Chapter 39 — Case Study 1: The Claisen Rearrangement — Pericyclic Pyrotechnics in Synthesis
"Heat an allyl vinyl ether and watch it rearrange. No reagents, no catalyst, no waste — just thermal energy and orbital symmetry. The Claisen rearrangement is one of the most elegant reactions in organic chemistry." — paraphrase of an organic synthesis review
The Claisen rearrangement is a [3,3]-sigmatropic rearrangement that converts an allyl vinyl ether to a γ,δ-unsaturated carbonyl via a concerted cyclic transition state. It was first described by Ludwig Claisen in 1912 and has been used in synthesis ever since. This case study explores the Claisen rearrangement in depth: mechanism, stereochemistry, variants, and applications.
The reaction
Generic Claisen rearrangement: $$\text{R}_1\text{-CH=CH-O-CH}_2\text{-CR}_2\text{=CH}_2 \xrightarrow{\Delta} \text{R}_1\text{-CH(=O)-CH}_2\text{-CH(R}_2\text{)-CH=CH}_2$$
(Or in a more visual way: allyl vinyl ether → γ,δ-unsaturated aldehyde.)
The bonds that break and form: - Old C-O σ bond breaks (between the vinyl-O and the allyl-CH₂). - New C-C σ bond forms (between the vinyl-CH and the allyl-CH₂). - Old C=C of vinyl ether becomes a new C-C single bond. - Old C=C of allyl group becomes a new C=C in the product. - Old C-C between vinyl O and α-vinyl C becomes a new C=O (with the old O migrating).
Six electrons total in the TS (3 σ + 3 π). Suprafacial-suprafacial. Thermally allowed via the 4n+2 rule.
The chair-like TS
The Claisen rearrangement goes through a chair-like TS: the 6 atoms involved (1, 2, 3, 4, 5, 6 in the [3,3] notation) are arranged in a 6-membered ring. The TS has chair conformation; substituents prefer equatorial positions.
This chair-like preference is critical for stereocontrol: - (E)-allyl group → preferred chair TS gives one diastereomer. - (Z)-allyl group → different chair gives opposite diastereomer. - Substituents on the vinyl ether end → also influence stereochemistry.
The Claisen is stereospecific: every starting geometry gives a predictable product geometry via the chair TS.
Variants
The original Claisen was just allyl vinyl ether → γ,δ-unsaturated aldehyde. Variants extend the chemistry:
Aliphatic Claisen
The classic version: heat the allyl vinyl ether without solvent or with mild solvent. ~170-200 °C is typical for pure compound. With Lewis acid catalysts (BF₃, AlCl₃), runs at lower temperature.
Ireland-Claisen (1972)
Robert Ireland extended the Claisen to ester enolates: - Form an ester enolate (e.g., with LDA + TMSCl to give a silyl ketene acetal). - The silyl ketene acetal is structurally similar to allyl vinyl ether. - [3,3] thermal rearrangement gives a γ,δ-unsaturated carboxylic acid (after hydrolysis of the silyl group).
The Ireland-Claisen is stereo-controlled: - Z-enolate → syn-product. - E-enolate → anti-product. This is exactly the same logic as the chair-TS preference of the Cope rearrangement (Section 39.4).
The Ireland-Claisen is one of the most-used pericyclic reactions in modern asymmetric synthesis.
Eschenmoser-Claisen (1964)
Albert Eschenmoser extended the Claisen to amides: an allyl alcohol + an amide-derived ortho-ester gives a γ,δ-unsaturated amide.
Johnson-Claisen (1970)
W. S. Johnson extended to ortho-esters: allyl alcohol + (CH₃CO)C(OEt)₃ → γ,δ-unsaturated ester. Convenient because no enolate generation is required.
Hetero-Claisen variants
Some Claisen-like reactions involve heteroatoms in the migrating chain: - Aza-Claisen: a [3,3] involving N (e.g., allyl iminium → β-amino enamine). - Thio-Claisen: with S.
[2,3]-Wittig rearrangement
A related (but not identical) rearrangement: allyl ether α-carbanion → homoallyl alcohol with C-C bond formed. Different electron count ([2,3] not [3,3]).
Applications in total synthesis
The Claisen rearrangement appears in dozens of total syntheses. Some notable examples:
Squalene total synthesis
Squalene (the C₃₀ precursor to cholesterol) is built from isoprene units. Some routes use Claisen to install C-C bonds with stereocontrol.
Vitamin E synthesis
α-Tocopherol (vitamin E) syntheses include Claisen rearrangements at strategic ring-junction or chain-extension positions.
Many terpenes
Mono-, sesqui-, di-, and triterpene syntheses use Claisen for stereo-controlled C-C bond formation. The chair-TS preference makes the stereochemistry predictable.
Steroid synthesis
In some steroid syntheses, a Claisen rearrangement closes a ring or installs a ring-junction stereocenter.
Why the Claisen is "elegant"
Several features make the Claisen rearrangement aesthetically pleasing in synthesis:
- No reagents needed: just heat. Atom-economical.
- No byproducts: the rearrangement is unimolecular; everything ends up in the product.
- Stereospecific: the chair TS gives predictable stereochemistry.
- Versatile: many variants (Ireland, Eschenmoser, Johnson) extend its scope.
- Concerted: no intermediates; clean kinetics.
- Well-understood mechanism: Woodward-Hoffmann predicts the geometry and selectivity.
These features make the Claisen a "go-to" reaction when the target retrosynthesis reveals a [3,3]-like disconnection.
Asymmetric Claisen
Modern variants of the Claisen are asymmetric: - Chiral catalyst: a chiral Lewis acid (e.g., chiral boron, lanthanide, or scandium catalyst) accelerates the rearrangement and directs the stereochemistry. - Chiral substrate: a chiral starting material gives a chiral product via stereospecific TS. - Chiral auxiliary: an auxiliary on the substrate guides the chair TS.
Asymmetric Claisen rearrangements give enantiomerically enriched γ,δ-unsaturated carbonyls in high ee. Used in some natural product syntheses.
Connection to biosynthesis
Some natural enzymatic reactions use Claisen-like chemistry: - Chorismate mutase: converts chorismate to prephenate via a [3,3] sigmatropic rearrangement. - Various terpene biosynthesis steps: cation-driven [3,3] rearrangements.
The chemistry of Chapter 39 (pericyclic) is the basis of some of biology's elegant biosynthesis.
The connection to the Cope rearrangement
The Claisen rearrangement is the oxa version of the Cope rearrangement: - Cope: 1,5-hexadiene → 1,5-hexadiene (degenerate). - Claisen: allyl vinyl ether (1-oxa-1,5-hexadiene) → γ,δ-unsaturated aldehyde (with the oxygen migrating to give a C=O).
Both are [3,3] sigmatropic rearrangements with a chair-like TS. The Claisen is preferred for synthesis because the product has a useful C=O group (vs. Cope's degenerate rearrangement, where reactant and product are usually the same).
Take-home
- The Claisen rearrangement is a [3,3]-sigmatropic rearrangement of an allyl vinyl ether to a γ,δ-unsaturated carbonyl.
- Concerted, cyclic chair-like TS, 6 electrons (4n+2) — thermally allowed.
- Stereospecific: chair TS gives predictable stereochemistry.
- Variants: Ireland (ester enolate), Eschenmoser (amide), Johnson (ortho-ester), aza-Claisen, thio-Claisen.
- Used in many natural product syntheses for stereocontrolled C-C bond formation.
- "Elegant": no reagents, no byproducts, stereospecific, versatile, well-understood.
- Asymmetric variants give enantiomerically enriched products.
- Connected to biology: chorismate mutase uses the same chemistry.
- Mastery of Chapter 39 + Claisen is a major step toward sophisticated synthesis design.