Howard W. Whitlock

1,8,15,22,30,34-hexaoxa-29,35-dioxo[8.8.7](1,4,2)cyclopha-3,5,17,19-tetrayne and 1,8,15,22,30,34-hexaoxa-29,35-dioxo[8.8.7](1,4,2)cyclophane, models for conformationally-defined hosts

Abstract The title molecules exhibit minimum barriers of 24-26 kcal mol -1 to ring inversion; an X-ray crystal structure of the saturated phane shows the aromatic rings to lie in contact and stacked.

Design of Host Molecules Capable of Forming Extremely Stable Host-Guest Complexes

Construction of extremely sticky host molecules, those capable of forming extremely stable complexes with suitable guests, is an interesting and important puzzle. The more important “design principles” for this class of compound are summarized: Hydrophobic complexation, as illustrated by the cyclodextrins, is historically the first and “defining” force in host-guest complex stabilization.1 Its great importance to biological systems has caused it to be the subject of intense scrutiny. While originally ascribed to entropie effects2 current thinking is revisionist in ascribing it primarily to enthalpic features of the hydrogen bond and differential solvation of host and guest.3 A particularly illuminating series of papers by Diederich summarizes the arguments for this viewpoint.4 The rather amorphous nature of hydrophobic effects is accented by Dougherty’s work on the importance of ion-dipole effects in several anthracenophane-based hosts. The hydrogen bond has been exploited to great effect in the design of hosts capable of acting primarily in aprotic organic solvents.5 Aromatic-aromatic stacking has been exploited by Rebek, Hamilton and others in building nucleoside binding hosts.6 The “lock and key effect”, refined as Cram’s preorganization concept has received increasing consideration7 recently in the context of immunophilin binding studies. Edge-face aromatic-aromatic interactions have been advanced as a stabilizing force on protein conformations. In favorable cases they exercise a positive effect on complex stability. Ion-ion and ion-dipole effects have proven effective in cases studied by Dougherty8 and others. Computational tools are increasingly important in this area with respect to both the nature of solvophobic interactions and the origins of host-guest interactions.9