Trimethyl Glycine as an Environmentally Benign and Biocompatible

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Trimethyl Glycine as an Environmentally-Benign and Biocompatible Organocatalyst for Ring-Opening Polymerization of Cyclic Carbonate Tatsuya Saito, Kaoru Takojima, Takafumi Oyama, Shintaro Hatanaka, Takashi Konno, Takuya Yamamoto, Kenji Tajima, Takuya Isono, and Toshifumi Satoh ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.9b00884 • Publication Date (Web): 04 Apr 2019 Downloaded from http://pubs.acs.org on April 7, 2019

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ACS Sustainable Chemistry & Engineering

Trimethyl Glycine as an Environmentally-Benign and Biocompatible Organocatalyst for Ring-Opening Polymerization of Cyclic Carbonate

Tatsuya Saito†, Kaoru Takojima†, Takafumi Oyama†, Shintaro Hatanaka‡, Takashi Konno‡, Takuya Yamamoto§, Kenji Tajima§, Takuya Isono§*, Toshifumi Satoh§*

†

Graduate School of Chemical Sciences and Engineering, Hokkaido University, N13W8, Kita-ku, Sapporo, 060-8628, Japan ‡

R&D Center, Organic Chemical Products Company, Daicel Corporation, Higashisakae 2-chome, Otake-shi, Hiroshima, 739-0695, Japan §

Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, N13W8, Kita-ku, Sapporo, 060-8628, Japan

E-mail: [email protected] [email protected]

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Abstract Trimethyl glycine (TMG), a natural product found in plants as well as in humans, was demonstrated to be an efficient catalyst for the ring-opening polymerization (ROP) of cyclic carbonate, enabling the environmentally-benign synthesis of aliphatic polycarbonate (APC). The ROP of trimethylene carbonate (TMC) using TMG proceeded under the bulk condition at 70 °C to give poly(trimethylene carbonate) possessing controlled molecular weight (~4,000) and low dispersity (~1.22). The results of a matrix-assisted laser desorption/ionization time-of-flight mass spectral analysis and a chain extension experiment confirmed the controlled/living nature of the present ROP system, where side reactions, such as inter- and intra-molecular transesterifications, were minimized during the polymerization. The screening of TMG analogues as a catalyst for ROP revealed that the combination of the carboxylate and quaternary ammonium moieties in TMG is an essential structural requirement. The FT-IR analyses of TMC and alcohol initiator in the presence/absence of TMG confirmed the bi-activation property of the TMG. End-functionalized APCs were obtained using alcohol initiators bearing clickable functionalities, such as azido and ethynyl groups. Furthermore, we demonstrated the synthesis of APC-diol and -triol, which can be used as a prepolymers for APC-based polyurethane.

Keywords: poly(trimethylene carbonate), biodegradable polymer, aliphatic polycarbonate, metalfree synthesis, controlled/living polymerization. 2 ACS Paragon Plus Environment

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Introduction Aliphatic polycarbonates (APCs) were first prepared by Carothers and Natta in the 1930s,1 and they have since been industrially utilized as raw materials for the synthesis of APC-based polyurethane (APC-PU), which is used in making artificial leather, adhesive agents, and as thermoplastic/thermosetting elastomers.2,3 In addition to such classical usages, in recent years, there has been an increasing demand for APCs for biomedical and environmental purposes, such as in drug/gene delivery systems, tissue/bone engineering, and biodegradable elastomers, owing to their biodegradability, biocompatibility, and low toxicity.4,5 APCs have been industrially synthesized via the polycondensation of aliphatic diols with phosgene or dialkyl carbonates. However, in the polycondensation method, the molecular weight and dispersity cannot be controlled. On the other hand, the ring-opening polymerization (ROP) of cyclic carbonates can help obtain APCs possessing controlled molecular weight and low dispersity with sufficient chain-end fidelity. Additionally, cyclic carbonates can be attained from renewable resources such as carbon dioxide and aliphatic diol.6,7 Therefore, the ROP method offers considerable advantages for both conventional and future APCbased materials syntheses. For the APC production, metal-based catalysts, particularly Sn-based catalysts, have been widely used in both polycondensation and ROP approaches.2,8 However, the potential toxicity of the metal catalyst residues in the resulting APCs is a concern when it comes to their biomedical and environmental applications. Therefore, an alternative approach to produce APCs free from metal 3 ACS Paragon Plus Environment


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contamination has been highly desired. To this end, an organocatalytic ROP has been developed as a metal-free approach for APC synthesis in the last decade.5,9-11 To date, organic acids12,13 and bases14,15 as well as bifunctional catalysts have been found to be effective for the ROP of cyclic carbonates.1621

In general, acidic and basic catalysts promote the ROP by activating the carbonyl group on the

monomer and hydroxyl group of the initiating/propagating chain end, respectively. In contrast, bifunctional catalysts simultaneously activate both the monomer and the chain end. For instance, Waymouth and Hedrick have developed a thiourea/amine catalytic system for the ROP of trimethylene carbonate (TMC), wherein the thiourea group activates the monomer, and the tertiary amine group activates the initiating/propagating chain end.14 Our group also reported the ROP of cyclic carbonates using diphenyl phosphate as a bifunctional catalyst.16 More recently, Guo et al. revealed the bi-activation property of guanidine-Brønsted acids adducts, which activate the monomer and chain end with the cationic and anionic parts, respectively.21 Such bi-activation properties help realize sufficient catalytic activity despite their relatively mild character. In general, the organocatalytic ROP of cyclic carbonates can be implemented in a mild reaction condition (typically in a solution at room temperature) to obtain well-defined APCs possessing targeted molecular weight and relatively low dispersity with high chain-end fidelity. Owing to these advantages, organocatalysts have been employed instead of conventional metal-based catalysts for laboratory-scale APC syntheses. However, this approach still has many drawbacks, particularly in terms of mass production. Organocatalysts intended for ROP are expensive compared with conventional metal-based catalysts 4 ACS Paragon Plus Environment

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and sometimes require multistep reactions to prepare from commercially available reagents, resulting in higher production cost. For industrial manufacturing, a readily available catalyst that can be used in the bulk condition is highly preferred. Apart from the economic viewpoint, the risk in using organocatalysts needs to be considered, because the catalyst residue in industrial-scale production is sometimes not removed. In fact, some recent works revealed the significant cytotoxicity in some of organocatalysts.22,23 Therefore, “organocatalyst” does not necessarily mean that the catalyst is nontoxic. For an environmentally-benign and practical APC synthesis via the ROP approach, we focused on trimethyl glycine (TMG), which is a zwitterionic compound existing in plants as well as in humans,24,25 as an appropriate candidate for the ROP catalyst. TMG possesses a quaternary ammonium cation and carboxylate anion, indicating its potential to exhibit bi-activation ability. The catalytic ability of TMG has been already revealed in organic reactions, such as the hydrosilylation of carbon dioxide with amine,26,27 which motivated us to apply TMG to polymer synthesis. In addition to its attractive chemical structure, TMG is safe and environmentally friendly. We intake TMG on a daily basis from food, and it is generated in the human body as a metabolite of the nutrient choline.24 Additionally, the European Food Safety Authority Panel reported that 6 mg/kg/day of TMG is acceptable for adults in addition to the daily ingestion from TMG- and choline-containing food,25 supporting the biomedical application of TMG-synthesized APC materials. Furthermore, TMG is commercially available and its major source is beets, which ensures the sustainable characteristic of 5 ACS Paragon Plus Environment


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TMG. Therefore, TMG has significant potential as a clean and environmentally-benign catalyst to achieve sustainable APC production. Herein, we report a novel ROP system of TMC using TMG as an environmentally-benign and biocompatible catalyst to obtain APCs possessing predictable molecular weight and low dispersity with desired end-group structures (Scheme 1).

Scheme 1. Trimethyl glycine-catalyzed ROP of cyclic carbonate


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Result and Discussion Ring-opening Polymerization of Trimethylene Carbonate Using Trimethyl Glycine as a Catalyst. To evaluate the catalytic ability of TMG, the ROP of trimethylene carbonate (TMC) was conducted with 3-phenyl-1-propanol (PPA) as an alcohol initiator at an initial [TMC]0/[PPA]0/[TMG] ratio of 50/1/0.1 at 70 ºC in the bulk (run 1 in Table 1). After 30 min, the monomer conversion reached 75%, indicating that TMG efficiently promoted the ROP of TMC. From the 1H NMR spectrum of the obtained poly(trimethylene carbonate) (PTMC), the signals due to the main chain of PTMC along with minor signals due to 3-phenyl-1-propoxy group are observed (Figure 1 (a)), implying that TMG and PPA worked as a catalyst and an initiator, respectively, in the ROP system. In addition, the peak area for the signal due to the benzylic protons of the 3-phenyl-1-propanyl group (a in Figure 1(a)) is comparable to that of the methylene protons adjacent to the ω-chain end hydroxyl group (g in Figure 1(a)), indicating a good chain-end fidelity (Figure S1). It is noteworthy that the ether linkage formation through the decarboxylation, which is a major side reaction in the ROP of cyclic carbonates, is not observed in the 1H NMR spectrum. The molecular weight determined from the 1H NMR measurement (Mn,NMR) was 3,900, which is in good agreement with the theoretical value (Mn,th.) of 4,000 calculated from the initial [TMC]0/[PPA]0 ratio and the monomer conversion. The size exclusion column chromatography (SEC) trace of the obtained PTMC is monomodal and the molecular weight (Mn,SEC) and dispersity (Ð) values are 3,700 and 1.12, respectively (Figure 1(b)). These results confirm that TMG undoubtedly has a catalytic ability for the bulk ROP of cyclic 7 ACS Paragon Plus Environment


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carbonate with good control over the molecular weight and dispersity.

Table 1. Bulk ROP of TMC using TMG as a catalyst a run

[TMC]0/[PPA]0/[TMG]

time (min)

conv. (%) b

Mn,th. c

Mn,NMR b

Mn,SEC d

Ðd

1 2 3

50/1/0.1 25/1/0.1 15/1/0.1

30 20 15

75 78 70

4,000 2,100 1,200

3,900 2,100 1,300

3,700 1,800 1,000

1.12 1.13 1.22

a

Polymerization conditions: atmosphere, Ar; temp., 70 °C. b Determined from 1H NMR spectrum recorded in CDCl3. c Calculated from [monomer]0/[PPA]0 × conv. × (M.W. of monomer) + (M.W. of PPA). d Determined by SEC measurement of the obtained polymer in THF using PSt standards. The Mn,SECs are calculated using the correcting factor of 0.56 28

Ð = 1.12

Figure 1 (a) 1H NMR spectrum (recorded in CDCl3; the asterisk indicates water) and (b) SEC trace (eluent, THF; flow rate, 1.0 mL min−1) of the PTMC obtained from run 1 in Table 1.

To access the detailed structural information of the obtained PTMC, a matrix-assisted laser desorption/ionization time-of-flight mass spectral (MALDI-TOF MS) analysis was conducted on the PTMC obtained from run 1. In the MALDI-TOF MS spectrum (Figure 2), a series of repeated peaks with ca. 102 Da intervals is observed in the range of 2000–5000 Da, which once again confirms that 8 ACS Paragon Plus Environment

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the ROP proceeded to give PTMC without decarboxylation. The peak appearing at m/z of 3015.97 can be closely matched with the calculated molecular weight of 28-mer of PTMC possessing a 3phenyl-1-propoxy group and a hydroxyl group at the α and ω chain ends, respectively ([M+Na]+ = 3016.97 Da), suggesting the initiation reaction from PPA. Furthermore, there are no evidence of intramolecular transesterification that could lead to cyclic oligomer formation. Therefore, the ROP proceeded with high selectivity for the initiation/propagation reaction relative to the undesirable side reactions to give PTMC possessing well-defined structure.

Figure 2. (a) MALDI-TOF MS spectrum of the obtained PTMC, (b) expanded spectrum ranging from 2900 to 3150, and (c) theoretical molecular weights.

Next, we conducted the ROP of TMC by varying the initial monomer-to-initiator ratio to control the molecular weight of the resulting PTMC. Here, we targeted low molecular weight PTMCs 9 ACS Paragon Plus Environment


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because the APC is mostly used as a raw material for polyurethane synthesis, where low molecular weight APC (ca. ~5,000) is required as the soft segment.3,

29-32

The ROP of TMC at a

[TMC]0/[PPA]0/[TMG] ratio of 25/1/0.1 gave a PTMC with an Mn,NMR of 2,100 in 20 min (run 2 in Table 1). The monomodal SEC trace of the obtained PTMC appears in the low molecular weight region compared with that of run 1 (Figure S2), and the Mn,SEC and Ð values are determined as 1,800 and 1.13, respectively. In addition, a lower molecular weight PTMC (Mn,NMR = 1,300, Mn,SEC = 1,000, and Ð = 1.22) was also obtained from the ROP of TMC at a [TMC]0/[PPA]0/[TMG] ratio of 15/1/0.1 (run 3 in Table 1). Thus, we controlled the molecular weight of PTMC while maintaining its low dispersity.


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Controlled/living Nature of the Present ROP System To investigate the polymerization behavior of the present ROP system, we analyzed the molecular weight and dispersity of the resulting PTMC as a function of the monomer conversion. During the polymerization, the monomer conversion increased over the reaction time (Figure S3). As shown in Figure 3(a), Mn,NMRs (○) linearly increases with the increase in monomer conversion, which is in good agreement with Mn,th. (dashed line). More importantly, the Ð value remains largely constant narrow (~1.3) throughout the polymerization. In addition, the SEC trace shifts to a higher molecular weight region with the increase in monomer conversion while maintaining the monomodal distribution (Figure 3(b)). A shoulder peak in the higher molecular weight region appears in the SEC trace when the monomer conversion is > 98% (Figure S4). This suggests that side reaction, such as inter-molecular transesterification, become more pronounced when the monomer conversion is high. To avoid such a side reaction and to obtain narrowly dispersed PTMC, the polymerization should be terminated when the monomer conversion rate is in the range of 70 – 80%.



Ð

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Figure 3. Kinetic analysis of the TMG-catalyzed ROP of TMC at the [TMC]0/[PPA]0/[TMG] ratio of 50/1/0.1 in the bulk. (a) Plot of Mn,NMR (○), Mn,th. (dashed line), and Ð (●) versus monomer conversion. (b) SEC traces of the resulting PTMC obtained at each stage of polymerization.

To confirm the living characteristic of the propagating chain end, a chain extension experiment was then carried out. The first polymerization of TMC was conducted at a [TMC]0/[PPA]0/[TMG] ratio of 25/1/0.1 at 70 ºC in the bulk. After the monomer conversion reached 83%, 25 eq. of TMC with respect to the initiator was added to the reacting mixture to start the second polymerization. After the second addition of TMC, the total monomer conversion reached 73%. The SEC trace of the final product shifts to a higher molecular weight region compared with that of the PTMC obtained from the first polymerization (Figure S5), clearly demonstrating that the second polymerization was initiated from the hydroxyl group of the PTMC propagating chain end. This strongly suggests that the propagating chain-end retains the living characteristic during the polymerization.


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Scope of Monomer We conducted the ROP of L-lactide (L-LA) and ε-caprolactone (CL) using TMG to evaluate the catalytic activity for the ROP of various cyclic esters (runs S1 and S2 in Table S1). The bulk ROP of L-LA with higher catalyst loading ([L-LA]0/[PPA]0/[TMG] = 50/1/1) at 100 °C proceeded to reach a conversion rate of 70% in 50 h, while the reaction mixture gradually turned brown during the ROP. The SEC trace of the obtained poly(L-lactide) (PLLA) is monomodal, and the Mn,SEC and Ð values are 6,000 and 1.09, respectively (Figure S6). This indicates the catalytic activity of TMG toward the ROP of L-LA, albeit the obtained PLLA was brown in color. The bulk ROP of CL was also examined with higher catalyst loading ([CL]0/[PPA]0/[TMG] = 50/1/1) at 100 ºC. However, the monomer conversion rate did not increase even after 24 h. A similar polymerization property was observed with the ROP using alkali metal carboxylates, which efficiently promote the ROP of lactide and TMC but have no catalytic ability toward the ROP of 6- and 7-membered lactones. 33

Structure-Activity Relationship of TMG Analogues We examined the catalytic ability of TMG analogues, such as tetramethylammonium acetate (TMAA), trimethylglycine hydrochloride (TMG-HCl), and N,N-dimethylglycine (DMG), to gain insight into the correlation between the catalyst structure and ability. The polymerizations with the TMG analogues were conducted under the same reaction conditions as in run 1 listed in Table 1. The TMG analogues were found to catalyze the ROP of TMC to give PTMC within 6 h (runs S3–S5 in 13 ACS Paragon Plus Environment


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Table S1) with good control over the molecular weight and dispersity. The SEC traces of the obtained PTMCs exhibit monodispersity, and their Ð values remain largely constant (1.13 for the PTMC obtained by TMAA and 1.12 for the PTMCs obtained by TMG-HCl and DMG). Note that the ROP did not proceed in the absence of the catalyst (run S6 in Table S1), demonstrating that all the TMG analogues promoted the ROP of TMC. As for the reaction rate, the ROP using TMAA shows the highest turnover frequency (TOF; 4,400 h−1), with the monomer conversion rate reaching 75% in 5 min (Figure 4). On the other hand, the ROP using TMG-HCl and DMG proceeded slowly, exhibiting lower TOF values than TMMA and TMG (TOF = 115 h−1 for TMG-HCl, and 62.5 h−1 for DMG). This shows that the combination of carboxylate anions and quaternary ammonium cations is essential to attain a good catalytic performance.

time; 30 min, conv. = 75% TOF = 750 h-1

time; 5 min, conv. = 75% TOF = 4,400 h-1

time; 6 h, conv. = 75% TOF = 62.5 h-1

time; 3 h, conv. = 69% TOF = 115 h-1

Figure 4. Catalytic performance of TMG and TMG analogues for the ROP of TMC.


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Polymerization Mechanism To reveal the catalytic mechanism of the ROP system, Fourier-transform infrared spectroscopy (FT-IR) measurements were conducted on TMC and PPA in the presence of an equimolar amount of TMG at 70 ºC (Figure 5). In the FT-IR spectrum of the mixture of TMC and TMG, the absorption peak due to the C=O stretching vibration of TMC shifts to a lower wavenumber region compared with that of TMC alone (Figure 5(a)), indicating the activation of the carbonyl group on TMC by TMG. Similarly, the FT-IR analysis of the mixture of PPA and TMG shows that TMG efficiently activated the hydroxyl group of the initiator and the propagating chain end, as evidenced by the broadening of the absorption peak due to the OH stretching vibration toward the lower wavenumber region after the addition of TMG (Figure 5(b)).33,34 Therefore, TMG catalyzed the ROP of TMC by activating both the monomer and initiator/propagating chain end, as shown in Figure 5(c),33-37 which is responsible for the outstanding catalytic ability of TMG even under relatively low catalyst loading. Additionally, a similar experiment was performed using DMG, which has lower TOF than TMG. As expected, only minor peak shifts are observed in the OH and C=O stretching vibration upon the addition of DMG to PPA and TMC, respectively (Figure S7). which again confirms that TMG is an efficient catalyst for the ROP of TMC via a bi-activation mechanism. To gain more insight of the polymerization mechanism, further investigation using computational modeling, such as DFT calculation, should be effective.



(a)

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(b)

(c)

Figure 5. FT-IR analysis of TMG/TMC and TMG/PPA mixtures. (a) Expanded FT-IR spectra for the C=O stretching vibration band of TMC in the absence (black line) and presence of TMG (red line). (b) Expanded FT-IR spectra for the O-H stretching vibration band of PPA in the absence (black line) and presence of TMG (red line). The FT-IR spectra were acquired at 70 °C and normalized at the peaks due to the stretching vibration of the C=O for TMC and O-H for PPA, and (c) Proposed reaction mechanism of the TMG-catalyzed ROP based on the FT-IR analysis.35

Synthesis of Functionalized APCs using Multi-functional Initiators To extend the possible applications of the present ROP system, the synthesis of endfunctionalized APCs was then examined using multi-functional initiators (Scheme 2). We first employed 6-azide-1-hexanol (AHA) as an initiator to produce an APC having a clickable azido group at the chain end; this can be used for the synthesis of block copolymers as well as macromolecular architectures.38,39 The ROP using AHA was conducted at a [TMC]0/[AHA]0/[TMG] ratio of 50/1/0.1 and proceeded to reach a monomer conversion rate of 74% (run 4 in Table 2). The 1H NMR spectra of the obtained PTMC show minor signals due to the initiator residue (Figure S8), and Mn,NMR (4,100) was in good agreement with the theoretical value (3,900). In the FT-IR spectrum, the characteristic 16 ACS Paragon Plus Environment

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absorption peak due to the azido group was observed at 2,100 cm−1 (Figure S9), strongly suggesting that the azido group was retained during the polymerization to give a PTMC having a clickable chain end group. Similarly, a PTMC having an ethynyl group, which is a clickable group for azido-alkyne and thiol-yne click reactions, was obtained using 4-ethynyl-benzenemethanol (EBM) as a functional initiator (run 5 in Table 2 and Figure S10). These demonstrations confirm the wide ranging application of the present ROP system for preparing APC-based advanced materials.

Scheme 2. Synthesis of end-functionalized APCs and APC-polyols using TMG as a catalyst

OH

OH

HO

HO

HO


OH


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Table 2. TMG-catalyzed bulk ROP of TMC using multi-functional initiators a

a

run

ini.

4 5 6 7

[TMC]0/[ini.]0

time

conv. b

Mn,th. c

Mn,NMR b

Mn,SEC d

Ðd

/[TMG]

(min)

(%)

AHA

50/1/0.1

30

74

3,900

4,100

3,600

1.13

EBM

50/1/0.1

30

75

4,000

4,100

4,100

1.15

BDM

25/1/0.1

20

89

2,400

2,200

2,400

1.14

BTM

37.5/1/0.1

25

83

3,300

2,700

3,600

1.23

b

1

Polymerization conditions: atmosphere, Ar; temp., 70 °C. Determined from the H NMR spectrum recorded in

CDCl3. c Calculated from [TMC]0/[ini.]0 × conv. × (M.W. of TMC) + (M.W. of ini.).

d

Determined by SEC

measurement of the obtained polymer in THF using PSt standards. The Mn,SECs are calculated using the correcting factor of 0.56 28

Next, we demonstrated the synthesis of APCs having multiple hydroxyl groups at the chain ends, which can be used for the polyurethane soft segments. Indeed, APC-PU has been investigated for the biomedical applications and environmental applications.29–32,40 The ROP using 1,4benzenedimethanol (BDM) as a difunctional initiator ([TMC]0/[BDM]0/[TMG] = 25/1/0.1) smoothly proceeded to give PTMC-diol (run 6 in Table 2; Mn,NMR = 2,200). The integration ratios of the signals due to the methylene protons adjacent to the ω-chain end hydroxyl group and the BDM aromatic protons were approximately 1:1, implying that the obtained PTMC has a hydroxyl group at each chain end (Figure 6). In addition, the relatively narrow dispersity of the product (Ð =1.14) indicated that the propagation of each arm was uniformly occurred. In a similar manner, PTMC-triol was also obtained using 1,3,5-benzenetrimethanol (BTM) as a multi-functional initiator (run 7 in Table 2; Mn,NMR = 2,700 and Ð =1.23). The 1H NMR and SEC analyses confirmed the star-shaped structure of the obtained PTMC-triol (Figure S11).


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Ð = 1.14

Figure 6. (a) 1H NMR spectrum (* indicates the residual solvent and water) recorded in CDCl3 and (b) SEC trace (eluent, THF; flow rate, 1.0 mL min−1) of the PTMC-diol obtained from run 6 in Table 2.

Finally, we applied the present ROP system to a one-pot synthesis of APC-PU (Scheme 3). The bulk ROP of TMC was firstly conducted using 1,3-propanediol (PPD) as a bi-functional initiator at a [TMC]0/[PPD]0/[TMG] ratio of 25/1/0.1 to produce a PTMC-diol. After the monomer conversion was >98%, 1 eq. of hexamethylene diisocyanate (HDI) with respect to PPD was added to the reaction mixture (Figure S12). The FT-IR and 1H NMR analyses of the obtained polymer strongly support the formation of polyurethane. In the FT-IR spectrum, the characteristic absorptions of the urethane bond were appeared at 1530 and 3350 cm−1 (Figure S13), which undoubtedly suggested that the urethane bond formation was occurred. In the 1H NMR spectrum of the soluble part of the final product, a peak due to N-H proton of the urethane bond were observed at 4.76 ppm along with peaks due to the PTMC main chain; peaks due to methylene proton resulting from the HDI residue are also seen



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(Figure S14). Therefore, the APC-diol obtained from the present ROP system can be used for APCPU production, which opened the industrial application of the present ROP system.

Scheme 3. One-pot synthesis of APC-based polyurethane.


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Conclusions In summary, we confirmed the excellent catalytic activity of naturally-occurring TMG for the bulk ROP of a cyclic carbonate. The ROP of TMC using the TMG catalyst proceeded in a controlled manner, with suppressed intra-/inter-molecular transesterification and decarboxylation even under the bulk condition. The obtained APCs exhibited well-defined structure and low dispersity. The catalyst screening of TMG analogues and the FT-IR analyses revealed that the zwitterionic structure containing carboxylate anions and quaternary ammonium cations in TMG helps efficiently produce APC materials via a bi-activation mechanism. In addition, we prepared end-clickable APCs for high value-added APC materials and industrial valuable APC-polyols by combining with the functional initiators. The ROP system established in this work can be implemented in bulk processes using a readily available, non-toxic catalyst. The system is suitable for manufacturing APCs for both conventional and future biomedical purposes. We believe that the present ROP system is an environmentally benign, sustainable, and practical strategy for producing APC materials production.



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ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at

AUTHOR INFROMATION Corresponding Authors *Takuya

Isono:

Faculty of Engineering, Hokkaido University, Sapporo 060-8628, Japan. Email:

[email protected] *Toshifumi Satoh: Faculty of Engineering, Hokkaido University, Sapporo 060-8628, Japan. Email: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENT This work was financially supported by the JSPS KAKENHI Grant Number JP18H04639 (Hybrid Catalysis for Enabling Molecular Synthesis on Demand), the Inamori Foundation, and Grant-in-Aid for JSPS Research Fellow. Tatsuya Saito gratefully acknowledges the JSPS Fellowship for Young Scientists.

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Table of Contents Graphics

Synopsis: Trimethyl glycine, a natural product found in plants as well as in humans, was found to be an efficient catalyst for the synthesis of aliphatic polycarbonate.


Trimethyl Glycine as an Environmentally Benign and Biocompatible

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