Article pubs.acs.org/IECR
Synthesis of Dual Thermosensitive and pH-Sensitive Hollow Nanospheres Based on Poly(acrylic acid‑b‑2-hydroxyethyl methacrylate) via an Atom Transfer Reversible Addition− Fragmentation Radical Process Pourya Panahian, Mehdi Salami-Kalajahi,* and Mahdi Salami Hosseini Department of Polymer Engineering and Institute of Polymeric Materials, Sahand University of Technology, P.O. Box 51335-1996, Tabriz, Iran ABSTRACT: A seven-step approach was developed to synthesize poly(acrylic acid-b-2-hydroxyethyl methacrylate) [P(AA-bHEMA)]-based temperature- and pH-sensitive hollow nanospheres. Silica nanoparticles were used as primary cores that could be etched with an aqueous hydrofluoric acid (HF) solution. A surface-attached atom transfer radical polymerization initiator was converted to a reversible addition−fragmentation chain transfer (RAFT) agent, and AA and HEMA were polymerized via “grafting from” RAFT polymerization. The PAA block was cross-linked partially via an esterification reaction with -COOH groups with 1,4-butanediol, and hollow nanospheres were obtained by etching silica cores with an aqueous HF solution. These hollow nanospheres exhibited dual pH-sensitive and thermosensitive properties as measured by the hydrodynamic diameter at different values of pH (3−12) and temperature (25−55 °C) at different concentrations (1 and 5 mg/mL). Results showed that this behavior could be changed at different concentrations; therefore, at low contents, the particles show one lower critical solution temperature (LCST), while at higher contents, two LCSTs are observed.
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INTRODUCTION Thermoresponsive polymers that have a lower critical solution temperature (LCST) or a solubility transition in water have attracted significant interest in recent years based on their broad potential in applications such as temperature-triggered drug delivery.1−3 Several thermoresponsive polymers such as poly(N-isopropylacrylamide) (PNiPAm),4,5 poly(2-oxazoline)s,6,7 and poly(2-hydroxyethyl methacrylate) (PHEMA)8,9 have been described. Also, some polymers such as poly(acrylic acid) (PAA)10,11 and poly(methacrylic acid) (PMAA)12,13 are known as pH-sensitive polymers. Among different structures, hollow nanospheres have attracted a great deal of attention.14−16 In such structures, a single-layer shell gives a single stimulus, including changes in temperature or pH, while a dual-stimulus response can be obtained by a two-layer shell with block copolymerization of two kinds of functional monomers. Etching a silica core from silica/cross-linked-polymeric-shell nanoparticles can be an effective method for synthesizing hollow nanospheres if a stimulus-responsive polymer is crosslinked around nanometric silica particles. Different strategies are known for grafting polymers on nanoparticles, including the “grafting to” method, in which the end-functionalized polymers react with an appropriate surface;17 the “grafting from” method, in which polymer chains are grown from the surface-attached initiators;18 and the “grafting through” method, in which polymerizable groups exist on the surface of particles.19 Among these strategies, the most applicable mechanism is the grafting from approach combined with living and controlled polymerization mechanisms that are widely applied for the synthesis of thermoresponsive polymers.20,21 Although atom transfer radical polymerization (ATRP) is the most investigated controlled radical polymerization technique,22,23 it is uncontrolled in the © 2014 American Chemical Society
polymerization of acid-functional monomers such as acrylic acid.24,25 In most cases, the block copolymers containing the PAA block have been prepared via ATRP of tert-butyl acrylate26 and the subsequent selective deprotection reaction with trifluoroacetic acid or trimethylsilyl iodide. However, these reagents could lead to the incomplete deprotection or the cleavage of other ester bonds.27 To overcome this problem, reversible addition−fragmentation chain transfer (RAFT) polymerization28,29 seems to be more applicable. However, the synthesis of RAFT end-functionalized initiators is not so facile. The possibility of converting ATRP initiators, which are readily accessible, into RAFT mediators using a simple methodology would, therefore, be of great value.30,31 In this method, the RAFT agent is prepared via ATRAF using a stoichiometric amount of bis(thiocarbonyl) disulfides and alkyl halides in the presence of copper(I) species. In this work, silica nanoparticles were modified with 2bromoisobutyryl bromide (BIBB) as the ATRP initiator. Then, via the ATRAF process, the ATRP initiator was converted to the RAFT agent and poly(acrylic acid-b-2-hydroxyethyl methacrylate) [P(AA-b-HEMA)] chains were grafted onto the surface via the grafting from approach. Partial cross-linking of PAA segments was performed by a condensation process with 1,4-butanediol. Finally, to synthesize hollow nanospheres, the silica core was removed using an aqueous HF solution, and the thermoresponsive behavior of nanospheres was investigated by dynamic light scattering (DLS). Received: Revised: Accepted: Published: 8079
March 1, 2014 April 18, 2014 April 28, 2014 April 28, 2014 dx.doi.org/10.1021/ie500892b | Ind. Eng. Chem. Res. 2014, 53, 8079−8086
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2. EXPERIMENTAL METHODS 2.1. Materials. Aerosil 200, as a silica nanoparticle, was purchased from Evonik Degussa, stirred in deionized water for 1 day, separated by centrifugation, filtered, dried, and finally stored in a vacuum oven (50 °C, 40 mmHg). Acrylic acid (AA, 99%, Merck) and 2-hydroxyethyl methacrylate (HEMA, 99%, Merck) were passed through a basic alumina column to remove the polymerization inhibitor before being used. Azobis(isobutyronitrile) (AIBN, 99%, Acros), Cu(I)Br (98%, SigmaAldrich), N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA, 99%), bis(thiobenzoyl) disulfide (99%, SigmaAldrich), copper powder [Cu(0), 99.5%, Sigma-Aldrich], 3aminopropyltriethoxysilane (APTES, 98%, Merck), 2-bromoisobutyryl bromide (BIBB, 98%, Sigma-Aldrich), dicyclohexylcarbodiimide (DCC, 60%, Sigma-Aldrich), 4(dimethylamino)pyridine (DMAP, 99%, Sigma-Aldrich), 1,4butanediol (99%, Sigma-Aldrich), triethylamine (99.5%, SigmaAldrich), maleic anhydride (99.9%, Merck), toluene (99%, Merck), acetone (99.8%, Merck), tetrahydrofuran (THF, 99%, Merck), methanol (99%, Merck), n-hexane (96%, Merck), dichloromethane (99.8%, Sigma-Aldrich), chloromethane (99.5%, Sigma-Aldrich), dimethylformamide (99.8%, SigmaAldrich), aqueous HF (48%, Merck), hydrochloric acid (HCl, 37%, Sigma-Aldrich), sodium hydroxide (NaOH, 98%, SigmaAldrich), methyltrioctylammonium chloride (97%, Aldrich), and basic aluminum oxide (Fluka) were used as received without further purification. 2.2. Synthesis of RAFT Agent-Grafted Silica Nanoparticles. First, in a 500 mL flask, 10.000 g of silica nanoparticles was dispersed in 200 mL of acetone via an ultrasonication process (20 min), and then the temperature was increased to 56 °C. The solution of 150 mg of maleic anhydride and 1 mL of water in 150 mL of acetone was added to the flask, and after the mixture had been stirred for 1 h, 5 mL of 3aminopropyltriethoxysilane was added dropwise. The reactants were refluxed at 56 °C for 4 h while being stirred under a nitrogen atmosphere. After the reaction, the resulting product was reprecipitated with n-hexane (600 mL), followed by centrifugation (10000 rpm, 30 min) to obtain modified nanoparticles. Moreover, nanoparticles were washed with acetone and n-hexane several times. The residue (Si-NH2) was dried for 12 h at 40 °C in a vacuum oven. To obtain ATRP initiator-grafted nanoparticles, 8 g of SiNH2 nanoparticles was dispersed in 250 mL of toluene via an ultrasonication process (20 min), and then 2-bromoisobutyryl bromide (2.8 mL, 0.023 mmol) and triethylamine (3.2 mL, 0.023 mmol) were added to the flask dropwise. The temperature was set at 0 °C by an ice bath, and the reaction was conducted for 4 h at this temperature, and then for 18 h at 25 °C. After the reaction, the resulting product was reprecipitated with n-hexane (500 mL), followed by centrifugation (10000 rpm for 30 min) yielding modified nanoparticles. Moreover, nanoparticles were washed with toluene and nhexane several times. The residue (Si-Br) was dried for 12 h at 40 °C in a vacuum oven. Finally, Si-Br nanoparticles (3.000 g), Cu(0) (0.380 g, 0.006 mol), and bis(thiobenzoyl) disulfide (0.400 g, 1.2 mmol) were dispersed in 250 mL of toluene via an ultrasonication process (20 min). Then, a mixture of CuBr (0.186 g, 1.3 mmol) and PMDETA (0.6 mL, 0.500 g) was added to the reactor, the temperature increased to 50 °C, and the reaction continued for 24 h. The resulting dark brown mixture was centrifuged (12000
rpm for 20 min). Then, the resultant was dispersed in methanol, chloromethane, and dichloromethane several times and separated via centrifugation. The residue (Si-RAFT) was dried for 12 h at 40 °C in a vacuum oven. 2.3. In situ RAFT polymerization of acrylic acid. In a 100 mL flask, 1.000 g Si-RAFT nanoparticles were dispersed in 50 mL DMF with ultrasonication process (20 min). After 30 min stirring, acrylic acid (3.4 mL, 50 mmol) was added to the reactor. After 15 min stirring, AIBN (0.02 g, 0.12 mmol) was added and polymerization was performed 24 h at 60 °C. To obtain the PAA-grafted nanoparticles, reaction mixture was centrifuged 30 min (10000 rpm). Moreover, nanoparticles were dispersed in DMF and dichloromethane followed by centrifuging several times. The nanoparticles (Si-PAA) were dried for 12 h at 40 °C in vacuum oven. 2.4. In Situ RAFT Polymerization of HEMA. In a 150 mL flask, 0.4 g of Si-PAA nanoparticles was dispersed in 40 mL of DMF via an ultrasonication process (20 min). After the sample had been stirred for 30 min, a mixture of HEMA (6.8 mL, 0.06 mol) and AIBN (0.04 g, 0.28 mmol) was added to the reactor and polymerization was performed for 48 h at 70 °C. To obtain the P(AA-b-HEMA)-grafted nanoparticles, the reaction mixture was centrifuged for 30 min (10000 rpm). Moreover, nanoparticles were dispersed in DMF and dichloromethane followed by several centrifugations. The nanoparticles [Si-P(AA-bHEMA)] were dried for 12 h at 40 °C in a vacuum oven. 2.5. Cross-Linking of the PAA Shell. In a 150 mL flask in an ice bath, 1 g of Si-P(AA-b-HEMA) nanoparticles was dispersed in 100 mL of DMF via an ultrasonication process (20 min). Then, a mixture of DCC (1 g, 4.8 mmol), DMAP (0.1 g, 0.8 mmol), and 1,4-butanediol (0.4 mL, 4.8 mmol) was added to the reactor and the reaction performed for 1 h in an ice bath and continued for 24 h at 25 °C. It is obvious that the -OH groups of the P(HEMA) block can react with the -COOH groups of the PAA block in this step, but the reaction was performed in DMF in which the polymer chains extend because of the good solubility behavior. Also, the stimulus-responsive behavior of obtained nanoparticles showed that the reaction between -OH groups of P(HEMA) and -COOH groups of PAA could be disregarded. To obtain nanoparticles, the reaction mixture was precipitated with n-hexane and centrifuged for 30 min (10000 rpm). Moreover, nanoparticles were dispersed in methanol (100 mL) followed by several centrifugations. The nanoparticles were dried for 12 h at 40 °C in a vacuum oven. 2.6. Elimination of Silica Cores To Synthesize Hollow Nanospheres. To etch the silica cores, cross-linked nanoparticles (1 g) were dispersed in toluene (20 mL) and then methyltrioctylammonium chloride (1.5 g) was added. After the addition of 5% aqueous HF (20 mL), the mixture was stirred at room temperature for 2 h. Then DMF (30 mL) was added, and the organic nanoparticles were separated by 10000 rpm centrifugation for 30 min and dried under vacuum overnight. The same route was used to cleave PAA and P(AA-b-HEMA) chains from the surface of Si-PAA and Si-P(AA-b-HEMA) nanoparticles to determine the molecular weight and polydispersity index values. 2.7. Instrumentation. Fourier transform infrared (FTIR) spectra were recorded on a Bruker Tensor 27 FTIR spectrophotometer, within a range of 400−4000 cm−1 using a resolution of 4 cm−1. An average of 24 scans were taken for each sample. The samples were prepared on a KBr pellet in vacuum desiccators under a pressure of 0.01 Torr. Thermal 8080
dx.doi.org/10.1021/ie500892b | Ind. Eng. Chem. Res. 2014, 53, 8079−8086
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Scheme 1. Synthetic Route for the Preparation of RAFT Agent- and Polymer-Grafted Silica Nanoparticlesa
a
Abbreviations: APTES, 3-aminopropyltriethoxysilane; BIBB, 2-bromoisobutyryl bromide.
subsequently, the ATRP initiator was grafted via a reaction between -NH 2 and C(O)-Br groups. Because of the uncontrolled reaction of acrylic acid via ATRP reaction, the ATRP initiator was converted to the RAFT agent via the ATRAF process.30,31 Then, grafting from RAFT polymerization was employed to synthesize the nanoparticles that were modified by P(AA-b-HEMA) as shown in Scheme 1. According to the FTIR results (Figure 1), after modification of silica nanoparticles with 3-aminopropyltriethoxysilane, a bending vibration of amine groups at 1580−1650 cm−1 and the characteristic absorption of CH3-O-Si at 2800−3000 cm−1 can be observed. Characteristic peaks at 1535 and 1655 cm−1 are related to the N-CO groups in Si-Br samples. Also, in the Si-
gravimetric analyses were conducted with a PL thermogravimetric analyzer (Polymer Laboratories). The thermograms were obtained from ambient temperature to 700 °C at a heating rate of 10 °C/min. A sample weight of ∼10 mg was used for all the measurements, and nitrogen was used as the purging gas at a flow rate of 50 mL/min. Weight loss for all samples around 100 °C has been attributed to the evaporation of water molecules absorbed by particles. Also, the weight loss was calculated between 120 and 600 °C. 1H nuclear magnetic resonance (NMR) (300 MHz) spectra were recorded on a Bruker Avance 300 spectrometer using deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard. Average molecular weights and molecular weight distributions were measured by size exclusion chromatography (SEC). A Waters 2000 ALLIANCE instrument with a RI detector and a set of three series of columns with pore sizes of 3000, 100, and 50 Å was utilized to determine the polymer average molecular weight and polydispersity index (PDI). DMF was used as the eluent at a flow rate of 1.0 mL/ min, and calibration was conducted using low-polydispersity PMMA standards with molecular weights ranging from 650 to 3001000 g/mol. A transmission electron microscope (TEM), Tescan Mira, with an accelerating voltage of 120 kV was used to study the morphology of the nanoparticles; the 70 nm thick samples were prepared with a Reichert-ultramicrotome (type OMU 3). Particle sizes and their distribution were analyzed using a dynamic light scattering (DLS) instrument (Malvern Nano Zetasizer ZS 90) with a scattering angle of 176.1°. The reported diameter is composed of three measurements, and the errors have been estimated to be ≤5%. The measurements were taken after the samples had been dispersed in distilled water (1 or 5 mg/mL) and allowed to be thermally stable for 1 h. Energy-dispersive X-ray spectroscopy (EDX) was conducted on a JSM-6360LV instrument.
3. RESULTS AND DISCUSSION As shown in Scheme 1, a three-step approach was employed to synthesize the RAFT agent-grafted silica nanoparticles (SiRAFT). Silica nanoparticles were functionalized by 3-aminopropyltriethoxysilane through a condensation process, and
Figure 1. FTIR spectra of pristine and different modified silica nanoparticles. 8081
dx.doi.org/10.1021/ie500892b | Ind. Eng. Chem. Res. 2014, 53, 8079−8086
Industrial & Engineering Chemistry Research
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Table 1. Results of EDX Analysis of Different Hybrid Nanoparticles weight % sample
Si (1.739 keV)
O (0.525 keV)
C (0.277 keV)
N (0.392 keV)
S (2.307 keV)
Si Si-NH2 Si-RAFT Si-PAA Si-P(AA-b-HEMA)
45.98 45.21 41.06 34.12 24.42
51.11 47.42 43.14 43.62 47.56
2.91 6.08 12.10 19.23 25.89
− 1.29 1.17 0.94 0.64
− − 2.53 2.09 1.49
RAFT sample, small peaks at 1500−1600 cm−1 are attributed to the aromatic CC group of the phenyl ring on the RAFT agent. After polymerization of acrylic acid, a strong peak at 1730 cm−1 related to carbonyl groups of acrylic acid appeared. Also, the characteristic peaks at 2800−3000 cm−1 related to the C-H groups become stronger. The peak at 3000−3100 cm−1 is related to the aromatic C-H groups of the phenyl ring on the RAFT agent, which shows that the RAFT agent possibly exists after polymerization and chain extension. There is no significant change in FTIR spectra after chain extension with HEMA. To confirm the formation of hybrid nanoparticles, and because of the weak peaks of the FTIR method, EDX analysis was employed to investigate the relative elemental percentage of the surface. As shown in Table 1, no N or S was observed in bare silica nanoparticles while 2.91 wt % C is related to the residue of the surfactant or solvent that was employed in the synthesis of the nanoparticles. After modification with 3aminopropyltriethoxysilane, the quantity of N increased to 1.29 wt % because of the existence of N atoms in the structure of the modifier. It is clearly observed that after the ATRAF process and the attachment of the RAFT agent to the surface, the content of S increased from 0.00 to 2.53 wt %. After acrylic acid polymerization, the content of Si decreased from 41.06 to 34.12 wt % and then to 24.42 wt % after HEMA polymerization. The same trend was observed for S when the content of O increased. Thermogravimetric analyses (TGA) were used to evaluate the modification quantity. Figure 2 shows TGA thermograms of pristine and hybrid silica nanoparticles. According to the results and considering the mass loss between 120 and 600 °C, pristine nanoparticles show a 0.9 wt % mass loss, whereas mass losses after modification with the aminosilane agent and ATRP initiator increased to 4.88 and 10.63 wt %, respectively. After the ATRAF process and the conversion of the ATRP initiator to the RAFT agent, the mass loss increased to 13.71 wt %. Also, the mass loss increased to 28.14 wt % after acrylic acid polymerization, and a two-step degradation of the Si-P(AA-bHEMA) sample shows a block copolymer attached to the surface with a mass loss of 51.49 wt %. 1 H NMR analysis was conducted in DMSO after the polymers had been cleaved from the surface of the nanoparticles. Figure 3 shows the 1H NMR spectra for the PAA and P(AA-b-HEMA). For the PAA, the characteristic signals are as follows: δ(CH(CH2), a) = 2.1−2.2 ppm, δ(CH(CH2), b) = 1.6−1.8 ppm. Also, chemical shifts at 2.4−2.6 and 2.7−2.9 ppm are related to DMSO and DMF, respectively. The RAFT agent aromatic cycle shows the signals at 5.8−6.4 ppm that are the best proof of converting the ATRP initiator to the RAFT agent before polymerization. After chain extension, the following characteristic chemical shifts of the P(HEMA) block appeared: δ(C(CH3), c) = 0.9−1.1 ppm, δ(COO(CH2), e) = 4.0−4.2 ppm, δ(CH2O, f) = 3.6−3.7 ppm.
Figure 2. TGA curves of pristine and different modified silica nanoparticles.
Also, to determine the molecular properties of attached chains and confirmation of chain extension, attached polymers were cleaved from the surface of silica nanoparticles and analyzed by SEC. As shown in Figure 4, the molecular weight (Mn) and polydispersity index (PDI) of cleaved PAA chains were 4300 g/mol and 1.18, respectively. The low PDI value (
