Having excellent photo- and electronic properties, NDIs have been employed widely in chemistry and biology. Their electron-poor nature makes them one of the most attractive building blocks in supramolecular chemistry.103–105 NDIs have been incorporated into plenty of macrocyclic structures. Most of the bridged NDIs use a tether linker between two imide positions. However, hash imide formation conditions usually prevent them from being directly linked to peptides.104 Introducing NDIs into peptides usually requires two steps. Firstly, the commercially available 1,4,5,8-Naphthalenetetracarboxylic dianhydride (NDA) is transformed to NDIs bearing other functional groups. Following modifications rely on other milder reactions rather than imide formations. The first example of peptide bridged NDIs was reported by Mallouk et al.106 With the intention to construct a chiral host molecule for indole derivatives, a tripeptide was integrated into structure of macrocycle NDI 91 (Figure 26a). Together with NDI surface, tripeptide Valine-Leucine-Alanine created an electron-deficient hydrophobic chiral pocket that is capable of binding to suitable guests. Despite being a strong π-donating guest, indole was weakly bound to the host NDI. A surprisingly low association constant of 13
± 1 M-1 was determined.106
41 Figure 26. (a) NDI-peptide host 91 for indole guest. (b) Disulfide-bridged conjugation with NDI for stabilization of peptides against proteolysis. Adapted from reference.106,107
Wu et al. have used NDI for peptide stapling.107 Having two Cysteine moieties at imide positions, NDI linker could easily form two disulfide bonds with Cysteine residues in the peptides (Figure 26b). When two Cysteines located at i and i+7 positions in peptide sequence, this strategy allowed to stabilize two turns of an α-helix. Thus, overall helicity was improved for stapled peptides 92. At the same time, stapled peptides experienced remarkable proteolytic stability as a result of steric effect from NDI linker and π-π interactions between NDI and aromatic side chains of amino acid residues.107 Even though the idea of incorporating NDI into peptide structure has been around, bridging NDI with peptide through imide positions required indirect methods which might complicate the synthesis. On the other hand, the approach of bridging NDI diagonally by covalent linker at core-substituted positions has not been explored.
As described in previous section, even with very big substituents at bay area of PDI, the interconversion between two atropo-enantiomers could be very fast at elevated temperatures.
To exploit the planar chirality of PDIs, it is necessary to develop methods for locking PDI conformations. Würthner et al. were successful to employ tethered linker for increasing
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racemization barriers of core-substituted PDIs. Introduction of such linkers to connect bay positions of PDIs could be done using etherification of 93 with ditosilates 94a-d at high dilution (Scheme 1).108
Scheme 1. Synthesis of bridged PDIs. Adapted from reference.108
After purification the diagonally bridged PDIs 95a-d and their laterally bridge isomers 96a-d were obtained in low yields. Different linker lengths were used to control the twisting angles of the PDI core. For the diagonally linked systems 95a-d, interconversion between two atropo-isomers was not possible since racemization required breaking the covalent linker. This type of structure was of interest since their spectroscopic properties were significantly altered in comparison with non-bridged PDIs 97. A substantial hypsochromic shift in absorption spectra and decreasing of fluorescent quantum yields were noticed for 95a-d. Covalent linkers in 95 could change the conjugation between phenoxy groups and PDI chromophore and led to
43 special features in spectroscopic properties. The energy barrier for the interconversion between 2 atropo-enantiomers (P) and (M) of 96 was determined using temperature-dependent 1H NMR.
The results showed a higher barrier for 96a with a short linker. For 96b-d there are only slightly higher energy barriers than acyclic reference 97. Therefore, to achieve PDI with permanent planar chirality, diagonally bridged linkers are more desired.95
The first example of isolation of two stable atropisomers of core twisted PDIs was presented in 2007.109 To restrict the interconversion of the two twisted enantiomeric conformers of PDI (P ↔ M), two macrocycles were introduced using oligo(ethelene glycol) bridges 98 following previously developed procedure to yield 99 (Scheme 2). Then, (P) and (M) isomers could be separated on chiral HPLC column. Even though both imide substituents of 99 were (R)-configured, two epimers showed a mirror image relation in CD spectra. This pseudo-enantiomeric behavior indicated that the CD signals came mostly from the planar chirality of PDI surface. In agreement with CD study, the optical rotation values of +6600 and -6600 were obtained for two diastereomers. Thus, chirality along the polyaromatic system greatly dominated point chirality. By comparison of experimental and simulated CD spectra, conformation of both diastereomers of 99 could be assigned. Conformational properties of these diastereomers were also studied using temperature-dependent 1H NMR, with the results showed strongly restricted inversion of the core PDI.
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Scheme 2. Synthesis and separation of atropo-diastereomers of PDI 99. Adapted from reference.109
Stabilization of PDI atropo-enantiomers could be achieved with a simpler approach.
Using only one covalent linker in 1,7-substituted PDIs, Würthner et al. were able to separate two stable enantiomers or macrocycle 101 (Figure 27a).110 Their chiral self-recognition and self-discrimination were realized using concentration-dependent UV-Vis absorption spectra and 1H NMR. The association constant for the recognition of two molecules owning the same stereochemistry was estimated to be one order of magnitude higher than molecules with different chirality. Having the same configuration, the π-π stacking in the case of homochiral
45 dimer was much greater. Thus, in racemic mixture of 101, monomer tend to form homochiral aggregate rather than heterochiral one (Figure 27b).
Figure 27. (a) Synthesis and separation of atropo-enantiomers of PDI 101. (b) Dimeric assembly of 101. Adapted from reference.110
Taking advantages of this self-recognition, supramolecular structures with different properties have been prepared using chiral pure or racemic starting monomers.111 In racemic homochiral dimers, building block formed a soft columnar crystalline phase of higher thermodynamic stability, whereas for enantio-pure monomer, a lamellar liquid crystalline
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phase was observed. Force field calculations supported that nano segregation and interaction between the bridges were important for the difference of condensed phase. Alternation of MM and PP homochiral dimers in racemic mono-bridged PDIs allowed better nanosegregation as well as more dense packing of building blocks. In contrast, for enantio-pure mono-bridged PDIs, steric shielding of the bridges prevented nanosegregation, resulting a lamellar organization with high fluidity.111
The influence of bridge linker length on the assembly of chiral PDIs was also examined.112 Upon increasing the length of the linker, CD signal decreased in intensity, which indicated the decrease in average twisting angle of PDI core. The larger Stockes shifts in fluorescence spectra observed for compounds with longer linkers also suggested more relaxation in these molecules during excitation. Dimerization constants increased with increasing linker length was in good agreement with increasing π-π stacking in less twisted PDI derivatives. However, the difference between KD (homochiral) and KD (heterochiral) decreased dramatically. This behavior could be explained by induced-fit dimerization mechanism as well as the possible interconversion between two atropo-enantiomers for compounds with longer linkers.112
The applications of chiral PDIs could be extended to deracemization of carbohelicenes when twisted PDI was incorporated into the design of cyclophane.113 With aliphatic tethered linker to block the configuration of PDI monomer, chiral PDI cyclophane MM and 103-PP could be synthesized. The electron-poor nature of PDIs rendered the cavity of cyclophane 103 to an excellent host to electron-rich helicenes. The binding affinity of 103 for [4]-helicene could reach nanomolar range. For [5]-helicene, its racemization barrier is higher than 100 kJmol-1. Therefore, enantiomers could be separated and stable at room temperature for several
47 hours. Since the [5]-helicene guest was sandwiched between two PDI surfaces, the cyclophane host would prefer to bind to the helicene with the same helical chirality. The enantiomer with the opposite configuration would be left in solution. Separation of the mixture containing guest and host-guest complex allowed enantiomeric excess (ee) of the guest to be enriched.
Figure 28. (a) Structure of homochiral PDI cyclophane 103. (b) Deracemization of [5]-helicene using cyclophane 103. Adapted from reference.113
Even though the tethered covalent bridge is excellent in maintaining the conformation of twisted PDIs, this strategy suffers from the difficulty in further chemical functionalization of the PDI core.114 To overcome this challenge, a rigid 2,2’-biphenol bridge has been used to block one bay area of PDIs (Scheme 3). The racemate of 104 could be separated with chiral HPLC to yield enantiopure product. Two positions left at bay area were easily further functionalized by aromatic nucleophilic substitution of chlorines. The free activation enthalpy for the racemization of 104 was estimated to be 98.5 kJmol-1 at 323K. Although this method did not completely block the interconversion, the rotation barrier of the core PDI was significantly increased in comparison with previously reported PDIs bearing large substituents.
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Using this strategy for disubstituted PDIs, Nuckolls et al. was successful in synthesizing chiral PDI cyclophane.115
Scheme 3. Synthesis and separation of atropo-diastereomers of PDI 104. Adapted from reference.109
Despite the fact that methods for preparation of enantiopure PDIs have been developed, their applications are barely studied. Most of the examples are limited in the context of supramolecular chemistry. Therefore, other potential applications of chiral PDIs, especially in asymmetric catalysis, could be of interest to be explored in the future.