New ultrahigh affinity host-guest complexes of cucurbit[7]uril with bicyclo[2.2.2]octane and adamantane guests: thermodynamic analysis and evaluation of M2 affinity calculations

Abstract

A dicationic ferrocene derivative has previously been shown to bind cucurbit[7]uril (CB[7]) in water with ultrahigh affinity (ΔG(o) = -21 kcal/mol). Here, we describe new compounds that bind aqueous CB[7] equally well, validating our prior suggestion that they, too, would be ultrahigh affinity CB[7] guests. The present guests, which are based upon either a bicyclo[2.2.2]octane or adamantane core, have no metal atoms, so these results also confirm that the remarkably high affinities of the ferrocene-based guest need not be attributed to metal-specific interactions. Because we used the M2 method to compute the affinities of several of the new host-guest systems prior to synthesizing them, the present results also provide for the first blinded evaluation of this computational method. The blinded calculations agree reasonably well with experiment and successfully reproduce the observation that the new adamantane-based guests achieve extremely high affinities, despite the fact that they position a cationic substituent at only one electronegative portal of the CB[7] host. However, there are also significant deviations from experiment, and these lead to the correction of a procedural error and an instructive evaluation of the sensitivity of the calculations to physically reasonable variations in molecular energy parameters. The new experimental and computational results presented here bear on the physical mechanisms of molecular recognition, the accuracy of the M2 method, and the usefulness of host-guest systems as test-beds for computational methods.

Figure 1

Cucurbit[7]uril, shown as a chemical drawing (left) and in 3-dimensional representations. Side view (center) highlights the repeating glycouril unit. Top view (right) highlights the circular shape of this host. Three-dimensional graphics here and in other figures were generated with the program VMD.

Figure 2

New, designed guest molecules based on a bicyclo[2.2.2]octane core.

Figure 3

Ferrocene-based guest molecules.

Figure 4

New, adamantane-based guest molecules.

Figure 5

a. Most stable computed conformation of compound B11 complexed with CB[7], from published calculations with overly coarse finite difference Poisson-Boltzmann grid spacings (ref. 7).

Figure 5

a. Most stable computed conformation of compound B11 complexed with CB[7], from published calculations with overly coarse finite difference Poisson-Boltzmann grid spacings (ref. 7).

Figure 6

Calorimetric entropic vs enthalpic contributions to binding free energy for CB[7] host-guest systems, with cyclodextrin data as reference. Red circles: ferrocenes (Table 2). Green squares: adamantanes (Table 4). Black triangles: bicyclo[2.2.2]octanes (Table 3). Blue diamonds: compiled cyclodextrin data from multiple sources. Lines of constant binding free energy, at −2 and −20 kcal/mol, are also provided. Entropy values are for 1M standard concentration.

Figure 7

Changes in configurational entropy (−TΔS_cfg, 1M standard concentration) on binding, versus changes in potential plus solvation energy (U+W), both computed with the M2 method (see text), in kcal/mol. Prior calculations for other, lower-affinity host-guest systems are included for reference. From top to bottom, results are presented for Corrected, Academic VDW and Academic VDW/Commercial Radii parameters (Tables 2,3,4). Red circles: ferrocenes (Table 2). Green squares: adamantanes (Table 4). Black triangles: bicyclo[2.2.2]octanes (Table 3). Blue diamonds: compiled M2 results data from prior studies of cyclodextrins (filled diamonds) and other hosts^, (hollow diamonds). Lines of constant binding free energy, −2 kcal/mol above and −20 kcal/mol below, are also provided.

Figure 8

Scatter plots of derived values for the changes in solvation entropy and solvation potential energy on binding. From top to bottom, results are presented for Corrected, Academic VDW and Academic VDW/Commercial Radii parameters (Tables 2,3,4). Red circles: ferrocenes (Table 2). Green squares: adamantanes (Table 4). Black triangles: bicyclo[2.2.2]octanes (Table 3).

Figure 9

Measured changes in entropy vs. enthalpy for desolvation of various cations, ranging from +1 to +3.