Dual-Gated Supramolecular Star Polymers in Aqueous Solution

Article pubs.acs.org/Macromolecules

Dual-Gated Supramolecular Star Polymers in Aqueous Solution Bernhard V. K. J. Schmidt,*,†,‡ Dennis Kugele,§,∥ Jonas von Irmer,⊥ Jan Steinkoenig,§,∥ Hatice Mutlu,§,∥ Christian Rüttiger,⊥ Craig J. Hawker,*,‡ Markus Gallei,*,⊥ and Christopher Barner-Kowollik*,§,∥,# †

Department of Colloid Chemistry, Max-Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany Materials Department and Materials Research Laboratory, University of California, Santa Barbara, Santa Barbara, California 93106, United States § Preparative Macromolecular Chemistry, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT), Engesserstrasse 18, 76131 Karlsruhe, Germany ∥ Soft Matter Synthesis Laboratory, Institut für Biologische Grenzflächen, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany ⊥ Ernst-Berl-Institute for Chemical Engineering and Macromolecular Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Straße 4, 64287 Darmstadt, Germany # School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), 2 George Street, Brisbane, QLD 4001, Australia ‡

S Supporting Information *

ABSTRACT: We introduce the formation of a dual responsive supramolecular star polymer system, displaying gated selfassembly behavior. The redox- and thermoresponsive star polymers are based on a 6-fold β-CD functionalized core molecule and RAFT-derived ferrocene end functionalized poly(N,N-dimethylacrylamide) (PDMA) and poly(N,N-diethylacrylamide) (PDEA) linear polymers. Complex formation is analyzed via various methods including dynamic light scattering (DLS). Chemical redox triggers, namely NaOCl and ascorbic acid, as well as electrochemical triggers can be utilized to shift the star polymers to the unbound state via CD/ferrocene complex dissociation. Moreover, heating above the lower critical solution temperature (approximately 34 °C) allows for a change from the coil to the globular state of the star polymers in the case of PDEA arms. For PDMA arms, heating to 70 °C allows shifting of the system to the unbound state. The response of the supramolecular star polymers is carefully studied via various methods including cyclic voltammetry (CV), DLS, and turbidimetry. Overall, the supramolecular star polymers can be transformed into predefined states via individually addressable temperature and/or redox stimuli, presenting a novel dual gated self-assembling supramolecular star polymer system in aqueous solution.

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INTRODUCTION Stimuli responsive polymers have been a major focus of polymer scientists in recent years.1−3 A broad range of stimuli have been investigated including thermo,4 redox,5−7 light,8 or chemical responses.9 The main reason for the extensive research in this field is a plethora of prospective applications for stimuli responsive polymers, e.g., in drug delivery,10 sensors,11 or surface coatings.12,13 Synthetically, polymers have been designed to respond to multiple stimuli,14−16 which allows changes in various materials properties, e.g., solubility and molecular encapsulation/release.14,17−19 To enable stimuli responsive features, supramolecular chemical principles have been widely utilized in polymer chemistry.2,20,21 Gated multistimuli responsive systems are of critical importance, and the system presented in the current contribution introduces a novel dual-gated responsive star polymer system that operates in an aqueous environment. The dynamic nature of supramolecular interactions can be utilized © XXXX American Chemical Society

to tailor material and polymer properties via external stimuli, e.g., the shape of materials or the solubility. In the realm of supramolecular chemistry, a variety of binding motifs are utilized in polymer science, e.g., hydrogen bonding,22 inclusion complexes,20,21,23,24 or metal complexation,25,26 that offer stimuli responsive bonding. Therefore, bonding depending on temperature, ionic strength, pH, or oxidation status has been explored. Of particular interest are supramolecular star polymers that combine the key properties of star polymers,27 such as high functional density, with dynamic supramolecular bonds. One of the most frequently employed supramolecular building blocks is cyclodextrin (CD), which is a cyclic oligosaccharide capable of forming inclusion complexes with Received: January 24, 2017 Revised: March 3, 2017

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DOI: 10.1021/acs.macromol.7b00165 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 1. Overview of Star Formation via Ferrocene (Blue Spheres) Guest and β-CD (Orange Cone) Host Supramolecular Interactions as Well as Dual-Gated Response to External Temperature and/or Redox Stimuli

hydrophobic molecules in aqueous solution.28 CDs have found a broad variety of uses in polymer science,29,30 e.g., for the formation of supramolecular star polymers,31−33 supramolecular brush polymers,34,35 supramolecular networks/hydrogels,24,36 supramolecular block copolymers, 37,38 sliding gels,39−41 molecular printboards,42,43 or in the formation of nanoparticles.44,45 Critically, not only can the polymer components in CD-derived supramolecular structures be utilized to introduce stimuli response properties into the system, but the CD complexes also display intrinsic stimuli responsiveness; i.e., the complex can be dissociated or associated depending on external stimuli.29 Here, light responsive azobenzene complexes,46 pH responsive benzimidazole complexes,38 and metal responsive bipyridine complexes47 with β-CD have been described. Furthermore, redox responsive complexation can be obtained in the complexes of β-CD and ferrocene.34,48 Importantly, ferrocene containing polymers have found various applications due to the redox responsive nature of the ferrocene unit that undergoes oxidation to the positively charged ferrocenium ion in a reversible fashion. This reversibility can be exploited to modulate surface wettability or achieve selective membrane gating.49,50 For example, ferrocene oxidation/reduction cycles have been utilized in host−guest interactions for self-healing

materials,36 controlled release of organics from gels,51 in (inverse) colloidal crystal films,52,53 for changing permeability in polyelectrolyte multilayer capsules,54 for a redox responsive release of organic molecules from patchy nanocapsules,7 or responsive supramolecular pillar[6]arene-based vesicles.55 In the context of CD-based supramolecular chemistry, ferrocene moieties and β-CD readily form 1:1 inclusions complexes with association constants of close to 3000 mol−1.56,57 In the case of β-CD/ferrocene complexes, oxidation to ferrocenium leads to expulsion of the guest from the host as the ferrocenium ion is too hydrophilic for the β-CD cavity.58,59 Combinations of ferrocene and β-CD have also been widely employed in polymer chemistry,60 e.g., in CD-mediated radical polymerization,61 for the formation of redox responsive supramolecular polymer brushes,34,62 self-healing hydrogels,36 or supramolecular block copolymers.63 Moreover, β-CD functionalized quantum dots were described as redox responsive linkers for temperature triggered hydrogel formation48 as well as four-arm star polymers with poly(ε-caprolactone)-b-poly(ethylene oxide) arms and β-CD/ferrocene block connection.64 Critically, however, no responsive star polymer system has been reported that combines the oxidation and reduction capabilities of ferrocene/CD complexes with the temperature responsive nature of the pendent star polymer arms. B


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solvents were of analytical grade and used as received. Milli-Q water was obtained from a purification system by Thermo Fisher Scientific (TKA Micro-Pure; 0.055 μS cm −1 ). 2,2′-Azobis(2-methylpropionitrile) (AIBN; Sigma-Aldrich, 98%) was recrystallized twice from methanol. N,N-Diethylacrylamide (DEA, TCI, 98%), 1,4-dioxane (Sigma-Aldrich, 99%), and N,N-dimethylacrylamide (DMA, Fisher, 99%) were passed over basic aluminum oxide prior to usage. 2(((Ethylthio)carbonothioyl)thio)-2-methylpropanoic acid (EMP),71 2ferrocenyl carboxylethyl 2-(((ethylthio)carbonothioyl)thio)-2-methylpropanoate (Fc-CTA),48 and per-β-CD-dipentaerythritol (β-CD6)72 were obtained according to the literature. Exemplary Synthesis of Ferrocene End Functionalized PDMA (Fc-PDMA61). The ferrocene functionalized polymers were obtained according to the literature.48 In a 50 mL vial DMA (3.00 g, 30.27 mmol, 50 equiv), Fc-CTA (291 mg, 0.61 mmol, 1.0 equiv), and AIBN (20.0 mg, 0.12 mmol, 0.2 equiv) were dissolved in 1,4-dioxane (15.0 mL). The vial was capped with a septum, and the mixture was bubbled with argon for 30 min. Subsequently, the polymerization was conducted at 60 °C for 2 h. Subsequently, the mixture was cooled with liquid nitrogen and the vial opened to air. The product was precipitated twice in cold diethyl ether; the solid was collected and dried under vacuum. Finally, the product was obtained as an orange solid (3.20 g, 97%). Mn,SEC = 7700 g mol−1, Đ = 1.16, Mn,NMR = 6500 g mol−1. Exemplary Synthesis of Ferrocene End Functionalized PDEA (Fc-PDEA84). The ferrocene functionalized polymers were obtained following a literature procedure.48 In a 50 mL vial, DEA (3.00 g, 23.62 mmol, 50 equiv), Fc-CTA (227 mg, 0.47 mmol, 1.0 equiv), and AIBN (15.5 mg, 0.09 mmol, 0.2 equiv) were dissolved in 1,4-dioxane (15.0 mL). The vial was capped with a septum, and the mixture was bubbled with argon for 30 min. Next, the polymerization was conducted at 60 °C for 3 h. Subsequently, the mixture was cooled with liquid nitrogen and the vial opened to air. The product was precipitated twice in cold hexane; the solid was collected and then dried under vacuum. Finally, the product was obtained as an orange solid (2.78 g, 86%). Mn,SEC = 10 100 g mol−1, Đ = 1.11, Mn,NMR = 11 200 g mol−1. Supramolecular Star Formation of PDMA61@β-CD6. Ferrocene functionalized Fc-PDMA61 (153 mg, 23.5 μmol, 6.0 equiv) and β-CD6 (29.1 mg, 3.9 μmol, 1.0 equiv) were dissolved in DMF (7.0 mL) and dialyzed against deionized water with a SpetraPor3 membrane (MWCO = 2000 Da) for 3 days at 10 °C. The solvent was removed in vacuo to yield the inclusion complex as a light solid (178 mg, 3.8 μmol, 97% yield). Supramolecular Star Formation of PDEA84@β-CD6. Ferrocene functionalized Fc-PDEA84 (120 mg, 10.7 μmol, 6.0 equiv) and β-CD6 (13.3 mg, 1.8 μmol, 1.0 equiv) were dissolved in DMF (7.0 mL) and dialyzed against deionized water with a SpetraPor3 membrane (MWCO = 2000 Da) for 3 days at 10 °C. The solvent was removed in vacuo to yield the inclusion complex as a light solid (128 mg, 1.7 μmol, 94% yield). Redox Response Investigations via Chemical Triggers. For redox response measurements via NOESY and DOSY, polymer solutions with a concentration of 10 mg mL−1 in D2O were prepared. NaOCl solution (0.2 mL mL−1) was added; the solution was stirred for 120 s and measured. For the reduction, ascorbic acid (12.5 mg mL−1) was added, and the solution was dialyzed against deionized water for 3 days. After freeze-drying the solid was dissolved in D2O and analyzed. For the DLS investigations, the samples for the redox response experiments were prepared as follows. Linear and star polymers were dissolved in deionized water at a concentration of 2 mg mL−1, and NaOCl solution (0.05 mL mL−1) was added. The samples were stirred for 120 s, filtered with a 0.2 μm regenerated cellulose syringe filter (Roth, Rotilabo), and analyzed. For the reduction, ascorbic acid (25 mg mL−1) was added; the sample was stirred for 1 h, filtered with a 0.2 μm regenerated cellulose syringe filter (Roth, Rotilabo), and measured. For turbidimetry investigations the polymer samples were dissolved in deionized water at a concentration of 1 mg mL−1. NaOCl solution (0.05 mL mL−1) was added, the samples were stirred for 120 s, and

CD containing polymeric building blocks can be prepared via reversible deactivation radical polymerization (RDRP) and/or modular ligation in a facile fashion,29 e.g., via copper catalyzed azide−alkyne cycloaddition and reversible addition−fragmentation chain transfer (RAFT) polymerization. Moreover, supramolecular CD chemistry allows for the modular assembly of various building blocks. Especially supramolecular star polymers are of interest that can be formed via self-assembly of core molecules and arms (Scheme 1). In addition, the supramolecular nature of CD inclusion complexes allows for the introduction of a stimuli response to the connection between arms and core, e.g., redox response if ferrocene is utilized as guest group (Scheme 1). Moreover, the polymer constituting the arms can be varied and imparted with a stimuli responsive nature as well, which leads to a multistimuli responsive star polymer. Potential applications for such stimuli responsive polymers might be in sensing, e.g., in electrochemical,65 ferric ion,66 or sugar sensing.67 Complex sensors can be obtained when the kinetics of complex formation are well-controlled. That way temperature sensors with a readout of the thermal history of the system can be designed via delayed complexation.68,69 Moreover, multistimuli responsive supramolecular systems can be utilized to store complex chemical information.70 Herein, the formation of an advanced multiresponsive supramolecular star polymer is introduced (Scheme 1), which entails individually addressable gated stimuli response. Based on a 6-fold β-CD functionalized core molecule and RAFTderived ferrocene end functionalized poly(N,N-dimethylacrylamide) (PDMA) or poly(N,N-diethylacrylamide) (PDEA), six-arm star polymers are formed via inclusion complexation. The complex formation is analyzed via dynamic light scattering (DLS), diffusion ordered spectroscopy (DOSY), nuclear Overhauser enhancement spectroscopy (NOESY), and transmission electron microscopy (TEM). Critically, the star polymers display a gated response to electrical and temperature stimulus as well as redox reagents, which is assessed via various methods including cyclic voltammetry (CV), DLS, and turbidimetry. We demonstrate that the complexes can be dissociated upon a redox or temperature stimulus as well as the addition of competing guest molecules, i.e., adamantyl derivatives. Furthermore, in the case of PDEA, the arms show thermoresponsive solubility behavior. Thus, the complexes can be transferred via temperature and redox stimuli into predefined states (refer to Scheme 1).

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EXPERIMENTAL PART

Materials. Acetone (Fisher, ACS grade), 1-adamantanecarboxylic acid (Sigma-Aldrich, 99%), ascorbic acid (Sigma-Aldrich, 99%), 2bromo-2-methylpropionic acid (Fisher, 98%), chloroform-d1 (CDCl3; Sigma-Aldrich, 99.8%), deuterium oxide (D2O; Euriso-top, 99.9%), N,N′-dicyclohexylcarbodiimide (DCC; Sigma-Aldrich, 99%), diethyl ether (Fisher, ACS grade), N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (EDC; AK Scientific, 99%), dimethyl sulfoxide-d 6 (DMSO-d 6 ; Euriso-top, 99.8%), N,N-dimethylaminopyridine (DMAP; Sigma-Aldrich, 99%), N,N-dimethylformamide (DMF; ABCR, 99%), ethanethiol (Alfa Aesar, 97%), ethylene glycol (Sigma-Aldrich, 99.8%), ethyl acetate (Fisher, ACS grade), ferrocenecarboxylic acid (FcCOOH; Fisher, 98%), hexane (Fisher, ACS grade), methanol (Fisher, ACS grade), potassium phosphate (Sigma-Aldrich, 98%), and sodium hypochlorite solution (NaOCl; Acros, 10−15% active chlorine in water) were used as received. Anhydrous dichloromethane (DCM) was purchased from Acros (extra dry over molecular sieves) and used as received. All other C


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min−1. The cloud point (Tc) was determined via evaluation of the point of inflection in the transmittance vs temperature plot. Polymer and star polymer solutions were investigated at a concentration of 1 mg mL−1 in deionized water. Cyclic voltammetry (CV) measurements were carried out with a multipotentiostat VMP2 (Princeton Applied Research) using EC-lab v6.81 software to collect the data. All measurements were carried out using an Ag/AgCl reference electrode, a Pt counter electrode, and a glassy carbon working electrode at a scan rate of 20 mV s−1 in a range of 0−0.8 V. A 50 mL five-necked round-bottom flask was used as measurement cell with aqueous LiCl solution (0.1 M) as electrolyte. The concentration of the analyte was chosen from 1.3−2.3 mg mL−1. TEM experiments were carried out on a Zeiss EM 10 electron microscope operating at 60 kV. All shown images were recorded with a slow-scan CCD camera obtained from TRS (Tröndle) in bright-field mode. Camera control was computer-aided using the ImageSP software from TRS.

turbidimetry was measured. For the reduction, ascorbic acid (25 mg mL−1) was added to the oxidized sample, and turbidimetry was measured. Samples for TEM imaging of redox response were prepared as follows: For the oxidation of linear as well as star polymers, 20 mg of the respective polymer was dissolved in deionized water (2 mL), and NaOCl solution (100 μL, 0.1 M in H2O) was added. The resulting solution was stirred overnight and then drop-casted on a carboncoated copper grid. Redox Response Investigations via Electrochemical Triggers. CV measurements with competing guest addition were performed as follows: The host−guest interaction of ferrocene functionalized polymers and β-CD6 was examined in the presence of 1-adamantanecarboxylic acid as a competing guest and monitored via CV. A solution of 32 mg of PDMA@ β-CD6 in 40 mL of 0.1 M LiCl(aq) was prepared. The analyte solution was saturated with adamantylcarboxylic acid and stirred at 40 °C overnight. As no exchange of adamantyl and ferrocene was observed by detection of free ferrocene moieties in solution, ultrasound was applied for 10 s, leading to an immediate detection of Fc/Fc+. Thermoresponsivity investigations via CV were carried out as follows: In a typical CV experiment, a solution of the analyte was prepared by dissolving 50−92 mg of polymer sample in 40 mL of the electrolyte (0.1 M LiCl(aq)). The solution was then transferred in the measurement cell and deoxygenized via nitrogen flow for 10 min. Measurements at other than ambient temperature were obtained by heating the cell in an oil bath while stirring. When the temperature had been reached, it was held for further 5 min before starting the measurement. The stirring was then switched off for the measurement itself to avoid disturbances in the electrolyte, which result in increased background noise in the recorded data. For each measurement three full cycles were recorded. Characterization Methods. 1H NMR measurements were carried out on a Bruker Ascend 400 MHz spectrometer. The same spectrometer was also employed for diffusion ordered spectroscopy (DOSY, refer to Table S1 for parameters) as well as for nuclear Overhauser enhancement spectroscopy (NOESY; pulse sequence: noesyetgp, D1 = 1.5 s and D8 = 0.1 s). Samples were measured at a concentration of 10 mg mL−1. 1H NMR spectroscopy was utilized to calculate the number-average molecular mass of the polymers synthesized via RAFT polymerization. Mn,NMR was determined by comparing the proton integrals of the unfunctionalized cyclopentadienyl (Cp) ring of the Fc group at δ = 4.2 ppm (Ha) with the integral of the polymer backbone protons (Hg) in the range 1.40 < δ < 2.05 ppm. Size exclusion chromatography (SEC) was performed on a Polymer Laboratories PL-GPC 50 Plus Integrated System, comprising an autosampler, a PLgel 5 mm bead-size guard column (50 × 7.5 mm) followed by three PLgel 5 mm MixedC columns (300 × 7.5 mm), and a differential refractive index detector using N,N-dimethylacetamide (DMAc) containing 0.03 wt % LiBr as eluent at 50 °C with a flow rate of 1.0 mL min−1. The SEC system was calibrated against linear polystyrene standards with molecular weights ranging from 1200 to 6 × 106 g mol−1. All SEC calculations were carried out relative to a polystyrene calibration. Dynamic light scattering (DLS) was performed on a Zetasizer Nano ZS light scattering apparatus (Malvern Instruments, UK) equipped with He−Ne laser (at a wavelength of 633 nm, 4 mW). The Nano ZS instrument incorporates a noninvasive backscattering (NIBS) optic with a detection angle of 173°. The polymer solutions were prepared in H2O with a concentration of 1 or 2 mg mL−1 and were subsequently filtered into quartz cuvettes. The prepared samples were stabilized prior to DLS analysis at 10 °C for 120 s. All values of the apparent hydrodynamic diameter for each polymer mixture were averaged over 20 measurements (average of 20 runs per measurement) and were automatically provided by the instrument using a cumulant analysis. Turbidimetry was performed with a UV−vis spectrometer (Nicolet UV 540) and a resolution of 0.2 nm in the indicated measurement range. Turbidity measurements were performed in a temperature range from 20 to 60 °C with a heating and cooling ramp of 0.5 °C

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RESULTS AND DISCUSSION Synthesis of Precursors. In order to investigate the formation of supramolecular star polymers, single-guest and multihost functionalized building blocks were utilized (Figure 1). As host, a multifunctional CD containing core molecule was

Figure 1. Structure of the utilized precursors.

selected (β-CD6; Figure S1).72 The arms of the stars were synthesized via RAFT polymerization, employing a ferrocenefunctionalized RAFT agent (Fc-CTA; Figure S2).48 Two types of water-soluble ferrocene functional polymers were synthesized, i.e., Fc-PDMA and Fc-PDEA. While FcPDMA is water-soluble over the entire temperature range, FcPDEA features thermoresponsive behavior, i.e., displaying lower critical solution (LCST) behavior when aqueous solutions of PDEA are heated. A variety of ferrocene end functional polymers were synthesized with different degrees of polymerization (DP), ranging from 61 to 322 for PDMA and from 84 to 370 for PDEA to study the effect of molecular mass on the self-assembly behavior (Table 1). Molecular masses ranging from 6500 to 47 500 g mol−1 (polystyrene calibration) were obtained by adjusting the CTA-to-monomer ratio. Moreover, well-defined molecular mass distributions were obtained with Đ between 1.11 and 1.17 (Figures S3−S6). The level of ferrocene functionalization was probed via 1H NMR in CDCl3, which shows the respective resonances of the ferrocene moieties and the resonances from the polymer backbones (Figures S7−S12). Self-Assembly for the Formation of Supramolecular Six-Arm Star Polymers. The self-assembly of the star polymers (pathway A in Scheme 1) was performed via the dialysis method. In brief, both building blocks were dissolved in DMF, added to each other in the respective ratio, and dialyzed D


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Macromolecules Table 1. Molecular Weight Properties of the Utilized Precursor Polymers (Figures S3−S6)

a

polymer

time [h]

M/Fc-CTA/AIBN

Mn,SECa [g mol−1]

Đa

Mn,NMRb [g mol−1]

DPNMRb

Fc-PDMA61 Fc-PDMA191 Fc-PDMA322 Fc-PDEA84 Fc-PDEA173 Fc-PDEA370

2 3 5 3 4 6

50/1.0/0.2 159/1.0/0.2 300/1.0/0.2 50/1.0/0.2 157/1.0/0.2 300/1.0/0.2

7700 19300 33800 10100 17800 31400

1.16 1.11 1.15 1.11 1.13 1.17

6500 19400 32400 11200 22500 47500

61 191 322 84 173 370

Measured via SEC in DMAC at 50 °C against polystyrene calibration. bObtained via 1H NMR in CDCl3.

Table 2. Hydrodynamic Diameters (Dh) of Precursors, Six-Arm Star Polymers before Oxidation, after Oxidation with NaOCl, and after Reduction with Ascorbic Acid polymer

Dh,crude [nm]

Dh,polymer@β‑CD6 [nm]

expansion ratio

Dh,polymer@β‑CD6 after oxidation [nm]

Dh,polymer@β‑CD6 after reduction [nm]

Fc-PDMA61a Fc-PDEA84a β-CD6a Fc-PDMA61b Fc-PDEA84b β-CD6b

3.6 4.5 3.7 5.4 7.1 4.4

6.9 8.5

1.9 1.9

12.1c 4.4

>146.3d 6.2

9.1 11.2

1.7 1.6

6.5 8.6

7.4 10.4

a Measured via DLS in water at 10 °C and 2 mg mL−1. bMeasured via DOSY in D2O at 25 °C and a concentration of 10 mg mL−1. cDue to aggregate formation see discussion. dAgglomeration

observed for distances of 4 Å and below.31,74 In the case of the inclusion complexes, the protons of host and guest moiety usually come sufficiently close to show correlation via the nuclear Overhauser effect. As shown in Figure 2 for the case of Fc-PDMA61@β-CD6 in D2O, cross-correlation resonances at the intersection of 5.0 and 3.5 ppm are present due to the close proximity of the cyclopentadienyl protons of the ferrocene groups as well as the H3 and H5 protons of β-CD, respectively. The occurrence of the corresponding cross-correlation peaks indicates a successful complex formation with similar crosscorrelations being observed for Fc-PDEA84@β-CD6 (Figure S16). The combined data obtained via DLS, DOSY, and NOESY clearly indicate that star polymer formation occurs (pathway A in Scheme 1). In the next sections, the stimuli response of the formed star polymers will be exploited. Redox Response of Supramolecular Six-Arm Star Polymers. Ferrocene/β-CD complexes are known to show redox activity; i.e., the complex can be dissociated depending on the oxidation state of the ferrocene moiety. Complex dissociation and complex formation via redox stimuli can be triggered via chemical or electrochemical means. Because of oxidation of ferrocene units to ferrocenium, the complexation between ferrocene and β-CD becomes less favorable and thus the complexes dissociate, which is an efficient way to decomplex the formed supramolecular star polymers. On the other hand, reduction of ferrocenium leads to re-formation of the complexes and thus the star polymers. In the following section the response of the star polymers with respect to chemical and electrochemical redox triggers is described (pathway B in Scheme 1). In the case of chemical triggering, NaOCl was utilized as oxidant to form ferrocenium moieties from the complexed ferrocene chain ends. Again, DLS was employed to investigate the apparent particle size after oxidation (Table 2). Indeed, a shift to lower Dh from 8.5 to 4.4 nm was observed for FcPDEA84@β-CD6 (Table 2 and Figure 3). DOSY measurements support the findings from DLS (Table 2). A decrease in Dh from 11.2 to 8.6 nm is observed, which is a comparable trend to the DLS results. Imaging via TEM shows particles with sizes

against water to induce self-assembly. Thus, effects of micelle formation of the hydrophobic guest containing polymers can be minimized, and the complexes can slowly form by equilibration. In order to study star formation, several methods were utilized. Initially, the building blocks and the formed complexes were probed via DLS (Table 2 and Table S1; Figure 3 and Figures S13 and S14). In all cases, a shift toward higher hydrodynamic diameters (Dh) was observed, e.g., from 4.6 to 6.6 nm for FcPDMA61@β-CD6 (Figure S14) or from 4.9 to 7.3 nm for FcPDEA84@β-CD6 (Figure 3). For other chain lengths of PDMA or PDEA arms, similar results were obtained (Table S2). Expansion ratios between 1.6 and 1.9 were found. It should be noted that due to the coil structure of the macromolecules in solution, an extraordinary high expansion ratio, i.e., higher than 2, cannot be expected.31 To underpin the DLS results, additional measurements assessing the particle size were performed via DOSY (Table 2). In line with the DLS results, expansion of the determined Dh after complexation was observed, yet slightly higher values for Dh and the expansion ratio were calculated. The discrepancy might be due to the measurements at different temperatures: 10 °C for DLS and 25 °C for DOSY. Moreover, differences of DLS and DOSY measurements are well-known in the literature, yet so far it was shown that the trends of both measurements are usually reliable.73 Furthermore, TEM imaging was utilized to support the findings from DLS (Figure S15). Complex structures with similar dimensions to the measured diameters from DLS were found, e.g., particles sizes below 10 nm for Fc-PDEA84@β-CD6 or 12−20 nm for Fc-PDMA61@β-CD6. In addition, the presence of aggregates composed of substructures of similar size to individual particles was evident. Overallbased on particle size measurements by DLS and DOSYit can be concluded that a size expansion occurs. Nevertheless, to illustrate that star polymer formation occurs via supramolecular complex formation, other methods have to be employed. Therefore, NOESY was utilized to study complex formation as protons in close proximity to each other show an enhanced nuclear Overhauser effect. Usually, this effect is E


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Figure 2. NOESY spectra of six-arm star polymer Fc-PDMA61@β-CD6 in D2O at 25 °C and a concentration of 10 mg mL−1: (a) before oxidation, (b) after oxidation with NaOCl, and (c) after reduction with excess ascorbic acid and dialysis.

samples for DOSY. Thus, equilibration over a longer period of time might be possible that leads to star polymer formation. Moreover, the formed superstructures were studied via TEM (Figure S15). After oxidation again particles with sizes of close to 12−20 nm are visible. Furthermore, the formed ferrocenium units can be reduced to trigger re-formation of the star polymers. In the present case, ascorbic acid was utilized as reductant. For Fc-PDEA84@β-CD6 an increase from 4.4 to 6.2 nm was observed after reduction, in line with the nonoxidized supramolecular star polymer (Figure

below 10 nm after oxidation (Figure S15), which is in line with DLS results. Moreover, aggregates are found that show a substructure consisting of particles with sizes comparable to the nonaggregated particles. Unexpectedly, after oxidation of FcPDMA61@β-CD6, an expansion from 6.0 to 12.1 nm was observed, which may be due to micelle formation (Table 2 and Figure S14). DOSY measurements contradict the findings from DLS (Table 2). Especially in the case of reduction after oxidation significant discrepancy is found, which might be due to the application of dialysis after reduction in the case of F


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Figure 3. Redox-responsive dissociation of six-arm star polymer FcPDEA84@β-CD6 at 10 °C measured via DLS at a concentration of 2 mg mL−1 before addition of NaOCl (red trace), after addition of NaOCl (blue trace), and after addition of excess ascorbic acid (green trace) as well as a linear reference sample (black trace).

ppm disappear, which is a strong indication of complex dissociation. Moreover, oxidation with ascorbic acid leads to the re-formation of the initial cross-correlation signals (Figure 2c), which is in contradiction to the DLS results. The contradicting results might be due to the application of dialysis after reduction in the case of samples for NOESY. Thus, equilibration over a longer period of time might be possible that leads to star polymer formation and the formation of crosscorrelation peaks. Similar, NOESY results after oxidation and reduction were obtained for Fc-PDEA84@β-CD6. Overall, reversible chemical redox triggered complex dissociation and re-formation was observed in the case of PDEA six-arm star polymers via NOESY, which is in line with DLS and DOSY results. Fc-PDMA61@β-CD6 does not show full reversibility in chemical redox triggered star dissociation. As redox stimuli can be triggered and studied via electrochemical methods, CV of the ferrocene functionalized homopolymers as well as the corresponding star polymers was examined (Figure 4). In the case of Fc-PDMA61, the CV trace shows an oxidation peak at 0.57 V and a reduction peak at 0.39 V. The oxidation and reduction process is occurring in a

3). Clearly Dh after re-formation of the star polymers did not match perfectly with the initial star polymer before oxidation treatment, which might be due to residual partially complexed star polymers with fewer arms. Therefore, the process is probably not completely reversible. In the case of FcPDMA61@β-CD6, the Dh increased from 12.1 to 146.3 nm after reduction, which appears to originate from agglomeration of the aggregates formed in the oxidation step (Table 2 and Figure S14). The agglomerate formation might be the preferred pathway for kinetic reasons as the oxidized species already form small aggregates; agglomeration after reduction might be the faster pathway compared to complex formation. A reason may be the formation of hydrophobic ferrocene end groups from hydrophilic ferrocenium that aggregate due to hydrophobic interactions. The formed aggregates are protected by the PDMA corona, and thus inclusion complexation is hindered that would lead to smaller star structures. Nevertheless, inclusion complexation might happen as well, as shown via NOESY (Figure 2), albeit not in a controlled way, and therefore the aggregates are not broken via inclusion complexation. Moreover, the observed effect only occurs in the case of PDMA61 arms; the balance between hydrophilicity of PDMA and ferrocenium might be the key factor in aggregate formation. During agglomerate formation, hydrophobic interactions from the restored ferrocene groups lead to more complex structures. Aggregates of Fc-PDMA61 formed after oxidation with NaOCl could be broken via ultrasonication, thus leading to Dh of 3.2−3.9 nm (Table S3 and Figure S14). Nevertheless, reduction with ascorbic acid of these oxidized Fc-PDMA61 arms in the presence of β-CD6 did not show conclusive results. Again aggregation was observed, leading to multimodal particle size distributions. It seems that ascorbic acid is not perfectly suited as reduction agent for the supramolecular star system. Therefore, only a one-way trigger is possible with ascorbic acid. Nevertheless, electrical current is an alternative mode of reduction for the ferrocenium ions. The complex dissociation can be followed via NOESY as well. As shown in Figure 2b, after oxidation of Fc-PDMA61@βCD6 with NaOCl, the cross-correlation peaks at 5.0 and 3.5

Figure 4. Investigation of the redox stimulus of six-arm star polymer via CV measured in 0.1 M LiCl at 20 mV s−1: (a) linear Fc-PDMA61 at 25 °C and Fc-PDMA61@β-CD6 at 25 °C; (b) Fc-PDMA61@β-CD6 at 92 °C and Fc-PDMA61@β-CD6 after addition of 1-adamantanecarboxylic acid (green sphere) at 25 °C. G


Article

Macromolecules reversible fashion, i.e., over 25 cycles. Interestingly, the supramolecular star polymers show a significantly different response in CV. Clearly, no oxidation or reduction peaks are observed for Fc-PDMA61@β-CD6. The effect of a low response in CV of ferrocene/β-CD complexes is well-known, although usually a weak peak potential signal is observed. Several reasons for the nondetectable oxidation and reduction signals may be cited for the present system.34,58 One reason is the decreased diffusion of the star polymers hindering the oxidation and reduction processes at the electrode. The other and more significant reason is the strength of complexation that might stop the ferrocene from being amendable for the electrode, especially in the case of the present multivalent β-CD system. In that way complexation with the multivalent β-CD core leads to a stealth effect that renders the complex nonelectrochemically addressable. In order to investigate if the signals are missing due to the complex formation, further investigations were conducted with PDMA-based stars. Addition of a competing guest molecule with higher complexation constant, namely 1-adamantanecarboxylic acid, the oxidation and reduction signals were present again, which supports the assertion that the missing signals are due to complex formation (Figure 4). Moreover, at elevated temperatures (92 °C) the signals were observed as well, which can be explained through thermal complex dissociation at higher temperatures (Figure 4).46,75 CV measurements of Fc-PDEA84 showsimilar to the PDMA caseoxidation and reduction at 0.49 and 0.39 V, respectively (Figure S17). Analogous to PDMA star polymers, Fc-PDEA84@β-CD6 shows no signals after star formation, which might be due to the same reason as for PDMA. As PDEA shows thermoresponsive behavior, the dissociation of the complexes at higher temperature could not be investigated due to the insolubility of the polymers at elevated temperatures and the associated decreased accessibility of the ferrocene moieties. Overall, redox response of the formed six-arm star polymers could be shown (pathway B in Scheme 1). In the case of PDEA arms a fully reversible process was observed. Nevertheless, for PDMA arms, DLS and TEM showed aggregation after oxidation that could not be reversed via reduction at ambient temperature. Even larger agglomerates were formed after reduction from aggregates or individual chains as shown via DLS and TEM. At higher temperatures nonsymmetrical CV behavior was observed, which might be another indication for irreversible aggregate formation. Thermoresponsivity of Supramolecular Six-Arm Star Polymers. In addition to redox response, the designed supramolecular star polymers also show thermoresponsivity. First of all, the solubility of PDEA arms can be switched from hydrophilic to hydrophobic via heating above the cloud point (Tc), where a switch from coil to globular state is observed the lower critical solution behavior. In such a way the star polymer system can be transferred into the globular state (pathway D in Scheme 1) after heating. Moreover, the star polymer can be adjusted to the nonbound and globular state (pathway C in Scheme 1) after oxidation and temperature treatment. A simple way to study the thermoresponsive behavior of PDEA in water is via turbidimetry measurements (Figure 5, Figures S18 and S19, and Table S4). The Tc of PDEA is in the range of 30−40 °C and depends strongly on the hydrophilicity of the polymer end groups.76,77 Thus, Tc can be utilized as probe for the complexation state of the ferrocene/βCD pair in the star polymers as well as the hydrophobicity of

Figure 5. Turbidimetry measurements of six-arm star polymer FcPDEA84@β-CD6 and reference samples in water at a concentration of 1 mg mL−1.

the PDEA end groups. In the case of pure linear Fc-PDEA84, a Tc of 31.0 °C was found. After complexation with β-CD6, the Tc shifts to 34.0 °C, which is expected as the hydrophobic ferrocene groups are masked via the hydrophilic 6-fold β-CD units. A reference sample shows a similar Tc of 34.6 °C. Thus, the thermoresponsive nature of the PDEA arms is preserved in the star polymers adding thermoresponsivity to the properties of the synthesized star polymers. Moreover, a combination of redox and thermoresponsivity could be observed via turbidimetry. Therefore, Fc-PDEA84@β-CD6 was treated with NaOCl, and the thermoresponsivity was checked. A shift of the Tc toward 46.3 °C was observed, which shows not only the complex dissociation of the ferrocene/β-CD but also the apparent oxidation of ferrocene. Because of oxidation, ferrocenium is formed that is positively charged. Therefore, a shift toward higher Tc is obtained as the end group is more hydrophilic than the initial Fc-PDEA sample as well as the complexed sample. In the case of PDEA173@β-CD6 and PDEA370@β-CD6 similar thermoresponsive behavior was found (Figures S18 and S19 and Table S4). Nevertheless, the observed shifts in the Tc were less pronounced, which can be explained by the longer PDEA chains that lead to a higher hydrophilic-to-hydrophobic ratio. Therefore, the effect of the end group on the Tc is weakened. Overall, the results indicate that a combination of thermoresponsivity and redox response is actually possible in the case of PDEA star polymers, and thus true multistimuli responsive star polymers are obtained. Moreover, the individual states of the star polymer can be triggered independently in a gated fashion. It is possible to switch the system to the unbound state (pathway B in Scheme 1) and then to the globular state (pathway C in Scheme 1). In addition, it is possible to switch the bound star polymers to the globular state (pathway D in Scheme 1). Unfortunately, no signals were observed in CV measurements at elevated temperatures above the Tc of the PDEA, which is probably due to the ferrocene moieties being inaccessible in the globular state. Further, the connection between core and arms itself can be disassembled via temperature treatment in the case of PDMA due to the negative complex association enthalpy (pathway E in Scheme 1).75 For PDEA-based star polymers complex dissociation after heat treatment cannot be readily observed H


Article

Macromolecules

PDMA or PDEA arms. These building blocks were utilized to form a supramolecular six-arm star via inclusion complexation. Analysis via dynamic light scattering (DLS), diffusion ordered spectroscopy (DOSY), nuclear Overhauser enhancement spectroscopy (NOESY), and transmission electron microscopy (TEM) clearly demonstrates star polymer formation. In addition, formation and disassembly of the star polymer to redox and thermal stimuli was probed via various methods, e.g., cyclic voltammetry (CV) and turbidimetry. Significantly, the presented star polymers show a gated response in aqueous solution that has the potential to advance the fields of supramolecular sensors or drug delivery.

as the PDEA arms show thermoresponsivity themselves. Although the arm-core connection might be thermoresponsive as well in the case of PDEA, this responsiveness is challenging to evidence. On the other hand, complex dissociation of FcPDMA61@β-CD6 via heating can be studied via DLS (Figure 6). Comparing the particle size distributions at 10 °C and after

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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.7b00165. Additional experimental procedures (polymerizations) and analytical data (NMR, SEC, DLS, TEM, DOSY, NOESY, CV, turbidimetry) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

Figure 6. Temperature-responsive dissociation of six-arm star polymer Fc-PDMA61@β-CD6 at 10 °C (red trace), 70 °C (blue trace), and 10 °C after heating to 70 °C (green trace) as well as a linear Fc-PDMA61 reference sample (black trace) measured via DLS at a concentration of 2 mg mL−1.

*(B.V.K.J.S.) Tel (+49) 331 5679509; Fax (+49) 331 5679502; e-mail [email protected]. *(C.J.H.) E-mail [email protected]. *(M.G.) Tel (+49) 6151 1621588; Fax (+49) 6151 1621584; e-mail [email protected]. *(C.B.K.) Tel (+49) 721 608 45641; Fax (+49) 721 608 45674; e-mail [email protected], [email protected].

heating to 70 °C for 30 min a significant shift from 6.9 to 4.4 nm is observed. The shift toward lower Dh can be explained with the expulsion of the ferrocenyl groups from the 6-fold βCD core, which leads to smaller particles in solution. After cooling to 10 °C, the initial star polymers formed again and a Dh of 6.3 nm was observed. Interestingly, the results from heat treatment of Fc-PDMA61@β-CD6 and redox treatment of FcPDMA61@β-CD6 differ significantly. Insignificant amounts of aggregates are formed in the case of heating, while aggregates and agglomerates are forming in the case of redox treatment. The different results from these two different stimuli underpin the assumption that the formation of ionic ferrocenium drives the irreversible aggregate formation. The effect of temperature-induced complex dissociation was also observed via CV (Figure 4). After heating the sample to 92 °C, weak oxidation and reduction signals were detected that did not occur at ambient temperature due to complexation. Thus, PDMA-based supramolecular stars can be triggered from the bound to the unbound state with heat (pathway E in Scheme 1). Moreover, a gated response with temperature and redox treatment is observed for PDMA stars. A switch to the unbound state or aggregates is possible depending on the utilized stimulus. Overall, the formed supramolecular six-arm star polymers show various thermoresponsive features. In the case of PDEA, the arms are thermoresponsive, while the armcore connection is thermoresponsive for PDMA.

ORCID

Bernhard V. K. J. Schmidt: 0000-0002-3580-7053 Christian Rüttiger: 0000-0003-0374-7890 Craig J. Hawker: 0000-0001-9951-851X Markus Gallei: 0000-0002-3740-5197 Christopher Barner-Kowollik: 0000-0002-6745-0570 Funding

Max-Planck Society (MPG), Karlsruhe Institute of Technology (KIT), German Academic Exchange Service (DAAD), National Science Foundation (NSF), U.S. Army Research Office (ARO), Smart Inorganic Polymer EU network (SIPS), and Hessen State Ministry of Higher Education, Research and the Arts. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS C.B.-K. acknowledges continued support from the Karlsruhe Institute of Technology (KIT) in the context of the BIFTM program as well as the Queensland University of Technology (QUT). This work was supported by the MRSEC Program of the National Science Foundation (NSF) under Award DMR1121053 (B.S., C.J.H.) and the Institute for Collaborative Biotechnologies through Grant W911NF-09-0001 from the U.S. Army Research Office (C.J.H.). The content of the information does not necessarily reflect the position or the policy of the US government, and no official endorsement should be inferred. B.S. was supported by a fellowship within the Postdoc-Program of the German Academic Exchange Service (DAAD). B.S. acknowledges financial support from the

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CONCLUSIONS In summary, the formation of a novel supramolecular star polymer system with dual gated stimuli-response is described. Individually addressable stimuli responses toward temperature and redox were achieved through a 6-fold β-CD functionalized core molecule and RAFT-derived ferrocene end functionalized I


Article

Macromolecules

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Max Planck society. M.G. acknowledges support in the frame of the Smart Inorganic Polymer EU network (COST CM10302, SIPS) and support in the frame of the LOEWE project iNAPO by the Hessen State Ministry of Higher Education, Research and the Arts. The authors acknowledge Dr. Florian Szillat (University Düsseldorf) and Prof. Helmut Ritter (University Düsseldorf) for the supply of cyclodextrin compounds as well as Dr. Pavel Levkin (KIT) for providing access to the DLS instrument.

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