Multiresponsive Vesicles Composed of Amphiphilic Azacalix[4

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Multi-responsive Vesicles Composed of Amphiphilic Azacalix[4]pyridine Derivatives Shixin Fa, Xu-Dong Wang, Qi-Qiang Wang, Yu-Fei Ao, De-Xian Wang, and Mei-Xiang Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b01815 • Publication Date (Web): 13 Mar 2017 Downloaded from http://pubs.acs.org on March 14, 2017

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ACS Applied Materials & Interfaces

Multi-responsive Vesicles Composed of Amphiphilic Azacalix[4]pyridine Derivatives Shi-Xin Fa,1 Xu-Dong Wang,1,3 Qi-Qiang Wang,1,3 Yu-Fei Ao,1 De-Xian Wang,1,3* Mei-Xiang Wang2,* 1

Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular

Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. 2 The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China. 3

University of Chinese Academy of Sciences, Beijing 100049, China

KEYWORDS: Vesicle, Heteracalixaromatics, Azacalix[4]pyridine, Amphiphile, Multi-responsive

ABSTRACT: Bio-mimicry of multi-responsive recognition of cell membrane with artificial membranes is challengeable. In this work, we designed azacalix[4]pyridine-based amphiphilic molecules 1 and 2. The self-assembly behaviours of 1 and 2 were investigated in aqueous medium. As demonstrated by DLS, SEM, TEM and LSCM measurements, 1 formed stable vesicles (size 322 nm) in a mixture of THF/water whereas 2 produced giant vesicles with decreased stability (size 928 nm). The vesicles composed of 1, with surface being engineered with the cavities of azacalix[4]pyridines, showed selective responses to a variety of guests including zinc ion, hydroquinone and proton as monitored by DLS.

ACS Paragon Plus Environment

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Inspired by the specific and multi-responsive surface recognition of biological membranes, fabrication of functional or stimuli-responsive artificial vesicles has been a fascinating topic.1-9 In particular, vesicles composed of amphiphilic structures that contain binding sites such as metal-ligand coordination,10-13 host-guest interaction,1,4,6,8 hydrogen bonding,14-16 Lewis acidbase17 and anion-π interaction 18,19 have been extensively developed. The specific non-covalent interactions render vesicles specific surface-guest recognition. However, the bio-mimicry of multi-responsive properties with artificial membranes remains a big challenge. Azacalix[4]pyridines is typical host molecules of the family of heteracalixaromatics or heteroatom-bridged calixaromatics.20 With the incorporation of four pyridine units and the bridging nitrogen atoms, this type of host molecules give unique 1,3-alternate structure due to the different conjugation between the bridging atoms and their neighbouring aromatic rings. In respect of molecular recognition properties, the four pyridine units can serve as metal coordination

ligands,

hydrogen

bonding

acceptors

and

bases.

As

a

consequence,

azacalix[4]pyridines show versatile molecular recognition abilities and can selectively form complexes with (1) transition metal ions through coordination interactions,21,22 (2) benzene diols, aliphatic diols and alcohols through hydrogen bonding,

23

and (3) protons to produce mono- to

tetra-protonation species when treated with acid.24 In addition, azacalix[4]pyridines are also a powerful molecular functionalization platform to construct high-level architectures.25,26 Very recently, we reported the first example of liquid crystal materials constructed by azacalix[4]pyridine derivative 2 (Figure 1). The intrinsic conformation of 2, and variation of conformation after coordinating with metal ion showed remarkable effects on LC behaviors.27 Our continuous interests on functional structures and vesicles encouraged us to carry out the current study. We envisioned that vesicles with azacalix[4]pyridine locating on the surface in


2

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aqueous medium would show multi- and selective responses to a variety of guests. Reported herein is the synthesis, self-assembly of azacalix[4]pyridine-based amphiphilic derivatives, and the multi-responsive properties of the formed vesicles towards metal ions, neutral molecules and protons.

Figure 1. Structures of azacalix[4]pyridine-based amphiphilic derivatives.

Utilizing the functionalization property and intrinsic 1,3-alternate conformation of azacalix[4]pyridine, we designed the target molecule 1, in which long alkyl chains as hydrophobic tails were introduced on the larger rim of the two face-to-face arrayed pyridine rings. According to our previous reports 18, such design can enable the amphiphilic molecule to produce a cone geometry, which is beneficial for forming curved double layer so that it can close as spherical vesicle in aqueous medium. As a comparison, the LC molecule 2 bearing long alkyl chains on the bridging nitrogen atoms (synthesized previously

27

) was also studied in order to

investigate the effect of molecular shape, the position and number of the long alkyl chain substitutes on the self-assembly.


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For the synthesis of 1, we set up a fragment coupling followed by post-macrocyclization functionalization protocol (Scheme 1). The monomer 3, p-methoxybenzyl (PMB) protected 2,6dibromo-4-hydroxypyridine

was

firstly

synthesized

from

commercial

available

2,6-

diboromopyridine through oxidation, nitration, reduction and nucleophilic substitution with a high yield in each step (Scheme S1). Excess of 3 was reacted with N2,N6-dimethylpyridine-2,6diamine 4 in THF with NaH as a base to afford the trimer 5 in 73% yield. The following palladium catalyzed 3+1 fragment coupling between 5 and 4 gave the macrocyclic compound 6 in 23% yield. Deprotection of 6 under Pd/C and hydrogen gas produced the hydroxyl substituted azacalix[4]pyridine 7 in 47% yield. The target azacalix[4]pyridine-based amphiphilic derivatives 1 was finally obtained by condensation with long alkyl chains substituted gallic acid 9

30

in high

yield of 90% (Scheme 1). The compound 1 was fully characterized by spectroscopic data and elemental analysis (see supporting information). Compound 2 was synthesized according to our previously reported methods. 27


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OPMB

Br

N H

3

N PMBO

4

N

Br

N

OPMB

N

N

N OPMB

Pd/C, H2 THF/MeOH rt, 24 h 47%

N

N

N

N

N

N

N N

N

OH

N

7

OCH3

OC14H29 OC14H29

N

N

HO

O

OH

i) SOCl2, reflux, 4 h ii) 7, NEt3, DCM, reflux, 3 h

KOH, EtOH reflux, 4 h C14H29O

23%

Br

6

O

4, Pd2(dba)3, dppp t-BuONa, toluene reflux, 6 h

5

N

N N

OPMB

N H

NaH, THF reflux, 6 h 73%

Br

N

N

99%

C14H29O

OC14H29 OC14H29

90%

9

8

N

N

OC14H29

N

O

N

O

OC14H29

C14H29O O

N

OC14H29

C14H29O O C14H29O

N

N

N

1

Scheme 1 Synthesis of 1. The self-assembly behaviours of the amphiphilic molecules 1 and 2 were investigated in a binary aqueous medium (THF/water). By dissolving 1 in THF (0.8 mL), following by the addition of water (1.2 mL) ([1] = 3.0 × 10-5 M, THF/water = 4/6), a colloidal solution was obtained. Such colloidal solution gave significant Tyndall effect under the irradiation of laser beam (Figure S1), indicating the formation of self-assembled aggregates. Dynamic light scattering (DLS) measurement reveals that the average size of the aggregates is 322 nm with a narrow distribution (PDI = 0.06) (Figure 2A). Spherical and vesicular morphology was demonstrated by means of SEM and TEM techniques, with the diameters of the spheres (~ 300 nm) in agreement with DLS results (Figure 2C and 2D). The vesicular feature of the aggregates


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was further confirmed by laser scanning confocal microscopic (LSCM) experiments with lucigenin as the fluorescent probe. After removing the fluorescent agent outside the vesicle through repeated dialysis, blue spots which represent the encapsulation of dye in the interior solution of the vesicles were observed (Figure S16). The membrane thickness was measured as 5.08 nm on the basis of XRD measurement (Figure 2B). Such thickness indicates the formation of ordered double layer as compared with the extended molecular length of 3.07 nm for 1 (Figure S17). Unlike 1, after screening a variety of the ratios of THF and water, 2 was found to form giant vesicles in a mixture of THF/water (5:5), as observed from SEM, TEM images (Figure S9 and S15). DLS measurement reveals the average diameter of the vesicles is as large as 928 nm (PDI = 0.063) (Figure S1). However, the vesicles are not stable, after keeping at room temperature for several days, the solution became turbid and visible phase separation was finally observed. The process was monitored by SEM technique and as shown in Figure S10 and S11, the vesicles gradually transformed into nanotubes after 8 days and into micro-sized tubes and fibres after 15 days. The significantly different self-assembly behaviours for 1 and 2 can be ascribed to their intrinsic molecular structures. On one hand, the 12 long hydrophobic chains attached on the bridging nitrogen atoms tend to shape 2 as column rather than cone, hence result in small curvature

of

the

self-assembled

double

layer.

On

the

other

hand,

the

high

hydrophobic/hydrophilic ratio of 2 might be unfavourable to form curved and closed double layer.


6

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Figure 2. DLS (A), XRD (B) results and SEM (C), TEM (D) images of the vesicles selfassembled from 1 in THF/water (4:6). The above investigations demonstrated that 1 can produce the expected vesicular structure, i. e. the cavity of azacalix[4]pyridine as the polar head directs towards the aqueous solvent whereas the long alkyl chains are embedded inside the double layer membrane. In other words, the surface of the vesicles is engineered with the cavities of azacalix[4]pyridines. Hence, with the versatile host-guest recognition properties of parent azacalix[4]pyridine demonstrated before, the multi-responsive behaviours of the vesicles formed by 1 was then investigated. The interaction of vesicles with metal ions was firstly studied as monitored by means of DLS. As illustrated in Figure 3A, the responses of the vesicles to different metal ions, as indicated by the change of hydrodynamic diameter of the aggregates, are in a selective way. For instance, while the size of the vesicles keeps intact with the addition of Mg(ClO4)2 or MgCl2, it


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dramatically increases with the increasing concentrations of Zn(ClO4)2 and ZnCl2 added. Upon addition of 1 equiv. of Zn(ClO4)2 and ZnCl2, the size of the vesicles increased by 4.2 and 3.4 times respectively. In the presence of 2 equiv. Zn(ClO4)2 the enlarged aggregates remain as vesicular morphology as confirmed by SEM and TEM images, but with the average size as large as 1 µm (Figure S3 and S13), which is consistent with the DLS measurement. The selective response towards Zn2+ rather than Mg2+ is in agreement with our previous report that azacalix[4]pyridines is a type of highly selective fluorescent probes for zinc ion while with no obvious affinity for alkali or alkaline earth metal ions. Specific binding between the vesicle surface and Zn2+ is therefore responsible for the selective vesicle-metal ion interaction and the corresponding changes of vesicular morphology. Furthermore, as reported before, the parent azacalix[4]pyridine host dramatically changes its conformation from 1,3-alternate into a much more flatten saddle form (with an approximate D2d symmetry) upon Zn2+ coordination. 21,22 This change would also lead to the decreased curvature of the self-assembled molecular lamella and hence account for the enlargement of the vesicles (schematic description is demonstrated in Figure 4). In addition, counter anions also have effect on the vesicle size. For instance, ZnCl2 shows overall smaller size increments than Zn(ClO4)2 at each given tested concentrations. Such outcome is most probably due to that Cl- tends to form more close ion pair contact with Zn2+ and weakens the interaction between azacalix[4]pyridine and Zn2+. Next, the response of vesicles towards hydrogen bonding donors was studied. These hydrogen bonding donors include catechol, resorcinol and hydroquinone, with the binding affinities to azacalix[4]pyridine following the order of resorcinol (Ka = 6000 M-1) > catechol (Ka = 100 M-1) > hydroquinone (Ka = 25 M-1).23 Surprisingly, the response of vesicles to the three diols gave a reversed selectivity. For example, the addition of catechol and resorcinol has no effect on the


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vesicle size at all as demonstrated by the DLS measurements. In contrast, hydroquinone despite of its lowest affinity to the macrocyclic cavity caused dramatic size increase. After addition of 240 equiv. of hydroquinone, the vesicle size increased by about 2.7 times (Figure 3B). Scrutiny of the binding modes between the three diols and azacalix[4]pyridine reveals that only hydroquinone forms a 2:1 sandwich-like rather than regular 1:1 complex as demonstrated by catechol and resorcinol.23 Hence if this particular binding mode holds in the vesicle system, e.g. one hydroquinone molecule bridges two azacalix[4]pyridine heads from the different patent vesicles, the formation of the larger aggregates could be expected as a result of inter-vesicular interactions (Figure 4). Generally, intermolecular hydrogen bonding is inhibited in an aqueous medium, however, it can be greatly enhanced in the presence of vesicular surface.28,29 Based on such a context, it is most likely that resorcinol and catechol can also be associated by the surface through hydrogen bonding. However, the disability to form inter-vesicular hydrogen bond probably account for their negligible effect on the morphology of the vesicles. To further confirm the selectivity of the vesicular surface to diols, we set up SEM and TEM experiments. The SEM and TEM images provided consistent results with DLS. For example, in presence of 200 equiv. hydroquinone, the observed vesicle diameter increased to around 1000 nm (Figure S5 and S14), whereas in presence of resorcinol and catechol the vesicle morphologies didn’t change at all (Figure S6 and S7).


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Figure 3. Responses of vesicles of 1 to (A) metal ions, (B) benzene diols, (C) and (D) acid/base. Finally, we treated the vesicle solution of 1 with HClO4 as promoted by the intriguing protonation property of azacalix[4]pyridine.24 The DLS results demonstrated that the size of the vesicles changed depending on the acid concentrations. For example, the addition of 0.2 equiv. HClO4 only caused marginal change within 60 min. However, when the concentration of HClO4 was increased to 0.4 and 0.6 equiv., the increasing size up to ~1 and 3 µm was observed respectively (Fig. 3C). The size enlargement upon interacting with acid was also confirmed with SEM images (Figure S8). As azacalix[4]pyridine is easily protonated, the regulation effect of HClO4 on the vesicle size can be ascribed to the electrostatic modification of the vesicle surface with protons (Figure 4). To confirm this assumption, we then investigated the regulation effect by adding acid and base alternatively. As demonstrated in Fig. 3D, the vesicle size is intact before adding HClO4, after addition of 0.4 equiv. HClO4, the size started to increase from 296


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nm to 1099 nm dramatically. With the subsequent addition of 0.4 equiv. NaOH, the vesicle size sharply decreased to 733 nm. The further addition of another 0.4 equiv. NaOH did not cause significant effect any more. These results indicate that the acid effect on the vesicle size can be eliminated partly by acid-base neutralization. However, it should be mentioned that the acid-base neutralization involved in the colloidal surface might be quite different from that in bulk solution, this could explain why addition of NaOH even up to 0.8 equiv. only led to partial recovery of the vesicle size increment.

Figure 4. Schematic illustration of multi-responsive vesicles composed of amphiphilic azacalix[4]pyridine derivative. In summary, the incorporation of both bridging nitrogen atoms and pyridine moieties in the backbone endows azacalix[4]pyridine a versatile host molecule and a functionalization molecular platform. Through a fragment coupling and post-macrocyclization functionalization protocol, the azacalix[4]pyridine-based amphiphilic molecules 1 and 2 have been efficiently synthesized. The molecular shape, position and number of the long alkyl chain substitutes showed significant effect on the self-assembly. Consequently, 1 self-assembled into vesicles with good stability, whereas 2 formed unstable giant vesicle in a mixture of THF and water. The vesicles composed of 1 show multi-responsive properties to zinc ion, hydroquinone and acid as a result of the


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specific interactions existed between the surface consisted of the azacalix[4]pyridine heads and the particular guests. This work hence demonstrates the promising application of heteracalixaromatics on fabrication of novel functional and stimuli-responsive materials. Supporting Information Experimental details and characterization of products, copies of 1H and

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C NMR spectra for

new compounds, SEM, TEM and LSCM images, XRD result are included in supporting information. This material is available free of charge on the ACS publication website. Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected]. Author Contributions The manuscript was written through contributions of all authors. Mr. Xu-Dong Wang manipulated the Tyndall effect, stability investigation of the compounds by NMR technique and NMR titrations during the revision. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We thank NNSFC (91427301, 21521002, 21502200) and MOST (2013CB834504) for financial support. REFERENCES


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Graphical Abstract 346x336mm (96 x 96 DPI)


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Multiresponsive Vesicles Composed of Amphiphilic Azacalix[4

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