Fig. 7.3 Structures of aryl oligoamide foldamers and the ammonium salts used as guest molecules.

strong hydrogen bonds independent of the concentration which ruled out intermolecular association.

Addition of ammonium salts 4 and 5 (Fig. 7.3) caused a substantial increase in the fluorescence intensity of the foldamers. Only a small increase in the fluorescence was observed when a quaternary alkyl ammonium salt was added suggesting that both the formal positive charge and the presence of free hydrogen bond donors in the guest molecule are essential for binding. 1H NMR titration experiments were carried out by monitoring the shift of the NH signals induced by the association with the ammonium salt in chloroform. The association constants (Ka) obtained ranged from 14 to 360 M-1, being higher for the less hindered primary amine 5. The stability of the complex increased with the length of the fol-damer, 2 being a better receptor than 1, presumably because of the presence of more available hydrogen bond acceptors. However, foldamer 3 showed decreased binding affinity which was rationalized as the result of an excess of steric repulsion caused by the methyl substituents within the binding cavity.

More recently the same authors presented a modified scaffold in which the me-thoxy substituents were replaced by fluorine atoms (Fig. 7.4) [18]. Although there are extensive studies that suggest that covalently bound fluorine is not a good hydrogen bond acceptor, the X-ray structure of the monomer unit proved that the fluorines are involved in hydrogen bonding. The fluorine atoms interact with the amide NHs leading to a rigid well-folded structure. Large down-field shifts in the NMR spectrum were observed for the NH peaks in solution for both foldamers (7 and 8) compared to those obtained in control compounds providing evidence of the presence of these F-H-N bonds in chloroform.

Titration experiments with the ammonium salt of dioctylamine 4 (Fig. 7.3) gave stability constants of 4.9 x 106 and 8.1 x 106 M_1 for foldamers 7 and 8, respectively, and Job plots suggested the formation of 1:1 complexes which was further corroborated by ESI-MS. Additionally, a series of NOE cross-peaks were also observed between the ammonium protons and some of the amide hydrogens of the foldamers suggesting inclusion of the ammonium ion into the cavity.

Fig. 7.4 Structure of the fluorine-containing aryl oligoamide foldamers.
Fig. 7.5 Structure of the naphthalene-based foldamers.

In the same study, the binding of the ammonium salt of a tyrosine derivative 6 (Fig. 7.3) was investigated. The addition of the chiral guest gave rise to a CD signal in the foldamers' absorption wavelength that increased as the concentration of the guest molecule rose. These results, along with the fact that the intensity of the CD signal decreased with the addition of methanol, suggest that the foldamers are indeed binding to the guest through electrostatic or hydrogen-bonding interactions.

Solvophobic effects have been often used as the driving force to obtain well-folded structures (see Chapter 3) [19-22]. Chen and co-workers took advantage of this principle in the design of a new family of foldamers [23]. The scaffolds consisted of a series of naphthalene groups connected by diethylene glycol spacers (Fig. 7.5). In polar solvents the oligomeric chain should adopt a helical conformation in which the hydrophobic naphthalene groups are stacked on top of each other minimizing their exposure to the solvent. As a result, the ethylene glycol spacers should create a cavity that resembles the well-studied crown ethers.

The UV-vis absorption spectra of the foldamers were recorded in different chloroform-acetonitrile mixtures at a concentration low enough to avoid intermolecular association. As the polarity of the mixture was increased with a higher percentage of acetonitrile, the samples underwent a significant hypochromic shift compared to the control. This effect was caused by the p-stacking of the aromatic subunits and was therefore an indicator of the progressive folding of the scaffolds with the increasing polarity of the media. The absorption of the longest oligomers reached a plateau and remained constant for mixtures having more than 50% acetonitrile, indicating that the foldamer was completely folded at that polarity. Moreover, the fact that the hypochromic changes occurred at a lower polarity for longer, more hydrophobic oligomers supports the idea that folding is facilitated by solvophobic forces and takes place in a cooperative manner. 1H NMR and fluorescence experiments also contributed compelling evidence of complete folding in polar solvents.

It is well known that macrocyclic crown ethers have high affinity for ammonium ions [24, 25]. Due to the resemblance of these foldamers to crown ethers, Chen et al. studied their ability to bind to ammonium ions. Indeed, addition of the diammonium salt of ethylenediamine in deuterated acetonitrile induced shifts in the foldamers' 1H NMR resonances confirming the complexation of the ions with stability constants around 104 Additional Job plots indicated the formation of 1:1 complexes. NOESY experiments of the complex with the longest oligomer (Fig. 7.5, where n = 5) revealed intermolecular NOE cross-peaks between the foldamer methylenes and the guest CH2 protons which further confirmed the formation of the complex. Interestingly, intramolecular NOE cross-peaks were also observed that were not present in the absence of the diammo-nium salt suggesting that the foldamer becomes even more compact and rigid upon binding.

Was this article helpful?

0 0

Post a comment