The ion-dipole effect is a force for molecular recognition and biomimetic catalysis

Abstract

Chapter 1: In aqueous and organic media, electron-rich synthetic macrocycles serve as hosts for positively-charged guests. Binding studies in different solvents have quantified hydrophobic, donor/acceptor, and ion-dipole interactions as forces for molecular recognition. We have found clear evidence for substantial host-guest donor/acceptor π-stacking interactions (ca. 1.5 kcal/mol) in aqueous media only. The ion-dipole effect is an appreciable driving force (worth up to 3.5 kcal/mol) for molecular recognition in both aqueous and organic media. Chapter 2: Variable-temperature binding studies were performed to assess enthalpic (ΔH°) and entropic (ΔS°) contributions to free energies (ΔG°) of host-guest complexation. The van't Hoff plots (RlnK_a vs T^(-1)), which are clearly non-linear, have revealed significant values for the heat capacities (ΔC_p) of complexation in both organic and aqueous media. The ΔC_p values reflect a phenomenon generally overlooked in molecular recognition studies: both ΔH° and ΔS° are strongly temperature-dependent. Hydrophobic, donor/acceptor, and ion-dipole interactions are tentatively partitioned into ΔH° and ΔS° contributions at 298K. Classic hydrophobic binding is characterized by a large, positive ΔS° and a near-zero ΔH° term. Strong donor/acceptor π-stacking interactions are typically balanced between large, favorable enthalpic and unfavorable entropic contributions. The ion-dipole effect is primarily an enthalpically-driven binding force. Chapter 3: Electron-rich synthetic macrocyclic host 1 accelerates a class of alkylation reactions in aqueous media. Specifically, host 1 catalyzes the reactions of pyridine-type nucleophiles with alkyl halides in an aqueous pD~9 borate buffer. The rate constants of catalyzed versus uncatalyzed reactions and the binding affinities for substrates and products demand that host 1 binds transition states more tightly than ground states. This extension of molecular recognition through ion-dipole interactions to biomimetic catalysis provides compelling evidence for transition-state stabilization via favorable dipole-dipole interactions in aqueous media. Chapter 4: A new class of high-symmetry, water soluble, hydrophobic binding sites is described that feature 1,5-substituents on a rigid ethenoanthracene (DEA) framework. These new 1,5-hosts are compared to the analogous 2,6-hosts described in the Ph.D. theses of Petti and Shepodd. Because of more favorable solvation (by water) of amide linker groups that line the cavity, the 1,5-hosts exhibit significantly reduced affinities for all guests considered: only positively-charged guests are bound to any appreciable extent. While the binding sites designed herein are composed of topographically well-defined, rigid units to give a chiral host (with a greater sense of twist), the disposition of the 1,5-substituents allows the collapse of hosts into a bowl conformation. We therefore suggest that the more successful high-symmetry, hydrophobic binding sites are to be found with 2,6-DEA-constructed hosts rather than with 1,5-DEA-constructed hosts. One benefit of the synthetic approach taken here is the development of a series of DEA building blocks for the construction of hosts with even more pronounced hydrophobic character.