Sigmatropic reaction

In organic chemistry, a sigmatropic reaction () is a pericyclic reaction wherein the net result is one sigma bond (σ-bond) is changed to another σ-bond in an intramolecular reaction. True sigmatropic reactions are usually uncatalyzed, although Lewis acid catalysis is possible. Sigmatropic reactions often have transition-metal catalysts that form intermediates in analogous reactions. The most well-known of the sigmatropic rearrangements are the [3,3] Cope rearrangement, Claisen rearrangement, Carroll rearrangement, and the Fischer indole synthesis.

Overview of sigmatropic shifts

Woodward–Hoffman sigmatropic shift nomenclature

Sigmatropic rearrangements are concisely described by an order term [i,j], which is defined as the migration of a σ-bond adjacent to one or more π systems to a new position (i−1) and (j−1) atoms removed from the original location of the σ-bond. which are impossible for transformations that occur within small- or medium-sized rings.

:center|500px

Classes of sigmatropic rearrangements

[1,3] shifts

Thermal hydride shifts

In a thermal [1,3] hydride shift, a hydride moves three atoms. The Woodward–Hoffmann rules dictate that it would proceed in an antarafacial shift. Although such a shift is symmetry allowed, the Mobius topology required in the transition state prohibits such a shift because it is geometrically impossible, which accounts for the fact that enols do not isomerize without an acid or base catalyst.

:center|400px|Impossible shift

Thermal alkyl shifts

Thermal alkyl [1,3] shifts, similar to [1,3] hydride shifts, must proceed antarafacially. Here the geometry of the transition state is prohibitive, but an alkyl group, due to the nature of its orbitals, can invert its geometry, form a new bond with the back lobe of its sp3 orbital, and therefore proceed via a suprafacial shift. These reactions are still not common in open-chain compounds because of the highly ordered nature of the transition state, which is more readily achieved in cyclic molecules.

:[[File:1,5hantarafacialfixed.png|center|600px|Antarafacial [1,5] hydride shift]]

In contrast to hydrogen [1,5] shifts, there have never been any observed [1,5] alkyl shifts in an open-chain compound.

Alkyl groups undergo [1,5] shifts very poorly, usually requiring high temperatures, however, for cyclohexadiene, the temperature for alkyl shifts isn't much higher than that for carbonyls, the best migratory group. A study showed that this is because alkyl shifts on cyclohexadienes proceed through a different mechanism. First the ring opens, followed by a [1,7] shift, and then the ring reforms electrocyclically:

:center|650px|alkyl shift on cyclohexadiene

This same mechanistic process is seen below, without the final electrocyclic ring-closing reaction, in the interconversion of lumisterol to vitamin D2.

[1,7] shifts

[1,7] sigmatropic shifts are predicted by the Woodward–Hoffmann rules to proceed in an antarafacial fashion, via a Mobius topology transition state. An antarafacial [1,7] shift is observed in the conversion of lumisterol to vitamin D2, where following an electrocyclic ring opening to previtamin D2, a methyl hydrogen shifts.

:center|800px|conversion of Lumisterol to Vitamin D2

Bicyclic nonatrienes also undergo [1,7] shifts in a so-called walk rearrangement, which is the shift of divalent group, as part of a three-membered ring, in a bicyclic molecule.

:center|300px|walk rearrangement of bicycle nonatriene

[3,3] shifts

[3,3] sigmatropic shifts are well studied sigmatropic rearrangements. The Woodward–Hoffman rules predict that these six-electron reactions would proceed suprafacially, via a Hückel topology transition state.

Claisen rearrangement

Discovered in 1912 by Rainer Ludwig Claisen, the Claisen rearrangement is the first recorded example of a [3,3]-sigmatropic rearrangement. This rearrangement is a useful carbon-carbon bond-forming reaction. An example of Claisen rearrangement is the [3,3] rearrangement of an allyl vinyl ether, which upon heating yields a γ,δ-unsaturated carbonyl. The formation of a carbonyl group makes this reaction, unlike other sigmatropic rearrangements, inherently irreversible.

:center|250px|The Claisen rearrangement

Aromatic Claisen rearrangement

The ortho-Claisen rearrangement involves the [3,3] shift of an allyl phenyl ether to an intermediate which quickly tautomerizes to an ortho-substituted phenol.

:center|500px|Aromatic Claisen rearrangement

When both the ortho positions on the benzene ring are blocked, a second [3,3] rearrangement will occur. This para-Claisen rearrangement ends with the tautomerization to a tri-substituted phenol.

:center|700px|Para-Claisen rearrangement

Cope rearrangement

The Cope rearrangement is an extensively studied organic reaction involving the [3,3] sigmatropic rearrangement of 1,5-dienes. It was developed by Arthur C. Cope. For example, 3,4-dimethyl-1,5-hexadiene heated to 300 °C yields 2,6-octadiene.

:center|300px|The Cope rearrangement of 3,4-dimethyl-1,5-hexadiene

Oxy-Cope rearrangement

In the oxy-Cope rearrangement, a hydroxyl group is added at C3 forming an enal or enone after keto-enol tautomerism of the intermediate enol:

:center|500px|Oxy-Cope rearrangement

Carroll rearrangement

The Carroll rearrangement is a rearrangement reaction in organic chemistry and involves the transformation of a β-keto allyl ester into a α-allyl-β-ketocarboxylic acid. This organic reaction is accompanied by decarboxylation and the final product is a γ,δ-allylketone. The Carroll rearrangement is an adaptation of the Claisen rearrangement and effectively a decarboxylative allylation.

:center|800px|Carroll Rearrangement

Fischer indole synthesis

The Fischer indole synthesis is a chemical reaction that produces the aromatic heterocycle indole from a (substituted) phenylhydrazine and an aldehyde or ketone under acidic conditions. The reaction was discovered in 1883 by Hermann Emil Fischer.

:center|900px|The Fischer indole synthesis

The choice of acid catalyst is very important. Brønsted acids such as HCl, H2SO4, polyphosphoric acid and p-toluenesulfonic acid have been used successfully. Lewis acids such as boron trifluoride, zinc chloride, iron(III) chloride, and aluminium chloride are also useful catalysts.

Several reviews have been published.

[5,5] Shifts

Similar to [3,3] shifts, the Woodward-Hoffman rules predict that [5,5] sigmatropic shifts would proceed suprafacially, Hückel topology transition state. These reactions are rarer than [3,3] sigmatropic shifts, but this is mainly a function of the fact that molecules that can undergo [5,5] shifts are rarer than molecules that can undergo [3,3] shifts. An example of such a rearrangement is the shift of substituents on tropilidenes (1,3,5-cycloheptatrienes). When heated, the pi-system goes through an electrocyclic ring closing to form bicycle[4,1,0]heptadiene (norcaradiene). Thereafter follows a [1,5] alkyl shift and an electrocyclic ring opening.

:center|700px|norcaradiene rearrangement

Proceeding through a [1,5] shift, the walk rearrangement of norcaradienes is expected to proceed suprafacially with a retention of stereochemistry. Experimental observations, however, show that the 1,5-shifts of norcaradienes proceed antarafacially. Theoretical calculations found the [1,5] shift to be a diradical process, but without involving any diradical minima on the potential energy surface.

1,5-hydride transfer-triggered cyclization

Formally, 1,5-hydride transfer reactions are a special side of the sigmatrope rearrangement. Cyclization reactions triggered by 1,5-hydride transfer is a very potent synthetic method and have been extensively studied as a reliable strategy for C(sp³)–C(sp³) bond formation, notably in the synthesis of tetrahydroquinolines and related unsaturated heteroaton containing frameworks.