Folded Conformations of p-conjugated Systems

The interactions that drive the local conformational preferences in fully predictable foldamers are largely two-dimensional (2-D); this can be attributed to the planar nature of the repeating unit(s), the linkages, and the relative positioning of consecutive units (Fig. 1.2). The curvature (or lack thereof) resulting from this 2-D folding relies on the nature and geometry of intramolecular hydrogen bonding, electrostatic repulsions, and/or steric interactions. The crystal structures of short sequences of monomers actually often reveal rigorously flat arrangements. It is this 2-D nature that makes structure prediction so easy; simple molecular modeling or even paper sketching allows one to determine the relative orientation of the consecutive units according to the conformational preferences shown in Fig. 1.2. When several units are connected within a sequence, the overall conformation results from the sum of each preferred rotamer. Crescents and Helices

The relative orientation of consecutive units within even a very short oligomer may result in a stable, planar, curved, crescent-like conformation. In this respect, fully predictable foldamers strongly differ from most other foldamer families where strand bending is hardly possible in the absence of contacts between functions remote in the sequence as found in helices or hairpin turns. As the length of a crescent-like oligomer is increased, deviation from planarity is imposed by steric repulsions between the extremities of the crescent, and the 2-D structure becomes three-dimensional, giving rise to a helical conformation. As shown in Fig. 1.4, such helices have been designed and characterized using various types of monomeric units and certainly represent the flagship of fully predictable fol-damers. The top views of the structures of Fig. 1.4 are illustrative of the structural differences between the helices highlighting the different number of units per turn and the variable inner diameters. The side views of the structures are remarkably similar despite the completely different nature of backbone compositions: in all cases, the helical pitch of these p-conjugated systems equals the thickness of one aromatic ring. Most of these oligomers are constructed by alternating two types of symmetrical units and do not possess a helical polarity such as that of peptides. However, the examples shown in Figs. 1.4a and d are built using directional units (3-amino-benzoic acid [45] and 8-amino-2-quinolinecarboxylic acid [97], respectively), but in both cases, these have been connected to a central symmetrical spacer in order to double the oligomer length in the last synthetic step.

Helices such as those of Fig. 1.4 emerge primarily from the preferred conformations of each rotatable bond. Yet, intramolecular p-p stacking between aryl moieties clearly provides additional conformational stabilization. It seems, however, that p-p stacking is not directional to the extent that it has an influence on the actual strand curvature so as to promote specific favorable contacts between aryl groups: curvature in helices is similar to that of crescents where no stacking

Fig. 1.4 Molecular formulae and X-ray structures - all at the same scale - of helical fully predictable foldamers. References for structures (a), (b), (c), (d), (e), and (f) are found in [45], [97], [93], [26], [20], and [31], respectively. Side chains, including solvent molecules and non-amide hydrogens have been omitted for clarity.

Fig. 1.4 Molecular formulae and X-ray structures - all at the same scale - of helical fully predictable foldamers. References for structures (a), (b), (c), (d), (e), and (f) are found in [45], [97], [93], [26], [20], and [31], respectively. Side chains, including solvent molecules and non-amide hydrogens have been omitted for clarity.

is involved. p-p stacking becomes critical in those cases where local conformational control is not complete [31, 42]. Considering, for example, the oligomer shown in Fig. 1.4f, conformations about aryl-CONH bonds are well defined [31] (see Fig. 1.2b) as opposed to conformations about aryl-NHCO bonds. Helical folding is thus partly driven by p-p stacking and, indeed, is promoted by protic solvents such as methanol [31]. Such foldamers are closely related to those presented in Chapter 3.

The stability of the helical foldamers shown in Fig. 1.4 is illustrated by the fact that their folding apparently occurs in any type of solvent. Though most solution conformations have been characterized in chlorinated, aromatic, or polar non-protic solvents [24, 36, 53], folding has been observed in water as well [30]. Rates of helix handedness inversion are considerably longer than for most other types of oligomers, which also suggest high conformational stability: several hours for the structure shown in Fig. 1.4d [26]. The stability and the compact shape of the helices are likely the origin of their high propensity to crystallize, and crystallography has clearly emerged as a method of choice to structurally characterize these oligomers.

Depending on the geometry of the repeating motifs (that is, the relative orientation between consecutive units in their preferred conformation), the conformation of fully predictable foldamers can display positive, negative, or zero curvature. For example, two 0° units, three 60° units, or six 120° units would be required to complete one turn of a helical foldamer. On the other hand, units that present an angle of 180° or with an overall zig-zag conformation (see Section will not combine to form helical conformations. In essence, one can tune helix diameter by changing the curvature imparted by each monomer in the sequence. Illustrations of this remarkable feature of fully predictable foldamers are given in Fig. 1.5 for aza-aromatic and aromatic amide oligomers. The propensity of oligoheterocyclic pyridine-pyrazine (Fig. 1.5a) [90, 91] pyridine-pyrimidine (Fig. 1.5b) [85, 89, 94] and pyridine-pyridazine (Fig. 1.5c) [86, 87] sequences to form a helical motif stems from structure-inducing "codons" that enforce helical winding due to the strongly favored transoid conformation of the a,a'-interheterocyclic bonds (Section 1.3.1; Fig. 1.2f). However, the curvature (and thus diameter) imposed by the position of the nitrogen(s) in the heterocyclic monomers and their connectivity strongly differ in these three oligomers. The geometrically-optimized structure has four heterocycles per helix turn with ortho-meta connectivity (Fig. 1.5a); six heterocycles per helix turn with meta-meta connectivity (Fig. 1.5b); and twelve heterocycles per helix turn with para-meta connectivity (Fig. 1.5c). Another means to increase helix diameter, though less dramatic than going from ortho- to meta- or para-substitution, was to replace the 2,6-substituted pyridine unit (meta) with a larger 2,7-substituted 1,8-naphthyr-idine ring (pseudo meta-substitution) [95].

Similarly, curvature and helix diameter have been tuned in amide-linked aromatic foldamers based on the intramolecular hydrogen bonds discussed in Section 1.3.1. Thus, an estimated 20 residues per turn is expected for the motif shown in Fig. 1.5d [45] with meta-para connectivity! The expected end-to-end NOE sig

Fig. 1.5 Tuning curvature and helix diameter. The structures shown in (a), (b), (c), (d), (e) and (f) are from references [90, 91], [85, 89, 94], [86, 87], [45], [45], and [35, 36], respectively.

nal was observed in an oligomer possessing 21 units [45]. The foldamer shown in Fig. 1.5e [45] (see also Fig. 1.4a) with meta-meta connectivity has approximately 7 residues per helix turn; once again, end-to-end NOE contacts indicate the expected helical conformation. Oligomeric strands based on quinoline amino acid monomers (Figs. 1.5f and 1.4d) possess a high curvature imparted by a pseudo-ortho connectivity and comprise 2.5 heterocyclic units per helix turn. It is noteworthy that the number of units observed for these three systems differ from the values expected if ortho, meta and para connectivities were associated exactly with 60°, 120° and 180° angles. In fact, intramolecular hydrogen bonding between consecutive units tends to decrease curvature when it occurs at the helix periphery (Figs. 1.5d and f) [35, 36], and to increase helix curvature when it occurs in the helix interior. It is important to note that decreasing curvature at each unit results in larger and potentially more useful cavities, but also increases the number of units per turn making it more difficult to synthesize multiple turn helices. In contrast, highly curved oligomers give access to helices with high aspect ratios after relatively short syntheses. Such highly tunable systems represent versatile frameworks for developing helical receptors that bind guests into their cavities (see Chapter 7). To this end, the next level of complexity consists of in corporating different types of units within the same sequence so as to tune the curvature along the length of the same strand, giving access to conical objects or closed shells [29]. Linear Strands

Upon controlling the relative orientation of consecutive units, the diameter of crescent oligomers may be increased indefinitely to produce linear objects such as those represented in Fig. 1.5. When para-para connectivity is used (Figs. 1.6c and d) [27, 28, 48], the conformation indeed resembles a linear tape, but crinkle-tapes may also be obtained using ortho-ortho (Fig. 1.6e) [14] or meta-meta (Figs. 1.6a and b) [18, 37, 55], connectivity where curvature is alternatively positive and negative at each unit. In the strand shown in Fig. 1.6c, the conformation also results from a periodic change of curvature sign, but it occurs at each unit and not between units. When such para connections are introduced within a helical sequence, an inversion of helix handedness (and thus a meso helix) results [39]. Some of these linear and zig-zag ribbons possess two different edges resulting in different line tensions which eventually gives rise to a slight bending (Figs. 1.6a, b, and d), and may in fact be considered as fragments of very wide helices. Other ribbons have two identical edges and are rigorously straight (Fig. 1.6c and e). Macrocycles

The underlying noncovalent interactions responsible for the conformational driving force of foldamers can be taken advantage of to form what can be considered as ''self-templated'' macrocycles. In essence, properly arranged functional groups during a reaction can be used to drive macrocyclization. The macrocycles depicted in Fig. 1.7 contain various combinations of one or two aromatic groups which can hydrogen bond to the linking unit in such a way as to rigidify the linkage in a well-defined conformation. The resulting ''directed conformational pre-organization'' is a powerful approach to overcome the unfavorable entropy associated with macrocyclization reactions [104]. Hunter et al. developed a series of macrocycles and catenanes to evaluate the role of intramolecular hydrogen bonding in macrocyclization [22].

It is not surprising that the same starting materials used in crescent or helical foldamers (Section, can be used for the synthesis of macrocycles. In fact, by taking advantage of intramolecular interactions during the synthetic process, macrocycles can be prepared from irreversible reactions in one step, without the need for external templates, even at relatively high concentrations (typically from 0.07 to 1 M). As expected, in the case of linear or zig-zag foldamers (Section, the geometry of the system does not allow for macrocyclization to occur. Ultimately, it is the precise shapes and conformations that result from intramolecular interactions that allow for macrocyclization.

In this regard, Bohme et al. have prepared heterocyclic formamidine and urea macrocycles in excellent yields from the reaction of 2,6-diaminopyridine with triethyl orthoformate and N,N-carbonyldiimidazole, respectively (Fig. 1.7a and b)

Fig. 1.6 Molecular formulae and representative X-ray structures - all at the same scale - of linear fully predictable foldamers. References for (a), (b), (c), (d), and (e) are from [55], [18, 37], [48], [27, 28] and [14], respectively. Not shown are examples of linear aza-aromatics and aza-aromatic amides [41, 98].

Fig. 1.6 Molecular formulae and representative X-ray structures - all at the same scale - of linear fully predictable foldamers. References for (a), (b), (c), (d), and (e) are from [55], [18, 37], [48], [27, 28] and [14], respectively. Not shown are examples of linear aza-aromatics and aza-aromatic amides [41, 98].

[75, 105]. In both cases, the driving force for macrocycle formation is intramolecular hydrogen bonding between the pyridyl nitrogen atom and the amino hydrogen of the urea or the C-H (or N-H) of the formamidine linkage. The importance of the pyridyl nitrogen for macrocyclization was demonstrated by the fact that when 2,6-diamino pyridine was substituted with 1,3-phenylenediamine, oli-

Fig. 1.7 Self-templated macrocycles (% yield). (a) n = 3 (97%) [105]; (b) n = 3 (90%) n = 4 (10%) [75]; (c) n = 3 (91%) [106]; (d) n = 6 (78%) [107]; (e) n = 4 (95%) [108]; (f) n = 2, R0 = H (46%) or CH3 (64%) [78]; (g) n = 2 (38%) [72]; (h) n = 3 (69%) [109]; (i) n = 3 (20%), n = 4 (20%) [110]. R and R0 indicate various types of alkyl chains.

Fig. 1.7 Self-templated macrocycles (% yield). (a) n = 3 (97%) [105]; (b) n = 3 (90%) n = 4 (10%) [75]; (c) n = 3 (91%) [106]; (d) n = 6 (78%) [107]; (e) n = 4 (95%) [108]; (f) n = 2, R0 = H (46%) or CH3 (64%) [78]; (g) n = 2 (38%) [72]; (h) n = 3 (69%) [109]; (i) n = 3 (20%), n = 4 (20%) [110]. R and R0 indicate various types of alkyl chains.

gomeric polyformamidines or polyureas were exclusively formed. Analogous self-templated macrocyclization reactions were reported by Xing et al. starting from 2,7-diamino[1,8]-naphthyridine for the preparation of the analogous trimeric for-mamidine macrocycle in 75% yield and the trimeric urea macrocycle in 64% yield [78].

Macrocycles are commonly synthesized by reactions of bifunctional monomers. However the kinetic competition between macrocyclization and polymerization can be a major problem. Chemists often use high-dilution and templating techniques to prevent undesirable polymerization reactions. In some cases dynamic (reversible) covalent chemistry provides an attractive synthetic strategy to yield thermodynamically favored macrocyclic products. The Schiff-base condensation of 2,3-dihydroxybenzene-1,4-dicarbaldehyde with 1,2-phenylenediamine gives a macrocyclic hexaimine in 91% yield (Fig. 1.7c) [106]. The selective formation of this cyclic trimer was rationalized by the stabilization of favorable conformations required for cyclization through intramolecular hydrogen bonding. Furthermore, because this product has low solubility in the reaction solvent, there was a ther-modynamic driving force for the formation of this macrocycle. An excellent example of using rigid precursors that are predisposed to a particular geometry was demonstrated in the preparation of a related Schiff-base macrocycle from the 6 + 6 reaction of 3,6-diformyl-2,7-dihydroxynaphthalene with 4,5-diamino-1,2-

dihexyloxybenzene (Fig. 1.7d) [107]. According to Hui et al. the ability to synthesize this 66-membered macrocyle can be attributed to maximizing intramolecular hydrogen-bonding and its poor solubility which again drives the reaction thermo-dynamically.

Zhang et al. have prepared a urea-linked macrocycle from a 2 + 2 reaction between two diarylurea units rigidified by intramolecular hydrogen bonding (Fig. 1.7e) [108]. The authors rationalize that the limited conformational freedom of the dimeric starting material and the tetrameric intermediate is expected to facilitate macroyclization. Another variety of urea-linked macrocycles was synthesized from N-isobutyl-3,6-diaminopyridazine reacting with either 1,3-phenylene diiso-cyanate or tolylene-2,6-diisocyanate (Fig. 1.7f) [78]. It is believed that both hydrogen bonding and steric interactions are involved in macrocyclization and that the formation of these intramolecular hydrogen bonds in the transition state directs the irreversible macrocyclic ring closing reaction to occur at such high yields in the absence of a template. The presence of the tolyl groups (R = CH3) versus the phenyl groups (R = H) illustrates the importance of steric repulsion to direct macrocyclization. This is supported by the difference in yield of the tolyl-containing macrocycle (64%), compared with the phenyl-containing macrocycle (46%). The tolyl methine group prevents alternative planar conformations due to unfavorable steric interactions with the urea carbonyl oxygens.

The one-step preparation of a macrocyclic polysulfonamide in 38% yield based on intramolecular three-center H-bonding was described by He et al. (Fig. 1.7g) [72]. In related work, Yuan et al. reported highly efficient (69% yield), one-step macrocyclization reactions by treating 4,6-dimethoxy-1,3-phenylenediamine with the appropriate diacid chloride (Fig. 1.7h) [109]. Three-center H-bonds rigidify the backbone and pre-organize the precursor oligomers for macrocyclization. Likewise, Jiang et al. attribute cyclization of oligoamide macrocycles to precursor pre-organization (Fig. 1.7i) [110]. In this case two different macrocycles (n = 3 and n = 4) were obtained. In all cases, it is believed that the strong conforma-tional preference of the building blocks once the linkage is formed gives rise to a thermodynamic preference for macrocyclization.

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