Topologically Reversible Transformation of Tricyclic Polymer into

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

Topologically Reversible Transformation of Tricyclic Polymer into Polyring Using Disulfide/Thiol Redox Chemistry Aruna Kumar Mohanty,† Jihwa Ye,† Junyoung Ahn,‡ Taeil Yun,§ Taeheon Lee,† Kyung-su Kim,† Heung Bae Jeon,*,§ Taihyun Chang,*,‡ and Hyun-jong Paik*,† †

Department of Polymer Science and Engineering, Pusan National University, Busan 46241, Korea Division of Advanced Materials Science and Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea § Department of Chemistry, Kwangwoon University, Seoul 01897, Korea Downloaded via UNIV OF SUSSEX on July 11, 2018 at 14:42:21 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: A polyring capable of reversible growth and dissociation is synthesized from a tricyclic polystyrene (PS) prepared by combining atom transfer radical polymerization of a 4-arm star-shaped PS and azide−alkyne click reactions. In the preparation of the tricyclic PS, a coupling agent containing a disulfide linkage is used in the click cyclization reaction. The reduction of the disulfide linkage in the tricyclic PS results in an 8-shaped PS with thiol groups which on oxidation leads to a high molecular weight polyring. The topology transformation between the polymers occurs via reversible redox reaction of disulfide/thiol. The high molecular weight of the polyring is realized due to the formation of flexible S−S linkage between the 8shaped PSs. Their structures are confirmed by FT-IR, 1H NMR, SEC, and MALDI-TOF MS analyses. In addition, molecular weight control of the polyring according to polymer concentration has been confirmed through SEC analysis.

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INTRODUCTION

Despite significant progress in the synthesis of cyclic polymers, there are not many reports on polyrings. Furthermore, the number of coupled rings in the polyrings is very few. This might be due to its complex topology or lack of innovative application of chemistry. Hence, there remains an interest to synthesize polyring with higher repeat units in a more universal and convenient method. In a recent publication, Liu and co-workers36 reported a polycyclic polymer architecture with dozens of macrocyclic repeating unit from a dicyclic scaffold in the reversible photochemical [2 + 2] cycloaddition reaction. This work is also interesting in terms of property study due to reversible topology transformation. Previously, cyclic macromonomer with azide and alkyne functionalities could react to give a polyring consisted of a few units and resulted in a relatively low molecular weight (for example, Mp = 10 500 in SEC, six units of cyclic macromonomer).18 This limited growth might be due to the involvement of a more rigid hetero cyclic structure as a linkage group between the cycles. It has been known that the rubber vulcanizing system with only S−S cross-links shows higher solvent diffusion in comparison to the system with only C−C because the S−S linkages are more flexible than the C−C linkages.37 It has also been known that the redox potential of the disulfide (R−S−S−

The advances of controlled polymerization methods and chemistry have enabled polymer researchers to develop polymers of more complicated topologies than the usual linear polymers such as star-like,1,2 comb-like,1,3,4 dendrimer,5 and cyclic polymers6−8 over the past decades. The researches of cyclic and multicyclic polymers are vigorously pursued because they have unique properties due to more compact topology and the absence of chain ends.9−13 For example, the molecular topological constraints such as internal cross-links and physical knots in complex cyclic structures could influence the glass transition temperature and other physical properties.13−15 Tezuka and co-worker synthesized different topological multicyclic poly(THF)s, including fused,16,17 spiro,9 and bridged forms,18 with the introduction of intriguing synthetic techniques based on living polymerization as well as selfassembly protocols (electrostatic self-assembly and covalent fixation). Various topologically appealing multicyclic polymers including sun-shaped,19,20 tadpole-shaped,21−25 8-shaped,26,27 manacle-shaped,28 paddle-shaped polymers,29 and spiro form multicyclic polymer30 are also prepared through controlled radical polymerization or anionic polymerization. Our group has also reported multicyclic polymers, like theta-shaped bicyclic,31−33 8-shaped polymers,14 and cage-shaped tricyclic polymers,14,34,35 by combining atom transfer radical polymerization (ATRP) and click reactions. © XXXX American Chemical Society

Received: April 4, 2018 Revised: June 5, 2018

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DOI: 10.1021/acs.macromol.8b00714 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Scheme 1. Overall Synthesis of Polyring

with vinyl monomers in terms of chain transfer to disulfide in the presence of radical initiators. The chain-transfer constants for aromatic disulfides are typically around 2 orders of magnitude larger than for the aliphatic ones.48 However, these types of reaction or conventional radical polymerizations are not suitable for the preparation of well-defined structures due to fast irreversible chain-terminating reactions, such as radical coupling or disproportionation and/or transfer. Since past decade, ATRP has been introduced as robust method due to its tolerance to a range of monomers and solvents of different polarity.49 ATRP is used to prepare relatively very well-defined polymers containing S−S/thiol groups.39,43 The success of ATRP in the presence of such a disulfide monomer or initiator relies on the significantly lower transfer constants of thioethers. However, it has also been reported that when the catalyst was present at high concentration (ratio of catalyst to initiator 1:1), high radical concentration with faster polymerization led to the occurrence of coupling reactions (at 40% of monomer conversion) while lower amount of catalyst (ratio 0.2:1 to the initiator) could suppress significantly the coupling reactions in the polymers leading to narrower and more symmetrical molecular weight distributions of SEC traces.43 Hence, careful and judicious design of synthetic method is still needed for easy and universal synthesis of cyclic structure in order to understand their complexity, especially in multicylic polymers.

R′)/thiol couple depends on the nature of the substituents R and R′ and the reaction medium composition (solvent polarity, pH, presence of complex forming ions, etc.).38,39 Monterio and co-workers reported monocyclic and linear PS using the reversible coupling/cleavage of thiol/S−S groups.40 The conformational folding process in a sulfide containing proteins is also generally analyzed through a redox-coupled oxidative folding pathway of S−S-reduced proteins as it is important to design novel artificial enzymes.41 In a recent paper, the disulfide linkage in the dicyclic polymers prepared via ATRP and atom transfer radical coupling cyclization has uniquely been exploited to establish the presence of isomeric structures of the polymers.42 These topologically different polymer isomers could demonstrate varied properties in terms of the number of terminals, physical knots, and hydrodynamic size. These facts can also be envisioned for a complicated cyclic polymer system with internal S−S linkage which on reversible reductive cleavage may lead to complex polymer topologies through reversible transformations for the interest of structure− property study in polymer isomers. Disulfide/polysulfide polymers are interesting class of polymers due to their properties such as high resistance to strong organic reagents (ozone, chlorine, etc.) and UV light.40,43 The (bio)degradable S−S linkage can be cleaved in the presence of reducing agents,38,44 nucleophiles, electrophiles,45,46 or photochemically.47 The presence of S−S in the polymer provides a facile route to functionalized copolymers B

DOI: 10.1021/acs.macromol.8b00714 Macromolecules XXXX, XXX, XXX−XXX

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potential of 20 kV in positive mode. Mass calibration was performed using homemade PS standards. trans-2-(3-(4-tert-Butylphenyl)-2methyl-2-propenylidene)malononitrile (DCTB) was used as MALDI matrix. Potassium trifluoroacetate (KTFA) was used as cationization agent. They were dissolved in THF, and a small aliquot was deposited on a MALDI plate. Synthesis of Tetra-Arm Star-Shaped Precursor Polymer. Synthesis of Tetrafunctional Initiator, Pentaerythritol Tetrakis(2bromoisobutyrate) (1). The tetrafunctional initiator (1) was synthesized as follows: pentaerythritol (3.0 g, 22.03 mmol) and TEA (14.74 mL, 105.77 mmol) were added to dry THF (30 mL) in a N2purged round-bottom flask and then kept stirring for 1 h. 2Bromoisobutyryl bromide (13.07 mL, 105.77 mmol) in THF (20 mL) was injected dropwise into the flask over 30 min at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature overnight. The mixture was transferred to a 1 L separating funnel with 300 mL of diethyl ether and extracted with 200 mL of H2O consecutively three times. The organic phase was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The product was isolated as white crystals after recrystallization in hexane (yield: 9.5 g, 57%). The structure is confirmed by 1H NMR (Figure S1) and FT-IR spectroscopy (Figure S3). 1H NMR (500 MHZ, CDCl3): δ (ppm) = 4.33 (s, 8H), 1.94 (s, 24H). 13C NMR (125 MHz, CDCl3): δ 170.9, 62.7, 55.2, 43.6, 30.6. HRMS (ESI) Calcd for C21H32Br4O8Na [M + Na]+: 754.8687 (100%), 752.8708, 756.8667. Found: 754.8689 (100%), 752.8714, 756.8667. Anal. Calcd for C21H32Br4O8: C, 34.45; H, 4.41. Found: C, 34.71; H, 4.57. Synthesis of Tetra-Arm Star PS (2). A dried 250 mL Schlenk flask was charged with 1 (1.52 g, 2.07 mmol), CuBr (0.29 g, 1.99 mmol), and CuBr2 (0.02 g, 0.10 mmol). After sealed with glass stopper, the flask was evacuated and backfilled with N2 three times. Then, degassed styrene (60.0 mL, 523.67 mmol), anisole (18 mL), and PMDETA (0.43 mL, 2.07 mmol) were added to the flask via N2-purged syringes. The mixture was reacted in an oil bath at 95 °C. At 20% monomer conversion (measured by gas chromatography), the polymerization was quenched by THF and exposed to air. Then, reaction mixture was passed through a neutral alumina column to remove Cu catalyst. After being concentrated using a rotary evaporator, the solution was dropped into methanol to obtain polymer as precipitates. The polymer was isolated as white powder (10.5 g) after filtration and drying under vacuum. The Mw,app = 4900, and the molecular weight dispersity Đ = Mw/Mn = 1.05 (Mw,LS = 5800, Đ = 1.03). Azidation of Tetra-Arm Star PS (3). A dried 100 mL round-bottom flask was charged with 2 (7 g, 1.27 mmol), sodium azide (0.41 g, 6.36 mmol), and DMF (70 mL). The reaction mixture was stirred at room temperature overnight. The polymer was purified by extraction with chloroform (300 mL) and deionized water (200 mL). This process was repeated for three times. The organic phase was dried over MgSO4 and filtered, and the solvent was evaporated. The product was dissolved in THF and precipitated in methanol. The polymer was isolated as white powder (6.7 g) after filtration and vacuum drying. The Mw,app = 4900 and Đ = 1.05 (Mw,LS = 5900, Đ = 1.03). The chainend functionality of 3 was determined as 89% by 1H NMR. Synthesis of Tricyclic Polymers. Synthesis of Coupling Agent Containing a Disulfide, Bis[2,3-di(2-propynyloxy)propyl] Disulfide (4). Bis[2,3-di(2-propynyloxy)propyl] disulfide is synthesized in two steps. First, synthesis of bis(2,3-dihydroxypropyl) disulfide: a solution of 1-thioglycerol (5.0 g, 46 mmol) in DMSO (20 mL) was stirred overnight at 90 °C. The excess of the DMSO was removed from the reaction mixture by distillation under vacuum. The residue, desired disulfide product, was used for next step without any purification. 1H NMR (400 MHz, D2O): δ (ppm) = 3.97−3.93 (m, 2H), 3.65 (dd, J = 12.0, 3.6 Hz, 2H), 3.55 (dd, J = 12.0, 6.0 Hz, 2H), 2.93 (dd, J = 14.0, 4.0 Hz, 2H), 2.78−2.70 (m, 2H). Second, synthesis of bis[2,3-di(2propynyloxy)propyl] disulfide: sodium hydride (NaH, 0.8 g, 20 mmol, 4.2 equiv) was added into a solution of bis(2,3-dihydroxypropyl) disulfide (1.0 g, 4.7 mmol) in DMF (10 mL). The solution was stirred at 0 °C for 30 min under argon. Propargyl bromide (1.8 mL, 24 mmol, 5.0 equiv) was added slowly with stirring at 0 °C. After the addition of propargyl bromide, the reaction mixture was stirred at room

Here, we try to synthesize a high molecular weight polyring by oxidation of highly reactive thiol groups in the cyclic structures by formation of relatively more flexible internal S−S linkages. The overall preparation of polyring PS is shown in Scheme 1. First, the tricyclic PS is prepared by combining ATRP, end termini substitution with azide, and coppercatalyzed alkyne−azide cycloaddition (Cu-AAC) click reaction.50,51 The S−S linkage is introduced in to the tricyclic system by using a newly designed coupling agent containing S− S linkage during the click ring closure step rather than through the monomer or initiator in the ATRP step. This further rules out the chances of any eventual chain transfer because click reaction is carried out at relatively mild conditions with very dilute condition. The reductive cleavage of the S−S linkage in the tricyclic PS leads to a topology of 8-shaped PS (HS− − SH) with pendant thiol groups. The polyring PS ((−S− − S−)n) is thus synthesized in metal-ion-catalyzed oxidative coupling reaction of HS− −SH through formation of internal S−S linkages. Finally, the reversible redox cleavage of the internal S−S linkage of the synthesized polyring is demonstrated. Polymers can behave in three dimensions differently from its linear counterpart of the same molecular weight, which result in different hydrodynamic volume and gyration radii. Thus, redox transformation of topologies of the same polymer provides an opportunity to study structure−property in terms of the hydrodynamic volume change in the size exclusion chromatography (SEC) results.

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EXPERIMENTAL SECTION

Materials. Styrene (Junsei, 99.5%) was purified by passing through a basic alumina column to remove inhibitor. Copper(I) bromide (CuBr, Aldrich, 98.0%) was purified by stirring with glacial acetic acid for 24 h and filtered. Then, the resulting solid was washed four times with ethanol and twice with diethyl ether. The solid was dried under vacuum for 2 days. Tetrahydrofuran (THF, 100%) was dried over CaH2. Pentaerythritol (Aldrich, 99.0%), trimethylamine (TEA, Aldrich, 99.5%), copper(II) bromide (CuBr2, Aldrich, 98.0%), 2bromoisobutyryl bromide (Aldrich, 98.0%), N,N,N′,N″,N″pentamethyldiethylenetriamine (PMDETA, Aldrich, 98%), zinc dust (Aldrich, 98%), glacial acetic acid (Aldrich, 99%), iron(III) chloride (FeCl3, Aldrich, 97%), 1-thioglycerol (Aldrich, 97%), dimethyl sulfoxide (DMSO, Aldrich, 99.7%), N,N-dimethylformamide (DMF, Aldrich, 99.8%), sodium hydride (NaH, Aldrich, 95%), propargyl bromide (Aldrich, 80 wt % in toluene), and tris(2-carboxyethyl)phosphine hydrochloride (TCEP, Aldrich, 98%) were used as received. Magnesium sulfate (MgSO4, TCI), sodium azide (NaN3, TCI), and all other chemicals were used as received. Instruments. In the ATRP stage, monomer conversion was confirmed by the HP 5890 gas chromatograph (GC) equipped with a HP101 column (methyl silicone fluid, 25 m × 0.32 mm × 0.30 μm). The SEC experiment was carried out by two different systems. One system was equipped with an Agilent 1100 pump, a refractive index detector, and PSS SDV (5 μm, 105, 103, and 102 Å 300.0 × 8.0 mm) columns. Another system was equipped with a Bischoff HPLC compact pump, two silica-based columns (Shodex KW-802.5 and KW803, both 300 × 8.0 mm), and a Viscotek TDA302 detector (differential refractometry (RI) and light scattering (LS)). THF was used as an eluent at a flow rate of 0.8 mL/min. The apparent molecular weight was determined by PS calibration (Mapp), and/or the absolute molecular weight was determined by light scattering detection (MLS). 1H NMR spectra were obtained on a 400 or 500 MHz Agilent Superconducting FT-NMR spectrometer using CDCl3 as solvent. Infrared spectra were recorded on a Nicolet 6700 FT-IR spectrophotometer. A Bruker Autoflex speed mass spectrometer equipped with a 2 kHz smart beam-II laser was used for MALDITOF MS experiments. The instrument operated at an accelerating C

DOI: 10.1021/acs.macromol.8b00714 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. 1H NMR spectra of (a) bromo chain-end PS (2), (b) azido chain-end PS (3), (c) tricyclic PS (6), (d) 8-shaped PS (7), (e) polyring (8), and (f) after reduction of polyring. 389.0857. Found: 389.0856. Anal. Calcd for C18H22O4S2: C, 58.99; H, 6.05; S, 17.50. Found: C, 59.00; H, 6.19; S, 17.67. Synthesis of Tricyclic PSs Containing Disulfide (6). A dried 1 L round-bottom flask was charged with CuBr (1.35 g, 9.43 mmol). The flask was sealed with glass stopper and then evacuated and backfilled with N2 three times. Then, degassed THF (620 mL) and PMDETA (1.97 mL, 9.43 mmol) were added to the flask. 3 (0.5 g, 0.09 mmol) and 4 (35.0 mg, 0.09 mmol) dissolved separately in 20 mL of THF were degassed and added to the flask at 35 °C by a syringe pump at the rate of 0.6 mL/h. After complete injection of 3 and 4, the reaction mixture was kept at 35 °C for 5 h. The resulting mixture was passed through a neutral alumina column. THF was removed by a rotary

temperature for 6 h. The reaction mixture was quenched with H2O and extracted with ethyl ether. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc = 7/1) to give the desired product (yield: 0.86 g, 50%). The structure is confirmed by 1H NMR (Figure S2) and FT-IR spectroscopy (Figure S3). 1H NMR (400 MHz, CDCl3): δ (ppm) = 4.34 (d, J = 2.4 Hz, 4H), 4.21 (d, J = 2.4 Hz, 4H), 4.03−3.97 (m, 2H), 3.78−3.69 (m, 4H), 3.02−2.93 (m, 4H), 2.48 (t, J = 2.4 Hz, 2H), 2.46 (t, J = 2.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 79.7, 79.4, 76.23, 76.21, 74.83, 74.75, 70.1, 58.6, 57.4, 40.3, 40.2. HRMS (ESI) Calcd for C18H22O4S2Na [M + Na]+: D

DOI: 10.1021/acs.macromol.8b00714 Macromolecules XXXX, XXX, XXX−XXX

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group (−CH2C(Ph)H−Br) in the 1H NMR spectrum. The bromines at chain-end groups of 2 were completely transformed to azido groups in the reaction with sodium azide in DMF as the signal of methine proton was shifted from 4.4 to 3.9 ppm in 1H NMR spectroscopy (Figure 1). The azido chainend functionality of 3 was determined as ∼89% using 1H NMR spectroscopy. The azido chain-end functionality could also be confirmed with appearance of a new peak at 2093 cm−1 in the FT-IR spectrum (Figure S6). Synthesis and Characterization of Tricyclic PS Containing a S−S Bond. Tricyclic PS 6 containing a S−S bond was prepared in a Cu-AAC click reaction between the azido-terminated tetra-arm star PS (3) and terminal alkynes of a coupling agent (4) containing a S−S linkage. The coupling reaction was carried out under dilute solution (0.8 g/L) to minimize side reaction such as high molecular weight branched polymers formation by intermolecular coupling.31 In Figure 2, after the cyclization the peak elution time (tp) of 3 (26.0 min) changed to 26.9 min for the PS 6. In the SEC traces, azidoterminated precursor showed the apparent peak molecular weight, Mp,app = 4700, whereas the PS 6 showed Mp,app = 3500. However, there was no significant change in the absolute peak

evaporator. Purity of tricyclic PS containing a S−S was estimated from SEC traces using Gaussian multiple peak fitting and subsequent peak integration. The cyclic PS was separated from the byproducts (5) using preparative SEC. The Mw,app = 3200 and Đ = 1.05 (Mw,LS = 6000, Đ = 1.02). Synthesis of 8-Shaped PS (7). A dried 250 mL Schlenk flask was charged with 6 (250 mg, 0.04 mmol) and zinc dust (573.60 mg, 8.77 mmol). The flask was sealed with a glass stopper and then evacuated and backfilled with N2 three times. Then, degassed THF (97 mL) and glacial acetic acid (0.50 mL, 8.77 mmol) were added to the flask via N2 purged syringes. The mixture was stirred at 40 °C for 10 h. The reaction mixture was passed through a basic alumina column and precipitated in methanol. The precipitates were filtered and dried in a vacuum oven overnight. The resulting product was analyzed by SEC. Synthesis of Polyring (8). FeCl3 (113.82 mg, 0.70 mmol) and 7 (80 mg, 0.01 mmol) were added to DMF (1 mL) in a 5 mL flask. The reaction mixture was stirred at 60 °C for 24 h. The reaction mixture was passed through a neutral alumina column and precipitated in methanol. The precipitates were filtered and dried in a vacuum oven overnight. The final product was analyzed by SEC. Reduction of Polyring. A dried 25 mL Schlenk flask was charged with 8 (30 mg) and TCEP (226.30 mg, 0.79 mmol). The flask was sealed with glass stopper and then evacuated and backfilled with N2 three times. Then, degassed DMF (3 mL) and deionized water (0.03 mL, 1.58 mmol) were added to the flask via N2-purged syringes. The mixture was stirred at room temperature for 24 h. The mixture was transferred to a 500 mL separating funnel with 200 mL of chloroform and extracted with 100 mL of H2O. This process was repeated three times. The organic phase was dried using MgSO4 and filtered. The resulting solution was concentrated using a rotary evaporator and poured into methanol to polymer precipitates. Then, the polymer was filtered and dried under vacuum. The final product was analyzed by SEC.

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RESULTS AND DISCUSSION ATRP has been used to prepare successfully a wide variety of well-defined polymeric materials including functional polymers in contrast to conventional radical polymerization having concerns of irreversible terminating reactions, such as radical coupling or disproportionation and/or transfer sensitive to monomer or initiator functional groups, particularly in the presence of disulfides/thiols.39,43 For example, a polymerization of MMA with 1.2 mol % of bis(2-methacryloyloxyethyl) disulfide ((MAOE)2S2) in the presence of 2,2′-azobis(2,4dimethyl-4-methoxyvaleronitrile) (V-70) as radical initiator resulted in a gel at 47% monomer conversion in contrast to 80% monomer conversion for gel formation in ATRP while maintaining the same reaction conditions.39 This indicates that in conventional radical polymerization the incorporation of the difunctional monomer is far less uniform, and the gel point is reached at markedly lower conversion than in ATRP due to undesired side reactions. The well-controlled molecular weight, narrow molecular weight distribution, and high degree of chainend functionalization are achieved in ATRP due to the rapid equilibrium between the active radicals and the dormant species.49 The bromo-terminated tetra-arm star PS, 2 was prepared by ATRP using a tetrafunctional initiator, pentaerythritol tetrakis(2-bromoisobutyrate) (1). The conversion of styrene was estimated about 20% by GC. The 1H NMR spectrum of 2 is shown in Figure 1. Each arm of 2 has 12 styrene units on the average determined by NMR analysis (Mn,NMR = 5565). The bromo chain-end functionality of 2 was also confirmed as ∼89% by comparing methyl protons (0.97−0.70 ppm) at the tetrafunctional initiator part (−OC(O)C(CH3)2−) to methine proton (4.59−4.36 ppm) adjacent to the terminal bromide

Figure 2. SEC traces of (a) all the synthesized polymers and (b) polyring from the oxidation of the 8-shaped PS (7) at three different polymer concentrations. The vertical dashed bars indicate the integration ranges to estimate the relative amounts of polyrings and tricyclic PS as listed in Table 1. Black solid line represents the PS standard calibration line. E

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while the signal due to combined methine (HS− CH2CHOCH2O−) and methylene (HS−CH2CHOCH2O−) protons adjacent to oxygen in the coupling agent appeared at 3.6 ppm. The polymer 7 with two difunctional mercaptan groups can be further used for the preparation of higher molecular weight polyring with internal S−S linkages ((−S− −S−)n). Oxidation of thiols is generally achieved with atmospheric oxygen, iodine, and metal salts. The ability of common metal ions to catalyze oxidation of thiols are in the order Cu2+ > Fe3+ > Ni2+ ≫ Co2+.55 In the redox reaction of thiol/disulfide, strong oxidizing agents is generally avoided because they can oxidize the thiol groups to sulfinate or sulfonate groups, thus preventing the possibility of reversible coupling. Here, the oxidation was carried out in the presence of FeCl3 in DMF.40,56 The reaction is carried out at three different concentrations of PS 7 as shown in Table 1. The SEC traces of the product are

molecular weight as determined by light scattering (Mp,LS = 5600, 3 and Mp,LS = 5900, 6). Thus, the tricyclic PS showed a longer elution time than its precursor azido-terminated star PS in the SEC traces due to its compact hydrodynamic volume. A broad multimodal peak was also observed at earlier retention time in comparison to the monomodal peak corresponding to tricyclic PS (Figure S5). Thus, there was simultaneous formation branched PS 5 as impurity along with tricyclic PS during the coupling reaction as evidenced by SEC. Complex branched polymers are formed even under a highly dilute condition because the click coupling reaction to create tricyclic PS is a competitive reaction between intermolecular and intramolecular coupling. Moreover, the reaction gets further complicated with loss of chain-end functionality in the precursor PS as ATRP is not a true living reaction.49 The precursor with imperfect end-functionality produce branched polymers: 3 (end-functionality, 89%) on coupling with 4 produces 5 with residual reactive acetylene groups which can react with the terminal azides of precursors resulting in high molecular weight branched polymers.14,31 Other potential sources of the higher molecular weight impurities may come from the loss of alkyne end group in Glaser coupling during polymerization.52 The purity of the tricyclic PS was determined by Gaussian multiple peak fitting of the SEC traces and peak integration and found as 63% (Figure S5). The undesired branched PS was removed using preparative SEC. The structure of the pure fraction of tricyclic PS 6 was characterized by 1H NMR spectroscopy. The cyclization was confirmed with appearance of a new signal at around 4.5 ppm due to methylene protons adjacent to the triazole group and the shift in the signal for methine proton of 3 from 3.9 to 5.1 ppm (Figure 1).53,54 In the FT-IR spectrum, the peak due to azide group at around 2100 cm−1 also disappeared after cyclization (Figure S6). Synthesis and Characterization of Polyring. In the synthesis of the PS 8 (Scheme 1), 8-shaped PS ((HS− −SH), 7) was first synthesized from PS 6. The S−S linkage in the PS 6 can be easily cleaved in the presence of reducing agents, leading to polymers with thiol groups. A variety of reagents for the reductive cleavage of the S−S linkage are described in the literature, due to their wide use in biochemistry, mostly to cleave the cystine S−S bridge in polypeptides and proteins.38 Here, the reduction of the S−S linkage in the tricyclic PS was carried out in THF in the presence of zinc and acetic acid.40 The degree of reduction could be conveniently followed by SEC. Oxygen responsible for possible coupling is removed by degassing the solutions and reagents with N2 bubbling. Very dilute condition was also preferably maintained to prevent any intermolecular coupling. The S−S linkage in the tricyclic PS was reduced in 48 h at 60 °C. In SEC, the 8-shaped PS was eluted earlier than tricyclic PS, implying higher apparent molecular weight of 7 than 6 (Figure 2) even though in reality there should not be any measurable change in molecular weight due to the ring-opening. The change in Mp,app in SEC is due to the larger hydrodynamic volume of PS 7 than PS 6. The fact that there should be no change in absolute molecular weight due to topology change was also confirmed from the Mp values obtained from the light scattering detection (Mp,LS = 5900, 6 and Mp,LS = 5800, 7). A small peak at a lower elution time also appeared in the SEC trace of the PS 7, indicating possible partial coupling during the precipitation of polymer in methanol.43 In the NMR spectrum of 7 (Figure 1), the signal at 2.8 ppm of PS 6 shifted to 2.6 ppm due to the methylene protons adjacent to the thiol group (HS−CH2CHOCH2O−)

Table 1. Conditions for the Preparation of Polyring after oxidation expt 1 2 3

a

[HS−

−1 b

−SH] (mol L ) −3

6.86 × 10 1.02 × 10−2 1.40 × 10−2

MW,LSc

Đd

Ae

30200 41600 50300

2.70 3.15 3.67

58:42 63:37 65:35

a

In the experiment,8-shaped PS with two pendant thiol groups was oxidized to polyring using FeCl3. bConcentration of 8-shaped PS (Đ = 1.03) during oxidation. cAbsolute weight-average molecular weight of the mixture of polyring with tricyclic PS formed alongside in the oxidation process. dPolydispersity index of the mixture of polyrings with tricyclic PS formed alongside in the oxidation process. eRatio of integration of polyrings to tricyclic PS (see Figure 2b).

shown in Figure 2b. The oxidation was efficient because after 24 h, the reaction lead to the formation of polyring 8 of a broad multimodal peak of sufficiently higher molecular weight of several hundred thousand (>100 000). At all the concentrations of the PS 7, the SEC curve also showed a low molecular weight peak ((Mp,app = 3500) which was lower than the starting polymer 7 corresponding to the formation of original tricyclic PS 6 of a reduced hydrodynamic volume along with the polymerization of PS 7 (dimer, trimer, tetramer, etc.) with internal S−S linkages. It has also been observed that the oxidation led to formation of higher molecular weight polyring with broad distribution with increasing concentration of the polymer 7 in the reaction and the highest concentration (1.4 × 10−2 M) yielded the highest molecular weight of polyring in the series. This indicates a kind of step-growth polymerization as broad higher molecular weight of polyrings could be synthesized with increasing conversion of the increased concentration of PS 7 in the reaction. However, the mechanism of thiol−thiol coupling is not simple and is complicated by various side reactions including exchange reaction between the thiol−disulfides. In NMR spectrum of 8 (Figure 1), the signal at 2.6 ppm of PS 7 shifted to 2.8 ppm due to methylene protons adjacent to the disulfide group (−S−S−CH2CHOCH2O−) while the signal of methine (−S−S−CH2CHOCH2O−) shifted from 3.6 to 3.8 ppm and methylene (−S− S−CH2CHOCH2O−) protons adjacent to oxygen shifted from 3.6 to 3.5 ppm. Interestingly, the S−S linkage in the polyring 8 can be readily cleaved back to thiol-terminated polymers of lower molecular weight by reducing agents. Since the redox potential of the F

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Figure 3. MALDI-TOF MS of the synthesized polymers in (a). (b) and (c) represent the expanded spectra.

methylene protons adjacent to the thiol group (HS−CH2CHOCH2O−) while the signal due to combined methine (HS− CH2CHOCH2O−) and methylene (HS−CH2CHOCH2O−) protons adjacent to oxygen at the coupling agent part shifted to 3.6 ppm. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is being increasingly used for polymer characterization in recent years for analysis of the chemical structure of repeating units and chain endfunctionality of low-MW synthetic polymers as well as sideproducts. MALDI is one of the most widely used soft ionization methods to analyze polymers, and its success depends on the preparation of sample considering desired compatibility among the matrix, the analyte polymer, and the cationization salt. The results of MALDI-TOF MS of the synthesized polymers are shown in the reflection mode in Figure 3. In the figure, the overall MALDI-MS peak envelops of all the polymers showed nearly the same molecular weight distribution centered around 5900, in agreement with the molecular weight determined by SEC-MALLS and 1H NMR. For 2, the major peak series were formed upon elimination of HBr during the MALDI process leaving a double bond at the terminal styrene unit (53mer, m/ zobs: 5967.6, m/zcal: 5967.5, C445H452O8K+). The few subsidiary peaks could be due to the sample preparation or reaction of terminal Br in the MALDI process.57 MS analysis of 3 showed a complex spectrum as expected in agreement with the previous MS characterizations.14 The expanded spectra near the maxima of the peak envelopes are shown in Figure 3b,c for more

thiol/disulfide couple depends on the polarity, composition of the reaction medium, and the nature of polymer, the decomposition rate of the polymers can be controlled by changes in the medium.38,43 In this study, TCEP was used to reduce the S−S linkage to thiols. In the presence of moisture, phosphines reduce the S−S linakge quantitatively and hence have been widely used in the study of proteins.38 Here, at first the phosphine nucleophile attacks of the S−S bond in a ratelimiting step forming a thiophosphonium salt. Next, rapid hydrolysis releases the second thiol fragment and the phosphine oxide. Thus, phosphines do not interfere with reagents typically used to bind to the formed thiol groups, which is especially important in protein analysis. In contrast to dithiothreitol (2,3-dihydroxy-1,4-butanethiol, DTT), it has major advantages of relative stability toward auto-oxidation and high affinity to S−S groups. This implies that large excess of this reagent is not needed for complete reduction.44 TCEP also dissolves readily in various organic compounds. The reduction was carried out at room temperature in DMF under ambient temperature and was completed in 48 h by following in SEC. The solutions and reagents were bubbled with nitrogen prior to the reaction to avoid any oxidative coupling of the eventually formed thiols. In Figure 2, on reduction the multimodal peak of polyring 8 was converted back to the starting thiols with a monomodal peak (Mp,app = 3600, Mp,LS = 6300) which was almost identical to the PS 7 obtained by ringopening of the tricyclic PS 6. In the 1H NMR spectrum (Figure 1), reduction shifted the signal from 2.8 to 2.6 ppm due to the G

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Macromolecules detailed analysis. The mass spectrum of 6 showed the potassium adducts of the expected tricyclic product along with some byproduct species. The m/z value for the mass distribution of 6 for 48 mer was found to be 5985.2, in excellent agreement with the calculated value (m/z cal : 5985.3, C423H438N12O12S2K+), indicating that the target tricyclic PS was synthesized successfully. For 7, the major peak series were formed due to ring-opening process of the tricyclic PS leading to 8-shaped PS having thiol groups (48 mer, m/zobs: 5987.3, m/ zcal: 5987.3, C423H440N12O12S2K+) with number of subsidiary peaks. In the MS of 8, the major series were formed due to S−S cleavage of the target polyring along with few minor peaks (48 mer, m/zobs: 5985.3, m/zcal: 5985.3, C423H438N12O12S2K+). In addition, reduction of polyring resulted in a major series of 8shaped PS in which the m/z value was measured as 5987.4 that is in good agreement with the calculated m/z value of 5987.3 for 48 mer of 7 (C423H440N12O12S2K+). This shows that the products 6−8 were obtained with reversible transformation of topology in excellent agreement with MALDI-TOF MS.

Author Contributions

CONCLUSIONS In this work, the polyring 8 with ability for reversible topology transformation was successfully synthesized with high molecular weight. We first synthesized the tricyclic PS 6 containing S−S functionality by combining ATRP and Cu-AAC click chemistry. Then, the PS 6 was converted into 8-shaped PS 7 with pendent thiols in a reduction reaction. Finally, the oxidation of thiols in PS 7 into S−S functionality enabled a high molecular weight polyring with rings connected through internal S−S linkages. In addition, the polyring could be converted back again to the PS 7 up on reduction of the S−S linkage. Thus, this new synthesis method is also an interesting study in a sense that one structure of tricyclic PS (6) could be converted into several structures such as 8-shaped PS (7) and polyring (8) depending on reversible reaction conditions. Besides, the scope of disulfide/thiol chemistry allows for the 8shaped PS with thiol groups to act as a cyclic macromonomer for reaction with various cyclic/acyclic macromonomer to expand into copolymers of totally new hybrid structures and properties.

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A.K.M., J.Y., and J.A. contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF2018R1A2B6005119). This work was supported by the Industrial Strategic Technology Development Program (10070127) funded by the Ministry of Trade, Industry and Energy (MOTIE) of Korea. T.C. acknowledges the support from NRF-Korea (2015R1A2A2A01004974 and 2016K2A9A1A06919960). H.B.J. thanks the research grant of Kwangwoon University in 2017.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b00714. 1 H NMR spectrum of initiator (1), coupling agent (4), and tricyclic PS (6), FT-IR spectra of 1 and 4, and polymers (2, 3, and 6), and SEC traces of precursor PS (3) and after click coupling (5) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*(H.P.) Tel +82-51-510-2402; e-mail [email protected]. *(T.C.) Tel +82-54-279-2109; e-mail [email protected]. *(H.B.J.) Tel +82-2-940-5583; e-mail [email protected]. ORCID

Aruna Kumar Mohanty: 0000-0001-5623-9510 Heung Bae Jeon: 0000-0001-6896-5499 Taihyun Chang: 0000-0003-2623-1803 Hyun-jong Paik: 0000-0002-0821-9096 H

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