Foldamers Stabilized by Adjacent Identical Aromatic Units

From the viewpoint of geometrical manipulation, it is not a good idea to start designing solvophobic foldamers from flexible aliphatic hydrocarbon chains. Instead, rigid aromatic rings represent much more reasonable solvophobes with higher levels of geometrical constraints - effective aromatic interactions are only obtained in three main geometries: edge-face, offset stacked, and stacked [7578]. For aromatic foldamers, geometrical manipulation is achieved through both the aromatic units and the spacers (Fig. 3.2). Strong van der Waals and solvopho-bic interactions are obtained with large aromatic units in the stacked or offset stacked configurations. Length and flexibility of the spacers are also important to the foldability of the chain.

Some of the earliest aromatic foldamers rely on cis-oriented amides, ureas, and guanidines (made possible by alkyl-substitution on the nitrogen) to form folded structures [79-84]. Both 7 and 8 adopted folded conformations in the solid state based on X-ray crystallography. In solution, p-p stacking was confirmed by NOE and upfield shifts of proton signals in the longer oligomers. The substituent on the nitrogen is not limited to methyl; bulkier groups such as benzyl and even (S)-1-(1-naphthyl)ethyl recently were found to promote cis conformations in several aromatic foldamers (9) with naphthalene in the main chain [85]. See Chapter 1 for more details for these and related molecules.

In an effort to synthesize tubular cyclophanes by ring closure of ladder-like molecules, Vogtle and co-workers prepared oligomers such as 10 [86-92]. Its crystal structure revealed S-shaped conformations with stacked aromatic rings [88]. The authors did not report whether the stacked conformers could unfold under thermal or solvent-denaturating conditions, but did show these S-shaped conformations were maintained in chloroform.

Scheme 3.4
Scheme 3.5

Rathore et al. reported oligofluorenes 11 with simple methylene as the spacer [93]. The difference between this and most other foldamers is that aromatic groups are in the side chains instead of the main chain of the molecule. With the fluorenes closely stacked, oxidation potential decreases from 1.74 V for the monofluorene to 1.14 V for the tetrafluorene derivative. Similar behavior was observed in photoelectron spectroscopy and may be relevant to electron-transport mechanisms in DNAs through p-stacked bases.

Unlike most noncovalent interactions, hydrophobic forces increase in strength with an increase in temperature [2-8]. This feature was exploited by Li et al. in perylene-DNA hybrid foldamer 12 [94-96]. (Because the DNA bases are not involved in base pairing and p-p stacking, the compound is classified as a foldamer stabilized by adjacent aromatic units.) The folding reaction was endothermic (AH = 2.7,4.4,4.8, and 6.9 kcal mol-1 for the folding of two, three, four, and five perylene units) but entropically favored. Consequently, 12 adopted more compact stacking structures at 90 °C than at 20 °C [94]. These foldamers were compared to proteins isolated from thermophilic and hyperthermophilic microorganisms that showed better folding propensity near the boiling point of water. Perylene units preferred to associate with one another despite the presence of many nucleotide bases present in the structure. The nucleotide bases are less hydrophobic and also do not match perylene in shape and size. Selective association of perylene in the presence of other heterocycles, therefore, is related to the concept of geometrical manipulation mentioned earlier. Perylene bisimide units also were connected with polytetrahydrofuran chains by Janssen and co-workers to form polymers [97]. The polymers were found to form stacked structures in o-dichlorobenzene, highlighting the stability of the aromatic interactions (even in aromatic solvents).

Scheme 3.6
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