Identifying the hydrolysis of COS as side reaction impeding the

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Identifying the hydrolysis of COS as side reaction impeding the polymerization of N-substituted glycine N-thiocarboxyanhydride Botuo Zheng, Tianwen Bai, Xinfeng Tao, Helmut Schlaad, and Jun Ling Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.8b01119 • Publication Date (Web): 26 Sep 2018 Downloaded from http://pubs.acs.org on October 2, 2018

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Biomacromolecules

Identifying the hydrolysis of COS as side reaction impeding the polymerization of N-substituted glycine N-thiocarboxyanhydride Botuo Zheng a, Tianwen Bai a, Xinfeng Tao * a,b,c, Helmut Schlaad d, Jun Ling * a a

MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of

Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China. b

Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine

Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China c

Chimie ParisTech, PSL Université Paris, CNRS, Institut de Recherche de Chimie Paris,

UMR8247, 11 rue Pierre et Marie Curie, Paris 75005, France. d

Institute of Chemistry, University of Potsdam, Karl-Liebknecht-Straße 24-25, 14476 Potsdam,

Germany

ACS Paragon Plus Environment

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Abstract: Polypeptoids are noticeable biological materials due to their versatile properties and various applications in drug delivery, surface modification, self-assembly, etc. N-Substituted glycine N-thiocarboxyanhydrides (NNTAs) are more stable monomers than the corresponding Ncarboxyanhydrides

(NNCAs)

and

enable

to

prepare

polypeptoids

via

ring-opening

polymerization even in the presence of water. However, larger amounts of water (> 10,000 ppm) causes inhibition of the polymerization. Herein, we discover that during polymerization hydrogen sulfide evolves from the hydrolysis of carbonyl sulfide, which is the by-product of ring-opening reaction, and reacts with NNTA to produce cyclic oligopeptoids. The capture of Nethyl ethanethioic acid as an intermediate product confirms the reaction mechanism together with density functional theory quantum computational results. By bubbling the polymerization solution with argon, the side reaction can be suppressed to allow the synthesis of polysarcosine with high molar mass (Mn = 11,200 g/mol, Ð = 1.25) even in the presence of ~10,000 ppm of water.

Keywords: Poly(amino acid)s, Ring-opening polymerization, N-Thiocarboxyanhydrides, Hydrolysis, Hydrogen sulfide


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Biomacromolecules

Introduction Polypeptides have been widely served as biological materials in recent years.1-7 They are composed of α-amino acids8 which have substituted groups on α-carbon. In comparison, polypeptoids, as analogues of polypeptides, consist of different repeating units, i.e., N-substituted glycines. Similar to polypeptides, polypeptoids have good biocompatibility and degradability due to their constitution of α-amino acids. Due to the absence of hydrogen bond between amide groups, polypeptoids are granted with extra advantages including better solubility in various solvents, which greatly boosts their processability.9 Polysarcosine (PSar)10, 11 and poly(N-ethyl glycine) (PNEG) are two typical water-soluble polypeptoids. At merit of their electric neutrality, excellent biocompatibility, nontoxicity and protein resistance, water-soluble polypeptoids, especially PSar, are considered as competent hydrophilic materials to replace poly(ethyl glycol) (PEG)12, 13 in certain fields.14-22 N-Substituted glycine N-carboxyanhydrides (NNCAs) are most widely used monomers to prepare polypeptoids owing to their high reactivity and controllability.23-29 NNCAs as well as αamino acid N-carboxyanhydrides (NCAs) are sensitive to nucleophiles, such as amine, water,30 alcohol,30-32 thiol,27,

33

etc., which can induce the nucleophilic opening of the N-

carboxyanhydride. A number of initiation systems have been developed to carry out the ringopening polymerization (ROP) of NCAs and NNCAs.30, 34-44 Solid phase submonomer synthesis (SPSS) is another efficient approach to synthesize peptoids, which greatly boosted their application in areas beyond drug discovery, e.g., diagnostics, drug delivery, and materials science.22, 45-48 SPSS enables the synthesis of sequence specific peptoids with a limitation around 50 repeat units in reasonable yields. However, the


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synthesis scale is limited by the purification step, and the preparation of long peptoids is timeconsuming and rather inefficient.45 In recent years, our group found that N-substituted glycine N-thiocarboxyanhydrides (NNTAs) are reactive but more stable monomers than NNCAs. Under optimized conditions, primary amines or rare earth borohydrides are able to initiate the controlled ROP of NNTAs (under release of COS instead of CO2) to prepare polypeptoids with high molar masses and low dispersities (Ð).49-52 By using amine-capped polymers as initiators or sequentially feeding NNTA monomers, we synthesized a series of block copolypeptoids.49, 53, 54 Moreover, hydroxyl and thiol groups alone were not able to initiate the polymerization of NNTAs.55,

56

α-Hydroxy-ω-

aminotelechelic and α-thiol-ω-aminotelechelic polypeptoids were prepared with aminoalcohol and cysteamine initiators, respectively.55, 56 The polymerization of NNTAs also showed some tolerance to water57 and unprotected phenolic hydroxyl groups.58 Zhang and coworkers reported that α-amino acid NTAs could be polymerized in a well-controlled way in open air through hexylamine-initiated interfacial ROP.52 These researches provided a handy pathway to prepare poly(amino acid)s. In our previous work, we reported that NNTA was stable in the presence of water even at high temperature.57 The primary amine-initiated ROP of NNTA was found to be tolerant to the presence of small amounts of water (~100-1,000 ppm), but larger amounts of water (> 10,000 ppm) caused inhibition of the polymerization. However, MALDI-ToF mass spectrometry (MS) revealed the existence of exclusively primary amine-initiated polymer chains and none with other end groups. In this contribution, we investigate in detail the role of water during the polymerization of NNTAs. We reveal that hydrogen sulfide (H2S), which is produced through hydrolysis of


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Biomacromolecules

carbonyl sulfide (COS), is responsible for the suppression of yields and molar masses of the obtained products. Experimental studies are supported by density functional theory (DFT) calculations.

Experimental Section Materials. Sarcosine (Sar, 98%, Energy Chemical, China), glyoxylic acid (50 wt % aqueous solution, Energy Chemical, China), ethylamine (50 wt % aqueous solution, Energy Chemical, China), acetonitrile (ACN, 99.9%, extra dry, Energy Chemical, China), ferrous sulfide (FeS, 60.0-72.0%, Energy Chemical, China), phosphorus tribromide (99%, Energy Chemical, China), sodium hydrosulfide hydrate (pure, Acros), butylamine (99.5%, J&K), trioxane (99.5%, Acros) were used as received. Benzylamine were stirred over CaH2 and followed by distillation under reduced pressure. All water was purified by a Millipore Milli-Q system and subsequently bubbled with argon to expel air. Tetrahydrofuran (THF, AR, Sinopharm Chemical Reagent, China) was refluxed over potassium/benzophenone ketyl before use. N-Ethylglycine (NEG), Nbutylglycine (NBG), Sar-NTA, NEG-NTA, and NBG-NTA were synthesized according to procedures reported in our previous work.49, 50 Homopolymerization. Polymerizations were performed using the Schlenk technique, and all polymerization tubes were flamed dried and purged with argon. Sar-NTA (0.4572 g, 3.486 mmol) was dissolved in 6.0 mL of dry ACN, followed by the addition of 0.87 mL of a mixture of 0.2 M benzylamine and 0.27 M water in ACN. The tube was sealed and heated in a 60 °C oil bath for 24 h. The polymer product precipitated from solution by adding diethyl ether. After centrifugation, the precipitation and the supernatant fraction were separated and dried under vacuum respectively. (0.236 g, yield 89%)


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Random copolymerization. NEG-NTA (0.3451 g, 2.377 mmol) and NBG-NTA (0.6179 g, 3.567 mmol) were dissolved in 5 mL of THF (as received), followed by the addition of 0.32 mL of 0.37 M benzylamine in THF solution. The tube was sealed and heated in a 60 °C oil bath for 48 h. The polymer product was precipitated into diethyl ether and dried under vacuum (0.490 g, yield 79%). Polymerization bubbled with argon. The feeding part followed the procedure described above. After all the substances were added and the tube was sealed and placed in 60 °C oil bath, the solution was bubbled by argon through a needle with a pressure of 770 mmHg during the polymerization for 24 h. The expelled gas was collected by a balloon. The balloon was changed every 8 hours. The polymer product was then precipitated from the solution and dried under vacuum. Degradation of NNTA by H2S. NEG-NTA (0.3767 g, 2.595 mmol) was dissolved in 4.7 mL of dry THF, to which were added 0.77 mL of 1.117 M trioxane in THF solution. A small amount of the solution was taken for 1H-NMR analysis. H2S was prepared by adding a concentrated HCl solution dropwise to ferrous sulfide. The evolved H2S gas was purified and dried by passing through saturated sodium hydrosulfide solution, molecular sieve, and anhydrous calcium chloride in sequence. After NEG-NTA solution was bubbled by H2S for 5 minutes, the tube was sealed and placed in a 60 °C oil bath for 24 h. Another drop of the solution was taken for 1HNMR analysis. The conversion of NEG-NTA and the yield of 1,4-diethylpiperazine-2,5-dione (DEP) were calculated from relative integral of methylene proton signals of NEG-NTA and DEP with respect to the one of trioxane. DFT calculation details. All geometries of intermediates and transition states (TSs) were optimized under tight criteria using B3LYP/6-31G(d,p) method. Frequency calculations


6

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Biomacromolecules

confirmed the intermediates and TSs had zero and one imaginary frequency, respectively. Reaction pathway for each TS was checked by intrinsic reaction coordinate (IRC). Thermal correction to Gibbs free energies was obtained at 298.2 K and 1.013×105 Pa. All calculations were carried out using Gaussian 09 program.59 Characterization. Nuclear magnetic resonance (NMR) spectra were collected on a Bruker Avance DMX 400 spectrometer (1H: 400 MHz and 13C: 100 MHz). CDCl3 and DMSO-d6 were used as solvent and tetramethylsilane (TMS) served as internal reference. Matrix-assisted laser desorption ionization-time of flight (MALDI-ToF) mass spectra were recorded on a Bruker UltraFLEX MALDI-ToF mass spectrometer in the reflector mode or linear mode with 2,5dihydroxybenzoic acid (DHB) as the matrix and potassium trifluoroacetate as the cationic agent. Size exclusion chromatography (SEC) instrument consisted of a Wyatt series 1500 HPLC pump, a Wyatt Opitlab T-rEX interferometric refractometer (RI), and two MZ-Gel SDPlus columns 102 Å and 104 Å (particle size: 10 µm). N,N-Dimethylformamide (DMF) containing 0.05 M LiBr and 2‰ triethylamine was used as the eluent at a flow rate of 0.8 mL/min; column temperature was set to 50 °C. Polystyrene standards were used for calibration. Electrospray ionization mass spectra (ESI-MS) were recorded on a LCD Deca XP Max ion trap mass spectrometer with APCI ion source. Moisture analyses were done by Karl-Fischer titrations with an 831 KF Coulometer (Metrohm China Ltd).

Result and Discussion Polymerization of NNTAs in the Presence of Water. We firstly carried out the polymerizations of Sar-NTA in ACN initiated by benzylamine (Scheme 1) in the presence of water (Table 1, Entries 2-6 and Figure 1). The results confirmed


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the reported conclusion57 that the yields and molar masses (number-average molar mass, Mn) slightly decreased when water was present at the same amount of the initiator (~100-600 ppm) and further decreased when water was present at the amount of monomer (~13,100 ppm).

Table 1. Polymerization of NNTAs Initiated by Benzylamine in the Presence of Water a

cwaterb (ppm)

Bubbling with argonc

Yield (%)

ntheod

Mn SECg Đ g (kg/mol) SEC

Entry

Monomer

[M]0/[I]0/ [H2O]0

1

Sar-NTA

20/1/0

-

No

92

18

21

21

4.3

1.09

2

Sar-NTA

20/1/1

600

No

89

18

19

21

4.2

1.13

3

Sar-NTA

49/1/1

220

No

80

39

50

36

6.8

1.16

4

Sar-NTA

97/1/1

100

No

82

80

82

-

8.7

1.20

5

Sar-NTA

20/1/10

5,500

No

77

15

19

15

3.0

1.18

6

Sar-NTA

20/1/23

13,100

No

75

15

19

15

3.2

1.16

7

Sar-NTA

105/1/101

9,700

Yes

79

83

107

-

11.2

1.25

8

Sar-NTA

99/1/256

29,200

Yes

48

48

75

-

7.4

1.27

9

NEG-NTA

20/1/0

-

No

96

19

21

22

5.4

1.12

10

NEG-NTA

No

41

8

16

8

2.5.

1.20

11

NEG-NTA

20/1/20

11,400

Yes

89

18

22

17

4.4

1.16

12

NEG-NTA

20/1/60

29,500

Yes

70

14

15

15

3.2

1.15

13

NEG-NTA

100/1/100 10,000

Yes

85

85

52

-

6.9

1.34

14h

NEG-NTA

20/1/0.9

190

No

89

18

21

22

4.7

1.18

15h

Sar-NTA

200/1/10.5

230

No

94

188

167

-

13.1

1.14

16h

NEG-NTA +NBG-NTA

50/1/2.5i

220

No

79

40

47

-

15.5

1.12

20/1/22.5 14,000

nNMRe nMSf

a

Polymerization conditions: [M]0 = 0.5 mol/L, 24 h at 60 °C in THF (NEG-NTA and NBGNTA) and acetonitrile (Sar-NTA). b Concentration of water. c The solution was bubbled with argon during polymerization. d Theoretical number-average degree of polymerization, ntheo = [M]0/[I]0 × yield. e Determined by 1H-NMR spectroscopy. f Determined by MALDI-ToF mass spectrometry. g Determined by SEC. h Commercial solvents are used, the concentration of water was determined by moisture analysis. i The feed ratio was [NEG-NTA]0/[NBGNTA]0/[I]0=20/30/1.


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Biomacromolecules

Figure 1. SEC traces of PSar samples (Entries 2-6 in Table 1). Although the yield of polymer decreased with the increasing amount of water, quantitative monomer conversion was found for [NH2]0/[H2O]0/[NEG-NTA]0 = 1/1.08/20 (Entry 17 in Table 2) after 24 h, by 1H-NMR analysis. Addition of second and third batches of NEG-NTA resulted in a further increase of molar mass (Entries 18 and 19 in Table 2) without obvious broadened polydispersity and appearance of multi-peaks, as evidenced by MALDI-ToF MS (Figure 2) and SEC traces (Figure S1), indicating that most the polymer chains were still active after the monomer was consumed and able to continue propagating. Although water was added to the system only at the beginning, the molar masses of the second and third blocks deviate from the feed ratios, which indicated that the suppression effect existed during the whole polymerization. Therefore, these results strongly suggested the existence of another side reaction accounting for the competitive consumption of monomer leading to the suppression of molar masses and yields.


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Table 2. Polymerization of NEG-NTA in the presence of water by multistep-feeding a

Mn MS d

Yield

/[M2]0/[M3]0

cwaterb (ppm)

17

1/1.08/20/0/0

220

57

18

1.5

1.15

18

1/1.08/20/18/0

220

64

30

2.3

1.17

19

1/1.08/20/17/25

220

68

42

2.9

1.15

Entry

[I]0/[H2O]0/[M1]0

(%)

nNMRc

(kg/mol)

ĐSECe

a

Polymerization conditions: [M]0 = 0.5 M, 24 h for every batch added at 60 °C with THF as solvent. b Concentration of water. c Number-average degree of polymerization, determined by 1 H-NMR spectroscopy. d Number-average molar mass, Mn MS. e Determined by SEC.

Figure 2. MALDI-ToF mass spectra of PNEGs (Entries 17-19 in Table 2). Investigation of Side Reaction.


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Biomacromolecules

To reveal the side reaction induced by water during the polymerization of NEG-NTA, we separated the polymers from the reaction solution by precipitation in diethyl ether. The supernatant was concentrated under vacuum to give a light pink solid. Its 1H- and

13

C-NMR

(Figure S2) and ESI mass spectra (Figure S3) identified the major side reaction products as 1,4diethylpiperazine-2,5-dione (DEP)60 and cyclic oligoNEG trimer. Note that a similar substance, i.e., 1,4-diallylpiperazine-2,5-dione, was also produced during the distillation of N-allyl glycineNCA.61 ESI mass spectra of the precipitated polymers (Figure S4) also revealed the presence of larger oligoNEG cycles with 4-5 units. Since water and the released COS (by-product during the polymerization of NNTA) themselves cannot react with NNTA, we thought that H2S generated from a hydrolysis of carbonyl sulfide62 could be responsible for the transformation of NNTA to DEP or cyclic oligoNEG (Scheme 1). Therefore, a THF solution of NEG-NTA was bubbled with dry H2S for 5 minutes. After that, the reaction ampoule was sealed and heated to 60 °C in an oil bath for 24 h. A small amount of acicular crystal precipitated from the solution. By comparing the 1H-NMR methylene signals of NEG-NTA and trioxane (TOX, serving as an internal standard) of the solution before and after the reaction (Figure 3), it was found that NEG-NTA was consumed and DEP formed. The precipitated acicular crystal was also isolated and characterized by 1H-NMR (Figure S5A),

13

C-NMR (Figure S5B) and ESI-MS (Figure S6) and identified it as N-ethyl

ethanethioic acid (EEA). The conversion of EEA to DEP in DMSO-d6 at 60 °C (Figure S7) indicated its identity as the intermediate of side reaction leading to DEP.


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Scheme 1. Reactions during ROP of NNTA in the presence of water: polymerization of NNTA (A), hydrolysis of COS by-product to form H2S, reaction of H2S with NEG-NTA (1) to produce N-ethyl ethanethionic acid (EEA, 2 and 3) (B), and formation of 1,4-diethylpiperazine-2,5-dione (DEP, 4) and cyclic oligoNEG (5) (C).


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Biomacromolecules

Figure 3. 1H-NMR (400 MHz) spectra of the THF solution of NEG-NTA before (B) and after (A) bubbling with H2S (TOX = trioxane, ** = H2O, * = DMSO, \\ = THF). According to the reaction mechanism depicted in Scheme 1, H2S is generated from the hydrolysis of COS, which then reacts with NNTA and induces its decomposition to EEA (compound 2 in Scheme 1B). The zwitterionic form of EEA (3) may be insoluble and precipitate from THF solution. From EEA, the cyclic species DEP (4) or larger cyclic oligomers (5) (Figure S3) are formed. However, this side reaction can well explain why the polymerization of NNTAs is limited to the synthesis of polypeptoids with ~200 repeat units.49 When the feed ratio is above 200, the concentration of initiator is too low and competes with the remaining few moisture and H2S evolution. Density functional theory calculations. Density functional theory (DFT) calculations were carried out to clarify the mechanism of side reactions (Figure 4). After the above-mentioned decomposition of NNTA induced by H2S, the


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formation of DEP from EEA consists of three major steps: a) condensation between EEA pair, b) intramolecular carbonyl addition, and c) desulfhydrylation. The self-condensation reaction of two molecules of EEA starts with the nucleophilic attack of the amine towards the thiocarboxylic acid group. The intramolecular carbonyl addition and desulfhydrylation step can be exchanged during the formation of DEP theoretically, leading to two paralleled reaction routes (Figure 4). DFT calculation reveals the Gibbs free energy barriers of 33.68 (TS2) and 17.94 kcal/mol (TS3) in the desulfhydrylation and carbonyl addition routes, respectively. The release of H2S is favored due to the reduced steric hindrance. After commutable intramolecular carbonyl addition and desulfhydrylation steps, DEP was produced with relative stable energy barrier (-39.97 kcal/mol). According to DFT calculations, the rate determining step in the three steps is the condensation between EEA pairs with 37.54 kcal/mol (TS1), leading to a preference of dimer structure without further condensation. Two equivalents of H2S are released so that it serves as a catalyst ready to decompose the remaining NNTA monomers.

Figure 4. DFT calculations of potential energy surface of side reaction mechanism with relative Gibbs free energy values of intermediates and transition states (TS).


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Biomacromolecules

Suppressing the Side Reaction. To suppress the side reaction induced by hydrogen sulfide, we bubbled the reaction solution with argon during polymerization. In this way, the dissolved COS and H2S were expelled by argon. The polymerization of NEG-NTA in the presence of large amount of water (>10,000 ppm, Entry 10), was greatly suppressed compared to the one in anhydrous condition (Entry 9), leading to the dramatic loss of yields (96% to 41%) and molar masses (Mn SEC, 5.4 kg/mol to 2.1 kg/mol) (Figure S8). As the solution was bubbled with argon (Entry 11), the polymerization of NEGNTA resulted in high yield (89%) and relatively good controllability of molar mass with low dispersity (Ð = 1.16) (Figure S8), i.e., very close to the results obtained for the polymerization under anhydrous conditions (Table 1, Entry 9). It also showed a good result when the [NEG]0/[I]0 increased to 100 with cwater = 10,000 ppm in the case of bubbling argon (Entry 13), giving PNEG (nNMR = 52, Mn SEC = 6.9 kg/mol) with a high yield (85%) and moderate dispersity (Ð = 1.34).We also applied this method to the polymerization of Sar-NTA (cwater ~10,000 ppm), and the Sar-NTA could be converted into high molar mass PSar (nNMR = 107, Mn SEC = 11.2 kg.mol) (Entry 7 in Table 1, Figure S8) with a reasonable yield (79%) and low dispersity (Ð = 1.25). As the concentration of water was increased to ~30,000 ppm (which is far above the usual water content in commercial solvents of

Identifying the hydrolysis of COS as side reaction impeding the

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