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Reversible Self-Assembly of Supramolecular Vesicles and Nanofibers Driven by Chalcogen-Bonding Interactions Liang Chen, Jun Xiang, Yue Zhao, and Qiang Yan J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 May 2018 Downloaded from http://pubs.acs.org on May 29, 2018
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Journal of the American Chemical Society
Reversible Self-Assembly of Supramolecular Vesicles and Nanofibers Driven by Chalcogen-Bonding Interactions Liang Chen,1,‡ Jun Xiang,2,‡ Yue Zhao,2 and Qiang Yan1,* 1
Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, CHINA 200433. Departement de Chimie, Université de Sherbrooke, Sherbrook, Québec, Canada J1K 2R1
2
Supporting Information Placeholder ABSTRACT: Chalcogen-bonding interactions have been viewed as new noncovalent forces in supramolecular chemistry. However, harnessing chalcogen bonds to drive molecular self-assembly processes is still unexplored. Here we report for the first time a novel class of supra-amphiphiles formed by Te···O or Se···O chalcogenbonding interactions, and their self-assembly into supramolecular vesicles and nanofibers. A quasi-calix[4]chalcogenadiazole (C4Ch) as macrocyclic donor and a tailed pyridine N-oxide surfactant as molecular acceptor are designed to construct the donor-acceptor complex via chalcogen-chalcogen connection between the chalcogenadiazole moieties and oxide anion. The affinity of such chalcogen-bonding can dictate the geometry of supra-amphiphiles, driving diverse self-assembled nanostructures. Furthermore, the reversible disassembly of these assemblies can be promoted by introducing competing halide ions or by decreasing systemic pH.
Molecular self-assembly, as a powerful and elegant technique to fabricate nanoscale architectures, is an eternal theme in supramolecular chemistry.1 Besides the plethora of assembling examples of covalent amphiphiles, there has been growing interest in noncovalent bond-based supra-amphiphiles.2 The dynamic and reversible nature of noncovalent interplay endows the supra-amphiphilic selfassembly with ideal tunability, adaptivity and responsivity. To date, chemists have exploited a variety of noncovalent driving forces, including H-bonding,3 coordination,4 π-π stacking,5 charge transfer6 and host-guest interactions,7 to build supra-amphiphile systems. Inspired by these common interactions, our interest on unconventional supramolecular forces motivates us to explore whether new forms of noncovalent bonds could drive the creation of supra-amphiphiles and related superstructures. Chalcogen-bonding, as an emerging noncovalent motif, stems from the σ-holes associated with the σ* orbitals of the electron-deficient group VI elements, such as sulfur (S), selenium (Se) and tellurium (Te).8 Such new interactions have been involved in catalytic, biological, and medicinal areas.9 Recent theoretical and experimental studies of close contacts between chalcogen centers and nucleophilic sites lift the veil on the existence of chalcogen-bonding interactions.10 A simple example is provided by the benzylselenocyanate crystal, whose neighboring selenocyanate groups have strong chalcogen-bonding effect between Se and N atoms (SeCN···Se).11 Quantum calculations further disclose the similarity of chalcogen-bonding to halogen-bonding, and show that they are more directional and tend to bind multivalently.8a,12 However, as compared to the familiar halogen-bonding, which have been widely used to create supramolecular materials,13 the application of chalcogen-bonding in self-assembly science is relatively unexplored.
Here we address this challenging issue and report an unprecedented supra-amphiphile system and its tunable self-assemblies on the basis of chalcogen-chalcogen interactions.
Scheme 1. (a) Structures of Macrocyclic Donors (C4Ch, Ch = Te or Se), Surfactant (DPN), and Control Compounds (1 and 2). (b) Schematic of the Formation of C4Ch•DPN Supra-amphiphiles Based on Chalcogen-Bonding Interactions and Their Reversible Self-Assembly into Vesicles and Nanofibers.
The design of a proper molecular donor that possesses a chalcogen-bonding center is key to constructing a chalcogen-bonding supra-amphiphile. Previously, 1,2,5-chalcogenadiazole (1, Scheme 1a) has been proven as a good chalcogen-bonding donor that can adduct with a Lewis basic acceptor (Y···ChN2, where Y is a nucleophilic group such as an anion and Ch is Te or Se atom).10 However, our attempt to obtain supra-amphiphile by directly mixing 1 and a classic anionic surfactant 4-dodecyl-pyridine N-oxide (DPN) failed, because the weak affinity of single-site association (O-···ChN2) is insufficient to sustain the complexation in solution (Figure S1). To overcome this difficulty, we designed and synthesized two macrocyclic donors containing different chalcogen elements, quasi-calix[4]telluradiazole (C4Te) and quasi-calix[4]selenadiazole (C4Se), replacing 1 (See detailed synthesis and characterization in Supporting Information, Figure S12-S19). C4Ch (Ch = Te and Se) possess four equivalent chalcogen centers sterically positioned on the rim of bucket-shaped hosts, which is conducive to enhancing their recognition to the DPN guest in aqueous media (Scheme 1b). We
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expected that the resulting chalcogen-bonding supra-amphiphiles would further self-assemble into various nanostructures, such as vesicles and nanofibers. Their large distinction in dimensionality and shape would derive from the difference in two chalcogen-bonding forces, which play decisive roles in dictating the geometry of supra-amphiphiles. Owing to the reversibility of chalcogen bonds, a controllable disassembly of these assemblies could be promoted by adding competitive anions or decreasing solution pH, as shown in Scheme 1.
Figure 1. TEM images showing the self-assembly structures of (a) C4Te and DPN, (b) C4Se and DPN. SAXS results of (c) C4Te and DPN, (d) C4Se and DPN. We first studied whether mixing C4Ch with DPN could realize the proposed supramolecular complexation and self-assembly behavior. In principle, as a typical surfactant, DPN itself can form spherical micelles above its critical micelle concentration (CMC, 8.5 × 10-4 M) in water (Figure S2). Thus, we chose a concentration far below its CMC for the investigation, and in such conditions DPN was molecularly dissolved. For the case of C4Te, when we added it into DPN aqueous solution at an equal molar amount (2.0 × 10-5 M), an opalescent colloidal solution appeared, implying the formation of a new kind of aggregates. Their CMC was determined to be 3.4 × 10-6 M using conductivity experiments (Figure S3),14 which is two orders of magnitude smaller than that of individual DPN. TEM image revealed that they can self-assemble into a large globular shape ranging from 40–130 nm (Figure 1a). Some nanoobjects with open mouths (indicated as arrows) illustrated that these aggregates are hollow vesicular. This membrane-bound structure was confirmed by atomic force microscope (AFM), as indicated by the clear contrast between protruding edge and central sag in the height-image of assemblies (Figure S4a). The bilayer nature was further analyzed by small-angle X-ray scattering (SAXS) (Figure 1c). The aggregates had a strong diffraction peak at 2θ ≈ 1.5º, corresponding to the wall thickness of 5.9 nm calculated by Bragg’s law. Interestingly, if we altered the central chalcogen atom from Te to Se, C4Se with DPN resulted in a significant structural transition. TEM image showed that they can generate a one-dimensional fibrous architecture with a uniform radial diameter of 6.5 nm (Figure 1b). This accorded well with the SAXS result of 6.8 nm (Figure 1d). AFM image also evidenced this cylindrical morphology (Figure S4b). In a control experiment, we designed a macrocyclic analogue 2 (Scheme 1a) in which the chalcogen centers were replaced by carbon atoms. However, 2 and DPN showed no regular aggregates under the same conditions (Figure S5). From these results, we inferred that the chalcogen-mediated noncovalent interactions play
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key roles in facilitating the supramolecular complexation, and the bonding chemistry of different chalcogen donors are likely to influence the molecular packing fashion.
Figure 2. (a-b) UV-Vis spectral monitoring of C4Ch in THF/H2O solution (1/2, v/v): (a) C4Te upon addition of DPN, (b) C4Se upon addition of DPN. (c-d) NMR titration of C4Ch with DPN in THFd8 (from bottom to top): (c) 125Te NMR changes of C4Te, (d) 77Se NMR changes of C4Se. The final molar ratio of C4Ch and DPN is 1:1 in all the experiments. To gain deep insight on the complexation mechanism, we used UV-Vis spectroscopy, chalcogen elemental nuclear magnetic resonance (NMR) and mass spectroscopy (MS) to survey the weak interactions between C4Ch and DPN. As shown in Figure 2a, addition of DPN guest in C4Te host solution caused a bathochromic effect of telluradiazole chromophore (red arrow, λmax = 427→438 nm), accompanied by an enhancement in a long-wavelength band at 461 nm (blue arrow). This result is similar to the report in telluradiazole-tetrabutylammonium bromide adduct,10a indicating that the four telluradiazole moieties in C4Te are the main supramolecular motifs to bind DPN. The binding stoichiometry was evaluated to be 1:1 by the UV-Vis Job plot (Figure S6). 125Te NMR titration further showed that in the absence of DPN, C4Te had a single Te peak at δ = 1684 ppm, ascribing to the four identical Te atoms; however, when DPN was gradually injected, the initial Te resonance split into two signals and yielded large downfield shifts (∆δ = 12 and 29 ppm, Figure 2c). These indicated the chalcogen-bonding occurs between the tellurium in C4Te macrocycle and the Noxide head group in DPN, and suggested that the quadruple Te···O interactions could be divided into two categories. Similar results have recently been found in the molecular tetramer of tellurazoleN-oxide.15 The above discussion was supported by ESI-MS data. After complexation, there is a peak with m/z 1203.04, which corresponds to the 1:1 orthogonal complex of C4Te•DPN (Figure S7). C4Se is also capable of binding with DPN via analogous Se···O interactions (Figure 2b and 2d; Figure S8-S9). By contrast, its spectral red-shift phenomenon (Figure 2b, λmax = 420→425 nm) and NMR chemical splitting (Figure 2d, ∆δ = 3.8 and 9.2 ppm) are both weaker than that of C4Te, probably meaning that the Te···O interactions are superior to the Se···O ones. To know the strength of chalcogen-bonding interactions, isothermal titration calorimetry (ITC) experiments were carried out.16 The association constant of C4Te and DPN was found to be Ka = 7.12 × 105 M-1 (Figure 3a), 5-fold larger than that of C4Se and DPN (Ka =
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1.4 × 105 M-1, Figure 3b), validating our conjecture. The stoichiometry of binding (n) approximates to 1.0 in both cases, consistent with the UV-Vis Job plot results. Moreover, the Gibbs free energies (∆G) were calculated to be -32.8 kJ mol-1 and -28.9 kJ mol-1 for C4Te•DPN and C4Se•DPN complexes, respectively. To eliminate other conceivable modes of supramolecular interactions (e.g. anion-π interactions), we carried out an extra ITC experiment using 2 and DPN, where only anion-arene interplay exists. However, the results showed its ∆G = -5.9 kJ mol-1, much weaker than the chalcogen-containing systems (Figure S10). This demonstrates that the major driving force forming the C4Ch•DPN supra-amphiphile is attributed to the chalcogen-bonding interactions.
Figure 3. ITC results showing the binding affinity of chalcogenbonding interactions between C4Ch and DPN: (a) C4Te•DPN complex and (b) C4Se•DPN complex.
Figure 4. DFT simulation of the stereochemical structures of C4Ch (left, front view) and their chalcogen-bonding supra-amphiphiles C4Ch•DPN (right, side view): (a) C4Te, (b) C4Te•DPN, (c) C4Se, and (d) C4Te•DPN. The noncovalent distances are marked and the colored sticks represent: tellurium (orange), selenium (cyan), carbon (green), nitrogen (blue) and oxygen (red), and hydrogen was omitted for clarity. We next aimed to figure out why different chalcogen bonds can dictate different assemblies. To this end, a density function theory (DFT) simulation was used to investigate the supra-amphiphiles.17 For C4Te, the four Te atoms are partitioned diagonally into two groups, inside and outside the ring plane, respectively (Figure 4a, front view). In the orthogonal complex, the distances from the oxygen to the two groups of Te are 2.74 and 3.42 Å (Figure 4b, side view), and the length of C4Te•DPN supra-amphiphile is 3.1 nm. In
comparison, the Se···O distances in C4Se•DPN are a little longer (3.15 and 3.61 Å), and its molecular length extends to 3.7 nm (Figure 4c-d). Such small distinctions not only decide the strength rule of chalcogen-bonding interactions (KTe···O > KSe···O), is also a main factor to result in different assembling structures. It is known that the geometry of amphiphiles can be predicted by critical packing factor (p = V/a0lc),18 where V, a0 and lc are, respectively, molecular volume, area of head group, and molecular length. Generally, spheres can form when 0 < p < 1/3, cylinders when 1/3 < p < 1/2 and lamellae for 1/2 < p < 1. Since C4Te•DPN has a shorter molecular length than that of C4Se•DPN whereas their macrocycle areas are nearly the same, thus the calculated p values for the two supraamphiphiles are 0.54 and 0.43, corresponding to the bilayer and worm-like shapes, respectively (Figure S11). Overall, the good match between experimental and theoretical data validates our initial assumption that chalcogen-bonding can act as a new type of noncovalent interaction to manipulate the molecular self-assembly.
Figure 5. DOX release curves from C4Te vesicles upon (a) competing halides (Cl- and Br-) and (b) pH decrease. The reversibility and responsivity of chalcogen-bonding interactions is highly desired. To probe this, we introduced competing anions into the C4Te•DPN vesicle system and observed whether the assemblies could be disrupted. After encapsulated a drug doxorubicin (DOX, 100 μg) in the vesicles, the release of DOX can reflect the vesicular disassembly. In the absence of stimuli, the fluorescence of DOX-loaded vesicles remained invariable, thus indicating no release happened (Figure 5a, black line). In contrast, large fluorescent enhancement was seen when halide anions (Cl- or Br-) that have far stronger interactions with C4Te were added, indicating a fast vesicle cracking (Figure 5a, blue and red line). Alternatively, decreasing the solution from pH 7.6 to pH 3.5 can lead to the same effect (Figure 5b). A possible reason is that the increase of pH can lead to the formation of H-bonding, which has a stronger competing effect to that of chalcogen-bonding. The quest to new noncovalent interactions offers impetus for the development of self-assembly science. This work demonstrate the first chalcogen-bonding-based supra-amphiphiles, and further present a new strategy that harnesses chalcogen-bonding interactions to drive and regulate molecular self-assembly. The intrinsic nature and mechanism of chalcogen bonds will need to be uncovered by more future studies; however, this study would open a promising direction of chalcogen-bonding-mediated self-assembly nanotechnology.
ASSOCIATED CONTENT Supporting Information
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Synthetic procedures, characterization data, AFM images, Job plot, and control experiments. This material is available free of charge on the ACS Publications website (pdf file).
AUTHOR INFORMATION Corresponding Author
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*
[email protected] Author Contributions ‡These authors contributed equally.
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ACKNOWLEDGMENT This work was financially supported by National Natural Science Foundation of China (21674022 and 51703034) and acknowledged the Natural Sciences and Engineering Research Council of Canada.
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Journal of the American Chemical Society
Reversible Self-Assembly of Supramolecular Vesicles and Nanofibers Driven by Chalcogen-Bonding Interactions Liang Chen,1,‡ Jun Xiang,2,‡ Yue Zhao,2 and Qiang Yan1,*
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