Bolaform Superamphiphile Based on a Dynamic Covalent Bond and

Sep 9, 2011 - We have employed a dynamic covalent bond to fabricate a bolaform superamphiphile, which can be used as building blocks for controlled ...
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Bolaform Superamphiphile Based on a Dynamic Covalent Bond and Its Self-Assembly in Water Guangtong Wang, Chao Wang, Zhiqiang Wang, and Xi Zhang* Key Lab of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084, P.R. China

bS Supporting Information ABSTRACT: We have employed a dynamic covalent bond to fabricate a bolaform superamphiphile, which can be used as building blocks for controlled assembly and disassembly. In alkaline environment, one building block bearing a benzoic aldehyde group can react with the other building block bearing an amino group to form a bolaform superamphiphile. It is found that the bolaform superamphiphiles can self-assemble in water to form micellar aggregates. When the pH is tuned down to slightly acidic values, the benzoic imine bond can be hydrolyzed, leading to the dissociation of the superamphiphile. The micellar aggregates will also disassemble, and the loaded guest molecules are released subsequently. This line of research has enriched the family of bolaform amphiphiles, and the resulting assemblies may find application in the field of controlled and targetable drug-delivery in a biological environment.

’ INTRODUCTION Bolaform amphiphiles refer to amphiphiles containing two hydrophilic groups linked by a hydrophobic skeleton.1 10 The solubility and the critical micelle concentration (cmc) of bolaform amphiphiles are relatively lower than those of conventional amphiphiles with the same hydrocarbon/headgroup ratio. Various types of aggregates, such as micelles, vesicles, nanofibers, and nanosheets, can be conveniently constructed by self-assembly of bolaform amphiphiles. It is worth noticing that some Archeae, whose membrane is composed of this kind of amphiphile, are resistant to low pH values and high temperatures, allowing them to survive in a volcanic environment.11,12 Superamphiphiles or supramolecular amphiphiles13,14 refer to amphiphiles that are fabricated by using noncovalent interactions or dynamic covalent bonds (DCBs). Due to the reversible and dynamic nature of these connections, superamphiphiles are easier to be modulated than amphiphiles formed by covalent bonds. Therefore, superamphiphile is a new and useful building block for controlled self-assembly and disassembly and fabrication of stimuli-responsive surfaces and nanocontainers.15 18 Various noncovalent interactions have been used to create superamphiphiles, such as hydrogen bonds, electrostatic interactions, host guest interactions, and charge transfer interactions.19 22 Dynamic covalent bonds23 27 have recently gained much attention in the field of supramolecular science, as they are in many aspects like noncovalent interactions, endowed with properties like reversibility and controllability. Therefore, they have been widely used as a new type of supramolecular linkage to construct supramolecular polymers,28 31 layered structures,32,33 responsive assemblies,34 36 and functional materials.37,38 Among DCBs, the benzoic imine bond is especially attractive due to its r 2011 American Chemical Society

dynamic equilibrium in water. It is stable in an alkaline environment but can be hydrolyzed under mildly acidic conditions. The unique nature of this dynamic covalent bond has been widely employed to fabricate pH-responsive assemblies. In 2009, Giuseppone and co-worker employed the dynamic imine bond to fabricate low molecular weight amphiphile for the first time.39,40 van Esch and his co-workers extended the similar concept to fabricate different types of low molecular weight amphiphiles for the self-assembly and disassembly.41,42 We employed this DCB to fabricate polymeric superamphiphiles very recently.43 Herein we report an example of a bolaform superamphiphile constructed by a benzoic imine bond (Scheme 1). In basic conditions, the two building blocks can be connected by a dynamic benzoic imine bond to form a bolaform superamphiphile. The bolaform superamphiphile can self-assemble into micellar aggregates. When the pH is changed to slightly acidic values, the benzoic imine bond can be hydrolyzed, leading to the dissociation of the superamphiphile. As a result, the micellar aggregates will disassemble, and the loaded guest molecules are released subsequently.

’ EXPERIMENTAL SECTION General Details. 1,10-Dibromodecane was purchased from Alfa Aesar. 4-Hydroxybenzaldehyde was purchased from Jinlong Chem. Ltd. (Beijing, China). Boc2O was purchased from GL Biochem. Ltd. (Shanghai, China). 4-(Aminomethyl)phenol was purchased from Accela Received: August 4, 2011 Revised: August 27, 2011 Published: September 09, 2011 12375

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Scheme 1. A Bolaform Superamphiphile Based on a Dynamic Covalent Bond

Scheme 2. Synthetic Route of (a) FDP and (b) AMDP

Chem Co. Ltd. All chemicals were used as received without further purifications. 1H NMR spectra were obtained using a JEOL JNMECA600 spectrometer. The ESI-MS were recorded using a BRUKER ESQUTRE∼LC mass spectrograph. More details of the synthetic procedures are included in the Supporting Information.

(d, 8.9 Hz, 2H), 4.46 (t, 6.8 Hz, 2H), 3.68 (t, 6.9 Hz, 2H), 1.70 1.85 (m, 2H), 1.34 1.46 (m, 2H), 0.80 1.20 (m, 12H). 13C NMR (D2O, 400 MHz): 192.5, 164.2, 145.8 144.2, 132.3, 129.3, 128.4, 114.8, 68.5, 61.8, 31.1, 29.3, 29.2, 29.1, 28.9, 28.8, 25.8, 25.7. ESI-MS: calcd for C22H30NO2+ 340.48, found 340.23.

Synthesis of 1-(10-(4-Formylphenoxy)decyl)pyridinium (FDP). The synthesis contains two steps, as shown in Scheme 2. Yield:

Synthesis of 1-(10-(4-(Ammoniomethyl)phenoxy)decyl)pyridinium (AMDP). The synthesis contains four steps, as shown in

77%. 1H NMR (DMSO-d6, 400 MHz): 9.55 (s, 1H), 8.74 (d, 5.5 Hz, 2H), 8.42 (t, 7.6 Hz, 1H), 7.95 (t, 6.9 Hz, 2H), 7.56 (d, 8.9 Hz, 2H), 6.70

Scheme 2. Yield: 24%. 1H NMR (DMSO-d6, 400 MHz): 9.09 (d, 5.6 Hz, 2H), 8.61 (t, 8.0 Hz, 1H), 8.17 (t, 7.0 Hz, 2H), 7.35 (d, 8.8 Hz, 2H), 12376

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Figure 1. (a) The 1H NMR of (a) FDP (solvent D2O, 3 mM, pH = 12.1), (b) AMDP (solvent D2O, 3 mM, pH = 12.1), and (c) a mixture of the building blocks in the molar ratio of 1:1 (solvent D2O, 3 mM FDP, 3 mM AMDP, pH = 12.1). 7.95 (d, 8.8 Hz, 2H), 4.59 (d, 7.6 Hz, 2H), 3.95 (s, 2H), 3.94 (d, 10.8 Hz, 2H), 1.85 1.97 (m, 2H), 1.60 1.75 (m, 2H), 1.17 1.42 (m, 12H). 13C NMR (D2O, 400 MHz): 162.7 (q), 158.9, 145.6, 144.1, 130.7, 128.2, 125.1, 117.8, 115.1, 68.5, 61.9, 42.6, 30.6, 28.7, 28.6, 28.5, 28.4, 28.2, 25.4, 25.3. ESI-MS: calcd for C22H33N2O+ 341.26, found 341.3. 1

H NMR Characterization with Different Amounts of Base.

To investigate the yield of the imine formation, a series of samples was prepared for the 1H NMR test. For each sample, the two building blocks were mixed together in H2O with a molar ratio of 1:1 (FDP 3 mM, AMDP 3 mM, total volume of the solution was 3 mL). Various amounts of Na3PO4 were added to the solutions to tune the pH value. The solutions were freeze-dried after 1 day, followed by addition of D2O to ensure that the total volume of each solution was still 3 mL. A 0.5 mL portion of each solution was removed to perform the 1H NMR using a JEOL JNM-ECX400 spectrometer, and the remaining 2.5 mL was used to measure the pH using a Mettler Toledo Delta 320 pH meter.

Transmission Electron Microscopy (TEM) and Dynamic Light Scattering Study (DLS). The self-assembled structures of the bolaform superamphiphiles were revealed using TEM and DLS. FDP and AMDP were mixed together in H2O in the molar ratio of 1:1 (FDP 1 mM, AMDP 1 mM). The pH of the solution was tuned to 12.0 ( 0.2 by adding Na3PO4. The samples were prepared by drop-coating the solution on a carbon-coated copper grid and then negatively stained with a 0.2% phosphotungstic acid solution. TEM experiments were performed with a HITACHI H-7650B electron microscope. The sample (FDP 3 mM, AMDP 3 mM, pH = 12 ( 0.2) solution was left to stand overnight before being used for DLS tests. The diameters of the assemblies were measured by a Nano ZS90 instrument, Malvern Instruments Ltd. Controlled Release under Different pH Values. Nile Red (NR), a hydrophobic dye, was used as a guest molecule to monitor the controlled release of the assemblies. The two building blocks and Na3PO4 were mixed together in H2O (FDP 3 mM, AMDP 3 mM, pH = 12 ( 0.2). NR (dissolved in THF, 0.1 mM, 50 μL) was then added dropwise into the solution under sonification to ensure that the NR was loaded into the assemblies. The solution was left to stand overnight and the release was monitored by time-dependent fluorescence emission microscopy according to the fluorescence intensity, using a HITACHI F-7000 fluorescence spectrophotometer. The excitation wavelength was 559 nm. Equal volumes (50 μL) but different concentrations of HCl were added to decrease the pH. The actual pH value was measured after the NR dye was completely released.

’ RESULTS AND DISCUSSION The Formation of Imine Bond. The formation of the imine bond was confirmed by 1H NMR. Compared with the 1H NMR

spectra of FDP and AMDP, the spectrum of their mixture in equimolar amounts under pH 12.1 shows obvious differences (Figure 1). The signal of the aldehyde group (9.6 ppm) becomes weaker significantly, and at the same time, a new peak at 8.3 ppm appears, indicating the formation of the imine bond. The Self-Assembly of the Bolaform Superamphiphile. To investigate the self-assembling behavior, the cmc of the bolaform superamphiphile, which refers to the minimal concentration of the building block needed for the formation of the assemblies, is monitored using NR as a probe. When pH = 12.0, the cmc is measured to be 0.5 mM, much lower than the cmc values of FDP and AMDP, which are around 2 and 5 mM, respectively (see the Supporting Information). The decrease of the cmc is in accordance with the typical feature of low cmc values seen with bolaamphiphiles because of the enhanced hydrophobic region relative to the hydrophilic area. To reveal the nanostructures formed by the self-assembly of the bolaform superamphiphile, TEM and DLS experiments were performed. As shown in Figure 2a, spherical micellar assemblies can be observed in the TEM image, and their average size is about 18 nm in diameter (see the Supporting Information). However, because of the dry state on the copper grid and the effect of the staining agent, the diameter measured by TEM may be enlarged. In other words, the micelles covered by staining agent will look larger than their real sizes. Therefore, to confirm the size of the aggregates, DLS was used to further investigate the diameter of the micelles. The results show that the diameter is 4 5 nm, corresponding to the estimated length of the bolaform superamphiphile (Figure 2b,c) The pH-Responsiveness. The pH-responsiveness of the superamphiphile was examined by 1H NMR. A series of aqueous solutions of the superamphiphile with the same concentration but different pH values was prepared and studied by 1H NMR. As shown in Figure 3, the intensity of the aldehyde signal decreases with an increase of pH, while at the same time, the peak of the imine group at around 8.3 intensifies significantly. The ratio I2/(I1 + I2), in which I1 is denoted as the integral value of the aldehyde signal and I2 as the integral value of the imine proton, can provide information about the extent of the reaction semiquantitatively. As shown in Table 1, when pH is 8.6, the ratio is only 0.01, indicating no superamphiphile formation; however, when pH = 12.1, about 60% of the building blocks reacted to form the imine bond. 12377

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Figure 2. (a) The TEM image of the aggregates. (b) The DLS result of the aggregates. (c) The molecular structure of the bolaform superamphiphile.

Figure 3. 1H NMR spectra obtained with different pH values (solvent D2O).

Table 1. Ratio of Imine Bond Formation in Function of the pH no. 1 2 concn of the two building blocks/mM 3.0 3.0

3 3.0

4 3.0

5 3.0

6 3.0

pH

8.6 9.5 11.3 11.7 11.8 12.1

I2/(I1 + I2)

0.01 0.09 0.29 0.39 0.50 0.60

When the pH value is decreased to 7.0, bolaform superamphiphile is hydrolyzed to FDP and AMDP along with the break of the imine bonds. As a result, the micelles will also be disassembled under this condition. Therefore, no regular aggregates can be detected by TEM (see the Supporting Information). It should be noted that cmc of the bolaform superamphiphile is very low (0.5 mM), so it can aggregate into

micelles at low concentration (1 mM). When bolaform superamphiphile is hydrolyzed to AMDP and FDP, the AMDP and FDP can not aggregate because their concentrations are lower than their cmc valuess. In addition, DLS does not give significant signal for both FDP and AMDP aggregates. Controlled Release. Due to the pH-sensitive nature of the imine bond, the superamphiphiles as well as the aggregates will dissociate when acid is added, releasing the loaded guest molecules in the micellar aggregates simultaneously. To this end, different amounts of HCl were added to monitor the release of NR molecules in solutions with different pH values. In general, an increasing release speed is observed with decreasing pH values. When the pH is lower than 5, NR is completely released within a few minutes. However, when using smaller amounts of acid, the releasing curves reveal an initial slow release, which will 12378

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Figure 4. Controlled release under different pH values.

speed up significantly after some time. (Figure 4) The reason for this behavior is probably due to the fact that the pH-sensitive imine bonds are buried in the hydrophobic core of the micelles, preventing the acid from entering the micelles and hydrolyzing the imine bonds easily at the very beginning. Once the micelles are partially destroyed, however, acid can reach the core much faster to break the bond, resulting in an instant acceleration of the release.

’ CONCLUSION In conclusion, we have fabricated a bolaform superamphiphile based on a dynamic covalent bond that can self-assemble into micellar aggregates in aqueous solution. The formation and dissociation of the bolaform superamphiphile are dependent on pH, leading to the controlled release of guest molecules loaded in the micelles. This new pH-sensitive bolaform superamphiphile based on a dynamic imine bond can enrich the family of amphiphiles, and its dynamic nature renders the assemblies formed by this kind of amphiphile as a new tool for controlled and targetable drug-delivery in a biological environment. ’ ASSOCIATED CONTENT

bS

Supporting Information. Details of synthesis, cmc measurement, statistics of the diameters in TEM image, and description of disassembly of the micelles. This materail is available free of charge via the Internet at http://pubs.acs.org/.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Tel: +86-10-62796283.

’ ACKNOWLEDGMENT This work was financially supported by NSFC (50973051, 20974059), NSFC-DFG joint grant (TRR61), and National Basic Research Program (2007CB808000). We thank Prof. Lidong Li and Dr. Ning Ma for DLS experiment. ’ REFERENCES (1) Fuhrhop, J. H.; Wang, T. Y. Chem. Rev. 2004, 104, 2901. (2) Okahata, Y.; Kunitake, T. J. Am. Chem. Soc. 1979, 101, 5231.

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