Mapping the Internal Recognition Surface of an Octanuclear Coordination Cage Using Guest Libraries

Size
and shape criteria for guest binding inside the cavity of
an octanuclear cubic coordination cage in water have been established
using a new fluorescence displacement assay to quantify guest binding.
For aliphatic cyclic ketones of increasing size (from C5 to C11), there is a linear relationship between ΔG for guest binding and the guest’s surface area:
the change in ΔG for binding is 0.3 kJ mol–1 Å–2, corresponding to 5 kJ
mol–1 for each additional CH2 group in
the guest, in good agreement with expectations based on hydrophobic
desolvation. The highest association constant is K = 1.2 × 106 M–1 for cycloundecanone,
whose volume is approximately 50% of the cavity volume; for larger
C12 and C13 cyclic ketones, the association
constant progressively decreases as the guests become too large. For
a series of C10 aliphatic ketones differing in shape but
not size, ΔG for guest binding showed no correlation
with surface area. These guests are close to the volume limit of the
cavity (cf. Rebek’s 55% rule), so the association constant
is sensitive to shape complementarity, with small changes in guest
structure resulting in large changes in binding affinity. The most
flexible members of this series (linear aliphatic ketones) did not
bind, whereas the more preorganized cyclic ketones all have association
constants of 104–105 M–1. A crystal structure of the cage·cycloundecanone complex shows
that the guest carbonyl oxygen is directed into a binding pocket defined
by a convergent set of CH groups, which act as weak hydrogen-bond
donors, and also shows close contacts between the exterior surface
of the disc-shaped guest and the interior surface of the pseudospherical
cage cavity despite the slight mismatch in shape.