Organocatalytic ring-opening polymerization of disulfide functional macrocyclic carbonates: An alternative strategy to enzymatic catalysis

Journal Pre-proofs Organocatalytic ring-opening polymerization of disulfide functional macrocyclic carbonates: an alternative strategy to enzymatic catalysis Bingkun Yan, Bingyu Liang, Jiaqian Hou, Chao Wei, Yan Xiao, Meidong Lang, Farong Huang PII: DOI: Reference:

S0014-3057(19)32203-7 https://doi.org/10.1016/j.eurpolymj.2019.109452 EPJ 109452

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European Polymer Journal

Received Date: Revised Date: Accepted Date:

26 October 2019 17 December 2019 18 December 2019

Please cite this article as: Yan, B., Liang, B., Hou, J., Wei, C., Xiao, Y., Lang, M., Huang, F., Organocatalytic ring-opening polymerization of disulfide functional macrocyclic carbonates: an alternative strategy to enzymatic catalysis, European Polymer Journal (2019), doi: https://doi.org/10.1016/j.eurpolymj.2019.109452

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Organocatalytic ring-opening polymerization of disulfide functional macrocyclic carbonates: an alternative strategy to enzymatic catalysis Bingkun Yan,1 Bingyu Liang,2 Jiaqian Hou,1 Chao Wei,1* Yan Xiao,1 Meidong Lang 1*and Farong Huang 1 1. Key Laboratory of Specially Functional Polymeric Materials and Related Technology of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology. Shanghai, 200237, China; 2. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China *E-mail: [email protected] Corresponding author(s): Meidong Lang ([email protected])

Abstract Ring-opening polymerization (ROP) of macrocyclic carbonates (≥ 12 ring) is still challenging due to the associated low ring-strain. Although organometallic and enzyme based catalysts have been studied, disadvantages such as organometallic residue and enzymic nature limit their applications. After screening commercially available organocatalysts, we report the use of organocatalysts for ROP of disulfidecontaining macrocyclic carbonates (MSS, 16 ring). It was found that organocatalysts (TBD) presented high active and living ROP of MSS, as evidenced by kinetic studies, yielding main chain disulfide-containing polycarbonates with tailor-made structures and predictable molecular weights with low molecular weight distribution. Copolymerizations with trimethylene carbonate (TMC) generated random copolymers with controlled components, regulating the density of disulfide functional groups. By comparing with the behaviors of enzyme catalysis in kinetic studies and (co-)polymerization, it is observed that organic catalyzed ROP showed more efficient (~ ten times faster), milder condition and more controlled behaviors than enzyme catalyzed ROP (N-435). Therefore, we believe this organic catalyzed strategy will provide an alternative to the current enzymatic and organometallic catalyst for ROP of macrocyclic carbonates.

Keywords Macrocyclic carbonate; disulfide; organocatalyst; aliphatic polycarbonate; ring-opening polymerization Introduction Aliphatic polycarbonates (APCs) as an important class of polymeric materials have received extensive applications including, but not limited to, biological imaging, drug/gene delivery and tissue engineering, mainly due to their excellent biodegradability, tissue biocompatibility, low toxicity and easy tunability.[17] These APCs are commonly synthesized by ring-opening polymerization (ROP) of cyclic precursors using organometallic-catalytic, enzymatic and organic-catalytic strategies, which provides precise control over polymer structures and properties of the final materials.[8-11] The past two decades have witnessed tremendous achievements in the ROP of small-medium cyclic carbonates (ethylene carbonate, trimethylene carbonate and their functional analogues, etc.).[12-17] However, the ROP of macrocyclic carbonates (more than 12-membered ring) is rarely reported due to their challenge in undergoing ROP,

despite their unique advantage of constructing targeted polymers with extended main chain structural elements.[18, 19] On the other hand, the synthesis of large cyclic carbonate is not so straightforward, and that could also hamper the investigations. The polymerization mechanism of macrocyclic monomers differs from that of small-medium ringsized monomers.[20] Unlike the ROP of small-medium cyclic monomers (large ring-strain) that is an enthalpy-driven process, the ROP of macrocyclic system (low ring-strain) is mainly entropy-driven, which hinders the ring opening process.[20-23] For this reason, to date, only few examples of organometallic catalyzed ROP of macrocyclic carbonates have been reported.[8, 24, 25] For example, the use of SnOct2 successfully resulted in the bulk ROP of cyclobis (decamethylene carbonate) and cyclobis (pentamethylenecarbonate) to produce the corresponding long-chain APCs with high molecular weight (Mn).[8] However, harsh reaction conditions often cause decarboxylation and SnOct2 is unsuitable for ROP of functionalized macrocyclic carbonates.[18] Besides, organometallic residue is difficult to be removed completely from the resultant polymers, limiting their applications such as biomedicines and packaging materials. On the other hand, enzyme-catalysts have been widely researched, affording high catalytic activity and green process in the ROP of macrocyclic carbonates.[18, 19, 26, 27] Since the activation of monomers depends on the preference of enzymes to the hydrophobic substrate rather than the ringstrain, enzyme-catalysts could be used in ROP of most macrocyclic carbonates. However, enzymes are generally high-cost and temperature sensitive as well as its ROP usually has slow kinetics and little control over polymer structures. Therefore, it is high significant to seek other metal-free catalytic strategies to lead to high efficient and controlled ROP of macrocyclic carbonates. Organocatalysts in ROP of cyclic monomers have become a powerful alternative to the traditional organometallic and enzyme catalysts since they offer high catalytic activity, excellently low cost, low toxicity, precise control of advanced polymer architectures, and easy purification.[28-33] Moreover, organic catalysis provides many potential opportunities to polymerize some monomers that are difficult to be polymerized using other existing catalysts. For example, the high activity and fast reaction rate may enable the ROP of macrocyclic monomers (low ring strain) to obtain high monomer conversion and high high molecular weight (Mn).[20, 34, 35] Hence, we propose that organocatalysts could achieve fast, controlled and robust ROP of macrocyclic carbonates, providing an alternative strategy to the current enzymatic catalysis. Herein, we focus on disulfide functional macrocyclic carbonates (MSS) because disulfides (S-S) are widespread in the human body, playing an important role in maintaining the tertiary structure of proteins and the intracellular redox potential. Moreover, disulfides have been widely used as redoxsensitive or self-healing groups.[36, 37] In particular, this monomer can be synthesized expediently by the well-established route in our previous work.[38] After screening several organocatalysts, TBD was found to achieve high active and controlled ROP of MSS, generating main chain disulfide-containing aliphatic polycarbonates (homopolymers and copolymers) with tailor-made structures and predictable Mn with low molecular weight distribution (Scheme 1). Polymerization kinetics was investigated in detail, displaying a living polymerization character. More importantly, through comparison with enzymecatalysis, organocatalytic ROP showed more efficient and controlled behaviors. Considering inexpensive

lost and low-toxicity of organocatalysts, this organic catalyzed method is very competitive to the current enzymatic catalysis.

Result and discussion

Scheme 1. The ROP of MSS with different kinds of catalysts used in this work.

In terms of chemical structure, disulfide-containing macrocyclic carbonates (MSS) is a 16-membered ring monomer with strain-free structure, thus, the polymerization behavior differs from that of smallmedium ring-sized monomers (6-8 ring). To test the efficiency of organocatalytic ROP, several common organocatalysts containing base catalysts and acid catalysts, for instance, TBD (pKa=26.0), MTBD (pKa=25.5), DBU (pKa=24.3), TU (pKa=13.2, as a two-component catalyst with DBU[39, 40]), DPP (pKa=2.0), DBSA (pKa = −2.5) were screened (Scheme 1).[41, 42] Polymerizations were performed in solution at room temperature with benzyl alcohol (BnOH) as the initiator. Dichloromethane (CH2Cl2) was chosen due to the good solubility of MSS in CH2Cl2. As the summarization of polymerization conditions and results in Table 1, it was inspiringly found that DBU/TU and TBD proved to be catalytically active in MSS polymerization, but other catalysts all failed (Figure S4-S6). Note that in the system of DBU/TU, the monomer conversion only reached about 80% after 8 h, indicating low polymerization efficiency (Entry 3, Table 1). On the other hand, the stronger base TBD could efficiently polymerize MSS with the conversion as high as 95% within 2 h (Entry 7, Table 1), which indicated that highly active organic bases were necessary for ROP of MSS. Therefore, we chose TBD as the highly efficient organocatalyst for the ROP of MSS.

Figure 1. (a) 1H NMR spectra (Dichloromethane-d2 25 oC) of TBD, MS, and the mixture of TBD and MSS. (b) 1H NMR spectra (Dichloromethaned2 25 oC) of TBD, BnOH, and the mixture of TBD and BnOH.

Different activation methods make the catalysts suitable for different polymerizations.[43, 44] Because MSS has little ring strain, resulting in the low polymerization reactivity, the organocatalysts must have high enough activity to active macrocarbonates to overcome the barrier in polymerization. The most favorable mechanism for the TBD catalytic ROP was the dual activation of the initiator and monomer through hydrogen-bonding.[20, 31, 39, 45] Meanwhile, the high basicity and low nucleophilicity allow TBD to have fast and efficient catalyst activity.[46] To probe this mechanism, TBD & BnOH and TBD & MSS were combined in 1:1 ratio to perform 1H NMR and 13C NMR (Figure 1, Figure S7), which showed the formation of the intermediate. It clearly showed that the proton of TBD disappeared and the chemical environment of C (C-N) of TBD changed when BnOH or MSS was added, which was a straightforward proof to verify the above proposed mechanism. Furthermore, the mechanism of dual activation can be well verified why the alkalinity of DBU/TU is not stronger than MTBD or DBU but can achieve polymerization of MSS. This is because MTBD and DBU can only activate the initiator benzyl alcohol, failing in improving the polymerization activity of MSS, while DBU/TU can simultaneously activate the monomer and initiator (Figure 2, Figure S8).[28, 31, 47, 48] However, the lower catalytic capability of DBU/TU

resulted in lower catalytic efficiency than TBD, which accorded with the experimental results (Entry 3, Entry 7, Table 1). Table 1.The ROP of MSS using different Organocatalysts. Entry[a]

catalyst

initiator

[M]:[I]:[C][b]

time/h

conv. (%)[c]

1

-

BnOH

20:1:1

24

0

2

DBU

BnOH

20:1:1

24

0

3

DBU/TU

BnOH

20:1:1/1

8

80

4

MTBD

BnOH

20:1:1

24

0

5

DPP

BnOH

20:1:1

24

0

6

DBSA

BnOH

20:1:1

24

0

7

TBD

BnOH

20:1:1

2

95

All reactions were reacted at R.T. with the specified initial monomer concentration [M]0 =0.64 M, catalyst and co-catalyst concentration was 5 mol% to MSS, no catalyst in Entry 1. [b] [Monomer]:[initiator]:[catalyst]. [c] conversion determined by 1H NMR spectroscopy. [a]

Figure 2. The difference activation mechanism of TBD, MTBD and DBU/TU.

Figure 3. MALDI-ToF MS spectrum of the BnOH-PSS (Entry7, Table1).

Afterwards, TBD was investigated intensively as the catalyst for ROP of MSS. Polymerization was carried out at room temperature in CH2Cl2 using BnOH as the initiator with the specified initial monomer concentration of [M]0 =0.64 M and catalyst concentration of 5 mol % relative to MSS. The rapid and

controlled polymerization can be realized with different degree of polymerization (DP) from 20 to 100 (Entry 1-3, Table 2; Figure S6, S9, S10). Correspondingly, the molecular weights (Mn) obtained by 1H NMR are very close to the theoretical Mn determined by the [MSS]/[BnOH] molar ratios, while maintaining narrow molecular weight distribution (ÐM=1.17-1.28). Significantly, the TBD catalyst enabled very effective initiation of BnOH, as evidenced by the MALDI-ToF-MS (Figure 3). The Figure 3 is only part of the MALDI-ToF MS spectrum, and the complete spectrum is shown in Figure S11. Obviously, the mass differences between two adjacent peaks were in accord with the molecular weight of the unit, which indicates that a small amount of transesterification is present in TBD/BnOH system.[11, 31, 32] Since MSS is a dimer macrocyclic carbonate, the repeating unit is half of the monomer. Two series of peaks with K+ and Na+ agreed well with the molecular weight of PSS processing the BnOH residual and the hydroxyl chain end.[49, 50] Hence, the preliminary results indicated the remarkable control of TBD-catalyzed ROP of MSS.

Figure 4. (a) Plot of monomer conversion as a function of reaction time with TBD (5 mol% MSS) as the catalyst and BnOH as the initiator ([M]0/[I]0 = 20:1). (b) Plot of ln(M0/Mt]) vs polymerization time for TBD catalyzed, BnOH initiated polymerization Kobs=1.9 h-1. (c) Plot of the number-average molecular weight (Mn) obtained by 1H NMR vs the monomer/initiator. (d) GPC curves with different degrees of polymerization.

To further prove the controllability over polymerization, the ROP kinetics of TBD was investigated. The monomer conversion (calculated by 1H NMR according to the characteristic peaks of the polymer relative to that of the monomer) can be as high as 95% in 80 mins ([M]0/[I]0 =20:1; Figure 4a, Figure S12). Besides, there was a good linear relationship between ln[M0/Mt] vs reaction time (Kobs=1.9 h-1), suggesting that the concentration of growing chains was kept approximately constant during the polymerization (Figure 4b), which was an important feature for living polymerization.[19] In the same manner, Mn increased linearly with monomer conversions with the narrow ÐM (<1.3) (Figure 4c), indicating that the number of macromolecules remained constant during the polymerization. It is worth noting that the Mn values determined by 1H NMR and GPC are discrepant (Figure 4c, Table 2), which is mainly due to the different hydrodynamic volumes of polymers PSS compared with poly(methyl methacrylate) (standards). Polymers PSS with different [M]0/[I]0 ratios (20-100) were also designed and it was found that the molecular weights were linearly increased with the increase of [M]0/[I]0, meanwhile accompanied by the low ÐM (1.17-1.28) (Table 2, Entry 1-3, Figure 4d). Besides, macro-

initiator such as hydrophilic poly(ethylene glycol) (PEG) was used to initiate ROP of MSS to generate A-B diblock (mPEG2000-b-PSS) and A-B-A triblock copolymers (PSS-PEG2000-PSS) with the targeted Mn and narrow ÐM values (~1.20) (Table 2, Entry 4-5, Figure S13-S17), which also exhibited a living polymerization characteristic. Such amphiphilic block copolymers could form nanoparticles or hydrogels for further application in biology and related fields. Both small molecular and macro initiator suggested good initiator efficiency of MSS to generate well-defined polymer structure. Moreover, the thermal analyses are show in Support Information (Figure S18-S19). Table 2. The result of ROP of MSS. Entry

catalyst[a]

initiator

monomer

[M]0/[I]0[b]

time/h

conv. (%)[c]

Mn (KDa) [d]

Mn NMR (KDa) [c]

Mn GPC (KDa)

ÐM

[e]

[e]

1

TBD

BnOH

MSS

20:1

3

95

7.3

6.9

9.3

1.26

2

TBD

BnOH

MSS

50:1

3

93

18.1

16.8

18.6

1.17

3

TBD

BnOH

MSS

100:1

3

93

36.1

33.6

37.2

1.28

4

TBD

mPEG2000

MSS

20:1

3

92

9.2

8.6

10.2

1.21

5

TBD

PEG2000

MSS

20:1

3

91

9.2

8.6

10.4

1.20

6

TBD

BnOH

MSS/TMC

10/40:1

3

87/93

7.8

7.0

9.6

1.38

7

TBD

BnOH

MSS/TMC

25/25:1

3

85/95

11.7

10.2

11.0

1.42

8

TBD

BnOH

MSS/TMC

40/10:1

3

84/87

15.5

13.1

14.8

1.41

9

N-435

BnOH

MSS

20:1

12

94

7.3

6.9

9.1

1.38

10

N-435

BnOH

MSS

50:1

12

93

18.1

16.8

17.2

1.45

11

N-435

BnOH

MSS

100:1

12

93

36.1

33.6

34.4

1.40

12

N-435

mPEG2000

MSS

20:1

12

92

9.2

8.6

9.0

1.46

13

N-435

PEG2000

MSS

20:1

12

90

9.2

8.5

8.9

1.53

14

N-435

BnOH

MSS/TMC

25/25:1

12

90/93

11.6

10.6

10.1

1.68

TBD: The reactions were reacted at R.T. with the specified initial monomer concentration [M]0 =0.64 M, catalyst TBD concentration was 5 mol% to MSS. N-435: The reactions were conducted in anhydrous toluene at 70 °C, MSS/solution (wt/vol, g/mL) = 1:8, catalyst N-435=10% of the weight of MSS. [b] [Monomer]:[initiator]. [c] Conversion and molecular weight (kDa) determined by 1H NMR spectroscopy. [d] Molecular weight (kDa) calculated by the feed ratios. [e] determined in DMF by PMMA calibrated GPC. [a]

We then investigated whether MSS could be copolymerized with other cyclic carbonate monomers in the presence of TBD, in order to expand the versatility of organic catalytic method. Trimethylene carbonate (TMC) was chosen to copolymerize at various molar fractions (20, 50, 80%) at room temperature in CH2Cl2 using BnOH as the initiator. High co-monomer conversions were observed within 3 h and the compositions and Mn values were close to that of the initial co-monomer feed ratio with a relatively low ÐM (~1.4). (Entry 6-8, Table 2, Figure S20) The microstructure was further analyzed by 13C NMR, indicating a random copolymer (Figure S21). The successful copolymerizations with TMC at

various molar fractions with the controlled compositions were significant not only to adjust physicochemical properties but also to tune density and content of disulfide, further tailoring desired reductive responsiveness. Compared with the previously reported enzymic catalytic ROP of macrocyclic carbonates by other researchers and our previous preliminary work about enzymic catalytic ROP of MSS[18, 38, 51], this work may provide a faster and more controlled method for ROP of macrocyclic carbonates. In order to clearly compare the organocatalyst and enzyme (N-435) catalyst for ROP of MSS, we then studied the polymerization conditions and kinetics for enzyme-catalyzed ROP of MSS. Enzyme-catalyzed polymerizations were carried out in anhydrous toluene at 70 °C with 10 wt % lipase CA (relative to MSS). We firstly found that BnOH initiated ROP of MSS requires the longer reaction time (12 h, monomer conversion of >90%) and higher temperature (Entry 9-11, Table 2, Figure S22-S24). Although enzymic catalytic method could also realize the good control over molecular-weight of the resulting polymers, the molecular-weight distributions (ÐM=1.38-1.45) are slightly bigger compared with organic catalytic ROP owing to a few adverse transesterification occurred via enzyme catalysis. This is because the reversible nature of enzymatic reactions results in the bimolecular transesterification, not changing number-average molecular weight (Mn) but increasing weight-average molecular weight (Mw).[52] Similar results were also reported in the enzymic catalytic ROP systems of other macrocyclic carbonates.[26, 53] Enzyme catalytic polymerization kinetics further suggested the above results. The almost complete conversion of MSS (>95%) needed ~12 h, which was quite slow. Similar to organic catalytic ROP, linear plots of ln(M0 /Mt) vs. time (Figure 5a, Figure S25) and Mn values vs. monomer conversion (Figure 5b) were observed during the polymerization, but ÐM (~1.4) became broaden when compared with TBD catalyzed results. More importantly, the apparent rate constant catalyzed by enzyme (Kobs=0.14 h-1) was about 13 times smaller than TBD (Kobs=1.9 h-1), which reflected the slow kinetics of enzyme catalytic polymerization.

Figure 5. (a) Plot of ln(M0/Mt]) vs polymerization time for lipase CA (10 wt% of enzyme to MSS) catalyzed, BnOH initiated polymerization ([M]0/[I]0 = 20:1). (b) Plot of the number-average molecular weight (Mn) obtained by 1H NMR vs the monomer/initiator, Kobs=0.14 h-1.

We then tested poly(ethylene glycol) (PEG) as the macroinitiator for ROP of MSS in the presence of enzyme. Correspondingly, A-B diblock (mPEG2000-b-PSS) and A-B-A triblock copolymers (PSS-PEG2000-PSS) were obtained with Mn values of 9.2 and 8.9 KDa, closing to the expected Mn and larger ÐM values of 1.46 and 1.53, respectively (Entry 12-13, Table 2; Figure S26-S27). Finally, the copolymerization of MSS and TMC at molar fraction of 50% was performed using enzyme as the catalyst and it was found that the composition of the obtained polymers was also approximate to that of the initial feed ratio, generating the random copolymer with Mn values of 10.1 KDa and ÐM values of 1.68 (Entry 14, Table 2; Figure S28S29). It was also clearly observed that the molecular weights (Mn) were well-controlled, but ÐM values became greater than unity at around 1.3, which seemed little control over polymer structures. These results provide a comprehensive indication that organic catalytic ROP of macrocyclic carbonates exhibits higher efficiency (shorter polymerization time), milder condition (room temperature) and more controlled manner (lower molecular-weight distribution), which is very competitive to the current enzyme catalyzed method. Note that because the activation of monomers depends on the preference of enzymes to the hydrophobic substrate instead of the ring-strain, enzyme catalyzed method seems more versatile and common in the ROP of macrocyclic carbonates for a long time. Therefore, we believe this work will provide an alternative strategy to enzymatic catalysis and organic catalytic strategy will be more popular in the ROP of macrocyclic carbonates in the future.

Conclusion In summary, we described the successful organic catalyzed ROP of disulfide functional macrocyclic carbonates (MSS) to generate well-defined main chain functional polycarbonate. Homopolymerization and copolymerization catalyzed by TBD all easily proceeded with excellent control over polymer structure, predictable molecular weights, narrow molecular-weight distributions and controlled copolymer compositions. Polymerization kinetic studies demonstrated the living polymerization characteristics. By further comparison of the polymerization with N-435, TBD exhibited higher efficiency (shorter polymerization time), milder condition (room temperature) and more controlled manner (lower molecular-weight distribution), which provided a robust and new approach toward more facile and efficient ROP of macrocyclic carbonates. We believe that this work not only opens up a window for organic catalyzed ROP of macrocyclic carbonates, which is very competitive to the current enzymatic catalysis, but also provides a new range of useful materials for future biomedical applications.

Experimental Materials: All reactions were performed under the atmosphere of argon, using Schlenk line techniques. Dichloromethane (CH2Cl2) was dried with anhydrous magnesium sulfate (MgSO4) for 48 h, followed by distillation. Toluene was dried over sodium silk, also followed by distillation. Polyethylene glycol monomethyl ether (mPEG, Mn = 2000) and Polyethylene glycol (PEG, Mn = 2000) were dried via azeotropic distillation in anhydrous toluene. DPP (diphenyl phosphate), DBSA (dodecyl benzene sulfonic acid), MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), TU (thiourea), TBD (1,5,7-triazabicyclo[4.4.0] dec-5-ene) and BnOH (benzyl alcohol) were distilled with CaH2 under dry argon. The benzyl alcohol used in the polymerization is a diluted solution in anhydrous toluene and the concentration is 0.5 mmol/mL. Candida antarctica lipase (Novozym-435, N-435) was vacuum dried for 48 h with phosphorus pentoxide (P2O5). All chemicals were purchased from Aladdin and Sigma-Aldrich Chemical Reagents Company and used without purification further stated otherwise. All organic solvents were of analytical-grade products obtained from Aladdin Chemical Reagents Company. Analytical Techniques: Relative number-average molecular weight (Mn) and dispersity index (ÐM) of all polymers were measured by Gel Permeation Chromatography (GPC) with a Waters 1515 equipped with N,N-dimethylformamide (DMF) as the eluent at a flow rate of 1.0 mL min-1 at 50 °C and polymethyl methacrylate (PMMA) as the standard. 1H NMR and 13C NMR experiments were performed on a Bruker Avance 400 and 600 MHz spectrometer at room temperature using deuterated reagents (CDCl3, CD2Cl2) as solvent, and the data were analyzed with MestReNova software. Fourier transform infrared spectrometer (FT-IR) was carried out on a Nicolet 5700 FT-IR spectrometer by KBr sample holder method. Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-ToF-MS) was performed on an AB/SCiex 4800 plus equipped a nitrogen laser emitting at 337 nm and 2,5dihydroxybenzoic acid (DHB) was used as matrices. The spectrum result was recorded in the linear mode. Baseline corrections and data analysis were performed using MassLynx version 4.1 and Polymerix Software, Sierra Analytics, Version 2.0.0.

The synthesis of disulfide functional macrocyclic carbonate (MSS): The macrocarbonate (MSS) was synthesized by the intermolecular cyclization of functional diols (2-hydroxyethyl disulfide) and diphenyl carbonate through our previous method.[38] Briefly, functional diols and diphenyl carbonate (150 mol % of functional diols) were dissolved in dried toluene (concentration of 1/(500−600) g mL−1 was appropriate for high yields). Then, N-435 (10 wt% of the monomer MSS to monomer) was rapidly added and the reaction was carried out at 70 oC for a certain time. After the reaction, N-435 was removed by filtration, and the solvent was evaporated under reduced pressure to get a crude product, which was then washed with cold methanol. The product was then purified by recrystallization from ethyl acetate and n-hexane to afford a white solid in ∼60% yield. 1H

NMR (400 MHz, CDCl3, δ, ppm): 4.38 (t, J=6.8 Hz, 8H), 3.06 (t, J=6.8 Hz, 8H);

13C

NMR (400 MHz, CDCl3, δ, ppm): 154.62, 66.03, 38.08.

The representative ROP of MSS with organocatalysts: The representative example of TBD mediated ROP as follows: MSS (144 mg, 0.4 mmol), benzyl alcohol (40 µL, 0.02 mmol) TBD (2.8 mg, 0.02 mmol), and the dry CH2Cl2 (0.625 mL) were added into a 3 mL vial containing a stir bar. The reaction mixture was stirred at room temperature. After 3 h, the reaction was terminated with acetic acid (~10 μL) and without any treatment to obtain the conversion of monomer, the molecular weight and polydispersity (ÐM) by 1H NMR and GPC, respectively. In addition, the filtered solution was then precipitated in anhydrous diethyl ether and dried in vacuum. White solid polymers, named as PSS (BnOH-PSS), were obtained with a yield about 80 %. The PSS with different degree of polymerization (DP) and macroinitiator were carried out according to the same procedure. Monomer conversion was calculated by the following equation: Monomer conversion (α)=m/(1+m)×100%. When the area integral of the triplet at 3.06 ppm (monomer, CH2SSCH2-) was normalized to 1, the area integral of the triplet at 2.96 ppm (polymer,-CH2SSCH2-) was m. The molecular weight (Mn) calculated by the ratio of the characteristic peak of the polymer repeating unit to the characteristic peak of the initiator. The PSS with different degree of polymerization (DP) and macroinitiator were carried out according to the same procedure. The copolymerization of MSS and TMC with TBD: MSS (180 mg, 0.5 mmol), TMC (51 mg, 0.5 mmol), benzyl alcohol (40 µL, 0.02 mmol), TBD (2.8 mg, 0.02 mmol), and the dry CH2Cl2 (1.56 mL) were added into a 3 mL vial containing a stir bar. The reaction mixture was stirred at room temperature. After 3 h, the reaction was terminated with acetic acid (~10 μL) and precipitated in anhydrous ether (~15 mL) to form transparent viscous products. The obtained product without any treatment was characterized with NMR and GPC instrument. The copolymerization of MSS and TMC with TBD in different degree of polymerization (DP) were carried out according to the same procedure. Polymerization kinetics experiment with TBD: MSS (360 mg, 1 mmol), benzyl alcohol (100 µL, 0.05 mmol) and TBD (7 mg, 0.05 mmol) were added into a 5 mL vial equipped with a stir bar, with the designed degree of polymerization (DP) of 20. Then, ~1.6 mL dry CH2Cl2 was added to initiate

polymerization. The reaction mixture was then stirred at RT. In addition, 200 μL of the solution was taken out from the reaction system for NMR spectroscopy and GPC analysis, at regular intervals. TBD catalytic mechanism study: 1:1 Mixtures of TBD with Benzyl Alcohol: 5 mg (0.036 mmol) TBD , 3.88 mg (0.036 mmol) BnOH and 0.6 mL CD2Cl2 (or CDCl3) were added into a NMR tube and analyzed by 1H NMR and 13C NMR after 3 h of the reaction. 1:1 Mixtures of TBD with monomer: 5 mg (0.036 mmol) TBD , 13 mg (0.036 mmol) MSS and 0.6 mL CD2Cl2 (or CDCl3)were added into a NMR tube and analyzed by 1H NMR and 13C NMR after 3 h of the reaction. The representative ROP of MSS with N-435: Typically, MSS (144 mg, 0.4 mmol) and N-435 (15 mg, 10 wt% of the monomer MSS) were added into a 5 mL vial equipped with a stir bar. Then, benzyl alcohol (40 µL, 0.02 mmol) and anhydrous toluene (~1.2 mL) were introduced via a gastight syringe to initiate the polymerization. The polymerization was stirred at 70 oC for 12 h. The final product was dissolved in ~1 mL of CH2Cl2 and filtered to remove the insoluble N-435. The obtained products dissolved in CH2Cl2 without any treatment, and the conversion of monomer, the molecular weight and polydispersity (ÐM) were analysed by 1H NMR and GPC respectively. The filtered solution was then precipitated in anhydrous diethyl ether and dried in vacuum. White solid polymers, named as PSS (BnOH-PSS), were obtained with a yield about 80 %. The copolymerization with N-435: MSS (180 mg, 0.5 mmol), TMC (51 mg, 0.5 mmol) and N-435 (15 mg, 10 wt% of the monomer MSS) were added into a 5 mL vial equipped with a stir bar. Then, benzyl alcohol (40 µL, 0.02 mmol) and anhydrous toluene (~1.9 mL) were introduced via a gastight syringe to initiate the polymerization. The polymerization was stirred at 70 oC for 12 h. The final product was dissolved in ~1 mL of CH2Cl2 and filtered to remove the insoluble N-435. The obtained products dissolved in CH2Cl2 without any treatment were monitored the conversion of monomer, the molecular weight and polydispersity (ÐM) by 1H NMR, 13C NMR and GPC respectively. The filtered solution was then precipitated in anhydrous diethyl ether and dried in vacuum. Polymerization kinetics experiment with N-435: MSS (360 mg, 1 mmol), benzyl alcohol (100 µL, 0.05 mmol) and N-435 (36 mg) were added into a 5 mL vial equipped with a stir bar, with the designed degree of polymerization (DP) of 20. Then, ~2.9 mL anhydrous toluene was added to initiate the polymerization. The reaction mixture was stirred at 70 oC. In addition, 200 μL of the solution was taken out from the reaction system for NMR spectroscopy and GPC analysis, at regular intervals.

Acknowledgments This research was supported by the National Key Research and Development Program (2016YFC1100703).

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Graphical abstract Organocatalytic ring-opening polymerization of disulfide functional macrocyclic carbonates: an alternative strategy to enzymatic catalysis Bingkun Yan,1 Bingyu Liang,2 Jiaqian Hou,1 Chao Wei,1* Yan Xiao,1 Meidong Lang 1*and Farong Huang 1 1. Key Laboratory of Specially Functional Polymeric Materials and Related Technology of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology. Shanghai, 200237, China; 2. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China *E-mail: [email protected] Corresponding author(s): Meidong Lang ([email protected])

The ROP of disulfide functional macrocyclic carbonate by organocatalysts was reported for the first time with higher effectiveness, milder condition and more controlled manner than enzyme catalyst N-435, which provided a robust and new approach toward more facile ROP of macrocyclic carbonates.

Highlights: 

The successful ring-opening polymerization of disulfide functional macrocyclic carbonates (MSS) expanded ring opening polymerization of macrocycles.



Organic catalyst TBD could effectively activate the ROP of MSS, affording tailor-made disulfide functional aliphatic polycarbonates (APCs) with high end group fidelity, high molecular weight and narrow molecular-weight distribution.



By further comparison of the polymerization, TBD exhibited higher effectiveness, milder condition and more controlled manner than enzyme (N-435), which illustrated that organic catalyzed strategy was indeed an alternative to the current enzymatic and metal catalysis in the ROP of macrocyclic carbonates.

Author Contributions

Bingkun Yan, Meidong Lang and Chao Wei conceived and performed experiments, wrote the manuscript, and secured funding. Bingyu Liang and Jiaqian Hou performed experiments and some characterizations. Yan Xiao provided reagents and experimental instruments. Farong Huang provided expertise and feedback.