Cope Elimination Reaction

The Cope elimination refers to the reaction in which a tertiary amine is oxidized to an "N-oxide" intermediate, followed by thermal decomposition to yield an alkene and an N,N-disubstituted hydroxylamine. This reaction is named after the American chemist Arthur C. Cope. The Cope elimination plays a significant role in organic synthesis, medicinal chemistry, and the development of new reactions. It efficiently converts amine compounds into diverse chemical products, making it one of the important reactions in organic chemistry.

Reagents: Oxidizing agents
Reactants: Tertiary amines with β-hydrogens
Products: Alkenes and N,N-disubstituted hydroxylamines
Reaction Type: Elimination reaction

Experimental Tips:

• Common oxidizing agents include H₂O₂ or mCPBA.

• The N-oxide intermediate generally does not require isolation or purification and can undergo Cope elimination directly upon heating.

• The Cope elimination is an intramolecular elimination reaction. Its regiochemistry does not follow the Zaitsev or Hofmann pathways but instead depends on whether the β-hydrogen can adopt a syn-periplanar geometry.

• Aprotic solvents can accelerate the reaction rate by up to several million-fold.

Reaction Mechanism:
The Cope elimination proceeds via the formation of an N-oxide intermediate, followed by a concerted [1,2]-elimination to produce the alkene and hydroxylamine.

Original Literature:

1. Arthur C. Cope, Theodore T. Foster, and Philip H. Towle. Thermal Decomposition of Amine Oxides to Olefins and Dialkylhydroxylamines. J. Am. Chem. Soc. 1949, *71*(12), 3929-3934.

2. Arthur C. Cope, Elmer R. Trumbull. Olefins from Amines: The Hofmann Elimination Reaction and Amine Oxide Pyrolysis. In: Org. React. Vol. 11, 1960, 317-493.

Popular Applications:

• Cope Elimination: Elucidation of Solvent Effects from QM/MM Simulations. J. Am. Chem. Soc. 2006, *128*(18), 6141–6146.

• Searching for Cyclin-Dependent Kinase Inhibitors Using a New Variant of the Cope Elimination. J. Am. Chem. Soc. 2006, *128*(18), 6012-6013.

• Identification and Characterization of a New Dapoxetine Impurity by NMR: Transformation of N-Oxide by Cope Elimination. Journal of Pharmaceutical and Biomedical Analysis, 2017, *134*(5), 187-194.