Ho Oh

p-D-ribose fi-maltose

{n-C8H17)0

Fig. 7.8 (a) Structures of the aryl 1,2-dibenzoyl hydrazide oligomers; (b) Saccharide derivatives employed for binding experiments.

sition the carbonyl groups in the interior of the cavity creating a circular array of hydrogen bond acceptors.

The addition of mono and disaccharides (Fig. 7.8b) to a solution of the fol-damer in chloroform induced a moderate CD signal. When methanol was added the CD absorption disappeared, indicating that the association between the fol-damer and the saccharide occurs mainly through hydrogen bonds. The formation of strong complexes with the longer oligomers induced an intense downfield shift of the saccharide OH signals. However, addition of the saccharides to solutions of short oligomers did not cause much change in the 1H NMR peaks. Job plots indicated the formation of 1:1 complexes and the stability constants were obtained by NMR titrations and fluorescence spectroscopy. The highest binding contant was 6.9 x 106 M-1 corresponding to the complex of the longest foldamer 12 and the disaccharide b-maltose (Fig. 7.8) indicating that the presence of numerous hydrogen bond donors and acceptors leads to greater stabilization of the complex. Additional NOE experiments showed cross-peaks between the foldamer and the guest molecules suggesting that the saccharides bind in the inner cavity of the foldamer.

Two similar foldamers based on an oligobenzamide scaffold were recently reported (Fig. 7.9) [36]. Binding of these oligomers to triol 15 and some saccharides was investigated by 1H NMR titrations in chloroform. The binding constants ranged from 5.5 x 102 M-1 for the shortest foldamer 13 with b-D-ribose, to 7.2 x 103 M-1 for the association of 14 with disaccharide b-maltose. The stability constant values indicate that the association is more favorable as more hydrogen bond donors and acceptors are available.

Fig. 7.9 Structure of foldamers 13 and 14, and triol 15.
Fig. 7.10 The role of protonation on the local conformation of the foldamer. Partial protonation maximizes dipole-dipole interactions by forcing a folded conformation.

Inouye et al. have recently reported the synthesis of poly(pyridine ethynylene) foldamers and their use as pH-dependent saccharide receptors [37]. In this study monomers of dialkylaminopyridine derivatives were used to obtain a polymer with an average length of 45 units (Fig. 7.10). Gradual addition of trifluoroacetic acid and subsequent protonation of the pyridines induced a progressive change in the UV-vis spectrum associated with the folding of the polymer into a helical conformation.

It had been previously shown that binding to hexoses can induce the transition of this type of foldamer from an unstructured to a helical conformation in chloroform [38]. The protonation-driven folding of the polymer should yield pre-organized saccharide receptors with higher affinities as entropic penalty upon binding is decreased. In fact, titration of the partially-protonated foldamer with a series of modified hexoses showed an increase in complex stability when compared to binding in the absence of acid. The increase in the binding constants ranged from a 2-fold for ¿S-d-mannose (3300 to 7200 M_1) to a 200-fold increase for b-d-fructose (100 to 20 000 M_1). Interestingly, a great excess of acid seemed to be detrimental as it induced the unfolding of the structure. The folding behavior of the polymer could be rationalized as being the result of the interaction between the monomer dipoles in solution. As shown in Fig. 7.10b, the individual dipoles created by the dialkylaminopyridine groups force the backbone to adopt an extended conformation to minimize dipole-dipole repulsion. However, protonation of one pyridine group induces an inversion of the local dipole and the rearrangement to a transoid conformation to maximize the dipole-dipole attraction. As more acid is added, the all-transoid conformation is favored leading to complete folding of the foldamer. When an excess of acid is added, however, the electrostatic repulsion between the positively-charged pyridinium ions forces the polymer to unfold. Other effects such as the presence of charge-transfer complexes between pyridinium and pyridine groups in consecutive loops of the helix certainly have an important role as well.

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