English

• Macrocycles have always been considered as an important component and a key point since the establishment of supramolecular chemistry [1-8]. Through their interaction with guest molecules, well-organized supramolecular assemblies could be created, which have attracted great interest in various research fields especially for materials and biomedical science [9-15]. Among the macrocycle family, chiral macrocycles exhibit a wide range of applications including enantioselective recognition, chiral switching, chirality sensing, chiral catalysis, circularly polarized luminescence and biomedical applications [16-21]. Therefore, chiral macrocycles' synthesis may open new paths for the development of supramolecular chemistry in the future.

  Tröger's base unit is a chiral building block with a V-shaped heterocyclic structure, which was first synthesized and reported by J. Tröger in 1887 [22], and confirmed by M. A. Spielman in 1935 [23]. Since then, Tröger's base unit has caught the attention of chemists due to their special V-shaped structure and inherent chirality. Based on Tröger's base unit, many interesting functional systems have been constructed and applied in various fields [24-31]. Recently, in our previous report, we have reported a Tröger's base-based macrocycle TBBM T2 constructed by two Tröger's base heterocycle (Scheme 1b) [32,33]. Herein, we report two new chiral macrocycles TBBM T1 and T3 with different bridging ethylene glycol chain lengths and different chiral selection behaviors during their crystallization (Scheme 1a). The crystal structure comparison revealed that these three TBBMs T1, T2 and T3 bridging with different ethylene glycol chains exhibited different chiral selectivity behavior during their crystallization. For T1, bridging with a shorter mono-ethylene glycol chains, a pair of enantiomeric isomers R_4N-T1 and S_4N-T1 were formed. Different from T1, for T2 bridging with a bit longer di-ethylene glycol chains, both a pair of enantiomeric isomers (R_4N-T2 and S_4N-T2) and a meso isomer (R_2NS_2N-T2) were formed. Whereas, for T3 bridging with a much longer tri-ethylene glycol chains, only a meso isomer R_2NS_2N-T3 was produced. These results indicate that Tröger's base units exhibited chiral selection during the crystallization of TBBMs. The synthesis of TBBMs T1 and T3 not only makes the study of TBBMs more systematical, but also helps to understand the relationship between the size of the rectangular cavity and the chiral selection of Tröger's base-based macrocycles during the crystallization of TBBMs.

  Scheme 1

  

  Scheme 1.  (a) Stereo-isomer structures observed in crystal analyses of TBBMs T1 and T3. (b) TBBM T2 previously reported by us.

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  As shown in Scheme 2, the target Tröger's base-based macrocycles TBBM T1, T2 and T3 were synthesized starting from glycol-bridged nitroaromatic compounds [33,34]. Firstly, the glycol-bridged p-nitrobenzene compound a1-a3 was reduced to the corresponding amine b1-b3. Then, the engendered amine group was reacted with formaldehyde in the presence of trifluoroacetic acid to form Tröger's base units. Through this synthetic route, T1, T2 and T3 were successfully synthesized in the yields of 18%, 13% and 18% respectively (Section 2.1-2.2 in Supporting information for more details). The structures of T1 and T3 were characterized by ¹H NMR, ¹³C NMR, and high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS). In the ¹H NMR spectrum (Figs. S2 and S6 in Supporting information), the characteristic peaks at chemical shifts (δ 4.49 ppm for T1, 4.60 ppm for T3) are observed which can be explained by the Tröger's base skeleton. In the HR-ESI-MS of T1 andT3 (Figs. S5 and S9 in Supporting information), peaks were found at m/z 561.2480 and 737.3543 assigned to [T1 + H]⁺ (calcd. 561.2496) and [T3 + H]⁺ (calcd. 737.3545), respectively.

  Scheme 2

  

  Scheme 2.  Synthetic route of TBBMs T1, T2 and T3.

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  After the successful synthesis of T1 and T3, we tried to grow single crystals of T1 and T3 in order to confirm the sizes of their cavities. Luckily, the single crystals of T1 and T3 suitable for X-ray crystallography were obtained by slow diffusion of isopropyl ether into trichloromethane and dichloromethane solution of T1 and T3. Similar to T2, due to the V-skeleton of Tröger's base, the single crystal structure analysis showed that both T1 and T3 presented structure with an approximately rectangular cavities. Theoretically, due to the inherent chirality of Tröger's base skeleton, TBBMs with two Tröger's base units should have one pair enantiomeric isomers and one meso isomer at the same time. However, by comparing chirality of T1, T2 and T3 in the crystal structure, different chiral selection phenomena were observed in the crystal structures. As shown in Fig. 1, for T1 bridging with a shorter mono-ethylene glycol chains (n = 1), only a pair of enantiomers R_4N-T1 and S_4N-T1 were observed in the crystal structure. Unlike T1, for T2 bridged with a bit longer di-ethylene glycol chains (n = 2), both a pair of enantiomeric isomers R_4N-T2 and S_4N-T2 and a meso isomer (R_2NS_2N-T2) were observed in the crystal structure which is completely consistent with the theoretical derivation. However, differently to both T1 and T2, for T3 bridging with a much longer tri-ethylene glycol chains (n = 3), only the meso isomer R_2NS_2N-T3 was found in the crystal structure. Thus, based on these finding, the crystallisation experiments showed that the reactions are diastereoselective in the case of T1 and T3, and non-diastereoselective in the case of T2. Moreover, the length of the bridging chains have a significant impact on the chiral behavior of Tröger's base-based macrocyclic molecules during their crystallization.

  Figure 1

  

  Figure 1.  Crystal structure of rac-T1, rac-T2, meso-T2 and meso-T3. Tröger's base units with S_NS_N were drawn in red, while Tröger's base units with R_NR_N were drawn in blue.

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  According to single crystal analysis, for TBBM T1, the cavity size defined as the maximum diagonal length distance between two bridging methylene carbons was 11.7 Å, and the average dimensions was 8.1 × 8.7 Ų. For T2, bridged with a bit longer di-ethylene glycol chains, the cavity size of rac-T2 was 14.2 Å in maximum diagonal length, and the average dimensions was 11.2 × 8.2 Ų, which is a slightly larger than that of T1 (Fig. 1). The cavity size of R_2NS_2N-T3 was 16.8 Å in maximum diagonal with average dimensions of 13.0 × 10.7 Ų, which is barely bigger than meso isomer R_2NS_2N-T2 with average dimensions of 10.9 × 8.8 Ų. These data indicate that the cavity size of macrocyclic molecules increases significantly with the lengthening of the ethylene glycol chain. In addition, the crystal structures show that, for all TBBMs T1, T2 and T3, the ethylene glycol units at the bridging corners exist in the highest energy cis-conformation rather than in the lowest energy trans-conformation, indicating that there are higher tensions in the TBBMs T1, T2 and T3. Due to this high tension during the synthesis process, the precursors of TBBMs do not easily form cyclic molecules, resulting in their lower synthetic yields.

  Furthermore, T1, and T3 exhibited different abilities in encapsulating solvent molecules. As shown in Fig. 2, rac-T1 can form 1:1 host-guest complex trichloromethane@T1, in which obvious one hydrogen bond between the hydrogen atom of trichloromethane and the oxygen atom on T1 could be observed. In contrast, meso-T3 can simultaneously combine two dichloromethane molecules to form a 1:2 host-guest complex two-dichloromethane@T3, four hydrogen bonds between chlorine atom of dichloromethane and the hydrogen atom of T3 could be observed. The other interesting phenomenon is that in the crystal packing structure of trichloromethane@rac-T1, if chloroform@rac-T1 is considered as a whole, an inversion center could be found in the crystal structure. Similarly, the same phenomenon was achieved for two-dichloromethane@meso-T3. These results suggest that the packing behavior of macrocyclic molecules in crystals also follows chirality rules. Moreover, there are some other interesting findings in the crystal. According to our previous reports, T2 was found to form long-range channels in the crystal packing structure. As shown in Fig. 3a, for T3, the long-range ordered channels could also be found although T3 and T2 have different chiral behaviors. But for rac-T1, when considering both R_4N-T1 and S_4N-T1, T1 does not stack into a channel in the crystal packing structure, however when only R_4N- or S_4N-T1 with a single chirality is considered, the crystal packing structure of T1 has obvious long-range channel packing (Fig. 3b).

  Figure 2

  

  Figure 2.  Single crystal of complex (a) trichloromethane@T1, (b) two-dichloromethane@T3. Corresponding molecule structural formulas: C, gray; H, pink; O, red; Cl, green. i: inversion center.

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  Figure 3

  

  Figure 3.  (a) meso-T3 was stacked along the c-axis as a channel. (b) rac-T1 was stacked as a channel across layer along the b-axis.

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  In conclusion, we synthesized two novel Tröger's based macrocycles TBBMs T1 and T3 with different ethylene glycol chain lengths. Although starting materials are very similar, the TBBMs T1 and T3 exhibit different chiral behavior during crystallization. Combined with T2 reported by us before, an obvious chiral selection during the crystallization process of TBBMs could be found. For T1, bridging with a shorter mono-ethylene glycol chains, a pair of enantiomeric isomers R_4N-T1 and S_4N-T1 were formed in the crystal structure. Different from T1, for T2 bridged with a bit longer di-ethylene glycol chains, both a pair of enantiomeric isomers (R_4N-T2 and S_4N-T2) and a meso isomer (R_2NS_2N-T2) were formed in the crystal structure. For T3 bridging with a much longer tri-ethylene glycol chains, only meso isomer R_2NS_2N-T3 was observed in the crystal structure. The length of the bridge chain (n = 1, 2, 3) affects the chiral selectivity during TBBM crystal formation, which provide new methods for the chiral synthesis and purification of macrocycles with high tension. The synthesis of two TBBMs T1 and T3 made the research of TBBMs more systematically, which is also helpful to understand the relationship between the size of the rectangular cavity and the chiral selection of Tröger's base-based macrocycles during the cyclization of TBBMs. We believe that our research may provide new references for the chiral synthesis and purification of chiral macrocycles. Based on this research, our ongoing research work are mainly focused on: (1) Looking for guest molecules (including chiral guest molecules) that have strong binding abilities to Tröger's base-based macrocycles. (2) Hydrophilic modification of Tröger's base-based macrocycles and study their recognition properties and applications in water. (3) Exploring their potential applications in chiral catalysis.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  We gratefully acknowledge the financial support from the National Natural Science Foundation of China (Nos. 21901113, 21871135) and the Natural Science Foundation of Jiangsu Province (No. BK20190287). This research work was also financially supported by the Starry Night Science Foundation of Zhejiang University Shanghai Institute for Advanced Study (No. SN-ZJU-SIAS-006). We also thank Dr. Khouloud Djebbi for her kind help with language modification.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2022.108038.

  
  
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  Scheme 1  (a) Stereo-isomer structures observed in crystal analyses of TBBMs T1 and T3. (b) TBBM T2 previously reported by us.

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  Scheme 2  Synthetic route of TBBMs T1, T2 and T3.

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  Figure 1  Crystal structure of rac-T1, rac-T2, meso-T2 and meso-T3. Tröger's base units with S_NS_N were drawn in red, while Tröger's base units with R_NR_N were drawn in blue.

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  Figure 2  Single crystal of complex (a) trichloromethane@T1, (b) two-dichloromethane@T3. Corresponding molecule structural formulas: C, gray; H, pink; O, red; Cl, green. i: inversion center.

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  Figure 3  (a) meso-T3 was stacked along the c-axis as a channel. (b) rac-T1 was stacked as a channel across layer along the b-axis.

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