Dual-responsive vesicles formed by an amphiphile containing two tetrathiafulvalene units in aqueous solution

Abstract

The first example of tetrathiafulvalene (TTF)-based vesicle fabricated in water solution with 1 vol.% tetrahydrofuran that could be prevented by chemical oxidant Fe(ClO₄)₃ or electron-deficient cyclobis(paraquat-p-phenylene) tetracation cyclophane (CBPQT⁴⁺) is described.

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Vesicles as enclosed compartments constructed by self-assembly membranes of amphiphiles, have attracted extensive attention in recent years because they are crucial building blocks for all living systems and have various potential applications in drug and gene delivery, nanomaterials, and artificial cell membranes.^1–8 Encouraged by Mother Nature, chemists have employed various amphiphilic polymers and small surfactants to construct artificial vesicles with defined sizes and functions. For example, calixarenes,⁹ cucurbiturils,¹⁰ cyclodextrin,^11,12 cyclophane,^13,14 foldamers,¹⁵ as well as block copolymers^16,17 have been reported. On the other hand, several strategies have been developed to endow the artificial vesicles “stimuli-responsive” characteristics by a range of photo-,^18,19 electro-,^20–22 pH-,^23–26 thermo-,^27,28 or enzyme-stimuli.^29,30 However, most of them could only respond to one single external stimulus. There are only a few examples regarding the multi-stimuli responsive supramolecular vesicles.^31–35

Tetrathiafulvalene and its derivatives (TTFs) have attracted extensive research interest as strong electron donors for the development of organic electrical conductors and superconductors over the past decades.^35–37 In addition, they are also used as building blocks in macromolecular and supramolecular systems for various applications.^38,39 Zhao and Li reported the first self-assembling vesicles from TTF derivatives in organic solvents.⁴⁰ However, their self-assembling behaviors and applications in aqueous environments have been far less explored⁴¹ owing to the pronounced hydrophobicity of TTFs. Recently, we reported that a water-soluble small molecular weight amphiphile with one TTF unit can self-assemble into micelles in water.⁴² The encouraging result prompted us to design a new different amphiphile 1 containing two TTF units and to explore further its assembly behaviors in aqueous environment (Scheme 1). In comparison to the reported amphiphilic molecule,⁴² the introduction of one more TTF units in 1 results in the whole molecular structural shape changing from wedge and dumbbell (Fig. S1†).^43,44 More importantly, the self-assembly of dumbbell-shaped 1 in aqueous solution results in TTF-based vesicles and shows different self-assembly aggregates as a result of the new balance and orientation of hydrophobic moiety and hydrophilic chain.

Scheme 1 Chemical structure of amphiphile 1.

The synthesis of amphiphile 1 was carried out as described in Scheme 2. The starting N-Boc protected compound 2 with hydrophilic group was deprotected under excess trifluoroacetic acid (TFA). Subsequently, an excess of triethylamine (TEA) was slowly added to neutralize TFA. The generated amine was directly coupled with 3,5-diiodobenzoic acid with the aid of PyBOP to give compound 3. The Sonogashira reaction of 3 with an excess (trimethylsilyl)acetylene (TMSA) yielded 4, which was then deprotected by excess K₂CO₃ to afford the terminal alkyne compound 5. Then, 5 was reacted with 2-iodotetrahiafulvalene to produce target amphiphilic compound 1. The target compound was identified by ¹H NMR and ¹³C NMR spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS).

Scheme 2 Preparation of 1. (a) Trifluoroacetic acid, CH₂Cl₂; (b) 3,5-Diiodobenzoic acid, PyBOP, TEA, DMF, CH₂Cl₂; (c) TMSA, [Pd(PPh₃)₄], CuI, TEA, THF; (d) K₂CO₃, CH₃OH, CH₂Cl₂; (e) 2-Iodotetrathiafulvalene, [Pd(PPh₃)₄], CuI, TEA, THF.

Due to the very limited solubility of 1 in water, it cannot directly dissolve into water for self-assembly. Therefore, a little amount of organic solvent tetrahydrofuran (THF) that may have some solvation or even templation effect was used to aid the solvation.⁶ Specifically, to initiate the self-assembly of 1 in aqueous solution, a schematic representation of the preparation procedure is shown in Fig. S2.† In a typical experiment, a concentrated THF solution of 1 (2 × 10⁻³ M, 20 μL) was injected into a rigoursly stirred water (2 mL) to induce aggregate formation.

The aggregated species of 1 in aqueous solution was corroborated by dynamic light scattering (DLS) experiments. CONTIN analysis of the DLS autocorrelation function of 1 shows a broad distribution of hydrodynamic diameter (D_h) of the aggregates centered at ∼70 nm in aqueous solution (Fig. 1a). The observation suggested the presence of large aggregates. Cryogenic transmission electron microscopy (cryo-TEM) was performed to gain a direct visualization of the size and morphology (Fig. 1b and S3†). As shown in Fig. 1b, these aggregate species have a typical vesicular structure by the distinct contrast between the dark periphery and the light central part with a diameter of 50–90 nm, which are consistent with the results of DLS measurement. The wall thickness (dark part) is estimated to be about 4–7 nm, which indicated the hydrophobic segments consisting of bilayer of amphiphilic molecules (Fig. 2). The driving force for the formation of vesicles of 1 lies with the balance of π–π and S–S interactions^45–51 and solvophobic interactions between TTF cores and interior hydrophilic interaction. Moreover, the absorption spectra of 1 in water exhibited a weaker absorbance with a red shift than that in CH₃CN (Fig. S4†), confirming the π–π interactions between TTF cores. We postulated, based on the evidence to be shown, that 1 self-assembled in a bilayer fashion with the hydrophilic ethoxy chains exposed both internally and externally to the polar solvent with the hydrophobic TTF groups interacting in the middle of the bilayer.

Fig. 1 DLS data (a) and cryo-TEM image of the vesicles (b) for amphiphile 1 obtained at concentration of 2.0 × 10⁻⁵ M in aqueous solution. The DLS data are shown as the size probability distribution obtained by a CONTIN analysis.

Fig. 2 Schematic illustration of the bilayered membrane vesicles.

Then, we explore the possibility of prevention of such vesicular aggregates by oxidation or complexation with TTF unit. Firstly, we found it was difficult to fully oxidize the TTF units of 1 in aqueous solution to its cation TTF²⁺, as shown in Fig. S5.† Whereas only 4 equiv. of Fe(ClO₄)₃ was needed to produce dication 1²⁺ (TTF²⁺) in CH₃CN. Such differences could be interpreted by the fact that the TTF moiety is buried in the hydrophobic core of vesicular aggregate that is not easily accessible for Fe(ClO₄)₃. Due to the low solubility of 1 in water, we first oxidized the TTF unit to its dication TTF²⁺ in CH₃CN, and then added it to deionized water for cryo-TEM measurement (Fig. 3, left). As shown in Fig. 3, no vesicular structures could be observed, indicating the prevention of such vesicular aggregates by the oxidation of TTF units to more hydrophilic TTF²⁺, together with the electrostatic repulsion between the oxidized species. However, the trial for regeneration of vesicles by addition of reductant, such as Vitamin C and NaBH₄, was unsuccessful mainly due to the limited solubility of 1 in water.

Fig. 3 The representative cryo-TEM images of 1 with TTF units being fully oxidized by Fe³⁺ (left) or complexation with CBPQT⁴⁺ (right).

Due to the high π-electron donating ability, TTFs can form stable charge-transfer complexes with electron-deficient species, tetracationic cyclobis(paraquat-p-phenylene) (CBPQT⁴⁺). Therefore, we took advantage of the complexation of 1 and CBPQT⁴⁺ in solution to disassemble the vesicular architectures. When amphiphile 1 and CBPQT⁴⁺ were mixed in water and CH₃CN, respectively (Fig S6†), a green solution appeared immediately accompanied with a very broad charge-transfer band around 800 nm in the absorption spectra. Additional insight into the complexation of 1 and CBPQT⁴⁺ was obtained by means of ¹H NMR spectroscopy studies in CD₃CN (Fig. S7†). A mixture of 1 and CBPQT⁴⁺ (1 : 2) exhibited a quite different spectrum from that of amphiphile 1 itself in CD₃CN. Upon addition of CBPQT⁴⁺ to solution, the proton H (●, ■) resonance of TTF unit shifted to upfield position, whereas the aromatic protons H (◆, ◊) neighboring the TTF unit shifted to downfield. These results suggested the formation of charge-transfer complex between 1 and CBPQT⁴⁺, and thereby leading to the strong shielding and deshielding effect of the aromatic rings in CBPQT⁴⁺. The disassembling vesicles of 1 upon complexation with CBPQT⁴⁺ were further studied using cryo-TEM techniques (Fig. 3, right). Fig. 3 (right) showed the typical cryo-TEM images of 1 after complexation with CBPQT⁴⁺. Also, no vesicular structures were observed, indicating the damage of vesicles. This prevention may be explained by considering the two factors: (1) the original hydrophobic part of 1 became more hydrophilic upon complexation with CBPQT⁴⁺; and (2) the strong electrostatic repulsion interactions between these terminus tetracationic species caused the separations of charge-transfer complexes.

Conclusions

In summary, we have designed and synthesized a dumb-bell shaped amphiphile having two redox-active TTF units by Sonogashira reaction in a good chemical yield. It can self-assemble in aqueous solution to form vesicular aggregates. More interestingly, the vesicular architectures could be prevented either by the addition of chemical oxidant Fe(ClO₄)₃ or by the complexation with electron-deficient ring CBPQT⁴⁺. This is, to the best of our knowledge, the first example of vesicles in aqueous media based on a small organic molecule featuring electro-active TTF unit. This work also has demonstrated that the aggregates’ morphologies and functions of amphiphilic TTFs are dependent on their molecular shapes and the number of TTF units. Furthermore, it is anticipated that this research line can lead to the rational design of new smarter and more complicated aggregates in aqueous environments.

Acknowledgements

We are grateful for financial support from the Ministry of Science and Technology of China (2013CB834505 and 2014CB239402), the National Science Foundation of China (21302072 and 91427303), Natural Science Foundation of Jiangsu Province (BK20130226), Jiangsu Normal University (12XLR015 and 12XLR018), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Chinese Academy of Sciences.

Notes and references

1. Y. Wang, H. Xu and X. Zhang, Adv. Mater., 2009, 21, 2849–2864.
2. H.-J. Kim, T. Kim and M. Lee, Acc. Chem. Res., 2010, 44, 72–82.
3. Y. Hizume, K. Tashiro, R. Charvet, Y. Yamamoto, A. Saeki, S. Seki and T. Aida, J. Am. Chem. Soc., 2010, 132, 6628–6629.
4. X. Zhang, S. Rehm, M. M. Safont-Sempere and F. Würthner, Nat. Chem., 2009, 1, 623–629.
5. J. Voskuhl and B. Ravoo, Chem. Soc. Rev., 2009, 38, 495–505.
6. D. Jiao, J. Geng, X. J. Loh, D. Das, T.-C. Lee and O. A. Scherman, Angew. Chem., Int. Ed., 2012, 51, 9633–9637.
7. X.-D. Xu, L. Zhao, Q. Qu, J.-G. Wang, H. Shi and Y. Zhao, ACS Appl. Mater. Interfaces, 2015, 7, 17371–17380.
8. L.-B. Meng, W. Zhang, D. Li, Y. Li, X.-Y. Hu, L. Wang and G. Licd, Chem. Commun., 2015, 51, 14381–14384.
9. Y. Tanaka, M. Miyachi and Y. Kobuke, Angew. Chem., Int. Ed., 1999, 38, 504–506.
10. Y. J. Jeon, P. K. Bharadwaj, S. W. Choi, J. W. Lee and K. Kim, Angew. Chem., Int. Ed., 2002, 41, 4474–4476.
11. B. J. Ravoo and R. Darcy, Angew. Chem., Int. Ed., 2000, 39, 4324–4326.
12. C. W. Lim, O. Crespo-Biel, M. C. A. Stuart, D. N. Reinhoudt, J. Huskens and B. J. Ravoo, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 6986–6991.
13. S. H. Seo, J. Y. Chang and G. N. Tew, Angew. Chem., Int. Ed., 2006, 45, 7526–7530.
14. Y. Murakami, J. Kikuchi, T. Ohno, O. Hayashida and M. Kojima, J. Am. Chem. Soc., 1990, 112, 7672–7681.
15. W. Cai, G.-T. Wang, Y.-X. Xu, X.-K. Jiang and Z.-T. Li, J. Am. Chem. Soc., 2008, 130, 6936–6937.
16. Y. Zhou and D. Yan, Angew. Chem., Int. Ed., 2004, 43, 4896–4899.
17. Q. Yan, J. Yuan, Z. Cai, Y. Xin, Y. Kang and Y. Yin, J. Am. Chem. Soc., 2010, 132, 9268–9270.
18. S. K. M. Nalluri, J. Voskuhl, J. B. Bultema, E. J. Boekema and B. J. Ravoo, Angew. Chem., Int. Ed., 2011, 50, 9747–9751.
19. G. Yu, C. Han, Z. Zhang, J. Chen, X. Yan, B. Zheng, S. Liu and F. Huang, J. Am. Chem. Soc., 2012, 134, 8711–8717.
20. C. Wang, Y. Guo, Y. Wang, H. Xu and X. Zhang, Chem. Commun., 2009, 5380–5382.
21. Q. Yan, J. Yuan, Z. Cai, Y. Xin, Y. Kang and Y. Yin, J. Am. Chem. Soc., 2010, 132, 9268–9270.
22. H. Kim, S.-M. Jeong and J.-W. Park, J. Am. Chem. Soc., 2011, 133, 5206–5209.
23. Q. Duan, Y. Cao, Y. Li, X. Hu, T. Xiao, C. Lin, Y. Pan and L. Wang, J. Am. Chem. Soc., 2013, 135, 10542–10549.
24. G. Yu, X. Zhou, Z. Zhang, C. Han, Z. Mao, C. Gao and F. Huang, J. Am. Chem. Soc., 2012, 134, 19489–19497.
25. M. Lee, S. J. Lee and L. H. Jiang, J. Am. Chem. Soc., 2004, 126, 12724–12725.
26. Y. Yao, M. Xue, J. Chen, M. Zhang and F. Huang, J. Am. Chem. Soc., 2012, 134, 15712–15715.
27. T. Ta, A. J. Convertine, C. R. Reyes, P. S. Stayton and T. M. Porter, Biomacromolecules, 2010, 11, 1915–1920.
28. W. M. Park and J. A. Champion, J. Am. Chem. Soc., 2014, 136, 17906–17909.
29. D.-S. Guo, K. Wang, Y.-X. Wang and Y. Liu, J. Am. Chem. Soc., 2012, 134, 10244–10250.
30. C. Wang, Q. Chen, Z. Wang and X. Zhang, Angew. Chem., Int. Ed., 2010, 49, 8612–8615.
31. Y. Cao, X.-Y. Hu, Y. Li, X. Zou, S. Xiong, C. Lin, Y.-Z. Shen and L. Wang, J. Am. Chem. Soc., 2014, 136, 10762–10769.
32. K. Wang, D.-S. Guo, X. Wang and Y. Liu, ACS Nano, 2011, 5, 2880–2894.
33. L.-B. Xing, S. Yu, X.-J. Wang, G.-X. Wang, B. Chen, L.-P. Zhang, C.-H. Tung and L.-Z. Wu, Chem. Commun., 2012, 48, 10886–10888.
34. L. Gao, B. Zheng, Y. Yao and F. Huang, Soft Matter, 2013, 9, 7314–7319.
35. F. Wudl, D. Wobschall and E. J. Hufnagel, J. Am. Chem. Soc., 1972, 94, 670–672.
36. J. Puigmartí-Luis, D. Schaffhauser, B. R. Burg and P. S. Dittrich, Adv. Mater., 2010, 22, 2255–2259.
37. Y. Geng, X.-J. Wang, B. Chen, H. Xue, Y.-P. Zhao, S. Lee, C.-H. Tung and L.-Z. Wu, Chem. – Eur. J., 2009, 15, 5124–5129.
38. D. Canevet, M. Salle, G. Zhang, D. Zhang and D. Zhu, Chem. Commun., 2009, 2245–2269.
39. J. L. Segura and N. Martín, Angew. Chem., Int. Ed., 2001, 40, 1372–1409.
40. K.-D. Zhang, G.-T. Wang, X. Zhao, X.-K. Jiang and Z.-T. Li, Langmuir, 2010, 26, 6878–6882.
41. J. Bigot, B. Charleux, G. Cooke, F. O. Delattre, D. Fournier, J. L. Lyskawa, L. N. Sambe, F. O. Stoffelbach and P. Woisel, J. Am. Chem. Soc., 2010, 132, 10796–10801.
42. X.-J. Wang, L.-B. Xing, F. Wang, G.-X. Wang, B. Chen, C.-H. Tung and L.-Z. Wu, Langmuir, 2011, 27, 8665–8671.
43. T. Shimizu, M. Masuda and H. Minamikawa, Chem. Rev., 2005, 105, 1401–1443.
44. X. Zhang, Z. Chen and F. Wuerthner, J. Am. Chem. Soc., 2007, 129, 4886–4887.
45. C. Wang, D. Q. Zhang and D. B. Zhu, J. Am. Chem. Soc., 2005, 127, 16372–16373.
46. T. Kitahara, M. Shirakawa, S. Kawano, U. Beginn, N. Fujita and S. Shinkai, J. Am. Chem. Soc., 2005, 127, 14980–14981.
47. H. Enozawa, M. Hasegawa, D. Takamatsu, K. Fukui and M. Iyoda, Org. Lett., 2006, 8, 1917–1920.
48. M. Hasegawa, H. Enozawa, Y. Kawabata and M. Iyoda, J. Am. Chem. Soc., 2007, 129, 3072–3073.
49. J. Luis Lopez, E. M. Perez, P. M. Viruela, R. Viruela, E. Orti and N. Martin, Org. Lett., 2009, 11, 4524–4527.
50. X.-J. Wang, L.-B. Xing, W.-N. Cao, X.-B. Li, B. Chen, C.-H. Tung and L.-Z. Wu, Langmuir, 2011, 27, 774–781.
51. U. Kauscher, K. Bartels, I. Schrader, V. A. Azov and B. J. Ravoo, J. Mater. Chem. B, 2015, 3, 475–480.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, and other supporting data. See DOI: 10.1039/c5ob02214b

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