Kinetic resolution of constitutional isomers controlled by selective protection inside a supramolecular nanocapsule

Abstract

The concept of self-assembling container molecules as yocto-litre reaction flasks is gaining prominence. However, the idea of using such containers as a means of protection is not well developed. Here, we illustrate this idea in the context of kinetic resolutions. Specifically, we report on the use of a water-soluble, deep-cavity cavitand to bring about kinetic resolutions within pairs of esters that otherwise cannot be resolved because they react at very similar rates. Resolution occurs because the presence of the cavitand leads to a competitive binding equilibrium in which the stronger binder primarily resides inside the host and the weaker binding ester primarily resides in the bulk hydrolytic medium. For the two families of ester examined, the observed kinetic resolutions were highest within the optimally fitting smaller esters.

Figure 1. Molecular structures of the host and guests used in this study

Deep-cavity cavitand host 1, and the two series of ester guests 2–6 (13 non-hydrogen atoms) and 7–11 (16 non-hydrogen atoms).

Figure 2. Binding of esters inside a deep-cavity cavitand

Main spectrum: ¹H NMR spectrum in D₂O of the 2:1 complex (~1 mM) formed between host 1 and ester 6. High-field guest signals are highlighted. The residual signal from DMSO-d₆ arises from the necessity to dissolve the ester in a small volume of DMSO-d₆. Upper spectrum: ¹H NMR guest binding region for a 2:1:1 ratio of host 1 and esters 5 and 6 (~1 mM host). Integration of selected bound guest signals gives a 0.8:1 ratio of complexes 1₂.5 and 1₂.6, respectively and allows calculation of the relative binding affinities of each guest.

Figure 3. Kinetics for the hydrolysis of ester 6 in the presence or absence of the cavitand

Triangles show the hydrolysis in 3:7 acetone-d₆:D₂O containing 10 mM NaOH_aq and ester 6 (0.5 mM) at 26 °C. Stars show the rate of hydrolysis in the presence of capsule 1₂ (0.5 mM) at 100 °C in 18 mM NaOH_aq (note that 8 equiv. of base are required to deprotonate the capsule). The rate of hydrolysis is slower even at a significantly higher temperature, because the capsule can protect the ester from the hydrolytic environment.

Figure 4. Hydrolysis of similarly sized esters encapsulated within host 1₂

a–d, Observed data are shown as points, and calculated fit curves are shown as dashed lines for the hydrolysis of methyl decanoate (2) (a), ethyl nonanoate (3) (b), propyl octanoate (4) (c) and pentyl hexanoate (6) (d). Ester 4 is hydrolysed at approximately four times the rate of the other guests.