Supramolecular nanocatalyst in water: successive click-driven assembly of click-derived rod amphiphiles

Abstract

A supramolecular vesicular nanocatalyst (VC) for successive Cu^I-catalyzed azide–alkyne cycloaddition in water was developed by self-assembly of a click chemistry-derived rod amphiphile (CA). The CA generated by click reaction of azide-terminated benzyl ether dendrons and diethynyl naphthalene self-assembles into vesicles in water. The excellent catalytic activity of the VC was endowed by Cu^I-chelation to triazole-containing rod block within VC wall. The VC performed click reaction of benzyl azide with phenylacetylene or trimethylsilylacetylene. The resultant hydrophobic products self-encapsulated in VC wall affect the interfacial curvature of the VC according to their structural compatibility with CA, inducing the increase in vesicular size or structural change to micelle. Interestingly, the morphology of VC-derived nanocatalyst was further controlled from micelle to vesicle and vice versa by successive click reactions, leading to controllable loading/release of hydrophilic payloads. This recyclable catalytic activity of the self-transformable nanocatalyst was confirmed by a visually detectable click reaction offering a fluorescent color change of the aqueous VC solution.

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Introduction

Supramolecular nanovesicles based on the aqueous self-assembly of amphiphiles possess two types of confined spaces: the aqueous core cavity and the hydrophobic wall.^1–3 The confined wall enables the vesicle to serve as a nanoreactor by providing a hydrophobic environment, where chemical reactions such as a Diels–Alder reaction,⁴ palladium-catalyzed carbon–carbon bond forming reaction,^5,6 and enzymatic cascade reaction^7–9 can be performed. This ability can be used to increase the conversion efficiency by locally concentrating the reacting species and pre-organizing them in a favored conformation for a desired reaction.¹⁰ The vesicles can also show a nanostructural change in response to external stimuli such as pH, light, temperature, and guest molecules,^11–13 resulting from the interfacial curvature change of vesicles by the dynamic assembly behavior of stimuli-responsive block-containing amphiphiles.^14,15 This makes them attractive candidates for developing transformable nanomaterials in smart chemo/biosensors and controlled drug/imaging agent delivery.^14–17 However, self-transformable nanoreactors that can act as an on-demand nanotransporter of payloads has rarely been reported.

Cu^I-catalyzed azide–alkyne cycloaddition (CuAAC) click chemistry, resulting in 1,4-disubstituted 1,2,3-triazole derivatives,^18–20 has led to a wealth of applications due to its synthetic simplicity, mild reaction conditions, and biocompatibility.^21–24 However, the instability of catalytically active Cu^I sites requires a large amount of Cu^I catalyst to accelerate the CuAAC click reaction. The complete removal of Cu^I is also a challenge and limits the utilization of click chemistry in electronics, biomedicine, and green chemistry.²⁵ Interestingly, the click-derived triazole group has also been attractive as a ligand providing several donor sites for chelating metal ions,^26,27 increasing its use in click chemistry with applications such as chemosensing,²⁸ catalysis,²⁹ and therapeutics.^30,31 Therefore, one can envision that the click reaction-derived rod amphiphiles spontaneously form vesicles in water, providing a hydrophobic space where catalytic Cu^I is chelated by a triazole group and can act as a vesicular nanocatalyst (VC) for click reactions.

Herein, we report the supramolecular self-transformable VC based on the self-assembly of a click-derived, Cu^I-chelating rod amphiphile (Fig. 1). The VC can carry out successive click reactions with an exceptional conversion efficiency owing to (i) stabilized catalytic Cu^I and reactants preserving the catalytic activity, and (ii) the reactive species in close proximity to the catalytic sites in the VC wall. Also, the self-encapsulation of the hydrophobic click products within the wall affects the interfacial curvature and thus the morphology of the VC, enabling the extensive use of VCs as smart nanomaterials.

Fig. 1 Interfacial curvature-controllable supramolecular vesicular nanocatalyst (VC) for successive click I-to-click II reactions, formed by self-assembly of a click-derived rod amphiphile (CA) in water, depending on the molecular structure similarity of click reaction products P1 and P2 with the rod segment of CA. P1 and P2 are the click reaction products of benzyl azide with phenylacetylene or trimethylsilylacetylene, respectively.

Results and discussion

The click-derived rod amphiphile (CA) was synthesized by the CuAAC reaction of azide-terminated benzyl ether dendrons and diethynyl naphthalene (Fig. S1–S3, ESI†) and showed vesicular formation by aqueous self-assembly (Fig. 1 and Fig. S6b, ESI†). The Cu^II-chelation to the triazolyl moiety of CA, to provide the Cu^I-chelated VC (Cu^I-VC), was examined by ultraviolet-visible (UV-Vis), fluorescence, and ¹H nuclear magnetic resonance (NMR) spectroscopies (Fig. S6 and S7, ESI†). CuSO₄ (0.5 equiv. mol to CA) and sodium ascorbate (NaAsc, 3.0 equiv. mol to CuSO₄) were added to an aqueous solution of CA for the in situ reduction of Cu^II to Cu^I (Fig. 2). The stoichiometric ratio of CA : Cu^II was 2 : 1 (Fig. S6c, ESI†).³² In the UV-Vis spectra, the characteristic d–d transition of Cu^II in the range 700–900 nm³³ disappeared, and new absorption peaks appeared at 600 and 750 nm after addition of CuSO₄ to the aqueous solution of CA, which could be assigned to a metal-to-ligand-transfer transition (Fig. S6d, ESI†).³⁴ The two peaks at 600 and 750 nm disappeared, and a band at 670 nm appeared after further reduction of Cu^II to Cu^I by NaAsc, indicating Cu^I-chelation by the triazolyl group of CA. The decrease in emission of CA after addition of CuSO₄, indicative of the Cu^II-chelation by the triazole group of CA, could be attributed to the reverse photoinduced electron transfer³⁵ involving electron donation from the excited naphthalene unit to the Cu^II-binding triazole group (Fig. S6e, ESI†).³⁶ The ¹H NMR signal of the triazole proton (H_c) of CA at 8.16 ppm measured in D₂O shifted upfield to 8.12 ppm upon addition of CuSO₄ (Fig. S7a, ESI†).²⁵ The H_g of CA shifted upfield by 0.06 ppm, suggesting the oxygen atoms next to the phenyl group were interacting with Cu^II. After further addition of NaAsc, the H_c- and H_g-signals showed a downfield shift of 0.04 and 0.03 ppm, respectively, indicating CA–Cu^I complex formation. Fig. S7b (ESI†) shows the plausible binding model of CA–Cu^I. The successful fabrication of vesicular structures of CA–Cu^I for Cu^I-VC was confirmed by transmission electron microscopy (TEM) (Fig. S8, ESI†). The unstained TEM images of both vesicular CA–Cu^II precatalyst and CA–Cu^I catalyst clearly showed the vesicular wall with enhanced contrast due to the chelation of Cu by the triazole group at the hydrophobic segment.

Fig. 2 Development of the Cu^I-VC for CuAAC.

The catalytic ability of Cu^I-VC was assessed by a ¹H NMR study. First, the CuAAC reaction using water-insoluble benzyl azide (5 mol equiv. to CA for Cu^I-VC) and phenylacetylene (5 equiv.) was performed for 24 h to generate click product P1 in the presence of Cu^I-VC (Fig. S5a, ESI† and Table 1). After dissolving the resultant nanocatalyst in CDCl₃, a conversion efficiency of 99% was reached (Table 1, entry 1). The reaction did not occur in the absence of Cu^I-VC (entry 2). The enhanced reactivity of Cu^I-VC was confirmed by comparison to the reaction with Cu^I, showing moderate catalytic conversion of 31% (entry 3). This could be attributed to a closer contact of preorganized hydrophobic reactants to stabilized catalytically active Cu^I sites confined in the walls of the supramolecular Cu^I-VC.³⁷

Table 1 Comparison of VC catalyst efficiency in CuAAC^a

Entry	Catalyst	Alkyne	Time (h)	Conversion^b (%)	Product name
a All reactions were carried out with 5 equiv. mol (12.5 μmol) of benzyl azide and alkyne in 0.5 mL distilled water at room temperature. b Reaction conversion was determined by ^1H NMR spectroscopy. c Cu^I was prepared by addition of 3.0 equiv. NaAsc into the 0.1 mM CuSO4 solution under Ar atmosphere.
1	Cu^I-VC		24	99	P1
2	·		24	0	·
3	Cu^I^c		24	31	P1
4	Cu^I-VC		24	98	P2
5	·		24	0	·
6	P2-loaded Cu^I-VC		24	99	P1
7	P1-loaded Cu^I-VC		24	36	P2

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Consequently, the water-insoluble click product P1 was generated and self-encapsulated in the hydrophobic vesicular membrane. The ¹H NMR spectrum of P1-loaded Cu^I-VC in D₂O showed the upfield shift of naphthyl protons (H_d, H_e, and H_f, around 0.10–0.14 ppm), benzylic H_b (0.05 ppm), and triazolyl H_c (0.06 ppm) protons of Cu^I-VC compared with that of the original one in D₂O (Fig. S9c, ESI†). The upfield shifts of H_b, H_c, H_d, H_e, and H_f could be ascribed to the shield effect of P1 by the π–π stacking with the rod amphiphile CA.³⁸ The absorbance of Cu^I-VC decreased and the emission was quenched after generation of P1 by the CuAAC reaction (Fig. S10, ESI† and Fig. 3a) which could be attributed to the energy transfer of Cu^I-VC to P1 due to the π–π stacking between the aromatic block of CA and P1.³⁹ TEM images revealed that the vesicular structure of Cu^I-VC remains intact after loading P1 by the CuAAC reaction (Fig. 3b). Even in the presence of excess reactants, precipitating P1 (white solid) by the constant reactivity of Cu^I-VC, the vesicular structure was maintained without rupture (Fig. S11a and b, ESI†).

Fig. 3 (a) Emission spectra (λ_ex = 260 nm) of Cu^I-VC, P1-, and P2-loaded Cu^I-VC in water. Negatively stained TEM image of (b) P1- and (c) P2-loaded Cu^I-VC (0.02 mM) with 2 wt% uranyl acetate. Insets of (b and c) show the cryo-TEM image. Inset scale bar equals (b) 100 and (c) 50 nm, respectively. (d) Hydrodynamic diameters of Cu^I-VC, P1-, and P2-loaded Cu^I-VC.

To confirm the catalytic activity of Cu^I-VC, P2 with a bulky trimethyl group was synthesized using the CuAAC reaction of trimethylsilylacetylene and benzyl azide (Fig. 1, Table 1 and Fig. S5b, ESI†). Cu^I-VC shows an excellent conversion efficiency of 98% (entry 4). When the P2-forming CuAAC reaction was carried out without Cu^I-VC, the reaction did not occur as expected (entry 5). The ¹H NMR spectrum of Cu^I-VC with P2 measured in D₂O showed an upfield shift similar to that observed for P1-loaded Cu^I-VC in D₂O, indicating the encapsulation of P2 by Cu^I-VC (Fig. S12c, ESI†). The P2-loaded Cu^I-VC showed the formation of micelles of diameter ∼10 nm (Fig. 3c and Fig. S13c, ESI†), which is twice the molecular length of fully extended CA (Fig. S6a, ESI†). The emission quenching of Cu^I-VC upon generation of P2 suggests the intercalation of P2 within the hydrophobic wall of Cu^I-VC (Fig. 3a). The smaller decrease in the emission of P2-loaded Cu^I-VC than that of P1-loaded Cu^I-VC could be the result of less effective π–π stacking of P2 with the hydrophobic rod segments of the CA nanocatalyst.⁴⁰ The bulky trimethyl groups of P2 may hinder the close packing of CA within the membrane of Cu^I-VC, resulting in morphological transformation of Cu^I-VC from vesicle to micelle. Dynamic light scattering (DLS) revealed an increase in the average hydrodynamic diameter (R_H) of P1-intercalated Cu^I-VC (from ∼21 nm to ∼600 nm) (Fig. 3d). A decrease in the R_H of P2-intercalated Cu^I-VC was observed (from ∼21 nm to ∼10 nm) compared with Cu^I-VC. Therefore, the molecular structure similarity of the click reaction products with the hydrophobic rod segment of CA may affect the interfacial curvature of supramolecular nanocatalyst Cu^I-VC, resulting in a morphological change. For instance, the high structural compatibility of P1 with CA could enable the effective encapsulation of P1 within the membrane of Cu^I-VC. The π–π stacking of P1 with CA could be optimized as P1 and the rigid hydrophobic segment of CA are arranged in parallel, which decreased the interfacial curvature of the wall, leading to an increase in Cu^I-VC size.⁴¹ These results are consistent with the entropic cost of intercalating molecules with increased volume, which is responsible for the vesicle-to-micelle morphological change.⁴²

As the interfacial curvature of Cu^I-VC can be tuned by the molecular architecture of click products, we studied whether the reversible morphological transformation of nanocatalyst from micellar aggregates to vesicles could be achieved by sequential click reactions to form P1 using P2-loaded Cu^I-VC (Fig. 4a). The CuAAC reaction of benzyl azide and phenylacetylene catalyzed by P2-loaded Cu^I-VC was performed (Table 1, entry 6). The catalytic activity of the P2-loaded nanoreactor still shows a tremendous conversion efficiency of 99% despite the pre-loading of P2 in Cu^I-VC. In the ¹H NMR spectrum of P2-loaded Cu^I-VC after the CuAAC reaction to form P1 in D₂O, H_b, H_c, H_d, H_e, and H_f are significantly downfield shifted (0.05–0.09 ppm), probably indicating a strong hydrogen bonding interaction between the triazolyl and naphthyl protons of CA and the aromatic protons and nitrogen atoms in the triazole moiety of P1 and P2 (Fig. 4b).³⁸ H_a and H_g showed a moderate downfield shift (0.05 ppm), which suggests the enhanced hydrogen bonding interaction of polyethylene oxide chains of CA with water. However, after dissolving the resultant nanocatalyst in CDCl₃, only P1 signals were detected in the ¹H NMR spectrum (Fig. 4b and Fig. S14, ESI†). Fluorescence quenching of P2-loaded Cu^I-VC was observed after the P1-forming CuAAC reaction (Fig. S15b, ESI†). The TEM experiment showed the presence of vesicles (Fig. 4c). These results can be explained by preloaded P2 in Cu^I-VC being replaced with P1 and released into the aqueous solution because P1 has greater molecular structure compatibility with CA, which can form a more stable vesicle through π-stacking. The released P2 to the aqueous phase was confirmed by ¹H NMR experiment. The transformation of P2-loaded nanocatalyst to a vesicular structure by successive click reactions was further confirmed using hydrophilic dye fluorescein isothiocyanate (FITC) that can be encapsulated in the interior cavity of the vesicle (Fig. S16a, ESI†).⁴³ As expected, the fluorescence micrograph clearly showed bright green-emitting spherical aggregates, indicating the formation of a vesicle (Fig. 4d and Fig. S16b, ESI†).

Fig. 4 (a) Successive click reactions of nanocatalyst, resulting in the morphological change of Cu^I-VC from micelle to vesicle. (b) ¹H NMR spectra of Cu^I-VC and P2-loaded Cu^I-VC measured in D₂O and P2-loaded Cu^I-VC after click reaction to generate P1 measured in D₂O and CDCl₃. Red hollow circle () and blue triangle () denote CA and P1, respectively. More detailed information is in the ESI.† (c) Negatively stained TEM image and (d) fluorescence micrograph of the P2-loaded Cu^I-VC after click reaction to synthesize P1. Inset of (d) shows the vesicle containing FITC within the inner aqueous medium separated by a wall from the outer aqueous solution. Green fluorescence: FITC.

The morphological transformation of P1-loaded nanocatalyst was also demonstrated by conducting P2-forming CuAAC reaction (Fig. 5, Fig. S14 and S17, ESI†). The P1-loaded vesicular nanocatalyst encapsulating FITC in inner aqueous compartment could release the FITC fluorescent dyes into the outer aqueous phase after performing a P2-forming CuAAC reaction as a result of the nanostructural transformation to micelle (Fig. 5b). The TEM image clearly showed the micellar structures with a diameter of ∼10 nm (Fig. 5c). The ¹H NMR spectrum of the resultant micelles dissolved in CDCl₃ indicated the presence of both P1 and P2 within the micelle core (Fig. S14, ESI†) which could be because the preloaded P1 is not fully replaced with P2 due to the higher structural compatibility of P1 with CA. The conversion efficiency of P2 production using P1-loaded Cu^I-VC was calculated to be relatively low (36%) (Table 1, entry 7). This result could be attributed to the strong mutual interaction between CA and P1, limiting the access of trimethylsilylacetylene and benzyl azide to the catalytic Cu^I located in the vesicular wall. Therefore, the molecular packing constraint induced by preloaded products within the hydrophobic wall of the nanocatalyst should be considered for performing successive click reactions.

Fig. 5 (a) Morphological transformation of Cu^I-VC from vesicle to micelle by successive click reactions of nanocatalyst, leading to controllable loading/release of FITC payloads. (b) Emission enhancement of the FITC-released aqueous solution of P1-loaded Cu^I-VC (0.5 mM) incorporating FITC after click reaction to form P2. (c) Negatively stained TEM image of P1-loaded Cu^I-VC after P2-forming CuAAC reaction with 2 wt% uranyl acetate.

The recyclable catalytic activity of Cu^I-VC with structural transformable capability was further confirmed by conducting a visually detectable click reaction via a fluorescent color change of a Cu^I-VC solution. The conversion of water-insoluble nonfluorescent reactants to fluorescent products by the CuAAC reaction can help detect the click reaction using the naked eye. The hydrophobic coumarin derivatives were utilized as a target click product. Upon adding coumarin into aqueous Cu^I-VC solution, characteristic absorption of coumarin (∼280 nm) appeared while the fluorescence of Cu^I-VC was quenched, indicating the presence of coumarin within the hydrophobic segment of Cu^I-VC (Fig. S18, ESI†). To generate a coumarin-based fluorescent click product with different structural similarities to CA, we synthesized 3-azido-7-hydroxycoumarin, a nonfluorescent azide (Fig. S4, ESI†).^44,45 The fluorescent emission of the coumarin moiety in 3-azido-7-hydroxycoumarin is quenched by the lone pair of electrons from the azido group.^46,47 Phenylacetylene and trimethylsilylacetylene were also used for the CuAAC reactions with 3-azido-7-hydroxycoumarin (Fig. 6a). The resulting click products of phenylacetylene and trimethylsilylacetylene with 3-azido-7-hydroxycoumarin were referred to as CP1 and CP2, respectively (Fig. 6a). As expected, the blue color of 5 mM Cu^I-VC solution became turquoise under irradiation at 365 nm, indicating the formation of CP1 and the subsequent loading within the Cu^I-VC vesicular membrane. In contrast, the CP2-containing Cu^I-VC solution showed relatively weak green emission under UV irradiation. A new absorption band around 340 nm appeared for both CP1- and CP2-loaded Cu^I-VC (Fig. 6b), and the fluorescence of Cu^I-VC was quenched (Fig. 6c). These results indicate that click products CP1 and CP2 were incorporated within the Cu^I-VC wall. Notably, a characteristic emission peak of CP1 at 480 nm appeared for CP1-loaded Cu^I-VC when excited at the wavelength of 260 nm which indicates the fluorescence resonance energy transfer (FRET) due to the close proximity of CP1 and the rod block of CA.⁴⁸ The electron lone pair of the azido moiety of 3-azido-7-hydroxycoumarin could be localized as the triazole ring is formed in CP1, leading to the activation of fluorescence.^46,47 The emergence of the FRET signal demonstrated efficient stacking between CP1 and the rod amphiphile CA. The fluorescence micrograph of the CP1-loaded Cu^I-VC confirmed the presence of spherical structures (Fig. 6d), and TEM revealed the intact vesicular structure of CP1-encapsulated Cu^I-VC (inset of Fig. 6d and Fig. S19, ESI†). Loading of CP2 with an unsymmetric structure imposed by the bulky trimethyl group into Cu^I-VC showed the formation of the micellar aggregates (Fig. 6e). These results are consistent with the morphological transition from vesicles to micelles observed for Cu^I-VC when synthesizing P1 and P2 based on the benzyl azide.

Fig. 6 (a) Cu^I-VC nanocatalyst with images of a 5 mM Cu^I-VC solution under UV irradiation (λ_ex = 365 nm). Change in (b) absorption and (c) emission spectra of 0.02 mM Cu^I-VC upon CuAAC reaction to generate CP1 and CP2, respectively (λ_ex = 260 nm). (d) Fluorescence micrograph of CP1-loaded Cu^I-VC. Inset shows the negatively stained TEM image of CP1-loaded Cu^I-VC with a scale bar of 50 nm. (e) Negatively stained TEM image of CP2-incorporated Cu^I-VC. Inset shows the diameter distribution of the micelle.

Conclusions

In summary, we have developed an aqueous supramolecular nanocatalyst based on the self-assembly of the click-derived rod amphiphile, capable of successive click reactions, which maintained excellent catalytic efficiency. The self-transformable behavior of the nanocatalyst was controlled by encapsulating structurally compatible hydrophobic click reaction products with a rod amphiphile, which, in turn, affects the interfacial curvature of the nanocatalyst. The morphological transformability enables the click nanoreactor/catalyst potential for in situ production of on demand payloads and controllable loading/release of such payloads, including drugs, imaging agents, and chemical species. This can further broaden the potential applications of supramolecular nanocatalysts into the field of smart nanobiomedicine and chemo/biosensors.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

This research was supported by Basic Science Research Program (2016R1A2B4012322) through the National Research Foundation of Korea (NRF). We thank Prof. B. K. Cho for the discussion of amphiphile CA synthesis.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9qm00059c

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