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H
O
N
N
O
H
H
R
H
H
H
N
O
O
N
H
N
O
N
H
N
N
O
O
N
N
O
N
N
R
N
H
anti
R
syn
X
R
anti
X
H
O
N
O
N
H
O
N
H
O
H
O
H
O
H
O
H
N
N H
O
N
N
O
N
O
O
N
N
O
H
O
N
syn
H
syn
H
Figure 2.28
Conformational preferences of various NHCO-aryl linkages.
and ones in which they are not. Figure 2.28 shows the conformational preferences of vari-
ous oligoamides NH . . . OC.
One of the first examples of an arylamide oligomer folding into helical strands was
published by Hamilton and coworkers [74], who demonstrated that anthranilic acid, a
structural analogue of a b-amino acid, forms intramolecular hydrogen bonding in the
resulting oligoamides, so that the strong tendency of the amide bond to adopt
trans
geom-
etry causes folding into helices and sheets. The DeGrado group exploited three-centered
hydrogen bond networks to design amphiphilic antibacterial foldamers. The sulfur atom
of the thioether functionality in these arylamide foldamers acts as a bifurcated hydrogen
bond acceptor, leading to a rigid conformation with segregation of hydrophobic and
hydrophilic character [75]. Lehn and coworkers reported helical foldamers based on
repeating 2,6-diaminopyridine and 2,6-pyridinedicarbonyl units [76]. These molecules
fold into helical conformations because of intrastrand hydrogen bonding and
-stacking,
both in chloroform and DMSO. Upon the addition of acid, the diaminopyridine rings are
preferentially protonated, leading to a change in conformational preferences and a con-
comitant loss of helical character. This loss of helicity is completely reversible and fold-
ing is restored when excess triethylamine is added to the system. These foldamers are
racemic in solution but display chirality when dissolved in chiral solvents (
L
-and
D
-
diethyl tartrate). In an attempt to obtain higher order assemblies from arylamide systems,
Huc and coworkers synthesized oligomers of 7-amino-8-fluoro-quinoline-2-carboxylic
acid; these subunits found a quadruplex helix arrangement in crystals grown from a mix-
ture of toluene, dichloroethane and hexane [77].
Other hydrogen-bonded foldamers have been prepared with aromatic rings connected
by groups different from amides. For instance, Gong reported aromatic oligoureas as
another class of intramolecular hydrogen-bonded foldamers, which are composed of aro-
matic rings connected through the urea functionality [78]. Meijer and coworkers reported
helically folding poly(ureidophthalimide) oligomers due to hydrogen-bonding interac-
tions between the urea hydrogens and the carbonyl group of the phthalimide moiety. The
incorporation of several PEG units into the side chains imparts water solubility to these
compounds [79]. The Li group reported hydrazide-based foldamers that form spherical
vesicles on heating in methanol [80].
Foldamers primarily driven by solvophobic or aromatic interactions are usually com-
posed of hydrophobic ring systems with polar side chains. Folding is driven by
p
p
-stacking
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