The Cope rearrangement is the thermal isomerization of a 1,5-diene. It is a pericyclic reaction that belongs to the group of [3,3]-sigmatropic rearrangements. The oxy-Cope variant involves a hydroxyl substituent on an sp3-hybridized carbon of the substrate.
- The Cope rearrangement is reversible since it does not involve any changes in the number or types of bonds. The equilibrium position depends on the relative stability of the starting material and the product. If the product is stabilized through conjugation or features a more highly substituted double bond, the equilibrium will favor product formation.
- The reaction is stereospecific and stereoselective and proceeds concertedly via a cyclic chair-like transition state (TS).
Reaction mechanism of Cope rearrangement
The Cope rearrangement proceeds via a chair-like transition state where there is minimal steric interaction between the substituents.
Experimental investigations of the Cope rearrangement of 1,5-hexadiene rule out the dissociative mechanism.
Other possible pathways include a Woodward-Hoffmann allowed concerted σ bond shift occurring in a chair-like TS; or a two-stage process involving a stable 1,4-diyl intermediate.
The conversions of the meso-3,4-dimethyl-1,5-hexadiene and rac-3,4-dimethyl-1,5-hexadiene stereoisomers showed nearly perfect stereospecificity, indicating a chair-like TS.
For more details on the reaction mechanism of the Cope rearrangement, see J. Mol. Struct. THEOCHEM 2001, 573, 81 and Wiley Interdiscip. Rev. Comput. Mol. Sci. 2011, 1, 172.
Examples and experimental procedures of Cope rearrangement
Example 1: J. Am. Chem. Soc. 2019, 141, 3440.
To a solution of the 1,5-dien-3-ol (84.2 mmol, 1.0 equiv) in THF (500 mL), 18-C-6 (1.2 equiv) was added. The round-bottom flask was immersed in an ice bath, and KH (1.2 equiv) was added in one portion. The reaction mixture was stirred for 2 h at the same temperature before it was slowly quenched with MeOH at -78 ºC. The solution was concentrated under vacuum, and the obtained residue was purified by flash column chromatography to afford the unsaturated carbonyl compound as an inseparable mixture of diastereomers.
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