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Local Conformational Control

Though the definition given above of fully predictable foldamers seems quite general, the families of molecules that fall in this category are, in fact, rather homogeneous and almost all consist of p-conjugated systems - for example, aryls, amides, esters or ureas - connected by single bonds. Evidently, p-conjugation is a very efficient means of restricting rotation about a single bond as it stabilizes conformers where two p-systems are close to being coplanar, allowing the p-orbitals of sp2-hybridized atoms to overlap. This effect is stronger in true p-conjugated systems where para- or ortho-connectivity between aryl rings gives rise to resonance, but it remains substantial even for meta-connected - cross-conjugated - systems. Upon effecting a 180° rotation about the single bond between two p-systems, two degenerate conformers may be possible, but degeneracy is easily lifted. Fig. 1.2 shows a number of conformational equilibria for which a single stable conformation exists at a single bond connecting two p-conjugated systems. These examples are representative of the families of fol-damers described in Sections 1.3.2 and 1.3.3, but it is clear that many alternate schemes could be devised along the same lines.

Thus, aryl-CONH single bonds adopt syn conformations when the aryl ring possesses a hydrogen bond donor ortho to the amide group (Fig. 1.2a). The hydrogen bond donor may be an exocyclic OH [12] or NH [13-17], or an endocyclic N+H [18]: all three moieties hydrogen bond to the amide carbonyl and repel the amide proton. Conversely, the anti conformation of aryl-CONH linkages is stabilized by hydrogen bond acceptors on the aromatic ring (Fig. 1.2b) which attract the amide proton and repel the amide oxygen. The most common groups used as hydrogen bond acceptors are endocyclic nitrogen atoms [13, 15-42] or exocyclic ether oxygen atoms [39, 43-55], but other functional groups have also been shown to be effective, for example, exocyclic fluorine [56], imino nitrogen [57], N-oxide oxygen [14] and phenolate oxygen [12].

Conformations about aryl-NHCO linkages are controlled in a very similar way by hydrogen bond donors or acceptors ortho to the amide function on the aromatic ring. For instance, a syn conformation is favored by a proton [18, 37, 38, 58-60] or a metal ion [40, 61, 62] that can coordinate to an amide carbonyl (Fig. 1.2c). An anti conformation is favored when a hydrogen bond acceptor is introduced which binds to the amide proton and/or repels the amide oxygen (Fig. 1.2d). Effective acceptors include exocyclic ether oxygen [12, 27, 28, 40, 44, 45, 47, 4955] or sulfur [43, 63-65] atoms; exocyclic fluorine [56]; endocyclic nitrogen [1821, 29, 33, 37, 38, 41]; exocyclic N-oxides [66] or phenolates [12]; exocyclic carbonyl oxygen [16, 17, 32, 39, 48, 67-70]; as well as sp2 nitrogen atoms belonging to connected [71] or fused [24-26, 29, 30, 34-36] aromatic rings.

Fig. 1.2 Stabilization of well-defined rotamers through local attractive (hashed lines) and repulsive (double headed arrows) interactions. The stabilized conformer is shown on the left side of each equilibrium. "X-A" and ''X-D'' correspond to hydrogen bond donor and hydrogen bond acceptor moieties, respectively. When ''X-D'' does not bear a hydrogen but a metal ion, it is an electron acceptor. (a)-(b) aryl-CONH linkage; (c)-(e) aryl-NHCO linkage; (f) aryl-aryl, aryl-imine and aryl-hydrazone linkages; (g) restricted rotation about an acetylene bond; (h) aryl-carboxyl bond where sp3 and sp2 hybridized oxygen atoms are discriminated.

Fig. 1.2 Stabilization of well-defined rotamers through local attractive (hashed lines) and repulsive (double headed arrows) interactions. The stabilized conformer is shown on the left side of each equilibrium. "X-A" and ''X-D'' correspond to hydrogen bond donor and hydrogen bond acceptor moieties, respectively. When ''X-D'' does not bear a hydrogen but a metal ion, it is an electron acceptor. (a)-(b) aryl-CONH linkage; (c)-(e) aryl-NHCO linkage; (f) aryl-aryl, aryl-imine and aryl-hydrazone linkages; (g) restricted rotation about an acetylene bond; (h) aryl-carboxyl bond where sp3 and sp2 hybridized oxygen atoms are discriminated.

These numerous examples are illustrative of the diversity of aromatic amide foldamers. The attractive interactions that stabilize a given rotamer often consist of bifurcated and not necessarily strong hydrogen bonds. However, the role of repulsive interactions (double headed arrows in Fig. 1.2) should not be underestimated. Although their exact contribution has not been quantified, it is likely that their strength is no less than that of hydrogen bonds.

Related structures involve aromatic sulfonamides [72], hydrazides [73], or diazo groups [42]. In some cases, conformational preference may appear as less obvious, but nevertheless exists. For example, in the 2-pyridyl-carboxyl linkage shown in Fig. 1.2h, both the sp2 and sp3 hybridized oxygen atoms of the carboxyl function are a priori involved in repulsive electrostatic interactions with the neighboring endocyclic nitrogen atom. However, a stronger repulsion involving the car-bonyl oxygen leads to a stabilization of the anti conformer [26]. For the 2-pyridyl ureas shown in Fig. 1.2e, attractive interactions exist both for the syn and anti conformers [74-78]. While both conformers are at equilibrium when the urea moiety is unsubstituted [76, 79, 80] the cis urea conformation and thus the syn conformation of the aryl-urea linkage are stabilized by an N-alkyl group [81] (see also Section 1.4.1).

The schematic equilibrium shown in Fig. 1.2f covers a number of aryl-aryl connections between pyridine, and other aza-aromatics, as well as aryl-hydrazone linkages. These have been used extensively by the group of Lehn to produce a wide variety of foldamers [82-98].

The restricted rotations presented above are all well documented in the literature. In particular, crystallographic data are available in most cases. The global trend that emerges from these data is a remarkable reliability of the predicted preferred conformations. Only three crystal structures were found showing significant deviations from the predicted more stable conformations. As shown in Fig. 1.3, they all concern the anthranilamide motif and represent interesting snapshots of presumably ill-folded conformations [14, 15].

Finally, rotamers stabilized by local interactions that involve weak p-conjugation or no conjugation at all should also be mentioned. This is the case for the equilibrium shown in Fig. 1.2h where rotation about a diaryl-acetylene linkage is restricted by hydrogen bonding between functions on either side of the triple bond [99-101]. This motif has been introduced within some solvophobically driven foldamers such as oligophenylethynylenes (see Chapter 3) to stabilize the folded conformations in solvents that do not promote solvophobic effects. Other examples include 3,5-linked oligopyrrolin-4-one [102] and some constrained dipeptides [103] (see Section 1.3.3).

Fig. 1.3 Top view and front view of three anthranilamide motifs observed in the crystalline state showing substantial deviations from the canonical planar six-membered NH-O=C intramolecularly hydrogen bonded ring [14, 15].

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