Investing in entropy: the strategy of cucurbit[<i>n</i>]urils to accelerate the intramolecular Diels–Alder cycloaddition reaction of tertiary furfuryl amines

Abstract

Cucurbit[<i>n</i>]urils, renowned for their host-guest chemistry, are becoming versatile biomimetic receptors. Herein, we report that cucurbit[7]uril (CB[7]) accelerates the intramolecular Diels-Alder (IMDA) reaction for previously elusive and unreactive tertiary <i>N</i>-methyl-<i>N</i>-(homo)allyl-2-furfurylamines by up to 4 orders of magnitude under mild conditions. Using ¹H NMR titrations and ITC experiments, we characterize the dissimilar thermodynamic and kinetic properties of the complexes. We also determine the activation parameters (Δ<i>G</i> ^≠, Δ<i>H</i> ^≠ and Δ<i>S</i> ^≠) leading to the transition state of the IMDA reactions, both in the bulk and included in CB[7], to shed light on the key role of the receptor on the acceleration observed. CB[7] acts as an "entropy trap" utilizing guest binding to primarily pay the entropy penalty for reorganizing the substrate in a high-energy reactive conformation that resembles the geometry of the highly ordered transition state required for the IMDA reaction. This study underscores the potential of cucurbit[<i>n</i>]urils as artificial active sites, emulating specific aspects of enzymatic catalysis.