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Branched copolymers with biodegradable core and pendant oxirane groups.

INTRODUCTION

Glycidyl methacrylate (GMA) contains two reactive groups, vinyl and oxirane, which can be used selectively depending on polymerization method. In anionic polymerization according to ring-opening mechanism polyethers with vinylic substituents are formed (1). In this case the polymers can be crosslinked by UV radiation in the presence of resins yielding stiff, glassy, and UV-resistant materials. The anionic polymerization with participation of unsaturated double bond was much more uncommon as it was reported for the synthesis of block copolymers using polystyrene as macroinitiator (2). However, polymethacrylates with oxirane substituents are usually prepared by radical polymerization. Both conventional free-radical polymerization initiated by benzoyl peroxide (3-5) and 2,2'-azobisisobutyronitrile (6-10) as well as the controlled radical methods, i.e., nitroxide-mediated polymerization (NMP) (11), reversible addition--fragmentation transfer polymerization (RAFT) (12), and atom transfer radical polymerization (ATRP) (13-15) are applied for the synthesis of reactive linear poly(glycidyl methacrylate) (PGMA). GMA was also copolymerized with a several vinyl monomers as styrene (16), and its derivatives (17), butyl acrylate (18), (19), methyl methacrylate (14), and allyl methacrylate (20).

The GMA grafted structures were obtained by "grafting from" multifunctional polyethylene and polycaproamide fibers (21), (22). polycaprolactone (23), and carbon surface (24) as well as by "grafting onto" cross-linked polystyrene beads (25). In another case four-arm star polystyrene with 2-bromoisobutyrate groups at the ends was used for the initiation of ATRP of GMA to yield the epoxy functionalized four-arm star diblock copolymers (26).

In this article, we demonstrate successful synthesis of branched macromolecules with side chains/arms containing reactive GMA units by the controlled ATRP method. The amorphous polymethacrylates with statistical distributions of a several units of 6-hydroxyhexanoic acid 2-(2-methacryloyloxy)ethyl ester, commercially known as caprolactone 2-(methacryloyloxy)ethyl ester (CLMA), functionalized with bromoester groups ([n.sub.Br] = 6 and 7), the crystalline poly(c-caprolactone) (PCL) ([n.sub.Br] = 3). and the acetal based D-glucopyranosides ([n.sub.Br] = 3 and 6) with biodegradable and biocompatible properties were used as ATRP (macro)initiators, which after polymerization of GMA or copolymerization with methyl methacrylate (MMA) form cores in the branched copolymers. GMA was selected as monomer due to the highly reactive oxirane rings, which introduced into the polymer can be easily opened and transformed via chemical reactions to the polymer with another properties, for example by hydrolysis to amphiphilic copolymer or by crosslinking to gel polymer. In other case the GMA copolymers can be matrices for biologically active molecules, which are able to be attached directly during the ring-opening reaction.

EXPERIMENTAL PART

Materials

PCL triol ([M.sub.n] ~ 900 g/mol), methyl [alpha]-D-glucopyranoside (Me[alpha]DGlu, [greater than or equal to]99%), 2-(hydroxymethyl)phenyl-[beta]-D-glucopyranoside (salicin, p-toluenesullonic acid (p-TsOH, [greater than or equal to]98.5%), Amberlyst-15 (Amb15), terephthalalcle-hyde (TPhA, 99%), [alpha]-bromoisobutyryl bromide (BriBuBr, 98%), triethylamine (TEA, >99%), anhydrous tetrahydro-furane (THF, 99.9%), 4,4'-dinonyl-2,2'-dipyriclyl (dNdpy, 97%), and copper (II) chloride (Cu[Cl.sub.2] >99%) were purchased from Sigma-Aldrich and used without purification. Salicylaldehyde (SLA, Sigma-Aldrich, [greater than or equal to] 98%) was distilled prior to use. GMA (Sigma-Aldrich, 97%) and methyl methacrylate (MMA, Sigma-Aldrich, 98%) were dried over molecular sieves and stored in a freezer under nitrogen. Copper (I) chloride (CuCI, Fluka, 97%) was purified by stirring in glacial acetic acid followed by filtration and washing with ethanol and diethyl ether. After that the solid was dried under vacuum. Solvents (POCh): N,N-dimethyl-formamide (DMF) was used after distillation over [P.sub.2][O.sub.5]. dimethyl sulfoxide (DMSO) was used after heating with calcium oxide and distillation, benzene was used after distillation over sodium, C[H.sub.2][Cl.sub.2] was distilled over Ca[H.sub.2] and dried with molecular sieves, pyridine (PYR) was purified by distillation from KOH pellets. The other solvents were applied without purification.

Synthesis of CLMA macroinitiators (MI1-MI2): The synthesis of prernacroinitiator P(MMA-co-CLMA) (5% of CLMA initial feed) and esteritication reaction yielding P(MMA-co-CLMABr) MI1 was described by authors earlier in Ref. 27. The similar procedure was applied for the preparation of PUBMA-co-CLMA) (28) and P(tBMA-co-CLMABr) MI2.

Grafting GMA from CLMA macroinitialor (Example for GP2): MI2 (0.6 g, which contains 0.024 mmol of initiating sites), GMA (2.0 ml, 14.6 mmol), dNhpy (15 mg, 0.037 mmol). and anisole (1.4 ml, 70 vol% of monomer) were added to a 10 ml Schlenk flask, and the mixture was degassed by three freeze-pump-thaw cycles. Alier stirring at room temperature for 1 h. CuCl (1.8 mg, 0.018 mmol) was added and the flask was placed in a thermostated oil bath at 30 [degrees]C. The polymerization was stopped by opening the flask to air. The reaction mixture was diluted in CH[Cl.sub.3] and passed through a column of activated (neutral) alumina to remove the copper catalyst. Next it was concentrated by rotary evaporation and further purified by precipitation in methanol. The copolymers were isolated by decantation and dried under vacuum to a constant mass.

Synthesis of PCL Macroinitiator [(PCL-Br).sub.3]: The esterification reaction was described by authors earlier in Ref. 29. Commercial PCL-triol (10 g. 5 mmol) was dissolved in dry toluene (75 ml). and then TEA (2.5 ml. 18 mmol) was added. This was followed by dropwise addition of BriBuBr (2.5 ml. 20 mmol) at 0 [degrees]C under argon atmosphere. Then the reaction mixture was stirred at 40 [degrees]C for 24 h. The solution was concentrated and THF was added. The quaternary ammonium salt was removed by filtration and the filtrate was again concent rated using rotary evaporator. Next, the macroinitiator was precipitated in methanol and dried tinder vacuum to the constant mass. [.sup.1]H NMR (CD[Cl.sub.3], 300 MHz. 25 [degrees]C) [sigma] (ppm): 4.18 (2H, t, -C[H.sub.2]OC(O)C[(C[H.sub.3].sub.2](Br)), 4.06 (6H, t, -[[C(O)C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]O].sub.n]-; 2H, t, -C-C[H.sub.2]-O-,), 2.31 (2H, t, -[[C(O)C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]O].sub.n])-, 2.0-1.9 (6H, s,-OC(O)C[(C[H.sub.3]).sub.2]Br), 1.65 (4H, m, -[[C(O)C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]O].sub.n]-), 1.44 (2H, m, -[[C(O)C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]O].sub.n]; 2H, t, C[H.sub.3]-C[H.sub.2]-C-), 0.95 (3H, -C-C[H.sub.2]-C[H.sub.3]). FTIR (KBr): 3100-2800 v(C-H), 1730 v(C=O), 1250-1175 v(C-O), 1450 [delta](C[H.sub.2]) [cm.sup.-1]. [M.sub.n, NMR] = 1.45 x [10.sup.3] g/mol: [M.sub.n, GPC] = 1.7 x [10.sup.3] g/mol, [M.sub.w] / [M.sub.n] = 1.6.

Synthesis of Star Copolymer [[PCL-b-(PGMA-co-MMA)].sub.3] (Example for SP2): PCL-[(Br).sub.3] (140 mg, which contains 0.092 mmol of initiating sites), GMA (1.6 ml, 11.7 mmol), MMA (1.2 ml, 11.2 mmol), anisole (4.0 ml, 140 vol% of monomer), dNdpy (78.6 mg, 0.19 mmol), and Cu[Cl.sub.2] (0.64 mg, 5 mol% of CuCl) were placed in a Schlenk flask and degassed by three freeze-pump-thaw cycles. Then, CuCl (9.5 mg, 0.096 mmol) was added and the reaction flask was immersed in an oil bath at 30 [degrees]C. The reaction was stopped by exposing the reaction mixture to air. Purification and precipitation procedures were the same as it was above described for PGMA grafted copolymers.

Preparation of sugar initiator SI1: Me[alpha]DGlu (46.9 mmol) and SLA (195.3 mmol) in benzene/DMF (40/30 ml/ml) containing catalyst p-TsOH (0.4 g) were placed in a round-bottom flask equipped with a magnetic stirrer. The solution was purged with argon and then was subjected to azeotropic removal of water (Dean-Stark apparatus). The catalyst was deactivated with CaC[O.sub.3] and filtered off. Next, the solvent was removed under reduced pressure and the product was precipitated with distilled water. The crude product was extracted in a Soxhlet apparatus using diethyl ether. Then the acetal was dissolved in C[H.sub.2][Cl.sub.2] (16 m1). The solution was cooled to 0 [degrees]C with an ice/water bath followed by dropwise addition of TEA (1.7 ml) and BriBuBr (1.2 equiv. per -OH group in acetal). The solution was stirred at ambient temperature overnight. Precipitated ammonium salt was filtered off and the filtrate was extracted with C[H.sub.2][Cl.sub.2]. The organic layer was washed with distilled water, 5% [Na.sub.2]C[O.sub.3]. and finally water (to neutral), than dried over anhydrous MgS[O.sub.4], filtered off and C[H.sub.2][Cl.sub.2] was removed under reduced pressure. [.sup.1]H NMR (CD[Cl.sub.3], 300 MHz, 25 [degrees]C) [delta] (ppm): 1.772.18 (m, 18H, -C[H.sub.3]); 3.38-3.49 (m, 3H, -OC[H.sub.3]); 3.68-3.84 (m, 2H. H-4, H-6); 3.98 (dt, 1H, J = 9.9 Hz, J = 4.8 Hz, H-5); 4.28 (dd, 1H, J = 10.2 Hz, J = 4.8 Hz, H-6); 4.93-5.03 (m, 2H, [H.sub.an], H-2); 5.69 (t, 1H, J = 9.9 Hz, H-3); 5.76 (s, IH. -OCHO-); 7.06 (d, 1H, J = 8.1 Hz, [H.sub.c]); 7.27 (t, 1H, J = 6.0 [H.sub.z], [H.sub.E]); 7.38 (t, 1H, J = 8.1 [H.sub.z], [H.sub.D]); 7.66 (d, 1H. J = 7.5 [H.sub.z], [H.sub.F]). [.sup.13]C NMR (CD[Cl.sub.3], 75 MHz, 25[degrees]C) [delta] (ppm): 30.3-30.8 (-C[H.sub.3]); 55.3-55.9 (-C-Br); 62.2 (-C[H.sub.3]); 69.0 (C-6); 70.1 (C-4); 72.5 (C-5); 77.2 (C-2); 79.1 (C-3): 97.1 (C-1); 97.3 (-OCHO-); 121.8 ([C.sub.C]); 126.5 ([C.sub.E]): 127.6 ([C.sub.AF]); 128.9 ([C.sub.A]); 130.2 ([C.sub.D]); 147.9 ([C.sub.B]): 168.7-171.0 (C=O). Elemental analysis: calcd: C, 41.90; H. 4.46; 0, 21.47, Br, 32.16; found: C. 41.71; H, 4.09. [[alpha].sub.D.sup.26] = +44[degrees]. [T.sub.m] = 233 [degrees]C.

Preparation of sugar initiator SI2: The procedure of acetalization step was the same as for SI1, but in the case of SI2 salicin (17.5 mmol) and TPhA (8.7 mmol) in benzene/DMSO (7/7 ml/m1) containing catalyst Amb-15 (0.2 g) were mixed in a flask. The crude product was extracted with ethanol and dissolved in THF. The esterification step was similar to above described using 1.2 equiv. of BriBuBr per -OH group in diacetal. After decantation the filtrate was precipitated in ethanol. Further, the purification was the same as for sugar SI1. [.sup.1]H NMR (CD[Cl.sub.3], 300 MHz, 25 [degrees]C) [delta] (ppm): 1.80-2.05 (m, 36H, -OC[H.sub.3]); 3.69 (dt, 2H, J = 9.6 Hz, J = 4.9 Hz, H-5); 3.77-4.03 (m, 4H, H-4, H-6); 4.42 (dd, 2H, J = 10.5 Hz, J = 4.8 Hz, H-6); 5.25 (s, 4H, -C[H.sub.2]OC(O)-); 5.33 (d, 2H, J = 7.4 Hz, Han); 5.40-5.59 (m, 6H, H-2, H-3, -OCHO-); 7.047.13 (m, 4H, Hi, HL); 7.31 (t, 214, = 7.9 Hz, HK); 7.40 (d, 2H, J = 7.7 Hz, [H.sub.1]); 7.44 (s, 4H, [H.sub.B]). [.sup.13]C NMR (CD[Cl.sub.3], 75 MHz, 25 [degrees]C) [delta] (ppm): 30.7-31.1 (C[H.sub.3]); 55.2-56.1 (C-Br); 62.6 (-C[H.sub.2]OC(O)-); 66.7 (C-6); 68.6 (C-5); 72.7 (C-4); 77.4 (C-2); 78.4 (C-3); 99.7 (C-1); 101.2 (-OCHO-); 115.3 (C[H.sub.3]): 123.8 ([C.sub.L]); 126.1 ([C.sub.B]); 126.2 ([C.sub.J]); 129.0 ([C.sub.1]): 129.5 ([C.sub.K]); 137.5 ([C.sub.A]); 154.0 ([C.sub.G]); 170.2-171.5 (C=O). Elemental analysis: calcd: C, 44.52; H, 4.38; 0, 20.45; Br, 30.64; found: C, 44.71; H, 4.35, [[alpha].sub.D.sup.26] = -43[degrees]. [T.sub.m] = 226 [degrees]C.

Synthesis of sugar star polymer (Example for SS1): SI1 (73.6 mg contains 0.281 mmol of initiating sites), GMA (1.85 ml, 14 mmol), and MMA (1.5 ml, 14 mmol), anisole (2.35 ml, 70 vol% of monomer), dNdpy (57.4 mg, 0.14 mmol), and Cu[Cl.sub.2] (0.47 mg, 5 mol% of CuCl) were placed in a Schlenk flask and degassed by three freeze-pump-thaw cycles. Then, CuCl (7.0 mg, 0.07 mmol) was added and the reaction flask was immersed in an oil bath at 30 [degrees]C. The reaction was stopped by exposing the reaction mixture to air. Purification and precipitation procedures were the same as it was described above for PGMA grafted copolymers.

[.sup.1]H NMR for PGMA chains (CDC[L.sub.3], 300 MHz, 25 [degrees]C) [delta] (ppm): 4.43-3.70 (2H, -OC[H.sub.2][C.sub.ox]), 3.24 (1H, C[H.sub.ox]), 2.83 and 2.65 (2H, C[H.sub.2][C.sub.ox]), 2.15-1.80 (2H, -C[H.sub.2]C(C[H.sub.3])-). 1.30-0.80 (3H, -C[H.sub.2]C(C[H.sub.3])-) ppm. [.sup.H] NMR for P(MMA-co-GMA) chains (CD[Cl.sub.3], 300 MHz, 25 [degrees]C) [delta] (ppm): the same signals as above listed for GMA units and at 3.65 (3H, -OC[H.sub.3]). FTIR (KBr) ([cm.sup.-1]): 3100-2800 v(C-H), 1730 v(C=O), 1250-1175 v(C-O), 1000-850 v(oxirane group), 1450 [delta] (C[H.sub.2]).

Characterization

Molecular weights and dispersities were determined by gel permeation chromatography (GPC) equipped with an 1100 Agilent isocratic pump, autosampler, degasser, thermostatic box for columns, a photometer MALLS DAWN EOS (Wyatt Technology Corporation, Santa Barbara. CA), and differential refractometer Optilab Rex. ASTRA 4.90.07 software (Wyatt Technology Corporation), which was used for data collecting and processing. Two PLGel 5microns MIXD-C columns were used for separation. The calibration of the DAWN EOS was carried out by p.a. grade toluene and normalization with a polystyrene standard of 30,000 g/mol molar mass. The measurements were carried out in methylene chloride as the solvent at room temperature with a flow rate of 0.8 ml/min. The refractive index increments of copolymers were calculated from the composition and dn/dc for MI1, MI2. PCL, PGMA, and PMMA, which were measured in C[H.sub.2][Cl.sub.2] and they reached values 0.069, 0.045, 0.053. 0.073, and 0.07 ml/g, respectively. Proton nuclear magnetic resonance (1H NMR) spectra were recorded with UNITY/INOVA (Varian) spectrometer operating at 300 MHz using CD[Cl.sub.3] as a solvent and tetramethylsilane (TMS) as an internal standard. Fourier transform infrared spectroscopy (FTIR) was conducted with BIORAD FTS 175L spectrophotometer at room temperature after dissolving samples in dichloromethane and coating KBr tablets to form film. Elemental analysis was determined with a PerkinElmer model 2400 CHN analyzer. Specific rotations [[alpha].sub.D.sup.26] were determined in chloroform or DMSO solution using AP-300 ATAGO Polarimeter with a sensitivity [+ or -]0.01[degrees].

RESULTS AND DISCUSSION

The loosely-grafted and star-like copolymers containing PGMA or GMA/MMA branches were obtained via ATRP method using CuCl/dNbpy catalyst system in anisole, which earlier was applied for synthesis of linear PGMA (14). The kind of (macro)initiator and number of initiating groups allowed the design of a shape of copolymers.

Polymethacrylates with statistical distribution of CLMABr units, that is P(MMA-co-CLMABr) M1 and P(IBMA-co-CLMABr) M2, were prepared by esterification of hydroxyl groups in the copolymers of CLMA and methacrylate comonomer (preM11 and preMI2) using [alpha]-bromoisobutyryl bromide. Previously, analogical ATRP macroinitiators were described for (co)polymers of 2-trimethylsilyloxyethyl methacrylate (30), (31), and 2-hydroxyethyl methacrylate (32). The [.sup.1]H NMR spectra of P(MMA-co-CLMA) (preMI1) and P(MMA-co-CLMABr) (MI1) shown in Fig. 1 confirm the successful esterification. The signal at 3.85 ppm assigned to methylene protons adjacent to the hydroxyl groups in CLMA units is observed in Fig. 1a, whereas in Fig. lb it is shifted and overlapped with the multiplet at 4.00-4.45 ppm. In addition, in Fig. 1 h the peaks at 1.9-2.0 ppm represent the protons of -C[H.sub.3] in the bromoester groups, which already replaced -OH groups. Because of highly efficient esterification the number of bromoester groups can be regulated by the proper initial feed of CLMA/methacrylate (D[P.sub.CLMA] ~ [n.sub.Br]). Subsequently, the bromoester-functionalized CLMA copolymers were used as macroinitiators in ATRP of GMA at 30[degrees]C. Data for the loosely-grafted copolymers P[MMA-co-(CLMA-graft-PGMA)] with 7 branches (GPI), and P[tBMA-co-(CLMA-graft-PGMA)] with 6 branches (GP2), are detailed in Table 1. Architecture of the resulted copolymers due to a small amount of side chains can also be concluded as six- and seven-arm stars (Scheme la and b). In [.sup.1]H NMR spectrum (Fig. 1c), compared with Fig. lb, a several new signals (2.65, 2.84, 3.24, 3.80, and 4.34 ppm) are observed due to the presence of PGMA side chains. Moreover, the intensities of signals assigned to protons in methyl groups of polymethacrylic chains (0.7-1.2 ppm) in PGMA side chains differ from that in the main chain. The total DP of GMA was estimated comparing the peak integrals of unreacted and incorporated GMA moieties at 2.84 ppm with that of GMA monomer at 5.6 and 6.16 ppm (unreacted vinyl group). As seen in Fig. 2, GPC traces are unimodal as well as a slight shift to higher molecular weight for P1MMA-co-(CLMA-graft-PGMA)]s with the increase in the length of PGMA side chains is also found. The molecular weight distributions of macroinitiators were around 1.3 (MI1) and 1.2 (MI2), which after ATRP polymerization, did not change significantly for the graft copolymers. The molecular weights determined by conventional GPC are lower than the values calculated with using MALLS detector (Table 1) since linear standards underestimate the molecular weights for branched polymers, which have lower hydrodynamic volumes.

TABLE 1. ATRP of GMA initiated by CLMA copolymers at 30[degrees]C.

                                                     [.sup.1]H NMR

No.     Monomer     Time    x       DP  D[P.sub.CLMA]  [F.sub.GMA]
        [M.sub.1]/   (h)  (%)                     (c)        (wt%)
        [M.sub.2]

preMI1  CLMA/MMA     2.0   27      137              7            -

MI1

preMI2  CLMA/lBMA    2.0   40      160              6           --

MI2                                                             --

                               D[P.sub        D[P.sub
                               .graft]          .GMA]

GP1A    GMA          1.0   15       13             92           45

GP1B                 2.0   23       20            137           55

GP1C                 3.0   36       31            217           66

GP2A    GMA          1.0   15       14             87           34

GP2B                 2.0   18       18            110           39

GP2C                 3.0   23       23            139           45

No.                        GPC (a)                        GPC-MALLS (b)

        [M.sub.n, th]  [M.sub.n] x  [M.sub.w]/  [M.sub.n] x  [M.sub.w]/
                    x  [10.sub.-3]   [M.sub.m]  [10.sub.-3]   [M.sub.m]
          [10.sub.-3]      (g/mol)                  (g/mol)
              (g/mol)

preMI1           14.8         20.6        1.31         20.7        1.25

MI1              15.8         31.0        1.29         25.5        1.30

preMI2           23.3         18.4        1.21         26.9        1.13

MI2              24.3         22.0        1.14         25.2        1.17

GP1A             28.9         36.3        1.28         37.9        1.37

GP1B             35.3         37.8        1.28         44.7        1.42

GP1C             46.6         34.3        1.30         44.9        1.34

GP2A             36.5         34.8        1.23         44.6        1.25

GP2B             39.9         35.6        1.22         48.9        1.25

GP2C             44.0         37.1        1.22         45.9        1.24

Conditions: GP1-GP2:
[[M].sub.0]/[[MI].sub.0]/[Cu[Cl.sub.0]/[dNbpyl.sub.0] =
600/1/0.75/1.5, anisole 70 vol% of mon.

(a. ) C[H.sub.2][Cl.sub.2]. RI detector, PS standards.

(b.) C[H.sub.2][Cl.sub.2], MALLS detector, the refractive
index increments of copolymers were calculated from the
composition dn/dc = [F.sub.GMA] x 0.073 + [F.sub.MMA] x
0.07 + [F.sub.MI] x dn/d[c.sub.MI]), where dn/d[c.sub.MI1]
= 0.069 ml/g, and dn/d[c.sub.MI2] = 0.045 ml/g.

(c.) After esterification it is number of initiating groups.


The copolymers with smaller amounts of PGMA branches were obtained using another bromoester functionalized macroinitiator based on polycaprolactone, that is 3-functional PCL-[Br.sub.3]. The commercially available hydroxyl-functionalized PCL-triol (DP = 10, [M.sub.n, NMR] 1000 g/mol; [M.sub.n.GPC-MALLS] = 1200 g/mol, [M.sub.w] / [M.sub.n] = 1.32) was modified by estrification, and then applied for ATRP. In this case the copolymers [(PCL-bl-PGMA).sub.3] SPI present star-like shapes with three arms (Scheme la The similar structures were obtained for star polymers with statistically distributed GMA and MMA units in each arm [[PCL-bl-P(GMA-co-MMA)].sub.3] SP2-SP3 (Scheme 1d). The initial ratio of monomer/macroinitiator yielded polymerization degree of PGMA ranged between 35 and 106 GMA units per arm, whereas the introduction of MMA comonomer reduced D[P.sub.GMA] to 17-33. It shows that the number of oxirane rings can be easily adjusted depending the future application, which can require the proper concentration of active molecules attached to the opened rings. The characterization of PCL based star copolymers is given in Table 2. Theoretical molecular weights of copolymers were calculated from [.sup.1]H NMR spectra, which confirm incorporation of GMA (Fig. 3c) or GMA/MMA (Fig. 3d) units into the chains attached to PCL-core (Fig. 3a and b). Molecular weights of polymers were also determined by GPC analysis, which gradually increased with the conversion of monomer what is presented for SPI (Fig. 4).

TABLE 2. ATRP of GMA initiated by trifunctional PCL at 30[degrees]C.

                                                      [.sup.1]H NMR

No    Monomer     Time   x  D[P.sub.arm]  D[P.sub.GMA]  [F.sub.GMA]
      [M.sub.1]/

      [M.sub.2]    (h)   %                                    (wt%)

SP1A  GMA          0.6  16            35           104           91

SP1B                 1  25            54           163           94

SP1C               3.5  49           105           319           97

SP2   GMA/MMA        4  20            17            26           48

SP3A                 1  17            23            37           54

SP3B                 3  27            33            53           55


                                       GPC (a)            GPC-MALLS (b)

No    [M.sub.n, th] x  [M.sub.n] x  [M.sub.w]/  [M.sub.n] x  [M.sub.w]/
          [10.sub.-3]  [10.sub.-3]   [M.sub.m]  [10.sub.-3]   [M.sub.m]
              (g/mol)      (g/mol)                  (g/mol)

SP1A             16.2         13.4        1.26         16.3        1.35

SP1B             24.5         20.0        1.32         26.2        1.22

SP1C             46.7         30.0        1.31         43.4        1.26

SP2               7.5         10.5        1.24         10.9        1.22

SP3A              9.8         13.7        1.19         13.7        1.16

SP3B             13.7         15.6        1.25         14.6        1.13

Conditions: SP1: [[M].sub.0]/[[PCL-[Br.sub.3].sub.0]/Cu[Cl.
sub.0]/[[dNbpy].sub.0] = 650/1/0.75/1.5, anisole/mon = 0.7/1
(v/v); SP4-SP3: [[M].sub.1]/[[M].sub.2] = 50/50 mol%; SP2:
[[M].sub.0]/[[MI].sub.0] = 250/1, anisole/mon = 1.4/1 (v/v),
SP2-SP3: [[Cu[Cl.sub.2]].sub.0] =5% of
[[Cu[Cl.sub.2].sub.0] = 400/1, anisole/mon = 0.7/1 (v/v);
PCL-[Br.sub.3]: [M.sub.n, NMR] = 1450 g/mol,
[M.sub.n, GPC] = 1700 gJmol, [M.sub.w]/[M.sub.n] = 1.6

(a.) C[H.sub.2][Cl.sub.2], RI detector, PS standards.

(b.) CH[2.sub.3][Cl.sub.2], MALLS detector, the refractive
index increments of copolymers were calculated from the
composition dn/dc = [F.sub.PCL] x 0.053 + [F.sub.GMA]
x 0.073 + [F.sub.MMA] X 0.07, which means it was in
the range 0.068-0.072 ml/g.


Third group of copolymers based on acetal derivatives of sugars also presents shape of stars with three (SS1) or six arms (SS2--SS3) depending the kind of bromoester functionalized sugar used as a initiator for ATR copolymerization of GMA and MMA at room temperature (Table 3, Scheme 1e-f). Both sugar initiators were synthesized via acetal ization of D-glucopyranoside with monoaldehyde (SI1) or dialdehyde (SI2) and esterification of hydroxyl groups to introduce ATRP initiating groups. The presence of acetal group(s) is not used to mask OH groups, but to enhance degradability of sugar unit. The [.sup.1]H NMR spectra presented in Fig. 5a and c confirm the structures of both initiators with bromoester groups, as well as the preparation of "sugar star" copolymers. The well-controlled polymerization is evidenced by narrow molecular distribution ([M.sub.w] / [M.sub.n] = 1.22-1.38) and symmetrical GPC traces, which are shifted toward higher molecular weight with the progress of reaction (Fig. 5b and d).

TABLE 3. ATR copolymerization of GMA and MMA initiated by sugar
initiators at 30[degrees]C.

                                                       [.sup.H] HMR

No    Initiator  Star    Time     x (%)  D[P.sub.arm]  D[P.sub.GMA]
                        (min)

SS1A  GluSLA     3-arm      1        13            13            23

SS1B                        2        36            36            60

SS1C                      3.5        47            47            77

SS1D                        6        66            66           105

SS2A  SatTphA    6-arm      2        38            19            60

SS2B                      3.5        57            28            87

SS3A                        2        3?            23            80

SS3B                      3.5        54            36           109

                                        GPC (a)

      [M.sub.n, th] x  [M.sub.n] x  [M.sub.w]/
          [10.sub.-3]  [10.sub.-3]   [M.sub.m]
              (g/mol)      (g/mol)

SS1A              5.7          --           --

SS1B             13.2         14.6        1.37

SS1C             17.3         17.9        1.38

SS1D             24.4         25.9        1.28

SS2A             15.5         16.0        1.25

SS2B             22.3         26.5        1.24

SS3A             18.7         24,4        1.26

SS3B             27.7         32.3        1.23

Conditions: SS1-SS3: [[GMA].sub.0]:[[MMA].sub.0]:
[[I].sub.0]:Cu[Cl.sub.0]: [[dNbpy].sub.0] = 150
:150:1:0.75:1.5: SS1: anisole/mon = 0.7/1 (v/v);
[[Cu[Cl.sub.2].sub.0] = 5% of Cu[Cl.sub.0];
SS2: anisole/mon = 0.5/1 (v/v); SS3: [[GMA].sub.0]:
[[MMA].sub.0]:[[I].sub.0] = 200/200/1:
anisole/mon = 1/1 (v/v).

(a.) C[H.sub.2][Cl.sub.2], RI detector, PS standards.


Figure 6a shows the relationships of In([[M].sub.0] / [[M].sub.t]) versus time for the selected GMA polymerizations performed in the presence of tBMA / CLMA-[Br.sub.6] macroinitiator MI2 (GP1), PCL-[Br.sub.3] macroinitiator (SP1) and sugar initiator SI1-[Br.sub.3] (SS1). As seen, the semilogarithmic plots of polymerizations initiated by sugar initiator and CLMA macroinitiator are linear, which means the concentration of growing radicals is constant during the polymerization, confirming the first-order kinetics in monomer concentration under the used reaction conditions. Additionally, the synthesis of "sugar" star SS1 was performed with the highest rate, which can be explained by the lowest ratio of monomer/initiator (180/1), especially in comparison to synthesis of SP1 obtained in the system with PCL macroinitiator containing the same number of initiating groups, but almost four times higher ratio of monomer/PCL (650/1). Different topologies of initiating molecules, that is the flexible PCL with short branches and twice higher molecular weight versus rigid more compact sugar core can also influence on the polymerization rate, particularly initiation step, which should be faster than propagation. In the case of SP1 the deviation from linear dependence is typical for occurrence of termination reactions. At the beginning within 2 h the kinetics of polymerization SP1 was very closed to GP1, where macroinitiator MI1 with seven loosely distributed bromoester groups and higher molecular weight [M.sub.n, th] = 16,000 g/mol was applied versus PCL-B[r.sub.3] with [M.sub.n, th] = 1450 g/mol. The number-average molecular weights of the branched copolymers increased with monomer conversions in all systems, which is shown in Fig. 6b. However, the dependence for GP1 presents the lowest growth of [M.sub.n.GPC] than it is observed for SP1 and SS1. This effect can be explained by twice higher number of branches, which makes difference in hydrodynamic volumes of the copolymers.

CONCLUSIONS

The GMA copolymers with loosely-grafted and star-shaped architectures were prepared at 30[degrees]C by ATRP "grafting from"/"core-first" methods using CuCl/dNbpy catalyst complex in anisole. Statistical copolymers CLMA containing a several initiating units ([n.sub.Br] = 6-7), and three-functional PCL were used as ATRP macroinitiators, whereas acetal functionalized D-glucopyranosides with 3 or 6 bromoester groups were applied as initiators. The well-defined branched copolymers were characterized with narrow molecular distributions ([M.sub.w] / [M.sub.n] < 1.4). The various lengths of arms, and their amounts, and additionally the incorporation of MMA units let to drive the concentration of oxirane rings in the copolymers, what can be useful for the future application as polymeric carriers of biologically active compounds in drug delivery systems. The GMA polymers present hydrophobic properties, which in further step can be changed to amphiphilic via opening oxirane ring. Moreover, the branched architecture should give more stable superstructures in comparison to linear polymers, which makes them a potential candidate for the long-term releasing systems.

Correspondence to: Dorota Neugebauer: e-mail: dorota.neugebauer@polsl.pl

Contract grant sponsor: National Science Center: contract grant number: N N204 122940.

DO1 10.1002/pen.23369

Published online in Wiley Online Library (wileyonlinelibrary.com).

[c] 2012 Society of Plastics Engineers

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Dorota Neugebauer, (1) Paulina Maksym-Bgbenek, (1) Anna Mielanczyk, (1) Tadeusz Biela (2)

(1.) Department of Physical Chemistry and Technology of Polymers, Faculty of Chemistry, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland

(2.) Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland
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Date:Jun 1, 2013
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