Stimuli-Responsive Zwitterionic Microgels with Covalent and Ionic

Article Cite This: Macromolecules XXXX, XXX, XXX−XXX

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Stimuli-Responsive Zwitterionic Microgels with Covalent and Ionic Cross-Links Ricarda Schroeder,†,‡,# Walter Richtering,§ Igor I. Potemkin,†,∥,⊥ and Andrij Pich*,†,‡ †

DWI − Leibniz Institute for Interactive Materials e.V., Aachen 52056, Germany Functional and Interactive Polymers, Institute of Technical and Macromolecular Chemistry, and §Institute of Physical Chemistry, RWTH Aachen University, Aachen 52056, Germany ∥ Physics Department, Lomonosov Moscow State University, Moscow 119991, Russian Federation ⊥ National Research South Ural State University, Chelyabinsk 454080, Russian Federation Macromolecules Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 08/22/18. For personal use only.

‡

S Supporting Information *

ABSTRACT: We describe a facile method for the synthesis of microgels with covalent and noncovalent ionic cross-links. Microgels were synthesized by copolymerization of various Nvinyllactams with zwitterionic monomer (methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide in the presence of a cross-linking agent (bis(acrylamide)) in waterin-oil emulsion. Monodisperse colloidally stable microgels with a high amount (>30 mol %) of zwitterionic groups were synthesized. High contents of zwitterionic groups in microgels led to the formation of reversible ionic cross-links along with permanent covalent cross-links generated by bis(acrylamide). The obtained microgels exhibit interesting temperaturetriggered swelling/deswelling behavior in aqueous solution. With an increase of the temperature above 10 °C, the microgels swell due to the destruction of the zwitterionic cross-links. Above the lower critical solution temperature of poly(N-vinyllactam) chains at T > 32 °C, the microgels shrink due to the destruction of the hydrogen bonds and enhanced hydrophobic interactions. The variation of zwitterionic groups and cross-linker concentrations influenced the extent of swelling/deswelling at different temperatures. New doubly thermoresponsive microgels were synthesized using three homologues: N-vinylcaprolactam (VCL), N-vinylpiperidone (VPi), and N-vinylpyrrolidone (VPy). It was shown that the temperature-triggered deswelling of microgels is strongly dependent on the size of the lactam ring.

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INTRODUCTION The great potential of microgels arises from their facile functionalization that opens the pathway for various applications in material science,1 biomedicine,2 sensing,3 or catalysis.4 Among different properties of microgels that can be controlled during synthesis steps such as porosity, swelling degree, or stiffness, the response to external stimuli is probably one of the most intriguing and challenging.5 Over the past years, numerous examples have been given for microgels that change their properties as a response to changes in temperature,6 pH,7 light,8 ionic strength,9 or electric fields.10 Microgels that are sensitive to changes in pH of the surrounding medium can be obtained by the incorporation of ionizable groups into the polymer network. Microgels can contain either basic (cationic) or acidic (anionic) side groups integrated into polymer chains. They swell in either low or high pH due to the repulsion of similarly charged groups and the osmotic pressure of counterions, which are localized inside the microgels.7 In polyampholyte microgels, both cationic and anionic groups are incorporated into the polymer network. They exhibit a double-swelling behavior at both low and high © XXXX American Chemical Society

pH while being in a collapsed state at the isoelectric point (IEP). The latter is caused by intraparticle electrostatic attraction of oppositely charged groups of the network. The ratio between charges greatly influences the swelling behavior of the particles.6 Aggregation of the microgels at the IEP due to interparticle electrostatic attractions can be prevented by the use of an ionic initiator (electrostatically) or through steric stabilization.11 A special class of polyampholyte microgels are microgels containing zwitterionic groups. In zwitterionic microgels, the charges of both signs are located in the same monomer unit, ensuring the exact same number of charged/ ionizable groups and thus maintaining an overall electroneutrality.12 Because the cationic and anionic groups are covalently bound to each other, a permanent dipole is created.13 Betaines are frequently used zwitterionic groups. They consist of a permanently positively charged quaternary ammonium group and a negatively charged terminal group, Received: April 1, 2018 Revised: August 7, 2018

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DOI: 10.1021/acs.macromol.8b00689 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules which is in many cases a phosphate, carboxylate, or sulfonate group.14 According to the anionic group they possess, the betaines are called phospho-, carboxy-, or sulfobetaine. Betaines impart several attractive features to the microgel’s polymer network. First, zwitterionic microgels show a so-called anti-polyelectrolyte behavior; i.e., the polymer network expands in aqueous solution through the addition of ions.15 This behavior is explained by the presence of inter- and intramolecular ionic bridges between the positively charged ammonium and the negatively charged terminal group.16 These charge−charge interactions are stronger than interactions with the surrounding water molecules.17 The addition of salt ions leads to the disruption of the internal ionic bridges, resulting in a swelling of the polymer network. Furthermore, these internal ionic bridges can be used for the preparation of physically cross-linked microgels. In contrast to chemically (covalently) cross-linked microgels, physical cross-links can be broken by the increase of temperature or addition of ions. This offers a facile and cheap method for a controlled degradation of microgels. Betaines are promising candidates to provide antifouling properties to materials.12 Nonfouling materials play an important role in medicine and nanotechnology where they can prevent chronic inflammation and infection. A combination of antifouling properties with stimuli-responsiveness in microgels allows the assembling of smart substrates and carriers. It is essential to adjust the nature of responsiveness to the respective field of application. For instance, thermosensitive microgels with a transition point close to the physiological temperature are of special interest for medical applications. One method to influence the stimuli-responsiveness of microgels is the right choice of the polymerization technique. Precipitation polymerization offers the possibility to tune the properties of microgels such as particle size, particle size distribution, surface charges, and internal polymer structure.18 Kumacheva et al., for instance, prepared zwitterionic microgels via surfactant-free precipitation polymerization and showed that the particle size was strongly dependent on the amount of SB incorporated.19 However, this polymerization technique is limited for the incorporation of high amounts (i.e., higher than ∼10 mol %) of hydrophilic SB. Free-radical precipitation polymerization is highly dependent on the hydrophilicity/ hydrophobicity of the monomers. The growing polymer chains need to be hydrophobic enough to precipitate from the solution and form microgel nuclei. Higher percentages of hydrophilic moieties result in either a high polydispersity or no microgel formation at all.20 Recently, microgels consisting of poly(N-isopropylacrylamide) (PNIPAm) core and poly(sulfobetaine) corona were synthesized using the RAFT polymerization approach.21 It has been shown that the PNIPAm core exhibits a lower critical solution temperature (LCST) behavior, while poly(sulfobetaine) chains grafted on the PNIPAm surface exhibit an upper critical solution temperature (UCST) behavior in aqueous solutions. However, using this approach microgels with copolymer chain structure cannot be obtained. Inverse mini- or microemulsion offers an attractive alternative to incorporate highly hydrophilic monomers into the polymer network of microgels. For instance, Neyret and Vincent used this technique to obtain purely polyampholyte microgels with a 50/50 ratio between the cationic and the anionic moieties.22

Herein, we describe the synthesis of poly(N-vinylcaprolactam-co-sulfobetaine) (VCL-co-SB) microgels with high content of sulfobetaine groups via inverse miniemulsion polymerization. The high amount of pendant SB groups in microgel network led to the formation of dynamic ionic cross-links originating from electrostatic interactions of zwitterions in addition to the covalent cross-links. We varied the ratio between VCL and SB and measured the influence of the amount of SB as well as the cross-linker N,N′-methylenebis(acrylamide) (BIS) on the temperature sensitivity of the zwitterionic microgels. The swelling behavior at varying temperature and pH was assessed by dynamic light scattering (DLS) and UV−vis measurements. Furthermore, we studied the influence of the ring size of the lactam ring on the phase transition of the particles. We found that a smaller lactam ring drastically shifts the transition temperature to higher temperatures.

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EXPERIMENTAL SECTION

Materials. N-Vinylcaprolactam (VCL, 98%), N-vinylpyrrolidone (VPy, >99%), [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (sulfobetaine, SB, 97%), 2,2′-azobis[2-methylpropionamidine] dihydrochloride (AMPA, granular, 97%), N,N′methylene(bis)acrylamide (BIS, 99%), Span 80, and Tween 80 were purchased from Sigma-Aldrich. N-Vinylpiperidone (VPi, 97.7%) was purchased from BASF. VCL and VPi were distilled and recrystallized from hexane before use. NaCl (for analysis) was obtained from Merck KGaA. Heptane (min. 99.5%) was obtained from VWR Chemicals. Water used in the experiments was purified using a Millipore water purification system with a minimum resistivity of 18 MΩ·cm. Microgel Synthesis via Inverse Miniemulsion. VCL, the appropriate amount of SB (Table 1), 1.70 wt % BIS, and 5 wt % NaCl

Table 1. Amounts of Monomers Used for the Synthesis of Microgels with Variable SB Content ratio VCL:SB

n(VCL) (mmol)

m(VCL) (g)

n(SB) (mmol)

m(SB) (g)

2:1 1:1 1:2a

2.443 2.443 1.222

0.340 0.340 0.170

1.222 2.443 2.443

0.341 0.682 0.683

a

For this batch, half of the amounts of solvents and monomers as stated above were used.

(lipophobe) were dissolved in 3.8 mL of H2O. In a second flask, 0.60 g (1.400 mmol) of Span 80 and 0.20 g (0.153 mmol) of Tween 80 (ratio 3:1) were dissolved in 100 mL of heptane and dispersed with ultrasonic treatment. Hexadecane could be used as continuous phase as alternative solvent to heptane to reduce leakage of VCL from aqueous droplets. The aqueous solution was added dropwise to the oil phase while ultrasonicating for 5 min under ice cooling to obtain a stable emulsion. Then the emulsion was heated up to 70 °C under a nitrogen atmosphere and vigorous stirring. The initiator AMPA was solved in 0.2 mL of H2O and quickly added to the emulsion. Alternatively, the initiator AMPA can be also dissolved along with VCL, SB, and BIS in water and directly integrated into aqueous droplets after sonication. The reaction was allowed to continue for 2 h. After cooling down, organic phase was removed from the emulsion via centrifugation at 11000 rpm. The precipitate was washed and centrifuged alternately with water and heptane (or hexadecane) for three times each. Between centrifugation, the microgels were shaken in the respective solvent for 30 min. Afterward, the samples were dialyzed against water for 7 days. The removal of nonreacted monomers and surfactants was monitored with 1H NMR. In further experiments, for a VCL:SB ratio of 1:1, the amount of cross-linker (see Table 2) was varied applying smaller batches of 50 mL of heptane and 2 mL of water. Additionally, VCL was substituted B


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(5.0 × 5.0 μm2) were acquired using the tapping mode. To prepare samples for AFM measurements diluted microgel solutions were dried on Si wafers. Colloidal Stability Measurements. Colloidal stability of the microgels was studied with a LUMiFuge 1112-33 (L.U.M. GmbH, Germany). This device measures sedimentation velocities of dispersions under centrifugal force. Microgel samples were measured in a 2 mm rectangular polycarbonate cell. Centrifugation was done at acceleration velocity 2000 rpm (corresponds to 800 g) at intervals of 10 s at T = 25 and 50 °C. The slope of sedimentation curves was used to calculate the sedimentation velocity and to gain information about colloidal stability of the samples.

Table 2. Microgels with a VCL:SB Ratio of 1:1 Synthesized with a Variable Amount of Covalent Cross-Linksa m(BIS) (g)

n(BIS) (mmol)

mol % BIS in microgel

0.0023 0.0047 0.0081 0.0128

0.0149 0.0305 0.0525 0.0830

0.30 0.62 1.07 1.70

a

The amounts of other monomers are identical to amounts given in Table 1.

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for N-vinylpyrrolidone (VPy) and N-vinylpiperidone (VPi) (see Table 3).

RESULTS AND DISCUSSION Microgels with superior colloidal stability and a high content of sulfobetaine (SB) were synthesized via inverse (W/O) miniemulsion polymerization. The successful incorporation of SB in the microgels was confirmed with FTIR spectroscopy by using a calibration curve (see Figures S1 and S2 in the Supporting Information). Table S1 shows that the SB amounts incorporated into microgels are in good agreement with the composition in the monomer feed. Because of differences in reactivity ratios of SB and VCL, the monomer groups may not be randomly distributed in the polymer chains, leading to formation of gradient or “blocky” chain architectures. Yang et al. suggested a higher polymerization reactivity for SB than for VCL due to steric hindrance of the caprolactam structure.23 However, due to the fact that the polymerization takes place in small aqueous droplets and this process does not require monomer transfer from the continuous phase, we believe that the overall distribution of the SB segments in the microgel network can be considered as random. The sizes of microgels were determined with dynamic light scattering (DLS) (see Table 4). Microgels become slightly

Table 3. Poly(N-vinylpyrrolidone) (PVPy) and Poly(Nvinylpiperidone) (PVPi) Microgels with a Vinylamide:SB Ratio 1:1a n(VPi) (mmol)

m(VPi) (g)

1.1730

0.1469

n(VPy) (mmol)

m(VPy) (g)

n(SB) (mmol)

m(SB) (g)

1.1922

0.1313

1.1777 1.1827

0.3290 0.3304

a

The amount of BIS was 1.70 mol %.

Microgel Characterization. Dynamic Light Scattering (DLS). The hydrodynamic radius RH of the microgel particles was measured using a Zetasizer Nano ZS (Malvern Instruments, UK) equipped with a 532 nm laser. DLS was used to determine the z-average microgel size in terms of the hydrodynamic diameter dH in aqueous solution obtained from the z-average diffusion coefficient via the Stokes− Einstein equation. Measurements were performed at a scattering angle of 173°. Temperature trends were measured in a temperature range 3−60 °C in 3 °C steps with five measurements per temperature step after equilibrating for at least 10 min. Before all measurements, the samples were filtered with a 1.2 μm PTFE filter. Water was filtered with 5, 1.2, and 0.45 μm filters prior to use. Electrophoretic Mobility. The electrophoretic mobility was measured at a Zetasizer NanoZS (Malvern Instruments, UK). Each sample contained 1 mM NaCl and was measured at 25 °C after an equilibration of at least 10 min. The size of microgels at different pH was measured using 0.1 M HCl and NaOH to adjust the pH. Measurements were taken between pH = 3 and 10 in 0.5 steps at 25 °C. Before all measurements, the samples were filtered with a 1.2 μm PTFE filter. Nuclear Magnetic Resonance (NMR). 1H NMR spectra were taken with a Bruker DPC at a frequency of 300 MHz. 5 wt % of freeze-dried microgels was dissolved in D2O and measured at room temperature. Fourier-Transformed Infrared Spectroscopy (FTIR). FTIR measurements were performed on freeze-dried microgel samples at a Bruker Alpha-P apparatus at room temperature. The samples were mixed with KBr powder and then pressed to form a transparent KBr pellet. To calculate the ratio of monomers in the polymer, the areas of the respective peaks at 1672 cm−1 (PVCL) and 1050 cm−1 (SB) were determined and calculated as a ratio to each other. UV−Visible Spectroscopy (UV−Vis). UV−vis spectra were taken at a UV−vis spectrophotometer using a CARY 100 Bio (Agilent Technologies, USA). A given concentration of microgel solution in water was measured at room temperature in the range 900−200 nm using 1 cm path length quartz cuvettes. For the determination of the swelling/deswelling of microgels, the temperature was controlled using a heating circulator and a cooler. The temperature was increased from 5 to 70 °C with a heating rate of 0.4 K/min. The transition temperature was defined as the temperature at the maximal slope for the absorbance against the temperature. Atomic Force Microscopy (AFM). AFM images were taken at an Asylum Research MFP-3D (Santa Barbara, CA) in ac mode. Cantilevers of silicon nitride were purchased from NanoWorld (Neuchatel, Switzerland) with a force constant of 42 N/m. Images

Table 4. Hydrodynamic Radii RH and Polydispersity Index (PDI) for Zwitterionic Microgels of Different Compositions (T = 20 °C) VCL:SB (mol:mol)

RH (nm)

PDI

RH (nm) (after 3 months)

PDI (after 3 months)

2:1 1:1 1:2

242 ± 16 227 ± 19 216 ± 8

0.043 0.044 0.047

243 ± 7 221 ± 8 211 ± 11

0.052 0.048 0.041

smaller with increasing content of SB, while the polydispersity index (PDI) remains constant at ∼0.04. According to Landfester and co-workers, the narrow particle size distribution is attributed to the fact that all droplets nucleate nearly at the same time.24 A decrease in microgel size with increasing SB amount could already be seen for microgels prepared via freeradical precipitation polymerization.25 The microgel size was measured a second time after a time period of 3 months. The sizes of all microgels as well as their PDI remained stable further indicating their excellent colloidal stability. UV−vis measurements were employed to assess the temperature responsiveness of the microgel particles by following a change of turbidity upon heating/cooling cycles (Figure 1). A change in absorbance can be monitored when the microgels switch from a swollen to a collapsed state, and vice versa. A collapse of microgels leads to an increase in the turbidity of the solution, thus resulting in an increased absorbance. Two transition temperatures can be seen for the C


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the increased hydrophilicity induced by the ability of zwitterionic pendant groups efficiently immobilize water molecules. A second transition at low temperatures appears if the content of SB is further increased. For a ratio of VCL:SB = 1:1, two transition temperatures can be seen at 9.7 and 42.9 °C. Both are shifted further to higher temperatures for a ratio of VCL:SB = 1:2, 18.7, and 48.5 °C. Microgels are in a collapsed state below the first and above the second transition temperatures. Between the two transition temperatures, the microgels are swollen. It should be noted that observed temperature-triggered transitions in microgels are fully reversible as proved by DLS measurements performed for heating and cooling cycles of selected microgel samples (Figure S3). Arotcarena et al. demonstrated that block copolymers containing the nonionic PNIPAm block and the zwitterionic poly(3-[N-(3-methacrylamidopropyl)-N,N-dimethyl]ammoniopropanesulfonate (PSPP) block exhibit double temperature-responsive behavior in water: the PNIPAm block shows a lower critical solution temperature (LCST), whereas the PSPP block exhibits an upper critical solution temperature (UCST).27 It was shown that both blocks of these copolymers dissolve in water at intermediate temperatures, whereas at high temperatures, the PNIPAm block forms colloidal hydrophobic associates surrounded by soluble PSPP block, and at low temperatures, the PSPP block forms colloidal polar aggregates that are kept in solution by the solvated PNIPAm blocks. In this manner, colloidal aggregates which switch reversibly their structure upon change of the temperature could be obtained. Recently, Yang et al. prepared linear PVCL-co-SB copolymers and reported a similar behavior.23 In contrast to PVCL-

Figure 1. Optical density of PVCL-co-SB microgels as a function of temperature. (a) VCL:SB = 2:1; (b) VCL:SB = 1:1; and (c) VCL:SB = 1:2. Measurements were performed at the wavelength of 400 nm.

microgel samples VCL:SB = 1:1 and 1:2 that shift to higher temperatures with increasing SB content. The occurrence of two transitions in the microgel particles has also been determined with dynamic light scattering (DLS). Pure PVCL microgels have a broad transition with a volume phase transition temperature (VPTT) of 30.7 °C (Figure 2a).26 The VPTT is shifted to a higher temperature of 37.7 °C for copolymers with a monomer ratio of VCL:SB = 2:1 due to

Figure 2. Hydrodynamic radius RH of PVCL-co-SB microgels as a function of temperature: (a) pure PVCL microgel (reference); (b) VCL:SB = 2:1; (c) VCL:SB = 1:1; (d) VCL:SB = 1:2. D


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Macromolecules co-SB microgels, however, linear copolymers aggregate above and below the lower critical solution temperature (LCST) and upper critical solution temperature (UCST), respectively, as indicated by an increase in the hydrodynamic diameter from ∼40 nm to above 2 μm. Yang et al. described how different polymer chain segment arrange in response to the temperature: VCL and SB are hydrophilic in the range between the transition temperatures, resulting in stretched linear chains.23 At low temperatures intra- and intermolecular ionic bridges between the zwitterionic groups. This leads to the formation of aggregates with an SB core surrounded by a VCL shell. Analogously, at temperatures above the LCST, PVCL becomes hydrophobic due to the breakage of hydrogen bonds between carbonyl groups and water, and subsequently, aggregates with a VCL core and an SB shell form. This behavior can only in parts be transferred to our VCLco-SB microgels. Because the polymer network is chemically cross-linked, a complete “turnover” of an SB/VCL core/shell is not possible. Still, induced by the change in particle size, a “shifting” of polymer segments to more favorable positions is likely. The shift of the transition temperatures to the higher values with the increase of SB content (Figure 2) can be expained as follows. The formation of the collapsed state of the microgel at low temperature is caused by electrostatic (dipole− dipole and multipole) attractions of SB groups. This attraction is opposed by excluded volume repulsion of VCL groups because pure PVCL microgels swell at such temperatures and by the thermal energy kT. Despite the fact that the electrostatic attraction by itself does not depend on the temperature, the aggregation−disaggregation of the zwitterions groups is temperature-controlled. Disruption of the aggregated SB complexes is induced via temperature increase: disaggregation occurs as soon as the energy of thermal motion of the SB and VCL groups (kT per group) exceeds the electrostatic attraction energy between the SB groups. Therefore, the higher the fraction of the SB groups in the microgel, the stronger the attraction between them and the weaker the repulsion between VCL groups. To induce the microgel swelling, one needs higher temperatures for a higher content of SB groups (i.e., lower content of VCL groups). Therefore, the VPTT1 shifts toward higher values. The second transition shifts to the higher temperatures because the microgel is less hydrophobic at smaller contents of VCL groups. The sulfonate group has a low pKa value of 3 whereby it remains deprotonated over the whole pH range.28 Therefore, the electrophoretic mobility is negative for all samples within a pH range of 3−10 and hardly pH-dependent (see Figure 3). Because of charge compensation in the microgel network, the colloids exhibit an almost constant size in a broad pH range. The colloidal stability of the microgel solutions was examined measuring their sedimentation velocities at T = 25 and 50 °C (i.e., in swollen and deswollen state, respectively). The higher the sedimentation speed is, the lower is the colloidal stability of the solution. Very similar sedimentation velocities for all microgels were found regardless of their chemical composition (see Figure S4). For microgels in swollen state (T = 25 °C) the sedimentation velocities are ∼20 μm/s. The sedimentation velocity increases by ca. 50% at T = 50 °C. This is caused by a decrease of steric repulsion and an increase of van der Waals attractions lowering the colloidal stability of microgels. At room temperature, swollen microgels have a Hamaker constant close to that of water at room

Figure 3. Hydrodynamic radius RH (right axis, upper curves) and electrophoretic mobility EM of microgels (left axis, lower curves) as a function of pH. VCL:SB = (1) 2:1, (2) 1:1, and (3) 1:2.

temperature, and attractive van der Waals attractions can be neglected.29 Attractive forces increase with increasing temperature, therefore leading to a decrease in colloidal stability. A complete aggregation is, however, prevented by an increase in electrostatic repulsion between charges on the surface originating from the initiator. The swelling behavior of the microgels can be modified by varying the amount of cross-links. It is well-known that an increase in cross-linker concentration suppresses the swelling behavior of the microgels.30−32 Microgel samples discussed above contain 1.70 mol % BIS. In addition, microgels with cross-linker contents of 1.07, 0.62, and 0.31 mol % were synthesized. Shah et al. showed that a small amount of crosslinker does not influence the position of the VPTT.33 However, beginning from 10 wt % of cross-linker content, the volume phase transition temperature of microgels is increased. Figure 4 shows that in our system the position of both transition temperatures is hardly affected by a variation in cross-linker content. Though while all microgels have roughly the same size of ∼205 nm at 5 °C, their degree of swelling is considerably different in the range 14−35 °C. The higher the cross-linking content, the smaller is the particle size in this range due to an increase in polymer network stiffness. Atomic force microscopy (AFM) was employed to visualize the deformability of microgels after adsorption and drying on solid substrates (see Figure S5) to confirm the variation in microgel stiffness with the amount of cross-links. Height profiles for dried microgels obtained from AFM line scans (Figure 4c) show that the microgels exhibit stronger spreading the lower the content of cross-linker is, thus appearing smaller on the Si-wafer surface. Both linear PVCL and PNIPAm exhibit an LCST of ∼31− 34 °C.34 It is well-known that the copolymerization with a hydrophobic comonomer lowers the transition temperature, while the incorporation of hydrophilic comonomers shifts the transition to higher temperatures.35 In the following, a different approach will be followed where PVCL is substituted for its five- and six-ring homologues (see Figure S6). N-Vinylpyrrolidone (VPy) contains a five-carbon ring. Its homopolymer, poly(N-vinylpyrrolidone) (PVPy), is water-soluble, hydrophilic, and nonionic and exhibits good biocompatibility and low cytotoxicity.36,37 Its transition temperature in aqueous solution is above 100 °C. E


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Figure 4. Temperature-responsive behavior of PVCL-co-SB microgels (VCL:SB = 1:1) synthesized with varying cross-linker contents: (a) hydrodynamic radius RH (measured with DLS); (b) optical density of microgel solutions (measured with UV−vis). (c) AFM height profiles of single microgels (VCL:SB = 1:1; amount of cross-linker varied from 0.31 to 1.70 mol %) adsorbed on Si wafers.

Compared to PVCL and PVPy, few reports have been published about the (co)polymerization of N-vinylpiperidone (VPi) and the properties of its homopolymer, poly(Nvinylpiperidone) (PVPi). In 2010, Kizhnyaev et al. were the first to polymerize VCL with VPi.38 Ieong et al. described the synthesis of homo- and copolymers via RAFT polymerization.39 Depending on the molecular weight, the homopolymer exhibits a sharp LCST between 68 and 87 °C. 1 H NMR spectra confirm the successful copolymerization of the respective N-vinylamide and SB. For the calculation of the ratio between the two monomers, the peaks of the Nvinylamide and SB at 2.99 and 3.25 ppm, respectively, were used (see Figure 5). The calculated ratios are in accordance with the feed ratios (see Table S2). In the following, the influence of the lactam ring size on the temperature behavior is examined. Microgels containing homologues of VCL with five- and six-rings are prepared in the same way as VCL-co-SB microgels via inverse miniemulsion polymerization. A ratio of N-vinylamide:SB of 1:1 with 1.70 mol % BIS was used. The temperature sensitivity of microgels is studied with DLS and UV−vis. DLS measurements reveal that the VPTT of the poly(N-vinylamide) microgels is shifted to higher temperatures with decreasing ring size. PVCL-co-SB and PVPi-co-SB microgels have a sharp VPTT of 42.9 and 73.0 °C, respectively,

while no VPTT can be observed for PVPy-co-SB microgels. An increase in LCST for the corresponding linear poly(Nvinylamide)s by ∼30 °C per −CH2− group added to the lactam ring was already observed by Burchard.40 A decrease in ring size decreases the hydrophobicity of the lactam ring, therefore shifting the VPTT to higher temperatures. Maeda et al. state that a phase separation of PVPy is only visible at high salt concentrations.41 The swelling induced by the disruption of the ionic crosslinks formed by dimerization of SB remains constant at around 10 °C, but it is noticeable that the transition from collapsed to swollen state becomes significantly broader with decreasing ring size. UV−vis measurements confirm the results obtained via DLS (see Figure 6). The broader transition range of VPy compared to VCL can be attributed to the greater hydrophilicity of VPy. The nitrogen lone pair electrons in the lactam rings participate in resonance structures with a positive charge on the nitrogen and a negative charge on the oxygen atom, resulting in large dipole moments. N-Methylpyrrolidone, Nmethylpiperidone, and N-methylcaprolactam are reported to have dipole moments of 4.06, 4.01, and 4.23 D, respectively.42,43 Generally, a greater dipole moment enhances a charged resonance structure resulting in a higher hydrophilicity of the molecule. The hydrophilicity can be expressed by the hydration number of a molecule as a very polar molecule is F


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Figure 5. 1H NMR spectra of monomers N-vinylpyrrolidone, N-vinylpiperidone, N-vinylcaprolactam, and sulfobetaine. Graphs in inset are closeups of the respective microgel spectra (vinylactam:SB = 1:1) that show peaks of the respective N-vinylamide and sulfobetaine that were used to calculate the ratio between the two monomers.

Figure 6. Thermoresponsive behavior of vinylamide-co-SB microgels (vinylamide:SB = 1:1) with varying ring size: (a) hydrodynamic radius RH (measured with DLS); (b) optical density of same samples as measured with UV−vis.

Scheme 1 shows a simplified model that illustrates the phase behavior of the vinylamide-co-sulfobetaine microgels in aqueous solution during heating and cooling. Below T1 (corresponding to the UCST of linear polymers), the microgels become hydrophobic due to strong intra- and intermolecular electrostatic attractions from ionic pairing between the SB comonomer units. Dipolar interactions between the SB segments play a major role in this temperature regime. We assume that formation of the SB multimers is energetically and entropically less favorable. Indeed, the dipole−dipole electrostatic attraction is dominating over the dipole−quadrupole, etc., interactions. Keeping in mind integration of the SB groups into the microgel network, their

more extensively hydrated. VPy has a hydration number of 8.5,44 while VCL has a hydration number of 3.6 and 1.8 at 28 and 43 °C, respectively.45 In this paper, we do not address the behavior of synthesized microgels in salt solutions. It has been shown that VPTT of the PNIPAm and PVCL microgels decreases with addition of NaCl due to the dehydration of polymer chains.46 Contrary, polyzwitterions exhibit “anti-polyelectrolyte” behavior and swell upon addition of salts due to the destruction of zwitterionic associates by counterions.15 Considering this, the addition of salt could be another stimulus to tune the swelling/ deswelling behavior of microgels, which should be considered in future work. G


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Macromolecules Scheme 1. Stimuli-Responsive Microgels with UCST and LCST Behavior

increasing sulfobetaine amount: the volume phase transition temperature related to the collapse of the PVCL network is shifted to higher temperatures due to the presence of hydrophilic SB. A high SB content further provoked the appearance of a second transition at temperatures below 10 °C induced by destruction of the ionic cross-links formed by dimerization of SB groups. It was shown that this transition is also shifted to higher temperatures with increasing SB content. A variation in cross-linker content greatly influences the swelling of PVCL-co-SB, while the position of the transition temperature remains constant. Another method to shift the VPTT is the use of the N-vinylcaprolactam (VCL) homologues N-vinylpyrrolidone (VPy) and N-vinylpiperidone (VPi) as monomers for the microgel synthesis. It was shown that a decrease in ring size drastically rises the transition temperature up to 70 °C and above 90 °C for PVPi and PVPy microgels, respectively. The dual temperature-responsiveness as well as the biocompatibility of SB and the vinylamides provides a molecular toolbox for the chemical design of complex microgel architectures with potential applications in diagnostic, biosensors, drug delivery, antifouling coatings, and smart membranes.

aggregation is accompanied by the entropic (conformational) penalty of the subchains: the higher the aggregation number of the SB groups, the higher the penalty. Therefore, we expect that majority of the SB aggregates are dimers, and the fraction of multimers is much smaller. At temperatures above T1, the thermal energy can break the ionic pairings, leading to a swelling of the hydrophilic microgel particle. Above T2 (corresponding to the LCST in linear polymers), the vinylamide becomes hydrophobic, resulting in the shrinkage of the polymer network. Around T2, the formation (T < T2) or breakage of hydrogen bonds (T > T2) between the vinylamide and the surrounding water molecules is the major driving force for the observed phase behavior. VCL is of special interest as it exhibits a transition temperature close to the physiological temperature. These novel dual-thermoresponsive poly(N-vinylamide-co-sulfobetaine) microgels can be used to produce a library of welldefined colloidal networks comprising varying amounts of Nvinylamide and sulfobetaine comonomer units to display tunable transition temperatures.

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CONCLUSIONS Temperature-responsive microgels with two types of crosslinks (covalent and ionic) were synthesized. Permanent crosslinks were integrated into the microgels by the copolymerization of cross-linking agents. Ionic cross-links were integrated into the microgels by the dimerization of the zwitterionic groups of sulfobetaine. Monodisperse poly(N-vinylcaprolactam-co-sulfobetaine) (VCL-SB) microgels with a high amount (i.e., higher than 10 mol %) of zwitterionic groups were synthesized via inverse miniemulsion polymerization. The ratio between VCL and SB greatly influences the thermoresponsiveness of the microgels. Two trends were observed with

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b00689. FTIR spectra of PVCL-co-SB microgels, calibration curve to determine the quantities of PVCL and SB via FTIR, AFM images of microgels synthesized with variable cross-linker amounts (DOCX) H


Article

Macromolecules

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (A.P.). ORCID

Walter Richtering: 0000-0003-4592-8171 Igor I. Potemkin: 0000-0002-6687-7732 Andrij Pich: 0000-0003-1825-7798 Present Address #

ESA − Advanced Concepts Team, European Space Research Technology Centre (ESTEC), Keplerlaan 1, Postbus 299, NL2200 AG Noordwijk, Netherlands.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Deutsche Forschungsgemeinschaft (DFG) within Collaborative Research Center SFB 985 “Functional Microgels and Microgel Systems” is gratefully acknowledged. The authors thank the Volkswagen Stiftung for financial support. Financial support from the Russian Foundation for Basic Research and the Government of the Russian Federation within Act 211, Contract # 02.A03.21.0011, is gratefully acknowledged.

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Stimuli-Responsive Zwitterionic Microgels with Covalent and Ionic

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