Fig. 7.6 (a) Structure of the m-phenylene ethynylene oligomer 9 and hydrophobic small molecules used as guests; (b) Association models of m-phenylene ethynylene foldamer (gray) and (-)-a-pinene (red). The polyethyleneglycol chains have been omitted for clarity.

Fig. 7.6 (a) Structure of the m-phenylene ethynylene oligomer 9 and hydrophobic small molecules used as guests; (b) Association models of m-phenylene ethynylene foldamer (gray) and (-)-a-pinene (red). The polyethyleneglycol chains have been omitted for clarity.

chloroform to a compact helical conformation in more polar solvents such as ace-tonitrile [21]. Folding created a tubular hydrophobic cavity that could potentially bind apolar molecules. This idea was tested by addition of enantiomerically pure (-)-a-pinene (Fig. 7.6a) to a solution of the foldamer in acetonitrile. The appearance of a strong CD signal was observed in the absorption range of the foldamer which was indicative of its association with the chiral a-pinene. The addition of (+)-a-pinene resulted in the mirror image of the CD trace and further confirmed that the Cotton effect was a direct consequence of the chiral environment present in the foldamer upon binding to the chiral small molecule. Interestingly, addition of the chiral guest did not result in major changes in the UV-vis spectrum of the foldamer. This result was in accordance with the presence of a well-folded structure prior to the addition of the guest molecule since changes in the absorption pattern would have indicated major alterations of the p-stacking interactions.

CD spectroscopy was used to perform a titration and corroborate the formation of a 1:1 complex in mixtures of acetonitrile-water. The value of the binding constant for this interaction increased as the percentage of water rose indicating that binding of the hydrophobic a-pinene to the foldamer was a solvophobically driven process. Even though the foldamer was insoluble in pure water, the complex stability in this solvent was estimated to be 6 x 104 by extrapolating the values of the binding constants with increasing water content. The high value of this binding constant and the perfect fitting of the titration to a 1:1 binding model ruled out the presence of nonspecific interactions. Additional hydrophobic mono-terpenes shown in Fig. 7.6a were tested and found to bind to the foldamer at 40% water in acetonitrile. They all formed 1:1 complexes with similar binding affinities. To confirm that the small hydrophobic molecules are binding within the cavity, two modified foldamers were synthesized that included aromatic methyl groups. The methyl substituents were designed to fill the cavity upon folding, disfavoring the binding of small molecules. Previous solvent denaturation studies showed that the addition of these methyl groups did not interfere with the folding process. Indeed, the affinity of these new structures for pure a-pinene was up to 100-fold lower than that of the foldamer with an unfilled cavity and therefore confirmed that binding occurred in the central cavity (Fig. 7.6b).

The insolubility of these receptors in pure water was addressed in a more recent study [27]. Complete water solubility was achieved by incorporating longer polyethylene glycol chains into the design. As before, a-pinene was used as the hydrophobic guest but in this case binding could be seen only when the amount of water was higher than 60%. The authors suggested that one of the polyethylene glycol chains could be folding inwards, interacting with the hydrophobic core and effectively competing with a-pinene at lower water percentages. Varying the water composition from 60 to 90% resulted in a nonlinear increase of the affinity constants ranging from 104 to 106 M_1. Interestingly, the binding equilibrium was reached more slowly in higher water content mixtures supporting the idea that the formation of a partially unfolded intermediate that exposes the hydropho-bic core to the solvent is the rate-limiting step in the binding process.

The cylindrical shape of the cavity led Moore et al. to consider using elongated chiral guest molecules such as the diphenylpiperazine derivative shown in Fig. 3.7 of Chapter 3 [28]. Addition of this small chiral molecule to m-phenylene ethynylene oligomers (16, 18, 20, 22 and 24-mer) induced a CD signal allowing the titration of the complex. The best stability constant for a 1:1 complex was 5.6 x 103 in 40% water. Further studies indicated that the piperazine derivative binds through insertion into the cavity rather than by intercalating between the helical loops. In order to obtain some insight into the binding mechanism, the researchers synthesized a guest with a voluminous trisaryl group at each end of a central piperazine core (Fig. 3.7, Chapter 3) [29]. The presence of bulky aryl groups did not prevent complexation although kinetic studies showed a slower rate of complexation suggesting that a partial unfolding was necessary prior to binding.

In an interesting variation of these experiments, the authors used the same hindered piperazine derivative to induce the formation of the optimal foldamer receptor through dynamic templation [30]. In this approach, imine derivatives of a group of oligomeric precursors were allowed to equilibrate with the guest (Fig. 7.7). When the experiment was carried out in an apolar solvent that did not induce folding, the result was a statistical mixture of all the possible products. However, when the experiment was repeated in a polar solvent such as acetonitrile, the composition changed with an increased ratio of the foldamer that had the optimal length that maximized the binding to the piperazine. This elegant study is the proof of concept that dynamic libraries can be used to optimize foldamer receptors.

Fig. 7.7 Schematic diagram of the dynamic library approach to find the optimal length of the foldamer (Reproduced with permission from the authors).

The same scaffold has been recently modified by increasing the polarity of the cavity interior [31, 32]. In one of these variations, Moore et al. introduced a series of arylamide monomers into the foldamer sequence. This modification was aimed at the creation of a more hydrophilic cavity and was used to study the recognition of a positively charged guest.

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