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Organocatalytic Stereoselective Cyclic Polylactide Synthesis in Supercritical Carbon Dioxide under Plasticizing Conditions Nobuyuki Mase 1,2,3, * ID , Moniruzzaman 1 , Shoji Yamamoto 1 , Yoshitaka Nakaya 1 , Kohei Sato 1 ID and Tetsuo Narumi 1,2,3 1

2 3

*

Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan; [email protected] (M.); [email protected] (S.Y.); [email protected] (Y.N.); [email protected] (K.S.); [email protected] (T.N.) Graduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan Research Institute of Green Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan Correspondence: [email protected]; Tel.: +81-53-478-1196

Received: 4 June 2018; Accepted: 26 June 2018; Published: 28 June 2018

 

Abstract: Cyclic polylactide (cPLA) is a structural isomer of linear polylactide (PLA) although it possesses unique functionalities in comparison to its linear counterpart. Hitherto, the control of stereochemical purity in conventional cPLA synthesis has not been achieved. In this study, highly stereochemically pure cPLA was synthesized in the absence of a metal catalyst and organic solvent, which required high consumption of the residual monomer. The synthesis was conducted in supercritical carbon dioxide under CO2 plasticizing polymerization conditions in the presence of an organocatalyst and thiourea additives. In comparison with the stereocomplexes synthesized through conventional methods, cPLA from L-lactide (cPLLA) and cPLA from D-lactide (cPDLA) were synthesized with higher stereochemical purity and improved thermal stability. Moreover, the method presented herein is environmentally friendly and thus, applicable on an industrial level. Keywords: organocatalyst; thiourea; cyclic polylactide; CO2 plasticizing polymerization; stereocomplexes

1. Introduction Linear polylactides (PLAs) have high biodegradability and biocompatibility, with their potential applications in the medical, pharmaceutical and materials fields having drawn a significant amount of attention [1–3]. Cyclic polylactide (cPLA), which is a structural isomer of PLA with an unique topology, also displays favorable properties [4–8]. For example, a study on the effect of cPLAs on tumor cells and tumor-bearing mice demonstrated that cPLAs effectively inhibit tumor cell growth [9]. Furthermore, in a recent study, cPLA was used as a stabilizer for palladium nanoparticles in the synthesis of a cPLA-clay hybrid material, which can be a recyclable catalyst, for use in the aminocarbonylation reaction of aryl halides with various amines [10]. Despite these attractive properties, cPLAs remain underexplored in comparison to linear PLAs both with respect to their synthesis and practical applications [10]. Until now, three strategies have been reported for the synthesis of cPLAs (Scheme 1): (1) polymerization and separation; (2) polymerization and cyclization; and (3) ring-opening polymerization (ROP) and cyclization. Strategy (1) has proved to be inefficient as even when fractionated by a reverse-phase octadecylsilyl (ODS) column chromatography, a mixture of linear Polymers 2018, 10, 713; doi:10.3390/polym10070713

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fractionated by a reverse-phase octadecylsilyl (ODS) column chromatography, a mixture of linear PLAs and cPLAs obtained Strategy(2) (2)requires requires several steps, although cPLAs can PLAs and cPLAs obtained [11]. [11].octadecylsilyl Strategy several steps, although uniform cPLAs be fractionated by aisisreverse-phase (ODS) column chromatography, auniform mixture of can linear be PLAs eventually separated using a gel filtration column [12–16]. Nevertheless, it is still inappropriate eventually separated using a[11]. gel filtration column [12–16]. Nevertheless, it is uniform still inappropriate and cPLAs is obtained Strategy (2) requires several steps, although cPLAs can for be foreventually large-scale syntheses. In contrast, strategy (3) allows for a simple and straightforward one-step large-scale syntheses. In contrast, strategy (3) allows for a simple and straightforward one-step separated using a gel filtration column [12–16]. Nevertheless, it is still inappropriate for synthesis ofof cPLAs. strategies wasfor reported 2007straightforward usingananorganocatalytic organocatalytic synthesis cPLAs.The The latter of of these these strategies was reported inin2007 using large-scale syntheses. In latter contrast, strategy (3) allows a simple and one-step method [17–23], while researchers have used a metal complex catalytic method in 2011 [24–29]. method [17–23], while researchers a metal complex catalytic method 2011 [24–29]. synthesis of cPLAs. The latter of have theseused strategies was reported in 2007 usinginan organocatalytic method [17–23], while researchers have used a metal complex catalytic method in 2011 [24–29].

Scheme1.1.Synthetic Synthetic strategies strategies of of cyclic Scheme cyclic polylactide polylactide(cPLA). (cPLA). Scheme 1. Synthetic strategies of cyclic polylactide (cPLA).

According to these reports, cPLA was obtained with high conversion (85–97%), moderate According totothese reports, cPLA was obtained with high conversion (85–97%), moderate polydispersity (PDI = 1.22–3.60) number-average molecular weight (Mnmoderate = 6400– According index these reports, cPLA and washigh obtained with high conversion (85–97%), polydispersity index (PDI = 1.22–3.60) and high number-average molecular weight (Mn = 6400–69,000). 69,000). The metal complex catalysts displayed poor reactivity and required high temperatures (30– polydispersity index (PDI = 1.22–3.60) and high number-average molecular weight (Mn = 6400– ◦ The metal complex catalysts displayed poor reactivity and required high temperatures (30–160 160 °C) The andmetal long complex reaction catalysts times (4–18.5 h). Inpoor contrast, the and reaction efficiency of N-heterocyclic 69,000). displayed reactivity required high temperatures (30– C) and long times (4–18.5 h). In contrast, reaction efficiency of N-heterocyclic carbene (NHC) carbene (NHC) as reaction an organocatalyst was extremely high and polymerization occurred 160 °C)reaction and long times (4–18.5 h). the In contrast, the the reaction efficiency reaction of N-heterocyclic as carbene an organocatalyst extremely and the polymerization reaction occurred within 30 s at within 30 s at 25 However, therehigh were several drawbacks in polymerization that the polymerization reactions (NHC) as°C. anwas organocatalyst was extremely high and the reaction occurred ◦ C. However, there were several drawbacks in that the polymerization reactions were conducted 25 within were conducted flammable orthere toxic were organic solvents, such as THF or the CH2polymerization Cl2, and required drybox 30 s at 25in°C. However, several drawbacks in that reactions in were flammable or toxic organic solvents, such solvents, as THF or CH required ordrybox Schlenk or Schlenk techniques under nitrogen, thereby limiting the potential forCH industrialization [19]. conducted in flammable or toxic organic such as2 Cl THF or 2Cl2, anddrybox required 2 , and In general, the available methodologies faillimiting to control the stereochemistry of PLAs, which techniques under nitrogen, thereby limiting the potential industrialization [19]. or Schlenk techniques under nitrogen, thereby thefor potential for industrialization [19]. is one of In the most important parameters in material development as stereochemistry it has a significant effect the is In general, theavailable available methodologies fail control thethe stereochemistry of PLAs, whichon is one general, the methodologies failto to control of PLAs, which properties [30,31]. In fact, in most examples of cPLA syntheses, racemic lactides are employed and of the most important parameters in material development as it has a significant effect on the one of the most important parameters in material development as it has a significant effect on the thus, control of the stereochemical purity is insufficiently achieved. To thelactides best of our knowledge, the properties [30,31]. fact,ininmost mostexamples examples of cPLA cPLA syntheses, syntheses, racemic are employed and properties [30,31]. InIn fact, of racemic lactides are employed and stereocomplexes of cPLA were reported in 2011 by Waymouth et al. [19]. However, the fraction ofthe thus, control thestereochemical stereochemicalpurity purityis is insufficiently insufficiently achieved. knowledge, the thus, control ofof the achieved.To Tothe thebest bestofofour our knowledge, isotactic (iii) tetrads of cPLA prepared L-lactide was 0.81–0.83, that the epimerization stereocomplexes cPLA were reportedfrom in 2011 2011 by Waymouth et [19]. fraction of of stereocomplexes ofofcPLA were reported in by Waymouth etal. al.suggesting [19].However, However, the fraction occurred during the polymerization step. Recently, et al. reported a racemization-free isotactic (iii) tetrads of cPLA prepared from L-lactideKricheldorf was 0.81–0.83, suggesting that epimerization isotactic (iii) tetrads of cPLA prepared from L-lactide was 0.81–0.83, suggesting that epimerization polymerization, in which a cyclic tin step. catalyst was employed under bulk polymerization conditions, occurred duringthe the polymerization Recently, Kricheldorf et occurred during polymerization step. Recently, Kricheldorf etal. al.reported reporteda aracemization-free racemization-free but a high temperature (160 °C) was required [29]. polymerization, in which a cyclic tin catalyst was employed under bulk polymerization conditions, polymerization, in which a cyclic tin catalyst was employed under bulk polymerization conditions, on our previous the synthesis but aBased high temperature (160findings °C) was on required [29]. of stereochemically pure linear PLA [32], in this but a high temperature (160 ◦ C) was required [29]. study, we have developed methodon forthe thesynthesis synthesisofofstereochemically highly pure cPLA in linear the absence of metals, Based on our previousafindings pure PLA [32], in this Based on our previous findings on the synthesis of stereochemically pure linear PLA [32], in this organicwesolvents or residual monomers. approach an absence organocatalyst in study, have developed a method for the Instead, synthesisthe of highly pureemploys cPLA in the of metals, study, we havecarbon developed a method for the synthesis of highly pure cPLA(CPP) in theconditions absence ofatmetals, supercritical (scCO 2) under CO 2 plasticizing polymerization low organic solvents ordioxide residual monomers. Instead, the approach employs an organocatalyst in organic solvents orThe residual monomers. Instead, the both approach employs an organocatalyst in supercritical temperatures. results were L- and D-cPLA were synthesized supercritical carbon dioxide (scCOpromising 2) under COas 2 plasticizing polymerization (CPP) conditionsinathigh low carbon dioxide (scCO ) under CO polymerization (CPP) at low temperatures. 2results 2 plasticizing stereochemical purity from Lwere - and D-lactide 1,as respectively (Scheme 2),conditions which hereafter denoted temperatures. The promising both L- and D-cPLA were are synthesized in high The promising andAn D-cPLA were synthesized in highare stereochemical asresults cPLLAwere andpurity cPDLA, respectively. improvement in the2), thermal properties of purity the stereochemical fromas L- both and DL-lactide 1, respectively (Scheme which hereafter denoted from Land D-lactide 1, respectively (Scheme 2), which are hereafter denoted as cPLLA and stereocomplexes also observed. as cPLLA and was cPDLA, respectively. An improvement in the thermal properties ofcPDLA, the respectively. An improvement in the thermal properties of the stereocomplexes was also observed. stereocomplexes was also observed.

Scheme 2. ROP of lactide, which creates PLA and cPLA. Scheme 2. ROP of lactide, which creates PLA and cPLA. Scheme 2. ROP of lactide, which creates PLA and cPLA.

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2. Materials and Methods 2.1. Materials In this study, 1-(3,5-Bis(trifluoromethyl)phenyl)-3-cyclohexyl thiourea was synthesized according to literature procedures [33]. All other chemicals and solvents were commercially available and used as received. L-Lactide was provided by Ricoh Co., Ltd. (Tokyo, Japan), while CO2 was obtained from Air Liquide Kogyogas Ltd. (Tokyo, Japan). 2.2. Synthesis Polymerization reactions were conducted in a scCO2 reaction system using the TVS-N2-type portable reactor (20 MPa, 260 ◦ C) manufactured by Taiatsu Techno Corporation (Tokyo, Japan) with the JASCO PU-1586 scCO2 pump (JASCO Corporation, Tokyo, Japan). L-Lactide (1, 864 mg, 6.0 mmol, 1.0 eq) and the organocatalyst (4-(dimethylamino)pyridine (DMAP), 0.40 mmol, 6.6 mol %) were added to a 12-mL pressure-resistant reactor, before the mixture was heated to 60 ◦ C using a water bath. The vessel was charged with scCO2 (60 ◦ C, 10 MPa) and the solution was stirred for 5 min. The reaction mixture was allowed to stand for 5 h, before the pressure was reduced from supercritical to atmospheric, yielding cPLA as a white solid. For the thiourea-mediated cPLLA synthesis, 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexyl thiourea (1 mol %) was added to the mixture of lactide and DMAP. This mixture was subjected to the polymerization reaction for 2.5 h as described above. cPLLA and cPDLA samples with different number-average molecular weights were isolated by preparative gel permeation chromatography (GPC) using a recycling high performance liquid chromatography (HPLC) system (YMC LC-Forte/R, YMC CO., Ltd., Kyoto, Japan) with a YMC-GPC T30000 (21.2 mm × 600 mm) and YMC-GPC T4000 (21.2 mm × 600 mm) columns in series (CHCl3 as the eluent, flow rate of 6.0 mL/min). For preparation of the stereocomplex of cPLA [19], cPLLA (50 mg) and cPDLA (50 mg) were dissolved separately in 5 mL of CH2 Cl2 . These solutions were mixed together in a 20-mL flask and stirred for 5 min at room temperature. The solvent was evaporated slowly (200 torr) at room temperature, before the residue was dried under a vacuum to remove the residual solvent. The resulting material was used for DSC measurements. 2.3. Characterization The conversion by polymerization was determined through 1 H NMR analysis. 1 H NMR (300 MHz) spectra were recorded using the JEOL JNM-AL spectrometer (JEOL, Tokyo, Japan) at ambient temperature. The spectra were recorded using CDCl3 as a solvent and tetramethylsilane (TMS) as an internal standard (δ = 0 ppm). The number- and weight-average molecular weights (Mn, Mw) and polydispersity index (PDI = Mw/Mn) of the products were determined by gel permeation chromatography (GPC) analysis using the SHIMADZU LC-5A pump (SHIMADZU, Kyoto, Japan) and JAI R1-3H RI detector (Japan Analytical Industry Co., Ltd., Tokyo, Japan) with GPC column GPC K-806L (Shodex, Tokyo, Japan, 8.0 mm × 300 mm, flow rate 0.8 mL/min), using polystyrene as a standard and CHCl3 as an eluent. LAsoft CDS-Lite software (LAsoft, Ltd., Chiba, Japan) was used for the molecular weight calculations. The topology of the polymer product being cyclic rather than linear was confirmed by 1 H NMR and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) (Supplementary Materials, Figures S1 and S2). The mass spectra were recorded using ultrafleXtreme mass spectrometry (MALDI-TOF-MS, Bruker Japan, Yokohama, Japan). For MALDI-TOF-MS measurements, the cPLA was dissolved in CHCl3 . Trans-2-[3-(4-tertbutylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB) was used as the matrix and silver trifluoroacetate was added as a cation source. In order to hydrolyze the polymer materials, an aqueous solution of NaOH (1 M, 10 mL) was added to the polymer. After 4 h under reflux conditions, the mixture was cooled down to the ambient temperature and an aqueous solution of HCl (2 M, 5.5 mL) was added. The resulting lactic acid

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was analyzed by chiral HPLC. The HPLC analysis was conducted under the following conditions: SUMICHIRAL OA5000 column (Sumika Chemical Analysis Service, Ltd., 4.6 mm × 150 mm, flow rate Polymers 2018, 10, 2 x FOR REVIEW 4 of 9 1.0 mL/min) with mMPEER CuSO 4 aq/2-propanol = 95:5; UV detection at 254 nm (L-lactide: retention time = 8.5 min; D-lactide: retention time = 10.3 min) (Supplementary Materials, Figure S3). SUMICHIRAL OA5000 column (Sumika Chemical Analysis Service, Ltd., 4.6 mm × 150 mm, flow rate Differential scanning calorimetry (DSC) analysis was performed using SHIMADZU DSC-60 1.0 mL/min) with 2 mM CuSO4 aq/2-propanol = 95:5; UV detection at 254 nm (L-lactide: retention time ◦ (SHIMADZU, Japan). Fortime DSC= 10.3 measurements, a 5-mg sample was heated = 8.5 min;Kyoto, D-lactide: retention min) (Supplementary Materials, Figure S3). from 25 to 250 C at ◦ 10 C/minDifferential rate underscanning an argoncalorimetry flow (50 mL/min). The was dataperformed collectionusing interval was 1.0 s.DSC-60 (DSC) analysis SHIMADZU (SHIMADZU, Kyoto, Japan). For DSC measurements, a 5-mg sample was heated from 25 to 250 °C

3. Results Discussion at 10 and °C/min rate under an argon flow (50 mL/min). The data collection interval was 1.0 s. The synthesis of cPLA via an organocatalytic ROP was examined according to previous findings 3. Results and Discussion on the synthesis of stereochemically pure linear PLA (Table 1) [32]. Notably, 1 H NMR analysis of the The synthesis of cPLA via an organocatalytic ROP was examined according to previous findings polymerization reaction mixture showed that the remaining unreacted monomers were less than 5% on the synthesis of stereochemically pure linear PLA (Table 1) [32]. Notably, 1H NMR analysis of the in any of the polymerization reactions. The monomer conversion rate and weight of the recovered polymerization reaction mixture showed that the remaining unreacted monomers were less than 5% polymer were higher than 95%. In theThe conventional solution polymerization method, the reaction in any of both the polymerization reactions. monomer conversion rate and weight of the recovered was slow and resulted the formation amorphous cPLLAsolution with low stereochemical purity, polymer were bothinhigher than 95%.ofIn the conventional polymerization method, thewhich was determined byslow HPLC hydrolysis to lactic acid with (Tablelow 1, entry 1). In contrast, reaction was andanalysis resultedafter in the formationofofcPLLA amorphous cPLLA stereochemical purity, proceeded which was smoothly determinedinbyscCO HPLC analysis after hydrolysis of cPLLA to lactic 1, the reaction crystalline cPLLA was obtained in a acid high(Table enantiomeric 2 and entry 1). In contrast, the reaction proceeded smoothly in scCO 2 and crystalline cPLLA was obtained excess (ee) of 90.5% (Table 1, entry 2). The success of the polymerization reaction under scCO2 in a high enantiomeric excess (ee) of 90.5% (Table 1, entry 2). The success of the polymerization conditions was attributed to the high concentration conditions similar to those in bulk polymerization reaction under scCO2 conditions was attributed to the high concentration conditions similar to those and uniform conditions similar to those in solution polymerization. We refer to this process as a CO2 in bulk polymerization and uniform conditions similar to those in solution polymerization. We refer plasticizing method [32]. Under CPP conditions, epimerization was suppressed to thispolymerization process as a CO(CPP) 2 plasticizing polymerization (CPP) method [32]. Under CPP conditions, since the reactive zwitterionic intermediate (3) was less likely to be solvated (dielectric epimerization was suppressed since the reactive zwitterionic intermediate (3) wasby lessscCO likely2 to be ◦ constant (εr ) =by1.15 at2 10 MPa, 60 C) as(εrthis hasata10lower εr than and hexane (εr solvated scCO (dielectric constant ) = 1.15 MPa, 60 °C) aspentane this has a(ε lower εr than pentane r = 1.84) r = 1.84) Thus, and hexane (εr = 1.89) Thus, thispreferred allows forover the ROP to be preferred over thewould = 1.89)(ε[34,35]. this allows for [34,35]. the ROP to be the epimerization, which epimerization, which would form the meso-lactide 1 (Scheme 3). It was assumed that the form the meso-lactide 1 (Scheme 3). It was assumed that the stereochemical purity of cPLLA could be stereochemical puritythe of cPLLA could be improved by increasing consumption improved by increasing polymerization consumption rate ofthe thepolymerization monomer. Thus, the additives rate of the monomer. Thus, the additives that selectively activated the carbonyl group of L-lactide that selectively activated the carbonyl group of L-lactide were investigated (Figure 1). In particular, were investigated (Figure 1). In particular, 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea accelerated the ROP reaction and improved accelerated the ROP reaction and improved the stereochemical purity, giving an ee of 93.5% (Table the stereochemical purity, giving an ee of 93.5% (Table 1, entry 3).reaction Givenconditions the success ofapplied the reaction 1, entry 3). Given the success of the reaction using L-lactide, the same were using to L-lactide, the same reaction conditions were applied to the ROP of D-lactide, with cPDLA the ROP of D-lactide, with cPDLA being obtained in high stereoselectivity (entries 4 and 5). The being PDIinofhigh the cPLA formed herein was 1.20–1.60, wasofcomparable to that obtained via 1.20–1.60, the obtained stereoselectivity (entries 4 and 5). which The PDI the cPLA formed herein was reported catalytic method [19].reported NHC catalytic method (1.3–1.4) [19]. whichpreviously was comparable toNHC that obtained via the(1.3–1.4) previously 1. Organocatalytic cPLA synthesis in supercritical carbon dioxide (scCO2). TableTable 1. Organocatalytic cPLA synthesis in supercritical carbon dioxide (scCO2 ).

Entry Entry Solvent Solvent 1 2 3 (d) 4 (e) 5 (d,e) (a)

1 2 3 (d) 4 (e) 5 (d,e)

CHCl CHCl 3 3 scCO scCO 2 2 scCO 2 2 scCO scCO2 scCO2 scCO2 scCO2

Time (h) Time (h) 120 120 55 2.5 2.5 5 5 2.5 2.5

(b) (c) (a) (a) MnMn PDI (b) PDI ee (%) 12,700 39.0 12,700 3.11 3.11 1.40 55005500 1.40 90.5 11,000 1.60 1.60 11,000 93.5 6000 1.31 6000 1.31 91.0 6800 1.20 6800 1.20 97.0

ee (%) (c) 39.0 90.5 93.5 91.0 97.0

(a) Determined by GPC analysis using a polystyrene standard. (b) Polydispersity index. (c) Determined Determined by GPC analysis using a polystyrene standard. (b) Polydispersity index. (c) Determined by HPLC (d) (d) analysis hydrolysis thehydrolysis polymer tooflactic acid. to 1-(3,5-Bis(trifluoromethyl)phenyl)-3-cyclohexyl thiourea byafter HPLC analysis of after the polymer lactic acid. 1-(3,5-Bis(trifluoromethyl)phenyl)(e) D -Lactide (ent-1) was used. (1 mol%) was added. 3-cyclohexyl thiourea (1 mol%) was added. (e) D-Lactide (ent-1) was used.

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Scheme 3. Competitive reaction between polymerization (and hence, cyclization) and epimerization.

Scheme 3. Competitive reaction between (andhence, hence, cyclization) and epimerization. Scheme 3. Competitive reaction betweenpolymerization polymerization (and cyclization) and epimerization.

Figure 1. Activation of L-lactide monomer by a thiourea additive.

Figure 1. Activation of L-lactide monomer by a thiourea additive.

1. Activation of L-lactide byvia a thiourea additive. cyclization, the In the cPLAFigure synthesis, since a cyclic structuremonomer was formed an intramolecular PDIIncould not besynthesis, improvedsince unless the linear intermediate of the via same weightcyclization, is selectively the cPLA a cyclic structure was formed anmolecular intramolecular the Incyclized. the cPLA synthesis, cyclic structure wasofformed via an intramolecular cyclization, PDI could not be improvedsince unlessa the linear intermediate the same molecular weight is selectively Similarnot to PLA, cPLA has been known form aintermediate stereocomplex of of cPLA (sc-cPLA) [19,36,37]. In cyclized. the PDI could be improved unless thetolinear the same molecular weight is thisSimilar work, to cPDLA was synthesized according to the same procedure as that of cPLLA, while PLA, cPLA has been known to form a stereocomplex of cPLA (sc-cPLA) [19,36,37]. In selectively cyclized. differential scanning (DSC) was applied create sc-cPLA (Figure this work, cPDLA wascalorimetry synthesized according thetosame procedure that 2). of Interestingly, cPLLA, while Similar to PLA, cPLA has been known to form to a stereocomplex of cPLAas(sc-cPLA) [19,36,37]. In this although the molecular weight was lower than the one reported in the literature (Table 2, entries 1 differential scanning calorimetry (DSC) was applied to create sc-cPLA (Figure 2). Interestingly, work, and cPDLA was synthesized according to the samethan procedure as thatreported of cPLLA, while which differential 2 vs.the 3), molecular the measured melting higher the previously value although weight waspoint lowerwas than the one reported in the literature (Table[19], 2, entries 1 scanning calorimetry (DSC) was applied to create sc-cPLA (Figure 2). Interestingly, although indicates stronger intermolecular forces. The melting point of sc-cPLA with the highest the and 2 vs. 3), the measured melting point was higher than the previously reported value [19], which molecular weight was lower than in the literature 2, entries 1 and 2point vs. 3), the stereochemical purity was 212the °C.one Asreported the stereochemical purity (Table decreased, the melting indicates stronger intermolecular forces. The melting point of sc-cPLA with the highest decreased to point 207 °Cwas (Table 2, than entriesthe1 previously vs. 2). Therefore, wevalue can conclude thatindicates the higher measured melting higher reported [19], which stronger stereochemical purity was 212 °C. As the stereochemical purity decreased, the melting point stereochemical purity of the D- and L-forms led to stronger intermolecular interactionspurity between the212 ◦ C. intermolecular forces. The melting point of sc-cPLA with the highest stereochemical was decreased to 207 °C (Table 2, entries 1 vs. 2). Therefore, we can conclude that the higher two forms in the stereocomplex and hence, a higher melting point (Figure 3).◦In addition, similar to As the stereochemical purity decreased, the melting point decreased to 207interactions C (Table 2,between entries the 1 vs. 2). stereochemical purity of the D- and L-forms led to stronger intermolecular the case of the stereocomplex of cPLA, the melting point of cPLA itself also depended on the Therefore, we can conclude that theand higher stereochemical purity the D- 3). and to stronger two forms in the stereocomplex hence, a higher melting pointof(Figure InL-forms addition,led similar to stereochemical purity. the case of the stereocomplex of cPLA, the melting point of cPLA itself also depended on the intermolecular interactions between the two forms in the stereocomplex and hence, a higher melting pointstereochemical (Figure 3). Inpurity. addition, similar the case ofof the stereocomplex of cPLA, the melting point of Table 2. DSC to measurements the stereocomplex of cPLA.

cPLA itself also depended on the stereochemical purity.

Entry Table cPLA2. DSCMn PDI Ee Tm (°C) Tmof(sc-cPLA) (°C) measurements of(%) the stereocomplex cPLA. cPDLA 6800 1.20 97.0 152 1 Table 212 2. DSCMn measurements of(%) the stereocomplex cPLA. Entry cPLA PDI Tm149 (°C) Tm of (sc-cPLA) (°C) cPLLA 11,000 1.60 Ee 93.5 cPDLA 6800 1.20 97.0 152 cPDLA 6000 1.31 91.0 143 212(sc-cPLA) (◦ C) 207 Entry 12 cPLA Mn PDI 93.5Ee (%) 149 T m (◦ C) T m cPLLA cPLLA 11,000 5500 1.60 1.40 90.5 145 cPDLA 6800 1.20 97.0 152 cPDLA 6000 1.31 91.0 143 (b) cPDLA 26,000 1.40 (0.81) 132 1 23 (a)cPLLA 207 212 11,000 1.60 93.5 179 cPLLA 5500 1.40 90.5 (b) 145 149 cPLLA 30,000 1.30 (0.83) 135 cPDLA 6000 1.31 (0.81) 91.0 143 (b) (a) cPDLA 26,000 1.40 in reference 19. (b) Fraction132 of isotactic tetrads. 2 3 (a) cPLLAData reported 179 207 5500 1.40 90.5 145 (b) cPLLA 30,000 1.30 (0.83) 135 3 (a)

(b) cPDLA 26,000 1.40 132 (a) Data reported in reference 19. (b)(0.81) Fraction of isotactic tetrads. cPLLA 30,000 1.30 135 (0.83) (b) (a)

Data reported in reference 19.

(b)

Fraction of isotactic tetrads.

179

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←endo. ←endo.

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cPLLA cPLLA cPDLA cPDLA sc-cPLA sc-cPLA 10 60 110 160 210 10 60 110 160 210 Temperature (℃) Temperature (℃) Figure 2. DSC measurements of the stereocomplex of cPLA (Table 2, entry 1). Figure 2. DSC measurements of the stereocomplex of cPLA (Table 2, entry 1). Figure 2. DSC measurements of the stereocomplex of cPLA (Table 2, entry 1). (0.81) 91.0% ee 97.0% ee (0.81) 91.0% ee 97.0% ee cPDLA

cPDLA

cPLLA

+

+

+

+ (0.83)

+ 90.5% ee

+ 93.5% ee

90.5% ee

93.5% ee

207 ºC

212 ºC

(0.83)

cPLLA

sc-cPLA

sc-cPLA Tm

179 ºC

Tm 179 ºC 207 ºC 212 ºC Figure 3. Effect of stereochemical purity on the intermolecular interactions in the stereocomplex formation. Figure 3. Effect of stereochemical purity on the intermolecular interactions in the stereocomplex Figure 3. Effect of stereochemical purity on the intermolecular interactions in the stereocomplex formation. Subsequently, the effect of the ring size on the thermal stability was investigated (Table 3 and

formation. Figure 4). Three stereocomplex samples with different number-average molecular weights were Subsequently, the effect of the ring size on the thermal stability was investigated (Table 3 and prepared using cPLLA and cPDLA, which are shown in Table 2, entry 2. These were obtained and Figure 4). by Three stereocomplex samples molecular weights were Subsequently, the effectGPC. of the ring size ondifferent the stability was investigated (Table purified a preparative Sample 1, with which hadthermal verynumber-average different molecular weights of cPLLA and3 and prepared using cPLLA and cPDLA, which are shown in Table 2, entry 2. These were obtained and FigurecPDLA, 4). Three with3, different molecular weights had astereocomplex melting point of samples 190 °C (Table entry 1). Innumber-average Sample 2, a more moderate difference in were purified by a preparative GPC. Sample 1, which had very different molecular weights of cPLLA the molecular weight distribution to anare increase in the melting °C (Table entryand 2). and prepared using cPLLA and cPDLA, led which shown in Table 2,point entryto2.200 These were3, obtained cPDLA, asmallest melting difference point of 190 °C (Table 3, entry 1). In Sample a more difference in Finally, in the molecular weights sample 2, 3 molecular gave themoderate highest melting point purified by had a the preparative GPC. Sample 1, which had veryindifferent weights of cPLLA and the(Table molecular weight distribution led to an increase in the melting point to 200of°Cthe (Table 3, entry 2). ◦ 3, entry 3). These results suggested that the degree of formation stereocomplex cPDLA, had a melting point of 190 C (Table 3, entry 1). In Sample 2, a more moderate difference in Finally, the smallest in the molecular weights in sample 3 gave highest point depended not onlydifference on the stereochemical but also the ring sizethe (and similarities thereof) ◦ C melting the molecular weight distribution led to an purity, increase in theon melting point to 200 (Table 3, entry 2). (Table 3, entry 3). These portion resultsbetween suggested thatand thecPDLA degreewas of limited formation ofathe stereocomplex because the overlapping cPLLA due to different radius of Finally, the smallest in the molecular gave thesimilarities highest melting depended not onlydifference on the stereochemical purity,weights but also in onsample the ring3size (and thereof)point the curvature. (Table 3, entry 3). These results suggested that the degree of formation of the stereocomplex depended because the overlapping portion between cPLLA and cPDLA was limited due to a different radius of not only on the stereochemical purity, but also on thewith ringdifferent size (and thereof) because the Table 3. Stereocomplex of PLA ring similarities sizes. the curvature.

overlapping portion between cPLLA and cPDLA was limited due to a different radius of the curvature. Entry cPLA Mn PDI Tm (sc-cPLA) Table 3. Stereocomplex of PLA with different ring sizes. cPDLA 7900 1.18 Table 3.1Stereocomplex of PLA with different 190ring sizes. Entry cPLA cPLLA Mn 2600 PDI 1.20 Tm (sc-cPLA) cPDLA 1.18 cPDLA 7900 5100 Entry Mn 1.23 PDI 190 T m (sc-cPLA) 1 2 cPLA 200 cPLLA 1.20 cPLLA 2600 7400 cPDLA 7900 1.23 1.18 190 1 cPDLA cPDLA 5100 6000 1.31 1.20 cPLLA 2600 1.23 23 200 207 cPLLA cPLLA 7400 5500 1.40 1.23 cPDLA 5100 1.23 2

3 3

cPLLA cPDLA

cPLLA cPDLA cPLLA

7400 1.31 1.23 6000 207 5500 6000 1.40 1.31 5500

1.40

200

207

been achieved. In comparison to stereocomplexes synthesized through the conventional methods, cPLA from L-lactide (cPLLA) and cPLA from D-lactide (cPDLA) stereocomplexes were synthesized with higher stereochemical purity and improved thermal stability. Based on these results, we concluded that the method presented herein could meet the increasing demands of medical and material applications in terms of safety and high functionality in the large-scale industrial Polymers 2018, 10, 713 7 of 9 manufacturing of cPLA and in academic research. cPDLA

cPLLA

(a)

Intensity

1

D

+

L

D

+

L

D

+

L

0.5

0 580

Elution time (s)

680

(b) Intensity

1

0.5

0 580

630 Elution time (s)

680

(c)

Intensity

1

0.5

0 550

650 Elution time (s)

750

Figure of sc-cPLA. Figure 4. 4. GPC GPC traces traces of of cPLA cPLA with with different different ring ring sizes sizes and and images images of sc-cPLA. Supplementary Materials: The experimental and 1H NMR spectroscopic and analytic data are available online 4. Conclusions at www.mdpi.com/xxx/s1.

In Contributions: this study, highly stereochemically pure cPLA was synthesized in the absence of aS.Y. metal Author All authors contributed equally. N.M. conceived and designed the experiments; and catalyst or organic solvent, which required high consumption of the residual monomer. The synthesis Y.N. performed the experiments and analyzed the data; K.S. and T.N. contributed reagents/materials/analysis was scCO2 under CO2 plasticizing polymerization conditions in the presence of an tools;conducted M. wrote theinpaper. organocatalyst and thiourea additives. In this approach, the epimerization of the obtained cPLA Funding: This work was funded in part by the Grant-in-Aid for Scientific Research on Innovative Areas (No. was suppressed and the purityCulture, was higher than those obtained from conventional 24105511, 26105722) from thestereochemical Ministry of Education, Sports, Science and Technology (MEXT). methods, although the control of stereochemical purity in conventional cPLA synthesis has not yet been Acknowledgments: We gratefully acknowledge the excellent technical assistance for MALDI-TOF-MS achieved. In comparison to stereocomplexes synthesized through the conventional methods, cPLA measurements T.N. and N.S. from Bruker Japan K.K. We express our appreciation to Ricoh Co., Ltd. for from L-lactide (cPLLA) and cPLA from D-lactide (cPDLA) stereocomplexes were synthesized with providing highly pure L-lactide. higher stereochemical purity and improved thermal stability. Based on these results, we concluded that the method presented herein could meet the increasing demands of medical and material applications in terms of safety and high functionality in the large-scale industrial manufacturing of cPLA and in academic research. Supplementary Materials: The experimental and 1 H NMR spectroscopic and analytic data are available online at http://www.mdpi.com/2073-4360/10/7/713/s1. Author Contributions: All authors contributed equally. N.M. conceived and designed the experiments; S.Y. and Y.N. performed the experiments and analyzed the data; K.S. and T.N. contributed reagents/materials/analysis tools; M. wrote the paper. Funding: This work was funded in part by the Grant-in-Aid for Scientific Research on Innovative Areas (No. 24105511, 26105722) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

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Acknowledgments: We gratefully acknowledge the excellent technical assistance for MALDI-TOF-MS measurements T.N. and N.S. from Bruker Japan K.K. We express our appreciation to Ricoh Co., Ltd. for providing highly pure L-lactide. Conflicts of Interest: The authors declare no conflict of interest.

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