A Bimolecular Diels–Alder Reaction Mediated by Inclusion in a Polar Bis-calix[4]pyrrole Octa-Imine Cage

Abstract

We describe using a dynamically self-assembled octa-imine cage as a molecular flask to accelerate a bimolecular Diels–Alder reaction. We investigate the cage’s binding properties using 1H NMR spectroscopic titrations, ITC experiments, and X-ray crystallography. We detect and characterize the formation of the ternary complex (Michaelis) in solution. A detailed kinetic analysis of the reaction data supports that the cage’s acceleration is provided by including the two reactants, resulting in an effective molarity (EM) of ∼40 M. Exo-selectivity and shift of the reaction’s chemical equilibrium are also encountered in the cage’s confined space. Our results mimic enzymes’ ability to bind two substrates in a polar cavity, using directional interactions, and accelerate their stereoselective reaction, with the potential for cavity engineering to enable other reactions.