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Cite This: ACS Appl. Mater. Interfaces 2018, 10, 3181−3185

Vesicles Constructed with Chiral Amphiphilic Oxacalix[2]arene[2]triazine Derivatives for Enantioselective Recognition of Organic Anions Qing He,† De-Hui Tuo,†,‡ Yu-Fei Ao,*,† Qi-Qiang Wang,†,‡ and De-Xian Wang*,†,‡ †

Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *

ABSTRACT: Chiral amphiphilic oxacalix[2]arene[2]triazine derivatives 1−3 bearing L-prolinol moieties were synthesized. The self-assembly behavior of the chiral macrocyclic amphiphiles was investigated. SEM, TEM, and DLS measurements demonstrated that 1 formed stable vesicles (size of ∼90 nm), whereas 2 and 3 formed micelles. As monitored by DLS, vesicles composed of 1 showed selective response to the chiral anions (2S, 3S)-2,3-dihydroxysuccinate (D-tartrate), S-mandelate and S-(+)-camphorsulfonate over their enantiomers. DFT calculations revealed that the enantioselectivity arises from cooperative anion-π interactions and hydrogen bonding between the chiral electron-deficient cavity and the organic anions. KEYWORDS: vesicle, anion−π interaction, anion recognition, enantioselectivity, oxacalix[2]arene[2]triazine

C

and enable selective response to inorganic anions.22,23 Our continued interests in anion−π interactions, and the motivations to probe the driving force that governs the chiral recognition on the artificial membrane surface, stimulated us to pursue this study. Reported herein is the design and selfassembly behavior of oxacalix[2]arene[2]triazine-based chiral amphiphilic building units, and chiral recognition of the formed vesicles toward organic anions. The chiral amphiphiles were designed by including L-prolinol moieties onto the triazines, taking advantage of the readily functionalization of oxacalix[2]arene[2]triazine.26−28 Alkyl chains in different length were incorporated in order to adjust the distance between the chiral center and the macrocyclic backbone (Scheme 1). To synthesize 1−3, a postmacrocyclization functionalization protocol starting from amphiphilic macrocycle 422 was applied. Nucleophilic reactions between 4 and commercially available L-prolinol 5, and its derivatives 6 and 7 (for synthesis of 6 and 7, see the Supporting Information), in the presence of DIPEA as the base and at room temperature gave the target chiral amphiphiles 1−3 in good yields (Scheme 1). The compounds of 1−3 were fully characterized by spectroscopic data and elemental analysis (see the Supporting

hiral recognition of biomembrane is of fundamental interest because it is perhaps related to the homochirality of biopolymers.1,2 Fabrication of self-assembled membrane models using artificial chiral units represents a fascinating topic.3−8 Such artificial membranes have been applied for efficient chiral separation3,5,7 and enantioselective catalysis.6,8−10 In general, an enhanced enantioselectivity can be achieved for ordered aggregates by taking advantage of the synergistic effect.3 Though multiple interactions including electrostatic interactions and hydrogen bonding can govern the chiral discrimination process on a surface,7 which driving force dominates usually remains unclear. To understand this fundamental process, rational design of chiral building units bearing specific binding sites is highly demanded. Anion−π interactions are a new type of noncovalent motif that describe the interactions between the electron-deficient aromatics and anions.11−13 Although the existence of anion−π interactions has been exemplified experimentally,14−18 their applications in supramolecular chemistry are still limited.19−25 In previous work, we have shown that the oxacalix[2]arene[2]triazine macrocycle is a powerful molecular model for studying anion-π interactions.14,15 The self-tuned and electron-deficient cavity can accommodate anions with different shapes through anion−π interactions. Furthermore, self-assembled vesicles were successfully prepared from oxacalix[2]arene[2]triazine derived amphiphilic molecules. By this strategy the electrondeficient cavities can then be engineered on vesicular surface © 2018 American Chemical Society

Received: December 9, 2017 Accepted: January 9, 2018 Published: January 9, 2018 3181

DOI: 10.1021/acsami.7b18723 ACS Appl. Mater. Interfaces 2018, 10, 3181−3185

Letter

ACS Applied Materials & Interfaces Scheme 1. Synthesis of the Chiral Macrocyclic Amphiphiles 1−3

vesicles. The spherical morphology was also confirmed by SEM (Figure 2A). Dynamic light scattering (DLS) measurement revealed an averaged size of ∼90 nm for the vesicles, which is in consistent with the SEM and TEM results. After the vesicle formation, the two CD bands of 1 was weakened and bathochromically shifted to 246 and 280 nm, respectively (Figure S9). Instead of forming vesicles, the chiral amphiphiles 2 and 3 formed micelles under the same conditions as revealed by TEM (Figure 2C, D). With the similar hydrophobic and hydrophilic moieties, the different morphologies from vesicles to micelles are obviously dependent on the linking distance of the L-prolinol moiety to the macrocyclic backbone in 1−3. Previously we have shown that oxacalix[2]arene[2]triazinederived amphiphile 4 tends to adopt cone shape due to the 1,3alternate macrocyclic backbone, and such geometry favored the curved lamellar formation in aqueous medium as driven by hydrophobic effect between the long alkyl tails and intermolecular hydrogen bonding between the amide groups.22 In 1−3, the incorporated L-prolinol moieties on the triazines can further elongate the conic shape as the hydrophilic Lprolinol moieties tend to extend in water.23 The longer linkers (in 2 and 3) therefore led to the formation of self-assembled lamella with larger curvature which is consequently curved into micelles, whereas the short analogue 1 prefers to form ordered double layer with smaller curvature (vesicle). Considering the vesicular structure formed by 1 in which the membrane surface was decorated with the chiral macrocyclic cavities, the chiral recognition toward different enantiopure organic anions was then investigated. Treatment of the vesicles with sodium salts of (2S,3S)-2,3-dihydroxysuccinate (D-tartrate) and (2R,3R)-2,3-dihydroxysuccinate (L-tartrate) respectively caused different changes on the hydrodynamic diameter, implying an enantioselective response. For instance, although the vesicle size remained unchanged in case of L-tartrate, it dramatically increased for D-tartrate and the increment is correlated with the amount of the anion added. Upon addition of D-tartrate from 0.5 to 2.5 equiv, the larger and larger hydrodynamic diameters were recorded. This suggested the association of D-tartrate to the vesicles. Moreover, in the presence of more than 1.25 equiv of D-tartrate, the vesicle size increased gradually with time, indicating the dynamic formation

Information). Their chirality character was investigated by circular dichroism (CD). All the three compounds show negative Cotton effect as induced by the same chiral center (Figure 1). While compound 1 shows two strong bands at 217

Figure 1. CD spectra of the chiral amphiphiles 1−3 (3.1 × 10−5 M in CH3CN).

and 256 nm, compound 3 also shows two bands at 222 and 270 nm but with decreased intensity. For 2, however, only one band at 239 nm exists. This suggests the chirality information can be affected by the distance of the chiral center to the macrocyclic backbone. Meanwhile, the CD signal was also weakened along with the increased distance, indicating diminished chiral transfer from L-prolinol to the macrocyclic chromophore. The self-assembly behavior of the chiral amphiphiles 1−3 was then investigated in water. By injection of water (1 mL) to a THF solution of 1-3 (5 × 10−4 M, 0.1 mL) followed by removal of THF through heating at 60 °C for 30 min, a colloidal solution was obtained, indicating the aggregate formation. The morphology of the aggregates was first investigated by TEM technique. As shown in Figure 2B, the chiral amphiphile 1 formed spherical aggregates with an averaged size of 70−100 nm. The sharp contrast between the periphery and center of the spheres suggested the formation of 3182


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Figure 2. (A) SEM and (B) TEM images of the vesicles self-assembled from 1, TEM images of the micelles self-assembled from (C) 2 and (D) 3.

Figure 3. (A) Response of vesicles self-assembled from 1 to the sodium salts of (2S,3S)-2,3-dihydroxysuccinate (D-tartrate) and (2R,3R)-2,3dihydroxysuccinate (L-tartrate) as monitored by DLS. (B) SEM images of the vesicles after treated with D-tartrate.

response of the vesicle toward D-tartrate was observed (Figure S14). The enantioselective anion recognition can be extended to chiral mandelate and camphorsulfonate. In both cases the similar S-selectivity was observed as that of D-tartrate, but under elevated concentrations (above 5 equiv., Figures S10−S13). Aggregated clusters of vesicles were also formed in the presence of S-mandelate and S-(+)-camphorsulfonate as observed from the SEM images (Figures S3 and S4). These outcomes indicated similar interactions between the vesicular surface and the three tested anions may exist as the driving forces for the aggregated cluster formation.

of larger aggregates (Figure 3A). The morphology of the enlarged aggregates was further revealed by SEM. In contrast to the original dispersed spherical morphology (Figure 2A), aggregated clusters were observed in the presence of sodium D-tartrate (Figure 3B). For this course the first step can probably be that the surface (chiral macrocyclic cavities)-Dtartrate interaction brings the already-formed vesicles into close contact, and the proximity of the membranes leads to the larger aggregate formation. Such an aggregation process can explain the hydrodynamic diameter increase and the kinetic character as measured by DLS. The interaction of the surface cavity with D-tartrate was further confirmed by adding competitive anions. In the presence of an excess of NO3− (250 equiv), diminished 3183


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Figure 4. Optimized (A) [8·D-tartrate]2−, (B) [8·(S)-mandelate]− and (C) [8·(S)-(+)-camphorsulfonate]− complexes at X3LYP/6-31G*//X3LYP/ 6-31G* levels.

revealed by DFT calculations. This study hence highlights the rational design and fabrication of artificial functional selfassembled membrane models for understanding the fundamental chiral discrimination process.

To probe the enantioselective discrimination of the anions by the vesicles from molecular level, we performed a DFT calculation on model compound 8 at X3LYP/6-31G*// X3LYP/6-31G* level29 (for details, see the Supporting Information) and obtained the optimized complexes of [8·Dtartrate]2−, [8·(S)-mandelate]−, and [8·(S)-(+)-camphorsulfonate]−. As shown in Figure 4, in all complexes the anionic head of the anion was included within the V-cleft surrounding by the electron-deficient triazines and chiral L-prolinol moieties. Similar to the typical macrocycle-carboxylate and sulfonate anion complexes,21,30 the oxygen atoms of the anionic head (O86 and O93 for D-tartrate, O1 and O2 for S-mandelate, and O1 for S-(+)-camphorsulfonate) interact with the triazines through anion-π interactions. The hydroxyl groups of L-prolinol moieties participate in the anion binding through hydrogen bonding.23 Enantioselective binding should be hence controlled by the cooperative anion−π interactions and hydrogen bonding. This particular binding mode could also contribute to the chiral discrimination in the vesicle system. In contrast to what observed in the S-enantiomer complexes, the single-point energies for the R-enantiomer complexes, namely 8·L-tartrate, 8·(R)-mandelate and 8·(R)-(−)-camphorsulfonate, are 10.1, 23.6, and 38.8 kJ/mol higher, respectively (Figure S16). These findings are in line with the fact that the vesicles composed of 1 enantioselectively responded to the S-enantiomers. In the case of D-tartrate, it may be easier for the dianion to bridge the two macrocyclic cavities on different parent vesicles, and hence the larger aggregate formation could be observed under lower concentration than the other two monoanionic analogues. Such an assumption could explain the above DLS results. In summary, the oxacalix[2]arene[2]triazine-based chiral macrocyclic amphiphiles 1−3 by incorporating L-prolinol moieties onto the triazine rings were efficiently synthesized and their self-assembly behavior was investigated. The aggregation formation was found to be dependent on the linker between L-prolinol moieties and the macrocyclic backbone. Whereas with the longer linkers the amphiphiles 2 and 3 formed micelles, the short analogue 1 assembled into vesicles. Because of the existence of the chiral cavity, the vesicles composed of 1 can enantioselectively respond to organic anions including D-tartrate, (S)-mandelate and (S)(+)-camphorsulfonate to form enlarged aggregates. The general S-selectivity for the anion recognition was dominated by cooperative anion−π interactions and hydrogen bonding as

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b18723. Experimental details and characterization of compounds; copies of 1H, 13C NMR, and MS spectra for new compounds; SEM and TEM images; and DFT calculation details (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Qing He: 0000-0003-3117-9587 Qi-Qiang Wang: 0000-0001-5988-1293 De-Xian Wang: 0000-0002-9059-5022 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank NNSFC (91427301, 21502202, 21502200, 21521002), MOST (2014CB643601) and Chinese Academy of Sciences (QYZDJ-SSW-SLH023) for financial support.

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