A diols-responsive triple-component supra-amphiphile constructed from pillar[5]arene-based recognition

Abstract

A triple-component supra-amphiphile WSP5⊃G1@A is constructed based on phenylboronic acid/diols dynamic covalent chemistry and water-soluble pillararenes/trimethylamine host–guest recognition. Diols-responsive self-assembly of this ternary supra-amphiphile is fully investigated in aqueous solution.

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Stimuli-responsive self-assembled materials have become a hot topic in the supramolecular community because they can be applied in the areas of controlled release,¹ drug delivery² and supramolecular polymers.³ Numerous external stimuli including gases, temperature, enzymes, redox conditions and pH, have been applied in the construction of stimuli-responsive supramolecular materials.⁴ Notably, diols-responsive self-assembly is especially attractive because several diols are of biological and environmental relevance, such as carbohydrates and nucleic acid derivatives,⁵ possessing excellent biocompatibility and biodegradability. These diols-responsive self-assembled nanomaterials show great promise for applications in drug delivery and controlled release. Therefore, it is urgently necessary to develop diols-responsive self-assembled functional materials.

Supra-amphiphiles,⁶ a class of charming molecules bearing both hydrophilic and hydrophobic part, can self-assemble in water or organic solvents to generate specific nanostructures depending on noncovalent interactions, such as hydrogen bonding, π–π stacking interactions, electrostatic interactions and charge–transfer interactions. Supra-amphiphiles with different chemical structures can self-assemble into form various fascinating nanostructures, which provide a facile platform to fabricate diverse advanced materials. As a class of fascinating macrocyclic hosts next to crown ethers,⁷ cyclodextrins,⁸ calixarenes⁹ and cucurbiturils,¹⁰ pillar[n]arenes¹¹ have gradually become a new driving force to stimulate the development of supramolecular chemistry since its first report. The self-assembly behaviors of the supra-amphiphiles based on pillar[n]arenes have been widely studied so far.¹² However, compared with ubiquitous binary supra-amphiphiles system, multi-component self-assembly based on water-soluble pillar[n]arenes has been rarely investigated.¹³ Herein, we utilize dynamic covalence and host–guest chemistry to fabricate a novel ternary supra-amphiphile, which self-assembles into the nanoparticles in water (Scheme 2). Interestingly, the obtained ternary supra-amphiphile possesses unique diols-responsive behavior. In the presence of diols, the nanoparticles transform into regular nanosheets, while simultaneously experience a pronounced fluorescence decrease in aqueous solution.

The triple-component supra-amphiphile WSP5⊃G1@A was constructed as shown in Scheme 1 and Scheme 2. The amphiphilic molecule (G1) possesses a phenylboronic acid group and a cationic trimethylamine, where the phenylboronic acid group can rapidly react with diethanol part of A via dynamic covalent chemistry, resulting in the generation of two five-membered rings. On the other hand, host–guest complexation occurred between a water-soluble pillar[5]arene (WSP5) bearing five carboxylate anionic groups on both rims and the cationic trimethylamine moiety of G1, resulting in the formation of a stable host–guest complex mainly driven by electrostatic interactions. In this ternary supra-amphiphile, the host–guest complex acts as the hydrophilic section, while the alkyl chain and anthracene ring linked by the dynamic covalent.

Scheme 1 Chemical structures of the compounds used in this article.

Scheme 2 Schematic representation of triple-component self-assembly and its fluorescence behavior in water.

The host–guest complexation was first investigated by using a model compound G2 through ¹H NMR spectroscopy due to the relatively poor water-solubility of G1 in water. Compared with the spectrum of free guest G2 (Fig. 1a), remarkable upfield shift changes were observed corresponding to the proton signals of G2 upon addition of an equimolar amount of WSP5 (Δδ = −0.89, −2.04, −2.62, −2.12 and −1.34 ppm for H₁, H₂, H₃, H₄ and H₅, respectively), which was ascribed to the shielding effect of the electron-rich cavity upon formation of a threaded structure.¹⁴ As shown in Fig. 1c, the signals related to the protons on WSP5 shifted downfield slightly, which was induced by the deshielding effect after the achievement of host–guest complexation between WSP5 and G2. Meanwhile, extensive broadening effect occurred caused by the complexation dynamic.¹⁵ 2D NOESY NMR spectroscopy also provided a convincing evidence for the formation of an inclusion complex (Fig. S5†).¹⁶ Strong nuclear overhauser effect (NOE) correlations were observed between the signals related to the protons H_a–c on WSP5 and the protons H_1–5 on G2, verifying the alkyl chain on G2 deeply threaded into the cavity of WSP5, in accordance with the conclusion obtained from ¹H NMR studies. Furthermore, the association constant was calculated to be (2.06 ± 0.04) × 10⁵ M⁻¹ for WSP5⊃G2 in 1 : 1 complexation by isothermal titration calorimetry (ITC) experiment,¹⁷ confirming strong interactions in this host–guest system (Fig. S6†). Additionally, the ITC data also indicated that the complexation was mainly driven by enthalpy changes (ΔH° < 0; TΔS° < 0; |ΔH°| > |TΔS°|).

Fig. 1 Partial ¹H NMR spectra (400 MHz, D₂O, 295 K): (a) G2 (2.00 mM); (b) WSP5 (2.00 mM) and G2 (2.00 mM); (c) WSP5 (2.00 mM).

After the establishment of the recognition motif between WSP5 and G2 in water, a supra-amphiphile was constructed by using G1 as a guest. The critical aggregation concentration (CAC) of A in water was calculated to be 5.49 × 10⁻⁷ M by using concentration-dependent conductivity (Fig. S7†).¹⁸ As shown in TEM image, A self-assembled into nanosheets in water (Fig. 2a). The thickness of A aggregates was measured to be 2 μm by scanning electron microscope because their packing structure was in a multi-layered antiparallel pattern (Fig. S18†). The main driving forces of the formation of nanosheets were the π–π stacking interactions between anthracene groups and the intermolecular hydrogen bonds between the diethanol groups.¹⁹ Upon formation of complex G1@A linked by dynamic covalent bond, the CAC value was enhanced to be 7.95 × 10⁻⁶ M (Fig. S8†), arising from the introduction of the water-soluble cationic trimethylamine group into the amphiphilic system. The nanosheets self-assembled from A became thinner upon addition of G1 into the solution of A (Fig. 2b) and its thickness was calculated to be 4 nm (Fig. S19†). The main reason was that the introduction of electrostatic repulsion destroyed the intermolecular hydrogen bonds between the layers due to the formation of boronate G1@A. Interestingly, the CAC value of G1@A in the presence of WSP5 was further increased to 4.74 × 10⁻⁵ M (Fig. S9†). The enhancement of the CAC value was attributed to stable host–guest complexation between WSP5 and G1@A.²⁰ Upon addition of WSP5, the nanosheets of G1@A disappeared, while nanoparticles with the average diameter about 150 nm were observed (Fig. 2c and d). Besides, the dynamic light scattering (DLS) experiment showed the main diameter distribution of these nanoparticles was 150 nm (Fig. S10†), which was in good agreement with TEM images.

Fig. 2 TEM images of (a) A aggregates, (b) G1@A aggregates, (c) WSP5⊃G1@A aggregates, (d) enlarged image of WSP5⊃G1@A aggregates, (e) WSP5⊃G1@A aggregates upon addition of 1 equiv of A1 and (f) enlarged image of (e).

A reliable mechanism was proposed to elucidate the morphology changes of E-mail: G1@A upon titration of WSP5. It's well-known that the microassembled structure of the aggregates formed by amphiphiles is determined by the curvature of the membrane.^6a Upon addition of WSP5, the hydrophilic head of G1@A bearing the cationic trimethylamine moiety threaded into the π-rich cavity of WSP5 mainly driven by electrostatic and hydrophobic interactions, forming a novel supra-amphiphile WSP5⊃G1@A. WSP5⊃G1@A self-assembled into small micelles with low curvature in water and the small micelles further aggregated together to form large multi-molecular nanoparticles. In other words, the large nanoparticles were a type of multimicelle aggregates with the basic building units (Fig. S20†).²³

Due to the dynamic nature of boronate, the diol A1 can replace molecule A of the complex WSP5⊃G1@A to form a new ternary complex WSP5⊃G1@A1. This competitive process was observed by TEM (Fig. 2e and f). Upon addition of A1 (1 equiv.) into the solution of WSP5⊃G1@A, the nanoparticles formed from WSP5⊃G1@A disappeared, while the multi-layered nanosheets self-assembled from A appeared again. The phenomena confirmed the occurrence of the competitive process. Notably, A was a typical fluorescence-quenched molecule caused by photoinduced electron transfer (PET) effect and π–π stacking.²¹ When G1 bound to the diethanolamine part of A, the quenched fluorescence of the anthracene group recovered because the PET effect and the π–π stacking were effectively inhibited. Accompanied with addition of the competitive diol A1 in water, A was disassociated from WSP5⊃G1@A and the fluorescence was quenched again. Hence, the diols-responsive behavior of ternary supra-amphiphile can be monitored by fluorescence spectroscopy.

To further investigate the fluorescence property of our ternary complex WSP5⊃G1@A, the fluorescence titrations of WSP5⊃G1@A in the presence of different diols were carried out in water (Fig. 3 and Fig. S11–S15†). As shown in Fig. 3, the fluorescence intensity decreased gradually by increasing the concentration of diethanolamine or triethanolamine (A2). The fluorescence intensity changes indicated that the addition of these diols stimulated the disassociation of G1@A instead by the formation of new complexes (G1@A1 and G1@A2). From Fig. 4, we found that the ternary supra-amphiphile exhibited higher selectivity towards diethanolamine than triethanolamine. However, A3, A4 and A5 were not able to quench the fluorescence of WSP5⊃G1@A effectively, indicating these diols were not able to substitute A from complex WSP5⊃G1@A in aqueous phase. The reason was that the existence of B–N bond played a vital role in the stabilization of boronate in aqueous solution.²² The results obtained from fluorescence titration demonstrated that the ternary supramolecular systems possessed highly selective diols-responsiveness, in line with the TEM investigations.

Fig. 3 The changes in fluorescence intensity of WSP5⊃G1@A (0.100 mM) upon gradual addition of (a) A1 and (b) A2 (0, 0.100, 0.300, 0.600, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00 and 7.00 equiv.) in water (λ_ex = 370 nm).

Fig. 4 Relative fluorescence intensity of WSP5⊃G1@A (0.1 mM) with different concentrations of diols or triols (0–7.00 × 10⁻⁴ mol L⁻¹) in water (λ_ex = 370 nm, F represented the fluorescence intensity at 427 nm).

In conclusion, we designed and synthesized an amphiphilic molecule G1, which assembled to form a triple-component supra-amphiphile WSP5⊃G1@A based on phenylboronic acid/diols dynamic covalent chemistry and pillararene/trimethylamine host–guest complexation. The ternary complex WSP5⊃G1@A self-assembled into nanoparticles in aqueous solution and showed appealing diols-responsive behavior: upon concomitant addition of diols, the nanoparticles transformed into regular nanosheets and simultaneously experienced a pronounced fluorescence decrease in aqueous solution. These interesting phenomena suggested the triple-component supra-amphiphile showed great potential for application in the biologically and environmentally relevant fields, such as controlled release and drug delivery.

Acknowledgements

This work was supported by the Fundamental Research Funds for the Central Universities and Zhejiang University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Synthetic procedures, characterizations, determination of association constants, fluorescence spectroscopy data and other materials. See DOI: 10.1039/c6ra07216j

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