Sigmatropic rearrangements: Cope, Claisen, and [1,5]-H shifts

Intuition Beginner

A sigmatropic rearrangement moves a sigma bond across a conjugated pi system. The prefix "sigma" refers to the single bond that migrates, and "tropic" means it shifts position. One sigma bond breaks while another forms, and the pi electrons reorganise to accommodate the change. Everything happens in one concerted step with no intermediate. These rearrangements are classified by the notation [i,j], where i and j count the atoms in the two fragments that exchange bonding partners.

The Cope rearrangement is a [3,3]-sigmatropic shift that converts one 1,5-diene into another. For unsubstituted 1,5-hexadiene the product is identical to the starting material (a degenerate rearrangement), but substituents change their connectivity. The Claisen rearrangement works the same way except one of the six atoms in the transition state is oxygen. An allyl vinyl ether rearranges to give an unsaturated aldehyde or ketone.

Hydrogen atoms can also migrate across pi systems. In a [1,5]-sigmatropic hydrogen shift, a hydrogen moves from one end of a conjugated pentadienyl system to the other, staying on the same face. This reaction is thermally allowed and occurs in many acyclic and cyclic dienes at moderate temperatures. It explains the facile interconversion of certain diene isomers during thermolysis.

Visual Beginner

The Cope rearrangement passes through a six-membered cyclic transition state. The chair-like arrangement is preferred over the boat-like arrangement, mirroring the stability difference between chair and boat cyclohexane. In the Claisen rearrangement, the oxygen atom occupies one vertex of the six-membered transition state ring, and the product gains carbonyl stabilisation that drives the reaction forward.

Worked example Beginner

Problem: Predict the product of the Claisen rearrangement of allyl vinyl ether.

Solution:

The Claisen rearrangement is a [3,3]-sigmatropic shift of an allyl vinyl ether. The sigma bond between the allyl group and the oxygen migrates to form a new carbon-carbon bond. The oxygen gains a double bond to carbon, producing an enol intermediate that tautomerises to the aldehyde.

In allyl vinyl ether, the six atoms in the cyclic transition state are C=C-C-O-C=C. During the rearrangement, the C-O sigma bond breaks, and a new C-C sigma bond forms between the terminal carbon of the allyl fragment and the terminal carbon of the vinyl fragment.

The product is pent-4-enal (CH2=CH-CH2-CH2-CHO). The carbonyl group provides thermodynamic driving force — the aldehyde is more stable than the starting vinyl ether. This is why the Claisen rearrangement proceeds readily at 200–250 degrees Celsius without a catalyst.

Check your understanding Beginner

Formal definition Intermediate+

A [i,j]-sigmatropic rearrangement is a pericyclic reaction in which a sigma bond migrates across a conjugated system. The indices i and j denote the number of atoms in the two fragments between which the sigma bond shifts. For a [3,3]-sigmatropic rearrangement, the sigma bond between two allyl fragments (each three atoms long) exchanges termini: the bond breaks at one end of each fragment and reforms at the other. The total electron count in the pericyclic array is six (four pi electrons from the two double bonds plus two sigma electrons from the migrating bond).

Woodward-Hoffmann selection rules for sigmatropic shifts. A thermal [i,j]-sigmatropic shift is allowed when the total number of (4q+2) suprafacial components and (4r) antarafacial components is odd. For a [3,3] shift with both components suprafacial, the six electrons satisfy the 4n+2 rule (n=1), and the reaction is thermally allowed. For a [1,j] hydrogen shift, the selection rule predicts that suprafacial migration is thermally allowed when j = 4n+3 (odd number of pairs of electrons): [1,3] is forbidden (4 electrons, antarafacial required), [1,5] is allowed (6 electrons, suprafacial), and [1,7] requires antarafacial geometry (8 electrons).

Suprafacial vs antarafacial migration. In a suprafacial shift, the new bond forms on the same face of the pi system as the old bond. In an antarafacial shift, the new bond forms on the opposite face. For [1,5]-hydrogen shifts, suprafacial migration is thermally allowed and geometrically feasible. For [1,3]-hydrogen shifts, the Woodward-Hoffmann rules require antarafacial migration, but a hydrogen 1s orbital cannot simultaneously overlap with p-orbitals on opposite faces of a three-atom fragment. The geometric constraint makes [1,3]-H shifts thermally forbidden in practice, even though they would be allowed if the antarafacial pathway were accessible.

Chair vs boat transition state for the Cope rearrangement. The Cope rearrangement proceeds through a six-membered cyclic transition state that adopts either a chair-like or boat-like geometry. The chair TS is lower in energy by approximately 5.7 kcal/mol, analogous to the conformational preference in cyclohexane. For substituted 1,5-dienes, the chair TS also controls the stereochemistry: substituents that are equatorial in the chair TS give the major product. The activation barrier for the parent 1,5-hexadiene is approximately 33 kcal/mol (observable at 200–300 degrees Celsius).

Stereospecificity of the Claisen rearrangement. The Claisen rearrangement is stereospecific: the configuration of the allyl group in the starting material determines the stereochemistry of the new stereocentre in the product. A (Z)-allyl ether gives the (E)-alkene in the product, and an (E)-allyl ether gives the (Z)-alkene. This stereospecificity arises because the chair-like transition state forces the allyl substituents into specific orientations relative to the forming C-C bond. The Claisen rearrangement is one of the most reliable methods for constructing quaternary stereocentres adjacent to a carbonyl group.

Ireland-Claisen rearrangement. The Ireland variant uses an ester enolate instead of a vinyl ether. An allylic ester is deprotonated with a strong base (typically LDA) to form a ketene acetal, which undergoes the [3,3]-sigmatropic shift at a lower temperature than the standard Claisen rearrangement. The product is a gamma,delta-unsaturated carboxylic acid after hydrolysis. The use of silyl ketene acetals (trapping the enolate with a silyl chloride) further extends the scope, and the stereochemistry of the enolate (E or Z, controlled by the solvent and counterion) is translated into the product stereochemistry with high fidelity.

Key results Intermediate+

1. Cope rearrangement. The [3,3]-sigmatropic rearrangement of 1,5-dienes proceeds through a chair-like transition state (preferred by 5–6 kcal/mol over boat). For 3,3-dimethyl-1,5-hexadiene the rearrangement is degenerate with an activation energy of approximately 33 kcal/mol. The reaction is stereospecific: the relative configuration of substituents is determined by the chair TS geometry.

2. Claisen rearrangement. The [3,3]-sigmatropic shift of allyl vinyl ethers gives gamma,delta-unsaturated carbonyl compounds. The reaction is thermodynamically driven by carbonyl formation and proceeds at 200–250 degrees Celsius. Variants include the Johnson-Claisen (orthoester), Eschenmoser-Claisen (amide acetal), and Ireland-Claisen (ester enolate). The Claisen rearrangement reliably installs quaternary stereocentres adjacent to a carbonyl.

3. [1,5]-Hydrogen shifts. A thermally allowed suprafacial migration of hydrogen across a pentadienyl system. The reaction proceeds readily at moderate temperatures in acyclic and cyclic dienes. The [1,3]-H shift is thermally forbidden (antarafacial geometry required but geometrically impossible for hydrogen). The [1,7]-H shift requires antarafacial geometry and is observed in extended systems such as the previtamin D3 to vitamin D3 conversion.

4. Woodward-Hoffmann summary. For thermal [i,j]-sigmatropic shifts: the reaction is allowed when the total number of (4q+2) suprafacial components plus (4r) antarafacial components is odd. All three reactions discussed here (Cope, Claisen, [1,5]-H shift) involve six electrons in a Huckel topology and are thermally allowed as suprafacial processes.

Exercises Intermediate+

Advanced sigmatropic rearrangements Master

Oxy-Cope and anionic oxy-Cope rearrangements. The oxy-Cope rearrangement places a hydroxyl group at C-3 of the 1,5-diene. The product of the [3,3] shift is an enol that tautomerises to a carbonyl, providing thermodynamic driving force analogous to the Claisen rearrangement. The activation barrier drops significantly: 3-hydroxy-1,5-hexadiene rearranges at approximately 60 degrees Celsius compared to approximately 200 degrees Celsius for the parent Cope.

The anionic oxy-Cope, first reported by Evans in 1976, deprotonates the C-3 hydroxyl to give an alkoxide. The alkoxide destabilises the starting material (negative charge on an sp3 carbon adjacent to the pi system) and stabilises the product enolate. The rate acceleration relative to the neutral oxy-Cope reaches 10^10 to 10^17, making the rearrangement feasible at room temperature or below. This represents one of the largest rate accelerations attributable to a single substituent change in organic chemistry. The anionic oxy-Cope is synthetically powerful because it constructs carbonyl-containing products under mild conditions with high stereocontrol.

Aza-Claisen rearrangements. Nitrogen analogues of the Claisen rearrangement replace oxygen with nitrogen. The most synthetically important is the Overman rearrangement: an allylic trichloroacetimidate (RO-C(=NH)-CCl3) rearranges to a trichloroacetamide (R'-NH-CO-CCl3) through a [3,3]-sigmatropic shift catalysed by a palladium(II) complex or promoted thermally. The Overman rearrangement converts an allylic alcohol to an allylic amine with inversion at the nitrogen-bearing carbon, providing direct access to allylic amines — common structural motifs in natural products and pharmaceuticals. The palladium-catalysed variant proceeds at room temperature with high enantioselectivity when chiral ligands are employed.

The aza-Cope rearrangement involves N-allyl enamines and produces amino-carbonyl compounds. The Mannich-aza-Cope cascade (Overman, 1970s) combines an aza-Cope rearrangement with an intramolecular Mannich reaction to construct nitrogen heterocycles in a single operation. This cascade strategy has been used in the synthesis of alkaloid natural products.

[2,3]-Sigmatropic rearrangements. The [2,3]-sigmatropic shift involves five atoms and six electrons in a cyclic transition state. The two most important examples are the Meisenheimer rearrangement and the Sommelet-Hauser rearrangement.

The Meisenheimer rearrangement converts a tertiary amine N-oxide to a hydroxylamine: R3N(+)-O(-) undergoes [2,3] shift to give R2N-O-CHR2. The migrating group moves from nitrogen to oxygen through a five-membered cyclic TS. This reaction competes with the Cope elimination (a non-concerted pathway) at elevated temperatures.

The Sommelet-Hauser rearrangement is a [2,3]-sigmatropic shift of a sulphonium ylide: ArCH2-S(+)(R2)-CH2(-) rearranges to Ar(CH2SR2)CH2(-) through a five-membered TS. The aryl group migrates from carbon to carbon with concomitant shift of the sulphur substituent. This reaction is synthetically useful for the ortho-alkylation of benzyl groups and proceeds with retention of configuration at the migrating aryl carbon.

Computational studies of the Cope transition state. The nature of the Cope rearrangement transition state has been the subject of extensive computational investigation. At the B3LYP/6-31G* level, the Cope TS of 1,5-hexadiene has C2h symmetry (chair-like) with forming/breaking bond distances of approximately 2.0 angstroms. Higher-level calculations (CCSD(T)/cc-pVTZ) confirm that the TS is concerted with no diradical character: the C1-C6 bond forms simultaneously as the C3-C4 bond breaks.

The question of whether the Cope rearrangement is truly concerted or proceeds through a diradical intermediate was debated for decades. Computational studies by Houk and Borden established that the parent Cope rearrangement of 1,5-hexadiene proceeds through a concerted but asynchronous TS. The degree of asynchronicity depends on substituents: electron-donating groups at C1/C6 favour a more diradicaloid TS with more biradical character, while electron-withdrawing groups favour a more synchronous, fully concerted pathway. For the parent system, the diradicaloid TS is only 1–2 kcal/mol lower than the fully synchronous TS, explaining the sensitivity of the mechanism to substituent effects. The nontrivial dependence on substitution pattern makes the Cope rearrangement a benchmark reaction for testing computational methods.

Connections Master

• Diels-Alder reaction 15.05.03 pending. The Diels-Alder cycloaddition and the sigmatropic rearrangements are both governed by the Woodward-Hoffmann rules. The Cope and Claisen rearrangements involve six electrons in a cyclic transition state — the same electron count as the Diels-Alder. The orbital symmetry analysis is topologically equivalent: all three reactions proceed through Huckel-aromatic transition states with 4n+2 electrons.

• Electrocyclic reactions 15.08.03 pending. Electrocyclic ring opening and closing share the same orbital symmetry principles as sigmatropic rearrangements. The Woodward-Hoffmann rules predict conrotatory vs disrotatory modes for electrocyclic reactions and suprafacial vs antarafacial pathways for sigmatropic shifts. Both reaction classes are unified by the conservation of orbital symmetry.

• Radical and pericyclic reactions 15.08.01. This unit builds on the classification of pericyclic reactions introduced in 15.08.01. The sigmatropic rearrangements are one of the three major pericyclic reaction classes (alongside cycloadditions and electrocyclic reactions).

• Retrosynthetic analysis 15.10.01. The Claisen rearrangement is a powerful retrosynthetic disconnection for forming carbon-carbon bonds adjacent to a carbonyl. The Ireland-Claisen variant is particularly useful because it starts from readily available allylic esters. The Cope rearrangement enables skeletal reorganisation in retrosynthetic planning.

• Terpene biosynthesis. Many terpene natural products are formed through enzyme-catalysed sigmatropic rearrangements. The Claisen rearrangement of chorismate to prephenate (with sigmatropic shift character) is a key step in the biosynthesis of aromatic amino acids. The [1,5]-hydrogen shift is common in the thermal rearrangements of terpenoid skeletons.

• Vitamin D biosynthesis. The conversion of 7-dehydrocholesterol to previtamin D3 is a photochemical electrocyclic ring opening, and the subsequent conversion of previtamin D3 to vitamin D3 involves a thermal [1,7]-sigmatropic hydrogen shift (antarafacial, allowed for 8 electrons). This biosynthetic pathway demonstrates the interplay of photochemical and thermal pericyclic reactions in biology.

• Stereochemistry and asymmetric synthesis 15.01.04 pending. The Claisen and Ireland-Claisen rearrangements are among the most reliable methods for stereocontrolled construction of quaternary stereocentres. The chair-like transition state translates starting material geometry into product stereochemistry with high fidelity, making these rearrangements indispensable in enantioselective synthesis.

Historical notes Master

The Claisen rearrangement was discovered by Ludwig Claisen in 1912, predating the Cope rearrangement by nearly three decades. Claisen observed that allyl phenyl ether rearranged to o-allylphenol on heating and correctly recognised the reaction as an intramolecular rearrangement rather than a fragmentation-recombination process. The [3,3]-sigmatropic mechanism was not established until the mid-twentieth century, when isotopic labelling experiments confirmed the concerted nature of the shift.

Arthur Cope reported the rearrangement of 1,5-dienes in 1940. Cope and his coworkers systematically studied the scope of the reaction, establishing that it was general for 1,5-dienes and proceeded through a cyclic transition state. The chair-like geometry of the TS was proposed by Doering and Roth in 1962 based on stereochemical studies of substituted substrates, a proposal confirmed by subsequent computational work.

The Woodward-Hoffmann rules, published in 1965–1969, provided the theoretical framework for understanding why these rearrangements are thermally allowed. Woodward and Hoffmann showed that [3,3]-sigmatropic shifts proceed through a Huckel-aromatic transition state with 6 electrons, making them thermally allowed as suprafacial processes on both components. The same analysis predicted that [1,5]-hydrogen shifts are thermally allowed (suprafacial) while [1,3]-hydrogen shifts are thermally forbidden (require antarafacial geometry).

Robert Ireland developed the ester enolate variant (Ireland-Claisen) in the 1970s, greatly expanding the synthetic utility of the Claisen rearrangement. Ireland demonstrated that silyl ketene acetals undergo the rearrangement at lower temperatures and that the enolate geometry is translated into product stereochemistry. Larry Overman reported the trichloroacetimidate rearrangement in 1974, providing direct access to allylic amines.

The anionic oxy-Cope rearrangement was discovered by David Evans in 1976. Evans observed that deprotonation of the C-3 hydroxyl group of 3-hydroxy-1,5-hexadiene accelerated the Cope rearrangement by a factor of 10^17, one of the largest rate accelerations ever observed for a single functional group modification. This discovery opened new avenues for the use of Cope rearrangements in synthetic chemistry.

Computational studies of the Cope transition state by Houk, Borden, and others in the 1980s–2000s resolved the long-standing debate about whether the reaction is concerted or stepwise. These studies established the concept of the "aromatic" pericyclic transition state and demonstrated that the Cope rearrangement proceeds through a concerted but flexible TS that can shift along a continuum between synchronous and asynchronous geometries depending on substituent effects.

Bibliography Master

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