Amphiphilic PEG-Functionalized Gradient Copolymers via Tandem Catalysis of Living Radical Polymerization and Transesterification

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1 Amphiphilic PEG-Functionlized Grdient Copolymers vi Tndem Ctlysis of Living Rdicl Polymeriztion nd Trnsesterifiction Yusuke gur, Tky Tershim, * Mitsuo Swmoto * Deprtment of Polymer Chemistry, Grdute School of Engineering, Kyoto University Ktsur, Nishikyo-ku, Kyoto , APAN Tel/Fx: E-mil: tershim@living.polym.kyoto-u.c.jp, swmoto@str.polym.kyoto-u.c.jp *Corresponding Author Contents Experimentl Section Supporting Dt Figure S1. MMA/PEGMA (n = 7.2) grdient copolymers vi tndem LRP with MS Figure S2. MMA/PEGMA (n = 7.2) grdient copolymers vi tndem LRP without MS Figure S3. MMA/MEGMA (PEGMA: n = 1) grdient copolymers vi tndem LRP Figure S4. MMA/DEGMA (PEGMA: n = 2) grdient copolymers vi tndem LRP S2 S6 S7 S8 S8 Figure S5. MMA/TEGMA (PEGMA: n = 4) grdient copolymers vi tndem LRP S9 Figure S6. 1 H NMR spectrum of MMA/DEGMA grdient copolymer S1 Figure S7. 1 H NMR spectrum of MMA/TEGMA grdient copolymer S1 Figure S8. MMA/PEGMA (n = 11.8) grdient copolymers vi tndem LRP S11 Figure S9. 1 H NMR spectrum of MMA/PEGMA bidirectionl grdient copolymer S11 Figure S1. DLS mesurement of MMA/TEGMA grdient copolymer S12 Figure S11. Cloud point of mphiphilic grdient copolymers S12 S1

2 Experimentl Section Mterils. Methyl methcrylte (MMA: TCI; purity >99.8%) nd tetrlin (1,2,3,4- tetrhydronphthlene: Kishid Chemicl; purity >98%; n internl stndrd for 1 H NMR nlysis) were dried overnight with clcium chloride nd distilled from clcium hydride under reduced pressure before use. Polyethylene glycol methyl ether (PEG-H) (Aldrich, = 35, 55), 2- methoxyethnol (MEG-H) (Wko, purity >99%), 2-(2-methoxyethoxy)ethnol (DEG-H) (Wko, purity >98%), tetr(ethylene glycol) monomethyl ether (TEG-H) (TCI, purity >98%), Ti(i-Pr) 4 (Aldrich, purity >97%), nd n-bu 3 N (TCI, purity >98%) were degssed by triple vcuum-rgon purge cycles before use. Ethyl 2-chloro-2-phenylcette (ECPA: Aldrich; purity >97%) nd 2,2- dichlorocetophenone (DCAP: TCI; purity >96%) were distilled under reduced pressure before use. Ru(Ind)Cl(PPh 3 ) 2 (Aldrich) ws used s received nd hndled in glove box under moisture- nd oxygen-free rgon (H 2 <1 ppm; 2 <1 ppm). Toluene (solvent) ws purified by pshing it through purifiction column (Glss Contour Solvent Systems: SG Wter USA). Moleculr sieves (MS) 4A (Wko) were bked with het gun under reduced pressure before use. Chrcteriztion. Moleculr weight distribution (MWD) curves,, nd M w / rtio of polymers were mesured by SEC in DMF contining 1 mm LiBr t 4 o C (flow rte: 1 ml/min) on three liner-type polystyrene gel columns (Shodex KF-85L: exclusion limit = ; prticle size = 1 µm; pore size = 5 Å;.8 cm i.d. 3 cm) tht were connected to sco PU-28 precision pump, sco RI-231 refrctive index detector, nd sco UV-275 UV/vis detector set t 27 nm. The columns were clibrted ginst 1 stndrd poly(mma) smples (Polymer Lbortories; = 1 12; M w / = ). To remove unrected monomers, PEG-H, nd ctlyst residues, polymer smples for the evlution of solution/solid properties were purified by preprtive SEC [TSH TSKgel -3: prticle size = 13 µm; 5.5 cm i.d. 3 cm; exclusion limit = g/mol; flow rte = 15 ml/min] connected to sco PU-286 precision pump, sco RI-213 refrctive index detector, nd sco UV-275 ultrviolet detector. 1 H NMR spectr were recorded in CDCl 3 nd CD 2 Cl 2 on EL NM-ECA5 spectrometer operting t 5.16 MHz. Dynmic light scttering (DLS) ws mesured on tsuk Photl ELSZ- equipped with semiconductor lser (wvelength: 658 nm) t 25 o C: [Polymer] = 1 mg/ml in methnol or cetone/h 2 (1/9, v/v). The mesuring ngle ws 165 nd the dt ws nlyzed by CNTIN fitting method. Turbidity mesurements of polymer solutions were conducted with Shimdzu UV-18 in methnol, H 2, nd 2-propnol t 25 o C (opticl pth length = 1. cm). Differentil scnning clorimetry (DSC) ws performed for smples (c. 5 mg weighed into n luminum pn) under dry nitrogen flow on DSC Q2 clorimeter (TA Instruments) equipped with RCS 9 electric freezing mchine. The S2

3 polymer smples were heted to 15 o C t the rte of 1 o C/min nd held t the temperture for 1 min to erse therml history. Then, the smples were cooled to -8 o C t the rte of -1 o C/min nd held t the temperture for 1 min, nd gin heted to 15 o C t the rte of 1 o C/min. The second heting runs were used for the therml nlysis of polymers in Figure 9 in the min text. Polymeriztion. The synthesis of MMA/PEGMA copolymers ws crried out by syringe technique under rgon in bked glss tubes equipped with three-wy stopcock. MMA/PEGMA grdient copolymer (entry 7 in Tble 1). A typicl procedure for grdient copolymer with MS 4A ws given: MS 4A (1. g) ws first plced nd dried in 3 ml glss tube under reduced pressure with het gun. Into the tube, Ru(Ind)Cl(PPh 3 ) 2 (.3 mmol, 2.33 mg) ws chrged, nd toluene (1.15 ml), PEG-H ( = 35) (1.32 ml), tetrlin (.4 ml), 5 mm toluene solution of Ti(i-Pr) 4 (.12 ml, Ti(i-Pr) 4 =.6 mmol), MMA (3 mmol,.32 ml), nd 274 mm toluene solution of ECPA (.5 ml, ECPA =.15 mmol) were dded sequentilly in tht order t 25 o C under rgon (the totl volume of the rection mixture: 3. ml). The glss tube ws then plced in n oil bth kept t 8 o C. At predetermined intervls, the mixture ws smpled with syringe under rgon, nd the smpled solutions were cooled to 78 C to terminte the rection. The totl monomer conversion, PEGMA content in monomer, nd cumultive PEGMA content in polymer (F cum,pegma ) were directly determined by 1 H NMR mesurements of the terminted rection solution in CDCl 3 t 25 o C with tetrlin s n internl stndrd. Instntneous PEGMA content in polymer (F inst,pegma ) ws estimted ccording to the following eqution: F inst,pegma = [ totl, i x F cum,pegma, i - totl, i-1 x F cum,pegma, i-1 ]/[ totl, i - totl, i-1 ], where totl is the totl conversion of both monomers. The quenched solutions were evported to dryness to give the crude product. To remove unrected monomers, solvents, nd ctlyst residue, the product ws purified by preprtive SEC before chrcteriztion ( 1 H NMR, physicl properties). SEC (DMF, PMMA std.): = 51,7 g/mol; M w / = H NMR [5 MHz, CD 2 Cl 2, 25 o C, δ = 5.33 CDHCl 2 ] δ (romtic), (-CCH 2 CH 2 -), (-CCH 2 CH 2 -), (- CH 2 CH 2 -), (-CH 3 ), (-CH 2 C(CH 3 )-), (-CH 2 C(CH 3 )-). (NMR, ) = 514; DP MMA /DP PEGMA = 12/98; F cum,pegma = 49%. MMA/PEGMA bidirectionl grdient copolymer (entry 14 in Tble 1). SEC (DMF, PMMA std.): = 41,7 g/mol; M w / = H NMR [5 MHz, CD 2 Cl 2, 25 o C, δ = 5.33 CDHCl 2 ] δ (romtic), (-CCH 2 CH 2 -), (-CCH 2 CH 2 -), (- CH 2 CH 2 -), (-CH 3 ), (-CH 2 C(CH 3 )-), (-CH 2 C(CH 3 )-). (NMR, ) = 521; DP MMA /DP PEGMA = 84/14; F cum,pegma = 54%. MMA/PEGMA grdient rndom copolymer (entry 12 in Tble 1). SEC (DMF, PMMA std.): = 4,4 g/mol; M w / = H NMR [5 MHz, CD 2 Cl 2, 25 o C, δ = 5.33 CDHCl 2 ] δ 7.3 S3

4 7.15 (romtic), (-CCH(CH 3 ) 2 ), (-CCH 2 CH 2 -), (- CCH 2 CH 2 -), (-CH 2 CH 2 -), (-CH 3 ), (-CH 2 C(CH 3 )-), (-CH 2 C(CH 3 )-). (NMR, ) = 37; DP MMA /DP PEGMA /DP iprma = 92/63/1; F cum,pegma = 38%. MMA/DEGMA (PEGMA: n = 2) grdient copolymer (entry 3 in Tble 1). SEC (DMF, PMMA std.): = 33,2 g/mol; M w / = H NMR [5 MHz, CD 2 Cl 2, 25 o C, δ = 5.33 CDHCl 2 ] δ (romtic), (-CCH 2 CH 2 -), (-CCH 2 CH 2 -), (- CH 2 CH 2 -), (-CH 3 ), (-CH 2 C(CH 3 )-), (-CH 2 C(CH 3 )-). (NMR, ) = 298; DP MMA /DP DEGMA = 119/94; F cum,degma = 44%. MMA/TEGMA (PEGMA: n = 4) grdient copolymer (entry 5 in Tble 1). SEC (DMF, PMMA std.): = 25,6 g/mol; M w / = H NMR [5 MHz, CD 2 Cl 2, 25 o C, δ = 5.33 CDHCl 2 ] δ (romtic), (-CCH(CH 3 ) 2 ), (-CCH 2 CH 2 -), (- CCH 2 CH 2 -), (-CH 2 CH 2 -), (-CH 3 ), (-CH 2 C(CH 3 )-), (-CH 2 C(CH 3 )-). (NMR, ) = 24; DP MMA /DP TEGMA /DP iprma = 84/56/1; F cum,tegma = 39%. MMA/PEGMA rndom copolymer. MS 4A (1. g) ws first plced nd dried in 3 ml glss tube under reduced pressure with het gun. In 3 ml glss tube, Ru(Ind)Cl(PPh 3 ) 2 (.3 mmol, 2.33 mg) ws chrged, nd toluene (2.6 ml), PEG-H ( = 35) (1.5 mmol,.49 ml), tetrlin (.4 ml), 5 mm toluene solution of Ti(i-Pr) 4 (.12 ml, Ti(i-Pr) 4 =.6 mmol) nd MMA (3 mmol,.32 ml) were dded sequentilly in tht order t 25 o C under rgon (the totl volume: ml). The glss tube ws plced in n oil bth kept t 8 o C. After 23 h, the solutions were cooled to 78 C to terminte trnsesterifiction (yield: MMA/PEGMA/iPrMA = 45%/49%/6%, by 1 H NMR in CDCl 3 t r.t. with tetrlin s n internl stndrd). Into the solution, toluene solution of ECPA (622 mm,.24 ml, ECPA =.15 mmol) ws then dded t 25 o C under rgon (the totl volume: 3. ml). The glss tube ws plced in n oil bth kept t 8 o C. After 66 h, the mixture ws cooled to 78 C to terminte the copolymeriztion (conv. MMA/PEGMA = 9%/9%). The quenched solution ws evported to dryness to give the crude product. To remove unrected monomers, solvents, nd ctlyst residue, the product ws purified by preprtive SEC. SEC (DMF, PMMA std.): = 954 g/mol; M w / = H NMR [5 MHz, CD 2 Cl 2, 25 o C, δ = 5.33 CDHCl 2 ] δ (romtic), (-CCH(CH 3 ) 2 ), (-CCH 2 CH 2 -), (-CCH 2 CH 2 -), (-CH 2 CH 2 -), (-CH 3 ), (-CH 2 C(CH 3 )-), (-CH 2 C(CH 3 )-). (NMR, ) = 591: DP MMA /DP PEGMA /DP iprma = 18/16/16; F cum,pegma = 46%. MMA/PEGMA block copolymer. Into 3 ml glss tube (A), Ru(Ind)Cl(PPh 3 ) 2 (.3 mmol, 2.33 mg) ws then chrged, nd toluene (.955 ml), tetrlin (.4 ml), MMA (3 mmol,.32 ml), S4

5 4 mm toluene solution of n-bu 3 N (.75 ml, n-bu 3 N =.3 mmol), nd 274 mm toluene solution of ECPA (.11 ml, ECPA =.3 mmol) were dded sequentilly in tht order t 25 o C under rgon (the totl volume: 1.5 ml). The glss tube ws plced in n oil bth kept t 8 o C. After 123 h, the polymeriztion reched 95% conversion (determined by 1 H NMR) to give PMMA-Cl ( = 13,5 g/mol; M w / = 1.9, by SEC in DMF with PMMA std.). Into nother 3 ml glss tube (B), MS 4A (1. g) ws first plced nd dried under reduced pressure with het gun. Into the tube, toluene (4.6 ml), tetrlin (.8 ml), PEG-H ( = 35) (3 mmol,.98 ml), MMA (6 mmol,.32 ml), nd 5 mm toluene solution of Ti(i-Pr) 4 (.24 ml, Ti(i-Pr) 4 =.12 mmol) were dded sequentilly in tht order t 25 o C under rgon (the totl volume: 6. ml). After 35h, MMA ws trnsesterified into PEGMA nd iprma (yield: MMA/PEGMA/iPrMA = 45%/49%/6%, determined by 1 H NMR). Then, the solution ws evported to remove voltile MMA nd iprma. Into the tube including non-voltile PEGMA, toluene (3.2 ml) ws dded to mke toluene solution of PEGMA (PEGMA = 2.9 mmol, totl volume: 4.5 ml). Into the tube (A), the toluene solution of PEGMA (4.5 ml, PEGMA = 2.9 mmol) ws dded under rgon. The mixture ws plce t 8 o C. After 3 h, the solution ws cooled to 78 C to terminte the rection (conv. 93%, determined by 1 H NMR). The quenched solution ws evported to dryness. To remove unrected monomers, solvents, nd ctlyst residue, the resulting crude ws purified by preprtive SEC. SEC (DMF, PMMA std.): = 46,8 g/mol; M w / = NMR [5 MHz, CD 2 Cl 2, 25 o C, δ = 5.33 CDHCl 2 ] δ (romtic), (- CCH 2 CH 2 -), (-CCH 2 CH 2 -), (-CH 2 CH 2 -), (-CH 3 ), (-CH 2 C(CH 3 )-), (-CH 2 C(CH 3 )-). (NMR, ) = 439: DP MMA /DP PEGMA = 99/81; F cum,pegma = 45%. 1 H S5

6 Supporting Dt () Ti: 1 mm (b) Ti: 3 mm (c) Ti: 4 mm (d) Ti: 1 mm (e) Ti: 3 mm (f) Ti: 4 mm (g) Ti: 1 mm M w / F cum. PEGMA 48 h 94% % 2. h 2% % (h) Ti: 3 mm 24 h 9% % 4. h 2% % (i) Ti: 4 mm 24 h 92% % 4. h 17% % Figure S1. Synthesis of MMA/PEGMA grdient copolymers vi concurrent tndem ctlysis with PEG-H ( = 35) nd MS 4A: [MMA]/[ECPA]/[Ru(Ind)Cl(PPh 3 ) 2 ]/[Ti(i-Pr) 4 ] = 1/5/1/1-4 mm in toluene/peg-h ( = 35) (1/1, v/v) with MS 4A (.33g/mL) t 8 o C. [Ti(i-Pr) 4 ] = (, d, g) 1, (b, e, h) 3, nd (c, f, i) 4 mm. (, b, c) totl monomer conversion nd PEGMA content in monomer. (d, e, f) cumultive (F cum,pegma ) nd instntneous (F inst,pegma ) PEGMA content in products. (g, h, i) SEC curves of the products. S6

7 () Ti: 4 mm (b) Ti: 6 mm (c) Ti: 8 mm (d) Ti: 4 mm (e) Ti: 6 mm (f) Ti: 8 mm (g) Ti: 4 mm M w / F cum. PEGMA 21 h 89% % 2. h 28% % (h) Ti: 6 mm 23 h 96% % 1. h 13% % (i) Ti: 8 mm 23 h 88% % 2. h 18% % Figure S2. Synthesis of MMA/PEGMA grdient copolymers vi concurrent tndem ctlysis with PEG-H ( = 35) in the bsence of MS 4A: [MMA]/[ECPA]/[Ru(Ind)Cl(PPh 3 ) 2 ]/ [Ti(i-Pr) 4 ] = 1/5/1/4-8 mm in toluene/peg-h ( = 35) (1/1, v/v) t 8 o C. [Ti(i-Pr) 4 ] = (, d, g) 4, (b, e, h) 6, nd (c, f, i) 8 mm. (, b, c) Totl monomer conversion nd PEGMA content in monomer. (d, e, f) Cumultive (F cum,pegma ) nd instntneous (F inst,pegma ) PEGMA content in products. (g, h, i) SEC curves of the products. S7

8 () Ti: 2 mm MEGMA Content in Monomer, % F inst.megma, % (b) Ti: 2 mm F cum.megma, % (c) Ti: 2 mm 2. h 2% 38 h 95% M w / F cum. MEGMA 8% F cum. MEGMA 38% (d) Ti: 3 mm MEGMA Content in Monomer, % F inst.megma, % (e) Ti: 3 mm F cum.megma, % (f) Ti: 3 mm 2. h 29% 21 h 92% M w / F cum. MEGMA 18% F cum. MEGMA 49% Figure S3. Synthesis of MMA/MEGMA (PEGMA: n = 1) grdient copolymers vi concurrent tndem ctlysis with 2-methoxyethnol nd MS 4A: [MMA]/[ECPA]/[Ru(Ind)Cl(PPh 3 ) 2 ] /[Ti(i- Pr) 4 ] = 1/5/1/2 or 3 mm in toluene/2-methoxyethnol (1/1, v/v) with MS 4A (.33g/mL) t 8 o C. [Ti(i-Pr) 4 ] = (, b, c) 2, (d, e, f) 3 mm. (, d) Totl monomer conversion nd MEGMA content in monomer. (b, e) Cumultive (F cum,megma ) nd instntneous (F inst,megma ) MEGMA content in products. (c, f) SEC curves of the products. () (b) (c) h 15% Figure S4. Synthesis of MMA/DEGMA (PEGMA: n = 2) grdient copolymer vi concurrent tndem ctlysis with 2-(2-methoxyethoxy) ethnol (DEG-H) nd MS 4A: [MMA]/[ECPA]/ [Ru(Ind)Cl(PPh 3 ) 2 ]/[Ti(i-Pr) 4 ] = 1/5/1/2 mm in toluene/deg-h (1/1, v/v) with MS 4A (.33g/mL) t 8 o C. () Totl monomer conversion nd DEGMA content in monomer. (b) Cumultive (F cum,degma ) nd instntneous (F inst,degma ) DEGMA content in products. curves of the products. DEGMA Content in Monomer, % F inst.degma, %.5 1 S8 F cum.degma, % 38 h 96% M w / F cum. DEGMA 11% F cum. DEGMA 47% (c) SEC

9 () Ti: 2 mm TEGMA Content in Monomer, % F inst.tegma, % (b) Ti: 2 mm F cum.tegma, % (c) Ti: 2 mm 2. h 21% 27 h 92% M w / F cum. TEGMA 4% F cum. TEGMA 3% (d) Ti: 4 mm TEGMA Content in Monomer, % F inst.tegma, % (e) Ti: 4 mm F cum.tegma, % (f) Ti: 4 mm 1. h 24% 23 h 96% M w / F cum. TEGMA 7% F cum. TEGMA 39% Figure S5. Synthesis of MMA/TEGMA (PEGMA: n = 4) grdient copolymers vi concurrent tndem ctlysis with tetrethylene glycol monomethyl ether (TEG-H) nd MS 4A: [MMA]/[ECPA]/ [Ru(Ind)Cl(PPh 3 ) 2 ]/[Ti(i-Pr) 4 ] = 1/5/1/2 or 4 mm in toluene/teg-h (1/1, v/v) t 8 o C. [Ti(i-Pr) 4 ] = (, b, c) 2, (d, e, f) 4 mm. (, d) Totl monomer conversion nd TEGMA content in monomer. (b, e) Cumultive (F cum,tegma ) nd instntneous (F inst,tegma ) TEGMA content in products. (c, f) SEC curves of the products. S9

10 i b c l F cum,mma /F cum,degma 56/44 % DP = 213 = 298 grd b Cl m d e f f g c f g d e b i 7 6 Figure S6. 1 H NMR spectrum of MMA/DEGMA (PEGMA: n = 2) grdient polymer (entry 3 in Tble 1) in CD 2 Cl 2 t 25 o C ppm i b l c grd b Cl m d e c f g f f g 3 d e b h F cum,mma /F cum,tegma /F cum,iprma 6/39/1 % DP = 141 = 24 i h Figure S H NMR spectrum of MMA/TEGMA (PEGMA: n = 4) grdient polymer (entry 5 in Tble 1) in CD 2 Cl 2 t 25 o C ppm S1

11 () (b) (c) F cum. PEGMA 18% F cum. PEGMA 26% 4. h 23% 7. h 37% M w / Figure S8. Synthesis of MMA/PEGMA grdient copolymers vi concurrent tndem ctlysis with long PEG-H ( = 55) nd MS 4A: [MMA]/[ECPA]/[Ru(Ind)Cl(PPh 3 ) 2 ]/[Ti(i-Pr) 4 ] = 1/5/1/4 mm in toluene/peg-h ( = 55) (1/1, v/v) with MS 4A (.33g/mL) t 8 o C. () Totl monomer conversion nd PEGMA content in monomer. F cum. PEGMA 45% h 79% (b) Cumultive (F cum,pegma ) nd instntneous (F inst,pegma ) PEGMA content in products. (c) SEC curves of the products. i b l c grd b Cl m d e f f c f e g g 6.2 d h b i h ppm Figure S9. 1) in CD 2 Cl 2 t 25 o C. 1 H NMR spectrum of MMA/PEGMA bifunctionl grdient polymer (entry 14 in Tble S11

12 Acetone/H 2 (1/9, v/v) MeH D h (nm) Figure S1. DLS intensity size distribution of MMA/TEGMA (PEGMA: n = 4) grdient copolymer (entry 5 in Tble 1) in methnol nd cetone/h 2 (1/9, v/v) t 25 o C: [Polymer] = 1 mg/ml. () 1 heting (b) 1 cooling (c) 1 cooling Grdient Grdient Rndom MMA/TEGMA (n = 4) Trnsmittnce, % 5 Grdient Rndom Rndom Trnsmittnce, % 5 Rndom Grdient Trnsmittnce, % 5 MMA/DEGMA (n = 2) Temperture, Temperture, Temperture, Figure S11. Turbidity mesurements of the () queous or (b) 2-propnol solutions of MMA/PEGMA (n = 7.2) rndom, grdient-rndom, nd grdient copolymers: () heting t 1 o C/min from 4 to 8 o C; (b) cooling t 1 o C/min from 5 to 2 o C: [Polymer] = 1 mg/ml. (c) Turbidity mesurements of the methnol solutions of MMA/DEGMA (PEGMA: n = 2) or MMA/TEGMA (PEGMA: n = 4) grdient copolymers: cooling t 1 o C/min from 3 to o C: [Polymer] = 1 mg/ml. S12