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Nitrogen-extrusion rearrangement family

Hofmann rearrangement: amide → amine

How the Hofmann rearrangement works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.

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In short. A 3-step mechanism. Typical reagents: Br₂, NaOH (or NaOBr), H₂O. Conditions: 0 °C then 50–70 °C. Bonds formed: C–N (R–N); N=C=O; N–H; bonds broken: N–H; C–R (migrates); N–Br. Stereochemistry: Migrating group retains configuration. Rate and selectivity: Concerted 1,2-shift is rate-determining; amine has one carbon fewer.

At a glance

ReagentsBr₂, NaOH (or NaOBr), H₂O
Solvent / conditions0 °C then 50–70 °C
Bonds formedC–N (R–N); N=C=O; N–H
Bonds brokenN–H; C–R (migrates); N–Br
StereochemistryMigrating group retains configuration
Rate / selectivityConcerted 1,2-shift is rate-determining; amine has one carbon fewer

Step 1: N-bromination and deprotonation

Br₂, NaOH(NaOBr)H₂ORONH₂RONBr1 · N-BROMINATION AND DEPROTONATIONprimary amideSUBSTRATEN-bromoamide anionINTERMEDIATEFirst N–Br formation, then a second deprotonation of the remaining N–H.

Br₂/NaOH brominate the amide nitrogen; base then deprotonates the remaining N–H, forming an anionic N-bromoamide.

Step 2: Concerted 1,2-shift

−Br⁻+RONBrRNOBr2 · CONCERTED 1,2-SHIFTN-bromoamide anionINTERMEDIATEisocyanateINTERMEDIATEbromideBr⁻LEAVING GROUPR shiftsR migrates with retention as Br⁻ departs: no free nitrene.

Loss of bromide triggers a concerted 1,2-shift: the R group migrates from carbon directly to nitrogen as bromide leaves, forming an isocyanate — the same migration logic as Curtius and Beckmann.

Step 3: Hydrolysis and decarboxylation

+−CO₂+RNOOHRNHOOHRNHOOHRNH₂OO3 · HYDROLYSIS AND DECARBOXYLATIONisocyanateELECTROPHILEhydroxideHO⁻NUCLEOPHILEcarbamic acidINTERMEDIATEcarbamic acidINTERMEDIATEprimary aminePRODUCTcarbon dioxideCO₂BYPRODUCTProduct amine is one carbon shorter than the starting amide.

Hydroxide adds to the isocyanate and the resulting carbamic acid loses CO₂ spontaneously, giving a primary amine with one fewer carbon than the starting amide.

Abbreviations and terms

R
R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
NaOH
Sodium hydroxide. Strong aqueous base and nucleophile.
H2
Hydrogen gas. Reductant for catalytic hydrogenation.
Hofmann
Hofmann product/rule. Elimination giving the less substituted alkene (bulky base or leaving group).

How it compares with related reactions

Hofmann rearrangementLossen rearrangementSchmidt reaction
ReagentsBr₂, NaOH (or NaOBr), H₂OHydroxamic acid, activator (Ac₂O, TsCl), baseHN₃ (or NaN₃), H₂SO₄ or polyphosphoric acid
Conditions0 °C then 50–70 °CMild base, 25–100 °C, then H₂OStrong acid, 25–80 °C; HN₃ is toxic and explosive
StereochemistryMigrating group retains configurationMigrating group retains configurationMigrating group retains configuration
Rate / selectivityConcerted 1,2-shift is rate-determining; amine has one carbon fewerRate set by leaving-group ability of the O-acyl/O-sulfonyl groupN₂ loss and R-shift are concerted and irreversible

Test yourself

Try to answer each question before opening it.

Which reagents and conditions are typical for the Hofmann rearrangement?

Br₂, NaOH (or NaOBr), H₂O. Conditions: 0 °C then 50–70 °C.

Which bonds are formed and which are broken?

Formed: C–N (R–N); N=C=O; N–H. Broken: N–H; C–R (migrates); N–Br.

What is the stereochemical outcome?

Migrating group retains configuration

What controls the rate or the selectivity?

Concerted 1,2-shift is rate-determining; amine has one carbon fewer

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