Substituent Effects and Nearly Degenerate Transition States: Rational Design of Substrates for the Tandem Wolff−Cope Reaction

Abstract
The substrate scope for a ketene-assisted Cope (tandem Wolff-Cope) reaction is elucidated from first-principles quantum mechanics. An alternate pathway (trans) leading to an undesired and unstable product lies perilously close ( approximately 2.5 kcal/mol) to the primary (cis) reaction pathway; this near-degeneracy arises from preferential ketene stabilization of a radicaloid trans transition state over an aromatic cis transition state. Normally, substitution at "forbidden" sites causes the alternate pathway to be favored and the reaction to fail, but using simple conformational analysis principles we design substrates that defy this rule.