Binding of Hydrophobic Guests in a Coordination Cage Cavity is Driven by Liberation of "High-Energy" Water.

Alexander J Metherell,Nicholas H Williams,William Cullen,Michael D Ward

doi:10.1002/chem.201704163

Alexander J Metherell, Nicholas H Williams + Show 2 more

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https://doi.org/10.1002/chem.201704163

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Abstract

The cavity of an M8L12 cubic coordination cage can accommodate a cluster of ten water molecules in which the average number of hydrogen bonds per water molecule is 0.5 H‐bonds less than it would be in the bulk solution. The presence of these “hydrogen‐bond frustrated” or “high‐energy” water molecules in the cavity results in the hydrophobic effect associated with guest binding being predominantly enthalpy‐based, as these water molecules can improve their hydrogen‐bonding environment on release. This contrasts with the classical form of the hydrophobic effect in which the favourable entropy change associated with release of ordered molecules from hydrophobic surfaces dominates. For several guests Van't Hoff plots showed that the free energy of binding in water is primarily enthalpy driven. For five homologous pairs of guests related by the presence or absence of a CH2 group, the incremental changes to ΔH and TΔS for guest binding—that is, ΔΔH and TΔΔS, the difference in contributions arising from the CH2 group—are consistently 5(±1) kJ mol−1 for ΔΔH and 0(±1) kJ mol−1 for TΔΔS. This systematic dominance of ΔH in the binding of hydrophobic guests is consistent with the view that guest binding is dominated by release of “high energy” water molecules into a more favourable solvation environment, as has been demonstrated recently for some members of the cucurbituril family.

Highlights

Of the factors that control host-guest binding in water, whether using biological or artificial receptors, the hydrophobic effect is probably the most important and yet is still poorly understood.[1,2,3,4] The favourable free energy change associated with bringing together hydrophobic surfaces of host and guest species that become desolvated was originally explained in terms of a favourable entropy change arising from the liberation of ordered water molecules at the interfaces.[2]
The degree of frustration per water molecule, multiplied by the number of water molecules liberated from the cavity when a guest binds, gives a rough estimate of the enthalpic stabilisation associated with the hydrophobic contribution to guest binding
The bound water molecules do not is substituted on the exterior surface with hydroxymethyl groups to aid water solubility[10b]) constitute a host system in which the factors responsible for guest binding in different solvents have been studied in considerable detail

Summary

Introduction

Of the factors that control host-guest binding in water, whether using biological or artificial receptors, the hydrophobic effect is probably the most important and yet is still poorly understood.[1,2,3,4] The favourable free energy change associated with bringing together hydrophobic surfaces of host and guest species that become desolvated was originally explained in terms of a favourable entropy change arising from the liberation of ordered water molecules at the interfaces.[2]. The degree of frustration per water molecule (i.e. the deficiency in the average number of hydrogen bonds formed, compared to what can happen in bulk solution), multiplied by the number of water molecules liberated from the cavity when a guest binds, gives a rough estimate of the enthalpic stabilisation associated with the hydrophobic contribution to guest binding This combination explains why the cucurbituril heptamer (CB7) provides remarkably strong binding of hydrophobic guests that is unmatched by any other synthetic host and makes it stand out from its smaller and larger analogues CB6 and CB8.[5] Whilst the water molecules in CB6 are individually more frustrated than those in CB7, there are far fewer of them. The octanuclear, approximately cubic, M8L12 coordination cages[9l,10] shown in Figure 1 (H is the parent cage that is water-insoluble;[10a] Hw guests in the cage cavity in water has a substantial enthalpy component, and propose that this arises from the energetic frustration of cage-bound water in the free cage—so-called “high-energy water”, as in the CB series of hosts.[4,5] Using an incremental approach, by comparing pairs of similar guests that differ by just a methylene (CH2) group, we show how we can quantify the additional DH and DS contributions to the hydrophobic effect of guest binding arising from the extra CH2 units

Results and Discussion

Conclusions

Conflict of interest