Hofmann rearrangement reaction

In 1881, the German chemist August Wilhelm Hofmann discovered that by treating acetamide with one equivalent of bromine and either sodium or potassium hydroxide, N-bromoacetamide was formed. Further deprotonation and heating under anhydrous conditions afforded methyl isocyanate. However, when an excess of base was used under aqueous conditions, the resulting product was methylamine. Since this discovery, the conversion of primary carboxamides to the corresponding one-carbon-shorter amines has become known as the Hofmann rearrangement.

Several modifications have been introduced since the original discovery. In the case of hydrophobic amines, the use of methanolic sodium hypobromite, made from reacting bromine with sodium methoxide in methanol, produces the corresponding methylurethanes in high yields. Where the substrate is either acid- or base-sensitive, the use of a neutral electrochemically-induced Hofmann degradation was developed. To broaden the scope of the reaction for base-sensitive substrates, an oxidative rearrangement can be induced using hypervalent iodine reagents such as (diacetoxyiodo)benzene (PIDA).

Pharmaceutical application are among the many industrial uses for the Hofmann rearrangement. The reaction is used, for example, in the manufacture of diuretics such as furosemide.

In the total synthesis of the antifungal agent (+)-preussin, a modified version of the Hofmann rearrangement was used as one of the key steps in the final stages of the synthetic route.

Mechanism of the Hofmann rearrangement reaction

Review available Thermo Scientific products for the Hofmann rearrangement reaction:

Catalog # Name Size Price (USD) Qty
B24531.22 Iodosobenzene diacetate, 98+% Each
173.65

Online Exclusive

193.00
Save 19.35 (10%)
B21872.0F Sodium methoxide, ca 30% w/w in methanol Each
108.65

Online Exclusive

121.00
Save 12.35 (10%)
A18395.36 Sodium hydroxide, flake, 98% Each
30.65

Special offer

Online exclusive

Ends: 26-Sep-2025

37.10
Save 6.45 (17%)
A16199.0C Potassium hydroxide, flake, 85% Each
260.65

Special offer

Online exclusive

Ends: 26-Sep-2025

321.00
Save 60.35 (19%)
L05673.22 Sodium methoxide, 98% Each
37.65

Online Exclusive

41.40
Save 3.75 (9%)
B24531.14 Iodosobenzene diacetate, 98+% Each
67.80
B24531.36 Iodosobenzene diacetate, 98+% Each
558.65

Special offer

Online exclusive

Ends: 26-Sep-2025

690.00
Save 131.35 (19%)
A16199.0E Potassium hydroxide, flake, 85% Each
104.00
A18854.0E Potassium hydroxide, pellets, 85% Each
96.65

Online Exclusive

107.00
Save 10.35 (10%)
A18395.0C Sodium hydroxide, flake, 98% Each
333.00
A16199.36 Potassium hydroxide, flake, 85% Each
34.10
A18395.0E Sodium hydroxide, flake, 98% Each
97.65

Online Exclusive

108.00
Save 10.35 (10%)
L05673.36 Sodium methoxide, 98% Each
61.50
A18854.36 Potassium hydroxide, pellets, 85% Each
32.65

Online Exclusive

36.00
Save 3.35 (9%)
L05673.0P Sodium methoxide, 98% Each
126.65

Special offer

Online exclusive

Ends: 26-Sep-2025

156.00
Save 29.35 (19%)
B21872.AP Sodium methoxide, ca 30% w/w in methanol Each
47.90
A16037.36 Sodium hydroxide, pellets, 98% Each
34.65

Online Exclusive

37.80
Save 3.15 (8%)

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