The Claisen Rearrangement

What the Claisen rearrangement does

Take an allyl vinyl ether — a molecule where an oxygen sits between a vinyl group (O–CH=CH₂) and an allyl group (O–CH₂–CH=CH₂). Heat it. In one smooth, concerted motion the molecule turns itself inside out: the C–O bond that held the allyl group snaps, a brand-new C–C bond forms at the far end of the allyl chain, and the two double bonds slide over by one position. The oxygen, which was a simple ether, becomes a carbonyl. The parent case gives 4-pentenal:

    CH₂=CH-O-CH₂-CH=CH₂   ──Δ (≈200 °C)──→   O=CH-CH₂-CH₂-CH=CH₂
      allyl vinyl ether                          4-pentenal
                                            (γ,δ-unsaturated aldehyde)

Nothing adds to the molecule and nothing leaves — every atom of the ether reappears in the product. This is an intramolecular isomerization. What makes it special is the machinery: no carbocation, no radical, no metal. Six electrons rotate around a ring of six atoms in a single elementary step. That places the Claisen firmly in the family of pericyclic reactions, alongside the Diels-Alder cycloaddition and the Cope rearrangement.

The name of the game is bookkeeping. Walk out from the σ bond that breaks — the allylic C–O bond — and number three atoms along each branch of the framework: 1-2-3 down the allyl carbons (atom 1 is the C attached to oxygen), and 1′-2′-3′ down the other branch, where atom 1′ is the oxygen itself and 2′-3′ are the two vinyl carbons. So the six atoms of the reacting array are five carbons and one oxygen. The old σ bond joins atoms 1 and 1′ (that C–O); the new σ bond forms between atoms 3 and 3′ (the two terminal carbons). Because the new bond is three atoms out on each branch, chemists call this a [3,3]-sigmatropic shift.

The mechanism, arrow by arrow

There is exactly one step, but three electron pairs move in a coordinated cycle. Picture the molecule folded into a six-membered ring, the atoms threaded O–C=C … C–C=C:

1. The σ bond breaks. The allylic C(sp³)–O bond does not ionize — nothing heterolyzes into ions. Instead its σ electron pair flows the other way, into the allyl fragment, becoming a new C=C π bond. Curved arrow #1 runs from the breaking C–O σ bond onto the allyl carbons.
2. The old vinyl π bond shifts. Curved arrow #2 moves the vinyl C=C π electrons onto the oxygen, converting the ether oxygen into a carbonyl C=O. This is the step that pays for the whole reaction thermodynamically — a strong π(C=O) bond is being born.
3. A new C–C σ bond forms. Curved arrow #3 takes the π electrons of the allyl double bond and uses them to forge the new σ bond between the terminal allyl carbon (atom 3) and the terminal vinyl carbon (atom 3′).

   the six-atom array (atom 1′ = oxygen)      chair-like transition state:

     3′ = 2′ — 1′(O)                             • σ bond 1–1′ (C–O) breaking
                 |                        →      • σ bond 3–3′ (C–C) forming
     3  = 2  —  1                                • three π/σ shifts, all at once
                                                   (no intermediate)
   old σ: 1–1′  (allylic C–O)          new σ: 3–3′  (terminal C–C)

  arrows:  (1) C1–O σ (the 1–1′ bond)  →  C1=C2 π      (new allyl C=C)
           (2) C2′=C3′ vinyl π          →  O=C carbonyl (1′ becomes C=O oxygen)
           (3) C2=C3 allyl π            →  C3–C3′ new σ bond

All three arrows are drawn head-to-tail around the ring, which is the signature of a concerted pericyclic process: the six electrons form an unbroken loop. There is no intermediate — the transition state is the single highest point on the energy surface, and it looks like a slightly loosened six-membered ring with partial bonds where the old ones are dying and the new ones are being born.

Why it is thermally allowed — orbital symmetry

A [3,3]-sigmatropic shift juggles six electrons. Under the Woodward-Hoffmann rules, the thermal, all-suprafacial pathway threads those six electrons through a cyclic transition state with normal Hückel topology (no phase inversion). Six is a 4n+2 number with n = 1, so the transition state is aromatic — exactly the same electron count that makes benzene stable. An aromatic transition state means a low barrier, and the reaction proceeds readily on heating.

The same counting explains why light does the opposite: a photochemically excited [3,3] shift would prefer an antarafacial component (Möbius topology), so the thermal and photochemical stereochemistries diverge. In practice the Claisen is almost always run thermally, and the suprafacial-suprafacial geometry is what enforces its clean, predictable stereochemistry.

   electrons in TS   topology     4n+2?    thermal outcome
   ───────────────   ─────────    ─────    ───────────────
   6 (3 pairs)       Hückel       yes      ALLOWED, suprafacial-suprafacial
   6 (3 pairs)       Möbius       no       forbidden thermally

Reagents, catalysts, and conditions

The classical Claisen needs only a substrate and heat. But the parent temperature (150–200 °C) is punishing for delicate molecules, so a large fraction of modern practice is about lowering the barrier. The activation enthalpy of the parent allyl vinyl ether is about 30 kcal/mol; every trick below chips away at it.

• Straight thermal. Neat or in a high-boiling solvent (decalin, diphenyl ether, N,N-dimethylaniline), 150–250 °C, sealed tube or reflux. No additives. Works, but functional groups must survive the heat.
• Lewis-acid catalysis. Coordinating a Lewis acid (e.g. Et₂AlCl, or a chiral B/Al complex) to the ether oxygen or the developing carbonyl lowers the barrier and can run the reaction near room temperature. This also opens the door to enantioselective Claisen variants.
• Aqueous acceleration. Water and polar solvents accelerate the rearrangement by up to ~1000-fold relative to the gas phase, because the transition state is more polar than the ground state and is stabilized by hydrogen bonding. This is the same "on-water" effect that speeds many pericyclic reactions.
• Transition-metal catalysis. Pd(II), Au(I), and Ir complexes catalyze Claisen and Claisen-type rearrangements, often with dramatic rate gains and, with chiral ligands, high enantiocontrol.
• Substrate design. A carbonyl, an aromatic ring, or a heteroatom placed on the framework can lower the barrier or bias the geometry — the workhorse variants below all exploit this.

Scope, selectivity, and stereochemistry

The chair-like transition state is the whole reason synthetic chemists reach for the Claisen. Because the six atoms fold into a ring resembling cyclohexane, substituents want to sit in pseudo-equatorial positions, and that preference translates directly into product stereochemistry:

• Chirality transfer. A stereocenter on the allyl fragment is relayed to the new sp³ carbon with typically >90% fidelity — the reaction "remembers" where the original substituent was and delivers the new one to a defined face.
• Alkene geometry. The E/Z ratio of the product double bond is set by which chair (or boat) the molecule adopts. For most substrates the chair with substituents equatorial dominates, giving predominantly the E-alkene.
• Diastereoselectivity. When both fragments carry substituents, the chair relates them through a defined 1,2- or 1,3-relationship, so the anti/syn ratio is high and predictable.

This combination — reliable transfer of a single stereocenter into a new stereocenter plus a defined alkene — is rare and valuable. It lets a synthetic chemist "walk" chirality down a growing chain, which is exactly what the Ireland-Claisen and its cousins are built to do.

Claisen variants at a glance

The parent allyl vinyl ether is often hard to make, so most named "Claisen" reactions replace the vinyl half with something easier to install in situ. They all rearrange through the same [3,3] chair; they differ in what functional group the oxygen becomes.

Variant	Reagent that builds the ether	Product carbonyl	Typical temperature
Classic (aliphatic) Claisen	Allyl vinyl ether (preformed)	γ,δ-unsaturated aldehyde/ketone	150–250 °C
Aromatic Claisen	Allyl aryl ether (preformed)	o-allyl phenol	~200 °C
Ireland-Claisen	Allyl ester → silyl ketene acetal (LDA, then TMSCl)	γ,δ-unsaturated carboxylic acid	−78 °C → 25–65 °C
Johnson orthoester Claisen	Allylic alcohol + triethyl orthoacetate + cat. acid	γ,δ-unsaturated ester	130–140 °C
Eschenmoser-Claisen	Allylic alcohol + N,N-dimethylacetamide dimethyl acetal	γ,δ-unsaturated amide	130–150 °C
Carroll rearrangement	Allylic β-keto ester (then decarboxylation)	γ,δ-unsaturated ketone	130–200 °C
Bellus-Claisen (ketene)	Allyl ether/amine + ketene (zwitterion)	γ,δ-unsaturated ester/amide	0–25 °C
Cope (all-carbon analog)	1,5-diene (no oxygen)	Isomeric 1,5-diene (no C=O)	150–350 °C

Worked example: the Ireland-Claisen

Say you want to convert an allylic ester into a γ,δ-unsaturated carboxylic acid while setting a new stereocenter — and you want to do it below room temperature so nothing else in the molecule cooks. The Ireland-Claisen is the standard answer.

  step 1:  allyl ester  +  LDA (−78 °C, THF)      →  ester enolate
  step 2:  enolate  +  TMSCl                        →  O-silyl ketene acetal
                                                        (this IS the "vinyl ether" half)
  step 3:  warm to 25–65 °C                          →  [3,3] Claisen shift
  step 4:  aqueous workup (removes the TMS)          →  γ,δ-unsaturated CARBOXYLIC ACID

• Why an ester? Esters are trivial to make from an allylic alcohol and an acid chloride. Deprotonating the α-carbon and trapping the enolate as a silyl ketene acetal manufactures the reactive "vinyl ether" you could never isolate cleanly.
• The temperature win. The electron-rich ketene acetal has a much lower barrier than a plain allyl vinyl ether, so the [3,3] shift happens on warming from −78 °C to room temperature instead of at 200 °C.
• Stereo control. Choosing the enolate geometry (E- vs Z-silyl ketene acetal, set by whether you use THF or THF/HMPA in the deprotonation) dictates which chair forms, and therefore the syn/anti relationship in the product. This is one of the most reliable ways to build two adjacent stereocenters in one operation.

The net transformation — allylic alcohol → C–C bond one carbon further along, carrying a defined stereocenter — is why the Ireland-Claisen appears in dozens of complex-molecule total syntheses.

The aromatic Claisen and a labeling surprise

Claisen's original 1912 report actually featured the aromatic version: heat an allyl aryl ether (allyl phenyl ether) and it rearranges to ortho-allyl phenol. The [3,3] shift first destroys the aromatic ring, producing a non-aromatic ortho-dienone; that high-energy species instantly tautomerizes — a proton hops, the enol becomes a phenol — and aromaticity is restored. The aromatic stabilization regained on tautomerization is part of the driving force. (See keto-enol tautomerism and aromaticity.)

Here is the surprise that proves the mechanism. Label the carbon of the allyl group that is attached to oxygen. After the ortho-Claisen, that same labeled carbon is no longer the one bonded to the ring — the allyl group has flipped end-for-end. The bond forms at the far (γ) carbon, exactly as the [3,3] bookkeeping predicts. This isotopic-labeling result was historically decisive in establishing the concerted, cyclic mechanism.

And there is a second twist: if you block both ortho positions of the ring, the reaction doesn't stall — it does a second [3,3] shift (a Cope-type rearrangement of the dienone) and delivers the para-allyl phenol. In the para product the allyl group has flipped twice, so the labeled carbon ends up back where it started, bonded to the ring. Two clean [3,3] shifts, two flips, one elegant proof.

Limitations and side reactions

• High temperature (parent). Uncatalyzed aliphatic Claisens can need 150–250 °C, which decomposes thermally sensitive substrates. This is the main reason the Ireland, Johnson, and Eschenmoser variants exist.
• Competing retro-ene and elimination. At high temperature, allyl vinyl ethers can fragment or undergo retro-ene side reactions, eroding yield if the desired [3,3] barrier is not clearly the lowest path.
• Boat vs chair leakage. Stereocontrol relies on a strong chair preference. Rigid or strained substrates can be forced through a boat-like transition state, inverting the expected diastereoselectivity — a feature to exploit, but a trap if unanticipated.
• Reversibility in the Cope limit. The all-carbon Cope is roughly thermoneutral and can equilibrate; the oxygen of the true Claisen (forming a strong C=O) makes it effectively one-way, but "aza" and other heteroatom analogs can be less biased.
• Regiochemistry in the aromatic case. Ortho by default, para only when both ortho sites are blocked; a single blocked ortho position simply directs to the other ortho.

History: Ludwig Claisen, 1912

Rainer Ludwig Claisen (1851-1930) reported the rearrangement of allyl aryl and allyl vinyl ethers in 1912, in Berichte der deutschen chemischen Gesellschaft. Claisen already had his name on the base-mediated Claisen condensation of esters — a completely different reaction, and a common source of confusion for students. The rearrangement was the first [3,3]-sigmatropic reaction discovered; its all-carbon sibling, the Cope rearrangement, was described by Arthur Cope in 1940.

For decades the concerted, cyclic mechanism was inferred from stereochemistry and isotopic labeling. It found its rigorous theoretical footing in 1965 when Woodward and Hoffmann formulated the conservation of orbital symmetry, which classified the thermal [3,3] shift as an allowed, aromatic-transition-state process — the framework that earned Hoffmann (with Fukui) the 1981 Nobel Prize in Chemistry.

Biology and industry

• Chorismate → prephenate (the enzymatic Claisen). In the shikimate pathway that plants, fungi, and bacteria use to make aromatic amino acids, the enzyme chorismate mutase catalyzes a genuine Claisen rearrangement of chorismate to prephenate. The enzyme accelerates the intramolecular [3,3] shift by roughly a factor of 10⁶ over the uncatalyzed reaction — a textbook demonstration of an enzyme stabilizing a pericyclic transition state. Because this pathway is absent in mammals, it is an attractive herbicide and antimicrobial target (the same pathway glyphosate hits at a different step).
• Total synthesis. The Ireland- and Johnson-Claisen variants are staples of complex-molecule synthesis, prized for stitching a new C–C bond with predictable stereochemistry. They appear in routes to terpenes, polyketides, prostaglandins, and steroids.
• Fragrance and flavor building blocks. Aromatic Claisen rearrangements of allyl aryl ethers give ortho-allyl phenols that are intermediates toward substituted phenols used in flavor and fragrance chemistry.
• Terpene biosynthesis motifs. Sigmatropic logic underlies several biosynthetic C–C bond formations; the Claisen/Cope framework is the mental model chemists use to rationalize them.