Diels-Alder Reactions in [Pd₆L₄]¹²⁺ Metallocages: The Key Roles of Preorganization and Confinement

The Diels-Alder reaction between maleimide and naphthalene-based compounds typically requires harsh conditions or electronic activation, such as the presence of Lewis acids. Fujita and co-workers, however, demonstrated that this reaction can proceed smoothly in confined spaces inside the [Pd₆L₄]¹²⁺ metallocage. In the present work, a computational study combining several techniques is performed in solution and within the metallocage to elucidate the origin of the rate acceleration as well as the regio- and stereoselectivity observed. MD simulations reveal how the reactants accommodate and behave inside the cavity and allow identification of pro-reactive conformations. QM/MM calculations provide Gibbs energy profiles for the reactions in solution and within the metallocage. The roles of confinement, microsolvation, and the metallocage environment are evaluated, showing that reaction acceleration mainly arises from confinement-induced preorganization of the reactants. The analysis also provides a unified mechanistic explanation for the substrate-dependent reactivity observed experimentally.