Poly(hydroxyalkanoate) Block or Random Copolymers of Î²

Article pubs.acs.org/Macromolecules

Poly(hydroxyalkanoate) Block or Random Copolymers of β‑Butyrolactone and Benzyl β‑Malolactone: A Matter of Catalytic Tuning Cédric G. Jaffredo, Jean-François Carpentier, and Sophie M. Guillaume* Institut des Sciences Chimiques de Rennes, Organometallics, Materials and Catalysis, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, F-35042 Rennes Cedex, France S Supporting Information *

ABSTRACT: The controlled copolymerization of racemic βbutyrolactone (BL) and racemic benzyl β-malolactone (MLABe) has been achieved under mild operating conditions (in bulk at 60 °C) with various systems derived either from a metal-based (pre)catalyst associated with isopropanol (iPrOH) acting as a coinitiator and a chain transfer agent or more simply from a neat basic organocatalyst. Among the metallic systems evaluated, only the neodymium triflate-based catalyst system, Nd(OTf)3/iPrOH, enabled the preparation, upon simultaneous addition of the two monomers, of poly(benzyl β-malolactone-ran-β-butyrolactone) random copolymers (P(MLABe-ran-BL)) with Mn,NMR up to 5800 g mol−1 (ĐM = ca. 1.4) as evidenced by 1H and 13C NMR. Simultaneous copolymerization of the comonomers mediated by the zinc β-diketiminate [(BDI)Zn{N(SiMe3)2}]/iPrOH system only afforded PMLABe, leaving BL unreacted. Also, the sequential copolymerization with this zinc catalyst proceeded effectively only when BL was introduced prior to MLABe. In contrast, both the Nd-based system and basic organocatalysts of the guanidine (1,5,7-triazabicyclo[4.4.0]dec-5-ene, TBD), amidine (1,8diazabicyclo[5.4.0]-undec-7-ene, DBU), and phosphazene (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2diazaphosphorine, BEMP) type effectively copolymerized MLABe and BL in a sequential approach, regardless of the order of comonomers addition, forming the corresponding P(MLABe-b-BL) block copolymers, with segments of significant length (ca. 88 BL and 360 MLABe units; Mn,NMR up to 73 500 g mol−1 with ĐM = 1.44). Remarkably, BEMP afforded P(MLABe-b-BL) from either a simultaneous or a sequential approach and regardless of the order of the comonomers addition. Kinetic and microstructural control in copolymerization of MLABe and BL can thus be achieved via catalytic tuning.

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INTRODUCTION

Poly(β-hydroxyalkanoate)s (PHAs) are natural or synthetic aliphatic polyesters which are biocompatible and biodegradable thermoplastics playing a prominent role in biomedical applications.1,2 In particular, they are used in tissue (bone, nerve, cartilage) engineering and drug delivery systems (drug or stem cells carrier systems such as nanoparticles or scaffolds).2,3 PHAs display a common molecular structure featuring a different substituent R at the β-position (Figure 1). Diversification of the nature of this R group (R = H, Me, hexyl, CO2H, CO2CH2Ph, etc.) results in polymers featuring different degradation profiles and thermomechanical properties ranging from glassy to softer materials. Also, the side chain can provide reactive sites for further chemical modification to improve the functionality of the PHAs and subsequently their potential applications. Thus, for instance, mild hydrogenolysis of the β-benzyloxycarbonyl in hydrophobic poly(benzyl βmalolactonate) (PMLABe) leads to an hydrophilic poly(malic acid) (PMLA), enabling anchoring of biologically active molecules4 and/or access to amphiphilic self-assembling PMLA-based copolymers.5,6a © XXXX American Chemical Society

Figure 1. General structure of β-butyrolactone (BL), benzyl βmalolactone (MLABe) and their corresponding PHAs, poly(3hydroxybutyrate) (PHB) and poly(benzyl β-malolactonate) (PMLABe), respectively.

Whereas both poly(3-hydroxybutyrate) (PHB, i.e. P(BL)) and poly(benzyl β-malolactone) (PMLABe) have been developed from polycondensation and anionic polymerization, there are more commonly synthetically prepared upon ringReceived: June 27, 2013 Revised: August 13, 2013

A

dx.doi.org/10.1021/ma401332k | Macromolecules XXXX, XXX, XXX−XXX

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tetraphenylporphirinato)aluminum chloride.16 In these latter studies, very long reaction times (>2 weeks) highlighted the low efficiency of the catalyst systems along with the possible formation of the random copolymers upon transesterification reactions. Finally, to our knowledge, P(MLABe-b-BL) block copolymers remain unknown; only random copolymers of MLABe and BL have been previously prepared by enzymatic or by pseudoanionic ROP.16 In this contribution, we report on the metal- and organocatalyzed copolymerization of MLABe and BL through sequential or simultaneous copolymerization. Depending on the catalytic system used in the simultaneous copolymerization of the two comonomers, either random or block copolymers have been synthesized, whereas sequential copolymerization selectively afforded block copolymers.

opening polymerization (ROP) of the corresponding fourmembered ring β-butyrolactone (BL) and benzyl β-malolactone (MLABe), respectively (Figure 1).6,7 In the past decade, the ROP of BL 7−10,11a and MLABe6,7,11b,12 has been investigated from either organic or metallic catalyst systems, with the synthesis of PHB being comparatively more intensively investigated than that of MLABe. Organocatalysts such as Nheterocyclic carbenes, guanidines, amidines, or phosphazenes have promoted the ROP of BL with, in most cases, a coinitiator (typically an alcohol) being added and with different efficiencies.8,10,11,13 In comparison, the ROP of MLABe promoted by these same class of organocatalysts remains centered on 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 1,8diazabicyclo[5.4.0]undec-7-ene (DBU), and 2-tert-butylimino2-diethylamino-1,3-dimethylperhydro-1,3,2diazaphosphorine (BEMP) organic bases.11b,14 These latter basic organocatalysts effectively neatly polymerized BL and MLABe under mild conditions (bulk, i.e., no solvent; 60 °C), affording the corresponding α-guanidine/amidine/phosphazene,ω-crotonate telechelic PHBs and PMLABes with controlled molecular features.11 Similarly, whereas the ROP of BL based on metallic catalysts has been quite developed,7,9 the metal-catalyzed ROP of MLABe has only been mediated, to our knowledge, by AlEt3, tin(II) bis(2-ethylhexanoate) (Sn(octoate)2 = SnOct2),6 and more recently by the zinc β-diketiminate compound [(BDI)Zn(N(SiMe3)2)] (BDI = CH(CMeNC6H3-2,6-iPr2)2) associated with benzyl alcohol (BnOH),12 as previously successfully used in the related ROP of BL.9c,d The controlled ROP of MLABe or BL promoted by this latter zinc catalyst system proceeded under mild operating conditions, at 40−60 °C in bulk monomer, affording well-defined linear α-hydroxy-ωalkoxycarbonyl telechelic PMLABes and PHBs, respectively. The living character of the ROP of BL and MLABe mediated by either TDB, DBU, BEMP, or the [(BDI)Zn{N(SiMe3)2}]/ BnOH system9a,c,d,11,12 thus offers opportunities in the copolymerization of these two β-lactones. In fact, in order to tune the chemical and physical properties of PHAs, copolymers have been developed. Besides the extensive work on bacterial PHA copolymers such as poly(3hydroxybutyrate-co-3-hydroxyvalerate) and poly(3-hydroxyoctanoate-co-3-hydroxy-10-undecanoate) known as PHBV and PHOU, respectively,1,2,15 the synthetic approach is again attracting growing attention. PMLA-derived copolymers are quite limited and include, besides this latter example, PHB,16 poly(propiolactone),17 poly(ε-caprolactone),18 poly(lactide)s,8e,19 poly(ethylene glycol),18d,20 or other poly(alkyl βmalolactone) segments.8e,21 True diblock copolymers of a poly(alkyl β-malolactone) with a cyclic ester have been prepared either from (i) the coupling of the two previously isolated homopolymers, (ii) a presynthesized homopolymer subsequently chemically modified at its terminus to next serve as a macroinitiator toward the ROP of the second monomer, or (iii) the successive purely anionic and tin-, aluminum-, or organo-catalyzed coordination−insertion two-step approach.8e,16,20 However, such block copolymers have never been obtained from the sequential coordination−insertion copolymerization of the two monomers promoted by a singlesite metallic system bearing (an) ancillary ligand(s) or by an organocatalyst, the approach followed in the present work (vide inf ra, Schemes 2 and 3). Besides, random copolymers of the type poly(alkyl β-malolactone-co-lactone) have been previously synthesized from such a simultaneous copolymerization using SnOct2,18b,19a,21c alkylaluminoxane, ZnEt2/H2O, or (5,10,15,20-

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EXPERIMENTAL SECTION

Methods and Materials. All polymerizations were performed under an inert atmosphere (argon) using standard Schlenk, vacuum line, and glovebox techniques. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (98%, Aldrich), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) (>98%, Aldrich), and racemic β-butyrolactone (BL) (>95%, TCI Chemicals) were distilled twice from CaH2 prior to use. Isopropanol (iPrOH) was dried over activated Mg and distillated twice. CDCl3 was dried over a mixture of 3 and 4 Å molecular sieves. Racemic benzyl β-malolactone (MLABe) was synthesized from (R,S)-aspartic acid according to the reported procedure.5b [(BDI)Zn{N(SiMe3)2}] was synthesized following the literature procedure.9a,22 Nd(OTf)3 (Strem), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (98%, Aldrich), and all other reagents were used as received. Instrumentation and Measurements. 1H (500 and 400 MHz) and 13C{1H} (125 MHz) NMR spectra were recorded on Bruker Avance AM 500 and Ascend 400 spectrometers at 25 °C and were referenced internally relative to SiMe4 (δ 0 ppm) using the residual solvent resonances. Note that the 1H NMR spectra of PMLABe homoand copolymers systematically featured broadened signals (typically ν1/2 = ca. 26 Hz), as always encountered in the literature.3b,18a,d Size-exclusion chromatography (SEC) giving number-average molar mass (Mn,SEC) and dispersity (ĐM = Mw/Mn) values of the PHAs was carried out in THF at 30 °C (flow rate 1.0 mL min−1) on a Polymer Laboratories PL50 apparatus equipped with a refractive index detector and a set of two ResiPore Mixed E 300 × 7.5 mm columns. The polymer samples were dissolved in THF (2 mg mL−1). All elution curves were calibrated with polystyrene standards; all Mn,SEC values of the PHBs, PMLABes, and P(MLABe-BL) copolymers were uncorrected for the potential difference in hydrodynamic radius vs polystyrene. The SEC traces of the (co)polymers all exhibited a unimodal, yet non-Gaussian-shaped peak tailing at longer elution times, inducing relatively large dispersities which yet remained below 1.65 (Figure 4). The Mn,SEC values thus obtained often remained much lower than the calculated values or the values determined by NMR (Mn,NMR, vide inf ra). The “plateau” of the measured Mn,SEC values was apparently lower for PMLABe homopolymers (ca. 2000 g mol−1) than for P(MLABe-BL) copolymers (ca. 7000 g mol−1). These observations possibly reflect the adsorption of the (co)polymer onto the columns. The molar masses of PHBs, PMLABes, and P(MLABe-BL) copolymers samples were determined by 1H NMR analysis in CDCl3 from the relative intensities of the signals of the main-chain methine hydrogens (δOCH(CO2Be)CH2 = 5.40−5.55, δOCH(CH3)CH2 = 5.15−5.20 ppm) relative to the chain-end signals of the chain-end vinylene (−C(O)CHCHCO2Be, δ 6.86, −C(O)CHCHCH3, δ 6.83 ppm), isopropoxide (−OCH(CH3)2 δ 1.14−1.23 ppm), or typical amidine/guanidine/phosphazene organobase hydrogens (these signals correspond to a significant number of hydrogens in the initiator and therefore emerge well from the spectrum baseline). This allowed a fairly reliable integration of the resonances as illustrated in Figure 7 as well as Figures S4 and S5 in the Supporting Information. B


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Table 1. Immortal ROP of MLABe Promoted by [(BDI)Zn{N(SiMe3)2}]/ROH (R = iPr, Bn) Catalyst Systems in Bulka entry 1 2 3 4 5 6 712 812 912 1012

[MLABe]0:[(BDI)Zn{N(SiMe3)2}]0:[ROH]0a 100:1:0 100:1:2 100:1:5 100:1:5 200:1:2 500:1:2 100:1:5 200:1:1 200:1:5 500:1:1

ROH − i

PrOH i PrOH i PrOH i PrOH i PrOH BnOH BnOH BnOH BnOH

temp (°C)

timeb (h)

convc (%)

Mn,theod (g mol−1)

Mn,NMRe (g mol−1)

Mn,SECf (g mol−1)

ĐM f

60 60 40 60 60 60 40 40 40 40

5 4 6 3 8 13 6 7.5 24 72

92 95 60 80 85 32 100 52 30 68

18 950 9850 2530 3360 17 570 16 540 4230 21 530 2580 70 150

− 9600 2000 3200 17 100 4700 −g −g −g −g

2200 2000 1700 1500 1500 900 900 1500 2100 1200

1.17 1.26 1.13 1.24 1.24 1.42 1.17 1.23 1.12 1.25

a

Reactions performed in toluene (0.1 mL). bThe reaction time was not necessarily optimized. cMonomer conversion determined by NMR analysis of the crude reaction mixture. dTheoretical molar mass calculated from the relation ([MLABe]0/[ROH]0 × convMLABe × MMLABe) + MROH, with MMLABe = 206 g mol−1, MiPrOH = 60 g mol−1, and MBnOH = 108 g mol−1. eAverage molar mass value determined by NMR analysis of the isolated polymer (refer to Experimental Section). fDetermined by SEC in THF at 30 °C vs polystyrene standards (uncorrected Mn values). gNot determined.12

Figure 2. 1H NMR (500 MHz, CDCl3, 25 °C) spectrum of a precipitated PMLABe synthesized from the [(BDI)Zn{N(SiMe3)2}]/iPrOH system (Table 1, entry 4; Mn,NMR = 3200 g mol−1). Monomer conversions were calculated from 1H NMR spectra of the crude polymer samples by using the integration (Int) ratio IntPMLABe/ [IntPMLABe + IntMLABe] of the methine hydrogen (δ−OCH(CO2Be)CH2 = 5.40−5.55 ppm for polymer, 4.88 ppm for monomer) for MLABe and IntBL/[IntBL + IntBL] of the methine hydrogen (δ−OCH(CH3)CH2 = 5.15− 5.20 ppm for polymer, 4.66 ppm for monomer) for BL. Note that the chemical shifts depend of the nature of the (co)polymer. Typical MLABe Homopolymerization. In a typical experiment (Table 1, entry 4), [(BDI)Zn{N(SiMe3)2}] (10 mg, 15.6 μmol) and a solution of iPrOH (6.0 μL, 78 μmol, 5 equiv vs Zn) in toluene (0.1 mL; in light of this small volume, the polymerization can be considered as a bulk procedure) were charged in a Schlenk flask in the glovebox and stirred at room temperature over 20 min, prior to the addition of MLABe (0.32 g, 1.56 mmol, 100 equiv). The mixture was then stirred at 60 °C over the appropriate reaction time (reaction times were not systematically optimized). The polymerization was quenched by addition of acetic acid (ca. 10 μL of a 1.6 mol L−1 solution in toluene). The resulting mixture was concentrated to dryness under vacuum, and the conversion was determined by 1H NMR analysis of the residue in CDCl3. The crude polymer was then dissolved in CH2Cl2 (2 mL) and precipitated in pentane (10 mL), filtered, and dried under vacuum at 45 °C overnight (typical isolated yield 90−95%). The final polymer was then analyzed by NMR and SEC analyses (Table 1). H-PMLABe-OiPr. 1H NMR (500 MHz; CDCl3, 25 °C): δ 7.33 (br m, 5nH, C6H5), 5.55 (br m, 1nH, CH2CH(CO2Be)O), 5.14 (br s,

2nH,OCH2C6H5), 4.56 (br m, 1H, OCH(CH3)2), 3.44 (br s, 1H, OH), 2.94 (br m, 2nH, CHCH2C(O)O), 1.23 (m, 6H, OCH(CH3)2) (Figure 2). 13C{1H} NMR (125 MHz; CDCl3, 25 °C): δ 168.0 (C O), 135.2 (C8), 128.3−128.7 (C9−11), 68.8 (C(O)CH2CH(CO2Be)O), 67.6 (OCH2C6H5), 64.7 ((CH3)2CHO), 35.4 (OC(O)CH2CH), 21.6 ((CH3)2CHO) (Figure S1). MALDI-ToF MS (Figure S11). Typical Synthesis of P(MLABe-ran-BL) Random Copolymers from the Simultaneous Addition of the Comonomers Using Nd(OTf)3/iPrOH. In a typical simultaneous copolymerization (Table 2, entry 5), Nd(OTf)3 (10.0 mg, 16.9 μmol) and a solution of iPrOH (6.5 μL, 84.5 μmol, 5 equiv vs Nd) in toluene (0.1 mL) were charged in a Schlenk flask in the glovebox and stirred at room temperature over 15 min, prior to the simultaneous addition of BL (140 μL, 1.69 mmol, 100 equiv) and MLABe (350 mg, 1.69 mmol, 100 equiv). The reaction mixture was then stirred at 60 °C over the appropriate reaction time (reaction times were not systematically optimized). The polymerization was quenched upon addition of acetic acid (ca. 10 μL of a 1.6 mol L−1 solution in toluene). The resulting mixture was concentrated to dryness under vacuum, and the conversion of both monomers was determined by 1H NMR analysis of the residue in CDCl3. The crude copolymer was then dissolved in CH2Cl2 (2 mL) and precipitated in pentane (10 mL), filtered, and dried under vacuum at 45 °C overnight (typical isolated yield 80−85%; Table 2). The recovered H− P(MLABe-ran-BL)-OiPr copolymer was analyzed by 1H, 13C, SEC, and DSC analyses. C


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Table 2. Simultaneous and Sequential Bulk Copolymerizations of MLABe and BL Promoted by Metal-Based Catalyst/iPrOH Systems at 60 °C [BL]0:[MLABe]0: [catalyst]0: [iPrOH]0a

entry

b

[catalyst]0

reaction time

18 h BL-1 h + MLABe-15 h BL-1 h + MLABe-15 h MLABe-5 h + BL-15 h 4 days 4 days 2 days MLABe-24 h + BL24 h BL-24h + MLABe-24 h 18 h 14 days 80 days

1 2 3 4 5 6 7 8

100:100:1:5 100:50:1:5 100:100:1:5 100:100:1:5 100:100:1:5 150:50:1:5 50:150:1:5 100:100:1:5

[Zn] [Zn] [Zn] [Zn] Nd(OTf)3 Nd(OTf)3 Nd(OTf)3 Nd(OTf)3

9 10 1116a 1216a

100:100:1:5 100:100:1:5 58:12:100:60h 475:100:1:-

Nd(OTf)3 Bi(OTf)3 ZnEt2 (TPP)AlCl

BL MLABe convc convc (%) (%)

PHB:PMLABe Comp.d

Mn,theoe (g mol−1)

Mn,NMRf (g mol−1)

Mn,SECg (g mol−1)

ĐM g

0 100 100 19 62 84 70 73

100 100 85 100 69 83 87 100

0:100 67:33 59:41 16:84 48:52 75:25 22:78 45:55

4100 3850 5900 4500 4000 3950 6000 5400

3500 3400 4200 3700 3300 3300 5800 4900

2430 3100 3200 2350 1800 1800 3100 3700

1.24 1.22 1.12 1.40 1.40 1.40 1.39 1.42

100 100

63 100

62:38 52:48 85:15 82:18

4300 5900

3800 2400

1200 1900 26 000 13 000

1.39 1.54 1.60 1.33

a General conditions unless otherwise stated: reactions performed in bulk monomer (no solvent) at 60 °C; [Zn] = [(BDI)Zn{N(SiMe3)2}]. bThe reaction time was not necessarily optimized. cMonomer conversion determined by NMR analysis of the crude reaction mixture. dMolar composition determined by NMR analysis of the isolated copolymer. eCalculated from the relation ([BL]0/[iPrOH]0 × convBL × MBL) + ([MLABe]0/[iPrOH]0 × convMLABe × MMLABe) + MiPrOH with MBL = 86 g mol−1, MMLABe = 206 g mol−1, and MiPrOH = 60 g mol−1. fDetermined by NMR analysis of the isolated copolymer, from 1H resonances of both terminal groups (refer to Experimental Section). gDetermined by SEC in THF at 30 °C vs polystyrene standards (uncorrected Mn values). hH2O was used as initiator.

Table 3. Simultaneous and Sequential Bulk Copolymerizations of MLABe and BL Promoted by the Organic Bases TBD, DBU, and BEMP entry 1 2 3 4 5 6 7 8 9 10

step step step step step step step step step step step step

1 2 1 2 1 2 1 2 1 2 1 2

catalyst

[BL]0:[MLABe]0:[catalyst]0a

timeb (h)

BL convc (%)

MLABe convc (%)

PHB:PMLABe compd

Mn,theoe (g mol−1)

Mn,NMRf (g mol−1)

Mn,SECg (g mol−1)

ĐM g

TBD DBU BEMP BEMP TBD

100:100:1 100:100:1 100:100:1 100:100:1 20:0:1 −:100:1 0:20:1 100:−:1 100:0:1 −:500:1 0:100:1 500:−:1 100:0:1 −:500:1 0:100:1 1000:−:1

18 18 18 72 1 4 0.5 8 4 8 2 48 8 8 0.7 18

0 4 42 80 100

100 100 100 100

0:100 2:98 21:79 46:54

79 100

23:77

20 800 21 100 24 500 27 800 1900 18 100 4300 7800 7500 74 500 17 900 26 500 7700 81 900 19 600 31 700

18 500 17 500 17 700 15 000 1700 16 300 4100 7200 7000 55 200 19 100 21 300 7600 73 500 18 700 30 000

3200 4200 4500 2700 1200 4200 1900 3600 6800 7000 6600 7100 6200 6900 6600 9100

1.20 1.32 1.44 1.65 1.13 1.25 1.30 1.40 1.18 1.33 1.29 1.42 1.19 1.44 1.30 1.46

TBD TBD TBD DBU BEMP

41 86

64:36 65 86

20 88

27:73 57:43

72 94 14

21:79 56:44

General conditions unless otherwise stated: reactions performed in bulk monomer (no solvent) at 60 °C. bThe reaction time was not necessarily optimized. cDetermined by NMR analysis of the crude reaction mixture. dDetermined by NMR analysis of the isolated copolymer. eCalculated from the relation: ([BL]0/[catalyst]0 × convBL × MBL) + ([MLABe]0/[catalyst]0 × convMLABe × MMLABe) + Mcatalyst with MBL = 86 g mol−1, MMLABe = 206 g mol−1, MTBD = 139 g mol−1, MDBU = 152 g mol−1, MBEMP = 274 g mol−1. fDetermined by NMR analysis of the isolated copolymer, from 1H resonances of both terminal groups (i.e., base and crotonate; refer to the Experimental Section). gDetermined by SEC in THF at 20 °C vs polystyrene standards (uncorrected values). a

H-P(MLABe-ran-BL)-OiPr. 1H NMR (500 MHz; CDCl3, 25 °C): δ 7.33 (br s, 5mH, C6H5), 5.42 (br m, 1mH, CH2CH(CO2Be)O), 5.17 (br m, 1nH, OCH(CH3)CH2), 5.01 (br s, 2mH,OCH2C6H5), 3.96 (br s, 1H, (CH3)2CHO), 3.44 (br s, 1H, OH), 2.82 (br s, 2mH, CHCH2C(O)), 2.55 and 2.30 (d of br s, 2nH, CH2C(O)O), 1.19 (br s, 3nH, OCH(CH3)CH2), 1.14 (shoulder of 1.19, br s, 6H, (CH3)2CHO) (Figure 5). 13C{1H} NMR (125 MHz; CDCl3, 25 °C): δ 169.2 (COBL), 168.2−168.0 (COMLABe), 135.0 (C8), 128.2−128.7 (C9−11), 68.8 (C(O)CH2CHCO2Be), 67.7 (C(O)CH2CH(CH3)), 67.6 (OCH2C6H5, C(O)CH2CH(CH3)O), 65.3 ((CH3)2CHO), 40.9 (OC(O)CH2CH(CH3)), 35.4 (OC(O)CH2CH(CO2Be)), 21.9 ((CH3)2CHO), 19.8 C(O)CH2CH(CH3) (Figure 6).

Typical Synthesis of P(MLABe-b-BL) Block Copolymers from the Sequential Addition of the Comonomers Using [(BDI)Zn{N(SiMe3)2}]/iPrOH. In a typical sequential copolymerization (Table 2, entry 2), [(BDI)Zn{N(SiMe3)2}] (5.0 mg, 7.8 μmol) and a solution of i PrOH (3.0 μL, 39 μmol, 5 equiv vs Zn) in toluene (0.10 mL) were charged in a Schlenk flask in the glovebox and stirred at room temperature over 20 min, just prior to the addition of BL (64 μL, 0.78 mmol, 100 equiv). The mixture was immediately stirred at 60 °C over the appropriate reaction time, allowing complete BL consumption (reaction times were not systematically optimized). MLABe (160 mg, 0.78 mmol, 100 equiv) was then added into the flask, and the mixture was immediately stirred at 60 °C. The polymerization was allowed to proceed over the appropriate reaction time and then quenched, and D


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the copolymer was finally purified as described above. The recovered H-P(MLABe-b-BL)-OiPr copolymer was analyzed by 1H, 13C, SEC, and DSC analyses. H-P(MLABe-b-BL)-OiPr. 1H NMR (500 MHz; CDCl3, 25 °C): δ 7.33 (br s, 5mH, C6H5), 5.42 (br s, 1mH, CH2CH(CO2Be)O), 5.17 (br m, 1nH, OCH(CH3)CH2), 5.01 (br s, 2mH,OCH2C6H5), 4.44 (br s, 1H, (CH3)2CHO), 3.44 (br s, 1H, OH), 2.82 (br s, 2mH, CHCH2C(O)), 2.55 and 2.30 (d of br s, 2nH, CH2C(O)O), 1.19 (s, 3nH, OCH(CH3)CH2), 1.14 (shoulder of 1.19, 6H, (CH3)2CHO) (Figure S2). 13C{1H} NMR (125 MHz; CDCl3, 25 °C): δ 169.3 (C OBL), 168.2−168.0 (COMLABe), 135.0 (C12), 128.7−128.2 (C13C15), 68.6 (C(O)CH2CHCO2Be), 68.1 (C(O)CH2CHCH3), 67.7 (OCH2C6H5, C(O)CH2CH(CH3)O), 67.0 ((CH3)2CHO), 40.8 (OC(O)CH2 CH(CH3)), 35.4 (OC(O)CH2 CH(CO 2Be)), 21.9 ((CH3)2CHO), 19.9 OC(O)CH2CH(CH3) (Figure S3). Typical Synthesis of P(MLABe-b-BL) Block Copolymers from the Sequential Addition of the Comonomers Using Organocatalysts (TBD, DBU, or BEMP). In a typical sequential copolymerization using an organocatalyst (Table 3, entry 5), a previously synthesized and isolated TBD-PHB-crotonate (10.0 mg, 5.6 μmol)11a was dissolved in MLABe (0.12 g, 0.56 mmol, 100 equiv). The neat mixture was then stirred at 60 °C over the appropriate reaction time. The polymerization was quenched with an excess of CH2Cl2 (2 mL), and the TBD-P(MLABe-b-BL)-crotonate copolymer was purified as described above. The sequential copolymerization upon addition of BL to previously synthesized and isolated TBD-PMLABe-benzyloxycrotonate (Table 3, entry 6) was carried out following the same procedure affording TBDP(BL-b-MLABe)-benzyloxycrotonate. The simultaneous copolymerization of MLABe and BL mediated by BEMP, allowing the preparation of BEMP-P(BL-b-MLABe)-benzyloxycrotonate copolymers (Figure S9), was performed according to a procedure similar to the random copolymerization described above with the Nd(OTf)3/iPrOH catalyst system. TBD-P(MLABe-b-BL)−CHCHCH3. 1H NMR (400 MHz; CDCl3, 25 °C): δ 7.19 (br s, 5mH, C6H5), 6.83 (br m, 1H, CHCHCH3), 5.71 (br d, 1H, OCHCHCH3), 5.43 (m, 1mH, CH2CH(CO2Be)O), 5.18 (br s, 1nH, OCH(CH3)CH2), 5.01 (br m, 2mH,OCH2C6H5), 3.11 (br m, 8H, NCH2CH2CH2N), 2.82 (m, 2mH, CHCH2C(O)), 2.59 and 2.32 (d of br s, 2nH, CH2C(O)O), 1.77 (br s, 7H, NCH2CH2CH2N, CHCHCH3), 1.19 (m, 3nH, OCH(CH3)CH2 (Figures S4 and S5). 13C{1H} NMR (125 MHz; CDCl3, 25 °C): δ 169.2 (COBL), 168.2−168.0 (COMLABe), 135.0 (C6), 128.1− 128.6 (C7−9), 68.6 (C(O)CHCHCO2Be), 67.5 (OCH2C6H5, C(O)CH2CH(CH3)O), 40.9 (OC(O)CH2CH(CH3)), 35.3 (OC(O) CH2CH(CO2Be)), 19.8 (CH3) (Figure S8). TBD-P(BL-b-MLABe)−CHCHCO2Be. 1H NMR (400 MHz; CDCl3, 25 °C): δ 7.26 (br m, 5n + 5H, C6H5), 6.86 (br m, 1H, OC(O)CHCHCO2Be), 5.54 (br s, 1H, OC(O)CHCHCO2Be), 5.43 (br s, 1nH, CH2CH(CO2Be)O), 5.19 (br s, 1mH, OCH(CH3)CH2), 5.03 (br s, 2n+2H, OCH2Be/Bn), 3.25 and 3.15 (m, 8H, NCH2CH2CH2N), 2.84 (br s, 2nH, OC(O)CH2CHO(CO2Be)), 2.60 and 2.25 (d of br s, 2mH, CH(CH3)CH2C(O)O), 1.88 (m, 4H, NCH2CH2CH2N), 1.20 (m, 3mH, OCH(CH3)CH2) (Figure 7). 13 C{1H} NMR spectrum is identical to that described for the TBDP(MLABe-b-BL)−CHCHCH3 related copolymer (Figure S8).

NMR analyses which demonstrated the end-capping of the polymers by a benzyloxy ester group originating from the initiator, and the presence of an hydroxyl group at the other chain end, as expected for a coordination−insertion ROP.10 However, the molar mass of the PMLABes thus prepared could not be reliably determined. Indeed, the molar mass values measured by SEC in our conditions remained uninformative, as they remained systematically limited to a maximal value of ca. 2000 g mol−1, whichever the actual molar mass of the polymers (Table 1, entries 7−10).12 In addition, the overlap in the 1H NMR spectrum of the −OCH2C6H5 end group with the alike pending substituent of the malolactonate repeating unit precluded the determination of the molar mass values by NMR (Mn,NMR). This was however circumvented upon using hexyl β-malolactone (MLAHe), which corresponding polymer (PMLAHe) produced by the same [(BDI)Zn{N(SiMe3)2}]/ BnOH system featured a good agreement between the anticipated value (Mn,theo) and the one determined experimentally by NMR (Mn,NMR).12 However, using this latter monomer does not allow the subsequent hydrogenolysis of the pending hexyl group, as sought with PMLABe precursors, toward desirable hydrophilic PMLA segments of amphiphilic self-assembling copolymers. Isopropanol (iPrOH) has thus been substituted to BnOH as initiator/chain transfer agent in the immortal ROP of MLABe catalyzed by [(BDI)Zn{N(SiMe3)2}] (Scheme 1). For the sake of comparison, a blank experiment conducted without alcohol was performed as well. Representative results of these experiments are summarized in Table 1. Scheme 1. Immortal ROP of MLABe Promoted by the [(BDI)Zn{N(SiMe3)2}]/iPrOH Catalyst System

Polymerizations were run in bulk (only a minute amount of toluene was used to allow dissolution of [(BDI)Zn{N(SiMe3)2}]) as previously performed with the analogous BnOH-derived catalyst system,12 yet at a higher temperature and without any detrimental effect on the control of the polymerization. The increase of the polymerization temperature from 40 to 60 °C thus enabled to slightly improve the activity of the [(BDI)Zn{N(SiMe3)2})]/BnOH catalyst system, as illustrated with the comparative experiments reported in Table 1, entries 3 and 4 (TOF40 °C = 10 vs TOF60 °C = 27 molMLABE molZn h−1, respectively). Changing the alcohol co-initiator from BnOH (TOFBnOH > 17 molMLABE molZn h−1; Table 1, entry 7) to iPrOH (TOFiPrOH = 10 molMLABE molZn h−1; Table 1, entry 3), under similar operating conditions (40 °C), did not significantly alter the efficiency of the zinc diketiminate catalyst. The primary alcohol afforded slightly faster polymerization rate as previously observed in the related homopolymerization of BL.9c As expected, use of iPrOH as co-initiator/chain transfer agent allowed the direct and accurate determination of the molar mass by NMR, from the resonances of the isopropoxide

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RESULTS AND DISCUSSION MLABe Homopolymerization. In our earlier work, we described the immortal10 ring-opening polymerization of MLABe catalyzed by [(BDI)Zn{N(SiMe3)2}] associated with benzyl alcohol (BnOH) acting as a co-initiator and a chain transfer agent.12 This efficient catalyst system (the actual initiating species is the alkoxide “[(BDI)Zn(OBn)]” formed in situ)12 afforded, at 40 °C in bulk operating conditions, PMLABes featuring theoretical molar mass values (Mn,theo) up to 70 150 g mol−1 and fairly narrow dispersities (ĐM < 1.46). The PHAs thus synthesized were well-defined, as evidenced by E


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Scheme 2. Schematic Representation of the Sequential (top) and Simultaneous (bottom) Bulk Copolymerization of MLABe and BL Mediated by the Metal-Based Catalyst Systems [(BDI)Zn{N(SiMe3)2}]/iPrOH and Nd(OTf)3/iPrOH

chain-end hydrogens (δCH3 = 1.23 ppm; δCH = 4.56 ppm; Figure 2). These Mn,NMR values could be corroborated from the integration ratio of the terminal hydroxyl groups (δOH = 3.44 ppm; Figure 2) and showed a good match with the calculated ones (Mn,theo; Table 1, entries 2−6). These molar mass values varied inversely and proportionally to the amount of alcohol introduced in the reaction medium, as expected for an immortal ROP10 (Table 1, entries 2 vs 4). The experimental molar mass values also increased with larger monomer loadings (Table 1, entries 2, 5, and 6). These observations thus demonstrate the living feature of this ROP process. A deviation is however noticed for PMLABe produced from 500 equiv of monomers, possibly reflecting more extensive side reactions at these large monomer loadings (vide inf ra). The 13C{1H} NMR spectrum of the recovered polymers confirmed the macromolecular architecture as H-PMLABe-OiPr (Figure S1). Finally, even though high molar mass values were not targeted, the [(BDI)Zn{N(SiMe3)2}]/iPrOH catalytic system allowed the formation of PMLABes with Mn,NMR up to 17 100 g mol−1 and with quite narrow dispersity ĐM < 1.25. Such ĐM values are within the same range as those reported from the analogous BnOH-based catalyst system (Table 1, entries 7−10)12 as well as those commonly found in the literature (typically 1.1 < ĐM < 1.5).18−21 Although all the SEC chromatograms exhibited a monomodal elution peak, these values suggest the occurrence of some (yet limited) side reactions typically encountered in the ROP of cyclic esters, namely intermolecular (reshuffling) and intramolecular (backbiting) transesterifications or other transfer reactions.23 Note that the same molar mass “ceiling” value (ca. 2000 g mol−1) measured by SEC (Mn,SEC) was obtained in the present homopolymerization study of MLABe (Table 1), as recalled above for the ROP of MLABe mediated by [(BDI)Zn{N(SiMe3)2}]/BnOH.12 Also, the use of racemic MLABe afforded atactic PMLABe, as later observed in the present study whichever the catalyst. MLABe/BL Copolymers Synthesized from MetalBased Catalyst Systems. Our previous studies have evidenced that the [(BDI)Zn{N(SiMe3)2}]/BnOH system enables the living-controlled ROP of BL9c and MLABe.12 This was demonstrated by (i) a double MLABe addition experiment which resulted in a resumed polymerization and in an increased molar mass as monitored by SEC and (ii) the successful synthesis of MLABe/trimethylene carbonate block copolymers.12 Hence, the copolymerization of MLABe and BL

with this zinc catalyst was then investigated using iPrOH as initiator/CTA. In the zinc-catalyzed simultaneous bulk copolymerization of MLABe and BL carried out at 60 °C, MLABe and/or PMLABe apparently inhibited the polymerization of BL since only MLABe was fully converted within 5 h, whereas BL remained unreacted over the next 13 h of reaction (Table 2, entry 1). This is in contrast to the simultaneous copolymerization of MLABe/TMC (feed ratio 100:200) which afforded, over 16 h at 40 °C in bulk, the expected P(MLABe-co-TMC) copolymer.12 The sequential copolymerization of MLABe/BL mediated by [(BDI)Zn{N(SiMe3)2}]/iPrOH was also investigated in bulk at 60 °C (Table 2, entries 2−4). When BL was introduced first, polymerization of both monomers (BL and then MLABe) proceeded with high conversions (85−100%) over reasonably short reaction times (Table 2, entries 2 and 3), in agreement with the corresponding homopolymerizations.9b On the contrary, when MLABe was introduced first and fully polymerized, the conversion of BL remained very sluggish. At best, ca. 20% conversion of BL was observed under our operating conditions. This dramatically tamed reactivity of BL is in line with the above-mentioned simultaneous copolymerization of both monomers. These results indicate that, with this zinc catalyst system, the BL conversion is significantly affected by the presence of MLABe and/or PMLABe in the reaction medium. Kinetic monitoring of the simultaneous copolymerization of MLABe/BL mediated by the Nd(OTf)3/iPrOH system at 60 °C in bulk revealed the simultaneous and equal consumption of MLABe and BL with respect to the feed ratio. This is in line with the homopolymerization of the individual monomers for which the rate of BL conversion is basically of the same order of magnitude as that of MLABe (Table S1). Within 2−4 days, 50−150 monomers units were converted in high yields (62− 87%), affording well-defined (vide inf ra) random copolymers P(MLABe-ran-BL), with Mn,NMR up to 5800 g mol−1 (ĐM = ca. 1.40) (Table 2, entries 5−7). The analogous bismuth triflate catalytic system, also efficient in homopolymerization of MLABe (Table S1), similarly enabled the preparation of such random P(MLABe-ran-BL) copolymers (Table 2, entry 10). These metal triflate-based catalytic systems thus appeared more effective than the previously reported ones based on ZnEt2 or tetraphenylporphyrin aluminum chloride which required at least 2 weeks and up to 2.5 months (thus favoring undesirable F


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Scheme 3. Schematic Representation of the (i) Simultaneous and (ii) and (iii) Sequential Bulk Copolymerization of BL and MLABe Mediated by the Organocatalysts TDB, DBU, and BEMP

Figure 3. 1H NMR (400 MHz; CDCl3, 25 °C) monitoring of the simultaneous copolymerization of MLABe and BL mediated by BEMP (Table 3, entries 3 and 4): (a) after 30 min of reaction, only MLABe is almost fully converted (□: δCH‑MLABe = 4.88 ppm vs ■: δCH‑PMLABe = 5.54 ppm; △: δCH‑BL = 4.66 ppm vs ▲: δCH‑PHB = 5.43 ppm), (b) after 4 h, MLABe is fully converted and BL begins to be converted, (c) and (d) spectra of the copolymerization reaction after 18 and 72 h, respectively, BL is slowly converted.

required as co-initiator in these homopolymerizations,11 the bases were similarly used alone in the MLABe/BL copolymerization (Scheme 3). Representative results are gathered in Table 3. The simultaneous copolymerization of BL and MLABe mediated by TBD, DBU, or BEMP in bulk at 60 °C revealed that block copolymers P(MLABe-b-BL) could be prepared effectively only from BEMP. An NMR monitoring of the copolymerization revealed that MLABe was fully and rapidly converted by BEMP in the early stage (within 4 h) of the copolymerization (Figure 3; Table 3, entries 3 and 4). Prolonged reaction times enabled to improve the conversion of BL, up to 80%. In contrast to the catalytic systems based on metal triflates, BEMP thus copolymerized MLABe faster than BL in the simultaneous approach, whereas the homopolymerizations of the individual monomers proceed at the same rate. Indeed, 100 equiv of MLABe was almost fully converted (94%) within 40 min in bulk at 60 °C,11b while 1 h was required to achieve full BL conversion under the same experimental conditions.11a Thus, block (and not random) copolymers of

side reactions which would similarly end up in the formation of such copolymers) for the formation of similar random copolymers (Table 2, entries 11 and 12).16a Investigations of the sequential MLABe/BL copolymerization promoted by the Nd(OTf)3/iPrOH catalyst system at 60 °C in bulk showed the formation of the expected block copolymers P(MLABe-b-BL) within 48 h, regardless of the order of comonomers addition (Table 2, entries 8 and 9). The second monomer remained comparatively more slowly copolymerized than the first one. Block copolymers featuring segments size ranging up to 17 monomer repeating units, with Mn,NMR up to 4900 g mol−1, monomodal SEC trace and rather narrow dispersity values (ĐM = ca. 1.31) were thus prepared from the metallic catalytic systems (Table 2). MLABe/BL Copolymers Synthesized from Organocatalysts. The living character of the ROP of BL11a and MLABe11b promoted by TBD, DBU, and BEMP, as we have previously established from their respective homopolymerization, further enabled to consider their copolymerization from these organic initiators. Of note, no added alcohol being G


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molar mass up to Mn,NMR = 17 700 g mol−1 (ĐM < 1.65) were prepared upon simultaneous addition of MLABe and BL copolymerized by BEMP. To our knowledge, this is the first catalyst reported to allow the formation of PMLABe/PHB block copolymers upon simultaneous copolymerization of MLABe and BL. Catalysts allowing the formation of block copolymers upon copolymerization of comonomers simultaneously loaded remain rare.24 In the case of TBD- and DBUmediated simultaneous copolymerization, under the experimental conditions used, only MLABe was consumed, somehow inhibiting the ROP of BL and thus (only) PMLABe homopolymers were produced within a reaction time similar to that enabling the conversion of BL with BEMP, namely 18 h (Table 3, entries 1, 2 vs 3; Scheme 3). The sequential copolymerization of MLABe and BL was successfully performed from any of the three bases, regardless of the order of monomer addition, thereby providing block copolymers P(MLABe-b-BL) (Scheme 3). Representative experiments are gathered in Table 3, entries 5−10. When starting from BL, subsequent addition of MLABe, in an amount sufficient enough to impart dissolution of the preformed αTBD,ω-crotonate-PHB, enabled its effective conversion, even though at a slower rate than that observed in its corresponding homopolymerization (Table 3, entries 5 and 7). Indeed, the homopolymerization of 100 equiv of MLABe was achieved in 88% yield within 2 h when promoted by TBD under the same operating conditions,11b whereas only 79 turnover numbers (TONs) were reached within 4 h in the presence of the preformed small PHB block (Table 3, entry 5). On the other hand, addition of BL to a preformed α-TBD,ω-crotonatePMLABe (Table 3, entries 6 and 8) afforded the P(MLABe-bBL) copolymer. Note that for this latter order of comonomers addition, the viscosity of the reaction medium is not problematic since the preformed PMLABe readily dissolves into (liquid) BL. In this case, the ROP of BL in presence of the preformed PMLABe block was much slower (41 TONs in 8 h, Table 3, entry 6) than the rate observed in its homopolymerization (86 TONs in 4 h),11a under the same experimental conditions. The sequential copolymerization with the other DBU or BEMP bases were successfully run under these same operating conditions and featured the same general behavior as observed with TBD (Table 3, entries 9 and 10). In particular, for all these sequential copolymerizations, whichever the order of monomer addition, the second monomer was always copolymerized at a slower rate than that reached in its homopolymerization, respectively; this trend is also more striking with BL. The organic base catalysts thus afforded block copolymers with molar mass up to Mn,NMR = 55 200 g mol−1 (ĐM < 1.46). Formation of these P(MLABe-b-BL) block copolymers obtained from organic base catalysts was supported first by the increase of the molar mass measured by NMR and SEC analyses, upon going from the first block (PHB: Mn,NMR = 1700 g mol−1, Mn,SEC = 1200 g mol−1, ĐM = 1.13) to the second (PMLABe: Mn,NMR = 16 300 g mol−1, Mn,SEC = 4200 g mol−1, ĐM = 1.25), in agreement with the feed ratio of the monomers (Table 3, entry 5). Indeed, a unique peak was recorded on the SEC traces (refer to Experimental Section), suggesting the formation of a true diblock copolymer instead of a mixture of the two homopolymers (Figure 4). Also, further characterization of the copolymers supported this blocky macromolecular architecture (see thereafter).

Figure 4. SEC chromatograms of a PMLABe (Mn,SEC = 1200 g mol−1, ĐM = 1.13) and a P(MLABe-b-BL) (Mn,SEC = 4200 g mol−1, ĐM = 1.25) block copolymer obtained by the sequential copolymerization of MLABe and then BL mediated by TBD (Table 3, entry 5).

Characterization of the Copolymers. The P(MLABeBL) copolymers synthesized were analyzed by NMR, SEC, and DSC. They all exhibited a molar mass value, as determined by NMR analysis (refer to Experimental Section), in quite good agreement with the calculated data taking into account both monomers conversion (Tables 2 and 3). However, the molar mass values determined by SEC (using a refractive index detector), calibrated from polystyrene standards featuring a hydrodynamic radius possibly different than those of either PMLABe and PHB homopolymers and of P(MLABe-BL) copolymers, did not vary proportionally to the comonomer feed ratio. Such a behavior was also observed with the PMLABes which molar mass values typically remained much lower than the ones determined by NMR (Mn,NMR) or calculated from the monomer loading (Mn,theo), as the result of their possible adsorption onto the silica columns (vide supra, Table 1).11b In contrast, the SEC analysis of related atactic PHB samples usually do not display this “saturation” phenomenon.9,10,11a One may thus suppose that in P(MLABe-BL) copolymers, the behavior of the PMLABe prevails over that of the PHB, whichever the block length. The dispersity of these PHA block and random copolymers remained fairly low (1.12 < ĐM < 1.65), suggesting the occurrence of some, yet minor, transesterification reactions,23 as already pointed out in the corresponding MLABe and BL homopolymerizations.9−12 NMR characterization is quite helpful to establish the chemical structure of the copolymers that is to identify the nature of the chain-end groups and of the repeating units. Moreover, valuable information about the mechanism of (co)polymerization can be gained from careful NMR analyses. Both block and random copolymers were then characterized by 1 H and 13C NMR spectroscopy. A typical 1H NMR spectrum of a random copolymer, HP(MLABe-ran-BL)-OiPr, synthesized from the simultaneous copolymerization of MLABe and BL promoted by the Nd(OTf)3/iPrOH system is depicted Figure 5 (Table 2, entry 5). It shows the characteristic resonances of both PMLABe (δ 7.33, 5.01, OCH2C6H5; 5.17, 2.82, OCH(Be)CH2C(O)) and PHB (δ 5.01, 2.55,2.30, 1.19, OCH(CH3)CH2C(O)), in agreement with the spectra of the corresponding homopolymers (Figure 2).9c,12 Besides, the chain-end signals corresponding to the hydroxyl (δCHOH = 3.44 ppm) and H


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Figure 5. 1H NMR (500 MHz; CDCl3, 25 °C) spectrum of a H-P(MLABe-ran-BL)-OiPr copolymer produced from the simultaneous copolymerization of MLABe and BL promoted by the Nd(OTf)3/iPrOH catalyst system (Table 2, entry 5) (∗ and ∗∗ markers stand for residual CH2Cl2 and 13C satellites of CHCl3, respectively).

Figure 6. 13C{1H} NMR (125 MHz; CDCl3, 25 °C) spectrum of a H-P(MLABe-ran-BL)-OiPr produced from the simultaneous copolymerization of MLABe and BL promoted by the Nd(OTf)3/iPrOH system (Table 2, entry 5), with a zoom of the methylene carbons region (∗ and ∗∗ markers stand for residual grease and CH2Cl2, respectively).

isopropoxyl (δCH(CH3)2 = 1.14 ppm; δCH(CH3)2 = 3.96 ppm) groups were clearly identified, further enabling the determination of experimental Mn,NMR values (Table 2). The 13C{1H} NMR spectrum also evidenced the signals classical of PMLABe (δCO = 168.2−168.0, δCO2Be = 135.0, δOCH2C6H5 = 67.6 ppm) and PHB (δCO = 169.4, δC(O)CH2CH(CH3) = 19.8 ppm) segments along with those corresponding to the end-capping −OiPr group (δMe2CHO = 65.3, δ(CH3)2CHO = 21.9 ppm) (Figure 6). In addition, the methylene carbons region displayed a series of resonances for MLABe/BL sequences (δBL‑BL = 40.8 ppm, δBL‑MLABe = 40.1 ppm, δMLABe‑BL = 35.8 ppm, δMLABe−MLABe = 35.5 ppm), as previously reported for the random copolymers prepared from the aluminoxane catalyst.16a These NMR data thus supported the formation of random atactic copolymers, HP(MLABe-ran-BL)-OiPr with the Nd(OTf)3/iPrOH system. Note that such detailed 13C{1H} NMR analyses providing evidence of the microstructure at the diad and even triad level

on random and alternated PHA copolymers has also been reported by Coates, Thomas, and co-workers.24c,25 The typical 1H and 13C{1H} NMR spectra of a block copolymer H-P(MLABe-b-BL)-OiPr synthesized from the [(BDI)Zn{N(SiMe3)2}]/iPrOH system (Table 2, entry 2), display the expected resonances of both PMLABe and PHB, along with the hydroxyl and isopropoxyl chain-end signals (Figures S2 and S3, respectively), also enabling the determination of experimental Mn,NMR values (Table 2). The spectra closely resemble those of the corresponding HP(MLABe-ran-BL)-OiPr (Figures 5 and 6), except that the methylene region in the 13C NMR spectrum is simpler, with essentially two strong resonances at δBL‑BL = 40.8 ppm and δMLABe−MLABe = 35.5 ppm for each block. Similarly, the 1H NMR spectra of precipitated P(MLABe-b-BL) block copolymers prepared from the organic bases all exhibited the typical signals of each β-lactone repeating unit, as illustrated with TBD-mediated copolymerizations (Figure 7 and Figures S4 and I


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Figure 7. 1H NMR (400 MHz; CDCl3, 25 °C) spectrum of a TBD-P(MLABe-b-BL)-benzyloxycarbonyl-crotonate prepared from the sequential copolymerization of MLABe followed by BL promoted by TBD (Mn,NMR = 7200 g mol−1; Table 3, entry 6) (∗ marker stands for a residual unidentified impurity).

S5). A careful analysis of the carbonyl (Figure S10) and methylene (Figure 6) regions of the 13C NMR spectra of the block and random copolymers did not allow the identification of diad or triad comonomers sequences, and the differentiation of such microstructures one from another, as elegantly reported by Coates, Thomas, and co-workers on related PHA copolymers.24c,25 The relatively poor resolution observed in our spectra most likely results from the presence of a PMLABe segment, as typically observed in alike PMLABe (co)polymers previously reported in the literature.3b,18a,d In addition, in the specific case of these basic organocatalysts, depending on which monomer is added first during the sequential copolymerization of MLABe and BL, the nature of functional groups at the terminus of each block can be unambiguously identified, upon comparison with the corresponding 1H NMR spectra of the PMLABe and PHB homopolymers (Figures S611b and S711a in the Supporting Information, respectively) prepared from the same organocatalyst. On one hand, the 1H NMR spectrum of copolymers obtained via addition of MLABe first shows signals indicative of a benzyloxycarbonyl-crotonate group −CH CHCO2Be (δ 6.86 and 5.54 ppm; Figure 7 and Scheme 3).11b In the case of addition of BL first (Table 2, entry 5), the crotonate resonances observed are characteristic of a −CH CHCH3 moiety (δ 6.83, 5.71, and 1.77 ppm, respectively; Figures S4, S5, and S7; Scheme 3).11 The 13C{1H} NMR spectra of the short-chains copolymers unfortunately did not display the corresponding chain-end signals because of their low intensity (Figure S8). The covalent linkage of the organic base catalyst at the terminus of the other block could be also clearly evidenced by NMR (see Figure 7 and Figures S4−S7, S9). The observation of these terminal groups at both ends of the copolymers (Scheme 3) is consistent with the previously proposed mechanism of the β-lactones polymerization.11 Copolymerization would then propagate by insertion of the second monomer between the first block and the end base. Thermal analysis by differential scanning calorimetry (DSC) of a random copolymer sample prepared from Nd(OTf)3/iPrOH (Table 2, entry 5) showed a unique glass transition temperature (Tg = +16 °C). This value is intermediate between those of PMLABe (Tg = +30 °C, Mn = 7900 g mol−1)18f and PHB (Tg = −3 °C, Mn = 6300 g mol−1)26

(Figure 8). This is different from the diblock copolymers, prepared from the sequential copolymerization using either the

Figure 8. DSC trace (second heating cycle) of a P(MLABe-ran-BL) synthesized from the simultaneous ROP of BL and MLABe promoted by Nd(OTf)3/iPrOH catalyst system (Table 2, entry 5).

metallic or organic catalyst systems, which display two distinct Tg values corresponding to each PHA segment (Figure 9). For instance, a diblock copolymer sample obtained from TBD featured two glass transition temperatures at Tg = +46 °C and +2 °C, corresponding to both blocks, PMLABe and PHB, respectively, as illustrated Figure 9a (Table 3, entry 7). Also, a copolymer prepared from the simultaneous loading of BL and MLABe in the presence of BEMP (Table 3, entry 3 or 4) exhibited the same two glass transition temperatures, further supporting in this one case the formation of a diblock copolymer rather than of a random one (Figure 9b).

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CONCLUSION The [(BDI)Zn{N(SiMe3)2}]/iPrOH system successfully mediates the controlled immortal ROP of MLABe. The use of i PrOH as initiator/chain transfer agent, in place of BnOH as previously reported,12 allowed the accurate determination of experimental molar mass values of PMLABes by 1H NMR, with an eventual good match with the awaited data based on MLABe conversion. Kinetic and microstructural control in the copolymerization of MLABe and BL under mild operating conditions (in bulk at 60 °C) was next achieved via catalytic tuning using various J


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ASSOCIATED CONTENT

S Supporting Information *

The complementing 1H and 13C NMR spectra of PMLABe synthesized from the [(BDI)Zn{N(SiMe3}2]/iPrOH system or TBD,11b a P(MLABe-b-BL) synthesized from the sequential copolymerization of BL followed by MLABe promoted by the [(BDI)Zn{N(SiMe3}2]/iPrOH system or TBD, a PHB synthesized from the TBD,11a a P(MLABe-b-BL) synthesized from the simultaneous copolymerization of BL and MLABe promoted by BEMP, details of the carbonyl regions of 13C NMR spectra of copolymers, MALDI-ToF mass spectrum of a i PrO-PMLABe-H polymer, and data for the immortal bulk ROP of MLABe promoted by the M(OTf)3/iPrOH catalyst systems, with M = Nd, Bi. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully thank the CNRS and the Region Bretagne for supporting part of this research (Ph.D. grant to C. G. J.).

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Figure 9. DSC traces (second heating cycle) of (a) a P(MLABe-b-BL) synthesized from the sequential ROP of BL and then MLABe promoted by TBD (Table 3, entry 7) and (b) a P(MLABe-b-BL) synthesized from the simultaneous copolymerization of BL and then MLABe promoted by BEMP (Table 3, entry 4).

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systems (previously demonstrated effective in each MLABe11,12 and BL9−11 homopolymerization) derived from either a metalbased (pre)catalyst associated with iPrOH acting as a coinitiator and a chain transfer agent or more simply from a neat basic organocatalyst. Well-defined random P(MLABe-ran-BL) copolymers (nonoptimized Mn,NMR up to 5800 g mol−1 with ĐM = 1.40; ca. 17 BL and MLABe repeating units) could be successfully prepared only with the Nd(OTf)3/iPrOH system. With [(BDI)Zn{N(SiMe3)2}]/iPrOH, TBD, or DBU, MLABe was first polymerized, then inhibiting the copolymerization of BL. All catalytic systems investigated enabled the synthesis of block copolymers (nonoptimized Mn,NMR up to 73 500 g mol−1 with ĐM = ca. 1.44; ca. 88 BL and 360 MLABe repeating units) upon sequential copolymerization of the comonomers; the order of comonomers addition proved however very important with the Zn-based catalyst, with BL necessarily having to be polymerized prior to MLABe. Remarkably, BEMP afforded P(MLABe-b-BL) block copolymers from either a sequential or a simultaneous approach and regardless of the order of the comonomers addition since the ROP of BL was always slower than that of MLABe. The chemical microstructure and topology of these copolymers were established from kinetic, spectroscopic and thermal (NMR, SEC, DSC) analyses. Evidence of the formation of α,ω-hydroxy,isopropoxy and α,ω-base,crotonate functionalized P(MLABe-BL) copolymers is thus provided. K


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