Multifunctional Poly(ethylene glycol): Synthesis, Characterization, and

Apr 30, 2013 - Poly(ethylene glycol) Mw = 2000 g/mol (PEG2K) was obtained from Fluka. ...... 1526 J/mm2) (UVP Blak- Ray UV Benchtop Lamps, P/N: 95-001...
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Multifunctional Poly(ethylene glycol): Synthesis, Characterization, and Potential Applications of Dendritic−Linear−Dendritic Block Copolymer Hybrids Oliver C. J. Andrén, Marie V. Walter, Ting Yang, Anders Hult, and Michael Malkoch* School of Chemical Science and Engineering, Dept. of Fibre and Polymer Technology, KTH Royal Institute of Technology, Teknikringen. 56-58, SE-100 44 Stockholm, Sweden ABSTRACT: Emerging dendritic−linear−dendritic (DLD) hybrids that possess synergetic properties of linear and highly functional branched dendritic polymers are becoming important macromolecular scaffolds in fields ranging from biomedicine to nanotechnology. By exploiting pseudo-one-step polycondensation reactions, a facile and scalable synthetic methodology for the construction of highly functional DLDs has been developed. A library of three sets of DLDs exhibiting a hydrophilic linear PEG core with covalently attached hyperbranched bis-MPA blocks was synthesized up to the seventh generation with 256 reactive peripheral hydroxyl groups. The degree of branching for the hybrids was found between 0.40 and 0.59 with dispersities ranging from 1.03 to 1.88. The introduction of hyperbranched components resulted in control over or even full disruption of the crystallinity of the PEG. Postfunctionalizations of the peripheral hydroxyl groups with azides, allyls, and ATRP initiators yielded reactive intermediates. These intermediates were successfully assessed through UV-initiated thiol−ene coupling reactions for the synthesis of charged hybrids. ATRP of styrene from the pheriphery afforded amphiphilic macromolecules. Finally, their scaffolding capacity was evaluated for the fabrication of 3D networks, i.e., novel dendritic hydrogels and highly ordered breath figures.

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INTRODUCTION Functional nonlinear polymers such as dendritic polymers have during the past decade attracted many researchers attention. An apparent reason is strongly coupled to the branched and layered structure of dendritic materials, along with the large number of end-groups enabeling state of the art materials fit for modern society.1−6 By carefully choosing the core, the type of monomer and the chemistry used, monodisperse dendrimers and dendrons, or polydisperse dendrigrafts, linear−dendritic hybrids and hyperbanched polymers can be produced.7,8 Dendrimers are the most studied dendritic structures due to their monodisperse nature that allows researchers to accurately correlate structure and final properties.8 In comparison to linear polymers, dendrimers have a constrained globular geometry with multiple peripheral end-groups, which has resulted in a myriad of proposed applications,9 such as drug delivery vehicles,10,11 catalysis,12 biosensors,13,14 and tissue adhesives.15 An elegant example of their promise was reported by Hawker et al. describing a layer-by-layer (LbL) approach for the fabrication of ultrathin functional films. The exploitation of 2,2-bismethylolpropionic acid (bis-MPA)-based dendrimers of different generations delivered exceptionally thin layers reaching values as low as 0.46 nm per layer.16 However, the multistep synthesis of dendrimers limits their accessibility to a wider scientific audience and results in expensive products with restricted scale-up capabilities.17 This is a direct consequence of the challenging synthetic schemes for dendrimers, requiring robust chemical reactions with iterative © 2013 American Chemical Society

growth and activation steps as well as tedious purification protocols. To circumvent these obstacles, more elegant approaches are nowadays reported including accelerated synthetic methodologies which capitalize on orthogonal and robust chemical reactions that exclude any activation steps.8,18,19 In another context, the hybridization between linear and dendritic polymers results in functional scaffolds with unique combined properties of both blocks. One such example was recently described by Aida et al. in which cationically charged dendritic−linear−dendritic (DLD) hybrids based on bis-MPA dendrons and linear PEG chains were successfully constructed and evaluated as dendritic binders for the fabrication of selfhealing hydrogels by ionic interactions with clay nanoparticles.20 The introduction of a linear PEG polymer facilitates the isolation of DLD precursors via simple precipitations in nonpolar organic solvents. Nonetheless, the dendron growth still requires a controlled synthetic stratergy that results in an impressive number of iterative reaction steps. From a scale-up and accessibility point of view, DLD hybrids based on the bisMPA hyperbranched block are of apparent interest.2 The polydisperse hyperbranched polymers based on bisMPA are commercially available under the trade name Boltorn. The properties of Boltorn are similar to those of the bis-MPA Received: February 24, 2013 Revised: April 15, 2013 Published: April 30, 2013 3726

dx.doi.org/10.1021/ma4003984 | Macromolecules 2013, 46, 3726−3736

Macromolecules

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used. A conventional calibration method was created using narrow linear poly(methyl methacrylate) standards. Corrections for flow rate fluctuations were made using toluene as an internal standard. PSS WinGPC Unity software version 7.2 was used to process data. Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC820. A heating and cooling rate of 10 °C min−1 was used. Starting from room temperature (25 °C), the sample was heated to 120 °C, held there for 2 min, cooled to −30 °C, held there for 2 min, and then heated to 120 °C. Analyses regarding midpoint Tg and midpoint Tm and ΔH were performed on the second heating cycle. IR analyses were performed on a PerkinElmer Spectrum 2000 FTIR equipped with a heat controlled single reflection attenuated total reflection (ATR) accessory (Golden Gate heat controlled) from Specac Ltd. Samples were analyzed from a starting wavelength of 600 to 4000 nm. A total number of 16 scans were performed for each sample with a resolution of 4 cm−1. The background normalization was performed between the wavelengths of 600 and 4000 nm using the average of 16 scans. Normalization was performed against the CH2 bending absorbance from the PEG core found at 1445 cm−1. Atom force microscopy (AFM) images were obtained from a CSM Instruments. AFM was performed in tapping mode using AppNano probes, with a resonance frequency of 145−230 kHz and a spring constant of 20−95 N/m. The cantilever had a length of 225 μm and a radius smaller than 10 nm. Analyses of the images were performed using the freeware Gwyddion version 2.12. Field-emission scanning electron microscopy (FE-SEM) images were attained using a Hitachi S-4300 FE-SEM. Samples were sputtered with 5 nm gold prior to imaging. All tensile tests were conducted on a Universal Testing Machine Instron 5944 with an advanced noncontacting video extensometer (Instron Korea LLC) at 23 °C and 50% relative humidity using a cross-head speed of 100 mm/min. Hydrogels swollen to equilibrium were cut into a dumbbell shape; each sample was done in triplicates. The central part of the cutting die had the dimensions 20.9 × 4.3 mm. The Young’s modulus (E) was obtained from the linear region of the stress (σ) and strain (ε) curve. The modulus was calculated using Bluehill software. Swelling studies were performed at room temperature in deionized water. All measurements were performed in triplicates, and the standard deviation was displayed as error bars in the swelling profile. The hydrogel samples were dried in ambient conditions overnight and a 50 °C in vacuum oven until no further weight loss. Thereafter the samples were immersed in deionized water, and the wet weight of each sample was recorded after 0 min, 10 min, 20 min, 60 min, 90 min, and 24 h. The degree of swelling was calculated by subtracting dry weight from the wet weight and dividing by the dry weight; the result was multiplied by 100 to afford the degree of swelling in percent. Gel fraction was attained by submerging dried samples in 5 mL of chloroform; the solvent was changed every third hour for a total leeching time of 12 h. All swollen hydrogels were air-dried overnight and vacuum-dried for 5 h. The gel fractions of samples were calculated by dividing the initial weight by the final weight of the samples multiplied by 100 to attain percent. General Polycondensation Procedure between Bis-MPA and PEG. PEG was added in a two-necked round-bottom flask equipped with argon inlet, magnetic stirrer, and distillation equipment and heated to 130 °C. Every 60 min bis-MPA equivalent to one increase in dendritic generation was added along with pTSA (wt % pTSA based bis-MPA added; 1.5 wt % PEG2K, 5 wt % PEG6K, and 5 wt % PEG20K). During addition of bis-MPA, argon was flushed through the reaction vessel. When the desired generation had been reached, an additional 1 h of argon flushing was applied, after which vacuum was induced in the reaction vessel for 18 h. The resin was extracted from the reaction vessel without further purification. Generations 2 to 7 (G2−7) were synthesized according to the same reaction scheme for three different PEG molecular weights, Mw = 2000, 6000, and 20 000 g/mol. Synthesis of PEG2K-G2-OH, 1a. Prepared according to general polycondensation procedure between bis-MPA and PEG. PEG2K

dendrimers with advantages of simple chemistry and large scale production making them ideal for industrial use. A recent study by Johansson et al.21 describes the use of Boltorn in coil coating systems in which the introduction of the hyperbranched polymer led to a decrease of volatile organic compounds (VOC) such as naphtha. However, Boltorn’s poor water solubility limits its usage in a number of applications related to biomedicine, paint, and food industries.22 As a result, the peripheral hydroxyl groups of the hyperbranched polymers are further modified with hydrophilic substitutes. One such study included the pegylation of Boltorn and resulted in a promising passive drug delivery system carrying doxorubicin to target breast cancer.23 In this report, a facile strategy is described for the fabrication of a library of DLD hybrids based on water-soluble poly(ethylene glycol) (PEG) and biocompatible bis-MPA hyperbranched polymers. Their scaffolding ability is thoroughly assessed including charged hybrids as well as cross-linked hydrogels and honeycomb films.

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EXPERIMENTAL SECTION

Materials. 2,2-Bis(hydroxymethyl)propionic acid (bis-MPA) was obtained from Perstorp. (Dimethylamino)pyridine (99%) (DMAP), trifluoroacetic acid sodium salt (98%), 3-mercaptopropionic acid (99%), poly(ethylene glycol) Mw = 6000 g/mol (PEG6K) and Mw = 20 000 g/mol (PEG20K), chromium(III) acetylacetonate (97%) (Cr(3)), copper(I) bromide (Cu(I)Br, 98%), carbon disulfide (CS2, 99%), styrene (99%), N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA, 99%), and α-bromoisobutyryl bromide (Br-eBiB, 99%) were obtained from Sigma-Aldrich. Methanol-d4, chloroform-d (CDCl3) (99.8%), and dimethyl-d6 sulfoxide (99.8%) (DMSO-d6) were acquired from Cil. Chloroform (HPCL grade) (CHCl3), diethyl ether (analytical reagent grade) (ether), and toluene (HPLC grade) were acquired from Fisher Chemicals. Dichloromethane (analytical grade) (DCM) and toluene-4-sulfonic acid (98%) (pTSA) were purchased from Merck. Pyridine (99.7%) and ethanol (99%) (EtOH) were obtained from VWR. Poly(ethylene glycol) Mw = 2000 g/mol (PEG2K) was obtained from Fluka. Tris[2-(3-mercaptopropionyloxy)ethyl] isocyanurate was purchased from Wako Chemicals. 2,2Dimethoxy-1,2-diphenylethan-1-one (Irgacure 651) was purchased from Ciba. 7-(But-3-en-1-yloxy)-4-oxoheptanoic 4-(2-(but-3-en-1yloxy)ethoxy)-4-oxobutanoic anhydride (allyloxy anhydride) was synthesized according to a published procedure.24 6-Azidohexanoic anhydride (azide anhydride) was synthesized according to previously published procedure.25 Methods. Nuclear magnetic resonance (NMR) was performed on a Bruker AM NMR. 1H NMR and 13C NMR were recorded at 400 and 100 MHz, respectively. Analyses of obtained spectra were performed using MestReNova version 7.1.1-9649 (Mestrelab Research S.L 2012). The degree of branching was calculated using the Fréchet equation derived by Fréchet et al.5 According to previous work performed by Magnusson et al., the quaternary bis-MPA carbon has a chemical shift δ (ppm ((100) MHz, DMSO-d6)) of 50.1 for terminal, 49.4 for unreacted bis-MPA, 48.2 for linear, 47.5 for linear acid, and 46.2 for dendritic.25 13C NMR spectroscopy was performed by dissolving 100 mg of sample in 1 mL of CDCl3 D6. 1H NMR spectroscopy was performed by dissolving 10−20 mg of sample in 1 mL of CDCl3 D6 or MeOD D4. Quantitative 13C NMR was performed by dissolving 15 mg of Cr(3) and 150 mg of sample in 1 mL of DMSO D6. An inverse gated decoupling method was used with 2048 scans and a relaxation time of 5 s. SEC was performed in dimethylformamide (DMF) (0.2 mL min−1) with 0.01 M LiBr as the mobile phase at 35 °C using a TOSOH EcoSEC HLC-8320GPC system equipped with an EcoSEC RI detector and three columns (PSS PFG 5 μm; Microguard, 100 Å and 300 Å) (MW resolving range: 300−100 000 Da) from PSS GmbH. Sample solutions with a concentration of 2.5 mg/mL were 3727

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Macromolecules

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MPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 17 635 g/mol, Đ = 1.66). Synthesis of PEG2K-G7-OH, 6. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG2K (0.90 mmol, 1.80 g), bis-MPA (254 equiv, 228 mmol, 30.7 g), and pTSA (1.5 wt %, 450 mg). The product 6 was collected as a transparent solid (84%, 18.7 g). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 4.95−4.07 (q, 508H, −CH2−OCO−, (bis-MPA)), 3.50 (q, 186.2H, CH2−CH2−O−, (PEG)), 1.17−1.01 (q, 762H, −CH3, (BisMPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis-MPA)), 69.76 (2C, CH2−CH2−O−, (PEG)), 63.7− 63.6 (1C, −CH2− (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 37 642 g/mol, Đ = 1.64). Synthesis of PEG6K-G2-OH, 7. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG6K (2.5 mmol, 15.0 g), bis-MPA (6 equiv, 15.0 mmol, 2.01 g), and pTSA (5 wt %, 100.6 mg). The product 7 was collected as a yellow viscous solid (81%, 14.1 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.30 (q, 12H, −CH2−OCO−, (bis-MPA)), 3.63 (q, 556.5, CH2−CH2−O−, (PEG)), 1.47−1.18 (q, 18H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis-MPA)), 69.75 (2C, CH2−CH2−O− (PEG)), 65.4−63.6 (1C, −CH2−, (bisMPA)), 50.2 (1C, −COO−C−((CH2− OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.8−16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 4554 g/mol, Đ = 1.42). DSC (Tm = 52.9 °C). Synthesis of PEG6K-G3-OH, 8. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG6K (1.00 mmol, 6.00 g), bis-MPA (14 equiv, 14.0 mmol, 1.88 g), and pTSA (5 wt %, 93.9 mg). The product 8 was collected as white viscous solid (83%, 6.33 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.41−3.31 (q, 28H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 556.5H, CH2−CH2− O−, (PEG)), 1.21−1.05 (q, 42H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis- MPA)), 69.75 (2C, CH2−CH2−O−, (PEG)), 65.4−63.6 (1C, −CH2−, (bisMPA)), 50.2 (1C, −COO−C−((CH2− OH)2, CH3) (bis-MPA)), 49.5 (1C,−COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C,−COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.8−16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 6494 g/mol, Đ = 1.30). DSC (Tm = 48.8 °C). Synthesis of PEG6K-G4-OH, 9. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG6K (1.70 mmol, 10.0 g), bis-MPA (30 equiv, 50.0 mmol, 6.71 g), pTSA (5 wt %, 335 mg). The product 9 was collected as a white solid (91.5%, 14.5 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 3.32 (q, 60H, −CH2− OCO−, (bis-MPA)), 3.62 (q, 556.5H, CH2−CH2−O−, (PEG)), 1.19−1.05 (q, 90H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis- MPA)), 69.75 (2C, CH2−CH2−O−, (PEG)), 65.4−63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2− OH)2, CH3) (bis-MPA)), 49.5 (1C,− COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C− (CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C, −COO− C−((CH2−OR)2, CH3) (bis-MPA)), 16.8−16.7 (1C, −CH3 (bisMPA)). SEC (Mw = 11 093 g/mol, Đ = 1.17). DSC (Tm = 48.0 °C). Synthesis of PEG6K-G5-OH, 10. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG6K (1.33 mmol, 8.00 g), bis-MPA (62 equiv, 82.7 mmol, 11.1 g), and pTSA (5 wt %, 554 mg). The product 10 was collected as a white transparent solid (83%, 14.7 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.27−3.201 (q, 124H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 556.5H, CH2−CH2−O−, (PEG)), 1.23−1.09 (q, 186H, −CH3, (BisMPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis-MPA)), 69.75 (2C, CH2−CH2−O−, (PEG)), 65.4− 63.6 (1C, −CH2− (bis-MPA)), 50.2 (1C, −COO−C−((CH2− OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bis-

(2.50 mmol, 5.00 g), bis-MPA (6 equiv, 15.0 mmol, 2.01 g), and pTSA (1.5 wt %, 30.2 mg). The product 1 was collected as a yellow viscous solid (84%, 5.70 g). 1H NMR (400 MHz, MeOD): δ (ppm) 4.23 (q, 12H, −CH2−OCO−, (bis-MPA)), 3.64 (q, 12H, CH2−CH2−O−, (PEG)), 1.22−1.15 (q, 18H, −CH3, (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.5−173.2 (6C, −COO− (bis-MPA)), 69.75 (91C, CH2−CH2−O−, (PEG)), 65.2−63.6 (1C, −CH2−, (bisMPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, − CH3 (bis-MPA)). SEC (Mw = 3562 g/mol, Đ = 1.02). DSC (Tm = 45.58 °C). Synthesis of PEG2K-G3-OH, 2. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG2k (2.00 mmol, 4.00 g). Bis-MPA (14 equiv, 28.0 mmol, 3.75 g), pTSA (1.5 wt %, 56.3 mg). The product 2 was collected as a white viscous solid (81%, 5.97 g). 1H NMR (400 MHz, MeOD): δ (ppm) 4.29− 3.24 (q,28H, −CH2−OCO−, (bis-MPA)), 3.64 (q, 28H, CH2−CH2− O− (PEG)), 1.28−1.15 (q, 42H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 175.2−173.0 (1C, −COO−, (bis-MPA)), 69.76 (2C, CH2−CH2−O−, (PEG)), 63.7−63.6 (1C, −CH2−, (bisMPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 4170 g/mol, Đ = 1.03). DSC (Tm = 35.18 °C). Synthesis of PEG2K-G4-OH, 3. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG2K (1.50 mmol, 3.00 g), bis-MPA (30 equiv, 45.0 mmol, 6.03 g), and pTSA (1.5 wt %, 90.5 mg). The product 3 was collected as a transparent viscous solid (73%, 5.45 g). 1H NMR (400 MHz, MeOD): δ (ppm) 4.32−3.26 (q, 60H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 186.2H, CH2−CH2−O−, (PEG)), 1.30−1.15 (q, 90H, −CH3, (BisMPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.8 (1C, −COO− (bis-MPA)), 69.76 (2C, CH2−CH2−O−, (PEG)), 63.7− 63.6 (1C, −CH2− (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 4744 g/mol, Đ = 1.05). Synthesis of PEG2K-G5-OH, 4. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG2K (1.00 mmol, 2.00 g), bis-MPA (62 equiv, 62.0 mmol, 8.31 g), and pTSA (1.5 wt %, 125 mg). The product 5 was collected as a transparent solid (83%, 7.76 g). 1H NMR (400 MHz, MeOD): δ (ppm) 4.30−3.27 (q, 124H, −CH2−OCO− (bis-MPA)), 3.64 (q, 186.2H, CH2−CH2−O−, (PEG)), 1.20−1015 (q, 186H, −CH3, (BisMPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.8 (1C, −COO−, (bis-MPA)), 69.76 (2C, CH2−CH2−O−, (PEG)), 63.7− 63.6 (1C, −CH2− (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bisMPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 6648 g/mol, Đ = 1.19). Synthesis of PEG2K-G6-OH, 5. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG2K (0.90 mmol, 1.80 g), bis-MPA (126 equiv, 116 mmol, 15.2 g), and pTSA (1.5 wt %, 228 mg). The product 5 was collected as a transparent solid (86%, 13.2 g). 1H NMR (400 MHz, MeOD): δ (ppm) 4.30−3.24 (q, 252H, −CH2−OCO−, (bis-MPA)), 3.64 (q, 186.2H, CH2−CH2−O−, (PEG)), 1.30−1.15 (q, 378H, −CH3, (BisMPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis-MPA)), 69.76 (2C, CH2−CH2−O−, (PEG)), 63.7− 63.6 (1C, −CH2− (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bis3728

dx.doi.org/10.1021/ma4003984 | Macromolecules 2013, 46, 3726−3736

Macromolecules

Article

MPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bis− MPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.8−16.7 (1C, −CH3 (bis−MPA)). SEC (Mw = 16 379 g/mol, Đ = 1.28). DSC (Tm = 46.4 °C). Synthesis of PEG6K-G6-OH, 11. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG6K (1.00 mmol, 6.00 g), bis-MPA (126 equiv, 126 mmol, 16.9 g), and pTSA (5 wt %, 845 mg). The product 11 was collected as a milky glassy solid (76.5%, 15.8 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.27 (q, 252H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 556.5H, CH2− CH2−O−, (PEG)), 1.23−1.06 (q, 378H, −CH3, (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis-MPA)), 69.75 (2C, CH2−CH2−O− (PEG)), 65.4−63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.8−16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 29 110 g/mol, Đ = 1.88). Synthesis of PEG6K-G7-OH, 12. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG6K (1.00 mmol, 6.00 g), bis-MPA (254 equiv, 254 mmol, 34.1 g), and pTSA (5 wt %, 1.70 g). The product 12 was collected as a lightly yellow glassy solid (78%, 27.6 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.06−3.76 (q, 508H, −CH2−OCO− (bis-MPA)), 3.45 (q, 556.5H, CH2−CH2−O−, (PEG)), 1.09−0.93 (q, 762H, −CH3 (BisMPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.2−171.6 (1C, −COO− (bis-MPA)), 69.75 (2C, CH2−CH2−O−, (PEG)), 65.4− 63.6 (1C, −CH2− (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.8−16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 99 508 g/mol, Đ = 1.66). Synthesis of PEG20K-G2-OH, 13. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG20K (0.75 mmol, 15.0 g), bis-MPA (6 equiv, 4.50 mmol, 0.60 g), and pTSA (5 wt %, 30.2 mg). The product 13 was collected as a white solid (92%, 14.3 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.03 (q, 12H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 1828H, CH2−CH2−O−, (PEG)), 1.23−1.11 (q, 18H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 173.8−172.6 (1C, −COO−, (bis-MPA)), 69.71 (2C, CH2−CH2−O− (PEG)), 63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO− C−(CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bisMPA)). SEC (Mw = 37 564 g/mol, Đ = 1.03). DSC (Tm = 62.6 °C). Synthesis of PEG20K-G3-OH, 14. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG20K (5.00 mmol, 100 g), bis-MPA (14 equiv, 70.0 mmol, 9.38 g), and pTSA (5 wt %, 469 mg). The product 14 was collected as a white solid (93.4%, 102.12 g). 1H NMR (400 MHz, MeOD): δ (ppm) 4.24−3.80 (q, 28H, −CH2−OCO−, (bis-MPA)), 3.64 (q, 1828, CH2−CH2−O−, (PEG)), 1.18−1.14 (q, 42H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 173.8−172.6 (1C, −COO− (bis-MPA)), 69.71 (2C, CH2−CH2−O− (PEG)), 63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C,− COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C− (CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C,−COO−C− ((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, − CH3 (bis-MPA)). SEC (Mw = 34 671 g/mol, Đ = 1.15). DSC (Tm = 58.8 °C). Synthesis of PEG20K-G4-OH, 15. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG20K (0.50 mmol, 10.0 g,), bis-MPA (30 equiv, 15.0 mmol, 2.02 g), and pTSA (5 wt %, 101 mg). The product 15 was collected as a white solid (84.7%, 9.91 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.32−3.85 (q, 60H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 1828H, CH2−CH2−O− (PEG)), 1.23−1.08 (q, 90H, −CH3, (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 173.8−172.6 (1C, −COO− (bis-MPA)),

69.71 (2C, CH2−CH2−O−, (PEG)), 63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C,− COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C− (CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C,−COO−C− ((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 15 455 g/mol, Đ = 1.41). DSC (Tm = 53.5 °C). Synthesis of PEG20K-G5-OH, 16. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG20K (0.50 mmol, 10.0 g), bis-MPA (62 equiv, 31.0 mmol, 4.16 g), and pTSA (5 wt %, 208 mg). The product 16 was collected as a white solid (85.5%, 11.6 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.31−3.80 (q, 124H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 1828H, CH2−CH2−O− (PEG)), 1.18−0.95 (q, 186H, −CH3, (Bis-MPA)). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 173.8−172.6 (1C, −COO− (bis-MPA)), 69.71 (2C, CH2−CH2−O−, (PEG)), 63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C,− COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C− (CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C,−COO−C− ((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 17 553 g/mol, Đ = 1.71). DSC (Tm = 52.3 °C). Synthesis of PEG20K-G6-OH, 17. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG20K (0.50 mmol, 10.0 g), bis-MPA (126 equiv, 63.0 mmol, 8.45 g), and pTSA (5 wt %, 422 mg). The product 17 was collected as a yellow glassy solid (85%, 14.7 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.29−3.81 (q, 252H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 1828H, CH2−CH2−O−, (PEG)), 1.23−1.05 (q, 372H, −CH3 (Bis-MPA)). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 173.8−172.6 (1C, −COO− (bis-MPA)), 69.71 (2C, CH2−CH2−O− (PEG)), 63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C,−COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)).) SEC (Mw = 19 606 g/mol, Đ = 1.55). DSC (Tm = 51.4 °C). Synthesis of PEG20K-G7-OH, 18. Prepared according to general polycondensation procedure between bis-MPA and PEG, PEG20K (0.40 mmol, 8.00 g), bis-MPA (254 equiv, 102 mmol, 13.6 g), and pTSA (5 wt %, 681 mg). The product 18 was collected as a yellow glassy solid (77%, 15.1 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.26−3.80 (q, 508H, −CH2−OCO−, (bis-MPA)), 3.62 (q, 1828H, CH2−CH2−O−, (PEG)), 1.16−1.05 (q, 762H, −CH3, (Bis-MPA)). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 173.8−172.6 (1C, −COO−, (bis-MPA)), 69.71 (2C, CH2−CH2−O−, (PEG)), 63.6 (1C, −CH2−, (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C,−COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C,−COO−C−((CH2−OR)2, CH3) (bis-MPA)), 16.7 (1C, −CH3 (bis-MPA)). SEC (Mw = 18 383 g/mol, Đ = 1.72). DSC (Tm = 44.6 °C). Synthesis of PEG6K-G4-Allyl, 19. DLD hybrid 9 (0.32 mmol, 3.00 g), pyridine (3 equiv/OH, 2.02 mmol, 2.44 mL), allyloxy anhydride (1.5 equiv/OH, 15.2 mmol, 5.87 g), and DMAP (0.2 equiv/ OH, 2.02 mmol, 247 mg) were dissolved in DCM in a round-bottom flask equipped with a magnetic stirrer. The reaction was allowed to proceed for 24 h and monitored with 13C NMR. Residual anhydride was quenched with water. Product was isolated by extraction with aqueous Na2CO3 (10 wt %) and NaHSO4 (10 wt %), dried with MgSO4, and solvent evaporated in vacuo. Product 19 was collected as a white solid (2.76 g, 74%). 1H NMR (400 MHz, CDCl3): δ (ppm) 6.87 (q, 31.6H, −CH (allyl)), 5.28−5.17 (q, 63H, −CHCH2 (allyl)), 5.27−5.18 (q, 64H, CH2−O (allyl)), 4.21 (q, 60H, −CH2− OCO− (bis-MPA)), 3.31 (s, 556H, CH2−CH2−O− (PEG)), 2.60 (q, 64H, CH2−CHCH2 (allyl)), 1.20−1.09 (q, 90H, −CH3 (BisMPA)). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.3 (1C, −COO− (allyl)), 171.8 (1C, −COO− (bis-MPA, Allyl)), 138.3 (1C, −C (allyl)), 117.6 (1C, CH2 (allyl)), 72.3 (1C, −CH2−O (allyl)), 70.75 (2C, −CH2−CH2−O (PEG)), 68.0−64.1 (1C, −CH2−O (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C,− COOH−C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C− 3729

dx.doi.org/10.1021/ma4003984 | Macromolecules 2013, 46, 3726−3736

Macromolecules

Article

−CH2−O (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C,−COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C, −COO−C−((CH2−OR)2, CH3) (bis-MPA)), 29.7 (1C, −CH2−CC (allyl)), 29.0 (1C, −CH2−COO (allyl)) 17.8 (1C, −CH3 (bis-MPA)). SEC (Mw = 25 185 g/mol, Đ = 1.29). Synthesis of PEG6K-G4-Azide, 23. DLD hybrid 3 (0.05 mmol, 440 mg), pyridine (3 equiv/OH, 4.46 mmol, 0.36 mL), azide anhydride (1.5 equiv/OH, 2.22 mmol, 659 mg), and DMAP (0.2 equiv/OH, 0.29 mmol, 36.3 mg) were dissolved in DCM in a roundbottom flask equipped with a magnetic stirrer The reaction was allowed to proceed for 24 h and monitored with 13C NMR. Residual anhydride was quenched with water. Product was isolated by extraction with aqueous Na2CO3 (10 wt %) and NaHSO4 (10 wt %), dried with MgSO4, and solvent evaporated in vacuo. Product 23 was collected as a white solid (83.1 mg, 12%). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.67 (s, 128H, −CH2−N3, COOR−CH2 (azide)), 4.22−2.19 (q, 120H, −CH2−O, (bis-MPA)), 3.61 (q, 120H, −CH2− CH2− (PEG)), 2.65 (q, 120H, −CH2−CH2−CH2− (azide), 2.45 (q, 32H, −CH2− CH2− CH2− (azide), 1.20 (q, 90H, −CH3 (Bis-MPA)). SEC (Mw = 12 147 g/mol, Đ = 1.10). Synthesis of PEG2K-G4-ebib, 24. DLD hybrid 3 (1 equiv, 0.33 mmol, 2.00 g), TEA (24 equiv, 13.2 mmol, 1.34 g), and DMAP (3.2 equiv, 1.77 mmol, 216 mg) were dissolved in 40 mL of THF in a round-bottom flask. α-Bromoisobutyryl bromide (1.2 equiv, 10.6 mmol, 1.30 mL) was dissolved in 10 mL of THF and slowly added to the previous solution. A white gas and white salt formed, and the reaction was allowed to react overnight. The raw reaction mixture was filtered. Product was isolated by extraction with aqueous Na2CO3 (10 wt %) and saturated NaCl and dried with MgSO4. Subsequently, it was passed through a neutral Al2O3 column and solvent evaporated in vacuo. Product 24 was collected as an orange viscous oily liquid (2.1 g, 65.3%). SEC (Mw = 4643 g/mol, Đ = 1.12). ATRP Polymerization of PEG2K-G4-ebib-Styrene-3K, 25. Compound 24 (1 equiv, 0.033 mmol, 200 mg) was dissolved in 3.6 mL of toluene in a round-bottom flask. Subsequently, styrene (922.2 equiv, 30.7 mmol, 3.2 g) and PMDETA (32 equiv, 1.1 mmol, 184.4 mg) were added. Two vacuum/argon degassing cycles were performed. CuBr(I) (16 equiv, 0.53 mmol, 71,5 mg) was added, and degassing cycles were repeated. The reaction vessel was lowered into a 60 °C preheated oil bath, and the reaction was monitored by 1H NMR. After 2 h the reaction had proceeded to 54% and was terminated by exposure to air and addition of DCM. The raw reaction mixture was passed through a neutral Al2O3 column and precipitated into cooled diethyl ether. Product was collected as a white powder (2.4 g, 54%). SEC (Mw = 4495 g/mol, Đ = 1.43). PEG20K-G3-COOH, 26. DLD hybrid 21 (1 equiv, 0.06 mmol, 1.5 g) was dissolved in chloroform. 3-Mercaptopropionic acid (19.2 equiv, 1.4 mmol, 128.0 mg) and 2,2-dimethoxy-2-phenylacetophenone (DMPA, 1 wt %, 1.60 mg) were added. The solution was irradiated at 365 nm for 60 min (dosage = 1526 J/mm2) (UVP Blak- Ray UV Benchtop Lamps, P/N: 95-00127-20M, 665 nm, 230 V, 50 Hz). The reaction was monitored with 1H NMR. When full consumption of allyl functionality was observed, the reaction was stopped. The reaction mixture was concentrated and precipitated in ether. Product was collected as a white solid (960.0 mg, 60%). SEC (Mw = 18 736 g/mol, Đ = 1.23). Preparation of Hydrogels. PEG20K-G3-allyl 20 and PEG20KG4-allyl 21 were mixed in equimolar amounts (allyl:thiol) with TMPtris-thiol or triazine-tris-thiol and dissolved in EtOH (solid content of 50 wt %). 3 wt % of Irgacure 651 based on solid weight was added as initiator, and the solutions were vortexed to clear solutions. The viscous mixtures were drop-cast in a Teflon mold (thickness 0.10 cm, length 1.0 cm, width 1.0 cm) and covered with a glass slide. After 5 min of UV-curing at ambient conditions (total exposure: 5 min, 365 nm, 28.5 mW/cm2, Black-Ray xx-15BlB UV benchtop lamp) fully cross-linked gels were obtained. All gels were leached in H2O and EtOH for 5 and 3 h, respectively, and dried in ambient conditions overnight and then in a vacuum oven (50 °C) for 1 h. A total of four different hydrogels were prepared of which two were based on TMP

(CH2−OH, CH3, CH2−OR) (bis-MPA)), 46.2, 45.5 (1C,−COO−C− ((CH2−OR)2, CH3) (bis-MPA)), 29.7 (1C, −CH2−CC (allyl)), 29.0 (1C, −CH2−COO (allyl)) 17.8 (1C, −CH3 (bis-MPA)). SEC (Mw = 11 681 g/mol, Đ = 1.26). Synthesis of PEG20K-G2-Allyl, 20. DLD hybrid 13 (0.48 mmol, 10.0 g), pyridine (3 equiv/OH, 11.6 mmol, 0.93 mL), allyloxy anhydride (1.5 equiv/OH, 5.8 mmol, 3.36 g), and DMAP (0.2 equiv/ OH, 0.77 mmol, 94.4 mg) were dissolved in DCM in a round-bottom flask equipped with a magnetic stirrer The reaction was allowed to proceed for 24 h and monitored with 13C NMR. Residual anhydride was quenched with water. Product was isolated by extraction with aqueous Na2CO3 (10 wt %) and NaHSO4 (10 wt %), dried with MgSO4 and solvent evaporated in vacuo. Product 20 was collected as a white solid (8.16 g, 74%). 1H NMR (400 MHz, CDCl3): δ (ppm) 6.54 (q, 8H, −CH (allyl)), 5.27−5.18 (q, 16H, −CHCH2 (allyl)), 5.27−5.18 (q, 16H, CH2−O (allyl)), 4.21 (q, 12H, −CH2−OCO− (bis-MPA)), 3.31 (s, 1828H, CH2−CH2−O− (PEG)), 2.60 (q, 64H, CH2−CHCH2 (allyl)), 1.20−1.09 (q, 18H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.3 (1C, −COO− (allyl)), 172 (1C, −COO− (bis-MPA, allyl)), 138.3 (1C, −C (allyl)), 117.6 (1C, CH2 (allyl)), 72.3 (1C, −CH2−O (allyl)), 70.75 (2C, −CH2− CH2−O (PEG)), 68.0−64.1 (1C, −CH2−O (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH− C−((CH2−OR)2, CH3) (bis-MPA)), 48.1 (1C, −COO−C−(CH2− OH, CH3, CH2−OR) (bis−MPA)), 46.2, 45.5 (1C,−COO−C− ((CH2−OR)2, CH3) (bis-MPA)), 29.7 (1C, −CH2−CC (allyl)), 29.0 (1C, −CH2−COO (allyl)) 17.8 (1C, −CH3 (bis-MPA)). SEC (Mw = 21 605 g/mol, Đ = 1.30). Synthesis of PEG20K-G3-Allyl, 21. DLD hybrid 14 (1. 39 mmol, 30.0 g), pyridine (3 equiv/OH, 6.65 mmol, 5.26 mL), allyloxy anhydride (1.5 equiv/OH, 3.33 mmol, 19.3 g), and DMAP (0.2 equiv/ OH, 0.44 mmol, 542 mg) were dissolved in DCM in a round-bottom flask equipped with a magnetic stirrer The reaction was allowed to proceed for 24 h and monitored with 13C NMR. Residual anhydride was quenched with water. Product was isolated by extraction with aqueous Na2CO3 (10 wt %) and NaHSO4 (10 wt %), dried with MgSO4, and solvent evaporated in vacuo. Product 21 was collected as a white solid (27.5 g, 80%). 1H NMR (400 MHz, CDCl3): δ (ppm) 6.54 (q, 16H, −CH (allyl)), 5.27−5.18 (q, 32H, −CHCH2 (allyl)), 5.27−5.18 (q, 32H, −CH2−OCO− (allyl)), 4.21 (q, 56H, −CH2−OCO− (bis-MPA)), 3.31 (s, 1828H, CH2−CH2−O− (PEG)), 2.60 (q, 64H, CH2−CHCH2 (allyl)), 1.20−1.09 (q, 42H, −CH3 (Bis-MPA)). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.3 (1C, −COO− (allyl)), 171.8 (1C, −COO−, (bis-MPA, allyl)), 138.3 (1C, −C (allyl)), 117.6 (1C, CH2 (allyl)), 72.3 (1C, −CH2−O (allyl)), 70.75 (2C, −CH2−CH2−O (PEG)), 68.0−64.1 (1C, −CH2−O (bis-MPA)), 50.2 (1C, −COO−C−((CH2−OH)2, CH3) (bis-MPA)), 49.5 (1C, −COOH−C−((CH2−OR)2, CH3) (bisMPA)), 48.1 (1C, −COO−C−(CH2−OH, CH3, CH2−OR) (bisMPA)), 46.2, 45.5 (1C,−COO−C−((CH2−OR)2, CH3) (bis-MPA)), 29.7 (1C, −CH2−CC (allyl)), 29.0 (1C, −CH2−COO, (Allyl)) 17.8 (1C, −CH3 (bis-MPA)). SEC (Mw = 29 100 g/mol, Đ = 1.12). Synthesis of PEG20K-G4-Allyl, 22. DLD hybrid 15 (0.21 mmol, 5.0 g), pyridine (3 equiv/OH, 20.4 mmol, 1.60 mL), allyloxy anhydride (1.5 equiv/OH, 10.2 mmol, 5.92 g), and DMAP (0.2 equiv/OH, 1.36 mmol, 166 mg) were dissolved in DCM in a roundbottom flask equipped with a magnetic stirrer The reaction was allowed to proceed for 24 h and monitored with 13C NMR. Residual anhydride was quenched with water. Product was isolated by extraction with aqueous Na2CO3 (10 wt %) and NaHSO4 (10 wt %), dried with MgSO4 and solvent evaporated in vacuo. Product 22 was collected as a white solid (6.33 g, 98.1%). 1H NMR (400 MHz, CDCl3): δ (ppm) 6.87 (q, 32H, −CH (allyl)), 5.28−5.17 (q, 64H, −CHCH2 (allyl)), 5.27−5.18 (q, 64H, CH2−O (allyl)), 4.21 (q, 60H, −CH2−OCO− (bis−MPA)), 3.31 (s, 1828H, −CH2−CH2−O− (PEG)), 2.60 (q, 64H, CH2−CHCH2 (allyl)), 1.20−1.09 (q, 90H, −CH3, (Bis-MPA)). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.3 (1C, −COO− (allyl)), 171.8 (1C, −COO− (bis-MPA, allyl)), 138.3 (1C, −C (allyl)), 117.6 (1C, CH2 (allyl)), 72.3 (1C, −CH2−O (allyl)), 70.75 (2C, −CH2−CH2−O− (PEG)), 68.0−64.1 (1C, 3730

dx.doi.org/10.1021/ma4003984 | Macromolecules 2013, 46, 3726−3736

Macromolecules

Article

Table 1. Material Data for Compounds 1−26 Including Core Molecular Weight, Functional Groups, Generation, Molecular Weight, Degree of Branching, Dispersity Index, and Thermal Properties Mn [g/mol] sample

Mn PEG core [g/mol]

pseudo generation

no. of functional groups (theor)

NMR

theor

SEC

DB

Đ

Tm [°C]

ΔH [J/g]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

2000 2000 2000 2000 2000 2000 6000 6000 6000 6000 6000 6000 20000 20000 20000 20000 20000 20000

2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7

8 16 32 64 128 256 8 16 32 64 128 256 8 16 32 64 128 256

2694 3510 5801 9194 16623 31330 6624 7636 9480 13182 20936 35168 20604 21625 23659 27454 34641 49503

2696.7 3625.6 5483.4 9199.1 16630.5 31493.2 6696.7 7625.6 9483.4 13199.1 20630.5 35493.2 20696.7 21625.6 23483.4 27199.1 34630.5 49493.2

3469 4041 4486 5579 10619 22814 3204 4982 9420 12718 15446 59885 36308 32086 10890 10277 12629 10639

0.59 0.51 0.53 0.42 0.40 0.42

1.03 1.03 1.06 1.19 1.66 1.65 1.42 1.30 1.18 1.29 1.88 1.66 1.03 1.08 1.42 1.71 1.55 1.73

45.6 35.2

76.2 52.8

52.9 48.8 48.0 46.4

139.3 91.8 74.5 38.3

62.6 58.8 53.5 52.3 51.4 44.6

155.5 141.3 111.1 90.5 64.2 2.9

0.50 0.43 0.47 0.41 0.46 0.51 0.44 0.48 0.45 0.478

Figure 1. Overall synthetic strategy for the polycondensation of DLD hybrids. cross-linker (PEG20K-G3-TMP hydrogel 27 and PEG20K-G4-TMP hydrogel 28), and two were based on triazine cross-linker (PEG20KG3-triazine hydrogel 29 and PEG20K-G4-triazine hydrogel 30). Fabrication of Honeycomb Membranes. Polystyrene functionalized DLD 26 was dissolved in carbon disulfide (CS2) at a concentration of 10 mg/mL. 25 μL of solution was deposited on a glass substrate placed in a chamber with a relative humidity of 90%. The volatile solvent was allowed to evaporate, and an opaque film was obtained. The films were thoroughly analyzed with optical microscopy, FE-SEM, and AFM.

2 to 7, (2) theoretical number of functional groups from 8 up to 256 hydroxyls per DLD hybrid, and (3) theoretical molecular weight reaching up to 49 500 g/mol (Table 1). All DLDs were straightforwardly constructed in up to 100 g scale and with yields of ≥90% using a stepwise monomer feed approach since it favors the attachment of bis-MPA to the PEG core and prevents the formation of free hyperbranched polymer.26 Initially, the second generation DLDs 1, 7, and 13 were targeted, and the hydrophilic PEG core and the AB2 monomer were mixed at a 1 to 6 molar ratio (PEG:bis-MPA) with 1 h in between each generation addition. One hour polycondensation reaction at 130 °C using 1.5 to 5 wt % of pTSA as an acidic catalyst in inert argon atmosphere was found sufficient to generate DLD materials. Generation increase was accomplished via slow monomer feed at 1 h cycles which enabled the seventh generation DLDs 6, 12, and 18 to be constructed in 7 h (Figure 1). After reaching the satisfied hybrid material, an overnight vacuum cycle procedure enabled removal of water and drove the reaction to completion. It should be noted that the choice of acid was carefully evaluated; stronger acids such as hydrochloric acid or sulfuric acid were found to result in uncontrolled condensation reactions with irreversible cross-links as an

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RESULTS AND DISCUSSION To date, hyperbranched polymers based on bis-MPA have been reported to include simple cores such as trimethylolpropane, PP50, and glycerol.26 To demonstrate the scaffolding potential of hyperbranched bis-MPA polymers with a linear polymer component as core, dendritic−linear−dendritic (DLD) hyperbranched hybrids were produced with the readily available biocompatible PEG as a linear hydrophilic core (2000, 6000, and 20 000 g/mol). An acid-catalyzed pseudo-one-step condensation esterification methodology enabled the construction of a library of hydroxyl functional DLD hybrids comprising 18 materials that covered (1) hybrids of generation 3731

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Figure 2. (a) Quantitative 13C NMR of PEG2K-G7-OH (6) in DMSO. (b) Zoom of carbonyl region 170−180 ppm. (c) Zoom of quaternary carbon region 45−51 ppm. (d) 1H NMR of PEG20K-G7-OH (18) in CDCl3.

Figure 3. (a) Zoom of the carbonyl region in IR spectra for compounds PEG6K-Gx-OH (7−12) and bis-MPA monomer. The spectra were normalized against the CH2 bending absorbance from the PEG core found at 1445 cm−1. (b) DB values calculated from inverse gated decoupling 13C NMR spectra for PEG2K-Gx-OH (1−6), PEG6K-Gx-OH (7−12), and PEG20K-Gx-OH (13−18). (c) Molecular weight obtained by SEC, calculated from 1H NMR, and theoretical molecular weight for PEG2K-Gx-OH (1−6) series.

Figure 4. (a) Enthalpy of melting and (b) melting temperature plotted against generation for PEG2K-Gx-OH (1−6), PEG6K-Gx-OH (7−12), and PEG20K-Gx-OH (13−18). 3732

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Figure 5. Scheme describing postfunctionalizations of DLD hybrids, where two different routes were explored: (1) addition of allyl or azide moieties for further coupeling/click reactions; (2) polymerization of styrene from the periphery via ATRP. Allyl moieties from (1) where used to form hydrogels and to attach ionic groups to the pheriphery.

Figure 6. (a) 1H NMR of PEG20K-G3-allyl (21) where full conversion of hydroxyl functionalities to allyl functionalities is confirmed. (b) 1H NMR of PEG20K-G3-COOH (26) showing full consumption of allyl functionalities after thiol−ene coupling reaction (TEC).

The 1H NMR peaks corresponding to the bis-MPA branched units were identified in the regions 1.0−1.4 ppm for the methyl groups R′CCH3 and at 4.2−4.5 ppm for methylene groups −CH2COC− (Figure 2d). As expected for hyperbranched bisMPA polymers, the carbon shifts of the quaternary carbons RC(CH2)2, CH3 in the regions of 45−50 ppm revealed distinct peaks related to the linear (L), terminal (T), and dendritic (D) units present in the DLD hybrids (Figure 2c). Using the integrals of the signals characteristic to the specific monomer units the degree of branching (DB) was calculated from eq 1.28

outcome. Furthermore, the rate of the condensation reaction was controlled by the wt % of pTSA added where increased wt % of acid catalyst increased the reaction rate. No apparent benefit was associated with initiator amounts beyond 1.5−5 wt %. Characterization of the hydroxyl functional DLD hybrids by conventional techniques confirmed the construction of hyperbranched DLD hybrids with enhanced physical properties that are generated from the PEG core. For example, all fourth generation DLD hybrids (3, 9, and 15) showed excellent solubility in water as well as in organic solvents such as ethanol, THF, DCM, and DMSO. This can be compared to the commercially available bis-MPA hyperbranched polymers (Boltorn) of a fourth generation (H40) typically known for its poor solubility in most organic solvents and insolubility in aqueous solution. Because of the layer by layer attachment of bis-MPA to the PEG core, several unique chemical shifts were observed by NMR. As can be seen in Figure 2b, the generated esters R′COOR show distinct 13C NMR carbonyl shifts in the regions of 172−175 ppm. Furthermore, the absence of the typical peak at 178 ppm corresponding to free R′COOH indicated the complete conversion of bis-MPA and the absence of nonattached dendritic precursors. IR spectroscopy further confirms the absence of any free carboxylic groups and the completion of the reaction. For instance, the R′COOR carbonyl stretching at 1756 cm−1 for the PEG6K-Gx-OH system (7−12) increased with increasing generation with untraceable stretching from the R′COOH carboxylic shift 1625 cm−1 (Figure 3a).

DB =

D+T D+T+L

(1)

As seen in Figure 3b, the DBs for all hybrids were found to be between 0.4 and 0.6, which are consistent with previously reported DB values for bis-MPA-based hyperbranched polymers constructed via slow monomer addition.26 For DLD hybrids based on the 6 and 20 kDa PEG core, the peak intensities of the quaternary carbon associated with PEG6KG2-OH (7), PEG20K-G2-OH (13), and PEG20K-G3-OH (14) decreased to such a level that DB calculations were made difficult. The average molecular weights (Mn) and dispersities (Đ) for the hybrids were acquired from NMR and SEC (Table 1). By comparing the 1H NMR integrals between the RCCH3 from bis-MPA units and −O−CH2−CH2− from PEG the Mn could be obtained (Figure 2c). An overall progression of the Mn is plotted in Figure 3c for the PEG2K-Gx-OH system (1−6). For this system, the molecular weights determined by 1H NMR 3733

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geometry at higher generations.27 Another factor to such deviations in the SEC results could be related to strong interactions between the numerous peripheral hydroxyl groups and the stationary column media. The Đ of all hybrids collected by SEC were found to be between 1.03 and 1.88. In another aspect, the introduction of branched and amorphous dendritic blocks on the crystalline PEG polymer was envisaged to efficiently control and completely suppress the crystallinity of the final materials.28 Indeed, thermal analysis (DSC) on the three series revealed a decrease of the melting temperature and enthalpy with increased dendritic generation, as can be seen in Figure 4. For the PEG2K-Gx-OH system with a melting point around 55 °C for the pure 2 kDa PEG, the crystallinity was fully disrupted upon reaching the fourth-generation dendritic block, while the system based on 6 kDa PEG reaches an intrinsic amorphous character for PEG6K-G6-OH 11. In the case of the PEG20K-Gx-OH system, crystallinity was detected for all generations. However, the PEG20K-G7-OH 18 with a melting temperature around 44 °C displayed weak thermal enthalpy of 2.9 J/g. Noticeably, for all systems the melting enthalpy followed an almost linear dependency on the weight percentage of the hyperbranched bis-MPA. For these systems, 60−70 wt % of branched bis-MPA block was found efficient to generate completely amorphous hybrid materials with multiple hydroxyl functional groups. Having demonstrated a facile approach to construct highly functional DLD hybrids materials, functionalization of peripheral hydroxyl end groups of the crude DLD hybrids by esterification reactions was examined. While the esterification strategy for both growth and postfunctionalization of bis-MPAbased dendritic scaffolds is by far the most reported, many potential applications require the introduction of alternative reactive intermediate at the periphery.29 Initially, azide and allyl anhydride were assessed on model DLD hybrids PEG6K-G4OH (9), PEG20K-G2-OH (13), PEG20K-G3-OH (14), and PEG20K-G4-OH (15) for the benign introduction of clickable groups allowing further functionalizations via copper-catalyzed click reactions (CuAAC) or UV-initiated thiol−ene coupeling reactions (Figure 5). Complete substitution of hydroxide to allyl and azide functionality was achieved in DCM at RT using a small excess of anhydride per hydroxyl group (1.5 anhydride/OH) in the presence of DMAP:pyridine (0.2 and 3 equiv/OH, respectively). After quenching of excess anhydride and simple extractions, allyl and azide functional DLD hybrids PEG6KG4-azide 23, PEG20K-G2-allyl 19, PEG20K-G3-allyl 20, and PEG20K-G4-allyl 21 were isolated as pure compounds without any acidic catalyst residues. Figure 6a shows the 1H NMR of fully allylated PEG20K-G3-allyl 20 with distinct allylic peaks found at 2.6 and 5−6 ppm. The reactive allyl functional DLD intermediates were further evaluated by both UV-initiated TEC chemistry and the fabrication of dendritic hydrogels. In the first approach, a chloroform solution containing PEG20K-G3-allyl 20 and 1.6 excess of 3-mercaptopropionic acid per allyl group were allowed to react during 1 h UV exposure at 365 nm using DMPA(1 wt %) as initiator. The 1H NMR spectrum in Figure 6b details the full disappearance of allyl groups, yielding a fully substituted and ionically charged DLD PEG20K-G3-COOH 26 with 16 carboxylic peripheral groups. In the second strategy, PEG20K-G3-allyl 20 and PEG20K-G4-allyl 21 with 16 and 32 allylic groups were allowed to react with triazine and TMP-

Figure 7. (a) A fully swollen and transparent PEG20K-G3-TMP hydrogel (27). (b) Swelling profile of hydrogels plotted against time for both triazine and TMP based systems. (c) Young’s modulus of gels acquired by tensile testing in fully swollen state.

were found to be in good agreement with the theoretical molecular weights while the SEC values were noted slightly higher for the lower generations and slightly higher for the higher generations. The Mn from SEC analysis of PEG6K-GxOH (7−12) and PEG20K-Gx-OH (13−18) were found to deviate more from theoretical values. Such deviations are apparent as SEC instruments are typically calibrated with linear standards, resulting in large errors for highly complex and branched structures known for altering their conformation from flexible at lower generation to a more constrained spherical 3734

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Figure 8. AFM and SEM images of an isoporous film cast from PEG2K-G3-Styrene3K. (a) AFM extracted profile. (b) AMF image. (c) SEM image of a cross section and schematic representation of the pores with approximate dimensions. (d) 3D zoom of a section of the isoporous film obtained by AFM.

chemistry which limits their accessibility. Consequently, the employment of large scale DLD hybrids based on hyperbranched bis-MPA blocks was identified as an elegant strategy to produce BFs. To generate DLD hybrids that allow such assessment, PEG2K-G3-OH (3) was successfully decorated with ATRP initiator bromoisbutyryl bromide, yielding PEG2KG3-BiB (24). ATRP of styrene monomer resulted in PEG2KG3-styrene3K 25 with 16 PS chains with an average chain molecular weight of 3 kDa. The resulting hybrid comprised a hydrophilic PEG interior encapsulated by a hydrophobic branched PS exterior. A short PEG linker was selected in order to achieve a low hydrophilic−hydrophobic balance and thus favor BF formation. Exploiting the breath figure method,33 PEG2K-G3-styrene 26 was drop-casted from CS2 at 10 mg/mL in 90% relative humidity on a glass substrate. Upon evaporation of the volatile solvent, highly ordered porous films with a pore diameter of about 500 nm were obtained (Figure 8). The 3D plot of an AFM image and a profile curve further supported evenly distributed pores. An examination of a cross section of the film by SEM revealed the formation of multilayers of interconnected circular pores, suggesting water droplets had diffused into the film (Figure 8c). A larger pore diameter (≈900 nm) can be observed under the surface of the film, revealing that the polymer material almost encircles the sinking water droplets.

based trifunctional thiol cross-linkers via UV-initiated TEC chemistry for the formation of cross-linked hydrogels (Figure 5). Four different dendritic networks were straightforwardly fabricated within 5 min UV exposure at 365 nm in ethanol (50 wt % solid content). After a solvent exchange from ethanol to water transparent dendritic hydrogels were obtained as can be seen in Figure 7a. All gels were swelled over a period of 24 h, reaching equilibrium within 90 min (Figure 7b). The triazine-based hydrogels exhibit a higher degree of swelling than the TMP-based counterparts. Furthermore, hydrogels with a higher generation dendritic block resulted in a lower degree of swelling for both systems. This is coupled to an increased number of cross-links and size of hydrophobic dendritic component. As a result, the swelling could be tuned to cover a window between 300% for PEG20KG4-TMP hydrogel (28) to 780% for PEG20K-G3-triazine hydrogel (29). A higher gel fraction (GF) due to more efficient cross-linking was observed for the TMP-based hydrogels compared to the triazine-based hydrogels.30 The GF for the hydrogels were noted 73.2% for PEG20K-G3-TMP 27, 85.5% for PEG20K-G4TMP 28, 77.6% for PEG20K-G3-triazine 29, and 68.0% for PEG20K-G4-triazine 30. A good correlation between degree of swelling and modulus was also observed as can be seen in Figure 7c. For the network with highest water swelling capacity, PEG20K-G3-triazine hydrogel 29 a modulus of 47 kPa was noted. The highest modulus was observed for PEG20K-G4TMP 30 with a value of 557 kPa. In contrast to the development of cross-linked 3D networks that can act as water reservoirs, amphiphilic DLD hybrids were sought out as a final construct for the fabrication of honeycomb membranes. Previously amphiphilic dendritic bis-MPA scaffolds comprising perfect dendrons attached to polystyrene (PS)27,31 stars or modified with polycaprolactone branches32 have been reported on for the development of functional porous films via the breath-figure (BF) technique. While efficient, the synthesis of monodisperse dendritic blocks requires iterative dendrimer

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CONCLUSION This work demonstrates a facile synthetic methodology for the construction of functional and scalable dendritic−linear− dendritic (DLD) hybrids displaying a hydrophilic linear PEG core decorated with hyperbranched bis-MPA blocks. A library of three sets of DLDs displaying up to 256 reactive hydroxyl groups were successfully synthesized via polycondensation in high yields and with no purification required. The DB for the hybrids was found to be between 0.40 and 0.59 with Đ of 1.03− 1.88. Their solubility profile includes typical organic solvents such as THF, DCM, and DMSO as well as water (increasing 3735

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(18) Montanez, M. I.; Campos, L. M.; Antoni, P.; Hed, Y.; Walter, M. V.; Krull, B. T.; Khan, A.; Hult, A.; Hawker, C. J.; Malkoch, M. Macromolecules 2010, 43, 6004−6013. (19) Antoni, P.; Robb, M. J.; Campos, L.; Montanez, M.; Hult, A.; Malmstrom, E.; Malkoch, M.; Hawker, C. J. Macromolecules 2010, 43, 6625−6631. (20) Wang, Q.; Mynar, J. L.; Yoshida, M.; Lee, E.; Lee, M.; Okuro, K.; Kinbara, K.; Aida, T. Nature 2010, 463, 339−343. (21) Johansson, K.; Bergman, T.; Johansson, M. ACS Appl. Mater. Interfaces 2009, 1, 211−217. (22) Ž agar, E.; Ž igon, M. Macromolecules 2002, 35, 9913−9925. (23) Zeng, X. H.; Zhang, Y. N.; Wu, Z. H.; Lundberg, P.; Malkoch, M.; Nystrom, A. M. J. Polym. Sci., Polym. Chem. 2012, 50, 280−288. (24) Trollsas, M.; Hedrick, J. L. Macromolecules 1998, 31, 4390− 4395. (25) Magnusson, H.; Malmstrom, E.; Hult, A. Macromolecules 2000, 33, 3099−3104. (26) Zagar, E.; Zigon, M. Prog. Polym. Sci. 2011, 36, 53−88. (27) Carlmark, A.; Malmstrom, E.; Malkoch, M. Chem. Soc. Rev. 2013, DOI: 10.1039/C3CS60101C. (28) Moorefield, M. E. Thermal Properties of Dendrimers and Hyperbranched Molecules; University of South Florida: Tampa, FL, 1998. (29) Ledin, P. A.; Friscourt, F.; Guo, J.; Boons, G. J. Chem.Eur. J. 2011, 17, 839−846. (30) Nandi, S.; Winter, H. H. Macromolecules 2005, 38, 4447−4455. (31) Connal, L. A.; Vestberg, R.; Hawker, C. J.; Qiao, G. G. Adv. Funct. Mater. 2008, 18, 3706−3714. (32) Lundberg, P.; Walter, M. V.; Montanez, M. I.; Hult, D.; Hult, A.; Nystrom, A.; Malkoch, M. Polym. Chem. 2011, 2, 394−402. (33) Bunz, U. H. F. Adv. Mater. 2006, 18, 973−989.

solubility with increased PEG length). By altering the generation of the hyperbranched component the melting enthalpy and crystallinity of the inherent PEG could efficiently be controlled and even fully disrupted. Functionalizations of the peripheral hydroxyl groups with azides, allyls, or ATRP initiators yielded reactive DLD hybrids that were further exploited for TEC reactions and ATRP polymerizations. Their scaffolding ability was also demonstrated with the fabrication of 3D networks, i.e., novel dendritic hydrogels and highly isoporous films.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (M.M.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge Vinnova (Challenge-driven Innovation: Grant 2012-01252), the Stockholm County Council (SLL), and the Swedish Research Council (VR) (Grants 20114477 and 897 2010-453) for their financial support. T.Y. acknowledges the China Scholarship Council 898 (CSC).

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ADDITIONAL NOTE PEGyK-Gx-OH (z)where y stands for the molecular weight of the linear poly(ethylene glycol) (PEG) core, x represents the pseudogeneration of the hyperbranched bis-MPA structure, and z the reaction number from the Experimental Section.

a

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