Sculpting New Shapes by Integrating H-Bonding, Aromatic Interactions and Multiple Levels of Pre-organization

As outlined in the previous sections, optimal backbone pre-organization for the formation of H bonds and stabilization of well-defined secondary structures (helices and hairpin type structure) has been achieved at an unprecedented level for a whole series of aliphatic oligoamides and related peptidomimetic oligomers. The design principles applied to homogeneous backbones have been extended successfully to heterogeneous backbones. Recent studies with aromatic oligoa-mides suggest that it is possible to design oligomeric sequences coding for more complex structural information. Hunter and Thomas have shown that 38, a C2-symmetric strand built of isophthalic acid, bisaniline and 4-nitro-1H-pyrrole-2-carboxylic acid residues adopt in nonpolar solvent (CDCl3) a well defined and unusual fold, stabilized by a combination of H-bonding and aromatic interactions between non-nearest neighbors (Fig. 2.19A) [185].

Experimentally measured folding-induced changes in 1H-NMR chemical shift (Ad) [186] compared with unfolded reference compounds were used to calculate the three dimensional structure of this "tailbiter". Experimental H-D exchange data reflect the difference of free energy in CDCl3 between the H-bonds at work, pyrrole-amide (@6 kJ mol-1) versus amide-nitro (@2 kJ mol-1) H-bonds) and support a noncooperative unfolding mechanism. Self-organization properties of related aromatic oligoamides composed of isophthalic acid, and bisaniline units in nonpolar solvents have been exploited for the synthesis of a whole series of supra-molecular entities [187, 188], including molecular trefoil knots [189, 190]. Folding of oligoamide 41 - which has been proposed to be formed transiently upon reaction of diamine 39 with 2,6-pyridinedicarboxylic acid dichloride 40 - into a helical loop stabilized by a complex collection of intrastrand H-bonding (both remote and between nearest neighbors) and aromatic interaction is thought to be an early and critical event prior to self-threading and successful closing to amide-knot 42 (Fig. 2.19B).

Fig. 2.19 Aromatic oligoamide foldamers (A) "Tailbiter" 38 [185]; (B) Proposed folding mechanism for the formation of amide knot 42 [189].
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