Rearrangement — N-oxide activation
Boekelheide rearrangement
How the Boekelheide rearrangement 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: 2-Methylpyridine N-oxide, Ac₂O (or TFAA); then aqueous base. Conditions: Ac₂O, reflux (TFAA works at 25 °C). Bonds formed: C–O (CH₂–OAc); N–C=C (aromatic ring restored); bonds broken: N–O; side-chain C–H. Stereochemistry: None (achiral product). Rate and selectivity: N-acylation fast; [3,3] shift rate-limiting.
At a glance
Step 1: Acylation turns N–O into a leaving group
A heteroaromatic N-oxide (like a 2-alkylpyridine N-oxide) reacts with an activating anhydride (commonly acetic anhydride), converting the N-oxide oxygen into a good leaving group tethered right next to the ring nitrogen.
Step 2: Deprotonation, then [3,3] shift
The benzylic-type C–H adjacent to the ring (on the alkyl substituent ortho to nitrogen) is deprotonated, and the resulting carbanion-like system undergoes an intramolecular [3,3]-sigmatropic-type shift, delivering the acyloxy group directly onto that benzylic carbon as the N–O bond breaks.
Step 3: Hydrolysis gives the alcohol
Hydrolysis of the resulting ester reveals a benzylic alcohol — net effect: an N-oxide oxygen has been transposed from nitrogen onto a side-chain carbon, the same conceptual outcome as an Overman rearrangement, just starting from a heteroaromatic N-oxide instead of an imidate.
Abbreviations and terms
- OAc
- Acetoxy. –OC(=O)CH₃, an acetate group.
- Ac2O
- Acetic anhydride. Acetylating agent.
How it compares with related reactions
| Boekelheide rearrangement | Meisenheimer rearrangement | Bamberger rearrangement | |
|---|---|---|---|
| Reagents | 2-Methylpyridine N-oxide, Ac₂O (or TFAA); then aqueous base | Allylic tertiary amine N-oxide | N-Phenylhydroxylamine, dilute H₂SO₄ (aq) |
| Conditions | Ac₂O, reflux (TFAA works at 25 °C) | Heat, 25–100 °C (neutral) | H₂O, 25–60 °C |
| Stereochemistry | None (achiral product) | Suprafacial [2,3]; chirality transfer from N-oxide to carbon | None; para-selective |
| Rate / selectivity | N-acylation fast; [3,3] shift rate-limiting | Concerted, 5-membered envelope TS; unimolecular | Loss of water to give the nitrenium ion is rate-limiting |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Boekelheide rearrangement?
2-Methylpyridine N-oxide, Ac₂O (or TFAA); then aqueous base. Conditions: Ac₂O, reflux (TFAA works at 25 °C).
Which bonds are formed and which are broken?
Formed: C–O (CH₂–OAc); N–C=C (aromatic ring restored). Broken: N–O; side-chain C–H.
What is the stereochemical outcome?
None (achiral product)
What controls the rate or the selectivity?
N-acylation fast; [3,3] shift rate-limiting
Study guides that help with this reaction
- Pericyclic reactions explained: cycloadditions, electrocyclisations and sigmatropic shifts
- Stereochemistry in mechanisms: inversion, retention, syn and anti