Catechol Acetonide Glycidyl Ether (CAGE): A Functional Epoxide

Article pubs.acs.org/Macromolecules

Catechol Acetonide Glycidyl Ether (CAGE): A Functional Epoxide Monomer for Linear and Hyperbranched Multi-Catechol Functional Polyether Architectures Kerstin Niederer,† Christoph Schüll,† Daniel Leibig,†,‡ Tobias Johann,† and Holger Frey*,†,‡ †

Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany Graduate School Materials Science in Mainz (MAINZ), Staudinger Weg 9, D-55128 Mainz, Germany

‡

S Supporting Information *

ABSTRACT: A protected catechol-containing epoxide monomer, catechol acetonide glycidyl ether (CAGE), is introduced. CAGE is conveniently obtained in three steps and enables the incorporation of surface-active catechol moieties into a broad variety of hydrophilic and biocompatible polyether architectures by copolymerization. Via acidic cleavage of the acetal protecting groups, the polymer-attached catechol functionalities are liberated and available for surface attachment or metal complexation. CAGE has been copolymerized with ethylene oxide and glycidol to obtain both linear poly(ethylene glycol) and hyperbranched polyglycerol copolymers, respectively, with multiple surface-adhesive catechol moieties. The CAGE content in the copolymers was varied from 1 to 16%, and all polymers exhibit moderate polydispersity (linear: Mw/Mn = 1.05−1.33; hyperbranched: Mw/Mn = 1.44−1.86). In situ kinetic studies of the simultaneous copolymerization of EO and CAGE via NMR spectroscopy have been performed to determine the microstructure of the linear poly(ethylene oxide-co-catechol acetonide glycidyl ether), P(EO-co-CAGE), copolymers. EO shows slightly higher reactivity than CAGE (rEO = 1.14, rCAGE = 0.88), leading to an almost ideally random copolymerization. Because of the catechol units, the copolymers form pH-induced cross-linked networks through metal−ligand interactions. ABA triblock copolymers of the type PCAGE-b-PEG-bPCAGE formed highly swellable hydrogels upon addition of FeCl3. Furthermore, static water contact angle measurements demonstrate an increase in the hydrophilicity of iron, PTFE, and PVC surfaces after coating with catechol-functional mf-PEGs.

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polymers and iron ions.13−15 In addition, covalent cross-linking of the catechol moieties and network formation were shown by Cha and Messersmith.16,17 When coating nanoparticles with catechol-containing polymers,18 the colloidal stability and aqueous solubility of the nanoparticles can be increased. This strategy can also be used to coat, e.g., manganese oxide nanoparticles, which are relevant in different biomedical imaging techniques such as magnetic resonance imaging (MRI).19,20 In general, different synthetic approaches to attach the catechol group to polymers have been described. Mostly two key strategies have been pursued: (i) direct introduction of the catechol moiety during polymerization by using catecholmodified monomers,21−23 functional initiators19,20 or terminating agents and (ii) postpolymerization modification,13,24,25 often by use of click reactions,18,26 via triazine linkers27 or based on demanding multistep procedures25,28−31 to obtain full polymer modification. Poly(ethylene oxide) (PEO), also known as poly(ethylene glycol) (PEG), is the most prominent biocompatible polymer.

INTRODUCTION The catechol unit (1,2-dihydroxybenzene) represents an important functional structure that is present in various biologically active molecules, such as the signaling molecule dopamine, but also in mussel foot proteins.1,2 The adhesion of mussels under most adverse conditions can mostly be traced back to catechol moieties in the respective adhesive proteins.3 Generally, the catechol group shows outstanding adhesion properties on nearly all kinds of materials. Although the exact mechanism of the adhesion is not fully understood in all cases,4,5 synthetic catechol-containing polymers offer a variety of interesting options for surface coating. Catechol-bearing polymers provide adhesive properties in humid environments and on a broad variety of materials, even on extremely hydrophobic surfaces like PTFE.6,7 Synthetic catechol-containing polymers have also been used for possible biomedical applications, such as antifouling surface coatings or adhesive hydrogels and networks in physiological environment. The respective catechol-functional polymers were obtained by polymer modification strategies.8−12 Catechol-containing hydrogel networks can be generated by capitalizing on the complex-forming properties of the o-dihydroxy aryl group. It has been demonstrated that pH-induced, self-healing hydrogels can be formed by formulations containing catechol-bearing © XXXX American Chemical Society

Received: November 10, 2015 Revised: February 5, 2016

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DOI: 10.1021/acs.macromol.5b02441 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

Synthesis. Catechol Acetonide Glycidyl Ether (CAGE); 2,2Dimethyl-1,3-benzodioxole-5-propanyl-1-glycidyl ether. 5 g (1 equiv) of 2,2-dimethyl-1,3-benzodioxole-5-propanol19 was dissolved in 30 mL of benzene. 30 mL of 40 wt % solution of potassium hydroxide in water and tetrabutylammonium hydrogen sulfate (0.1 equiv) was added; the solution was stirred vigorously and cooled to 0 °C. Epichlorohydrin (5 mL, 4.4 g, 2 equiv) was slowly added via a dropping funnel. The reaction mixture was allowed to warm up to room temperature and stirred for 24 h. On the next day diethyl ether was added, and the mixture was extracted twice with water, saturated sodium hydrogen carbonate solution, and brine. The organic phase was dried with magnesium sulfate, and the solvent and residual epichlorohydrin were removed in vacuo. Purification was performed via column chromatography in hexane/ethyl acetate 4:1. The product was obtained as a yellow liquid. Yield: 65%. 1H NMR (300 MHz, CDCl3): δ [ppm] = 6.64−6.56 (m, 3H, 7), 3.71 (dd, 1H, 3), 3.52−3.44 (m, 2H, 4), 3.37 (dd, 1 H, 3), 3.16−3.13 (m, 1H, 2), 2.79 (dd, 1H, 1), 2.62− 2.57 (m, 3H, 1, 6), 1.88−1.83 (m, 2H, 5), 1.65 (s, 6H, 8). 13C NMR (100 MHz, CDCl3): δ [ppm] = 147.4 (11), 145.5 (10), 135.0 (7), 120.5 (13), 117.5 (8), 108.7 (12), 107.9 (9), 71.5 (3), 70.6 (4), 50.9 (2), 44.3 (1), 32.0 (6), 31.5 (5), 25.9 (14). For the 13C NMR spectrum see Figure S3. Poly(catechol glycidyl ether-block-ethylene glycol-block-catechol glycidyl ether) (P(CAGE-b-EO-b-CAGE)); ABA Block Copolymer. In a typical reaction 2 g of poly(ethylene glycol) (Mn = 2000 g mol−1, 1 equiv) was dissolved in 5 mL of benzene, and 90 mol% cesium hydroxide monohydrate (related to the hydroxyl groups) was added to deprotonate the hydroxyl end-groups. The solution was stirred under vacuum at 60 °C for 30 min, the solvents were removed, and the formed initiator salt was dried at 80 °C under high vacuum for 18 h. The initiator salt was dissolved in 6 mL of dry 1,4-dioxane, and the appropriate amount of CAGE monomer was added via syringe. The polymerization was quenched by adding methanol after 72 h. Solvents were removed in vacuo, and the polymer precipitated from methanol in cold diethyl ether. The product appeared clear to orange in color. Yields: 88%. 1H NMR (300 MHz, DMSO-d6, P(CAGE-b-EO-bCAGE)): δ [ppm] = 6.63 (br, aromat, 2), 3.56−3.34 (br, polyether backbone), 2.47 (br, CH2, 3), 1.69 (br, CH2, 4), 1.58 (br, CH3, 1). Poly(ethylene glycol-co-catechol glycidyl ether) (P(EO-co-CAGE)). To synthesize random copolymers of EO and CAGE, 2-propoxyethanol (1 equiv) was dissolved in benzene in a 250 mL Schlenk flask. Cesium hydroxide monohydrate (0.9 equiv) was added, and the mixture was stirred at 60 °C for 1 h. To remove benzene and water, the flask was evacuated overnight (10−3 mbar) at 60 °C. 30 mL of dry THF was distilled in the cold into the Schlenk flask, and 2 mL of dry DMSO was added to dissolve the initiator. CAGE was added via syringe, and EO was first distilled in the cold into a graduated ampule and subsequently into a 250 mL Schlenk flask. The mixture was heated to 60 °C and stirred for 2 days. Subsequently, 1 mL of methanol was added to stop the reaction, and precipitation was performed in cold diethyl ether. Yields: 95%. 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 6.57 (br, aromat, 2), 3.64−3.33 (br, polyether backbone), 2.47 (br, CH2, 3), 1.71 (br, CH2, 4), 1.59 (br, CH3, 1), 1.23 (br, CH2, 6), 0.84 (br, CH3, 5). 1 H NMR Online Kinetic Measurements. In a Schlenk flask propoxyethanol and cesium hydroxide monohydrate were mixed and dried in benzene to obtain the initiator salt. Under high vacuum benzene and water were removed overnight. The initiator was redissolved in DMSO-d6 and transferred to a Norell S-500-VT-7 NMR tube, lockable by a special cap. The NMR tube was cooled to −80 °C, and CAGE (dissolved in THF-d8 (400 μL of THF, 25 μL of CAGE)) was transferred to the NMR tube. EO was distilled in the cold and filled into the NMR tube. After the mixture was frozen with liquid nitrogen, the NMR tube was evacuated and sealed. The still frozen sample was placed in the NMR spectrometer and rapidly heated to 60 °C. Immediately after melting the first spectrum was recorded. Measurements were carried out every 10 min for 16 h (16 scans, 400 MHz, 60 °C). Hyperbranched Poly(glycerol-block-CAGE) (hbP(G-b-CAGE)). In a typical procedure, 1,1,1-trimethylolpropane (TMP) (1 equiv) was

It is nontoxic, mostly nonimmunogenic, chemically inert, and soluble in many organic solvents and water.32,33 Consequently, PEG is used in an immense variety of biomedical applications, such as PEGylated enzymes, cytokines, and antibodies, which are all approved by the US Food and Drug Administration.34,35 The drawback of PEG for some applications is the low number of functional groups of the polymer. Only the two end-groups can be functionalized, e.g., with using functionalized initiators or specifically modified terminating agents.36 To achieve multifunctionality of the polyether chain, ethylene oxide (EO) can be copolymerized with various glycidyl ethers, leading to multifunctional PEG (mf-PEG).37,38 In recent years, PEGs with catechol termini have been used to impart antifouling properties to surfaces7 to fabricate composite materials39 and to stabilize nanoparticles.24 Moreover, multiarm star PEGs modified with catechol moieties can form supramolecular polymer networks in the presence of iron ions. The self-healing properties of such hydrogels bear potential for tissue engineering.14,17,40 Polyglycerols (PGs) represent a multi-hydroxyl-functional alternative to PEG. Both hyperbranched and linear PG (hbPG, linPG) show high biocompatibility, low toxicity, excellent water solubility,41,42 and higher thermal43 and oxidative stability44 than PEG. Catechol-initiated hbPG with precisely one catechol unit has recently been described by our group and was used to coat MnO nanoparticles.20 Incorporation of several catechol moieties into hbPG was put into practice by Haag and coworkers, relying on a multistep postpolymerization procedure.28−31 The respective catechol-containing hbPGs showed good biocompatibility and surface adhesion. In this work, we describe a new catechol-containing epoxide monomer, the catechol acetonide glycidyl ether (CAGE).45,46 CAGE is widely applicable for anionic ring-opening polymerization (AROP). Most likely biocompatible random and block copolymer structures have been obtained in one-step procedures using CAGE as a comonomer in the copolymerization with ethylene oxide (EO) and glycidol, respectively. Convenient removal of the acetonide protecting group is possible under mild acidic conditions without affecting the stability of the polyether backbone. Network formation of the polymers with Fe(III) salts and surface modification by coating of different materials have also been explored.

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EXPERIMENTAL SECTION

Materials. All reagents were used without further purification, unless otherwise stated. Glycidol and N-methylpyrrolidone (NMP) were freshly distilled from CaH2. THF was dried over sodium and distilled in the cold prior to use. CAGE and PEG were dried by azeotropic distillation of benzene. NMP, cesium hydroxide monohydrate, and 1,1,1-trimethylolpropane were purchased from Acros. FeCl3 hexahydrate, diglyme, glycidol, THF, ethylene oxide, benzene, 2propoxyethanol, PEG, and epichlorohydrin were obtained from SigmaAldrich and used as received. Deuterated solvents were obtained from Deutero GmbH and Sigma-Aldrich. Characterization. 1H NMR spectra at 300 and 400 MHz and 13C spectra at 100 MHz were recorded on a Bruker Avance III HD 300 and a Bruker Avance III HD 400. The spectra are referenced internally to residual proton signals of the deuterated solvent. SEC chromatography was performed in DMF (containing 0.25 g L−1 lithium bromide as an additive) at an Agilent 1100 Series including a PSS HEMA column (300/100/40 Å porosity), a UV (275 nm), and RI detector. Calibration was achieved using poly(ethylene oxide) standards provided by Polymer Standard Service (PSS). Contact angle measurements were performed on a Dataphysics Contact angle System OCA using Milli-Q water as interface agent. B


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Table 1. Overview of Prepared Random (ran1−ran4) and Block (b1−b4) Copolymers of CAGE and PEG and Hyperbranched Copolymers (hb1−hb4) of CAGE with Glycidol, Respectively

a

no.

sample

CAGE content (%)

Mna (g mol−1)

Mnb (g mol−1)

PDI (SEC)

TG (°C)

yield (%)

b1 b2 b3 b4 ran1 ran2 ran3 ran4 hb1 hb2 hb3 hb4

P(CAGE1-b-EO132-b-CAGE1) P(CAGE3.5-b-EO132-b-CAGE3.5) P(CAGE1.5-b-EO45-b-CAGE1.5) P(CAGE1.5-b-EO23-b-CAGE1.5) P(EO400-co-CAGE10) P(EO245-co-CAGE12) P(EO430-co-CAGE41) P(EO212-co-CAGE39) hbP(G40-b-CAGE0.5) hbP(G51-b-CAGE2) hbP(G55-b-CAGE3) hbP(G50-b-CAGE7)

1.5 4.8 6.3 11.5 2.5 4.7 9.5 15.5 1.2 3.8 5.2 12.3

6500 7800 2800 1800 20300 14100 29800 19700 2000 2900 3300 4200

4300 6200 2000 1000 9800 5600 4800 6500 2300 1100 1200 1300

1.05 1.07 1.15 1.27 1.33 1.14 1.29 1.19 1.44 1.45 1.57 1.86

−25 −18 −32 −23 −38 −18 −34 −49 −29 −11 −5 2

94 91 80 87 91 97 97 93 38 41 45 52

Calculated via 1H NMR measurements. bDetermined via SEC, DMF as solvent, PEG standard.

deprotonated by 30 mol% cesium hydroxide monohydrate in 5 mL of benzene. After stirring for 30 min at 60 °C under vacuum, the temperature was increased to 80 °C, and the solvents were removed with high vacuum overnight. The initiator salt was dissolved in 1 mL of dry N-methylpyrrolidone (NMP) or diglyme. A 50 vol% mixture of glycidol in NMP (or diglyme in some of the polymerizations) was added slowly via syringe pump overnight. After full addition of glycidol, the solution was stirred for 2 h to complete the polymerization. CAGE (also 50 vol% in NMP or diglyme) was added to the flask subsequently. After stirring for another 4−6 h, the reaction was quenched by adding 1 mL of methanol. The orange polymer was precipitated twice from methanol in cold diethyl ether. Yield: 44%. 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 6.63 (br, aromat, 2), 4.61 (br, OH), 3.68−3.27 (br, polyether backbone), 2.47 (br, CH2, 3), 1.73 (br, CH2, 4), 1.60 (br, CH3, 1), 1.24 (br, CH2, 6), 0.78 (br, CH3, 5). Removal of the Acetal Protecting Groups. 1 g of the respective catechol-containing copolymer was dissolved in 20 mL of 1 M HCl in methanol and shaken for 2 days. The solvents were removed in a vacuum, and the polymer was precipitated from methanol in cold diethyl ether. Copolymers were obtained as sticky viscous slightly yellow to red materials. The samples were stored under an argon atmosphere at 6 °C. Yield: quantitative. Cross-Linking with Fe(III) Salts and Investigation of Swelling Behavior. Gelation experiments were performed with a representative sample with a catechol content of 5 mol% (b2, ran2, hb3, Table 1) chosen from every copolymer-type described above. Copolymers with a concentration of 0.03 mol of catechol groups were dissolved in 300 μL of Milli-Q water to obtain an overall concentration of 0.1 mol L−1. Dissolving 0.135 g of FeCl3·6H2O in 5 mL of Milli-Q water results in a 0.1 M solution. To achieve gelation, the ratio of Fe3+ and catechol group has to be 1:3. To obtain a 500 μL metal−ligand cross-linked gel, 300 μL of copolymer solution was mixed with 1/3 FeCl3 solution (100 μL). The mixture was strongly agitated, obtaining a slightly darker color (orange). 100 μL of NaOH (c = 1 mol L−1) was added, leading to a dark red to black color. After mixing with Fe(III) salt, the P(CAGE-b-EO-b-CAGE) block copolymers and random P(EO-coCAGE) copolymers gelled immediately, whereas the hyperbranched PG−catechol copolymers showed only higher viscosity at first. In this case, gelation occurred slowly after 2 days. Equilibrium swelling of the gels was determined by preparing the cross-linked gels as described in the previous section. The dry polymer weight is denoted Wd. The gels were immersed in 10 mL of Milli-Q water for 24 h to reach swelling equilibrium. The swollen samples were removed from the water, and after removal of surface water, the samples were weighed (Ws). The water uptake was calculated from (Ws − Wd)/Wd × 100%. Contact Angle Measurements. The appropriate copolymers (P(CAGE-b-EO-b-CAGE), P(EO-co-CAGE), P(G-b-CAGE), b3, ran3, hb3, Table 1) with a CAGE content of 5−9 mol % were dissolved in 1 mL of Milli-Q water to achieve a polymer concentration of 10 mg/mL.

The different materials (PTFE, PVC, Fe, glass) were obtained as commercially available technical samples. The pieces were not treated in any special manner to obtain a perfectly even surface. Cleaning of the different surfaces was achieved by sonification of the materials in ethanol and acetone. Then solutions of the CAGE-containing polymers were used to wet the respective surfaces, and the samples were stored overnight at room temperature. After rinsing with water and drying under nitrogen flow, the surface properties were studied by contact angle measurements. For this purpose, a drop of Milli-Q water was applied on the catechol-functional copolymer-coated surface, and the apparent angle between liquid and solid was determined. Every measurement was performed three times to ensure consistency.

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RESULTS AND DISCUSSION A. CAGE Monomer Synthesis and Polymerization. Catechol Acetonide Glycidyl Ether. The targeted oxirane monomer CAGE (catechol acetonide glycidyl ether) for anionic ring-opening polymerization was synthesized under phase transfer conditions.45,46 For this purpose, epichlorohydrin was reacted with 2,2-dimethyl-1,3-benzodioxole-5-propanol in a benzene/KOHaq mixture (Figure 1). The precursor

Figure 1. Synthesis of CAGE (catechol acetonide glycidyl ether).

2,2-dimethyl-1,3-benzodioxole-5-propanol is synthesized in a two-step reaction and was recently introduced by our group as a protected, catechol-functional initiator suitable for the oxyanionic ring-opening polymerization.20 In a typical literature method for the attachment of the epoxide functionality 50 wt % NaOH is used in the phase transfer reaction.47 In the case of the monomer synthesis presented here, undesired side products form, which can impede polymerization and are difficult to separate from the CAGE monomer (see Figures S1 and S2, Supporting Information). A derivative of epichlorohydrin, namely 3-chloroprop-2-en-1-ol, is formed, if strongly basic reaction conditions are used. This alcohol is capable of transfer reactions, limiting molecular weights of the oxyanionic polymerization due to the protic hydroxyl group. Another possible side product is formed, if the aforementioned alcohol reacts with another epichlorohydrin molecule. An alternative glycidyl ether monomer is found, which also copolymerizes, but C


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Macromolecules does not possess desired catechol functionality. Hence, 40 wt % KOH was used to reduce the basicity, and the reaction time was shortened from 2 days to 18 h. These reaction conditions were established as most appropriate to suppress the formation of these side products. The resulting monomer 2,2-dimethyl-1,3benzodioxole-5-propanyl-1-glycidyl ether (in short: “catecholacetonide glycidyl ether”, CAGE) was obtained in 65% yield without side products after purification using column chromatography. The 1H NMR spectrum of CAGE is shown in Figure 2 (13C NMR spectrum available in the Supporting Information, Figure S3).

Figure 2. 1H NMR spectrum of CAGE monomer (300 MHz, CDCl3). Figure 3. Synthesis of different CAGE-containing polyether architectures: (A) ABA block copolymer P(CAGE-b-EO-b-CAGE), (B) random P(EO-co-CAGE), and (C) hyperbranched P(G-b-CAGE).

Also, the unreacted 2,2-dimethyl-1,3-benzodioxole-5-propanol can be retrieved and used again. CAGE exhibits orthogonal chemical behavior: The epoxide group acts as a polymerizable moiety, while the acetal protective group at the catechol moiety is stable under the harsh basic conditions of the anionic polymerization. Nevertheless, the acetal can conveniently be cleaved subsequent to polymerization under acidic conditions to generate the free catechol moiety. Using this functional monomer, both homopolymerization on a PEG macroinitiator and copolymerization has been studied to generate catechol-containing polyethers in two reaction steps. Table 1 gives an overview of all polymers synthesized as well as their characterization data. CAGE was employed as a comonomer for the generation of different polyether architectures, as shown in Figure 3. PEO−b−PCAGE Block Copolymers. Targeting ABA type (P(CAGE-b-EO-b-CAGE)) block copolymers (Figure 3A), the CAGE monomer was polymerized directly from a poly(ethylene oxide) (PEO, PEG) macroinitiator. To obtain these ABA-type triblock copolymers with different molecular weights and adjustable CAGE contents (2−8 units, 1.5−11.5%, respectively), deprotonated dihydroxy-functional PEG samples with molecular weights between 1000 and 6000 g mol−1 were used as initiators, and cesium was employed as a counterion. Reactions were performed in 1,4-dioxane as a solvent under high-vacuum conditions at 80 °C. The number of catechol groups could be adjusted by the monomer/PEG-initiator ratio to a certain extent. The degree of polymerization of CAGE in the resulting block copolymers was determined via 1H NMR spectroscopy (Figure 4). The signal of the initial PEG block (3.56−3.34 ppm) was used as a reference to determine the average number of repeating CAGE units attached. The CAGE units provide two clearly distinguishable signals: one in the

aromatic region at 6.63 ppm and the signal of the methyl groups of the acetonide protecting groups at 1.58 ppm. An overview of the characterization data of the polymers prepared is given in Table 1 (samples b1−b4). One to seven CAGE repeating units (2−12 mol %, see Table 1) could be polymerized onto the difunctional PEG-initiators with varying molecular weights, resulting in a multivalent catechol-containing block copolymer structure. Up to ten repeating units of CAGE were targeted, but most likely due to steric effects of the catechol-functional monomer, a degree of polymerization of seven units turned out to be the maximum number of CAGE units achievable for the PCAGE homopolymer block. Size exclusion chromatography (SEC) revealed narrow and monomodal molecular weight distributions for all samples with short PCAGE block (see Table 1 and Figure 5). Using PEG standards for calibration of the SEC, lower molecular weights (Mn) were detected than the values determined from 1H NMR spectroscopy. The discrepancy, which is evident from the data in Table 1, can be explained by the different hydrodynamic volume due to the incorporated CAGE monomers in comparison to the PEG standards. DSC measurements revealed only one glass transition temperature (Tg) for the block copolymers (Table 1). The homo PCAGE segments of the blocks are not of sufficient length to lead to phase segregation and a second Tg. Random P(EO-co-CAGE) Copolymers. Besides the block copolymerization of CAGE initiated by difunctional macroinitiators, the CAGE monomer was also studied with respect to simultaneous copolymerization with ethylene oxide (EO). This approach may afford copolymers with catechol moieties D


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Figure 4. 1H NMR spectrum of P(CAGE-b-EO-b-CAGE) triblock copolymers (DMSO-d6).

and the incorporated CAGE content. Molecular weights and composition were determined by 1H NMR spectroscopy, comparing the integral intensity of the propoxy-initiator signals at 0.84 ppm with the aromatic signals of the CAGE unit at 6.57 ppm and the resonances of the polyether backbone at 3.64− 3.33 ppm (see Figure S4). SEC measurements showed a monomodal molecular weight distribution with PDIs in the range of 1.07−1.33 (see Table 1 and Figure 5). It should be emphasized that the refractive index signal and the UV signal of the distribution are superimposable, which is unequivocal evidence for successful copolymerization of CAGE and its homogeneous presence in the whole molecular weight distribution of the polymers (Figure S5). Once again, the molecular weights obtained from SEC were somewhat lower than by 1H NMR spectroscopy, which again is explained by the different hydrodynamic radii of PEG and PCAGE. Only one glass transition (Tg) was found for every P(EO-co-CAGE) copolymer (Table 1). This is in agreement with expectation, since commonly random copolymers exhibit only one single Tg. To obtain a more profound understanding of the monomer sequence as well as the relative monomer reactivity of EO and CAGE, the simultaneous copolymerization behavior of CAGE and EO was studied by in situ 1H NMR kinetic studies, carrying out the copolymerization directly in an argon flushed valved NMR tube in deuterated solvents.49,50 1H NMR kinetic measurements were performed at 60 °C in the NMR spectrometer. The decrease of the monomer signals was monitored to evaluate the incorporation behavior of the two monomers in the growing copolymer chains. The integrals of the epoxide signals at 2.61 ppm (Figure 6A) and at 3.08 ppm

Figure 5. Typical molecular weight distribution of CAGE-containing functional polyethers with different topology (SEC, DMF); the linear ABA triblock samples P(CAGE-b-EO-b-CAGE), black line and the linear random copolymer P(EO212-co-CAGE39), blue line show symmetric and narrower distribution in comparison to the hyperbranched random copolymer (red distribution curve).

distributed along the backbone. Since copolymerization of EO with other functional glycidyl ether monomers is known to lead to random copolymerization behavior, it is likely that CAGE and EO may also react in this manner.48−50 Initiated by cesium propoxy ethoxide, EO and CAGE have been copolymerized by AROP at 70 °C using THF as a solvent. The CAGE content in the monomer mixture was varied from 3 to 16 mol %, and welldefined poly(ethylene oxide-co-catechol acetonide glycidyl ether) (P(EO-co-CAGE)) copolymers were obtained, with respect to both molecular weights of 7−30 kg/mol (Table 1) E


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Figure 6. 1H NMR spectra for the copolymerization of CAGE and EO at 60 °C in THF-d4 recorded after 20, 60, 110, 130, 160, 200, 230, 280, 340, 440, 510, and 830 min. Zoom-in A: decrease of EO proton signals. Zoom-in B: decrease of methine proton of the CAGE monomer.

for the methine proton (Figure 6B) of CAGE were used for this purpose. These signals are referenced to the methyl peak at 0.84 ppm corresponding to the characteristic three protons of the propoxyethanol initiator. The monomer conversion was plotted against the initial monomer concentration, resulting in a linear graph, which confirms the living character of the copolymerization (Figure S6). The two zoom-in images (2.61 and 3.08 ppm) in Figure 6 show the gradual reduction of the monomer signals, while the backbone signal increases. Concerning the microstructure of the copolymers formed, evaluation of the data shows only small differences in the reactivity of EO and CAGE. Remarkably, even though CAGE possesses a sterically more demanding structure in comparison to EO, both monomers exhibit an almost equal incorporation rate and conversion (Figures 7 and 8). The polymerization rate of CAGE appears to be slightly lower, but nevertheless an almost ideal random copolymer structure was obtained. The conversion of both monomers plotted versus the total monomer conversion is shown in Figure 8. The plot in Figure 8 shows slightly faster monomer incorporation for ethylene oxide, which permits the conclusion that CAGE is slightly less reactive than EO. This is tentatively explained by steric effects of the CAGE monomer. Nevertheless, complete incorporation of the functional monomer into the polymer chain is observed, with a slight deviation from an ideally random distribution of the catechol-containing monomer structure in the polyether chains. Monomer reactivity ratios (r parameters) were determined from the NMR data. The values were calculated using the Fineman−Ross approach.51 EO shows slightly higher reactivity than CAGE (rEO = 1.14, rCAGE = 0.88). To sum up, almost ideally random copolymers with a slight gradient structure are obtained from the copolymerization of EO and CAGE.

Figure 7. Monomer conversion versus time determined by 1H NMR in THF-d4 at 60 °C. Red dots: CAGE monomer conversion; blue dots: EO monomer conversion. Final composition: P(EO36-co-CAGE8).

Hyperbranched Catechol-Containing Polyethers. To demonstrate the versatility of the new CAGE monomer, it has also been used for the synthesis of catechol-functional hyperbranched polyglycerol copolymers (hbpoly(glycerolblock-catechol acetonide glycidyl ether)). Preparation of the hbP(G-b-CAGE) polymers was achieved using the cesium salt of 1,1,1-trimethylolpropane as an initiator as well as diglyme and N-methyl-2-pyrrolidone (NMP) as solvents. It should be noted that in the case of the copolymerization in diglyme without NMP only a small amount of CAGE (0.4−1.2%) could be incorporated into the polymers formed. In contrast, in NMP the content could be increased to 12 mol %, employing a slow monomer addition protocol.52 In a typical procedure, the initiator salt was dissolved in a small amount of NMP, and a solution of glycidol and CAGE (50 wt % in NMP) was subsequently added slowly via a syringe pump at 80 °C. When F


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Figure 5). After purification via precipitation into diethyl ether, all hbP(G-b-CAGE) samples show monomodal molecular weight distributions with little tailing to lower molecular weights. Because of the hyperbranched structure the hydrodynamic volume differs significantly from linear PEG and the polymers exhibited lower apparent molecular weights by SEC than determined from 1H NMR spectroscopy. Furthermore, all hyperbranched copolymers showed moderate molecular weight distributions (PDI = 1.44−1.86), and the overlay of RI and UV detector signals unequivocally confirmed homogeneous incorporation of CAGE over the whole molecular weight distribution. The lower yields for the hyperbranched copolymers (38− 52%, Table 1) are ascribed to the precipitation procedure employed to remove low molecular weight oligoglycerol products. With increasing CAGE content in the copolymers the solubility in diethyl ether increased. However, cold diethyl ether was employed for precipitation of the hyperbranched materials. Therefore, a certain fraction of the product may have been lost in this step. Further optimization of the work-up procedure may result in higher amounts of the final copolymers; however, in the current study we aimed at monodisperse polymers, putting up with a certain loss of final product. Via DSC measurements the Tgs of the hyperbranched copolymers were determined. The Tg increases linearly from −29 to 2 °C with the amount of CAGE incorporated in the copolymers. The respective values are also listed in Table 1. Removal of the Acetonide Protecting Group to Regenerate Catechol Moieties. Acidic hydrolysis of the acetonide protecting groups provides reactive catechol (odihydroxyaryl) moieties (Figure S8). After removal of the protecting group, poly(catechol acetonide glycidyl ether) is

Figure 8. CAGE monomer conversion (%) vs total monomer conversion for the copolymerization of EO (blue dots) and CAGE (red dots), determined from 1H NMR kinetics at 60 °C measured in THF-d4.

the whole amount of glycidol had been added dropwise into the reaction flask, stirring was continued for another 2 h. Subsequently, CAGE was added, and the reaction mixture stirred for another 4−6 h. 1 H NMR spectroscopy permits determination of the copolymer composition and the number-average molecular weight by comparison of the integrals of the TMP initiator signals (CH3 at 0.78 ppm and CH2 at 1.24 ppm) with the integrals of the CAGE signals in the aromatic region (6.63 ppm) and the OH resonance (4.61 ppm) of glycidol (Mn, see Table 1 and Figure S7). The molecular weight has also been determined using SEC calibrated with PEG standards (see

Figure 9. NMR study of the removal of the acetal protecting group, monitored via 1H NMR measurements. Blue: signal of the acetonide protecting group; orange: disappearance of signal after mild acidic treatment. G


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(CaGE-b-EO-b-CaGE), and hbP(G-b-CaGE) with a CaGE content exceeding 3 mol % form networks with the typical dark red to black color due to the charge transfer of the iron complexes (Figure 11, Figure S11). Below 3 mol % catechol units in the copolymers no gelation was detected. As a general observation, the linear PEG-CaGE copolymers (block and random) showed faster gelation than the hyperbranched P(Gb-CaGE) copolymers. The gelation time was determined using the simple vial tilting method. The absence of flow within 1 min after inverting the vial was regarded as indication of a gel state. Specifically, for P(CaGE-b-EO-b-CaGE) and P(EO-coCaGE) copolymers immediate gelation after the addition of base was observed (samples b2 and ran2, Table 1). Using samples b2 and ran2 with a catechol content of ∼5% resulted in gelation approximately 3 s after mixing 300 μL (0.1 mol L−1) copolymer solution with 100 μL of Fe3+ solution (0.03 mol L−1) and 100 μL of 1 mol L−1 NaOHaq solution at pH = 11. Stiff gels with a dark red to black color were obtained (Figure S12). With respect to the hyperbranched copolymers (hb3, Table 1), the gelation experiment was performed in the same way as in the P(CaGE-b-EO-b-CaGE) and P(EO-co-CaGE) cases. The typical dark color appeared, but gelation occurred only after 48 h, as shown by the vial tilting method. This delay is tentatively explained by the highly branched structure of hbPG-b-CaGE, which appears to limit the accessibility of the catechol moieties. To obtain stiff gels, the catechol moieties have to rearrange to form the tris-complex, which is a slow process due to the high complexation constants. Targeting Fe(III)-based supramolecular hydrogels, in explorative experiments, the swelling behavior of networks formed of the different polymer topologies has also been investigated. To determine the degree of swelling, every stiff gel was immersed in 10 mL of Milli-Q water for 24 h to reach swelling equilibrium. Samples ran2 and hb3 did not exhibit swelling in water, which is explained by the short linear polymer segments present in the respective Fe(III) complexed gels. However, as expected, in the case of the ABA block copolymers (P(CaGE-b-EO-b-CaGE)) strong and reversible swelling in water was obtained for sample b2 (P(CAGE3.5-b-EO132-bCAGE3.5, Figure S13). This copolymer possesses a linear PEO midblock with a DPn exceeding 130 EO units between the metal-complexing, short CaGE blocks. For the supramolecular hydrogels consisting of this copolymer and FeCl3 the water uptake was 3600% in the swollen state. Further rheological characterization of the supramolecular hydrogels is in progress at present. Contact Angle Measurements. To investigate the potential of the prepared catechol-containing polymers for surface modification, static water contact angle measurements of different surfaces have been performed after treatment with polymer solutions. In order to demonstrate the effect for actual application, no specifically polished model surfaces were used. For the measurements 10 mg of the appropriate copolymers (b3, ran3, hb3, Table 1) with 5−9 mol % catechol were dissolved in 1 mL of Milli-Q water. Different substrates, i.e., glass, PVC, PTFE and iron, were stored in these solutions overnight. After rinsing with water several times and drying in a nitrogen flow the static contact angles of water on the surfaces were measured. For these measurements a droplet of Milli-Q water was placed on respective surfaces. The contact angles found for P(CaGE-b-EO-b-CaGE), P(EO-co-CaGE), and hbP(G-b-CaGE) on the respective surfaces are shown in Figure 12.

converted to poly(catechol glycidyl ether), designated P(CaGE) in the following. It is important to note that in the ensuing paragraphs all abbreviated samples contain free catechol groups, so the abbreviations of the three polymergroups are P(CaGE-b-EO-b-CaGE), P(EO-co-CaGE), and hbP(G-b-CaGE). These were obtained after 2 days of treatment with 1 M hydrochloric acid in methanol (Figure S8). The reaction progress was monitored by 1H NMR spectroscopy (Figure 9, Figures S9 and S10). After removal of the protecting group a new signal next to the DMSO-d6 signal occurs. This peak corresponds to the CH2 group adjacent to the catechol functionality. The deprotected, catechol-containing polyethers were generally obtained as highly viscous and sticky materials. Since small fractions of catechol groups were unavoidably oxidized to quinones (due to the reaction conditions), the copolymers were yellowish to pale brown materials. However, UV−vis measurements supported that the catechol functionality was hardly affected because no absorption band typical of quinones was detected (Figure S11). B. Network Formation and Surface Modification. With increasing number of catechol moieties at the polyethers the complexing properties for metal ions compared to established PEGs with merely a single catechol end-group can be expected to increase due to multiple and multivalent interactions. Catechols form complexes with a broad variety of metals and also interact strongly with metal oxides. The stability constant of bis- and tris-catechol−Fe3+ complexes is one of the highest known (log KS ≈ 37−40).53 Messersmith et al. demonstrated that dopamine units attached to PEG via amidation also form stable complexes with Fe3+, leading to gelation and hydrogel formation.13 In this system, the pH value plays an important role and controls, if mono-, bis-, or tris-complexes are formed (see Figure 10).14

Figure 10. pH dependence of complex formation of catechol moieties and Fe(III) ions.

The different complexes can be monitored by a typical color change from orange (pH < 5) over dark red (pH 5−9) to almost black (pH > 9) of diluted polymer solutions.11 For several CaGE-containing polymer samples with different structure the respective color changes upon addition of FeCl3 have been studied in aqueous solution. UV−vis measurements show the different pH stages and complex formation (Figure S11). All deprotected copolymers (P(CaGE-b-EO-b-CaGE), P(EO-co-CaGE), hbP(G-b-CaGE)) show the typical color changes upon complexation with Fe3+ in aqueous basic solution. Without added CaGE-containg polyether, aqueous Fe(OH)3 rapidly precipitates from an orange Fe3+ solution. When iron salts were added to the aqueous copolymer solutions, generally no precipitate was formed and the Fe(III) ions were complexed and solubilized. P(EO-co-CaGE), PH


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Figure 11. Network formation of the catechol-containing polyethers. Possible arrangement of the polymers at metal ions. A: P(CaGE-b-EO-bCaGE); B: P(EO-co-CaGE); C: hbP(G-b-CaGE).

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CONCLUSION Inspired by the strong adhesion and complexation properties of the catechol moiety, we introduce an epoxide monomer bearing an acetal-protected catechol functionality as a versatile building unit for a wide variety of polymer structures obtained by (oxy)anionic polymerization techniques. The CAGE structure is conveniently available in a three-step synthesis from the readily available starting compounds 3,4-dihydroxyphenylpropionic acid, 2,2-dimethoxypropane, and epichlorohydrin. The universal character of CAGE for polyether synthesis has been demonstrated by polymerization to short homosequences at the termini of PEG to generate ABA block copolymers as well as by direct copolymerization with both EO and glycidol to obtain random, multi-catechol functional copolyethers. Different polymer architectures, linear and hyperbranched polyethers bearing protected catechol units are accessible. Between 1 and 16 mol% CAGE were incorporated, and well-defined linear and hyperbranched polymers have been obtained that can be viewed as multi-catechol functional PEG, combining the biocompatibility of PEG with multivalent interaction sites. The monomer sequence of linear P(EO-co-CAGE) copolymers obtained from simultaneous copolymerization of EO and CAGE was determined by in situ 1H NMR kinetic measurements, revealing almost perfectly random monomer incorporation. Cleavage of the acetonide protecting group at the catechol moiety permits to capitalize on the typical characteristics of catechol: the adhesion to almost every surface and supramolecular gelation by addition of metal ions. Effective network formation for all types of catechol-containing copolymers (catechol monomer content ≥3 mol%) was achieved by complex formation with Fe(III) ions under basic conditions. Various surfaces showed an enhancement in their hydrophilicity after coating with the catechol-functional polymers. This confirms the outstanding adhesion properties of the multiple catechol groups. In future works the coated materials will be studied with respect to both antifouling and cell adhesion/growth. Additionally, the CAGE monomer may be used as a terminating agent for the carbanionic polymerization, affording catechol end-functionalized polymer architectures, which is under investigation. In summary, CAGE represents an almost universally applicable monomer structure for the introduction of catechol units into a variety of polymer architectures due to the high reactivity of the epoxide structure.

Figure 12. Contact angles of the different catechol containing polymers. Black squares: catechol containing polymers coated on a PTFE surface; red dots: catechol containing polymers coated on a PVC surface; blue triangles: catechol containing polymers coated on an iron surface; green triangles: catechol containing polymers coated on a glass surface.

All four materials coated with the catechol-functional polymers exhibit altered contact angles compared to the untreated surfaces. Three of the four materials, i.e., iron, PTFE, and PVC, possess a rather hydrophobic surface (lit.Fe: 70°; lit.PTFE: 126°; lit.PVC: 72°).7,54 After application of the hydrophilic polymers, the contact angles decreased. The most hydrophobic material, namely PTFE,7 showed the most impressive shift in the contact angle, from originally 110° a drop to 57° was observed upon coating with P(EO-co-CaGE). Consequently, these results indicate successful coating of the materials, in most cases strongly increasing the hydrophilicity of the respective surfaces. In comparison, coating of the hydrophilic glass surface leads to a contrary behavior. The contact angle of glass increased from 15° (lit.: 0−30°)55 of the pristine glass to values between 41° and 48°. This translates to a slightly more hydrophobic behavior against water. All coated surfaces exhibited contact angles below 90°, in most cases between 31° and 60°, implying all catechol-modified surfaces are hydrophilic and water droplets exhibit good wetting properties. I


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near-covalent elastic moduli. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (7), 2651−2655. (15) Krogsgaard, M.; Behrens, M. A.; Pedersen, J. S.; Birkedal, H. Self-healing mussel-inspired multi-pH-responsive hydrogels. Biomacromolecules 2013, 14 (2), 297−301. (16) Kim, B. J.; Oh, D. X.; Kim, S.; Seo, J. H.; Hwang, D. S.; Masic, A.; Han, D. K.; Cha, H. J. Mussel-mimetic protein-based adhesive hydrogel. Biomacromolecules 2014, 15 (5), 1579−1585. (17) Lee, B. P.; Dalsin, J. L.; Messersmith, P. B. Synthesis and Gelation of DOPA-Modified Poly(ethylene glycol) Hydrogels. Biomacromolecules 2002, 3 (5), 1038−1044. (18) Goldmann, A. S.; Schödel, C.; Walther, A.; Yuan, J.; Loos, K.; Müller, A. H. E. Biomimetic Mussel Adhesive Inspired Clickable Anchors Applied to the Functionalization of Fe3O4 Nanoparticles. Macromol. Rapid Commun. 2010, 31 (18), 1608−1615. (19) Wilms, V. S.; Bauer, H.; Tonhauser, C.; Schilmann, A. M.; Muller, M. C.; Tremel, W.; Frey, H. Catechol-initiated polyethers: multifunctional hydrophilic ligands for PEGylation and functionalization of metal oxide nanoparticles. Biomacromolecules 2013, 14 (1), 193−199. (20) Thomas, A.; Bauer, H.; Schilmann, A.-M.; Fischer, K.; Tremel, W.; Frey, H. The “Needle in the Haystack” Makes the Difference: Linear and Hyperbranched Polyglycerols with a Single Catechol Moiety for Metal Oxide Nanoparticle Coating. Macromolecules 2014, 47 (14), 4557−4566. (21) Chung, H.; Glass, P.; Pothen, J. M.; Sitti, M.; Washburn, N. R. Enhanced adhesion of dopamine methacrylamide elastomers via viscoelasticity tuning. Biomacromolecules 2011, 12 (2), 342−347. (22) White, E. M.; Seppala, J. E.; Rushworth, P. M.; Ritchie, B. W.; Sharma, S.; Locklin, J. Switching the Adhesive State of Catecholic Hydrogels using Phototitration. Macromolecules 2013, 46 (22), 8882− 8887. (23) Xu, H.; Nishida, J.; Ma, W.; Wu, H.; Kobayashi, M.; Otsuka, H.; Takahara, A. Competition between Oxidation and Coordination in Cross-Linking of Polystyrene Copolymer Containing Catechol Groups. ACS Macro Lett. 2012, 1 (4), 457−460. (24) Black, K. C. L.; Liu, Z.; Messersmith, P. B. Catechol Redox Induced Formation of Metal Core−Polymer Shell Nanoparticles. Chem. Mater. 2011, 23 (5), 1130−1135. (25) Preuss, C. M.; Zieger, M. M.; Rodriguez-Emmenegger, C.; Zydziak, N.; Trouillet, V.; Goldmann, A. S.; Barner-Kowollik, C. Fusing Catechol-Driven Surface Anchoring with Rapid Hetero Diels− Alder Ligation. ACS Macro Lett. 2014, 3, 1169−1173. (26) Mattson, K. M.; Latimer, A. A.; McGrath, A. J.; Lynd, N. A.; Lundberg, P.; Hudson, Z. M.; Hawker, C. J. A facile synthesis of catechol-functionalized poly(ethylene oxide) block and random copolymers. J. Polym. Sci., Part A: Polym. Chem. 2015, 53 (23), 2685−2692. (27) Xie, J.; Xu, C.; Xu, Z.; Hou, Y.; Young, K. L.; Wang, S. X.; Pourmand, N.; Sun, S. Linking Hydrophilic Macromolecules to Monodisperse Magnetite (Fe3O4) Nanoparticles via Trichloro-striazine. Chem. Mater. 2006, 18 (23), 5401−5403. (28) Wei, Q.; Becherer, T.; Mutihac, R. C.; Noeske, P. L.; Paulus, F.; Haag, R.; Grunwald, I. Multivalent anchoring and cross-linking of mussel-inspired antifouling surface coatings. Biomacromolecules 2014, 15 (8), 3061−3071. (29) Wei, Q.; Becherer, T.; Noeske, P. L.; Grunwald, I.; Haag, R. A universal approach to crosslinked hierarchical polymer multilayers as stable and highly effective antifouling coatings. Adv. Mater. 2014, 26 (17), 2688−2693. (30) Wei, Q.; Krysiak, S.; Achazi, K.; Becherer, T.; Noeske, P. L.; Paulus, F.; Liebe, H.; Grunwald, I.; Dernedde, J.; Hartwig, A.; Hugel, T.; Haag, R. Multivalent anchored and crosslinked hyperbranched polyglycerol monolayers as antifouling coating for titanium oxide surfaces. Colloids Surf., B 2014, 122, 684−692. (31) Wei, Q.; Achazi, K.; Liebe, H.; Schulz, A.; Noeske, P. L.; Grunwald, I.; Haag, R. Mussel-inspired dendritic polymers as universal multifunctional coatings. Angew. Chem., Int. Ed. 2014, 53 (43), 11650− 11655.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.5b02441. Additional characterization data (Figures S1−S13) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (H.F.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS K.N. thanks the IRTG 1404 for financial support and Steffen Hildebrand for technical assistance. REFERENCES

(1) Waite, J. H.; Tanzer, M. L. Polyphenolic Substance of Mytilus edulis: Novel Adhesive Containing L-Dopa and Hydroxyproline. Science 1981, 212 (4498), 1038−1040. (2) Faure, E.; Falentin-Daudré, C.; Jérôme, C.; Lyskawa, J.; Fournier, D.; Woisel, P.; Detrembleur, C. Catechols as versatile platforms in polymer chemistry. Prog. Polym. Sci. 2013, 38 (1), 236−270. (3) Yu, M. E.; Hwang, J. Y.; Deming, T. J. Role of L-3,4dihydroxyphenylalanine in mussel adhesive proteins. J. Am. Chem. Soc. 1999, 121 (24), 5825−5826. (4) Ye, Q.; Zhou, F.; Liu, W. Bioinspired catecholic chemistry for surface modification. Chem. Soc. Rev. 2011, 40 (7), 4244−4258. (5) Lee, H.; Scherer, N. F.; Messersmith, P. B. Single-molecule mechanics of mussel adhesion. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (35), 12999−13003. (6) Lee, H.; Dellatore, S. M.; Miller, W. M.; Messersmith, P. B. Mussel-inspired surface chemistry for multifunctional coatings. Science 2007, 318 (5849), 426−430. (7) Lee, H.; Lee, K. D.; Pyo, K. B.; Park, S. Y.; Lee, H. Catecholgrafted poly(ethylene glycol) for PEGylation on versatile substrates. Langmuir 2010, 26 (6), 3790−3793. (8) Sedó, J.; Saiz-Poseu, J.; Busqué, F.; Ruiz-Molina, D. CatecholBased Biomimetic Functional Materials. Adv. Mater. 2013, 25 (5), 653−701. (9) Madhurakkat Perikamana, S. K.; Lee, J.; Lee, Y. B.; Shin, Y. M.; Lee, E. J.; Mikos, A. G.; Shin, H. Materials from Mussel-Inspired Chemistry for Cell and Tissue Engineering Applications. Biomacromolecules 2015, 16 (9), 2541−2555. (10) Patil, N.; Falentin-Daudré, C.; Jérôme, C.; Detrembleur, C. Mussel-inspired protein-repelling ambivalent block copolymers: controlled synthesis and characterization. Polym. Chem. 2015, 6 (15), 2919−2933. (11) Ryu, J. H.; Lee, Y.; Kong, W. H.; Kim, T. G.; Park, T. G.; Lee, H. Catechol-functionalized chitosan/pluronic hydrogels for tissue adhesives and hemostatic materials. Biomacromolecules 2011, 12 (7), 2653− 2659. (12) Dang, Y.; Quan, M.; Xing, C.-M.; Wang, Y.-B.; Gong, Y.-K. Biocompatible and antifouling coating of cell membrane phosphorylcholine and mussel catechol modified multi-arm PEGs. J. Mater. Chem. B 2015, 3 (11), 2350−2361. (13) Barrett, D. G.; Fullenkamp, D. E.; He, L.; Holten-Andersen, N.; Lee, K. Y.; Messersmith, P. B. pH-Based Regulation of Hydrogel Mechanical Properties Through Mussel-Inspired Chemistry and Processing. Adv. Funct. Mater. 2013, 23 (9), 1111−1119. (14) Holten-Andersen, N.; Harrington, M. J.; Birkedal, H.; Lee, B. P.; Messersmith, P. B.; Lee, K. Y.; Waite, J. H. pH-induced metal-ligand cross-links inspired by mussel yield self-healing polymer networks with J


Article

Macromolecules (32) Bailey, F. E. J.; Koleske, J. V. Poly(ethylene oxide); Academic Press: 1976. (33) Herzberger, J.; Niederer, K.; Pohlit, H.; Seiwert, J.; Worm, M.; Wurm, F. R.; Frey, H. Polymerization of Ethylene Oxide, Propylene Oxide, and Other Alkylene Oxides: Synthesis, Novel Polymer Architectures, and Bioconjugation. Chem. Rev. 2015, DOI: 10.1021/ acs.chemrev.5b00441. (34) Veronese, F. M.; Pasut, G. PEGylation, successful approach to drug delivery. Drug Discovery Today 2005, 10 (21), 1451−1458. (35) Alconcel, S. N. S.; Baas, A. S.; Maynard, H. D. FDA-approved poly(ethylene glycol)−protein conjugate drugs. Polym. Chem. 2011, 2 (7), 1442−1448. (36) Thompson, M. S.; Vadala, T. P.; Vadala, M. L.; Lin, Y.; Riffle, J. S. Synthesis and applications of heterobifunctional poly(ethylene oxide) oligomers. Polymer 2008, 49 (2), 345−373. (37) Mangold, C.; Wurm, F.; Frey, H. Functional PEG-based polymers with reactive groups via anionic ROP of tailor-made epoxides. Polym. Chem. 2012, 3 (7), 1714−1721. (38) Obermeier, B.; Wurm, F.; Mangold, C.; Frey, H. Multifunctional Poly(ethylene glycol)s. Angew. Chem., Int. Ed. 2011, 50 (35), 7988− 7997. (39) Podsiadlo, P.; Liu, Z.; Paterson, D.; Messersmith, P. B.; Kotov, N. A. Fusion of Seashell Nacre and Marine Bioadhesive Analogs: HighStrength Nanocomposite by Layer-by-Layer Assembly of Clay and L3,4-Dihydroxyphenylalanine Polymer. Adv. Mater. 2007, 19 (7), 949− 955. (40) Haller, C. M.; Buerzle, W.; Brubaker, C. E.; Messersmith, P. B.; Mazza, E.; Ochsenbein-Koelble, N.; Zimmermann, R.; Ehrbar, M. Mussel-mimetic tissue adhesive for fetal membrane repair: a standardized ex vivo evaluation using elastomeric membranes. Prenatal Diagn. 2011, 31 (7), 654−660. (41) Kainthan, R. K.; Janzen, J.; Levin, E.; Devine, D. V.; Brooks, D. E. Biocompatibility Testing of Branched and Linear Polyglycidol. Biomacromolecules 2006, 7 (3), 703−709. (42) Imran ul-haq, M.; Lai, B. F.; Chapanian, R.; Kizhakkedathu, J. N. Influence of architecture of high molecular weight linear and branched polyglycerols on their biocompatibility and biodistribution. Biomaterials 2012, 33 (35), 9135−9147. (43) Kainthan, R. K.; Hester, S. R.; Levin, E.; Devine, D. V.; Brooks, D. E. In vitro biological evaluation of high molecular weight hyperbranched polyglycerols. Biomaterials 2007, 28 (31), 4581−4590. (44) Lange, M.; Braune, S.; Luetzow, K.; Richau, K.; Scharnagl, N.; Weinhart, M.; Neffe, A. T.; Jung, F.; Haag, R.; Lendlein, A. Surface Functionalization of Poly(ether imide) Membranes with Linear, Methylated Oligoglycerols for Reducing Thrombogenicity. Macromol. Rapid Commun. 2012, 33 (17), 1487−1492. (45) First conference presentation of the CAGE structure: Niederer, K.; Schüll, C.; Johann, T.; Frey, H. at MACROMEX 2014, Nuevo Vallarta, Mexico, 2014. (46) In a recent thesis, synthesis and polymerization of the CAGE monomer has also been targeted: Shin, E.; Kim, B.-S. Mussel-inspired Polyglycerol: Synthesis and Versatile Surface Modification. Master Thesis, Ulsan National Institute of Science and Technology, 2015. (47) Mangold, C.; Dingels, C.; Obermeier, B.; Frey, H.; Wurm, F. PEG-based Multifunctional Polyethers with Highly Reactive VinylEther Side Chains for Click-Type Functionalization. Macromolecules 2011, 44 (16), 6326−6334. (48) Tonhauser, C.; Alkan, A.; Schömer, M.; Dingels, C.; Ritz, S.; Mailänder, V.; Frey, H.; Wurm, F. R. Ferrocenyl Glycidyl Ether: A Versatile Ferrocene Monomer for Copolymerization with Ethylene Oxide to Water-Soluble, Thermoresponsive Copolymers. Macromolecules 2013, 46 (3), 647−655. (49) Obermeier, B.; Wurm, F.; Frey, H. Amino Functional Poly(ethylene glycol) Copolymers via Protected Amino Glycidol. Macromolecules 2010, 43 (5), 2244−2251. (50) Mangold, C.; Wurm, F.; Obermeier, B.; Frey, H. Functional Poly(ethylene glycol)”: PEG-Based Random Copolymers with 1,2Diol Side Chains and Terminal Amino Functionality. Macromolecules 2010, 43 (20), 8511−8518.

(51) Fineman, M.; Ross, S. D. Linear method for determining monomer reactivity ratios in copolymerization. J. Polym. Sci. 1950, 5 (2), 259−262. (52) Sunder, A.; Hanselmann, R.; Frey, H.; Mülhaupt, R. Controlled Synthesis of Hyperbranched Polyglycerols by Ring-Opening Multibranching Polymerization. Macromolecules 1999, 32 (13), 4240−4246. (53) Avdeef, A.; Sofen, S. R.; Bregante, T. L.; Raymond, K. N. Coordination chemistry of microbial iron transport compounds. 9. Stability constants for catechol models of enterobactin. J. Am. Chem. Soc. 1978, 100 (17), 5362−5370. (54) Wu, W.; Wu, J.; Kim, J. H.; Lee, N. Y. Instantaneous room temperature bonding of a wide range of non-silicon substrates with poly(dimethylsiloxane) (PDMS) elastomer mediated by a mercaptosilane. Lab Chip 2015, 15 (13), 2819−2825. (55) Tong, W. L.; Tan, M. K.; Chin, J. K.; Ong, K. S.; Hung, Y. M. Coupled effects of hydrophobic layer and vibration on thermal efficiency of two-phase closed thermosyphons. RSC Adv. 2015, 5 (14), 10332−10340.

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Catechol Acetonide Glycidyl Ether (CAGE): A Functional Epoxide

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