Trimethylammonium-Based Polymethacrylate Ionic Liquids with

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Trimethylammonium-based polymethacrylate ionic liquids with tunable hydrophilicity and charge distribution as carriers of salicylate anions Rafa# Bielas, Anna Aneta Miela#czyk, Agnieszka Siewniak, and Dorota Neugebauer ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.6b00690 • Publication Date (Web): 09 Jun 2016 Downloaded from http://pubs.acs.org on June 12, 2016

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ACS Sustainable Chemistry & Engineering

Trimethylammonium-based polymethacrylate ionic liquids with tunable hydrophilicity and charge distribution as carriers of salicylate anions

Rafał Bielas1, Anna Mielańczyk1, Agnieszka Siewniak2, Dorota Neugebauer1*

1

Department of Physical Chemistry and Technology of Polymers, Faculty of Chemistry,

Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland 2

Department of Chemical Organic Technology and Petrochemistry, Faculty of Chemistry,

Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland

*corresponding author: [email protected]

1 ACS Paragon Plus Environment


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ABSTRACT Copolymers of [2-(methacryloyloxy)ethyl]trimethylammonium chloride, salicylate or bis(trifluoromethanesulfonate)imide (Cl-, Sal- or Tf2N-) and methyl methacrylate (MMA) were synthesized by atom transfer radical polymerization (ATRP). The effect of different molar fractions of ionic monomer (0.05 - 1.0) on physicochemical properties was investigated. The relative reactivity ratios of MMA and ionic monomer with chloride anion (0.88 and 1.13, respectively) were determined by the linearization Jaacks method. The particles formed in water by copolymers with trimethylammonium chloride (≥50 mol %) reached sizes below 10 nm, whereas salicylate containing copolymers supported strong selfassembly yielding superstructures of 200 nm. The copolymers after modification by exchange of Cl- and Sal- with Tf2N- demonstrated the influence of the anion on solubility, glass transition temperature and morphology. The anion modified trimethylammonium copolymers compared with directly synthesized from Tf2N containing monomer indicated different properties. Both chloride monomer (Cl- replaced by Sal- or Tf2N-) and its (co)polymers are able to anion exchange, including biologically active ones, what extends their future applications as poly(ionic liquid)s with therapeutic properties for the controlled drug delivery.

Key words: trimethylammonium cation, poly(ionic liquid)s, ATRP, anion exchange, salicylate


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INTRODUCTION [2-(Methacryloyloxy)ethyl]trimethylammonium

(2-(trimethylammonium)ethyl

methacrylate) monomer also known as methacryloylcholine (ChMA as we refer below) is ester derivative of biologically active choline (2-(hydroxyethyl)trimethylammonium cation), which exists in the form of a salt. Natural choline plays important functions in the human body. For example it takes a part in building cell membranes and cholinergic transmission or shows vitamine-like properties. Moreover, in the enzymatic reaction it is employed to prepare the acetylcholine (neuromediator), and is also involved in the biosynthesis of phosphatidyl choline (lecithin). Depending on the current anion, it has various applications. Choline chloride is used as an additive in feed for chickens1, as well as a deep eutectic solvent component2, whereas choline salicylate is a popular antibacterial agent used in the treatment of aphtous ulcers3. Choline ions are also used for delivery of range of active pharmaceutical ingredients what lead to better solubility and bioavailability of these drugs4. In addition, some choline salts, which are melting below 100°C, are classified in the group of ionic liquids, which show chemical and thermal stabilities, low vapor pressure and high ionic conductivity properties.5 Because of its biocompatibility, choline functionalized with polymerizable groups, can be used for synthesis of the macromolecular compounds, which belong to the group of cationic polymers. Among the methacrylic monomers as the choline derivatives, the most popular is 2(methacryloyloxy)ethyl phosphorylcholine. There are several reports describing its polymerization and many applications of the obtained polymers. The first one from 1997 concerned the preparation of modified microspheres for protein adsorption6. In the next few years the uses of poly(phosphorylcholine methacrylate)s as materials improving mechanical properties and biocompatibility of silicone rubber7, as well as biomimetic gelators8 and drug delivery systems9 have been described. Some of them have been obtained by controlled



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polymerization methods, such as atom transfer radical polymerization (ATRP)10, reversible addition-fragmentation chain-transfer polymerization (RAFT)11 and cobalt-mediated catalytic chain-transfer polymerization (CCTP)12. These methods allowed to obtain cationic polymers of different topologies: blocks13,14, stars8 and brushes15. Another choline based monomer, that is 2-(methacryloyloxy)ethyl choline phosphate zwitterion, was used to prepare the welldefined membrane adhesive, which could be applied in tissue engineering and drug delivery16. The polymers obtained by free-radical polymerization (FRP) of 2-cholinium lactate methacrylate have facilitated the preparation of biocompatible poly(ionic liquid)/cellulose composite coatings.17 Studies on the polymerization of ChMA monomer seems to be not sufficient employing mostly FRP. The representative examples show that ChMA containing different anions (halide, acetate, lactate) was used in photopolymerization to obtain ion gels,17 whereas poly(ionic liquid)s based on ChMA with bis(trifluoromethanesulfonate)imide anion (Tf2N-) have been used as a new family of hydrorepellent materials18. This monomer was also applied for preparation of thin films19 and monodisperse particles20–23. In the case of ChMA with chloride anion these are only three reports, which are referred to the controlled radical polymerization. Armes et al.24 obtained the well characterized double hydrophilic block copolymers of ChMA/Cl by ATRP method with investigation of the influence of macroinitiator on molecular weight and dispersity index. Shell cross-linked micelles from ABC triblock copolymers containing thermo-responsive core-forming poly(propylene oxide), cross-linkable central poly(glycerol monomethacrylate) block and amine-functional corona based on ChMA/Cl were studied by Pilon et al.25 Makuska and Visnevskij26 compared application of activator generated by electron transfer (AGET) ATRP and supplementary activator and reducing agent (SARA) ATRP for polymerization of ChMA/Cl in water


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solutions to offer the novel simple method providing better reproducibility of results and good control over polymerization. Here we report for the first time the synthesis of polycations with variation of distributed trimethylammonium moieties (statistical vs gradient) using ATR copolymerization of ChMA with methyl methacrylate (MMA) and their physicochemical characteristics. The investigations were focused on the influence of various contributions of positively charged units in (co)polymers (5-100 %) on hydrodynamic diameter of particles formed in aqueous solution. Moreover, different anions (Cl- vs Tf2N- and Sal- vs Tf2N-) were used to adjust solubility, thermal properties and morphology of the polymers. The Tf2N anions were introduced in two ways by pre-polymerization (synthesis of ChMA/Tf2N monomer) and postpolymerization via anion exchange to compare effectiveness of methods and properties of resulted in polymers. These studies are important for design of the trimethylammonium-based poly(ionic liquid)s with biological activity, which can be improved by broad range of pharmaceutical anions as the polymeric drug delivery systems.

EXPERIMENTAL Materials Methyl methacrylate (MMA) was purchased from AlfaAesar and dried under molecular sieves.

[2-(Methacryloyloxy)ethyl]trimethylammonium

chloride

known

as

methacryloylcholine (ChMA/Cl, Sigma-Aldrich) as 80% solution in water was dried under reduced pressure until achieving a constant weight. Copper(I) bromide, lithium bis(trifluoromethanesulfonate)imide (LiTf2N), sodium salicylate (NaSal), dry tetrahydrofuran (THF),

N,N,N’

,N’’,N’’-pentamethyldiethyltriamine

(PMDETA)

and

ethyl

2-

bromoisobutyrate (EBiB) were purchased from Sigma Aldrich. Methanol and acetone were purchased from Chempur.



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Characterization Size exclusion chromatography (SEC) equipped with an 1100 Agilent 1260 Infinity isocratic pump, autosampler, degasser, thermostatic box for columns and differential refractometer MDS RI Detector has been used for molecular weights and dispersities determination. Addon Rev. B.01.02 data analysis software (Agilent Technologies) was used for data collecting and processing. The SEC calculated molecular weight was based on calibration using linear polystyrene standards (580–300,000 g/mol). Precolumn guard 5 µm (50 x 7.5 mm) and PLGel 5µm MIXED-C column (300 x 7.5 mm) were used for separation. The measurements were carried out in 1 mmol of LiNTf2 solution in THF (HPLC grade) as the solvent at 40oC with flow rate of 0.8 mL/min. Fourier transformation infrared (FT-IR) analysis was carried out with a Perkin Elmer Spectrum Two spectrometer at room temperature by attenuated total refection (ATR) method. Spectra were recorded at 16 scans per spectrum and 4 cm-1 resolution in the range of 4000– 450 cm-1. 1

H and

13

C NMR spectra of the polymer solutions in DMSO-d6 were collected on Varian

Inova 300 MHz spectrometer at 25oC using TMS as an internal standard. Differential scanning calorimetry (DSC) was performed using Mettler Toledo (DSC822e) apparatus for a temperature range from -60oC to 200oC at heating rate of 10oC/min. Dynamic light scattering (DLS) was performed on Malvern Zetasizer Nano-S90 equipped with an 4 mW He–Ne ion laser operating at λ= 633 nm. Samples were placed in PMMA cells after dilution with deionized water or were put in the thermostated cell compartment of the instrument at 25oC ± 0.1 oC. All of the sample measurements were performed at a fixed scattering angle of 90. At least 5 correlation functions were analyzed per sample in order to obtain an average value.


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Ultrahigh Performance Liquid Chromatography (UPLC) was carried on Waters Technologies ACQUITY UPLC system with ACQUITY Photodiode Array Detector (λ=210nm). The analyses were carried out using an ACQUITY UPLC® BEH C18 1.7µm 2.1x100mm column, mobile phase consisted of 15% water and 85% of methanol v/v. The column temperature was kept at 30°C. The optimal settings were as follows: Vinjection=2 mL; flow rate = 1 mL/min. Scanning electron microscopy was performed on Phenom ProX microscope. Samples were coated with 5 nm gold nanoparticles previously to the analysis by Q150R Rotary-Pumped Sputter Coater Quorum Technologies. Synthesis of P(MMA-co-ChMA/Cl) by ATRP (example for 25% of initial feed of ionic monomer) The comonomers ChMA (1 g, 4.81 mmol) and MMA (1.4 mL, 14.44 mmol), methanol (1 mL), THF (0.3 mL), PMDETA (10 µL, 0.048 mmol) and catalyst CuBr (6.9 mg, 0.048 mmol) were placed into a Schlenk flask and degassed by two freeze-pump-thaw cycles. The initial sample was taken and an initiator EBiB (7 µL, 0.048 mmol) was introduced to a mixture. Next the reaction flask was immersed into an oil bath at 40oC. The reaction was stopped at significantly increased viscosity, which disable further stirring, by exposing to air. Then it was dissolved in methanol and precipitated in ethyl acetate twice, to remove catalyst. Yield 72%. 1H-NMR (DMSO-d6, δ, ppm): 4.37 (2H, -CH2-O-), 3.78 (2H, -CH2-N+-), 3.55 (3H, OCH3), 3.26 (9H, -N+-(CH3)3), 1.98-1.66 (2H, -CH2-), 1.15-0.65 (3H, -CH3).

13

C-NMR

(DMSO-d6, δ, ppm) 177.31 (C=O), 64.75 (-CH2-N+-), 58.76 (-CH2-O-), 53.44 (-CH2- in backbone, -N+-(CH3)3), 52.44 (CH3-O-), 44.39 (-C-), 18.88 (-CH3). Synthesis of [2-(methacryloyloxy)ethyl]trimethylammonium salicylate (ChMA/Sal) Vacuum dried ChMA/Cl (50 mmol) was dissolved in 20 ml of water. Then sodium salicylate (50 mmol) was added. Solution was stirred for 24 hours in room temperature. Solution was



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then extracted three times with chloroform. Organic phase was then concentrated under reduced pressure for 24 hours. Yield 62%. Synthesis

of

[2-(methacryloyloxy)ethyl]trimethylammonium

bis(trifluoromethane-

sulfonyl) imide (ChMA/Tf2N) Vacuum dried ChMA/Cl (50 mmol) was dissolved in 20 mL of water. Then LiTf2N (50 mmol) was added. Solution was stirred for 24 hours in room temperature. Next organic phase was extracted three times with water to remove lithium chloride. Organic phase was then dried under reduced pressure for 24 hours. Yield 97%. Synthesis of P(MMA-co-ChMA/Sal) by ATRP (example for 25% of initial feed of ionic monomer) The comonomers ChMA/Sal (1.93 g, 6.24 mmol) and MMA (2 ml, 19 mmol), methanol (2.5 ml), THF (0.8 ml), PMDETA (8.7 µl, 0.04 mmol) and catalyst CuBr (6 mg, 0.04 mmol) were placed into a Schlenk flask and degassed by two freeze-pump-thaw cycles. The initial sample was taken and an initiator EBiB (8.3 µl, 0.04 mmol) was introduced to a mixture. Further steps were performed similarly to described above synthesis of P(MMA-co-ChMA/Cl), but reaction was stopped after 24 hours. Yield 74%. 1H-NMR (DMSO-d6, δ, ppm): 7.67, 7.11, 6.55 (C-H aromatic), 4.38 (2H, -CH2-O-), 3.88 (2H, -CH2-N+-), 3.55 (3H, -OCH3), 3.24 (9H, N+-(CH3)3), 2.09-1.61 (2H, -CH2-), 1.31-0.65 (3H, -CH3).

13

C-NMR (DMSO-d6, δ, ppm)

182.42 (C=O), 131.52, 130.40 (-C= aromatic), 64.52 (-CH2-N+-), 59.21 (-CH2-O-), 53.97 (CH2- in backbone, -N+-(CH3)3), 51.95 (CH3-O-), 44.75 (-C-), 18.94 (-CH3) Ionic exchange (example for copolymer containing 25% of trimethylammonium moieties) Sample of P(MMA-co-ChMA/X) (0.5 g, where X = Cl-, Sal-) was dissolved in methanol. Then LiTf2N (0.3 g, 0.96 mmol) was added. Polymer with exchanged anions, which precipitated immediately was next dried under reduced pressure to give 0.376 g of P(MMA8 ACS Paragon Plus Environment

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co-ChMA/NTf2). Yield 53%. 1H-NMR (DMSO-d6, δ, ppm): 4.36 (2H, -CH2-O-), 3.82 (2H, CH2-N+-), 3.56 (3H, -OCH3), 3.21 (9H, -N+-(CH3)3), 2.12-1.51 (2H, -CH2-), 1.25-0.59 (3H, CH3). 13C-NMR (DMSO-d6, δ, ppm) 183.13 (C=O), 126.16, 122.84, 117.85 (-CF3), 65.01 (CH2-N+-), 58.25 (-CH2-O-), 54.10 (-CH2- in backbone, -N+-(CH3)3), 52.65 (CH3-O-), 44.42 (C-), 18.88 (-CH3). Synthesis of P(MMA-co-ChMA/Tf2N) by ATRP (example for 25% of initial feed of ionic monomer) The comonomers ChMA/Tf2N (1.5 mL, 6.26mmol) and MMA (2 mL, 18.78 mmol), THF (0.35 mL), PMDETA (13 µL, 0.063 mmol) and catalyst CuBr (8.9 mg, 0.063 mmol) were placed into a Schlenk flask and degassed by three freeze-pump-thaw cycles. The initial sample was taken and an initiator EBiB (9 µL, 0.063 mmol) was introduced to a mixture. Next the reaction flask was immersed into an oil bath at 40oC. The reaction was stopped by exposing to air when an increase of viscosity made it impossible to continue stirring. Then it was dissolved in THF and precipitated in methanol twice, to remove catalyst. Yield 65%. 1HNMR (DMSO-d6, δ, ppm): 4.37 (2H, -CH2-O-), 3.78 (2H, -CH2-N+-), 3.55 (3H, -OCH3), 3.26 (9H, -N+-(CH3)3), 1.98-1.66 (2H, -CH2-), 1.15-0.65 (3H, -CH3).

13

C-NMR (DMSO-d6, δ,

ppm) 177.31 (C=O), 126.16, 122.84, 117.85 (-CF3), 64.75 (-CH2-N+-), 58.76 (-CH2-O-), 53.44 (-N+-(CH3)3), 52.44 (CH3-O-), 44.39 (-C-), 18.88 (-CH3).

RESULTS AND DISCUSSION Copolymers P(MMA-co-ChMA/Cl) were prepared by copolymerization of MMA and ChMA/Cl (Scheme 1) using CuBr/PMDETA catalytic system and EBiB initiator. ATRP reactions were performed at 40oC and 70oC at different monomer to initiator ratios (M:I) and various initial content of both monomers (5, 25, 50, 75, 95, 100 mol.% of ChMA/Cl). The resulted ionic (co)polymers with chloride anions (I-X) were well-soluble in water and



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methanol. In order to determine molecular weight and dispersity index the ChMA/Cl based polymers were modified by anion exchange to make them soluble in THF, which is the common nonpolar solvent in SEC analysis. For this purpose the commercially available salt of bis(trifluoromethanesulfonyl)imide anion (Tf2N-) was selected as the most effective for ion exchange among typical anions used for ionic liquids27, to change solubility of trimethylammonium containing copolymers. The modification reactions were performed in methanol solution yielding immediately precipitated copolymers containing ChMA/Tf2N (IaXa). Copolymers decorated by both types of anions are summarized in Table 1.

Scheme 1. Synthesis of poly(ionic liquid)s containing trimethylammonium cations by ATRP

Methanol has been chosen as a solvent for synthesis because of limited solubility of ChMA/Cl in other solvents. Reactions in methanol in 70°C occurred with various rates depending on initial ratio of monomer/initiator, that is ratio of 200/1 yielded polymer I within 25 min with high monomer conversion (>80%), whereas at higher ratios, 400/1 (II) and 600/1 (III), conversions were significantly reduced indicating slower polymerizations corresponding to 54% and 43% after 45 min and 6.5 h, respectively. In the latter case lower temperature was additional parameter responsible for this drastic difference in reaction time. Effect of


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temperature was also confirmed comparing reactions II and IV (70oC vs 40oC) with similar total conversions within 45 min and 2h, respectively. The another opportunity to extend the time of reaction and to avoid precipitation of polymer with higher MMA content, was the use of mixture of methanol and THF (75%/25% v/v) as a reaction medium (IV vs V corresponding to MeOH vs solvent mixture). The solvent ratio was restricted because higher amount of THF caused undesirable precipitation of polymer during reaction. The copolymerizations performed with various initial ratios of comonomers indicated the increase in reaction rate with the content of ChMA/Cl. At 25 and 50% of ionic liquid monomer the polymers were resulted in 2.5 - 3 h (V-VI), whereas higher content of ChMA/Cl (75 and 100%) provided polymers VII and VIII at nearly the same conversions within two and three times shorter reactions, respectively. However, the amount of incorporated monomer with trimethylammonium pendent group into copolymer did not influence on control over reaction keeping dispersity induces of polymers in similar level (1.3-1.5). During polymerization the transesterification of ChMA/Cl to MMA was observed as side reaction, due to the presence of methanol in the reaction mixture. This effect was reported in the previous studies on controlled radical polymerization of ChMA by Armes24 and Makuska26. Our studies performed by UPLC for reaction X showed that transesterification occurred with higher contribution at larger content of methanol, where within 0.5 hour ~5% of starting quantity of ChMA/Cl was converted to MMA. After 24h of that polymerization the transformation of ChMA was almost complete (>99%), whereas at significant excess of ChMA (IX) it reached 32%. In the latter case the amount of generated MMA was larger than in homopolymerization with lower amount of methanol (VIII: 19%) at similar total conversion of monomer(s). Transesterification may also occur on the polymer chain but due to steric hindrance this reaction seems to be slow. In the model reaction the



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homopolymer of ChMA/Cl was dissolved in methanol and catalytic PMDETA was added. Mixture was stirred at 40°C and after 48h only 7% of ChMA/Cl has been converted to MMA. According to the 1H NMR spectrum in Figure 1 for the reaction VIII, the additional signals of vinyl protons at 5.6 and 6.1 ppm as well as -OCH3 protons at 3.6 ppm are observed indicating MMA presence during homopolymerization of ChMA/Cl.

Figure 1. 1H NMR spectra of the reaction mixture of ChMA/Cl homopolymerization (VIII) at the start (a), and after 45 min (b).

1

H NMR spectrum for the modified polymers shows the same signals, which were

observed before modification (Figure 2a-b), because it was related only to the anion changes. The anion exchange was also monitored by 13C NMR spectrum, where characteristic signals of NTf2 anion may be seen in the range of 110-130 ppm (Figure 3). However, the studies


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indicated that exchange did not occur completely and this method do not allow to obtain products free of chloride anions, which was corresponding with observation that only part of polymer dissolved in methanol was precipitated after ion exchange. The quantitative

13

C

NMR spectrum for precipitated polymer presented two bistriflimide anions per one ammonium cation. This effect may be explained by the occlusion of lithium salts in polymer precipitate or the formation of coordination complexes involving Tf2N anions, as it was described for low molecular weight ionic liquids28,29. Although the contamination of polymer with LiTf2N can be excluded due to good solubility of this salt in methanol improving purification process. Lower content of bistriflimide anion in the polymer remaining in solution was not high enough to precipitate it in methanol.

Figure 2. Comparison of 1H NMR spectra for trimethylammonium copolymers with various anions, Cl- V (a), after anion exchange Cl- to Tf2N- Va (b), Tf2N- XI (c) and Sal- XV (d) at 25% of initial concentration of ionic monomer 13 ACS Paragon Plus Environment


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Figure 3. 13C NMR spectrum of trimethylammonium based copolymer after anion exchange (Va)

The precipitated polymers had been analyzed by SEC in THF as a eluent with addition of LiTf2N salt to reduce the association of ionic groups and interactions of polymer with column. The used analysis conditions were described previously by Matyjaszewski30. Dispersity induces (Ð) corresponding to molecular weight distributions were relatively low (1.25-1.5) indicating formation of the well-defined polymers with dominated fraction of homogeneous chains as the consequence of low content of chain transfer and termination reactions during ATRP known as the pseudoliving process. The molecular weights of modified polymers (Ia-Xa) were underestimated by SEC in comparison to Mn,NMR values (calculated on the base of monomer conversion by NMR) representing absolute molecular weights. Progressive escalation of discrepancy from Mn,NMR correlated with the content of ionic moieties is observed in Figure 4a, where decreasing tendency is demonstrated by Mn,SEC 14 ACS Paragon Plus Environment

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values (27000-5000 g/mol) in opposition to increasing values of Mn,NMR (34000-160000 g/mol). Such effect was probably caused by several factors, such as the presence of bistriflimide anions with steric hindrance, the increasing polarity of analyzed samples, effectiveness of anion exchange (possible mixture of anions) and finally difference between hydrodynamic volumes of the studied ionic copolymers and PS standard for SEC calibration in the same solvent.

Figure 4. Mn,NMR vs Mn,SEC dependence on initial content of ionic monomer, after exchange of Cl- to Tf2N- (a), after exchange of Sal- to Tf2N- (b), and containing Tf2N- without ion exchange (c).

The structures of polymers before anion exchange were also confirmed by FT-IR (Figure 5a) showing characteristic absorption bands for carbonyl bond (1716 cm-1), C-H (1458, 1488 and 2970, 3026 cm-1), C-O (1158 cm-1) and ester C-O bond (958 cm-1), whereas ammonium ion exhibits characteristic bands at 1326 cm-1 and 1640 cm-1. Broad band at 3400 15 ACS Paragon Plus Environment


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cm-1 was assigned to moisture, which contaminated products. In the case of various proportions of ChMA/Cl to MMA in copolymers the changes of band intensities at 1495, 1182 and 950 cm-1 were distinguished. After anion exchange the new bands appeared at 513, 570, 615, 741, 790 and 1181 cm-1 (CF3), 1055, 1132 and 1350 cm-1 (S=O), and 3565 cm-1 (NS) demonstrating the polymer modification with introduction of Tf2N counterion (Figure 5b).

Figure 5. Comparison of FT-IR spectra for copolymers VI (a), VIa (b), XII (c), XVI (d), and XVIa (e) with various anions at 50% of initial concentration of ionic monomer

The chloride containing copolymers were also analyzed by DLS to determine their hydrodynamic diameters (Dh) in water solutions. The higher amount of trimethylammonium 16 ACS Paragon Plus Environment

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moieties in polymers VI-VIII (≥ 50 mol %, DPn > 300) provided small particles with sizes of 8-10 nm, whereas at 25% of ChMA/Cl polymer V with shorter chain (DPn = 233) formed significantly bigger aggregates reaching almost 150 nm (Figure 6). These results suggest that the repulsions of ionic moieties at properly high concentration and polymerization degree of polymers were sufficient to avoid aggregation of polymer chains with formation of nanosized particles, which in the connection with its biocompatibility are good candidates for studies on drug nanocarriers.

Figure 6. Size distribution plots by volume for particles based on chloride (V, VII, VIII) or salicylate (XV, XVII) containing polymers in deionized water at 25oC.

The comonomer relative reactivity ratios were determined by Jaacks method31 employing system containing high excess of ChMA/Cl (X), The analogical reaction with 95% of MMA could not be used due to concurrent transesterification, which at very low amount of ionic monomer provided kinetic results with too high error. However, the previous reports for copolymerization of two methacrylates, for example MMA and glycidyl methacrylate (r1=0.86, r2=1.19)32 or MMA and n-butyl methacrylate (r1=0.98, r2=1.26)33, which were 17 ACS Paragon Plus Environment


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incorporated into polymeric chain with comparable reactivity ratios, were taken under consideration. Because of that the formation of statistical copolymers was also assumed in the studied system, what allowed to calculate rMMA by the inversion of the rChMA/Cl as it was practiced earlier for systems with macromonomers34,35 and hydroxyl-functionalized monomers36. The reactivity parameters were obtained from the slope of linear relationship as rChMA/Cl = −ln(1 − XChMA/Cl)/−ln(1 – XMMA) and rMMA=1/rChMA/Cl giving values, 1.13±0.08 and 0.88±0.08, respectively. Slightly higher reactivity of ionic monomer explained the increase in reaction rate with its initial concentration in the reaction mixture. Additionally, instantaneous diagram of copolymer composition versus feed composition of comonomer mixture in Figure 7 displayed azeotropic behavior. However, the transesterification effect has to be respected as the explanation of discrepancy from full content of ChMA/Cl in homopolymer.

Figure 7. Instantaneous composition diagrams of systems based on trimethylammonium monomer with various anions.

The water-soluble ChMA/Cl was also applied for the ion exchange with Tf2N salt to form monomer well-soluble in THF and with salicylate salt to introduce pharmaceutically 18 ACS Paragon Plus Environment

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active anion into the monomer. For comparison the ATR copolymerizations of ChMA/Tf2N and MMA were performed to obtain polymers (XI-XIV) with ratio of ammonium cation to bistriflimide anion 1:1 (Table 2). The ChMA/Tf2N monomer showed typical properties of ionic liquids, such as low melting point (below room temperature) and good solubility of other compounds. Because of that small amount of THF as solvent was applied for polymerization without side reaction of transesterification. All reactions occurred with similar tendency to the systems with chloride counterion, that is their rates were increased with initial concentration of ionic monomer, but in these cases they were significantly faster (up to 30 min). The copolymers (XV-XVII) with salicylate anions were obtained at ~50% of total monomer conversion after 24h of ATRP in MeOH/THF due to limited solubility of ChMA/Sal in THF (Table 3), which means that analogically to ChMA/Cl based copolymers the anion exchange was required to determine molecular weight. As it was expected the SEC measurements yielded lower values of Mn,SEC than Mn,NMR. However, the anion modified polymers of ChMA/Cl or ChMA/Sal (Figure 4a-b) showed similar tendency of increasing Mn,NMR/Mn,SEC with the content of ionic units, whereas in the case of directly synthesized ChMA/Tf2N copolymers (Figure 4c) this correlation seems to be constant as Mn,NMR ≈ 2-3 x Mn,SEC, with exception of significant discrepancy for fully charged homopolymer XIV. In aqueous solution the copolymers with salicylate counterions formed significantly larger particles with higher polydispersity than that with chloride anions, reaching sizes of 200-300 nm (Table 3, Figure 6). This effect can be explained by the presence of bigger aromatic anions containing hydroxyl and ester groups with specific preferences for aggregation via hydrogen bonding and stacking interactions between salicylate moieties. However Dh value is lower for copolymer with higher ionic moiety content (XVII), although this effect is weaker than in copolymers with similar amount of chloride anions (VII).



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The dependencies in Figure 7 for ChMA/Tf2N and ChMA/Sal polymers show deviations from the diagonal (typical for r1 = r2 =1) as the curve below and above, what means the copolymer formed instantaneously was poorer in ChMA/Tf2N and richer in ChMA/Sal units, respectively, than the monomer mixture it originated from. These observations suggested various relative reactivity of the ionic monomer copolymerized with MMA and let to conclude that the reverse gradient structures could be assigned for that systems. The relatively low monomer conversion (~50 %) provided lower content of bistriflimide monomer with steric hindrance of anion. Additionally, highly polar nature of the ionic liquid monomer, probably was working as accelerator of MMA polymerization. However, different nature of salicylate anion and solvent environment shows that the ionic monomer can be dominating in the monomer mixture and to be incorporated expansively into the chain. The 1H NMR spectra of ChMA/Tf2N and ChMA/Sal copolymers in Figure 2c-d present signals characteristic for protons in polymethacrylate chains with methoxy and 2(trimethylammonium)ethoxy groups, the same as that before and after modification of chloride anion. Similarly, typical IR absorption bands for all these groups as well as bistriflimide anion at 510-1000, 1179 cm-1 (-CF3), 1055, 1132, 1350 cm-1 (-SO2), and 3565 cm-1 (N-S) were distinguished in Figure 5c. In the case of ChMA/Sal units additional signals of CHaromatics in the range of 6.5-7.7 ppm and bands of C=C stretch (in ring) at 1390 and 1590 cm-1 were assigned to aromatic group in salicylate anions, which are missing after exchange with Tf2N anions (1H NMR: Figure 2d, whereas after anion exchange the proton spectrum looks like on Figure 2b and FT-IR: Figure 5d-e, respectively). The thermal analysis by DSC was used to determine glass transition temperatures (Tg) of (co)polymers. Polymers with chloride anions presented the highest values of Tg (130150°C, Table 1), which were reduced after anion exchange (90-100°C, Table 1), whereas directly synthesized ChMA/Tf2N copolymers had the lowest Tg (-8 to 80°C, Table 2).


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Significant difference in Tgs for two latter groups confirmed different structures, that is modified statistical copolymers vs gradient copolymers, where -N+(CH3)3 : Tf2N- = 1:1. Figure 8 shows the changes of Tg proportionally to the used initial content of ionic monomer with one exception for copolymer XIII with Tf2N-. It was probably caused by steric hindrance of trimethylammonium groups attached to the shortest chains, what increased rotation energy yielding higher Tg than it could be expected. In the case of salicylate anions the copolymers did not show any dependence of ammonium cation content and the anion exchange (Sal- to Tf2N-) on thermal properties (Tg ~ 110oC, Table 3). These results suggest that both MMA and ChMA/Sal yield polymers with glass transition temperatures in similar range, whereas after modification their Tg,s are closed to that of the modified ChMA/Cl copolymers.

Figure 8. Correlation of polymer glass transition temperature with initial content of ionic monomer.



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Various morphologies of trimethylammonium based polymers were monitored by SEM. Powdered copolymers with chloride anion were more scrappy and brittle with porous texture in cross-sections (Figure 9a-c), whereas Tf2N containing polymers with tendency to create thin elastic films were more monolithic (Figure 9g-i). The presence of salicylate anions also provided films, which were easily crushed (Figure 9j-l). After ionic exchange the polymers seem to be more similar to chloride based copolymers, but their porosity and roughness are significantly reduced (Cl- to Tf2N- Figure 8d-f and Sal- to Tf2N- Figure 8m-o).


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Figure 9. SEM images of copolymers containing 25% of ionic units with Cl anions V (a-c), modified to Tf2N anions Va (d-f), Tf2N anions without anion exchange XI (g-i), Sal anions XV (j-l), and modified to Tf2N anions XVa (m-o).



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CONCLUSIONS The controlled synthesis of (co)polymers P(ChMA-co-MMA)s with various content of ionic pendant groups and different counterions (Cl vs NTf2 and Sal vs NTf2) was investigated. The standard ATRP conditions with CuBr/PMDETA catalytic system allowed to obtain the well-defined (co)polymers with dyspersity indices ranged in 1.3-1.5 at DPn=170-370 for the containing ChMA/Cl, and 120-240 for that with ChMA/Sal or ChMA/Tf2N. Because of different nature of ionic monomers driven by anion, the polymerizations were performed in the presence of various solvents. The relative reactivity ratios of comonomers (rChMA/Cl = 1.13 and rMMA = 0.88) were determined by the Jaacks method assuming the statistical composition, whereas gradient structures were postulated for copolymers with Tf2N and Sal anions. The properties of water soluble Cl and Sal based (co)polymers were successfully modified by ion exchange with LiTf2N. The detailed studies on the first one indicated not complete exchange yielding two fractions of (co)polymers, that is soluble in methanol (low content of Tf2N-) and precipitation (-N+(CH3)3:Tf2N- = 1:2). The comparison of thermal properties of polymers showed variable influence of anion types demonstrating the following relation: Tg,Cl > Tg,Sal = Tg,Sal→Tf2N ≥ Tg,Cl→Tf2N > Tg,Tf2N. Similarly, the polymer morphology can be adjusted by introduction of proper counterions. Both polymerization, pre-polymerization and postpolymerization modifications used in our studies showed that the trimethylammonium based ionic monomer and (co)polymers with chloride anions are great materials for further investigations to improve these systems as the carriers of biologically active anions.

ACKNOWLEDGEMENTS R.B. was supported by grant no. BKM/507/RCh4/2015 from Silesian University of Technology. Authors also thank to Dr T. Bieg for help with 13C NMR analysis.


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Graphical abstract Trimethylammonium-based polymethacrylate ionic liquids with tunable hydrophilicity and charge distribution as carriers of salicylate anions Rafał Bielas, Anna Mielańczyk, Agnieszka Siewniak, Dorota Neugebauer*

Synopsis: Both [2-(methacryloyloxy)ethyl]trimethylammonium chloride monomer and its (co)polymers are able to anion exchange, including introduction of biologically active ones for design of poly(ionic liquid)s with therapeutic properties.



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Table 1. ATR (Co)polymerization of MMA with ChMA/Cl (I-X) and anion exchange with LiTf2N (Ia-Xa)

Initial monomer ratio of MMA to ChMA/Cl Time wt % mol % (h)

NMR Conversion (%) xMMA xChMA/Cl

Mn,NMR (g/mol)

SEC

DSC

DLS

Mn,SEC (g/mol)

Tg (oC)

Dha (nm)

Nr DPn Ð FChMA 60/40 75/25 0.4 78 100 167 22100 0.3 I 68700 9900 1.34 Ia 60/40 75/25 0.75 54 55 217 27600 0.24 II 41100 7900 1.70 IIa 60/40 75/25 6.5 40 51 257 34000 0.3 III 35100 8400 1.31 IIIa 60/40 75/25 2 69 39 258 29000 0.2 IV 38600 7700 1.38 IVa 60/40 75/25 2.5 62 47 233 28000 0.26 141 149 V 40000 10400 1.36 102 Va 32/68 50/50 3 75 77 304 47000 0.51 130 8 VI 84700 8800 1.49 91 VIa 14/86 25/75 1.5 84 84 337 61000 0.75 139 10 VII 123100 5400 1.31 93 VIIa 0.75 86 344 71500 0.81 146 8 VIII 0/100 155600 9400 1.37 90 VIII 2.5/97.5 5/95 24 86 93 372 75400 0.68 158 IX 162300 4900 1.23 IXa 90.5/9.5 95/5 24 66 100 266 29400 0.003 131 X 34300 27000 1.35 Xa Conditions: [MMA + ChMA/Cl]0/[EBiB]0/[CuBr]0/[PMDETA]0 = 400/1/1/1, except I: 200:1 and III: 600:1, in MeOH (I-IV), MeOH/THF=75/25 (where MeOH/ChMA = 1/1 v/w (V-VIII) or MeOH/ChMA = 2.5/1 v/w (IX-X)), at 40oC (III, V-X) and 70oC (I-II, IV); a results for >90% of particles, with exception of VI determined for 68% of particles (another particle fraction with size of 4.5 nm).

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Table 2. ATR (Co)polymerization of MMA with ChMA/Tf2N at 40oC NMR SEC Initial monomer ratio of Time MMA to ChMA/Tf2N Conversion (%) Mn,NMR FChMA/Tf2N Mn,SEC (min) Nr wt % mol % xMMA xChMA/Tf2N DPn (g/mol) (mol%) (g/mol) 30/60 75/25 30 53 46 205 69500 0.24 30400 XI 18/82 50/50 15 65 48 226 56500 0.26 29400 XII 7/93 25/75 10 44 27 125 41000 0.39 12200 XIII 0/100 5 55 218 98600 1.00 8000 XIV Conditions: [MMA + ChMA/Tf2N]0/[EBiB]0/[CuBr]0/[PMDETA]0=400/1/1/1, THF is 10% of both monomers volume

27


Ð 1.54 1.44 1.27 1.46

DSC Tg (oC) 80 60 58 -8


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Table 3. ATR (Co)polymerization of MMA with ChMA/Sal at 40oC Initial monomer ratio of NMR MMA to ChMA/Sal Conversion (%) wt % mol % xMMA xChMA/Sal 49/51 75/25 22 53

SEC Mn,SEC (g/mol)

DSC Mn,NMR FChMA/Sal Tg Nr DPn (g/mol) (mol%) Ð (oC) 119 22700 0.44 1.36 106 XV 25900 7200 116 XVa 24/76 50/50 20 73 187 27100 0.78 1.26 109 XVI 32800 5800 108 XVIa 10/90 25/75 40 67 242 43500 0.83 1.54 107 XVII 60500 7200 102 XVIIa Conditions: [MMA + ChMA/Sal]0/[EBiB]0/[CuBr]0/[PMDETA]0=400/1/1/1, MeOH/THF=3/1, whereas MeOH/ChMA = 1/1 v/w, 24 h

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DLS Dh (nm) 232 293 201

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