The Cope Reaction of N-oxides, which can easily be prepared in situ from tertiary amines with an oxidant such as peracid, leads to alkenes via a thermally induced syn-elimination in aprotic solvents.
Mechanism of the Cope Elimination
The Cope Elimination is a syn periplanar elimination in which six electrons move in a five-membered ring according to a concerted, thermally-induced mechanism to yield an alkene and a hydroxylamine:
The sterically demanding amine oxide function reacts preferentially with the more easily accessible hydrogens, and often gives good selectivity favoring the less-substituted alkene. Thus, for simple alkenes, the reaction follows the Hofmann Rule.
The following structures exemplify the stereochemical requirement for reaching a five-membered cyclic transition state and the influence of sterically demanding groups for some cyclic compounds:
For an early review on the Cope Elimination and similar reactions showing more examples, please refer to DePuy and King (Chem. Rev. 1960, 60, 432. DOI).
One synthetically useful exception to the general preference for more accessible hydrogens is the reaction of substrates that bear a β-phenyl group, or more generally speaking, an electron-withdrawing group in the β-position:
Compared with alkyl-substituted derivatives, a phenyl group provides a 100-fold rate increase. Phenyl and other electron-withdrawing groups lower the electron density of the carbon-hydrogen bond, making the hydrogen more acidic, and stabilizing the transition state. Computed minimal energy paths suggest that the Cope Elimination is slightly dissymmetric and nonsynchronous, with the H-transfer occurring slightly in advance of the other bond reorganizations (I. Komaromi, J. M. Tronchet, J. Phys. Chem. A 1997, 101, 3554).
Another interesting feature is the solvent dependence of the reaction rate. The Cope Elimination is extraordinarily sensitive to solvent effects, and a million-fold rate increase can be obtained going from protic to aprotic solvents. Within aprotic solvents, decreasing polarity significantly increases the reaction rate. The relative rate retardation for Cope Eliminations in protic solvents arises from hydrogen bonding between the amine oxide and the solvent. In addition, a fully solvated amine oxide in a protic solvent such as MeOH can even be relatively more favorable energetically than the less polar hydroxylamine, which can displace the equilibrium to favor the retro-Cope Elimination (O. Acevedo, W. L. Jorgensen, J. Am. Chem. Soc. 2006, 101, 6141):
Searching for Cyclin-Dependent Kinase Inhibitors Using a New Variant of the Cope Elimination
R. J. Gruffin, A. Henderson, N. J. Curtin, A. Echalier, J. A. Endicott, I. R. Hardcastle, D. R. Newell, M. E. M. Noble, L.-Z. Wang, B. T. Golding, J. Am. Chem. Soc., 2006, 128, 6012-6013.