Unraveling the Structure–Affinity Relationship between Cucurbit[<i>n</i>]urils (<i>n</i> = 7, 8) and Cationic Diamondoids

Abstract

We report the measurement of the binding constants ( K a ) for cucurbit[ n ]uril ( n = 7, 8) toward four series of guests based on 2,6-disubstituted adamantanes, 4,9-disubstituted diamantanes, 1,6-disubstituted diamantanes, and 1-substituted adamantane ammonium ions by direct and competitive 1 H NMR spectroscopy. Compared to the affinity of CB[7]·Diam(NMe 3 ) 2, the adamantane diammonium ion complexes (e.g., CB[7]·2,6-Ad(NH 3 ) 2 and CB[7]·2,6-Ad(NMe 3 ) 2 ) are less effective at realizing the potential 1000-fold enhancement in affinity due to ion–dipole interactions at the second ureidyl C═O portal. Comparative crystallographic investigation of CB[7]·Diam(NMe 3 ) 2, CB[7]·DiamNMe 3, and CB[7]·1-AdNMe 3 revealed that the preferred geometry positions the + NMe 3 groups ≈0.32 Å above the C═O portal; the observed 0.80 Å spacing observed for CB[7]·Diam(NMe 3 ) 2 reflects the simultaneous geometrical constraints of CH 2 ···O═C close contacts at both portals. Remarkably, the CB[8]·IsoDiam(NHMe 2 ) 2 complex displays femtomolar binding affinity, placing it firmly alongside the CB[7]·Diam(NMe 3 ) 2 complex. Primary or quaternary ammonium ion looping strategies lead to larger increases in binding affinity for CB[8] than for CB[7], which we attribute to the larger size of the carbonyl portals of CB[8]; this suggests routes to develop CB[8] as the tightest binding host in the CB[ n ] family. We report that alkyl group fluorination (e.g., CB[7]·1-AdNH 2 Et versus CB[7]·1-AdNH 2 CH 2 CF 3 ) does not result in the expected increase in K a value. Finally, we discuss the role of solvation in nonempirical quantum mechanical computational methodology, which is used to estimate the relative changes in Gibbs binding free energies.