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.The simple act of compartmentalization is essential to chemistry. To an organic chemist, a round-bottomed flask is both a means of promoting a reaction by keeping reagents in, and stopping reactions by keeping species such as adventitious water out. In parallel with these concepts, in recent years supramolecular chemists have developed the idea of using container molecules as yocto-litre flasks to promote new reactions . However, there has been little progress in using container molecules as a means of protection. Indeed, to our knowledge, there has been only one reported example of supramolecular protection, where a primary amine product was prevented from over-alkylation by complexation to a cavitand 24 .While considering the idea of protection via compartmentalization, it occurred to us that one of the strengths of container molecules that fully envelop their guests is their ability to recognize subtle differences between the gross overall forms of molecules. Consequently, many of the container molecules in the literature could theoretically bring about not just the familiar kinetic resolution of stereoisomers [25][26][27][28] , but also the as yet unexplored topic of the kinetic resolution of constitutional isomers. Regarding the latter, there are of course many examples of compounds only being available as mixtures with constitutional isomers or constitutionally similar molecules. Hence, establishing a proof-of-principle that container molecules could effect such purifications could be quite powerful. In this Article, we report on the ability of supra-molecular nanocapsules to bring about the kinetic resolution of constitutionally isomeric long-chain esters. More specifically, we show that the capsule formed by water-soluble host * Correspondence and requests for materials should be addressed to B.C.G. bgibb@uno.edu. Author contributionsB.C.G. and S.L. conceived and designed the experiments. S.L. synthesized esters 2-6 and performed the experiments involving these guests. H.G. and A.T.H contributed equally to the syntheses and experiments involving esters 7-11. B.C.G. wrote the paper. Additional informationThe authors declare no competing financial interests. Supplementa...

Simulation optimization of spherical non-polar guest recognition by deep-cavity cavitands

“…3 Second, the pocket entrance is rimmed with aromatic rings that bestows OA a predisposition to assemble into dimeric capsules. 4 These capsules have been used as yoctoliter reaction vessels, [5][6][7] separation devices, 8,9 for modulating the properties of redox-active 10 or fluorescence guests, 11,12 as well as controlling electron transfer 13 and electron-electron communication. 14 In addition to this capsule chemistry, three classes of guests bind to OA without triggering assembly and consequently allow the study of a range of 1:1 complexes.…”

A polyaromatic molecular tube that binds long hydrocarbons with high selectivity

“…), indicating tight contacts between the central part of 6a and the anthracene frameworks of 1. The NOESY NMR spectrum showed several sets of correlation signals between the tube and the bound guest (for example, H B,b -H 10 , H C,c -H 10 and H F,f -H 8,9 ). An optimized structure of 1 0 Á 6a (R ¼ H), which is in good agreement with the NOESY study, shows that the long hydrocarbon chain (2.7 nm in diameter) of 6a is partially sandwiched by the anthracene panels of 1 (Fig.…”

“…However, the recognition of long hydrocarbons by synthetic hosts is a challenging task due to their conformational flexibility and the lack of distinguishing recognition sites. Thus it is not surprising that the selective binding of simple or functionalized (for example, branched methyl groups or unsaturated carbon-carbon double bonds) long hydrocarbon chains, essential components for biological function 1,2 , has not yet been achieved with artificial host molecules [10][11][12][13][14] . We envisioned that a tubular host providing a well-defined but open cavity encompassed with polyaromatic frameworks resembling a carbon nanobelt 15 could accomplish the selective binding of such long hydrocarbons through effective polyaromatic-aliphatic host-guest interactions (Fig.…”

On the Nature of the Transition State Characterizing Gated Molecular Encapsulations

“…In line with this mechanistic hypothesis, varying the size of solvent molecules should have an effect on the rate by which guest 2 departs the basket: more sizeable compounds should create a greater van der Waals strain, while entering or exiting the host (vide infra), to affect the in/out exchange! Accordingly, we measured ( (6). The rate coefficients k out were, importantly, found to increase (while k in decreased) for smaller solvents (Table 1).…”

“…Indeed, elucidating the mechanism of the operation of cavitands [2][3][4][5] has been an interest for controlling the outcome of chemical reactions [6], stabilizing reactive intermediates [7], or delivering useful molecules [8,9]. Accordingly, for the complexation of metal cations with crown ethers, Schneider and Cox reported that the rates by which cations access (k in ) the macrocycles are fast (approaching a diffusion-controlled limit) while their departure from the complex (k out ) is much slower corresponding to the thermodynamic stability (∆G°) of the complex OPEN ACCESS itself [10].…”