Studying the Ring-Opening Polymerization of 1,5-Dioxepan-2-One with Organocatalysts

polymers

Article Studying the Ring-Opening Polymerization of 1,5-Dioxepan-2-one with Organocatalysts

Jinbao Xu *, Yang Chen, Wenhao Xiao, Jie Zhang, Minglu Bu, Xiaoqing Zhang and Caihong Lei *

Guangdong Provincial Key Laboratory of Functional Soft Condensed Matter, School of Materials and Energy, Guangdong University of Technology, Guangzhou 510006, China; [email protected] (Y.C.); [email protected] (W.X.); [email protected] (J.Z.); [email protected] (M.B.); [email protected] (X.Z.) * Correspondence: [email protected] (J.X.); [email protected] (C.L.)

Received: 23 September 2019; Accepted: 8 October 2019; Published: 10 October 2019

Abstract: Three diﬀerent organocatalysts, namely, 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris 5 5 (dimethylamino) phosphoranylidenamino]-2Λ ,4Λ -catenadi(phosphazene) (t-BuP4), 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), have been used as 1,5-dioxepan-2-one (DXO) ring-opening polymerization (ROP) catalysts at varied reaction conditions. 1H NMR spectra, size exclusion chromatography (SEC) characterizations, and kinetic studies prove that the (co)polymerizations are proceeded in a controlled manner with the three organocatalysts. It is deduced that t-BuP4 and DBU catalysts are in an initiator/chain end activated ROP mechanism and TBD is in a nucleophilic ROP mechanism.

Keywords: 1,5-dioxepan-2-one; t-BuP4; DBU; TBD; organocatalyst

1. Introduction During the last several decades, for the ring-opening polymerization (ROP) of cyclic esters, transition metal and organometallic compounds were commonly used as initiators or polymerization catalysts [1–4]. Notwithstanding the polymerization processes are very successful in producing degradable polyesters and polycarbonates, it is clear that the metallic-based compounds are environmentally sensitive, and a lack of residual metal contaminants is required in biomedical and microelectronic applications [5–7]. For the last two decades, organocatalysts have provided a powerful strategy for the ROP of cyclic monomers, e.g., lactones, epoxides or carbonates, as the advantages of convergence of convenience, fast rates, functional group tolerance, selectivity and easy separating. Polyesters, polycarbonates, poly(ethylene oxide)s, polyphosphoesters and polysiloxanes, etc., have been well deﬁned with a controlled manner in molecular weight, molecular weight distribution, end groups, architecture, stereoregularity and monomers sequence by an organic acid or base catalysts [8–16]. Among the various organocatalysts, the most studied were phosphazenes, guanidines, and amidines. Hedrick and coworkers have prepared polycarbonates, polylactides with excellent controlling and functionality using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the organocatalysts [17–22]. Zhao and Zhang’s group have developed a number of poly(ethylene oxide) based copolymers and polymerization methods with phosphazene catalysts [23–26]. Although organocatalysts have been widely studied for ROP, they have not been used as catalyst for ROP of cyclic 1,5-dioxepan-2-one (DXO) as far as we know. DXO homopolymer is hydrophilic and completely amorphous with a low glass transition temperature (Tg) of approximately 39 C[27]. DXO based (co)polymers undergo hydrolysis in vitro − ◦ and vivo, and is, therefore, a possible candidate in the design of bio-absorbable materials [28–30]. In the same time, these properties are very useful in a degradable copolymer with the hydrophobic

Polymers 2019, 11, 1642; doi:10.3390/polym11101642 www.mdpi.com/journal/polymers Polymers 2019, 11, 1642 2 of 11 Polymers 2019, 11, x FOR PEER REVIEW 2 of 11 semiand- semi-crystallinecrystalline segment segments,s, suchsuch as aspoly( poly(ε-caprolactone)ε-caprolactone) (PCL) (PCL) and and poly( poly(lactide)lactide) (PLA). (PLA). Copolymerization of of DXO DXO and and other other cyclic cyclic esters esters has has been been investigated investigated to modify to modify and and improve improve the degradationthe degradation properties. properties. Statistical Statistical copolymers copolymers of DXO of with DXO lactide with have lactide shown have interesting shown interestingproperties onproperties degradation on degradation rates and stiffness, rates and which stiffness, could which be easily could altered be easily [31] altered. [31]. In the the present present work, work, we we have have studied studied the the ROP ROP of ofDXO DXO with with three three different different organacatalyst organacatalysts,s, 1- 1-terttert-butyl-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)phosphoranylidenamino]-2-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)phosphoranylidenamino]-2ΛΛ5,45Λ,45Λ- 5- MeCNMeCN MeCNMeCN catenadi(phosphazene) ( t--BuPBuP4,, pKpKa ais is 42.6), 42.6), 1,5,7 1,5,7-triazabicyclo[4.4.0]dec-5-ene-triazabicyclo[4.4.0]dec-5-ene (TBD, (TBD, pKpaK isa 26)is 26) and and 1,8 1,8-diazabicyclo[5.4.0]undec-7-ene-diazabicyclo[5.4.0]undec-7-ene (DBU, (DBU, MeCNMeCNpKpaK isa is 24.3), 24.3), which which have have verified verified basicity basicity,, catalcatalyticytic reactivityreactivity and and chemical chemical structure structure (Scheme (Scheme1)[ 8]. We 1) have [8] also. We explored have thealso copolymerization explored the copolymerof DXO withization CL of and DXO the with initiation CL and with the initiation poly(ethylene with poly(ethylene glycol) monomethyl glycol) mono ethermethyl (mPEG) ether as (macroinitiator,mPEG) as macroinitiator our aim is, to our well aim know is to the well ROP know process the ofROP DXO proc withess organocatalystsof DXO with organocatalysts which may be whichuseful may in synthesizing be useful in biodegradable synthesizing biodegradable materials. materials.

Scheme 1. 1.Ring-opening Ring-opening polymerization polymerization of 1,5-dioxepan-2-one of 1,5-dioxepan (DXO)-2-one with(DXOt-BuP) with4, 1,8-diazabicyclo t-BuP4, 1,8- diazabicyclo[5.4.0]undec[5.4.0]undec-7-ene (DBU)-7 and-ene 1,5,7-triazabicyclo[4.4.0]dec-5-ene (DBU) and 1,5,7-triazabicyclo[ (TBD)4 as.4.0]dec organocatalysts.-5-ene (TBD) as organocatalysts. 2. Materials and Methods

2.2.1. Materials Materials and Methods

2.1. MaterialDXO wass synthesized through Bayer-Villiger oxidation according to the literature, then puriﬁed by recrystallization from the dry ether, and two subsequent distillations under reduced pressure [32,33]. DXO was synthesized through Bayer-Villiger oxidation according to the literature, then purified ε-Caprolactone (CL) from Aldrich (Shanghai, China) was dried over calcium hydride (CaH2) and by recrystallization from the dry ether, and two subsequent distillations under reduced pressure distilled under reduced pressure prior to use. Ethylene glycol (EG) and benzyl alcohol (BnOH) [32,33]. ε-Caprolactone (CL) from Aldrich (Shanghai, China) was dried over calcium hydride (CaH2) from Sinopharm (Shanghai, China) were dried over sodium with protective nitrogen atmosphere and distilled under reduced pressure prior to use. Ethylene glycol (EG) and benzyl alcohol (BnOH) and distilled under reduced pressure prior to use. Tetrahydrofuran (THF) and toluene (TOL) from from Sinopharm (Shanghai, China) were dried over sodium with protective nitrogen atmosphere and Sinopharm (Shanghai, China) were freshly distilled from sodium/benzophenone and stored under distilled under reduced pressure prior to use. Tetrahydrofuran (THF) and toluene (TOL) from an argon atmosphere. DBU, TBD, t-BuP4 from Aldrich (Shanghai, China) were used as received, and Sinopharm (Shanghai, China) were freshly distilled from sodium/benzophenone and stored under other reagents from Sinopharm (Shanghai, China) were also used as received. an argon atmosphere. DBU, TBD, t-BuP4 from Aldrich (Shanghai, China) were used as received, and o2.2.ther Characterizations reagents from Sinopharm (Shanghai, China) were also used as received.

1 2.2. CharacterizationsProton nuclear magnetic resonance ( H NMR) spectra were recorded on a Bruker AV400 NMR spectrometer (Rheinstetten, Germany) by using deuterated chloroform (CDCl3) or benzene (C6D6) as theProton solvent nuclear and tetramethylsilane magnetic resonance (TMS) (1H asNMR) the internal spectra standard.were recorded The apparenton a Bruker number AV400 average NMR spectrometer (Rheinstetten, Germany) by using deuterated chloroform (CDCl3) or benzene (C6D6) as molecular weight (Mn) and polydispersity index (PDI) were measured at 35 ◦C on a Waters size theexclusion solvent chromatography and tetramethylsilane (SEC) (Milford, (TMS) as USA) the equipped internal standard. with a model The 510 apparent pump, number two identical average PL moleculargel columns weight (5 µm, (M MIXED-C)n) and polydispersity and a diﬀerential index refractive (PDI) were index measured detector at model 35 C 410on a (RI). Waters A series size exclusionof monodisperse chromatography polystyrenes (SEC) were (Milford, used USA as the) equipped standards with with a model THF as510 the pump, eluent two at identical a ﬂow rate PL gelof 1.0 columns mL/min. (5 μm, MIXED-C) and a differential refractive index detector model 410 (RI). A series of monodisperse polystyrenes were used as the standards with THF as the eluent at a flow rate of 1.0 mL/min.

2.3. Synthesis of PDXO homopolymer

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2.3. Synthesis of PDXO Homopolymer A typical polymerization was performed as follows: DXO (0.58 g, 5.0 mmol, 100 equiv) and BnOH (5.0 µL, 0.05 mmol, 1.0 equiv) were added to a flask with purified THF (2 mL) at room temperature. t-BuP4 (50 µL, 0.05 mmol, 1.0 equiv in hexane) was then added with a syringe to initiate the polymerization (most of the polymerization was handled in the glove box). For kinetic study, aliquots were withdrawn in an argon flow with designed time in order to monitor monomer conversions and evolution of molar masses. The polymerization was quenched by adding 0.1 mL acetic acid, a small 1 amount of the polymerization mixture was withdrawn and dissolved with CDCl3 for H NMR analysis and further diluted with THF for SEC measurement to obtain Mn and PDI. The rest polymerization mixture was diluted with THF and poured into a large excess of cold ether to precipitate the polymer which was then dried under vacuum. Polymerization of DXO with TBD, DBU and t-BuP4 as the catalyst under other conditions was carried out in a similar procedure (Table1). 1H NMR (400 MHz, CDCl3, δ, ppm): 4.22 (–COCH2CH2OCH2CH2O–, 2H), 3.75 (–COCH2CH2OCH2CH2O–, 2H), 3.65 (–COCH2CH2OCH2CH2O–, 2H), 2.61 (–COCH2CH2OCH2CH2O–, 2H).

Table 1. Characterization data of ring-opening polymerization (ROP) of DXO with three organocatalysts at various conditions a.

4 4 b Time Conv. Mn,NMR’ Mn,theo’ 10− Mn,SEC 10− e Samples Cat. f T (◦C) c 4 × c × d × e PDI (min) (%) 10− (g/mol) (g/mol) (g/mol)

H1 t-BuP4 50 25 5 95 0.55 0.56 0.60 1.24 H2 t-BuP4 100 25 15 96 1.10 1.17 1.08 1.28 H3 t-BuP4 200 25 120 >99 1.84 2.32 2.04 1.40 H4 t-BuP4 300 25 180 >99 2.45 3.49 3.25 1.35 H5 t-BuP4 500 25 600 >99 3.41 5.81 3.92 1.42 H6 t-BuP4 100 60 480 – – – gel – H7 t-BuP4 50 60 800 – – – gel – H9 t-BuP4 100 40 600 >99 1.13 1.17 1.22 1.28 H10 t-BuP 50 20 15 >99 0.58 0.59 0.61 1.31 4 − H11 TBD 50 25 30 >99 0.56 0.59 0.78 1.15 H12 TBD 100 25 50 >99 1.10 1.17 1.04 1.12 H13 TBD 500 25 600 >99 3.25 5.81 3.34 1.15 H14 TBD 50 60 1080 – – – gel – H15 DBU 50 25 180 >99 0.56 0.59 0.59 1.15 H16 DBU 100 25 600 >99 1.15 1.17 0.98 1.10 H17 DBU 500 25 1200 98 4.01 5.81 2.98 1.13 H18 DBU 50 60 1440 – – – gel – a BnOH was used as initiator (H6, H7, H9, H14, H18 with EG), T = 25 °C, THF as solvent, other polymerization at b c 1 d 60 ◦C was in bulk; molar ratio of DXO to initiator; calculated from H NMR analysis; calculated from ([M]0/[I]0) e monomer conversion (MW of DXO) + (MW of initiator); Obtained from SEC (size exclusion chromatography) analysis.× PDI, polydispersity× index.

2.4. Synthesis of Copolymer A typical procedure for copolymerization was performed as follows: DXO (0.58 g, 5.0 mmol, 50 equiv), CL (0.57 g, 5.0 mmol, 50 equiv) and BnOH (5.0 µL, 0.05 mmol, 1.0 equiv) were added to a flask with THF at room temperature in glove box. t-BuP4 (50 µL, 0.05 mmol, 1.0 equiv in hexane) was then added with a syringe to initiate the polymerization. The polymerization was quenched by adding 0.1 mL acetic acid and diluted with THF, which was then poured into a large excess of cold ether to precipitate the copolymer. The obtained copolymer was then dried under vacuum for further analysis. Copolymerization of mPEG and DXO was proceeded in a similar manner. 1H NMR (400 MHz, CDCl3, δ, ppm): 4.22 (–COCH2CH2OCH2CH2O–, 2H), 4.06 (–COCH2(CH2)3CH2O–, 2H), 3.75 (–COCH2CH2OCH2CH2O–, 2H), 3.65 (–COCH2CH2OCH2CH2O–, 2H), 2.61 (–COCH2CH2OCH2CH2O–, 2H), 2.25 (–COCH2(CH2)3CH2O–, 2H), 1.66 (–COCH2CH2CH2CH2CH2O–, 4H), 1.33 (–COCH2CH2CH2CH2CH2 O–, 2H). Polymers 2019, 11, x FOR PEER REVIEW 4 of 11

Polymers 2019, 11, 1642 4 of 11 H18 DBU 50 60 1440 ------gel -- a BnOH was used as initiator (H6, H7, H9, H14, H18 with EG), T = 25 ℃, THF as solvent, other 3. Resultspolymerization and Discussion at 60 C was in bulk; b molar ratio of DXO to initiator; c calculated from 1H NMR analysis; d calculated from ([M]0/[I]0)  monomer conversion  (MW of DXO) + (MW of initiator); e 3.1. PolymerizationObtained from SEC (size exclusion chromatography) analysis. PDI, polydispersity index. Polymerization of DXO was firstﬁrst proceeded with benzyl alcohol as the initiator because the 1 incorporation of benzyl benzyl-ester-ester end group could be easily detected by 1H NMR measurement measurement.. Table Table 11 presents thethe results results of of DBU, DBU, TBD TBD and andt-BuP t-BuP4 catalyzed4 catalyzed ROP ROP of DXO of atDXO varied at v reactionaried reaction conditions. conditions. The Mn ofThe PDXO Mn of increases PDXO withincreases the increasing with the of increasing monomer / ofinitiator monomer/initiator ratio indicates ratio that the indicates polymerization that the ispolymerization in a controlled is manner, in a controlled and we can manner prepare, and the we polymers can prepare with the molecular polymers weightwith the as molecular designed. Theweight PDI as for designed. all the preparedThe PDI for polymers all the prepa are narrow,red polymers and it are becomes narrow a,little and it wider becomes with a thelittle catalyst wider basicitywith the increasing. catalyst basicity Reaction increas time foring. reaching Reaction the time designed for reachingMn of these the organocatalysts designed Mn of is much these lowerorganocatalysts compared is with much other lower DXO compar ROPed catalysts, with other and DXO it decreases ROP catalysts with the, and organocatalysts it decreases with basicity the increasing [34,35]. The conversion can reach 99% even proceeding the polymerization at 20 C organocatalysts basicity increasing [34,35]. The conversion can reach 99% even proceeding− the◦ indicatespolymerization that the at reactivity−20 °C indicates of t-BuP that4 catalyzed the reactivity DXO polymerizationof t-BuP4 catalyzed is so DXO high. polymerization When we raise is the so temperaturehigh. When we to 60raise◦C, the there temperature is some interesting to 60 °C, phenomenon there is some for interesting all the three pheno catalysts.menon We for just all the obtained three gelcatalysts. after the We designed just obtained reaction gel time,after the and designed this will bereaction discussed time below., and this will be discussed below. 1 Figure1 1 shows shows thethe 1H NMR spectra of DXO and PDXO withwith tt-BuP-BuP44 as the catalyst catalyst.. The The signals signals,, due to the protons of DXO, PDXO main chain along with minor signals at 7.34,7.34, 5.20 ppm,ppm, due to the phenyl protons of BnO–BnO– and the methylene protons adjacent to the ester linkage for BnOH moiety of the initiator are observed.observed. In In addition, the peak peak,, due to the methylene protons beingbeing adjacent to the ω-chain-chain end ofof thethe hydroxylhydroxyl group,group, is is clearly clearly observed observed at at 3.70 3.70 ppm, ppm and, and the the peak peak area area is comparableis comparable to thatto that of of the the methylene methylene protons protons of of BnOH, BnOH, indicating indicating good good chain-end chain-end ﬁdelity.fidelity. Moreover,Moreover, thethe number 1 average molecular weight of the polymerpolymer estimated from 1H NMR fairly agrees with that calculated from the monomermonomer/initiator/initiator ratio and the monomer conversion (Table 1 1).). TheseThese resultsresults indicateindicate thatthat polymers havehave the expected structure with a ω-chain-end-chain-end hydroxyl group and α-chain-end-chain-end benzyl group, providing one way to synthesize telechelictelechelic PDXOPDXO and PDXO PDXO-based-based block copolymers. Similar results could also be concluded from TBDTBD andand DBUDBU catalyzedcatalyzed ROPROP ofof DXO.DXO.

Figure 1.1. 1HH NMR NMR spectr spectraa for for DXO DXO and and P PDXODXO (Table (Table 11,, H1).H1).

3.2. Ether Bond Fragmentation Figure2 shows 1H NMR spectrum of PDXO synthesized in bulk at 60 C with t-BuP as the Figure 2 shows 1H NMR spectrum of PDXO synthesized in bulk at 60 ◦°C with t-BuP44 as the catalyst (Table 1 1,, H6).H6). TheThe aliquotaliquot samplesample waswas takentaken outout ofof reactionreaction ﬂaskflask afterafter 22 hh andand quenchedquenched forfor 1 1H NMR analysis.analysis. InIn additionaddition toto the the signals signals for for PDXO PDXO main main chain, chain three, three new new signals signa appearls appear at 5.8, at 5.8, 6.2, 6.56.2, ppm6.5 ppm which which could could be attributed be attributed to the to threethe three protons protons of double of double bonds, bonds respectively., respectively Albertsson. Albertsson et al. have reported this phenomenon in stannous 2-ethylhexanoate (Sn(Oct) ) catalyzed ROP of DXO with et al. have reported this phenomenon in stannous 2-ethylhexanoate (Sn(Oct2 )2) catalyzed ROP of DXO awith temperature a temperature high thanhigh 120than◦ C120 and °C the and unsaturated the unsaturated chain-end chain were-end deducedwere deduced from thefrom ether the bondether fragmentationbond fragmentation [36].However, [36]. However, in our in experiments, our experiments the ether, the ether bond bond fragmentation fragmentation proceeded proceed onlyed atonly 60

Polymers 2019, 11, 1642 5 of 11 Polymers 2019, 11, x FOR PEER REVIEW 5 of 11 Polymers 2019, 11, x FOR PEER REVIEW 5 of 11 atC 60 when °C when using using the three the three organocatalysts, organocatalyst ands the, and resulted the resulted double double bonds reactedbonds reacted spontaneously spontaneously to form at◦ 60 °C when using the three organocatalysts, and the resulted double bonds reacted spontaneously tocrosslinks form crosslinks between between the polymer the polymer chains producing chains producing a gel after a 6,gel 16 after and 6, 24 16 h, and respectively. 24 h, respectively We speculate. We to form crosslinks between the polymer chains producing a gel after 6, 16 and 24 h, respectively. We speculatethat the organocatalysts that the organocatalysts with high with basicity high could basicity accelerate could accelerate the ether bond the ether fragment, bond andfragment a suggested, and a speculate that the organocatalysts with high basicity could accelerate the ether bond fragment, and a suggestedfragment pathwayfragment ispathwa showny is in shown Scheme in2 .Scheme The spontaneous 2. The spontaneous reaction reaction of unsaturated of unsaturated double double bonds suggested fragment pathway is shown in Scheme 2. The spontaneous reaction of unsaturated double bondsinduced induced during thermalduring thermal fragmentation fragmentation of ether bonds of ether may bonds provide may one provide new way one for new synthesizing way for bonds induced during thermal fragmentation of ether bonds may provide one new way for synthesizingdegradable hydrogels. degradable hydrogels. synthesizing degradable hydrogels.

Figure 2. 1H NMR spectrum of PDXO catalyzed with t-BuP4 in bulk at 60 °C (2 h) (Table 1, H6). Figure 2. 1HH NMR NMR spectr spectrumum of PDXO cataly catalyzedzed with tt--BuPBuP4 inin bulk bulk at at 60 60 °C◦C ( (22 h h)) (Table (Table 11,, H6).

Scheme 2.2Suggested. Suggested ether ether bond fragmentationbond fragmentation pathway during pathway organo-catalytic during organo DXO-cataly polymerization.tic DXO Scheme 2. Suggested ether bond fragmentation pathway during organo-catalytic DXO polymerization. 3.3. Kineticpolymerization Study . 3.3. Kinetic Study 3.3. KineticTo further Study confirm the controlled manner of organo-catalyzed ROP of DXO, we analyzed the M and PDI of the resulting PDXO as a function of the monomer conversion. The plot of M versus n To further confirm the controlled manner of organo-catalyzed ROP of DXO, we analyzedn the Mn conversionTo further is almost confirm linear the up controlled to a high manner monomer of conversionorgano-catalyzed suggesting ROP that of DXO, the depletion we analyzed of monomer the Mn and PDI of the resulting PDXO as a function of the monomer conversion. The plot of Mn versus and PDI of the resulting PDXO as a function of the monomer conversion. The plot of Mn versus conversionin the reaction is almost system linear is constant up to during a high the monomer polymerization conversion process suggesting (Figure3 A). that The the PDI depletion of PDXO of conversion is almost linear up to a high monomer conversion suggesting that the depletion of monomerremains constant in the reaction narrow system throughout is constant the polymerization, during the polymerization indicating that process the transesterification (Figure 3A). The e ffPDIect monomer in the reaction system is constant during the polymerization process (Figure 3A). The PDI ofis faint PDXO for theremains three organacatalysts. constant narrow In addition,throughoutMn increasesthe polymerization to higher value, indicating with the increase that the in ofmonomer PDXO conversionremains and constant the final narrowM becomes throughout higher withthe higherpolymerization monomer, toindicating initiator ratio that while the transesterification effect is faint for then three organacatalysts. In addition, Mn increases to higher value transesterificationmaintaining narrow effect PDI is with faintt-BuP for theas three the catalystorganacatalysts (Figure3.B). In addition These results, Mn increases clearly indicate to higher that value the with the increase in monomer conversion4 and the final Mn becomes higher with higher monomer to withorgano-catalyzed the increase in ROP monomer of DXO conversion is in a controlled and the manner. final Mn becomes higher with higher monomer to initiator ratio while maintaining narrow PDI with t-BuP4 as the catalyst (Figure 3B). These results initiator ratio while maintaining narrow PDI with t-BuP4 as the catalyst (Figure 3B). These results clearlyKinetics indicate experiments that the organo were-catalyzed carried out ROP to verify of DXO the is kinetic in a controlled order throughout manner. the polymerization clearly indicate that the organo-catalyzed ROP of DXO is in a controlled manner. process. As shown in Figure4A, the first-order relationship between ln([DXO] 0/[DXO]) and the reaction time with DBU, TBD and t-BuP4 as the ROP catalysts of DXO is observed. When TBD is used as a catalyst, the conversion of DXO reaches a level of more than 75% within 20 min, and the conversion is just 38% with DBU as the catalyst. Nevertheless, the conversion of DXO reaches a level of more than

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99% within 10 min when t-BuP4 is used as the catalyst. We speculate that the highest catalytic activity forPolymerst-BuP 42019is attributed, 11, x FOR PEER to itsREVIEW super basicity. 6 of 11

Figure 3. (A) Mn (solid) and PDI (hollow) versus monomer conversion for the ROP of DXO with t-

BuP4 (square), TBD (triangle) and DBU (circle) as catalysts ([M]0/[I]0 = 100/1); (B) Mn (solid) and PDI

(hollow) versus monomer conversion for different monomer to initiator ratio with t-BuP4 as catalyst.

Kinetics experiments were carried out to verify the kinetic order throughout the polymerization process. As shown in Figure 4A, the first-order relationship between ln([DXO]0/[DXO]) and the reaction time with DBU, TBD and t-BuP4 as the ROP catalysts of DXO is observed. When TBD is used as a catalyst, the conversion of DXO reaches a level of more than 75% within 20 min, and the Figure 3. (A) Mn (solid) and PDI (hollow) versus monomer conversion for the ROP of DXO with t- conversionFigure 3. is(A just) Mn 38%(solid) with and DBU PDI as (hollow) the catalyst. versus monomerNevertheless, conversion the conversion for the ROP of ofDXO DXO reach withest-BuP a level4 (square),BuP4 (square) TBD (triangle), TBD (triangle) and DBU and (circle) DBU as(circle) catalysts as catalysts ([M] /[I] ([M]= 1000/[I]/01); = 100/1) (B) M; ((solid)B) Mn (solid) and PDI and (hollow) PDI of more than 99% within 10 min when t-BuP4 is used as0 the0 catalyst. We speculaten that the highest versus(hollow monomer) versus conversionmonomer conversion for diﬀerent for monomerdifferent monomer to initiator to ratioinitiator with ratiot-BuP withas t-BuP catalyst.4 as catalyst. catalytic activity for t-BuP4 is attributed to its super basicity. 4 Kinetics experiments were carried out to verify the kinetic order throughout the polymerization process. As shown in Figure 4A, the first-order relationship between ln([DXO]0/[DXO]) and the reaction time with DBU, TBD and t-BuP4 as the ROP catalysts of DXO is observed. When TBD is used as a catalyst, the conversion of DXO reaches a level of more than 75% within 20 min, and the conversion is just 38% with DBU as the catalyst. Nevertheless, the conversion of DXO reaches a level of more than 99% within 10 min when t-BuP4 is used as the catalyst. We speculate that the highest catalytic activity for t-BuP4 is attributed to its super basicity.

Figure 4. (A) Kinetic plots ([DXO]0/[I]0 = 50/1) and (B) dependence of monomer conversion on reaction Figure 4. (A) Kinetic plots ([DXO]0/[I]0 = 50/1) and (B) dependence of monomer conversion on reaction time for the ROP of DXO with t-BuP4 (square), TBD (triangle) and DBU (circle) as catalysts. time for the ROP of DXO with t-BuP4 (square), TBD (triangle) and DBU (circle) as catalysts. 3.4. Copolymerization and Macroinitiator Initiation 3.4. Copolymerization and Macroinitiator Initiation Copolymerization is the most-used route to modify and improve the properties of polymers, Copolymerization is the most-used route to modify and improve the properties of polymers, we we proceeded the copolymerization of DXO/CL, and mPEG (Mn = 2000) was also used as the macroinitiatorproceeded the with copolymerization the three catalysts. of DXO From/CL Table, and2 mwePEG can (M seen = that 2000)m PEGwas with also usedone chain-end as the macroinitiator with the three catalysts. From Table 2 we can see that mPEG with one chain-end hydroxyl could initiate the ROP of DXO successfully; thus, a new kind of amphiphilic copolymers hydroxylFigure could 4. (A )initiate Kinetic plotsthe ROP ([DXO] of0 /[I]DXO0 = 50/1) successfully and (B) dependence; thus, a new of monomer kind of conversionamphiphilic on reactioncopolymers could be obtained. The Mn of the copolymers are as designed, the PDI are narrow, and the monomer couldtime be obtained. for the ROP T heof DXOMn of with the tcopolymers-BuP4 (square), are TBD as designed,(triangle) and the DBU PDI (circle) are narrow as catalysts, and .the monomer molar ratio in the ﬁnal copolymers are consistent with the initial monomers feeding calculated from molar ratio in the final copolymers are consistent with the initial monomers feeding calculated from 1H NMR (Figure5). These results deeply demonstrate that the organo-catalyzed ROP of DXO is in 13.4.H NMR Copolymerization (Figure 5). These and Macroinitiator results deeply Initiation demonstrate that the organo-catalyzed ROP of DXO is in a a controlledcontrolled manner. Copolymerization is the most-used route to modify and improve the properties of polymers, we a proceeded the copolymerizationTable 2. Characterization of DXO/CL data, and of DXOmPEG based (M copolymersn = 2000) was. also used as the Table 2. Characterization data of DXO based copolymers a. macroinitiator with the three catalysts. From Table 2 we can see that mPEG with one chain-end b 4 c c Samples Initiators Catalysts f Mn 10 (g/mol) PDI hydroxyl could initiate the ROP of DXO successfully; thus, a newMn kind× 10-4 − of amphiphilic copolymers Samples Initiators Catalysts f b PDI c could be obtained.S1 TmhePEG M2000n of -OHthe copolymerst-BuP4 are as designed,DXO the(g/mol) PDI are 0.72c narrow, and the 1.24 monomer S2 mPEG -OH TBD DXO 0.70 1.14 molar ratio in S1the final copolymersm2000PEG2000-OH are consistentt-BuP4 with DXOthe initial monomers0.72 feeding1.24 calculated from S3 mPEG -OH DBU DXO 0.73 1.10 1H NMR (Figure 5). These2000 results deeply demonstrate that the organo-catalyzed ROP of DXO is in a S4 c BnOH t-BuP CL/DXO 1.03 1.37 controlled manner. 4 S5 BnOH TBD CL/DXO 1.03 1.27 S6 BnOH DBU CL/DXO 1.12 1.09 Table 2. Characterization data of DXO based copolymers a. a b c T = 25 ◦C, THF as solvent; Molar ratio of monomer to initiator is 100:1, molar ratio of CL:DXO = 1:1; Obtained from SEC. -4 Mn  10 Samples Initiators Catalysts f b PDI c (g/mol) c S1 mPEG2000-OH t-BuP4 DXO 0.72 1.24

PolymersPolymers 2019 2019, 11, 11, x, xFOR FOR PEER PEER REVIEW REVIEW 7 7of of 11 11

S2S2 mmPEGPEG20002000--OHOH TBDTBD DXO 0.700.70 1.141.14 S3S3 mmPEGPEG20002000--OHOH DBUDBU DXO 0.730.73 1.101.10 c S4S4 c BnOHBnOH tt--BuPBuP44 CL/DXO 1.031.03 1.371.37 S5S5 BnOHBnOH TBDTBD CL/DXO 1.031.03 1.271.27 S6S6 BnOHBnOH DBUDBU CL/DXO 1.121.12 1.091.09 Polymersa Ta 2019T= =25 25, ℃11 ℃, 1642THF, THF as as solvent; solvent; b bMolar Molar ratio ratio ofof monomermonomer to initiator is 100:1,100:1, molarmolar ratio ratio o of fCL:DXO CL:DXO = =1:1 1:1; ;7 of 11 c Obtainedc Obtained from from SEC SEC. .

FigureFigure 5. 5.1H 1H NMR NMR spectra spectra of P(CL- of P(coCL-DXO)-co-DXO and) m andPEG mPEG-b2000-PDXO-b-PDXO copolymers copolymers with twith-BuP t-asBuP a catalyst.4 as a Figure 5. 1H NMR spectra of P(CL-co-DXO) and m2000PEG2000-b-PDXO copolymers with4 t-BuP4 as a catalyst. 3.5. Proposedcatalyst. Mechanism 3.5. Proposed Mechanism 3.5. ProposedWe finally Mechanism focused on the mechanism of these polymerizations, and 1H NMR was used to explore the possibleWe finally interaction focused of theon componentsthe mechanism in the of polymerization these polymerizations system., Hedrickand 1H NMR and coworkers was used have to We finally focused on the mechanism of these polymerizations, and 1H NMR was used to alsoexplore used the NMR possible to elucidate interaction the mechanism of the components of ROP with in the organocatalysts, polymerization and system. they indicatedHedrick and that explore the possible interaction of the components in the polymerization system. Hedrick and MTBDcoworkers form have hydrogen also used bonds NMR to the to alcoholelucidate of t anhe initiatormechanism [20 ].of Figure ROP with6A shows organo thecatalysts1H NMR, and spectra they coworkers have also used NMR to elucidate the mechanism of ROP with organocatalysts, and t1hey ofindicated BnOH, t -BuPthat MTBD4 and their form 1:1 hydrogen complex bonds in C6 toD 6the. For alcohol the mixture, of an initiator the downfield [20]. Figure shift 6A of shows the peaks the H for indicated that MTBD form hydrogen bonds to the alcohol of an initiator [20]. Figure 6A shows the 1H theNMR methylene spectra protonsof BnOH of, t- benzylBuP4 and alcohol their 1:1 is observed complex in from C6D 4.36. For to 5.4the ppm,mixture, while the the downfield upfield shift shift of for NMRthe peaks spectra for of the BnOH methylene, t-BuP 4protons and their of 1:1benzyl complex alcohol in Cis6 Dobserved6. For the from mixture, 4.3 to the 5.4 downfield ppm, while shift the of tert-butyl protons of t-BuP4 is observed from 1.80 to 1.36 ppm and from 2.74 to 2.48 ppm for methyl theupfield peaks shift for thefor tertmethylene-butyl protons protons of tof-BuP benzyl4 is observed alcohol fromis observed 1.80 to 1.36from ppm 4.3 toand 5.4 from ppm, 2.74 while to 2.48+ the protons. These results indicate that BnOH is deprotonated by t-BuP4 to form BnO− [t-BuP4,H] as upfield shift for tert-butyl protons of t-BuP4 is observed from 1.80 to 1.36 ppm and from· 2.74 to− 2.48 shownppm for in Schememethyl protons.3, which These act as results the initiating indicate activationthat BnOH center is deprotonated in the ROP by process t-BuP4 to of form DXO. BnO ROP∙[t of- − ppmBuP for4,H] methyl+ as shown protons. in Scheme These results3, which indicate act as thethat initiating BnOH is activationdeprotonated center by int-BuP the 4ROP to form process BnO of∙[t - DXO with t-BuP4 catalyst then occurs through an initiator/chain-end polymerization mechanism by BuP4,H]+ as shown in Scheme 3, which act as the initiating activation center in the ROP process of activationDXO. ROP initiator of DXO or with chain-end t-BuP4 hydroxyls. catalyst then Figure occur6Bs showsthrough the an1 Hinitiator/chain NMR spectra-end of BnOH,polymerization DBU and DXO. ROP of DXO with t-BuP4 catalyst then occurs through an initiator/chain-1end polymerization theirmechanism 1:1 complex by activation in C D and initiator we conclude or chain- theend similar hydroxyls results. Figure as in 6tB-BuP shows. the H NMR spectra of 6 6 4 1 mechanismBnOH, DBU by and activation their 1:1 initiator complex or in chain C6D6 -andend wehydroxyls conclude. Figure the similar 6B shows results the as inH t -NMRBuP4. spectra of BnOH, DBU and their 1:1 complex in C6D6 and we conclude the similar results as in t-BuP4.

1 Figure 6. H NMR spectra of (A) BnOH, t-BuP4 and their 1:1 complex in C6D6,(B) BnOH, DBU and

their 1:1 complex in C6D6.

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Figure 6. 1H NMR spectra of (A) BnOH, t-BuP4 and their 1:1 complex in C6D6, (B) BnOH, DBU and Figure 6. 1H NMR spectra of (A) BnOH, t-BuP4 and their 1:1 complex in C6D6, (B) BnOH, DBU and Polymerstheir2019 ,1:111, complex 1642 in C6D6. 8 of 11 their 1:1 complex in C6D6.

+ SchemeScheme 3. 3Generation. Generation of of B nBOnO−−[∙[tt-BuP-BuP44,H],H]+ asas the the initiating initiating species species for for the the ROP ROP of of DXO DXO.. Scheme 3. Generation of BnO−·∙[t-BuP4,H]+ as the initiating species for the ROP of DXO. 1 FigureFigure7A 7A shows shows the the H1H NMR NMR spectra spectra ofof BnOH,BnOH, TBDTBD andand theirtheir 1:1 complex in C 6DD66, ,and and,, in in this this Figure 7A shows the 1H NMR spectra of BnOH, TBD and their 1:1 complex in C6D6, and, in this condition,condition we, we conclude conclude the the similar similar resultsresults asas inin tt-BuP-BuP44 and DBU. TBD and DBU DBU have have comparable comparable condition, we conclude the similar results as in t-BuP4 and DBU. TBD and DBU have comparable basicitybasicity in in MeCN; MeCN thus,; thus the, the large large di differenceﬀerence inin catalyticcatalytic activityactivity observed for TBD TBD and and DBU DBU impl impliesies basicity in MeCN; thus, the large difference in catalytic activity observed for TBD and DBU implies thatthat the the thermodynamic thermodynamic basicity basicity is is not not the the solesole criterioncriterion for th thee ROP of of DXO DXO with with these these two two catalysts catalysts.. that the thermodynamic basicity is not the sole criterion for the ROP of DXO with these two catalysts. AccordingAccording to to the the previous previous publications, publications the, the role role of of TBD TBD in in ROP ROP may may be be bifunctional, bifunctional and, and it canit can also also act According to the previous publications, the role of TBD in ROP may be bifunctional, and it can also asact a nucleophile as a nucleophile [21,37 [21,37]]. Figure. Figure7B shows7B shows the the1H 1H NMR NMR spectra spectra of of DXO, DXO, TBDTBD and their 1:1 1:1 complex complex act as a nucleophile [21,37]. Figure 7B shows the 1H NMR spectra of DXO, TBD and their 1:1 complex inin C 6CD6D6.6. There There is is quite quite aa didifferenceﬀerence betweenbetween DXODXO andand TBDTBD/DXO/DXO mixture. TBD TBD could could catalyze catalyze the the in C6D6. There is quite a difference between DXO and TBD/DXO mixture. TBD could catalyze the ring-openingring-opening of of DXO, DXO, and and the the formed formed hydroxylshydroxyls endend shouldshould act as the initiator initiator center center just just as as in in the the ring-opening of DXO, and the formed hydroxyls end should act as the initiator center just as in the catalyticcatalytic system system of of DBU DBU and andt -BuPt-BuP4.4. TheseThese resultsresults areare consistent with with that that the the catalytic catalytic activity activity of of TBD TBD catalytic system of DBU and t-BuP4. These results are consistent with that the catalytic activity of TBD isis much much higher higher than than DBU, DBU and, and we we speculate speculate aa possiblepossible nucleophilicnucleophilic mechanism f foror the the ROP ROP of of DXO DXO is much higher than DBU, and we speculate a possible nucleophilic mechanism for the ROP of DXO withwith TBD TBD as as the the catalyst catalyst (Scheme (Scheme4). 4). with TBD as the catalyst (Scheme 4).

Figure 7. 1H NMR spectra of (A) BnOH, TBD and their 1:1 complex in C6D6; (B) DXO, TBD and their 1 1 FigureFigure 7. 7. HHNMR NMR spectraspectra ofof ((AA)) BnOH,BnOH, TBDTBD andand their 1:1 complex in in C C66DD6;6 ;((BB) )DXO, DXO, TBD TBD and and their their 1:1 complex in C6D6. 1:11:1 complex complex in in C C6D6D6.6.

Scheme 4. Proposed nucleophilic mechanism for the ROP of DXO with TBD as the catalyst.

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4. Conclusions 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino) phosphoranylidenamino]- 5 5 2Λ ,4Λ -catenadi(phosphazene) (t-BuP4), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), were used as the 1,5-dioxepan-2-one (DXO) ring-opening polymerization (ROP) catalysts at varied reaction conditions. Both 1H NMR spectra and kinetic studies prove that the polymerization was proceeded in a controlled manner. We have also synthesized the copolymers of DXO with CL and mPEG by the above catalysts. Among them, t-BuP4 shows the highest catalytic behavior and DBU plays the lowest one, which is attributed to the much higher basicity of t-BuP4 than DBU. It is demonstrated that t-BuP4 and DBU proceed the ROP of DXO in an initiator/chain-end mechanism and TBD is in a nucleophilic mechanism, which can also explain the higher catalytic activity of TBD than DBU while with comparable basicity. The organocatalyzed ROP of DXO may provide one useful way for preparing PDXO based biodegradable materials and the application of polyurethane with PDXO as the soft segments are under investigation.

Author Contributions: Writing—original draft preparation and funding acquisition, J.X.; investigation and data curation, Y.C.; formal analysis, W.X.; methodology, J.Z. and M.B.; writing—review and editing, X.Z. and C.L. Funding: This research was funded by the National Natural Science Foundation of China, grant number 21604015 and 51303193. This research was also funded by Guangdong Key Laboratory Foundation of High Performance and Functional Polymer Materials, grant number 20160003. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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