Aqueous RAFT Photopolymerization with Oxygen ... - ACS Publications

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Aqueous RAFT Photopolymerization with Oxygen Tolerance Sivaprakash Shanmugam,*,† Jiangtao Xu,† and Cyrille Boyer*,†,‡ †

Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, and ‡Australian Centre for NanoMedicine, School of Chemical Engineering, UNSW Australia, Sydney, NSW 2052, Australia S Supporting Information *

ABSTRACT: The emergence of light regulated controlled/ living radical polymerization adds a new layer of control over polymerization. Light mediated polymerizations afford simple and facile route to modulate polymerization rate through manipulation of light intensity and by switching on/off the light source. Such mediation has resulted in the synthesis of 3D surfaces with both spatial and temporal control. However, these techniques present a major limitation in terms of oxygen tolerance and require the use of organic solvent. In this contribution, we report an efficient aqueous polymerization system capable of being activated under visible light in the presence of oxygen. We perform aqueous photopolymerization in the presence of water-soluble zinc porphyrin photocatalyst (Zn(II) meso-tetra(4-sulfonatophenyl)porphyrin, ZnTPPS4−) with ascorbic acid as singlet oxygen quencher in both open and closed vessels. Polymers could be prepared without prior deoxygenation with good control over the molecular weight and polydispersity. In addition, polymerization in the presence of air could be achieved with a short inhibition period.

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presence of oxygen rapidly oxidizes CuI activator to CuII, which is then reduced back to CuI in the presence of a reducing agent.67 The removal of oxygen only upon attachment to metals may lead to unwanted inhibition period as polymerization can only be initiated after complete removal of oxygen from the system.66 Recently, our group focused on providing oxygen tolerance in RAFT photopolymerizations through the use of metal-based photocatalysts, which can transfer energy to triplet oxygen (3O2) to generate singlet oxygen (1O2).83−86 Unlike triplet oxygen, singlet oxygen (1O2) is an energetic, electrophilic molecule that can react rapidly with electron-rich molecules such as ascorbic acid,87,88 thioether, 89,90 sulfone compounds,91,92 and others.93 In our previous works, we were able to carry out successful polymerizations without removal of air; however, our systems we limited by the use of organic solvents, such as dimethyl sulfoxide (DMSO).83−86,92 In an effort to promote green chemistry and accommodate RAFT photopolymerizations under biologically relevant conditions, we developed a polymerization system in water using a water-soluble zinc porphyrin photocatalyst (Zn(II) meso-tetra(4-sulfonatophenyl)porphyrin, ZnTPPS4−)). Successful polymerizations were achieved at room temperature in neutral pH. Unfortunately, this system did not provide oxygen tolerance in water.

INTRODUCTION Commercial synthesis of high molecular weight polymers rely on the use of free radical polymerization (FRP) as this technique affords synthesis of polymers and copolymers with different functional monomers in green solvents such as water.1 As FRP often leads to synthesis of polymers with poor regulation of molecular weights and molecular weight distributions, controlled/living radical polymerization (CLRP) techniques such as atom transfer radical polymerization (ATRP),2−5 reversible addition−fragmentation chain transfer polymerization (RAFT),6−10 and nitroxide mediated polymerization (NMP)11−13 were introduced to regulate chain growth for precise polymer synthesis. A recent advent in RAFT, NMP, and ATRP, led by Hawker and Fors,14−19 Matyjaszewski,20−24 Haddleton and Anastasaki,25−29 Yagci,30−33 Johnson,34−36 Miyake,37,38 Lalevee and Poly,39−41 Qiao,42−44 Kamigaito,45,46 Cai,47,48 Junkers,49−53 and others,54−65 has seen a surge in visible light mediated polymerization for the synthesis of polymers and materials with spatial and temporal control. Nevertheless, one of the major disadvantages of controlled/ living radical polymerization (CLRP) in both thermal and light mediated polymerizations is the premature termination of growing chains in the presence of oxygen.66,67 In order to overcome this limitation, ATRP systems,68 such as AGET and ARGET ATRP,67,69−71 and single electron transfer polymerization living radical polymerization (SETLRP)72−75 have been developed to accommodate limited amounts of air by using reducing agents such as tin(II) 2ethylhexanoate,76 glucose,77 hydrazine,70 phenols,78 amines,79 copper(0),30,80−82 and ascorbic acid.69,70 In these systems, the © 2016 American Chemical Society

Received: September 21, 2016 Revised: November 10, 2016 Published: December 14, 2016 9345

DOI: 10.1021/acs.macromol.6b02060 Macromolecules 2016, 49, 9345−9357

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Figure 1. Investigating the effects of ascorbic acid on RAFT photopolymerization at pH 7.6 by monitoring online Fourier transform near-infrared (FTNIR) measurement of DMA polymerization at room temperature using ZnTPPS4− as the photoredox catalyst under red light irradiation (λmax = 635 nm, intensity = 0.828 mW/cm2) with BTPA-PEG750 as the chain transfer agent ([DMA]:[BTPA-PEG750]:[ZnTPPS4−] = 300:1:1.5 × 10−2, 10 M monomer concentration with 50 ppm catalyst concentration). (A) Plot of ln([M0]/[M]t) vs exposure time for degassed reaction vessels in the presence and absence of ascorbic acid. (B) Plot of ln([M0]/[M]t) vs exposure time for reaction in the presence/absence of ascorbic acid and oxygen. (C) Plot of Mn vs conversion for degassed reaction in the absence of ascorbic acid. (D) GPC profiles for evolution of molecular weight at different time points for degassed reaction in the absence of ascorbic acid. (E) Plot of Mn vs conversion for degassed reaction in the presence of ascorbic acid. (F) GPC profiles for evolution of molecular weight at different time points for degassed reaction in the presence of ascorbic acid. (G) Plot of Mn vs conversion for polymerization in the presence of oxygen and ascorbic acid. (H) GPC profiles for evolution of molecular weight at different time points for polymerization in the presence of oxygen and ascorbic acid. 9346


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Figure 2. Effects of ascorbic acid on temporal control of RAFT photopolymerization at pH 7.6 by monitoring online Fourier transform near-infrared (FTNIR) measurement of DMA polymerization at room temperature using ZnTPPS4− as the photoredox catalyst under red light irradiation (λmax = 635 nm, intensity = 0.828 mW/cm2) with BTPA-PEG750 as the chain transfer agent ([DMA]:[BTPA-PEG750]:[ZnTPPS4−] = 300:1:1.5 × 10−2, 10 M monomer concentration). (A) “ON/OFF” online FTNIR kinetics for degassed reaction vessels in the absence of ascorbic acid. (B) “ON/OFF” online FTNIR kinetics for [RAFT]:[ascorbic acid] = 1:1 for degassed reaction vessels in the presence of ascorbic acid. (C) “ON/OFF” online FTNIR kinetics for [RAFT]:[ascorbic acid] = 1:1 for polymerization in the presence of oxygen and ascorbic acid.

Interestingly, previous studies on ZnTPPS4− have been focused on exploiting the generation of reactive oxygen species (1O2) in photodynamic therapy for melanoma94 and antimicrobial resistance.95 Therefore, we concurred that the addition of a compound capable of reacting with singlet oxygen such as ascorbic acid will aid in rapid removal of reactive singlet oxygen species generated by ZnTPPS4− and avoid unwanted inhibition period. In this contribution, we introduce a novel route for oxygen tolerance in aqueous polymerization by the use of ascorbic acid to remove singlet oxygen generated upon interaction of triplet oxygen with excited state zinc porphyrin.

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acetamide (DMAc). The DMAc instrument consists of a Shimadzu modular system with an autoinjector and a Phenomenex 5.0 μM bead size guard column (50 × 7.5 mm) followed by four Phenomenex 5.0 μM bead size columns (105, 104, 103, and 102 Å), a differential refractive-index detector, and a UV detector (λ = 305 nm). DMAc GPC was calibrated based on narrow molecular weight distribution of polystyrene and poly(methyl methacrylate) standards with molecular weights of 200−106 g mol−1. Nuclear Magnetic Resonance (NMR). NMR spectroscopy was carried out with a Bruker Avance III HD operating at 400 and 600 MHz for 1H using CDCl3, MeOD, and DMSO-d6 as solvents. Tetramethylsilane (TMS) was used as a reference with chemical shift (δ) of sample measured in ppm downfield from TMS. Online Fourier Transform Near-Infrared (FTNIR). FTNIR was used to determine monomer conversion by mapping the decrease in the integration of the vinylic C−H stretching overtone of monomer at ∼6200 cm−1. A Bruker IFS 66/S Fourier transform spectrometer equipped with a tungsten halogen lamp, a CaF2 beam splitter, and a liquid nitrogen cooled InSb detector was used. Polymerizations in blue or red LED lights were carried out using FT-NIR quartz cuvette (1 cm × 2 mm). Each spectrum composed of 16 scans with a resolution of 4 cm−1 was collected in the spectral region between 7000 and 4000 cm−1 by manually placing the sample into the holder at time intervals of 5, 10, or 30 min. The total collection time per spectrum was about 10 s, and analysis was carried out with OPUS software. UV−Vis Spectroscopy. UV−vis spectra were recorded using a CARY 300 spectrophotometer (Varian) equipped with a temperature controller. pH/Ion Meter. pH measurements of reaction mixtures were carried out using a Mettler Toledo SevenCompact pH meter calibrated to standard pH buffers. Photopolymerization. Photopolymerization was carried out in the reaction vessel where the reaction mixtures were irradiated by RS Component PACK LAMP LED lights (5 W). The samples were irradiated at 635 nm for red light at intensity of 0.828 mW/cm2. The multicolored LED light bulb with remote control was purchased from RS Components Australia. General Procedure for Kinetic Studies of RAFT Photopolymerization of N,N-Dimethylacrylamide with Online Fourier Transform Near-Infrared (FTNIR) Spectroscopy in the Presence of Air/Purged with Nitrogen and Presence/Absence of Ascorbic Acid at pH 7.6. A reaction stock solution consisting of Milli-Q water (1.732 mL), DMA (5.119 mL, 4.92 g, 49.68 mmol), BTPA-PEG750 (241 mg, MW: 970.4 g/mol), and ZnTPPS4− (MW: 1302.49 g/mol, 3.235 mL of 0.768 mM (1 mg/mL) of ZnTPPS4− stock solution in water, 2.484 μmol) was prepared in a glass vial covered in aluminum foil. Because of the presence of slight excess of unreacted PEG750 even after flash chromatography, 1H NMR was carried out to determine the accurate ratio of [DMA]:[BTPA-PEG750]

EXPERIMENTAL SECTION

Materials. N,N-Dimethylacrylamide (DMA, 99%), poly(ethylene glycol) methyl ether (PEG750, Mn = 750 g/mol), dicyclohexylcarbodiimide (DCC), and 4-(dimethylamino)pyridine (DMAP) were all purchased from Aldrich. Dichloromethane (DCM) was purchased from Merck Millipore. Deinhibition of monomers was carried out by percolating over a basic alumina column (Ajax Chemical, AR). Milli-Q water was obtained from arium pro Ultrapure Water Systems (Sartorius). Zn(II) meso-tetra(4-sulfonatophenyl)porphyrin (ZnTPPS4−) was purchased from Frontier Scientific and used as received. Thiocarbonylthiol compound: 2-(n-butyltrithiocarbonate)propionic acid (BTPA) was synthesized according to literature procedures.96 Because of the poor stability of ascorbic acid in aqueous conditions for a prolonged period of time, we only added ascorbic acid to the reaction mixture before commencing polymerization. By doing this, we reduce the degradation of ascorbic acid and try to minimize any unwanted formation of side products that can be detrimental to the polymerization. Synthesis of BTPA-PEG750. BTPA was further modified through DCC coupling with PEG750 to yield BTPA-PEG750 according to literature procedures.60 A solution of BTPA (377.4 mg, 1.58 mmol) in 10 mL of DCM was introduced in a dry Cospak bottle under nitrogen in an ice bath (0 °C) to PEG750 (2.411 g, 3.17 mmol). A solution of DCC (360 mg, 1.74 mmol) and DMAP (20 mg, 0.164 mmol) in 5 mL of DCM was then added dropwise to the reaction mixture in the ice bath. The reaction mixture was degassed for 20 min followed by stirring for 48 h at room temperature to allow esterification reaction to take place. Flash chromatography (95:5, chloroform/methanol) was then carried out to purify the final product. The product was then dried at 45 °C under vacuum to obtain a yellow viscous liquid. NMR of the final product is as shown in Figure S2 (Supporting Information). Instrumentation. Gel Permeation Chromatography (GPC). GPC was used for characterization of synthesized polymer with dimethyl9347


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General Procedure for Preparation of PDMA-b-PDMA Diblock Copolymers by RAFT Photopolymerization in the Presence of Air under Red Light Irradiation. In the preparation of PDMA-b-PDMA block copolymer, PDMA macroRAFT agent was initially prepared. A reaction stock solution consisting of Milli-Q water (0.483 mL), DMA (1.426 mL, 1.372 g, 13.84 mmol), BTPA-PEG750 (89.5 mg, MW: 970.4 g/mol), and ZnTPPS4− (MW: 1302.49 g/mol, 0.901 mL of 0.768 mM of ZnTPPS4− stock solution in water, 0.692 μmol) was prepared in a 20 mL sample vial covered in aluminum foil. Because of the presence of slight excess of unreacted PEG750 even after flash chromatography, 1H NMR was carried out to determine the accurate ratio of [DMA]:[BTPA-PEG750] before proceeding with the reaction. In this case, the ratio of [DMA]:[BTPA-PEG750] was determined to be 240:1. The polymerization was carried out at 50 ppm catalyst concentration which is the molar ratio between [ZnTPPS4−]: [DMA]. Ascorbic acid (1.62 mg, 176.12 g/mol) was then added in the ratio of [BTPA-PEG750]:[ascorbic acid] of 1:0.1. The reaction mixture was then sonicated for 10 min for homogeneous mixing. The final pH of the reaction mixture was then measured to be pH 5.7 ± 0.3 using a pH meter with no pH adjustments done. The reaction solution was then filtered using a 0.45 μm PTFE filter. The glass vial with the reaction mixture was then irradiated for 18.5 h under red LED light (λmax = 635 nm, 0.828 mW/cm2) at room temperature (25 °C). The reaction mixture was then analyzed by 1H NMR and GPC (DMAc) to determine monomer conversion and number-average molecular weights (Mn) and polydispersities (Mw/ Mn). (PDMA macroinitiator: Mn,theo = 24 800 g/mol, Mn,GPC = 28 400 g/mol, Mw/Mn = 1.09, and 99% monomer conversion). No purification was carried for the synthesized PDMA macroinitiator. The resultant polymer was then diluted in 3 mL of water. Chain extension of PDMA macroRAFT agent with DMA was carried out in a 5 mL glass vial sealed with a rubber septum in the presence of DMA (713 μL, 0.686 g, 6.92 mmol) and ascorbic acid (MW: 176.12 g/mol, 1.62 mg) with no additional ZnTPPS4−. The ratio of [DMA]:[PDMA macroRAFT] was determined to be 280:1 using 1H NMR. The reaction mixture was irradiated under red LED light at room temperature for 7 h. The final reaction mixture was analyzed in 1H NMR and GPC (DMAc) to determine monomer conversion and number-average molecular weights (Mn) and polydispersities (Mw/ Mn): Mn,theo = 52 600 g/mol, Mn,GPC = 57 200 g/mol, Mw/Mn = 1.18, and 99% monomer conversion. General Procedure for Nuclear Magnetic Resonance (NMR) Spectroscopy of Hydrogen Peroxide Formation from Reaction between Singlet Oxygen and Ascorbic Acid. A reaction stock solution consisting of Milli-Q water (1.472 mL), ascorbic acid (176.12 g/mol, 25 mg), and ZnTPPS4− (MW: 1302.49 g/mol, 0.6945 mL of 0.768 mM (1 mg/mL) of ZnTPPS4− stock solution in water, 0.533 μmol) was prepared in a glass vial covered in aluminum foil. The final pH of the reaction mixtures was determined to be pH 3.0 ± 0.3 using a pH meter with no pH adjustments. The reaction mixture was then transferred to a 5 mL glass vial followed by sealing with a septum. The glass vial with the reaction mixture was then irradiated under red LED light (λmax = 635 nm, 0.828 mW/cm2) at room temperature (∼25 °C) for 20 min. About 100 μL of the reaction mixture was transferred to 500 μL of DMSO-d6 for analysis with Bruker Avance III 600 MHz Cryo NMR. These steps were repeated for a near-neutral stock solution (pH 7.2 ± 0.3) under three different irradiation conditions: (A) 20 min irradiation under red light, (B) 20 min irradiation under red light followed 1 h in darkness, and (C) 1 h continuous irradiation under red light.

before proceeding with the reaction. In this case, the ratio of [DMA]: [BTPA-PEG750] was determined to be 300:1. All polymerizations were carried out at 50 ppm catalyst concentration, which is the molar ratio between [ZnTPPS4−]:[DMA]. The reaction mixture was then sonicated for 10 min for homogeneous mixing. Next, pH of the reaction mixture was measured using a pH meter. The initial pH of the reaction mixture without any pH adjustments was determined to be pH 7.6. The reaction mixture was then aliquoted into six sample vials with each having 1.681 mL of reaction mixture. Three of the sample vials with reaction mixtures were used while the other were stored away in the fridge. Ascorbic acid (7.3 mg, 176.12 g/mol) was added to two of the three reaction mixtures in the ratio of RAFT:BTPA-PEG750 of 1:1. The final pH of the reaction mixtures was then adjusted to pH 7.6 ± 0.3 using a pH meter through titration with 2.5 M NaOH/1 M HCl. The reaction solution was then filtered after pH adjustments using a 0.45 μm PTFE filter. The reaction mixture was transferred from the glass vial to a 1 mL FTNIR quartz cuvette (1 cm × 2 mm) covered with aluminum foil followed by sealing with a septum. The cuvette with the reaction mixture was then irradiated under red LED light (λmax = 635 nm, 0.828 mW/cm2) at room temperature (∼25 °C). The cuvette was transferred to a sample holder manually for FTNIR measurements every 10 min. After 15 s of scanning, the cuvette was transferred back to the light source. Monomer conversions were calculated by taking the ratio of integrations of the wavenumber area 6250−6150 cm−1 for all curves at different reaction times to that of 0 min. Aliquots of reaction samples were taken at specific time points during the reaction to be analyzed by GPC (DMAc) to determine number-average molecular weights (Mn) and polydispersities (Mw/Mn). General Procedure for Kinetic Studies of RAFT Photopolymerization of N,N-Dimethylacrylamide (DMA) with Online Fourier Transform Near-Infrared (FTNIR) Spectroscopy in the Presence of Air and Ascorbic Acid at pH 7.2 for BTPA-PEG750 to RAFT Ratio of 1:0.1, 1:1, and 1:10 in Open and Closed Vessels. A reaction stock solution consisting of Milli-Q water (1.721 mL), DMA (2.547 mL, 2.45 g, 24.72 mmol), BTPA-PEG750 (120 mg, MW: 970.4 g/mol), and ZnTPPS4− (MW: 1302.49 g/mol, 1.607 mL of 0.768 mM (1 mg/mL) of ZnTPPS4− stock solution in water, 1.234 μmol) was prepared in a glass vial covered in aluminum foil. Because of the presence of slight excess of unreacted PEG750 even after flash chromatography, 1H NMR was carried out to determine the accurate ratio of [DMA]:[BTPA-PEG750] before proceeding with the reaction. In this case, the ratio of [DMA]:[BTPA-PEG750] was determined to be 300:1. All polymerizations were carried out at 50 ppm catalyst concentration which is the molar ratio between [ZnTPPS4−]:[DMA]. The reaction mixture was then sonicated for 10 min for homogeneous mixing. The reaction mixture was then aliquoted into three sample vials with each having 1.958 mL of reaction mixture. Ascorbic acid (176.12 g/mol) was added to the three reaction mixtures ([BTPAPEG750]:[Asc acid] = 1:0.1 (∼0.73 mg), 1:1 (∼7.3 mg), and 1:10 (∼73 mg)). The final pH of the reaction mixtures was then adjusted to pH 7.2 ± 0.3 using a pH meter through titration with 2.5 M NaOH/1 M HCl. The reaction solution was then filtered after pH adjustments using a 0.45 μm PTFE filter. Each concentration of ascorbic acid (1:0.1, 1:1, and 1:10) was then divided into two glass vials. The reaction mixture was then transferred from the glass vial to a 1 mL FTNIR quartz cuvette (1 cm × 2 mm) covered with aluminum foil. The quart cuvettes was then either sealed with septa for closed vessel polymerization or left unsealed for open vessel polymerization. The cuvette with the reaction mixture was then irradiated under red LED light (λmax = 635 nm, 0.828 mW/cm2) at room temperature (∼25 °C). The cuvette was transferred to a sample holder manually for FTNIR measurements every 10 min. After 15 s of scanning, the cuvette was transferred back to the light source. Monomer conversions were calculated by taking the ratio of integrations of the wavenumber area 6250−6150 cm−1 for all curves at different reaction times to that of 0 min. Aliquots of reaction samples were taken at specific time points during the reaction to be analyzed by GPC (DMAc) to determine number-average molecular weights (Mn) and polydispersities (Mw/Mn).

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RESULTS AND DISCUSSION Aqueous Polymerization with Oxygen Tolerance. In recent studies with metalloporphyrins,84,96−98 we reported the unique potential of porphyrin and phthalocyanine molecules in catalyzing RAFT photopolymerization in an organic solvent under red light irradiation. More recently, we extended this polymerization in aqueous environment using ZnTPPS4− as water-soluble catalyst.99 Although synthesis of well-defined 9348


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Figure 3. Online Fourier transform near-infrared (FTNIR) measurement of DMA polymerization at pH 7.2 in closed vessels in the presence of oxygen at room temperature using ZnTPPS4− as the photoredox catalyst under red light irradiation (λmax = 635 nm, intensity = 0.828 mW/cm2) with BTPA-PEG750 as the chain transfer agent ([DMA]:[BTPA-PEG750]:[ZnTPPS4−] = 300:1:1.5 × 10−2, 7.4 M monomer concentration) using varying ratios of BTPA-PEG750 to ascorbic acid. (A) Plot of ln([M0]/[M]t) vs exposure time in the presence of two different ratios of [BTPA-PEG750]: [ascorbic acid] (1:1 and 1:0.1). (B) “ON/OFF” online FTNIR kinetics for [RAFT]:[ascorbic acid] = 1:1. (C) Plot of Mn vs conversion for [RAFT]: [ascorbic acid] = 1:1. (D) GPC profiles for evolution of molecular weight at different time points for [RAFT]:[ascorbic acid] = 1:1. (E) Plot of Mn vs conversion for [RAFT]:[ascorbic acid] = 1:0.1. (F) GPC profiles for evolution of molecular weight at different time points for [RAFT]:[ascorbic acid] = 1:0.1.

restore this property. Ascorbic acid and amines are both excellent candidates to enable oxygen tolerance. In comparison with amines, ascorbic acid is a naturally occurring biological molecule with excellent antioxidant properties. The oxygen scavenging ability of ascorbic acid has led to its addition to food products such as meat, bread, wine, etc.101 Therefore, unlike amine-based oxygen scavenger, ascorbic acid is considered to be biocompatible and safe for consumption. Realizing the potential of ascorbic acid to rapidly react with singlet oxygen,88 initial

polymers was made possible in water, this system lacked an important feature of previous PET-RAFT systemsoxygen tolerance.85,86 In contrast to oxygen tolerance for PET-RAFT polymerization performed in DMSO, where the singlet oxygen generated by energy transfer from the catalyst to the triplet oxygen can rapidly react with the organic solvent,100 aqueous RAFT photopolymerization does not afford such tolerance. Therefore, we hypothesized that the addition of water-soluble compounds capable of reacting with singlet oxygen could 9349


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Macromolecules polymerization of N,N-dimethylacrylamide (DMA) in the presence of oxygen was tested in the presence of water-soluble RAFT agent. BTPA-PEG750 was prepared through N,N′dicyclohexylcarbodiimide (DCC) coupling of 2-(n-butyltrithiocarbonate)propionic acid (BTPA) with poly(ethylene glycol) methyl ether (Mn = 750 g/mol) (Supporting Information, Figures S1 and S2). BTPA-PEG750 was used instead of BTPA as conjugation with PEG increases solubility of the RAFT agent in water. PET-RAFT polymerizations were performed using BTPA-PEG750 RAFT agent in the presence of ZnTPPS4− under red light irradiation using a ratio of [DMA]:[BTPAPEG750]:[ZnTPPS4−] of 250:1:1.5 × 10−2 (8 M monomer concentration, pH 8.9). For the initial tests, a fixed concentration of ascorbic acid relative to BTPA-PEG750 was tested (BTPA-PEG750:ascorbic acid = 1:1) in Milli-Q water. After addition of different reactants, the vessel was sealed with a septum with no nitrogen purging. Surprisingly, we were able to achieve 77% monomer conversion in 2.5 h with reasonable control over molecular weight and molecular weight distributions (Mn,theo = 20 100 g/mol, Mn,GPC = 24 800 g/mol, Mw/Mn = 1.18). In the absence of ascorbic acid, no monomer conversion was determined. Inspired by our finding, we decided to monitor the kinetics of aqueous RAFT photopolymerization in the presence of oxygen with ascorbic acid by utilizing online Fourier transform near-infrared (FTNIR) spectroscopy. A stock solution of [DMA]:[BTPA-PEG750]:[ZnTPPS4−] ratio of 300:1:1.5 × 10−2 (10 M monomer concentration) was made before distributing the reaction mixture into three vials. The first vial was prepared in the absence of ascorbic acid, whereas in the second and third vial, ascorbic acid in the ratio of [BTPAPEG750]:[Asc acid] = 1:1 was added. In addition, only the first and second vials were purged with nitrogen while oxygen was not removed for the third vial. The addition of ascorbic acid in the reaction mixture affects the pH, which led to an acidic environment (pH 4.1 ± 0.3) due to deprotonation of ascorbic acid (pKa ∼ 4.1−4.2).102,103 In the absence of ascorbic acid, the pH is slightly basic (around pH 7.6 ± 0.3) as DMA is a basic monomer. To limit the experimental variability, pH of the reaction mixtures in the vials containing ascorbic acids was adjusted to pH 7.6 through titration with a few drops of 2.5 M NaOH/1 M HCl. Polymerization of DMA was then performed in the presence and absence of ascorbic acid in degassed and oxygenated systems under red light (λmax = 635 nm, intensity = 0.828 mW/cm2). In the degassed system, the absence of ascorbic acid led to a lower apparent propagation rate constant (kpapp = 0.94 × 10−2 min−1) than in the presence of ascorbic acid (kpapp = 1.14 × 10−2 min−1) (Figure 1A). The slight increase of kpapp was attributed to the electron donor property of ascorbic acid, resulting in a reductive pathway. In contrast to the oxidative pathway, reductive pathway tends to show faster polymerization rate.40,104−106 In the presence of oxygen, the addition of ascorbic acid provides oxygen tolerance with a slight increase in the apparent propagation rate constant (kpapp = 1.32 × 10−2 min−1) in comparison to the degassed system with no ascorbic acid (Figure 1B). In agreement with our first control experiment, in an oxygenated system without ascorbic acid, no polymerization was observed upon irradiation for 3 h. Molecular weight distributions for the three different systems were symmetrical with monomodal distributions (Figures 1D,F,H). Furthermore, all three reactions portrayed reasonable correlations between theoretical and experimental molecular weights (Figures 1C,E,G). 1H NMR analysis (Figures S3−S5)

shows a high retention of end group using the ratio between the signal at 4.1 ppm (assigned to CH2 adjacent to the ester group (4)) and 0.8 ppm (CH3 of butyl group (1)). Furthermore, good GPC overlaps between the UV and RI traces were seen for the three different systems (Figure S6) which reinforce the presence of the thiocarbonylthio moiety. Finally, UV−vis analysis of purified polymers shows the Table 1. Aqueous Polymerization of DMA Using ZnTPPS4− and BTPA-PEG750 under Red Light (λmax = 635 nm, Intensity = 0.828 mW/cm2) as the Light Source no. e

1 2 3

exp conda [DMA]: [BTPA-PEG750]: [ZnTPPS4−] −3

88:1:4.4 × 10 907:1:4.5 × 10−2 1373:1:6.9 × 10−2

time (h)

αb (%)

Mn,thc (g/mol)

Mn,GPCd (g/mol)

Mw/Mnd

8.75 3 2

86 82 72

8500 75000 99300

12000 74700 101600

1.16 1.17 1.21

a

Reactions were performed in a closed vessel with 10 M monomer concentration in the presence of oxygen at room temperature in water with [BTPA-PEG750]:[Asc acid] ratio of 1:1 at 50 ppm catalyst concentration. bMonomer conversion was determined by using 1H NMR spectroscopy. cTheoretical molecular weight was calculated using the following equation: Mn,th = [M]0/[RAFT]0 × MWM × α + MWRAFT, where [M]0, [RAFT]0, MWM, α, and MWRAFT correspond to initial monomer concentration, initial RAFT concentration, molar mass of monomer, conversion determined by 1H NMR, and molar mass of RAFT agent. dMolecular weight (Mn,GPC) and polydispersity index (Mw/Mn) were determined by GPC analysis (DMAC as eluent) calibrated to poly(methyl methacrylate) standard. eMonomer concentration of 5 M.

characteristic signal of trithiocarbonate at 305 nm (Figure S7). Nevertheless, in the presence of ascorbic acid, both the degassed and oxygenated systems showed slightly higher molecular weight values in comparison with theoretical ones. More importantly, we observe a continued increase of polydispersity during the polymerization, which could be attributed to the formation of dead polymers. However, the presence of ascorbic acid did not lead to a loss in temporal control during the course of the polymerization (Figure 2). In the presence of ascorbic acid under basic conditions, polymerization of DMA is activated under light and completely stopped in the dark. Although we were able to confer oxygen tolerance through the addition of ascorbic acid to the polymerization mixture, optimizations were still required in terms of control over polydispersities. In order to do this, we proceeded to carrying out DMA polymerization with a lower monomer concentration (7.4 M) and, at the same time, manipulating the ratios of BTPA-PEG750 to ascorbic acid (1:1 and 1:0.1). As expected, analysis of FTNIR kinetics for BTPA-PEG750:ascorbic acid ratios of 1:1 and 1:0.1 revealed a slower kinetics (Figure 3A) than the previous reaction with higher monomer concentration (Figure 1). Both concentrations of ascorbic acid led to pseudofirst-order kinetics with constant concentration of propagating radicals throughout the reaction. Nevertheless, the propagation rate constant for the 1:1 ratio (kpapp = 1.01 × 10−2 min−1) was much higher than the 1:0.1 ratio (kpapp = 4.48 × 10−3 min−1) of BTPA-PEG750 to ascorbic acid. For both concentrations of ascorbic acid, temporal regulation was made possible with efficient polymerization in the presence of light and suppression of polymerization in the absence of light (Figure 3B and Figure S8). 9350


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Scheme 1. Singlet Oxygen (1O2) Generated through Energy Transfer from Excited State ZnTPPS4− to Ground State Oxygen (3O2) Which React with Monohydroascorbate Ion (AH−) To Form Hydrogen Peroxide (H2O2) and Dehydroascorbate (DHA) Leading to Oxygen Tolerance

consumption (Figure S11). The retention of end-group fidelity was seen with minimum dead chains forming in the final block copolymer (PDMA240-block-PDMA280) where a good correlation was established between theoretical and experimental molecular weights with acceptable molecular weight distributions. Upon attempting DMA polymerization at much higher concentrations of ascorbic acid with BTPA-PEG750 to ascorbic acid ratio of 1:10 in a closed vessel, no rate acceleration was seen (Figure S11A). In fact, reactions with 1:1 and 1:10 of RAFT to ascorbic acid ratios initially proceeded at similar rates. However, the presence of 1:10 ratio of RAFT to ascorbic acid led to early termination at 40% monomer conversion. Analysis of the molecular weights of the final polymer revealed that the experimental and theoretical molecular weights in the presence of 1:10 of RAFT to ascorbic acid (Mn,theo = 14 300 g/mol, and Mn,GPC = 18 650 g/mol) were fairly close with poor control over molecular weight distributions (Figure S11C). The increase in ascorbic acid concentration did not lead to a faster polymerization but only to poor regulation of molecular weight distributions which can be attributed to poor trithiocarbonate exchange. To demonstrate the versatility of this system, we decided to prepare polymers with different molecular weights using the optimal ratio of RAFT agent to ascorbic acid, i.e., 1:1. Polymers with molecular weights ranging from 10 000 to 100 000 g/mol were successfully synthesized in the presence of ascorbic acid and oxygen as shown in Table 1 with reasonable control over molecular weight and distributions. Successfully polymerization in the presence of oxygen convinced us to push the limits of oxygen tolerance in aqueous

The presence of RAFT end group for 1:0.1 of RAFT to ascorbic acid ratio was determined through 1H NMR analysis (Figure S13). In addition, a good correlation was seen for both experimental and theoretical molecular weights (Figure 3E): Mn,theo = 23 000 g/mol, Mn,GPC = 24 760 g/mol, and Mn,NMR = 21 900 g/mol. Similarly, in the case of 1:1 of RAFT to ascorbic acid ratio, 1H NMR analysis revealed the presence of the RAFT end group (Figure S12), and a close correlation was established between experimental and theoretical molecular weights (Figure 3C): Mn,theo = 25 000 g/mol, Mn,GPC = 27 000 g/mol, and Mn,NMR = 25 100 g/mol. The presence of thiocarbonylthio moiety for both concentrations of ascorbic acid was also detected through overlaps of UV and RI GPC traces (Figure S15A,B) as well as UV−vis detection (Figures S16A,B) at 305 nm. Despite a slower polymerization rate, a better control over molecular weight distributions was achieved with 1:0.1 ratio compared to 1:1 ratio of BTPA-PEG750 to ascorbic acid over the course of the polymerization (Figure 3C,E). In addition, the control over polydispersities of polymer chains was also reflected in the GPC traces where the absence of low molecular weight shoulder was observed in lower concentration of ascorbic acid (Figure 3F) in comparison to the higher concentration of ascorbic acid (Figure 3D). In addition, the presence of end-group fidelity was reinforced through successful chain extensions even at high monomers conversions. Synthesis of PDMA240 macroRAFT was carried out to high monomer conversions (∼99%) in the presence of oxygen (Figure S10). Successful chain extension was carried out in the presence of oxygen by adding ascorbic acid and DMA without the need for additional photocatalyst or purification. The reaction was then allowed to proceed to complete monomer 9351


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Figure 4. Online Fourier transform near-infrared (FTNIR) measurement of DMA polymerization at pH 7.2 in open vessel in the presence of oxygen at room temperature using ZnTPPS4− as the photoredox catalyst under red light irradiation (λmax = 635 nm, intensity = 0.828 mW/cm2) with BTPAPEG750 as the chain transfer agent ([DMA]:[BTPA-PEG750]:[ZnTPPS4−] = 300:1:1.5 × 10−2, 7.4 M monomer concentration). (A) Plot of ln([M0]/ [M]t) vs exposure time in the presence of two different ratios of BTPA-PEG750:ascorbic acid (1:1 and 1:0.1). (B) “ON/OFF” online FTNIR kinetics for [RAFT]:[ascorbic acid] = 1:1. (C) GPC profiles for evolution of molecular weight at different time points for [RAFT]:[ascorbic acid] = 1:1 in an open vessel. (D) GPC profiles for evolution of molecular weight at different time points for [RAFT]:[ascorbic acid] = 1:1 in an open vessel.

termination with poor control over molecular weight distribution of the final polymer (Figures S11B,D) as previously observed in the closed vessel polymerization. Piecing Together the Puzzle of Aqueous RAFT Photopolymerization in the Presence of Oxygen. Generation of reactive oxygen species (ROS) with porphyrins has been the focus of photodynamic therapy (PDT) for treatment of several types of cancer.107 In the presence of visible light, photosensitizers, such as ZnTPPS4−, are able to generate ROS through either electron transfer (type I reaction) which forms superoxide or energy transfer (type II reaction) which forms singlet oxygen.108 In PDT, singlet oxygen (type II reaction) was found to predominate over generation of superoxide (type I reaction) and therefore provides the lethal dose needed for cellular damage.95,109 In addition, studies with photofrin87 and hematoporphyrin88 observed electrophilic singlet oxygen chemically quenching reducing agents such as monohydroascorbate ion to generate peroxides and dehydroascorbate. Although characterization of dehydroascorbate is quite difficult as this intermediate undergoes further degradation, the formation of hydrogen peroxide has been well characterized through real time measurements.87 Likewise, oxygen tolerance in RAFT photopolymerization could be primarily due to quenching of singlet oxygen by ascorbate (Scheme 1). In order to test this theory, 1H NMR was utilized to characterize hydrogen peroxide formed after 20 min irradiation of ascorbic acid/ZnTPPS4− mixtures under

conditions by carrying out open vessel polymerization. As the reaction for 1:1 proceeded faster than 1:0.1 of RAFT to ascorbic acid in an open vessel (Figure 4A), kinetic studies were primarily focused on the former. In agreement with closed vessel kinetics (Figure 3B), temporal regulation for 1:1 of RAFT to ascorbic acid was made possible where polymerization of DMA was only observed in the presence of light with complete suppression in the absence of light (Figure 4B). A constant concentration of propagating radical was observed throughout the polymerization as demonstrated by a linear relationship with ln[M0]/[M]t versus time. Interestingly, the rate of polymerization in open and closed vessel appears in the similar range (kpapp = 1.15 × 10−2 min−1). In addition, an acceptable correlation of molecular weights between experimental values determined by 1H NMR and GPC and theoretical values (Mn,NMR = 22 100 g/mol, Mn,theo = 24 600 g/mol, and Mn,GPC = 28 000 g/mol) (Figure 4C) were observed. Similar to the closed vessel polymerization, the fast rate of polymerization led to a slight increase of polydipersity and slightly broader molecular weight distributions (Figure 4C). Furthermore, GPC curves revealed a fairly symmetrical profile with monomodal feature (Figure 4D). A good overlap of RI and UV traces (Figure S15C) confirms the retention of the trithiocarbonate end group. The presence of the thiocarbonylthio moiety was also detected using UV−vis spectroscopy (Figure S16C). Repeating the open vessel polymerization with BTPA-PEG750 to ascorbic acid ratio of 1:10 led to early 9352


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Scheme 2. Proposed Mechanism for RAFT Photopolymerization in the Presence of Ascorbic Acid at Basic/Neutral pH

stability of hydrogen peroxide in near neutral and basic conditions suppressed the formation of exogenous radicals during the course of the polymerization and therefore ensured temporal regulation in the polymerization system (Figure 2). Control studies (Table 2, entries 1−5) revealed that both BTPA-PEG750 and ZnTPPS4− are critical for photopolymerization of DMA. In the absence of ZnTPPS4− (Table 2, entries 1 and 2) or BTPA-PEG750 and ZnTPPS4− (Table 2, entries 3 and 4), no successful photopolymerization is possible in both dark and irradiated conditions. As BTPA-PEG750 has no absorption in the red region, direct RAFT photolysis to generate radicals is not possible. Previously, Cunningham and co-workers102 have shown that in the absence of an external radical source the interaction between ascorbic acid and sulfonate could lead to generation of radicals that can activate monomers for polymerization. However, in near-neutral conditions (Table 2, entry 5), the presence of both sulfonate and ascorbic acid led to negligible monomer conversion. In comparison to ascorbic acid (AH2), the presence of high population of monohydroascorbate ion (AH− = ∼99%)102,103 in near-neutral conditions can be less ideal for reduction due to electrostatic repulsion between negatively charged ascorbates and sulfonates. Therefore, the presence of repulsion between ZnTPPS4− and monohydroascorbate ion reduces the likelihood of exogenous radical generation. In our experiments (pH ∼ 7.2−7.6), polymerization is likely to proceed in a manner that is described in Scheme 2 upon removal of singlet oxygen. Although the concentration of AH2 is much lower compared to AH− (>99%) in near-neutral and basic conditions,102 reduction of zinc porphyrin by trace

Table 2. Control Experiments for Polymerization of DMA in the Presence and Absence of Light with Ascorbic Acid and ZnTPPS4− no. e

1 2f 3e 4f 5f

exp conda [M]:[RAFT]:[ZnTPPS4−]:[Asc acid]

time (h)

280:1:0:1 280:1:0:1 280:0:0:1 280:0:0:1 280:0:0.014:1

14 14 14 14 2

αb (%) 0 0 0 0 1

± ± ± ± ±

5 5 5 5 5

a

Reactions were performed in the presence of oxygen at room temperature in water at pH 7.2. bMonomer conversion was determined by using 1H NMR spectroscopy. cTheoretical molecular weight was calculated using the following equation: Mn,th = [M]0/ [RAFT]0 × MWM × α + MWRAFT, where [M]0, [RAFT]0, MWM, α, and MWRAFT correspond to initial monomer concentration, initial RAFT concentration, molar mass of monomer, conversion determined by 1H NMR, and molar mass of RAFT agent. dMolecular weight and polydispersity index (Mw/Mn) were determined by GPC analysis (DMAC as eluent) calibrated to poly(methyl methacrylate) standard. e Reaction was performed in darkness. fReaction was performed in the presence of light.

near-neutral conditions (pH 7.2). Previous reports showed that hydrogen peroxide produced a peak between 10 and 11 ppm depending upon the interaction between the solvent and peroxide molecule.110,111 Consistently, 1H NMR revealed a sharp peak at 10.6−10.7 ppm under both acidic and nearneutral conditions (Figures S17 and S18). This peak was monitored for up to an hour, in near-neutral conditions, with no significant degradation of hydrogen peroxide observed. The 9353


Macromolecules amounts of AH2 to generate dehydroascorbic acid could still be taking place during the course of polymerization.112 A recent study by Maximiano et al.113 exploited the use of inorganic sulfite to perform direct electron transfer to RAFT agents that resulted in the formation of stable thiocarbonylthio radical anions. These thiocarbonylthio radical anions can then dissociate to form radicals that initiate polymerization and thiocarbonylthio anions which can recombine with propagating radicals to form dormant RAFT agent (Scheme 2). Similarly, reduction of ZnTPPS4− to generate (ZnTPPS4−)•− reduced porphyrin leads to the activation of BTPA-PEG750 through an electron transfer. The reduced anionic RAFT radical can then undergo dissociation to generate an anionic RAFT and a propagating radical that enters the RAFT cycle similar to previously proposed PET-RAFT mechanism. The presence of ascorbic acid not only aids in quenching singlet oxygen but also acts as a sacrificial electron donor to accelerate polymerization. Consequently, the apparent propagation rate constants for the oxygenated system and degassed system in the presence of ascorbic acid were slightly higher, 1.4 times and 1.2 times respectively, than degassed system with no ascorbic acid (Figure 1A,B). Similarly, the increase in BTPA-PEG750 to ascorbic acid ratios from 1:0.1 to 1:1 (Figure 2) also led to polymerization that is twice as fast in the latter compared to the former. Moreover, the trace amounts of AH2 in the reaction mixtures at near-neutral and basic pH does not lead to significant production of AH• radicals and therefore enabling temporal control to be imposed.

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ACKNOWLEDGMENTS

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REFERENCES

C.B. acknowledges Australian Research Council (ARC) for his Future Fellowship (FT12010096). The authors acknowledge Dr. Donald Thomas and Dr. Doug Lawes of the NMR Facility within the Mark Wainwright Analytical Centre at the University of New South Wales for NMR support.

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In this contribution, we demonstrated that light regulated polymerization in the presence of oxygen could be achieved in water in neutral/basic pH. The oxygen tolerance is conferred by the addition of ascorbic acid, which serves as singlet oxygen quencher in neutral/basic pH. The presence of trace amounts of ascorbic acid in comparison to monohydroascorbate ion in neutral/basic pH led to acceleration of polymerization rate through reduction of ZnTPPS4−, which in turn reduces BTPAPEG750 to initiate polymerization. We are currently exploring other biocompatible reducing agents such as amines that may provide similar oxygen tolerance.

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b02060.

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Article

UV−vis spectra, GPC curves, and NMR spectra (Figures S1−S19) (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail [email protected] (C.B.). *E-mail [email protected] (S.S.). ORCID

Cyrille Boyer: 0000-0002-4564-4702 Notes

The authors declare no competing financial interest. 9354


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