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

Abstract

Cucurbit[n]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 N-methyl-N-(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 (ΔG^≠, ΔH^≠ and ΔS^≠) 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[n]urils as artificial active sites, emulating specific aspects of enzymatic catalysis.