Polyglycidol-Based Prepolymers to Tune the Nanostructure of Microgels

Article pubs.acs.org/Macromolecules

Polyglycidol-Based Prepolymers to Tune the Nanostructure of Microgels Bjoern Schulte, Andreas Walther, Helmut Keul,* and Martin Möller* DWI − Leibniz Institute for Interactive Materials and Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Forckenbeckstraße 50, D-52056 Aachen, Germany S Supporting Information *

ABSTRACT: The use of prepolymers for microgel synthesis via miniemulsification allows predefining the chemical functionality and the nanostructure of microgels. We report on tailor-made polyglycidol-based prepolymers using three protected glycidol monomers (allyl glycidyl ether, AGE; ethoxy ethyl glycidyl ether, EEGE; and tert-butyl glycidyl ether, tBGE). AGE with its pendant double bonds serves as site for cross-linking or functionalization, whereas the EEGE and tBGE building blocks represent precursors for hydroxyl functionalities. Following the prepolymer approach, we design statistical and block copolymers to control the nanostructure of the microgel. Cross-linking of the prepolymers is achieved in miniemulsions under UV irradiation in a thiol−ene click type reaction addressing the allyl groups with 2,2′(ethylenedioxy)diethanethiol. Analysis with cryo-TEM reveals that microgels derived from poly(glycidol)-block-poly(AGE) show larger hydrophobic domains than microgels derived from statistical copolymers. Additionally, the cross-linking of pH responsive tBGE/AGE prepolymers with different microstructures leads to microgels with nanostructures differing in local charge distributions.

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INTRODUCTION Microgels are a unique class of colloidal particles, due to their physical properties,1 especially their deformability2,3 and flexible network structure, and their role as potential hosts for the incorporation and release of guest molecules.4,5 Further characteristics include a diffuse interface at the transition to the continuous phase, in which they are dispersed. Recently, their ability to stabilize emulsions has been studied in detail.6−10 The way microgels stabilize emulsions is only at first glance comparable to the known Pickering effect reported for hard spheres. A more detailed analysis reveals that the stabilization of the oil−water interface is linked to the swelling degree, the presence of charges and the structure of the microgel at the oil−water interface. These results have been obtained with core−shell microgels based on poly(Nisopropylacrylamide) (PNIPAM) and methacrylic acid building blocks. For further studies addressing the physics of soft colloids at interfaces, the synthesis and characterization of microgels with new chemical properties is necessary. In general, it is possible to distinguish four different strategies for the synthesis of microgels: The most straightforward approach is a precipitation polymerization of water-soluble monomers and cross-linkers in aqueous environment. On the basis of this principle, PNIPAM, poly(N-ispropylmethacrylamide) (PNIPMAM) and poly(N-vinylcaprolactam) derived microgels were widely synthesized with different architectures, such as core−shell11−18 or dirty snowball.19 This approach permits a high control of particle size and particle dispersity. However, high polymerization temperatures are needed, which © 2014 American Chemical Society

makes the incorporation of guest molecules such as biomacromolecules into the microgels difficult. Furthermore, the synthesis is limited to polymers, which show a lower critical solution temperature in water. This requirement also restricts possible ratios of functional comonomers in the microgel, which limits the overall functionality. Another strategy makes use of water-soluble prepolymers, which can be cross-linked in aqueous environment. For instance, γ-rays are the radical source for the initiation of cross-linking and this route is important for the synthesis of sterile materials with biomedical applications. Inter- and intramolecular cross-linking yields micrometer-sized microgels. Examples include the synthesis of microgels based on poly(vinyl alcohol)20 and poly(methyl vinyl ether).21 However, this strategy suffers from drawbacks due to the limited availability of sources for γ-rays. Heterogeneous oil in water (o/w) and water in oil (w/o) emulsions provide viable alternatives to the above-mentioned homogeneous procedures. Heterogeneous systems allow applying rather mild polymerization or cross-linking conditions. The idea of cross-linking prepolymers in emulsion allows consideration of the large group of (multi)functional, linear polymers for microgel synthesis. A distinct advantage of this strategy is that the control of molecular weight, end group as well as side chain functionality, and especially microstructure Received: July 12, 2013 Revised: January 7, 2014 Published: February 14, 2014 1633

dx.doi.org/10.1021/ma401465c | Macromolecules 2014, 47, 1633−1645

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Scheme 1. Prepolymer Approach for the Synthesis of Structurally Well-Defined Microgels

4−5 nm sized hydrophobic domains, whereas smaller domains result from the use of statistical copolymers. Finally, we show how decoration of hydrophobic prepolymers (statistical and block copolymers of tBGE and AGE) with 3-mercaptopropionic acid can be used to obtain pH sensitive microgels with an increased hydrophilicity. This reaction underlines the versatility of the prepolymer approach, since microgels with different local distributions of charges are obtained and the solubility behavior of the prepolymers is directly translated into the swelling behavior of the cross-linked microgels.

as it is known for linear polymerscan be transferred to the microgel architecture. The linear prepolymers serve as welldefined structured building blocks, which encode the nanostructure of the microgel. Surprisingly, this route has hardly been followed in the literature.22−25 The existing reports comprise poly(ethylene glycol)-block-poly(propylene glycol)block-poly(ethylene glycol), gelatin, dimethylmaleinimide-functionalized polyacrylamide or polyglycidol. In particular, multifunctional prepolymers with reactive groups (allyl, propargyl) in their side chains, which can easily be addressed in click-type reactions, are versatile materials for the synthesis of nanoparticles26 or microgels. First, they allow easy cross-linking with suitable cross-linkers, such as, e.g., dithiols. Second, they open the route to straightforward modification of the microgel with pH sensitive moieties (amino, carboxyl groups) or biomolecules before, during or after cross-linking. Herein, we use two sets of polyglycidol-derived, linear prepolymers with different microstructures for the synthesis of soft microgel particles (Scheme 1). In the first set of prepolymers, ethoxy ethyl glycidyl ether (EEGE) and allyl glycidyl ether (AGE) serve as monomer pairs. In the second set, tert-butyl glycidyl (tBGE) ether and allyl glycidyl ether are used as monomer pairs. Hence, both sets of copolymers consist of a building block with a protective group for hydroxyl functions (EEGE and tBGE) and allyl groups (AGE) as site for cross-linking or further chemical modification. We conduct the anionic polymerization of the monomer pairs simultaneously or consecutively, which leads to prepolymers with different microstructures resulting in a block wise or statistical arrangement of functional groups. Surprisingly, we observe contrasting behaviors of the ethoxy ethyl and tert-butyl protecting group during the thiol−ene cross-linking reaction. Through in situ hydrolysis of the acetal group in the ethoxy ethyl building block the cross-linking reaction yields directly hydrophilic microgels. Since the tert-butyl protecting group is stable under the cross-linking conditions the use of the respective prepolymers leads to hydrophobic microgels. A detailed analysis of the nanostructure of EEGE/AGE based microgels using cryogenic transmission electron microscopy (cryo-TEM) reveals the presence of hydrophobic domains within the microgels. The use of blocky prepolymers leads to

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EXPERIMENTAL SECTION

Materials. Allyl glycidyl ether (>99%, Sigma-Aldrich, Steinheim, Germany), cesium hydroxide monohydrate (99.5%, Acros Organics, Geel, Belgium), cesium chloride (99.9%, Sigma-Aldrich), 2,2dimethoxy-2-phenylacetophenone (99%, Sigma-Aldrich), 2,2′(ethylenedioxy)diethanethiol (95%, Sigma-Aldrich), ethyl vinyl ether (99%, Sigma-Aldrich), glycidol (96%, Sigma-Aldrich), hexadecane (98%, Fluka), sodium dodecyl sulfate (Biorad Laboratories, München, Germany), tert-butyl glycidyl ether (99%, Sigma-Aldrich), and triethylene glycol monomethyl ether (>97%, Merck, Hohenbrunn, Germany) were used as received. Allyl glycidyl ether, ethoxy ethyl glycidyl ether, and tert-butyl glycidyl ether were dried over CaH2 and distilled before use. Instrumentation. 1H NMR spectra (400 MHz) and 13C NMR spectra (100 MHz) of the prepolymers were recorded using a Bruker DPX 400. 1H NMR spectra (700 MHz) of the microgels were recorded using a Bruker Ultrashield 700 WB Plus. 13C NMR spectra (150 MHz) of the microgels were recorded using a Bruker Ultrashield 600. All spectra were referenced internally to residual proton signals of the deuterated solvent (CDCl3) or calibrated with ex situ calibration (D2O). For SEC measurements THF was used as solvent (flow rate 1.0 mL/min). The SEC system consisted of four columns with MZ-SDplus gel. The length of each column was 300 mm, the diameter was 8 mm, the diameter of the gel particles was 5 μm, and the nominal pore widths were 50, 100, 1000, and 10 000 Å. A Jasco 2075 detector was used for RI-detection. For calibration poly(methyl methacrylate) (PMMA) standards were used. The number-average molecular weight Mn, the weight-average molecular weight Mw, and the polydispersity PDI = Mw/Mn were calculated by the program WinGPC UniChrom. MALDI−TOF mass spectrometry was performed on a Bruker ultrafleXtreme equipped with a 337 nm smartbeam laser in the reflective mode. THF solutions of trans-2-[3-(4-tert-butylphenyl)-21634


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Scheme 2. Anionic Ring-Opening Polymerization of Ethoxy Ethyl Glycidyl Ether and Allyl Glycidyl Ether as well as tert-Butyl Glycidyl Ether and Allyl Glycidyl Ether, respectively, leading to Statistical or Block Copolymersa

a

CsOH serves as base and triethylene glycol monomethyl ether as initiator (R = CH3-(O−CH2CH2)3O--).

methyl-2-propenylidene]malononitrile (DCTB) (5 μL of 20 mg/mL), sodium trifluoroacetate (0.1 μL of 10 mg/mL), and analyte (5 μL of 10 mg/mL) were mixed and 0.5 μL thereof were applied on the sample plate. Laser shots (6000) with 24% laser power were collected. The laser repetition rate was 1000 Hz. Molecular weights and polydispersities were calculated with the help of Bruker polytools (version 1.15). Infrared spectra were carried out on a ThermoNicolet FT-IR Nexus spectrometer and were recorded using an ATR unit (ThermoNicolet, Smart SplitPEA). Transmission maxima are reported in wavenumbers (cm−1) and only selected intensities are reported. Raman spectroscopy was carried out on a Bruker FT-Raman spectrometer RFS 100/S with a Nd:YAG-laser. The power of the laser was 200 mV at 1064 nm with a spectral resolution of 4 cm−1. For each spectrum 500 scans were recorded. Dynamic light scattering (DLS) measurements were performed with a commercial laser light scattering spectrometer (ALV/DLS/SLS-5000) equipped with an ALV-5000/EPP multiple digital time correlator and laser goniometry system ALV/CGS-8F S/N 025 with a helium neon laser (Uniphase

1145P, output power of 22 mW and wavelength of 632.8 nm) as a light source. As solvents Milli Q water was used for noncross-linked emulsions and 0.1 M NaCl solution for cross-linked microgel particles. The hydrodynamic radius of the particles was determined through cumulant analysis. TEM micrographs were taken on a Carl Zeiss LibraTM 120 microscope (Oberkochen, Germany). The electron beam accelerating voltage was set at 80 kV. A drop of the sample was trickled on a piece of carbon-coated copper grid. The TEM grid was hydrophilized in a plasma oven for 90 s before use. Before being placed into the TEM specimen holder, the copper grid was air-dried under ambient conditions. Cryogenic TEM samples were prepared by rapid vitrification from aqueous dispersion (1 mg/mL) using plasma-treated lacey grids and a vitrobot system. Titrations and turbidity measurements were performed with a Mettler Titrando 905 autotitrator with optrode and pH meter. The wavelength for the turbidity measurement was 520 nm. Syntheses. Ethoxy ethyl glycidyl ether was prepared according to Fitton et al.27 and purified by distillation. 1635


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Table 1. Composition, Microstructure, Molecular Weights and Polydispersities of Prepolymers polymer

microstructure

molar ratio of monomersa

DPn

Mn(NMR)

Mn(SEC, THF)

PDI

22 20 21 22 21 25

2900 2700 2900 2900 2900 3500

3100 3500 4000 3000 3600 3900

1.13 1.19 1.12 1.20 1.16 1.13

19 21 19 19 28 23

2300 2800 2400 2300 3700 3000

3200 2900 3900 3100 3900 3300

1.23 1.21 1.17 1.16 1.21 1.14

EEGE/AGE I II III IV V VI

stat.

VII VIII IX X XI XII

stat.

block

1:1 2:1 4:1 1:1 2:1 4:1 tBGE/AGE

a

block

1:1 2:1 4:1 1:1 2:1 4:1

The composition in the copolymer is identical with the composition in the feed.

Synthesis of Poly(ethoxy ethyl glycidyl ether)-block-poly(allyl glycidyl ether) (IV−VI, Described for VI). The procedure is based on work by Frey and co-workers28 and is briefly summarized here. A mixture of cesium hydroxide (0.305 g, 1.83 mmol, 1/24 equiv) and triethylene glycol monomethyl ether (0.300 g, 1.83 mmol, 1/24 equiv) was dissolved in benzene (5 mL) and stirred for 30 min at 60 °C. Afterward, the benzene−water azeotrope was removed by distillation for 3 h at 90 °C. Ethoxy ethyl glycidyl ether (5.12 g, 35.0 mmol, 0.8 equiv) was added at room temperature and the reaction mixture was heated up to 40 °C and stirred for 2 h. After conversion of EEGE, allyl glycidyl ether (1.00 g, 8.76 mmol, 0.2 equiv) was added and polymerized for 24 h. The polymerization was terminated by addition of ethanol (1 mL). Next, the reaction mixture was dissolved in ethanol and precipitated in cold water. Yield: 4.87 g (80%). 1H NMR (400 MHz, CDCl3; δ): 1.17 (t, 3H, −OCH2CH3), 1.26 (d, 3H, −CHCH3), 3.36 (3H, s, −OCH 3 ( i n i t i a t o r ) ), 3.41−3.75 (m, (7+5)H, −OCH2CH(backbone), −OCH2CH(backbone), −OCH2CH(backbone)CH2, −OCH2CH3), 3.97 (2H, br s, −OCH2CHCH2), 4.61 (1H, d, CH 3 CH−), 5.12 (1H, d, −OCH 2 CHCH 2 ), 5.26 (1H, d, −OCH2CHCH2), 5.82−5.90 (1H, m, −OCH2CHCH2). 13C NMR (100 MHz, CDCl3; δ): 15.2, 19.7, 58.9, 60.7, 64.6−64.9, 70.0−70.1, 71.8, 72.2, 78.7, 99.6, 116.6, 134.8. In case of the statistical copolymers (I−III) the monomers were added simultaneously to the initiator. The conversion was in all cases quantitative. The obtained molecular weights range from Mn = 3000− 4000 g/mol (determined by end group analysis with 1H NMR spectroscopy and SEC (THF)). Using the same procedure poly(tert-butyl glycidyl ether)-blockpoly(allyl glycidyl ether) (X−XII) was prepared. Yield: 3.84 g (69%). 1 H NMR (400 MHz, CDCl3; δ): 1.11 (s, 9H, −OC(CH3)3), 3.32 (3H, s, −OCH3 (initiator)), 3.36−3.60 (m, (5+5)H, −OCH2CH(backbone), −OCH2CH(backbone), −OCH2CH(backbone)CH2), 3.93 (2H, br s, −OCH2CHCH2), 5.12 (1H, d, −OCH2CHCH2), 5.26 (1H, d, −OCH2CHCH2), 5.82−5.90 (1H, m, −OCH2CHCH2). 13C NMR (100 MHz, CDCl3; δ): 27.5, 58.9, 61.8−61.9, 69.0−70.4, 71.8, 72.2, 72.5, 78.9−79.2, 116.6, 134.8. In case of the statistical copolymers the comonomers (VII−IX) were added simultaneously to the initiator. The conversion was in all cases quantitative. The obtained molecular weights range from Mn = 2900−3900 g/mol (determined by end group analysis with 13C NMR spectroscopy and SEC (THF)). Thiol−Ene Reaction of Poly(tBGE-stat-AGE) (XIII) and Poly(tBGE)block-poly(AGE) (XIV) with 3-Mercaptopropionic Acid. Poly(tBGE)co-(AGE) (1.50 g, 6.14 mmol allyl groups, 1 equiv) was dissolved in THF (10 mL). Subsequently, 3-mercaptopropionic acid (0.323 g, 3.07 mmol, 0.5 equiv) was dissolved in THF (5 mL) and added. Next, 2,2dimethoxy-2-phenylacetophenone (0.0755 g, 0.295 mmol, 0.05 equiv) was added, and nitrogen was flushed through the reaction mixture for 10 min. The reaction mixture was irradiated with UV light (λ = 356

nm) for 24 h. Afterward, the solvent was removed and the obtained raw product was dissolved in THF and precipitated in water (pH = 6). The product was obtained as colorless oil. Yield: 1.49 g (80%). 1H NMR (400 MHz, CDCl3; δ): 1.15 (s, 9H, −OC(CH3)3), 1.82 (m, 2H, −OCH 2 CH 2 CH 2 S-), 2.60 (m, 4H, −OCH 2 CH 2 CH 2 S− and −SCH2CH2COOH), 2.76 (m, 2H, −SCH2CH2COOH), 3.36 (3H, s, −OCH3(initiator)), 3.36−3.60 (m, (5+5+5)H, −OCH2CH(backbone), −OCH 2 CH ( b a c k b o n e ) , −OCH 2 CH ( b a c k b o n e ) CH 2 ), (m, 2H, −OCH2CH2CH2S−), 3.98 (2H, br s, −OCH2CHCH2), 5.15 (1H, d, −OCH2CHCH2), 5.22 (1H, d, −OCH2CHCH2), 5.82−5.90 (1H, m, −OCH2CHCH2). 13C NMR (100 MHz, CDCl3; δ): 26.8, 27.4, 28.5, 29.6, 34.8, 58.9, 61.8−61.9, 69.5, 69.9−70.5, 71.8, 72.1, 72.8, 78.6− 79.2, 116.6, 134.8, 175.4. Synthesis of all Prepolymer-Based Microgels (Described for Microgel 9). For the synthesis of microgel particles, the prepolymer (0.5 g, 0.79 mmol allyl groups, 1 equiv), hexadecane (40 mg), 2,2dimethoxy-2-phenylacetophenone (19.4 mg, 0.076 mmol, 0.096 equiv), 2,2’-(ethylenedioxy)diethanethiol (79.9 mg, 0.433 mmol, 0.55 equiv) and toluene (2 mL) were mixed. Then, sodium dodecyl sulfate (2.5 mg, 0,5 wt % to prepolymer) and Milli Q water (8 mL) were added. Subsequently, the mixture was treated at a Branson ultrasonifier 450 for 15 min (output control 4, duty cycle 50%). After that, the miniemulsion was irradiated with two UV handlamps (λ = 365 nm) under vigorous stirring with a mechanical stirrer (1000 rpm) for 3 h. The microgel particles were isolated and purified by centrifugation (3 times, 12 000 rpm for 20 min) and dialyzed against water (molecular weight cutoff 25 000 Da). Yield: 0.240 g (48%). In case of prepolymers functionalized with 3-mercaptopropionic acid the prepolymer (0.5 g) was mixed with hexadecane (40 mg), 2,2dimethoxy-2-phenylacetophenone (32.8 mg, 0.128 mmol) 2,2’(ethylenedioxy)diethanethiol (134 mg, 0.734 mmol) and toluene (2 mL) and the above-mentioned procedure was applied.

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RESULTS AND DISCUSSION Synthesis and Characterization of Prepolymers. Nowadays, a rich toolbox of polyglycidol-based polymers with numerous microstructures and functionalities in the side chains can be obtained by anionic ring-opening polymerization of functional monomers.29,30 The major side-chain functionalities include amino,31,32 hydroxyl,33−36 allyl,28,37 phosphonic acid,38 and most recently ferrocenyl39 groups, which are accessible without or with only simple postpolymerization modifications. In the context of nano- and microgel synthesis, only hyperbranched polyglycidol homopolymer was used so far.40,41 The focus of these studies was the realization of gel particles on different length scales (nanometer to micrometer 1636


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Figure 1. 1H (a, b) and tBGE:AGE = 1:1.

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13

C NMR spectra (c, d) of poly(EEGE-stat-AGE), I, ratio EEGE:AGE = 1:1 and of poly(tBGE-stat-AGE), VII, ratio

composition of the polymer. Figure 1 shows typical 1H and 13C NMR spectra of poly(EEGE-stat-AGE) (I, ratio of EEGE:AGE = 1:1) and of poly(tBGE-stat-AGE) (VII, ratio tBGE:AGE = 1:1). In Figure 1a, the triplet signal at δ = 1.17 ppm and the duplet signal at δ = 1.26 ppm are assigned to the methyl groups of the acetal protecting group. The singlet signal at δ = 3.36 ppm is assigned to the methyl group of the initiator and is used for the calculation of Mn, (NMR). The doublet signal at δ = 4.61 ppm is assigned to the proton of the acetal group. The signals at δ = 3.97, 5.12, and 5.85 ppm are assigned to the allyl group. The 13 C NMR spectrum (Figure 1c) shows distinct signals for the acetal carbon at δ = 99.6 ppm and the carbon atoms of the allyl double bond at δ = 116.6 ppm and δ = 134.8 ppm. Thus, NMR spectroscopy confirms that the protecting groups are stable under the chosen conditions of AROP and that the composition of the copolymer is identical with the composition in the feed. For poly(tBGE-stat-AGE) (ratio of tBGE: AGE = 1: 1) the 1 H NMR spectrum (Figure 1b) shows a clear signal for the protons of the tert-butyl group at δ = 1.11 ppm. The singlet signal at δ = 3.32 ppm is assigned to the methyl group of the initiator. However, since the signal overlaps with the signals for the polymer backbone, it cannot be considered for the calculation of the degree of polymerization. Instead, quantitative 13C NMR measurements allow calculation of the degree of polymerization from the ratio of the signal of the methyl group of the initiator at δ = 58.9 ppm and the signals for the primary carbons atom in the tert-butyl group at δ = 27.3 ppm and for the allyl group at δ = 134.8 ppm. 1H and 13C NMR spectroscopy show clearly that the composition in the copolymer is identical with the composition in the feed.

range) and their use for biological applications, e.g., for the incorporation of yeast cells. In our study, we use two differently protected monomers, EEGE (Scheme 2a) and tBGE (Scheme 2b), in conjunction with AGE. Generally, the acetal group of EEGE is susceptible to mild, acidic hydrolysis. Hydrolysis of the tert-butyl protecting group is only possible in strongly acidic medium, such as trifluoroacetic acid. The possible decoration of some AGE units with mercaptopropionic acid is an alternative to increase the hydrophilicity of the microgel particles in the presence of the tert-butyl group. In both sets of monomer pairs, AGE may serve as a building block for cross-linking and for modification with 3-mercaptopropionic acid. We synthesized block copolymers and statistical copolymers based on AGE/EEGE and AGE/tBGE with different molar ratios of AGE/EEGE and AGE/tBGE, respectively, ranging from 1: 1, to 1: 2 and 1: 4. According to SEC, polymers with AGE and EEGE as monomer pairs show molecular weights between Mn, SEC (THF) = 3,000−4000 g/mol and narrow polydispersities (PDI = 1.12−1.20). For AGE and tBGE based polymers, molecular weights are between Mn, SEC (THF) = 2900 g/mol − 3900 g/mol with equally narrow polydispersities (PDI = 1.14−1.23) (Table 1). In all cases the molecular weights determined by SEC exceed the calculated molecular weights on the basis of end group assignment via NMR. We ascribe this deviation to the PMMA standards used for calibration of SEC and their different dependence of the hydrodynamic radius on the molecular weight compared to polyglycidol derivatives. On the basis of NMR analysis it is possible to calculate the molecular weight of the prepolymers through end group assignment. Furthermore, NMR permits to monitor the stability of the protective groups and to determine the overall 1637


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Figure 2. First order kinetic plots for the statistical copolymerization of ethoxy ethyl glycidyl ether and allyl glycidyl ether (1: 1 molar ratio) (a), and tert-butyl glycidyl ether and allyl glycidyl ether (1:1 molar ratio) (b), respectively, and dependences of the molecular weight Mn SEC (THF) on monomer conversion (c, d).

Figure 3. SEC traces of poly(EEGE) (black) as first block and poly(EEGE)-block-poly(AGE) (red), IV, ratio EEGE:AGE = 1:1 (a), SEC traces of poly(tBGE) (black) as first block and poly(tBGE)-block-poly(AGE) (red), X, ratio tBGE:AGE = 1:1 (c) and MALDI TOF MS data for the respective block copolymers (b, d). Parts a and c show oligomer separation in the SEC traces of the first block.

and EEGE under the aforementioned conditions are kapp(AGE) = 2.31 × 10−5 s−1 and kapp(EEGE) = 1.88 × 10−5 s−1. This means that AGE polymerizes slightly faster than EEGE. Interestingly, the analysis of the kinetic investigation of the simultaneous copolymerization of tBGE and AGE (VII−IX) proves the formation of a gradient copolymer. The respective slopes of the first order plot show that AGE reacts faster than tBGE (kapp(AGE) = 2.95 × 10−4 s−1 and kapp(tBGE) = 1.33 × 10−4 s−1), so that it is incorporated preferentially at the beginning of the polymerization (Figure 2b). The slight deviation from linear behavior at the beginning of the

Kinetic experiments of the statistical copolymerization of EEGE/AGE and tBGE/AGE (ratio 1:1) are necessary to assess the microstructure of the copolymer. The statistical copolymerization of EEGE/AGE shows a first order kinetic for this monomer pair (Figure 2a). Thus, a statistical microstructure is expected for the copolymers I−III. Furthermore, the statistical copolymerization of AGE and EEGE proceeds as a controlled polymerization, since the relationship between Mn SEC (THF) and conversion is linear (Figure 2c). On the basis of the slope in the first order kinetic plot the rate constants for the copolymerization of AGE 1638


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analogous block copolymer X containing a tBGE block instead of EEGE block (Figure 3d). The assessment of the efficiency of the block extension is possible by analysis of the signals for the homopolymer and the block copolymer. We assume that the ionization probability for the precursor homopolymer and the block copolymer is the same, so that quantitative conclusions, as to what extent the block extension was successful, can be drawn from the integration of the different signals (for further details, see Tables SI 1−6 and Figures SI 3−8). In summary, the results show that the block extension is nearly quantitative. Synthesis and Characterization of Microgels. We adopted a miniemulsion strategy to synthesize microgels with tailored nanostructures. The prepolymers I−XII were dissolved in toluene and stabilizers (sodium dodecyl sulfate as surfactant, hexadecane as ultrahydrophobe), as well as 2,2-dimethoxy-2phenylacetophenone (DMPA) as photoinitiator and 2,2′(ethylenedioxy)diethanethiol as cross-linker, were added. Ultrasonication of these mixtures provided stable miniemulsions. Irradiation with UV light under vigorous stirring for 180 min leads to cross-linking in a thiol−ene click-type reaction. Attempts to use copolymers with a higher ratio of potentially hydrophilic building blocks (ratio EEGE/AGE or tBGE/AGE = 6:1 or 9:1) did not succeed. This may be due to a lowered efficiency of the thiol−ene reaction, as recently reported for the use of thiol−ene reactions for polymer conjugation42 and related to the low share of allyl groups in the prepolymers. The obtained microgel particles were purified by centrifugation, dialysis against water and analyzed with Raman and FT-IR spectroscopy. The results of Raman spectroscopy for microgels 1−6 based on EEGE and AGE as monomer pairs (see Figure SI 9) show that the band for the double bond quantitatively disappears after the cross-linking reaction. Interestingly, FT-IR analysis (see Figure SI 10) of the EEGE/AGE based copolymers reveals a strong increase in intensity for the hydroxyl band after crosslinking. This increase indicates a surprising removal of the acetal protecting group under the conditions of the crosslinking reaction in miniemulsion. Indeed, subsequent analysis with 1H (Figure 4a) and 13C NMR (Figure 4b) spectroscopy confirms the quantitative removal of the acetal protecting group. In the prepolymer (see Figure 1) the signal for the acetal group has a chemical shift of 4.61 ppm and signals at 5.12 and 5.85 ppm are assigned to the allyl group. Figure 4a does not show any signals for the acetal and allyl group, which means

polymerization is due to thermal inhomogeneities. At a later stage of the polymerization, when the reaction mixture is depleted of AGE, tBGE is incorporated exclusively into the polymers. The varying molar ratio of tBGE and AGE present in the reaction mixture reflects the gradient structure of the resulting copolymer in contrast to the copolymerization of EEGE and AGE (see Supporting Information, Figures SI 1 and SI 2). However, the copolymerization of AGE and tBGE proceeds with good control of molecular weight (Figure 2d). In the case of the block copolymers IV−VI and X−XII SEC is suitable to control whether the molecular weight of the polymer increases after addition of the second monomer. As an example, the SEC traces (Figure 3a) show the poly(EEGE) homopolymer as first block (black) and the block copolymer IV (red) after addition of AGE as the comonomer. The SEC traces of the block copolymer are shifted to lower retention volume as compared to the homopolymer, which confirms an increase in molecular weight after addition of the second monomer. For poly(tBGE)-block-poly(AGE) block copolymer X the results are equivalent (Figure 3c). MALDI−TOF MS allows to determine molecular weights and to look in detail at the efficiency of block extension. The molecular weights Mn,MALDI (Table 2) are smaller than those Table 2. Molecular Weight Mn,MALDI, Polydispersity (PDI), and Purity of Poly(EEGE)-block-poly(AGE) determined with MALDI TOF MS polymer

molar ratio

IV V VI

1:1 2:1 4:1

X XI XII

1:1 2:1 4:1

Mn,MALDI EEGE/AGE 2900 3000 3100 tBGE/AGE 2400 2900 2900

PDI

block extension [%]

1.02 1.03 1.03

99.7 98.9 98.4

1.03 1.04 1.03

96.9 97.3 93.2

calculated on the basis of end group analysis with the help of NMR spectroscopy, which may be due to discrimination of longer polymer chains in MALDI−TOF MS analysis. Nevertheless, the trends are the same for both methods. The MALDI−TOF MS analysis of poly(EEGE)-blockpoly(AGE) IV (Figure 3b) confirms a narrow distribution of molecular weights. Similar results are obtained for the

Figure 4. 1H NMR spectrum (a) and 13C NMR spectrum (b) of microgel 1 after cross-linking of poly(EEGE-stat-AGE), ratio EEGE:AGE = 1:1. Hex. = Hexadecane. 1639


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Figure 5. 1H NMR (a) and 13C NMR spectrum (b) of microgel 7 after cross-linking of poly(tBGE-stat-AGE), ratio tBGE/AGE = 1:1. Hex. = Hexadecane.

that the hydrolysis of the acetal group and the cross-linking occur quantitatively. The 13C NMR spectrum of the microgel particles (Figure 4b) confirms these results since the signal for the acetal carbon at δ = 99 ppm, which is clearly visible in the prepolymer (see Figure 1c), is absent. However, a signal at 63 ppm is assigned to the carbon atom adjacent to the newly formed hydroxyl groups. Additionally, the 13C NMR spectrum clearly reveals new signals for the carbon atoms adjacent to the thio ether group at δ = 29 ppm. During the cross-linking reaction, we observe that the pH value decreases from pH 7 to pH 3. Thus, the formation of acid under conditions for the cross-linking leads to hydrolysis of the acetal protecting group. A model reaction with phosphate buffer (pH = 7.4) shows that the hydrolysis of the protecting group can be prevented if the decrease of the pH is suppressed (for further details, see the Supporting Information: Table SI 7 and following text). The situation for microgels based on tBGE/AGE prepolymers is different. 1H (Figure 5a) and 13C (Figure 5b) NMR analysis of the respective microgel particles proves that the tertbutyl protecting group is stable under the acidic conditions of the cross-linking. In summary, the acidification of the reaction medium during the cross-linking reaction leads to a removal of the acetal protecting group in the case of EEGE/AGE based microgels, whereas the tert-butyl protecting group of the tBGE/AGE based microgels is stable under these conditions. Apart from the chemical structure of the microgels, their hydrodynamic radius (⟨Rh,DLS⟩z) and polydispersity was investigated by dynamic light scattering (DLS). As a starting point, we investigated the relationship between droplet size and amount of surfactant in the reaction mixture (Figure 6). As expected, the size of the emulsified droplets decreases with increasing amount of surfactant and varies between 75 and 110 nm. We decided to focus the further experiments on a surfactant concentration of 0.25 mg/mL, yielding an intermediate size of the emulsified droplets. A subsequent investigation of the hydrodynamic radius of the resulting EEGE/AGE and tBGE/AGE based microgel particles showed that the hydrodynamic radius ranges from z = 115− 245 nm and ⟨Rh, DLS⟩z = 100−129 nm, respectively (Table 3). The corresponding CONTIN plots show monomodal particle size distributions (Figure 7, parts a and b) and

Figure 6. Influence of surfactant concentration on size of emulsified droplets.

cumulant analysis allows one to deduce that the polydispersities of the purified particles range from 1.06 to 1.17. For EEGE/AGE based microgels (microgels 1− 6), the increase of ⟨Rh,DLS⟩z between the emulsified droplets and the cross-linked microgel particles (Table 3) ranges from 18 to 87%. In all cases the ⟨Rh,DLS⟩z of the microgel particles exceeds the initial droplet size, which we ascribe to the hydrolysis of the acetal protecting group, leading to an increased hydrophilicity of the microgel particle and promoted swelling. Furthermore, one has to consider that the purification steps after the crosslinking reaction remove multiple components, such as nonadsorbed SDS and non-cross-linked polymer. Generally, the increase in the ⟨Rh,DLS⟩z is higher, for higher amounts of EEGE in the prepolymer and correspondingly for lower cross-linking densities in the microgel. Remarkably, the swelling behavior of microgels based on statistical copolymers differs from microgels based on block copolymers. For the microgel particles based on statistical copolymers, the ⟨Rh,DLS⟩z increases from 18−68%. So even with a high cross-linking density (ratio EEGE/AGE = 1:1, microgel 1) an increase of ⟨Rh,DLS⟩z of 18% is observed. For lower cross-linking densities of microgels based on statistical copolymers the ⟨Rh,DLS⟩z increases to 34% (EEGE/AGE = 2:1, microgel 2) and 68% (EEGE/AGE = 4:1, microgel 3). However, for the block copolymer based microgels, the increase of ⟨Rh,DLS⟩z is more pronounced (⟨Rh,DLS⟩z increases to 38% for EEGE/AGE = 2:1, microgel 5 and 87% for EEGE/ AGE = 4:1, microgel 6). This means that the swelling properties depend for microgels based on block copolymers stronger on the cross-linking density than for microgels based on prepolymers with a statistical microstructure. We suggest that these differences in the swelling behavior are directly 1640


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Table 3. Hydrodynamic Radius (⟨Rh,DLS⟩z) and Dispersity of EEGE/AGE and tBGE/AGE based Microgels determined by Dynamic Light Scattering (DLS) microstructure of prepolymer

monomer pair (molar ratio)

1 2 3 4 5 6

stat.

1:1 2:1 4:1 1:1 2:1 4:1

7 8 9 10 11 12

stat.

microgel

block

block

1:1 2:1 4:1 1:1 2:1 4:1

⟨Rh,DLS⟩z [nm] emulsified droplets EEGE/AGE 98 94 97 96 101 131 tBGE/AGE 100 99 96 96 92 97

PDIa

⟨Rh,DLS⟩z [nm] microgel particlesb

PDIa

increase of ⟨Rh,DLS⟩z [%]

1.13 1.12 1.11 1.12 1.13 1.14

116 126 163 115 139 245

1.09 1.07 1.09 1.09 1.09 1.17

18 34 68 19 38 87

1.12 1.13 1.13 1.11 1.13 1.12

112 118 123 100 101 129

1.16 1.13 1.09 1.06 1.08 1.12

12 19 28 4 10 33

a Determined via a second cumulant analysis. bHydrolysis of the protecting group occurs for EEGE/AGE based microgels but not for tBGE/AGE based microgels.

Figure 7. CONTIN plots of microgels based on EEGE/AGE prepolymers (a) and microgels based on tBGE/AGE prepolymers (b).

The TEM micrographs of EEGE/AGE based microgels underline that the synthesis yields soft microgel particles. The softness depends on the cross-linking density as evident from the contrast in the TEM micrographs. With a molar ratio of EEGE/AGE = 1: 1 compact particles with good contrast are observed (Figure 8a), whereas the contrast is weaker if the cross-linking density is lower (Figure 8b). For tBGE/AGE based microgel particles the results are similar: they yield more contrast if the cross-linking density is high (Figure 8c) as compared to a low cross-linking density (Figure 8d). Direct comparison of TEM micrographs for EEGE/AGE and tBGE/AGE based microgels shows that EEGE/AGE microgels give altogether a weaker contrast and underlines that EEGE/AGE based microgels are softer due to the hydrolysis of the acetal protecting group, increased swelling in aqueous environment and subsequent collapse in a flat structure upon deposition on the TEM grid. For a more detailed investigation of the nanostructure of the microgels we performed cryo-TEM experiments of microgels based on EEGE/AGE copolymers with different microstructures (Figure 9). Since the microstructure of the prepolymers varies in both cases, but the cross-linking density is the same, we analyze directly the influence of the prepolymer microstructure of the nanostructuration of the microgel. Strikingly, the microgel particles show hydrophobic domains with different sizes. The microgels based on statistical copolymers display smaller

related to the nanostructure of the corresponding prepolymers. For the statistical copolymers the cross-linking occurs at regular intervals along the polymer chain. Thus, the resulting network structures in the microgel have homogeneously distributed cross-links. In contrast to that, a block copolymer based nanostructure of the microgel is characterized by a heterogeneous distribution of cross-links in the polymer network, since cross-linking can only occur in the poly(AGE) blocks. This heterogeneous distribution of cross-links leads to a more compact nanostructure in case of a large fraction of poly(AGE) building blocks in the microgel and a more diffuse and swollen nanostructure if the fraction of poly(AGE) in the prepolymers is low. Since the tert-butyl protecting group is stable under the conditions of the cross-linking, there is only a moderate increase of the ⟨Rh,DLS⟩z of the microgels compared to the ⟨Rh,DLS⟩z of the emulsified droplets (33% in maximum). Here the differences between statistical and block copolymers are not as clearly visible as for EEGE/AGE based microgels, since the microgel particles are hydrophobic and thus collapsed in an aqueous environment. But still with decreasing cross-linking density, both systems show an increase of ⟨Rh,DLS⟩z, which correlates with the results for the EEGE/AGE based microgels. Later we will show how to add pH-responsive functionalities and switchable hydrophilic segments to these tBGA/AGE microgels. 1641


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Figure 8. TEM micrographs of EEGE/AGE block copolymer based microgels 4 and 6, molar ratio EEGE/AGE = 1:1 (a) and 4:1 (b), and tBGE/ AGE block copolymer based microgels 10 and 12, molar ratio tBGE/AGE = 1:1 (c) and 4:1 (d).

Figure 9. Cryo-TEM micrographs of microgels 1 and 4 based on EEGE/AGE statistical copolymer (a) and block copolymer (b). In both cases the molar ratio between EEGE and AGE is 1:1.

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Figure 10. 1H (a) and tBGE:AGE = 1:1.

Article

13

C NMR spectrum (b) of poly(tBGE-stat-AGE) (XIII) partially decorated with 3-mercaptopropionic acid, initial ratio

reaction, as seen in the increase of the polydispersity and larger Mn(SEC, THF) (Table 4).

domains around 1−2 nm (Figure 9a), while the microgels based on block copolymers exhibit more than double the domain size at ca. 4−5 nm (Figure 9b). This can be understood by considering that the hydrophobic segment of the blocky structure is larger and gives rise to a larger length scale in the domain size. These results clearly demonstrate that the molecular structure of the prepolymer, which can be readily altered by straightforward macromolecular engineering, can be translated to tune the nanostructuration of microgel particles. Furthermore, the cryo-TEM data show that the microgels are well-defined in shape and do not possess a fuzzy transition as observed for particles obtained by precipitation polymerization. Control of pH Responsiveness through Polymer Microstructure. The easy introduction of a variety of functional groups is a distinctive feature of the prepolymer approach for microgel synthesis. To increase the hydrophilicity of the tBGE/AGE based microgels, we decorated 50% of the allyl groups in the prepolymers VII (statistical copolymer tBGE/AGE = 1:1) and X (block copolymer tBGE/AGE = 1:1) with 3-mercaptopropionic acid in a thiol−ene click-type reaction. The 1H and 13C NMR spectra for the reaction of the prepolymers VII prove partial functionalization of the allyl groups with 3-mercaptopropionic acid (Figure 10, parts a and b). After decoration the molar ratio between tert-butyl groups/ carboxylic groups/allyl groups =3.17:1.48:1 for prepolymer XIII (decorated prepolymer VII) and 3.03:1.48:1 for prepolymer XIV (decorated prepolymer X). This is different to the theoretically expected ratio of 3:1.5:1.5 (supposing that 50% of allyl groups are converted with a ratio of 1:1 between tert-butyl groups and allyl groups in the prepolymers), but in very close molar agreement with each other. This deviation is related to direct coupling reactions of the allyl groups in a side

Table 4. Composition, Molecular Weights and Polydispersities for Statistical and Block Copolymers based on AGE and tBGE and partially decorated with 3Mercaptopropionic Acid polymer

tBGE:−COOH:AGE

microstructure

Mn(SEC, THF)

PDI

XIII XIV

3.17:1.48:1 3.03:1.48:1

stat. block

4900 3800

1.87 1.61

Nevertheless, since we aim at cross-linked microgels, we still consider the modified prepolymers to be useful candidates for the conversion into microgels. After successful miniemulsification and photo-cross-linking (proven by 13C NMR spectroscopy, see Supporting Information Figure SI 12), distinct differences in the dimensions to the microgels based on nonfunctionalized prepolymers can be found. According to DLS experiments (Table 5), the initial droplet size and the size of the final particles are smaller than the ones based on the non pH responsive prepolymers (microgels 9 and 12 are included in the table, since the ratio between allyl groups and other functional groups is similar). This decrease in particle size compared to the non pH responsive microgel particles is due to partial dissociation of the carboxyl groups, which leads to surface active molecules that are also able to take part in the stabilization of the oil droplets. The results are in accordance with the results obtained for the decreasing of droplet size by simultaneous increase of amount of surfactant. The pH dependent measurement of the size of the microgels (Figure 11a) underlines in both cases the successful 1643


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Table 5. Hydrodynamic Radius (⟨Rh,DLS⟩z) and Polydispersity of non-decorated tBGE/AGE based Microgels and Microgels decorated with 3-Mercpatopropionic Acid as determined with Dynamic Light Scattering (DLS) at pH = 7 microgel

molar ratio (tBGE:−COOH:AGE)

microstructure

⟨Rh,DLS⟩z [nm] emulsified droplets

PDI

⟨Rh,DLS⟩z [nm] microgel particles

PDI

increase of ⟨Rh,DLS⟩z [%]

9 13 12 14

4:0:1 3.17:1.48:1 4:0:1 3.03:1.48:1

stat. stat. block block

96 68 97 67

1.13 1.17 1.08 1.20

123 89 129 97

1.09 1.12 1.12 1.09

28 31 33 45

Figure 11. pH dependent size measurement (a) of microgel 13 based on decorated statistical copolymer (red), microgel 14 based on decorated block copolymer (black), and nondecorated block copolymer (blue) and (b) turbidimetric titration experiments of prepolymers (line through the data points serves as guidance for the eye) and (c) cryo-TEM data for microgel 14 based on poly(tBGE)-block-poly(AGE) partially decorated with 3mercaptopropionic acid after equilibration in CsOH/CsCl (0.05M) for 12 h.

incorporation of 3-mercaptopropionic acid since the microgels show pH responsive behavior. Clearly, a microgel based on prepolymer without decoration of 3-mercaptopropionic acid, which served as control sample, does not show any pH responsiveness. For microgel particles 14 based on decorated block copolymer swelling starts at pH = 5. They swell up to a size of ⟨Rh,DLS⟩z = 115 nm (60%), whereas the microgel particles 13 based on statistical copolymer start to swell at pH = 6 and to ⟨Rh,DLS⟩z = 102 nm (50%). Strikingly, the infliction points of the swelling curves for the microgels based on block copolymers and statistical copolymers are different, with the one of the block copolymer being lower. The infliction points are at pH = 5.7 and at pH = 7.4, respectively. On the basis of classical polyelectrolyte behavior, we would have expected the opposite, i.e. that the block structure shows later swelling due to closer proximity of acidic groups. However, since this is obviously not the case, we investigated the pH responsiveness of the prepolymers to investigate effects beyond simple distribution of ionic groups. Titration of the prepolymers XIII and XIV (Figure 11(b)) with simultaneous turbidity measurement shows that the solubility of the statistical copolymer is more strongly restricted to alkaline pH than the solubility of the block copolymer. Starting with dissolved prepolymers at pH = 11, the statistical prepolymer precipitates at pH = 7.5, whereas the block copolymer only precipitates at pH = 6.5. This means that the microstructure of the prepolymer strongly influences the solubility of the prepolymer. We suggest that for the statistical copolymer, the protonation of isolated carboxylate moieties leads to the formation of rather large hydrophobic sequences in the polymer. For the block copolymer, nonprotonated carboxylate moieties remain in the close vicinity of protonated carboxylate moieties, and accordingly, this polymer part remains soluble until protonation takes place to a large extent, while hydrophobic segments remain in stable desolvated micellar structure. This behavior is directly reflected in the swelling behavior of the microgels: the

microgel based on block copolymers starts to swell at lower pH, since deprotonation of the carboxyl groups leads to larger expansion and better interaction of constituting polymer segments with water as solvent. Contrastingly, the microgel based on statistical prepolymer starts to swell at higher pH since only advanced deprotonation promotes good solubility and swelling. Cryo-TEM data for the decorated block copolymer clearly proves the presence of domains within the microgel (Figure 11c). In conclusion, the functionalization with 3-mercaptopropionic acid underscores the scope of the prepolymer concept for microgel synthesis, since it shows that the properties of the prepolymers encode directly the properties of the cross-linked microgel particles.

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CONCLUSIONS We successfully demonstrate a concept allowing the synthesis of microgels with tailored nanostructures based on polyglycidol prepolymers in a facile, straightforward reaction sequence. Our strategy comprises an elegant in situ hydrolysis of acid labile groups at ambient temperature under the conditions of thiol− ene click-type reactions. The high degree of control in the polymerization of glycidol derivatives allows tailoring the microstructure of the prepolymers, which transfers into different local environments in the microgels. Thus, it is possible to encode the nanostructure of tailor-made microgels in the microstructure of the prepolymers and to synthesize structurally diverse microgels with the same overall chemical composition. This, in turn, enables new methods to tailor functionalities by design of compartments and locally enriched volumes. The rich polyglycidol chemistry is an attractive platform for the incorporation of numerous functional groups into microgels in the future. In particular, the biocompatibility of polyglycidol and the mild conditions for synthesis will open the route for well-structured colloidal systems, with interesting biochemical properties. 1644


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ASSOCIATED CONTENT

S Supporting Information *

Relative share of monomers in the feed for statistical copolymerizations, MALDI TOF MS data for the block copolymers IV−VI and X−XII, representative FT-IR and Raman spectra for microgel 3, as well as ESI TOF MS data of the model reaction between DMPA and 2,2′-(ethylenedioxy)diethanethiol and 13C NMR spectrum of microgel 13 modified with 3-mercaptopropionic acid, and data of titration of prepolymers XIII and XIV decorated with 3-mercaptopropionic acid. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

* Fax: +49 241 8023301. Telephone: +49 241 8026438. E-mail: [email protected] (H.K.). * Fax: +49 241 8023301. Telephone: +49 241 8023300. E-mail: [email protected] (M.M.). Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank Ines Bachmann-Rémy and Prof. Dan E. Demco for the measurement of the NMR spectra of the microgel particles. Furthermore, support with cryo-TEM experiments by Manuel Noack and help with the autotitration experiments by Thomas Heuser is most gratefully acknowledged. We thank the Deutsche Forschungsgemeinschaft (International Research Training Group “Selectivity in Chemo- and Biocatalysis” and Sonderforschungsbereich 985 “Functional Microgels and Microgel Systems”) for their funding of this work. A.W. is financed by the German Federal Ministry of Education and Research.

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Polyglycidol-Based Prepolymers to Tune the Nanostructure of Microgels

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