International Journal of Molecular Sciences

Review Progress in the Preparation of Functional and (Bio)Degradable Polymers via Living Polymerizations

Si-Ting Lin 1, Chung-Chi Wang 2, Chi-Jung Chang 3, Yasuyuki Nakamura 4,* , Kun-Yi Andrew Lin 5,* and Chih-Feng Huang 1,* 1 Department of Chemical Engineering, i-Center for Advanced Science and Technology (iCAST), National Chung Hsing University, Taichung 402-27, Taiwan; [email protected] 2 Division of Cardiovascular Surgery, Veterans General Hospital, Taichung 407-05, Taiwan; [email protected] 3 Department of Chemical Engineering, Feng Chia University, 100 Wenhwa Road, Seatwen District, Taichung 40724, Taiwan; [email protected] 4 Data-Driven Polymer Design Group, Research and Services Division of Materials Data and Integrated System (MaDIS), National Institute for Materials Science, Tsukuba 305-0047, Japan 5 Department of Environmental Engineering, Innovation and Development Center of Sustainable Agriculture & Research Center of Sustainable Energy and Nanotechnology, i-Center for Advanced Science and Technology (iCAST), National Chung Hsing University, Taichung 402-27, Taiwan * Correspondence: [email protected] (Y.N.); [email protected] (K.-Y.A.L.); [email protected] (C.-F.H.)



Received: 26 November 2020; Accepted: 14 December 2020; Published: 16 December 2020


Abstract: This review presents the latest developments in (bio)degradable approaches and functional aliphatic polyesters and polycarbonates prepared by typical ring-opening polymerization (ROP) of lactones and trimethylene carbonates. It also considers several recent innovative synthetic methods including radical ring-opening polymerization (RROP), atom transfer radical polyaddition (ATRPA), and simultaneous chain- and step-growth radical polymerization (SCSRP) that produce aliphatic polyesters. With regard to (bio)degradable approaches, we have summarized several representative cleavable linkages that make it possible to obtain cleavable polymers. In the section on functional aliphatic polyesters, we explore the syntheses of specific functional lactones, which can be performed by ring-opening copolymerization of typical lactone/lactide monomers. Last but not the least, in the recent innovative methods section, three interesting synthetic methodologies, RROP, ATRPA, and SCSRP are discussed in detail with regard to their reaction mechanisms and polymer functionalities.

Keywords: aliphatic polyesters; aliphatic polycarbonates; ring-opening radical polymerizations; simultaneous step- and chain-growth polymerizations; atom transfer radical polyadditions

1. Introduction (Bio)degradable plastics contain degradable units that include several components including at least one initiator, monomer, and cross-linker [1]. As demonstrated in Scheme1, numerous studies and reviews have reported on degradable or cleavable structural designs and their wide range of application in biomedicine, biotechnology, agriculture, environmental protection and microelectronics. In synthetic degradable polymers, the most prevalent degradable units are ester and disulfide linkages and the other groups include hemiacetal ester, trithiocarbonate, retro-Diels–Alder, carbonate, amino-ester, thio-ester, acetal, olefin, ortho-nitrobenzyl ester, and so on. Table1 presents the cleavable units and their corresponding cleavage methods/agents. Among the cleavable (bio)polymers, aliphatic polyesters, including the well-known FDA-approved poly(ε-caprolactone) (PCL) and polylactide (PLA) have

Int. J. Mol. Sci. 2020, 21, 9581; doi:10.3390/ijms21249581 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 17 presents the cleavable units and their corresponding cleavage methods/agents. Among the cleavable (bio)polymers, aliphatic polyesters, including the well-known FDA-approved poly(ε-caprolactone) Int. J. Mol. Sci. 2020, 21, 9581 2 of 17 (PCL) and polylactide (PLA) have attracted significant attention, not only due to their high (bio)degradability and biocompatibility but also their cost-effect features [2]. Several simple approachesattracted to functionalized significant attention, po notlyester-based only due to their copolymers high (bio)degradability have been and biocompatibilitydemonstrated but through also the their cost-effect features [2]. Several simple approaches to functionalized polyester-based copolymers copolymerization of epoxides and cyclic anhydrides [3–5], Passerini reactions [6–8], or Baylis– have been demonstrated through the copolymerization of epoxides and cyclic anhydrides [3–5], HillmanPasserini reactions reactions [9,10]. [6 –In8], orthis Baylis–Hillman review, we reactions have [mainly9,10]. In thisfocused review, on we haverepresentative mainly focused studies of functionalon aliphatic representative polyesters studies ofand functional several aliphatic new types polyesters of degradable and several polyesters new types and of degradable polycarbonates. We startpolyesters by examining and polycarbonates. innovative synthetic We start by methods, examining innovativeincluding synthetic the design methods, of functional including the lactone (f- lactone) designand trimethylene of functional lactone carbonate (f-lactone) monomers, and trimethylene radical carbonatering-opening monomers, polyme radicalrization ring-opening (RROP), atom polymerization (RROP), atom transfer radical polyaddition (ATRPA), and simultaneous chain- transfer radical polyaddition (ATRPA), and simultaneous chain- and step-growth radical and step-growth radical polymerization (SCSRP) and investigate their degradable properties and polymerizationrelated applications. (SCSRP) and investigate their degradable properties and related applications.

SchemeScheme 1. Representative 1. Representative applications applications of functionalfunctional and and degradable degradable polymers. polymers. Table 1. Cleavable units, cleaving methods/agents, and main generated group(s) after cleavage. Table 1. Cleavable units, cleaving methods/agents, and main generated group(s) after cleavage. Generated End-Group(s) Name of Cleavable Unit Cleaving Method/Agent Ref after Cleavage Name of Cleaving Generated End-Group(s) after Ester acids/bases/enzymes hydroxyl & carboxylic acid [11] Ref Cleavable UnitDisulfide Method/Agent DTT/GSH/Bu 3PCleavage thiol [12–14] EsterHemiacetal ester acids/bases/enzymes acids/alcohols hydroxyl carboxylic & carboxylic acid acid [15 ,16] [11] Trithiocarbonate amines thiol [17,18] DisulfideCarbonate DTT/GSH/Bu acids/bases3/Penzymes hydroxylthiol [19,20] [12–14] HemiacetalAmino-ester ester acids/alcohols acids/bases/enzymes amine carboxylic & carboxylic acid acid [21,22] [15,16] Thio-ester acids/bases thiol & carboxylic acid [23,24] Trithiocarbonateretro-Diels–Alder 1 amines heat furan & maleimide thiol [25,26] [17,18] 2 CarbonateAcetal acids/bases/enzymesacids/TFA(g) hydroxyl hydroxyl [27] [19,20] ortho-nitrobenzaldehyde & ortho-Nitrobenzyl ester UV (350 nm) [28,29] Amino-ester acids/bases/enzymes aminecarboxylic & carboxylic acid acid [21,22] Thio-ester Olefin acids/bases ozone thiol & aldehyde carboxylic acid [30] [23,24] 1 2 retro-Diels–AlderAn example 1of rDA reactions basedheat on a pair of furan and maleimide moieties. furan &TFA maleimide(g): vapor of trifluoroacetic [25,26] acid (DTT: dithiothreitol; GSH: glutathione; Bu3P: tributylphosphine; TFA: trifluoroacetic acid). Acetal acids/TFA(g) 2 hydroxyl [27] ortho2.-Nitrobenzyl Synthesis of Functional Aliphatic Polyesters and Polycarbonatesortho-nitrobenzaldehyde by Ring-Opening Polymerization (ROP) UV (350 nm) [28,29] ester & carboxylic acid Ring-opening polymerization (ROP) is one of the most widely used methods for the syntheses of Olefin ozone aldehyde [30] aliphatic polyesters [31]. In the presence of the initiator or the catalyst, lactones and lactides can be 1 2 Anpolymerized example of efficiently rDA reactions through based the fragmentation on a pair of thefuran ring, and typically maleimide in an anionic moieties. pathway TFA under(g): vapor mild of trifluoroacetic acid (DTT: dithiothreitol; GSH: glutathione; Bu3P: tributylphosphine; TFA: trifluoroacetic acid).

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 17

2. Synthesis of Functional Aliphatic Polyesters and Polycarbonates by Ring-Opening Polymerization (ROP) Ring-opening polymerization (ROP) is one of the most widely used methods for the syntheses of aliphatic polyesters [31]. In the presence of the initiator or the catalyst, lactones and lactides can be

Int.polymerized J. Mol. Sci. 2020 efficiently, 21, 9581 through the fragmentation of the ring, typically in an anionic pathway under3 of 17 mild reaction conditions, which produces aliphatic polyesters with highly (bio)degradable and biocompatible features. This analog of aliphatic polyesters can be reacted with the chain-end reactionhydroxyl conditions, group(s) to which perform produces further aliphatic functionalization, polyesters with modification highly (bio)degradables, or chain extensions. and biocompatible Thus, the features.limited numbers This analog of offunctionalizable aliphatic polyesters end(s) can thus be reacted can be with anticipated the chain-end [32–34]. hydroxyl However, group(s) rendering to perform a furthervariety functionalization,of functional groups modifications, on aliphatic or chainpolyester extensions. backbones Thus, remains the limited challenging numbers ofsince functionalizable ROP cannot end(s)usually thus tolerate can behigh-polar anticipated groups [32–34 [35–39].]. However, As sh renderingown in Scheme a variety 2a, (co)polymerization of functional groups of on functional aliphatic polyesterlactones (f-lactones) backbones and remains lactones/lactides challengingsince provides ROP a cannot simple usually synthetic tolerate approach high-polar to render groups groups [35 –that39]. Asare shownless polar in Scheme but compatible2A, (co)polymerization with typical ROP of functional catalysts. lactones Numerous (f-lactones) studies and on lactonesthe synthesis/lactides of providesfunctional a simplealiphatic synthetic polyesters approach (f-APs) to renderare listed groups in Scheme that are 2b. less Most polar butnotably, compatible Jérôme with et al. typical [40] ROPreported catalysts. the first Numerous case of studiescontrolle ond/living the synthesis ROP of of 5-ethylene functional aliphaticketal ε-caprolactone polyesters (f-APs) to produce are listed well- in Schemedefined2 PCLB. Most with notably, cleavable J érô pendantme et al. groups [40] reported (Mn = theca. first7000 case and of M controlledw/Mn = 1.15)./living PCL ROP backbones of 5-ethylene with ketalhydroxylε-caprolactone pendant groups to produce can well-defined be quantitatively PCL with obtained cleavable through pendant an groups efficient (M n deacetalization= ca. 7000 and Mreaction.w/Mn = The1.15). novel PCL backbonesamphiphilic with PCL hydroxyl can also pendant form stable groups and can homogeneous be quantitatively colloidal obtained solutions through anin efficientwater. The deacetalization study presented reaction. the pioneering The novel idea amphiphilic of functional PCL cancyclic also monomer form stable designs and homogeneousand explored colloidalthe synthesis solutions of f-APs in water. and their The study application presented in aque the pioneeringous solutions. idea ofIn functionalanother example cyclic monomer of the synthesis designs andof f-AP explored and their the synthesis related applications, of f-APs and their Chang application et al. [41] in reported aqueous solutions.the synthesis In another of f-APs example possessing of the synthesispendant ( ofpen f-AP) chlorides and their via related ROP applications,of α-chloro-ε Chang-caprolactone et al. [41 ]and reported ε-caprolactone the synthesis (i.e., of PCL– f-APspen possessing–(n Cl), pendantn = 10, M (penn = )ca. chlorides 17,800 and via ROPMw/M ofn α= -chloro-1.5). Theε-caprolactone pendent chlorides and ε -caprolactonecan subsequently (i.e., PCL–be convertedpen–(n Cl), to nazides= 10, Mandn = usedca. 17,800 in Cu(I)-catalyzed and Mw/Mn = 1.5).alkyne-azide The pendent cycloaddition chlorides can reactions subsequently to graft be convertednucleobase to azideshydrogen and bonding used in Cu(I)-catalyzedunits, i.e., uracil alkyne-azide (U)/adenine cycloaddition(A) along the PCL reactions backbones. to graft Mediation nucleobase by hydrogen multiple bondinghydrogen units, bonding i.e., uracilunits results (U)/adenine in two (A) types along of thecomplementary PCL backbones. macromolecules Mediation by that multiple can form hydrogen stable bondingand reversible units results physical in two crosslinking types of complementary networks. Fu macromoleculesrther evaluation that by can L929 form cell stable cytotoxicity and reversible tests physicalrevealed crosslinkingthat the PCL-based networks. supramolecular Further evaluation networks by L929possess cell excellent cytotoxicity biocompatible tests revealed properties. that the PCL-basedThis innovative supramolecular study demonstrates networks possess the preparation excellent biocompatible of physically properties. crosslinked This and innovative mechanically study demonstratesstable PCL materials the preparation with excellent of physically biocompatible crosslinked properties and mechanically that have stablepotential PCL for materials biomedical with excellentengineering biocompatible applications. properties that have potential for biomedical engineering applications.

(B)

ref [45-49]

ref [42] ref [40]

ref [49-52]

ref [43] ref [41] ref [44]

Scheme 2. (A) Synthesis of functional aliphatic polyesters (f-Aps) via ring-opening polymerization Scheme 2. (a) Synthesis of functional aliphatic polyesters (f-Aps) via ring-opening polymerization (ROP). (B) Examples of f-lactones to attain f-APs (α-propargyl-δ-valerolactone [42]; 5-ethylene ketal (ROP). (b) Examples of f-lactones to attain f-APs (α-propargyl-δ-valerolactone [42]; 5-ethylene ketal ε-caprolactone (m’ = 3, X = H, Y = ketal) [40]; α-fluoro-ε-caprolactone (m’ = 3, X = F, Y = H) [43]; α-chloro-ε-caprolactone (m’ = 3, X = Cl, Y = H) [41]; α-iodo-ε-caprolactone (m’ = 3, X = I, Y = H) [44]; racemic 4-alkyl methylene-β-propiolactones (m’ = 0, X = H, Y = -CH3, -C2H5, -C4H9, -CH2C4F9) and racemic 4-alkoxymethylene-β-propiolactones (m’ = 0, X = H, Y = -OCH = CH2, -O(CH2)3CH3, -OCH2Ph) [45–49]; alkyl β-malolactonates (m’ = 0, X = H, Y = -COOCH3, -COOCH2CH = CH2, -COOCH2Ph) [49–52]). Int. J. Mol. Sci. 2020, 21, 9581 4 of 17

On the other hand, β-propiolactone derivatives can be regarded as a renewable type monomer obtained by effective and eco-friendly carbonylation of racemic epoxides [53]. Interestingly, Thomas et al. [54] addressed the polymerization mechanism of “syndio-control” from stereo-monomers. For example, ROP of racemic 4-alkyl-β-propiolactones (racBPL-Rs) with various alkyl groups (e.g., -R: -CH3, -C2H5, -C4H9, -CH2C4F9) produces functional polyhydroxyalkanoates (PHAs) with well controlled tacticity. As revealed from the in situ 1H NMR measurements, the formation of a highly alternating PHA was achieved. The elegant syndio-controlled ROP provides a new type of promising (bio)degradable aliphatic polyesters. With the design of effective and specific catalysts, Carpentier et al. [45–47,49] recently reported an elegant strategy that uses rare-earth complexes that incorporate dianionic diamino-oramino-alkoxy-bis(phenolate) ligands to obtain novel PHA copolymers. Basically, a simple and effective chain-end syndio-control mechanism is used, which results in the stereo-selective ROP of chiral β-lactones. For example, the ring-opening copolymerization of racemic 4-alkoxymethylene-β-propiolactones (racBPL-ORs) was studied (-OR: -OCH2CH = CH2, -OCH3, -OCH2Ph, -OSi(CH3)2C(CH3)3). The results revealed stereo-control via the catalysts and specific alternative poly(3-hydroxybutyrate) (PHB) copolymers of 1 2 1 2 P[(HB-OR )-alt-(HB-OR )] with various alkoxy groups (e.g., -OR : -OCH2CH = CH2; -OR : -OCH3) were obtained. The main factors for achieving a high degree of alternation include the use of: (i) a highly syndio-selective catalyst; and (ii) a proper ratio of (R)-BPL-OR1/(S)-BPL-OR2 monomers. Accordingly, we can expect the formation of novel stereo-complexes through the blending of the resulting enantiomorphic polyesters. Besides the well-known aliphatic polyesters, another family of emerging, highly (bio)degradable and biocompatible aliphatic polycarbonates, poly(trimethylene carbonate) (PTMC), have also been extensively investigated [55]. Being the starting material for trimethylene carbonate (TMC), 1,3-propanediol can be acquired from the degradation of natural carbohydrates or ring-closure carbonylation of carbon dioxide [56]. The analog of TMC monomers is thus referred to as a renewable resource. As shown in Scheme3a, f-PTMCs can be synthesized by ROP of f-TMCs through either typical organometallic catalysts or organo-catalysts [57]. As illustrated in Scheme3b, several representative functional groups (FG) on the TMC ring are addressed, including (i) OH, (ii) COOH, (iii) allyl/SH, (iv) propargyl, (v) epoxide, (vi) norbornene, (vii) maleimide, and so on. In order to further graft specific (macro)molecules, post-reactions between FG and PG can be performed via (i) etherification, (ii) esterification, (iii) thiol-ene, (iv) alkyne–azide cycloaddition, (v) epoxide–amine, (vi) Diels–Alder, (vii) Michael addition, and so forth. For example, Harth et al. [58] reported the synthesis of PTMC-based hydrogels with various crosslinking reagents. They first synthesized PTMCs with pendant functional groups of both ethyl ester (i.e., PTMC-pen-(O)COEt) and allylic ester (i.e., PTMC-pen-(O)COCH2=). Subsequently, thio-ene click reactions of the (PTMC-=) and (HS-(EG)n-SH) (EG: ethylene glycol; n = 1 or 35) were conducted to obtain PTMC-crosslinked hydrogels. A polyol of branched polyglycidol (PGY) and a transesterification catalyst of zinc acetate (Zn(OAc)2) were further introduced into the hydrogels. Interestingly, the composite underwent a chemical self-modification from the PTMC/PGY/(Zn(OAc)2) hydrogels at high temperature (ca. 120 ◦C) on the basis of dynamic covalent bonds. Accordingly, the attractive renewable feature of f-TMC monomers and their ability to render diverse pendant functional (macro)molecules on f-PTMCs has led to very high expectations for their application to variousInt. J. Mol.practical Sci. 2020, 21 uses., x FOR PEER REVIEW 5 of 17

Scheme 3. Cont.

Scheme 3. (a) General structures of f-TMCs with functional groups (FGs) on trimethylene carbonates (TMCs) and post-reactions with R-PG (macro)molecules. (b) Examples of post-reactions between f- PTMCs and R-PG (macro)molecules through the formation of new linkages (i.e., forming “Link”).

3. Synthesis of Aliphatic Polyesters by Radical Ring-Opening Polymerization (RROP) Polyesters are typically synthesized by either ROP of lactones/lactides [31] or polycondensation of hydroxyl and acid monomers [59]. In the 1980s, Bailey et al. [60–64] reported the pioneering cases of free radical ring-opening polymerizations (RROPs) of specific cyclic ketene acetal (CKA) and cyclic acrylate (CA) monomers initiated by conventional thermal initiators (i.e., peroxide and azo compounds). These studies established an innovative approach for producing a variety of functional polyesters on the basis of radical chemistry. Thereafter in the 1990s, Endo et al. [65–67] and Rizzardo et al. [68] designed a series of specific vinylcyclopropane (VCP) and cyclic allylic sulfide (CAS) monomers, respectively, to produce f-APs as well. RROP of VCPs rendered ester linkages in the backbone and also improved the introduction of other functionalities into the backbone (e.g., olefin and phenyl) and at the pendent sides (e.g., benzyl and ethylene ketal) (Mn = 22,000 and Mw/Mn = 2.05). In the case of the RROP of CASs, polyester backbones with sulfide linkages and pendant double bonds were obtained (Mn = 46,200 and Mw/Mn = 2.3). The monomers for RROP are classified into two types: the vinyl type such as VCP and the exo- methylene type such as CKA. In the RROP mechanism of both monomers, a radical species is added to the carbon–carbon double bond and thus generates a carbon-centered radical, then the radical ring- opening reaction generates a new carbon-centered radical via the cleavage of a carbon–carbon bond or a carbon-heteroatom bond (Scheme 4). The polymerization of these monomers proceeds inherently

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 5 of 17

Int. J. Mol. Sci. 2020, 21, 9581 5 of 17

Scheme 3. (a) General structures of f-TMCs with functional groups (FGs)(FGs) onon trimethylenetrimethylene carbonatescarbonates (TMCs)(TMCs) and post-reactions wi withth R-PG R-PG (macro)molecules. (macro)molecules. (b (b) )Examples Examples of of post-reactions post-reactions between between f- f-PTMCsPTMCs and and R-PG R-PG (macro)molecules (macro)molecules through through the the formation formation of of new new link linkagesages (i.e., (i.e., forming forming “Link”). “Link”). 3. Synthesis of Aliphatic Polyesters by Radical Ring-Opening Polymerization (RROP) 3. Synthesis of Aliphatic Polyesters by Radical Ring-Opening Polymerization (RROP) Polyesters are typically synthesized by either ROP of lactones/lactides [31] or polycondensation Polyesters are typically synthesized by either ROP of lactones/lactides [31] or polycondensation of hydroxyl and acid monomers [59]. In the 1980s, Bailey et al. [60–64] reported the pioneering cases of hydroxyl and acid monomers [59]. In the 1980s, Bailey et al. [60–64] reported the pioneering cases of free radical ring-opening polymerizations (RROPs) of specific cyclic ketene acetal (CKA) and cyclic of free radical ring-opening polymerizations (RROPs) of specific cyclic ketene acetal (CKA) and cyclic acrylate (CA) monomers initiated by conventional thermal initiators (i.e., peroxide and azo compounds). acrylate (CA) monomers initiated by conventional thermal initiators (i.e., peroxide and azo These studies established an innovative approach for producing a variety of functional polyesters on the compounds). These studies established an innovative approach for producing a variety of functional basis of radical chemistry. Thereafter in the 1990s, Endo et al. [65–67] and Rizzardo et al. [68] designed polyesters on the basis of radical chemistry. Thereafter in the 1990s, Endo et al. [65–67] and Rizzardo a series of specific vinylcyclopropane (VCP) and cyclic allylic sulfide (CAS) monomers, respectively, et al. [68] designed a series of specific vinylcyclopropane (VCP) and cyclic allylic sulfide (CAS) to produce f-APs as well. RROP of VCPs rendered ester linkages in the backbone and also improved monomers, respectively, to produce f-APs as well. RROP of VCPs rendered ester linkages in the the introduction of other functionalities into the backbone (e.g., olefin and phenyl) and at the pendent backbone and also improved the introduction of other functionalities into the backbone (e.g., olefin sides (e.g., benzyl and ethylene ketal) (Mn = 22,000 and Mw/Mn = 2.05). In the case of the RROP of CASs, and phenyl) and at the pendent sides (e.g., benzyl and ethylene ketal) (Mn = 22,000 and Mw/Mn = 2.05). polyester backbones with sulfide linkages and pendant double bonds were obtained (M = 46,200 and In the case of the RROP of CASs, polyester backbones with sulfide linkages and pendantn double Mw/Mn = 2.3). bonds were obtained (Mn = 46,200 and Mw/Mn = 2.3). The monomers for RROP are classified into two types: the vinyl type such as VCP and the The monomers for RROP are classified into two types: the vinyl type such as VCP and the exo- exo-methylene type such as CKA. In the RROP mechanism of both monomers, a radical species is methylene type such as CKA. In the RROP mechanism of both monomers, a radical species is added added to the carbon–carbon double bond and thus generates a carbon-centered radical, then the radical to the carbon–carbon double bond and thus generates a carbon-centered radical, then the radical ring- ring-opening reaction generates a new carbon-centered radical via the cleavage of a carbon–carbon bond opening reaction generates a new carbon-centered radical via the cleavage of a carbon–carbon bond or a carbon-heteroatom bond (Scheme4). The polymerization of these monomers proceeds inherently or a carbon-heteroatom bond (Scheme 4). The polymerization of these monomers proceeds inherently via the RROP mechanism or a conventional vinyl polymerization mechanism. Only RROP provides an ester structure in the polymer main chain, thus it is essential to use monomers that have high RROP selectivity. Kinetic and thermodynamic factors are required for the selectivity: (i) the ring-opening reaction is accelerated due to the strain of the ring; and (ii) the resulting new carbon-centered radical is stabilized and/or the ring-opening reaction involves thermodynamically favored isomerization of the functional group. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 6 of 17 via the RROP mechanism or a conventional vinyl polymerization mechanism. Only RROP provides an ester structure in the polymer main chain, thus it is essential to use monomers that have high RROP selectivity. Kinetic and thermodynamic factors are required for the selectivity: (i) the ring- opening reaction is accelerated due to the strain of the ring; and (ii) the resulting new carbon-centered Int.radical J. Mol. is Sci. stabilized2020, 21, 9581 and/or the ring-opening reaction involves thermodynamically favored6 of 17 isomerization of the functional group.

Y (a) X Y R Y (i) R R X X X Y X Y n (ii) n Y X X Y

X (b) Y (i) Z X X X X R Y R Y R Z Z Z Y Z Y n (ii) X, Z = O: Polyester X n Y Z X Z Y

Scheme 4. MechanismMechanism of ofradical radical ROP ROP (RROP) (RROP) for forvinyl vinyl type type (a) (anda) and exo-methyleneexo-methylene type type (b) (monomers.b) monomers. For For both both monomer monomer types, types, two two possible possible polymerization polymerization mechanisms mechanisms exist: exist: (i) (i) RROP RROP and (ii) vinyl polymerization.polymerization.

Scheme 55aa displaysdisplays representativerepresentative CKAsCKAs withwith highhigh oror exclusiveexclusive RROPRROP selectivity.selectivity. OneOne ofof thethe most attractive features of RROP of CKA is the copolymerization with conventional vinyl monomers including (meth)acrylates, (meth)acrylates, styrenes, styrenes, vinyl vinyl pyridine, pyridine, vinyl vinyl acetate, acetate, and and N-vinylpyrrolidone,N-vinylpyrrolidone, which which can canreadily readily provide provide various various (bio)degradable (bio)degradable f-PE. f-PE.The size The of size the ofring the of ring CKA of is CKA one of is onethe major of the factors major factorscontrolling controlling the selectivity the selectivity in the inmechanism. the mechanism. CKA CKAwith withstrained strained rings, rings, for example, for example, the the7 and 7 and 8- 8-memberedmembered ones ones are are more more favorable favorable in in the the RROP RROP compared compared to to the the stable stable 5 5 and and 6-membered 6-membered ones. ones. Namely, thethe polymerizationpolymerization of of the the 7-membered 7-membered ring ring monomer monomer MDO MDO exclusively exclusively provides provides polyester polyester via thevia selectivethe selective RROP; RROP; however, however, the selectivity the selectivity of the RROP of the mechanism RROP mechanism of the corresponding of the corresponding 6-membered 6- ringmembered monomer ring 2-methylene-1,3-dioxane monomer 2-methylene-1,3-dioxane decreases to about decreases 50%. Another to about important 50%. Another structural important factor is thestructural introduction factor ofis the a stabilizing introduction group of fora stabil the carbon-centeredizing group for the radical carbon-centered generated by radical the ring-opening, generated whichby the arering-opening, typically phenyl which or are alkyl typically groups. phenyl While or the alkyl ring-opening groups. While occurs the from ring-opening both sides occurs of an acetal from ring,both sides the introduction of an acetal ofring, a radical the introduction stabilizing of group a radical regulates stabilizing the side group of the regulates ring-opening the side that of hasthe thering-opening group. In addition,that has the the group. relative In reactivity addition, between the relative CKA andreactivity the vinyl between monomer CKA is and critical the invinyl the copolymerizationmonomer is critical to preparein the copolymerization f-PE. Because the to olefin prepare of CKA f-PE. is veryBecause electron-rich, the olefin theof reactionCKA is withvery propagatingelectron-rich, radicals the reaction formed with from propagating common vinylradicals monomers, formed from which commo are nucleophilicn vinyl monomers, or amphiphilic, which isare relatively nucleophilic unfavored or amphiphilic, [69]. Therefore, is relatively the reactivity unfavored ratio [69]. in the Therefore, copolymerization the reactivity of CKA ratio and in vinyl the monomerscopolymerization is often of rCKA CKA<< and1 < rvinylvinyl, whichmonomers impedes is often the incorporation rCKA << 1 < ofrvinyl the, which CKA monomer impedes andthe causesincorporation a deviation of the between CKA monomer the composition and causes of polymer a deviation from between the monomer the composition feeding ratio. of polymer For example, from inthe the monomer copolymerization feeding ratio. of MDO For andexample, MMA, in the the reactivity copolymerization ratios are r MDOof MDO= 0.057 and and MMA, rMMA the= 34.12reactivity [70], andratios the are composition rMDO = 0.057 of and MDO rMMA in the= 34.12 resulting [70], and polymer the composition is 4% (polymerization of MDO in at the 40 ◦ resultingC) or 30% polymer (at 120 ◦ C)is from4% (polymerization copolymerization at 40 with °C) or a monomer30% (at 120 feeding °C) from ratio copolymerization of MDO/MMA with= 54 /a46 monomer or 50/50, feeding respectively. ratio Onof MDO/MMA the other hand, = 54/46 the or copolymerization 50/50, respectively. of CKAOn th withe other vinyl hand, acetate the copolymerization (VAc) undergoes of in CKA an almost with randomvinyl acetate manner (VAc) (i.e., undergoes more statistical in an distributionalmost random of monomers manner (i.e., in the more chain), statistical which isdistribution confirmed byof rmonomersCKA = 0.93 in and the r VAcchain),= 1.71 which in the is copolymerizationconfirmed by rCKA with = 0.93 MDO and [r71VAc], and= 1.71 this in providesthe copolymerization a copolymer with MDO a homogeneous [71], and this composition provides a of copolymer CKA and with VAc a that homogeneous is similar tocomposition the monomer of CKA feeding and ratio.VAc Thisthat featureis similar is notto the limited monomer to VAc, feeding and other ratio. vinyl This carboxylate feature is monomers not limited also to giveVAc, a and copolymer other vinyl with CKAcarboxylate in an almostmonomers random also give manner. a copolymer Additionally, with CKA the copolymerizationin an almost random of vinylmanner. bromobutanoate Additionally, and MDO [72], with post-modification through alkyne-azide cycloaddition results in PEG-grafted degradable polyester. Recently,interesting progress in the scope of copolymerization has been reported. Guillaneuf et al. [75] reported the copolymerization of vinyl ether and MDO in a highly random manner. The composition of monomers during the polymerization reaction was found to follow the initial feeding ratio of the monomers. The copolymerization reactivity ratio was rMDO = 0.73 and rvinyl ether = 1.61, which is Int. J. Mol. Sci. 2020, 21, 9581 7 of 17 consistent with of the theoretical calculation of the reaction rate for the α-oxyethyl radical and MDO. The highly random manner could also be related to the fact that vinyl ethers are not homopolymerized by the radical polymerization. The synthetic benefit of vinyl ether for f-PE is the ready availability of various functional monomers, and indeed, Cl, oligo(ethylene glycol) and terminal alkene functionalized vinyl ethers have been shown to give copolymers with MDO. These copolymers were further modified to obtain a fluorescent probe functionalized polymer and a degradable elastomer. Another recent example is the copolymerization of BMDO and maleimide reported by Sumerlin [76]. The copolymerization proceeded with the quantitative ring-opening of BMDO to the ester and in a highly alternating manner. The copolymer was readily functionalized by utilizing N-substituent of maleimide, and the alternating structure might be suitable for fast degradation to low molecular weight fragments. Interestingly,Int. J. Mol. Sci. 2020 although, 21, x FOR the PEER alternative REVIEW copolymerization of other CKAs such as MDO and maleimide7 of 17 has been reported, the selectivity of the ring-opening of CKA was not enough, which indicates that the appropriatecopolymerization combination of vinyl of monomerbromobutanoate and the reactivityand MDO is [72], quite with important post-modification in designing thethrough CKA copolymeralkyne-azide as cycloaddition a f-PE. results in PEG-grafted degradable polyester.

Scheme 5. (a(a) )Representative Representative cyclic cyclic ketene ketene acetal acetal (CKAs) (CKAs) with with high high or exclusive or exclusive RROP RROP selectivity. selectivity. (b) (Anb) Anexample example of ofatom atom transfer-mediated transfer-mediated RRO RROPP (AT-RROP) (AT-RROP) for for the the synthesis synthesis of of P(MMA- co-MPDO) copolymers [[73,74].73,74].

InRecently, conventional interesting free radicalprogress polymerization, in the scope of radicalscopolymerization are produced has inbeen the reported. initiation Guillaneuf step (kd = caet. 4 6 1 10al.− [75]–10 −reporteds− ) through the copolymerization the decomposition of of thermalvinyl ether or photo-initiators. and MDO in a Subsequently, highly random a moderate-to-fast manner. The 2 4 1 1 chaincomposition propagation of monomers (depending during on the the polymerization monomers: kp reaction= ca. 10 was–10 foundM− tos− follow) and the very initial fast feeding radical 6 8 1 1 terminations (kt = ca. 10 –10 M s ) occur [77]. Due to the irreversible radical generating step, ratio of the monomers. The copolymerization− − reactivity ratio was rMDO = 0.73 and rvinyl ether = 1.61, which ratheris consistent high concentrations with of the theoretical of the unstable calculation species of cause the reaction a significant rate for number the α-oxyethyl of terminations, radical which and MDO. leads toThe broad highly molecular random weight manner distributions could also and be uncontrollable related to kinetics.the fact Althoughthat vinyl RROP ethers provides are not an alternativehomopolymerized approach by to the the radical synthesis polymerization. of f-APs, the RROP The methodsynthetic has benefit to meet of somevinyl applicationether for f-PE demands is the thatready require availability a narrow of range various of molecular functional weight monomers, distributions. and indeed, In the mid-1990s, Cl, oligo(ethylene reversible-deactivation glycol) and radicalterminal polymerization alkene functionalized (RDRP) was vinyl discovered ethers have and it been is still shown being developedto give copolymers in academia with and MDO. industry These [78]. Incopolymers RDRP, reagents were offurther dormant modified molecules to obtain and regulators a fluorescent (which probe act as functionalized activators and deactivators)polymer and are a necessarilydegradable present. elastomer. The keyAnother to achieving recent controlledexample /isliving the polymerizationcopolymerization is to of follow BMDO a number and maleimide of general stepsreported [78]: by (i) Sumerlin the initiating [76]. rate The of co thepolymerization reaction between proceeded the activators with th ande quantitative dormant molecules ring-opening should of beBMDO faster to thanthe ester that and of thein a chain highly propagating alternating ma rate;nner. (ii) The meanwhile, copolymer deactivators was readily and functionalized active radicals by areutilizing produced N-substituent in order toof proceedmaleimide, with and certain the monomeralternating additions; structure(iii) might the concentrationbe suitable for of fast the (macro)radicalsdegradation to is low quickly molecular deactivated weight by deactivators; fragments. and Interestingly, (iv) meanwhile, although activators the and alternative dormant (macro)moleculescopolymerization areof other reversibly CKAs generated such as MDO so that and another maleimide cycle has can been be conducted reported, starting the selectivity from step of (i).the Inring-opening a controlled of/living CKA polymerization, was not enough, the which concentrations indicates of that active the radicals appropriate should combination remain low inof ordermonomer to achieve and the the reactivity suppression is quite of termination important reactions in designing and so the that CKA all polymercopolymer chains as a canf-PE. grow evenly and consecutively. A homogeneous dispersion of a regulator in the polymerization mixture provides In conventional free radical polymerization, radicals are produced in the initiation step (kd = ca. an10−4 effectively–10−6 s−1) through controlled the/living decomposition process. However, of thermal the or initiatingphoto-initiators. sites (i.e., Subsequently, active centers) a moderate-to- can be either homogeneously dispersed in the polymerization mixture or attached to various heterogeneous surfaces of fast chain propagation (depending on the monomers: kp = ca. 102–104 M−1s−1) and very fast radical silicon, metals, and plastics (e.g., wafers, plastic tubes, porous materials, (nano)fibers, (nano)particles, etc.). terminations (kt = ca. 106–108 M−1s−1) occur [77]. Due to the irreversible radical generating step, rather high concentrations of the unstable species cause a significant number of terminations, which leads to broad molecular weight distributions and uncontrollable kinetics. Although RROP provides an alternative approach to the synthesis of f-APs, the RROP method has to meet some application demands that require a narrow range of molecular weight distributions. In the mid-1990s, reversible- deactivation radical polymerization (RDRP) was discovered and it is still being developed in academia and industry [78]. In RDRP, reagents of dormant molecules and regulators (which act as activators and deactivators) are necessarily present. The key to achieving controlled/living polymerization is to follow a number of general steps [78]: (i) the initiating rate of the reaction between the activators and dormant molecules should be faster than that of the chain propagating rate; (ii) meanwhile, deactivators and active radicals are produced in order to proceed with certain monomer additions; (iii) the concentration of the (macro)radicals is quickly deactivated by deactivators; and (iv) meanwhile, activators and dormant (macro)molecules are reversibly generated so that another cycle can be conducted starting from step (i). In a controlled/living polymerization, the concentrations of active radicals should remain low in order to achieve the suppression of

Int.Int. J. Mol.J. Mol. Sci. Sci. 2020 2020, 21, 21, x, FORx FOR PEER PEER REVIEW REVIEW 8 of8 of18 18

terminationtermination reactions reactions and and so so that that all all polymer polymer chains chains can can grow grow evenly evenly and and consecutively. consecutively. A A Int.Int. J. Mol.J. Mol. Sci. Sci. 2020 2020, 21, 21, x, FORx FOR PEER PEER REVIEW REVIEW 8 of8 of18 18 homogeneoushomogeneous dispersion dispersion of of a aregulator regulator in in the the polymerization polymerization mixture mixture provides provides an an effectively effectively Int.terminationcontrolled/livingterminationcontrolled/livingInt. J. Mol.J. Mol. Sci. Sci. 2020 reactions2020 reactions, 21 , 21, process.x, process. FORx FOR and PEERand PEER However,so REVIEWHowever,so REVIEWthat that all all thepolymer thepolymer initiatiinitiati chains ngchainsng sites sitescan can (i.e.,grow (i.e.,grow active activeevenly evenly centers) centers)and and consecutively. consecutively. cancan bebe either8 eitherof8 of18A 18A homogeneoushomogeneouslyhomogeneoushomogeneously dispersion dispersiondispersed dispersed of in of in a the aregulatorthe regulator polymerization polymerization in in the the polymerization mixturepolymerization mixture or or attached attached mixture mixture to to provides various providesvarious heterogeneous an heterogeneousan effectively effectively Int.terminationInt.termination J. Mol.J. Mol. Sci. Sci. 2020 reactions2020 reactions, 21, 21, x, FORx FOR and PEERand PEER so REVIEWso REVIEWthat that all all polymer polymer chains chains can can grow grow evenly evenly and and consecutively. consecutively.8 of8 of18A 18 A controlled/livingsurfacescontrolled/livingsurfaces of of silicon, silicon, process. metals,process. metals, and However, andHowever, plastics plastics the(e.g.,the (e.g., initiati wafeinitiati wafers,ngrs,ng plastic sitesplasticsites (i.e.,tubes, (i.e.,tubes, active porousactive porous centers) materials,centers) materials, can can(nano)fibers, (nano)fibers, bebe eithereither homogeneoushomogeneous dispersion dispersion of of a aregulator regulator in in the the polymerization polymerization mixture mixture provides provides an an effectively effectively terminationhomogeneously(nano)particles,Int.homogeneously(nano)particles,terminationInt. J. Mol.J. Mol. Sci. Sci. 2020 reactions2020 reactions, etc.).21,dispersed etc.).21, dispersedx, FORx FOR and PEERand PEER inso REVIEWin so REVIEWthe that thethat polymerization polymerizationall all polymer polymer chains mixture chainsmixture can canor or grow attached growattached evenly evenly to to various and variousand consecutively. consecutively.heterogeneous heterogeneous8 of8 of18A 18A controlled/livingcontrolled/living process.process. However,However, the the initiatiinitiatingng sitessites (i.e.,(i.e., activeactive centers)centers) cancan bebe eithereither homogeneoussurfacessurfaceshomogeneousAmongAmong of of silicon, RDRPs,silicon, RDRPs,dispersion dispersion metals, themetals, the most most of and of and awidely awidelyregulatorplastics regulatorplastics used used (e.g., (e.g.,in techniquesin techniques thewafe thewafe polymerization rs,polymerizationrs, plasticinclude plasticinclude tubes, atomtubes, atom mixture mixtureporoustransfer poroustransfer provides materials,radical provides materials,radical polymerization anpolymerization (nano)fibers,an (nano)fibers,effectively effectively homogeneouslyterminationterminationhomogeneously reactions reactions dispersed dispersed and and inso in so the that thethat polymerization polymerizationall all polymer polymer chains mixturechains mixture can canor or grow attached growattached evenly evenly to to various and variousand consecutively. consecutively.heterogeneous heterogeneous A A controlled/living(nano)particles,(ATRP)(nano)particles,(ATRP)controlled/living [79–82], [79–82], etc.). nitroxide-mediated etc.). process.nitroxide-mediatedprocess. However,However, radical radical thethe polymeinitiati polymeinitiatingrizationng rization sitessites (NMRP) (i.e.,(NMRP)(i.e., active active[83], [83], centers)and centers)and reversible reversible cancan beaddition- beaddition- eithereither surfaceshomogeneoushomogeneoussurfaces of of silicon, silicon, dispersion dispersion metals, metals, of and of anda aregulatorplastics regulatorplastics (e.g., (e.g.,in in thewafe thewafe polymerization rs,polymerizationrs, plastic plastic tubes, tubes, mixture mixtureporous porous provides materials, providesmaterials, an (nano)fibers,an (nano)fibers,effectively effectively homogeneouslyfragmentationfragmentationhomogeneouslyAmongAmong RDRPs, RDRPs,chain chaindispersed dispersed transferthe transferthe most most in (RAFT)in widely(RAFT)the widelythe polymerization polymerization used polymerization used techniques techniques mixture [84–87].mixture [84–87].include include or Accordingly, or atomAccordingly,attached atomattached transfer transfer to theto thevariousradical variousdiverseradical diverse polymerizationheterogeneous polymerizationtechniquesheterogeneous techniques of of (nano)particles,RDRPscontrolled/livingRDRPscontrolled/living(nano)particles, have have been beenetc.). etc.). process. introducedprocess. introduced However,However, to to RROP RROP the thesystems systems initiatiinitiati tong tong obtain sitesobtainsites well-defined (i.e., well-defined(i.e., activeactive (co)polymerscenters) (co)polymerscenters) cancan withbe withbe eitherester eitherester Int. J. Mol.surfaces(ATRP)(ATRP)surfaces Sci. 2020 [79–82],of [79–82],of silicon,, 21silicon,, 9581nitroxide-mediated nitroxide-mediated metals, metals, and and plastics plastics radical radical (e.g., (e.g., polyme wafepolyme wafers,rizationrs, rizationplastic plastic (NMRP) tubes,(NMRP) tubes, porous [83],porous [83], and materials,and materials, reversible reversible (nano)fibers, (nano)fibers, addition- addition- 8 of 17 homogeneouslyhomogeneouslyAmongAmong RDRPs, RDRPs, dispersed dispersed the the most most in in widelythe widelythe polymerization polymerization used used techniques techniques mixture mixture include include or or atomattached atomattached transfer transfer to to variousradical variousradical polymerizationheterogeneous polymerizationheterogeneous (nano)particles,fragmentationlinkages.fragmentationlinkages.(nano)particles, For For instance, chaininstance, etc.).chain etc.). transfer transferMatyjaszewski Matyjaszewski (RAFT) (RAFT) polymerization etpolymerization et al. al. [73] [73] carried carried [84–87]. [84–87]. out out the Accordingly,the Accordingly, atom atom transfer-mediated transfer-mediated the the diverse diverse techniques techniquesRROP RROP (AT- (AT- of of (ATRP)surfacessurfaces(ATRP) [79–82],of [79–82],of silicon, silicon, nitroxide-mediated nitroxide-mediated metals, metals, and and plastics plastics radical radical (e.g., (e.g., polyme wafepolyme wafers,rizationrs, rizationplastic plastic (NMRP) tubes,(NMRP) tubes, porous [83],porous [83], and materials,and materials, reversible reversible (nano)fibers, (nano)fibers, addition- addition- RDRPsRROP)RDRPsRROP)AmongAmong ofhave of haveCA CA RDRPs, been or RDRPs, beenor CKA CKA introduced theintroduced monomersthe monomers most most widely towidely towith RROPwith RROP used typical used typical systems techniquessystems techniques MMA MMA to toor obtainor include Stobtain include St monomers. monomers. well-defined atomwell-defined atom transfer Schemetransfer Scheme (co)polymers (co)polymersradical 5bradical 5b shows shows polymerization polymerization an withan withexample example ester ester fragmentation(nano)particles,(nano)particles,fragmentation chain etc.).chain etc.). transfer transfer (RAFT) (RAFT) polymerization polymerization [84–87]. [84–87]. Accordingly, Accordingly, the the diverse diverse techniques techniques of of Among(ATRP)linkages.oflinkages.of(ATRP) the the AT-RROP [79–82], RDRPs, ForAT-RROP[79–82], For instance, instance, nitroxide-mediated thenitroxide-mediatedof of mostMMAMatyjaszewski MMAMatyjaszewski widelyand and MPDO radicalMPDO usedetradical et al. al. to[73] techniquespolyme to[73] polymeprovide carriedprovide carriedrizationrization outhydrolysable out includehydrolysable the(NMRP) the(NMRP) atom atom atom transfer-mediated[83], P(MMA- transfer-mediated[83],P(MMA- transfer and and reversibleco reversibleco-MPDO)-MPDO) radical RROP RROP addition- random addition- polymerizationrandom (AT- (AT- RDRPsRDRPsAmongAmong have have RDRPs,been RDRPs,been introduced theintroduced the most most widely towidely to RROP RROP used used systems techniquessystems techniques to to obtain includeobtain include well-defined atomwell-defined atom transfer transfer (co)polymers (co)polymersradical radical polymerization polymerization with with ester ester fragmentationRROP)copolymersRROP)copolymersfragmentation of of CA CA(M or( chainM nor chainCKA=n CKA=ca. ca.transfer 16,300monomerstransfer 16,300monomers (RAFT)and (RAFT)and withM withMw polymerization/wM polymerization/typicalM ntypical =n =1.31). 1.31). MMA MMA Interestingly, Interestingly, or[84–87]. or[84–87]. St St monomers. monomers. Accordingly, Accordingly,repeatin repeatin Scheme Schemeg gunits the units the 5bdiverse of5bdiverse showsof ring-openedshows ring-opened techniques techniquesan an example example (i.e., (i.e.,of of (ATRP)linkages.(ATRP)(ATRP)linkages. [79 –[79–82], 82For[79–82], For], instance, instance, nitroxide-mediatednitroxide-mediated nitroxide-mediated Matyjaszewski Matyjaszewski radical etradical et al. radical al. [73]polyme [73]polyme carried carried polymerizationrizationrization out out the(NMRP) the(NMRP) atom atom transfer-mediated[83], transfer-mediated[83], (NMRP) and and reversible reversible [83 ],RROP RROPaddition- addition- and (AT- (AT- reversible RDRPsofformingofformingRDRPs the the AT-RROP have αAT-RROP have-ketoesterα-ketoester been been of introduced linkages)of introduced linkages)MMA MMA and and toand andto RROP MPDOnon-ring-opened RROPMPDOnon-ring-opened systems systemsto to provide provide to to (i.eobtain (i.e obtain.,hydrolysable .,hydrolysableproceeding proceeding well-defined well-defined 1,2-vinylP(MMA- 1,2-vinylP(MMA- (co)polymers (co)polymers additions)co additions)co-MPDO)-MPDO) with fromwith random fromrandom ester theester the addition-fragmentationRROP)MPDOfragmentationMPDOfragmentationRROP) ofmonomer of monomerCA CA or chain or chainCKA CKAwere weretransfer monomerstransfer chain monomersattained. attained. (RAFT) transfer(RAFT) with Similarwith Similarpolymerization polymerizationtypical (RAFT)typical results results MMA MMA polymerizationwere orwere[84–87]. or[84–87]. St foundSt monomers.found monomers. Accordingly, Accordingly, in in comparisons comparisons [Scheme84 Scheme– 87the the]. 5bdiverse 5bdiverse Accordingly,showsof showsof AT-RROP AT-RROPtechniques techniquesan an example example and theandof of diverse linkages.copolymerscopolymerslinkages. For For ( M instance,( Minstance,n =n =ca. ca. 16,300 Matyjaszewski 16,300 Matyjaszewski and and M Mw/w Met/ Mnet al.=n al. = 1.31).[73] 1.31).[73] carried Interestingly,carried Interestingly, out out the the repeatinatom repeatinatom transfer-mediated transfer-mediatedg gunits units of of ring-opened ring-opened RROP RROP (AT-(i.e., (AT-(i.e., ofRDRPsRDRPsof the the AT-RROPhave AT-RROPhave been been of introduced of introducedMMA MMA and toand to RROP MPDO RROPMPDO systems systemsto to provide provide to to obtain obtainhydrolysable hydrolysable well-defined well-defined P(MMA- P(MMA- (co)polymers (co)polymerscoco-MPDO)-MPDO) with withrandom random ester ester techniquesRROP)formingconventionalformingconventionalRROP) of of αof RDRPs CA-ketoesterα CA-ketoester RROPor RROPor CKA haveCKA methods.linkages) monomersmethods.linkages) monomers been introducedSomeand Someand with withnon-ring-opened othernon-ring-opened othertypical typical AT-RROPs to AT-RROPs MMA RROP MMA or(i.esystems or(i.e ofSt .,of St CA.,monomers.proceeding CAmonomers.proceeding or or to CKA CKA obtain Scheme1,2-vinyltype Scheme1,2-vinyltype well-defined monomers monomers5b additions)5b showsadditions) shows with an with (co)polymersan fromexample fromtypicalexample typical the the with copolymerslinkages.linkages.copolymers For For ( M instance,( Minstance,n =n =ca. ca. 16,300 Matyjaszewski 16,300 Matyjaszewski and and M Mw/w Met/ Mnet al.=n al. = 1.31).[73] 1.31).[73] carried Interestingly,carried Interestingly, out out the the repeatinatom repeatinatom transfer-mediated transfer-mediatedg gunits units of of ring-opened ring-opened RROP RROP (AT-(i.e., (AT-(i.e., ester linkages.ofMPDOvinylMPDOvinylof the the monomers monomersAT-RROPmonomer AT-RROPmonomer For instance, have werehaveof wereof MMA also MMAalsoattained. attained. Matyjaszewskibeen beenand and demonstrated SimilardemonstratedMPDO SimilarMPDO resultsto results etto provide al.[74,88–96].provide [74,88–96]. were [73were ] hydrolysable carriedfound hydrolysable foundAccordingly, Accordingly, in outin comparisons comparisons theP(MMA- P(MMA-nitroxide-mediated atomnitroxide-mediatedco transfer-mediatedofco-MPDO) of -MPDO)AT-RROP AT-RROP random randomRROP RROPand and RROP forming(NM-RROP)RROP)(NM-RROP)RROP)forming of αof CA-ketoesterα CA-ketoester [97,98] or [97,98] or CKA CKA andlinkages) andmonomerslinkages) monomers reversible reversible and and with withnon-ring-openedaddition-fragmentation non-ring-openedaddition-fragmentation typical typical MMA MMA or(i.e or(i.e St., St .,monomers.proceeding monomers.proceedingchain chain transfer-mediated transfer-mediated Scheme1,2-vinyl Scheme1,2-vinyl 5b additions)5b showsadditions) shows RROP RROP an an fromexample (RAFT- fromexample (RAFT- the the (AT-RROP)copolymersconventionalconventionalcopolymers of CA ( M RROP or( MnRROP =n CKA =ca. ca.methods. 16,300methods. monomers16,300 and Someand Some M Mw with/otherwM other/Mn =n typical AT-RROPs=1.31). AT-RROPs1.31). Interestingly,MMA Interestingly, of of orCA CA St or monomers.repeatinor CKArepeatin CKA type gtype gunits unitsmonomers Schememonomers of of ring-opened ring-opened5 bwith with shows typical typical (i.e., an(i.e., example MPDORROP)ofRROP)ofMPDO the the [99,100]AT-RROPmonomer [99,100]AT-RROPmonomer have have wereof alsowereof alsoMMA MMA beenattained. beenattained. andeffectively andeffectively SimilarMPDO SimilarMPDO applied appliedresultsto resultsto provide provideto to wereobtain wereobtain hydrolysable found well-definedhydrolysablefound well-defined in in comparisons comparisons P(MMA- polymers P(MMA-polymersco withofco-MPDO) withof -MPDO)AT-RROP esterAT-RROP ester linkagesrandom linkagesrandom and and of theformingvinyl AT-RROPvinylforming monomers monomers α -ketoesterα-ketoester of MMA have have linkages) linkages) andalso also been MPDO been and and demonstrated demonstratednon-ring-opened tonon-ring-opened provide [74,88–96]. hydrolysable[74,88–96]. (i.e (i.e., .,proceeding Accordingly,proceeding Accordingly, P(MMA- 1,2-vinyl 1,2-vinyl nitroxide-mediated conitroxide-mediated-MPDO) additions) additions) random from from RROP RROP the copolymersthe conventionalcopolymerscopolymersconventional ( M RROP( MnRROP =n =ca. ca.methods. 16,300methods. 16,300 and Someand Some M Mw other/wM /otherMn =n AT-RROPs=1.31). AT-RROPs1.31). Interestingly, Interestingly, of of CA CA or repeatinor CKArepeatin CKA type gtype gunits unitsmonomers monomers of of ring-opened ring-opened with with typical typical (i.e., (i.e., MPDO(NM-RROP)in(NM-RROP)inMPDO the the backbone. monomer backbone.monomer [97,98] [97,98] Table wereTable andwere and 2attained. reversible 2summarizesattained.reversible summarizes Similar addition-fragmentationSimilar addition-fragmentation the the resultsmonomers, resultsmonomers, were were polyme foundpolyme found chain chain rin rstructures, in transfer-mediatedstructures, comparisons transfer-mediatedcomparisons their their of relatedof related AT-RROP RROP AT-RROPRROP synthetic (RAFT-synthetic (RAFT- and and (Mn =vinylformingformingvinylca. monomers 16,300 monomers α -ketoesterα-ketoester and have have Mlinkages) linkages)walso /alsoM beenn been =and and 1.31).demonstrated demonstratednon-ring-opened non-ring-opened Interestingly, [74,88–96]. [74,88–96]. (i.e (i.e.,repeating .,proceeding Accordingly,proceeding Accordingly, units1,2-vinyl 1,2-vinyl nitroxide-mediated nitroxide-mediated of ring-openedadditions) additions) from from RROP (i.e.,RROP the the forming conventionalRROP)methods,RROP)methods,conventional [99,100] [99,100] and and RROPapplications RROPhaveapplications have methods.also alsomethods. been beenon on theeffectivelySome theeffectivelySome basis basis other otherof ofapplied a applied AT-RROPsaRROP AT-RROPsRROP to approach. to obtainapproach. obtain of of CA well-defined CAwell-defined or or CKA CKA type polymers type polymers monomers monomers with with ester withester with linkages typicallinkages typical α-ketoester(NM-RROP)MPDOMPDO(NM-RROP) linkages)monomer monomer [97,98] [97,98] wereand andwere and non-ring-openedattained.reversible attained.reversible Similar addition-fragmentationSimilar addition-fragmentation results results (i.e., were proceedingwere found found chain chain in in transfer-mediated1,2-vinyl comparisons transfer-mediatedcomparisons additions) of of AT-RROP RROP AT-RROPRROP from (RAFT- (RAFT- and and the MPDO vinylininvinyl the the monomers backbone.monomers backbone. haveTable haveTable also 2also 2summarizes beensummarizes been demonstrated demonstrated the the monomers, monomers, [74,88–96]. [74,88–96]. polyme polyme Accordingly, Accordingly,r rstructures, structures, nitroxide-mediated nitroxide-mediated their their related related synthetic synthetic RROP RROP RROP)conventionalconventionalRROP)TableTable [99,100] [99,100] 2. 2.RROPSummary RROPhaveSummary have alsomethods. methods.also of beenof beenmonomers, monomers, effectivelySome effectivelySome other otherpolymer polymerapplied appliedAT-RROPs AT-RROPs structures tostructures to obtain obtain of of , CAwell-defined ,their CAwell-definedtheir or or related CKA relatedCKA type polymers synthetictype polymerssynthetic monomers monomers withmethods, withmethods, ester withester with linkagesand typicallinkagesand typical monomer(NM-RROP)methods,methods,(NM-RROP) were and and attained.[97,98] applications[97,98] applications and and Similar reversible onreversible on the the results basis basisaddition-fragmentation addition-fragmentation of of werea aRROP RROP found approach. approach. in comparisons chain chain transfer-mediated transfer-mediated of AT-RROP RROP RROP and (RAFT- (RAFT- conventional invinylvinylin the theapplications. monomers applications. backbone.monomers backbone. have Table haveTable also 2also 2summarizes beensummarizes been demonstrated demonstrated the the monomers, monomers, [74,88–96]. [74,88–96]. polyme polyme Accordingly, Accordingly,r rstructures, structures, nitroxide-mediated nitroxide-mediated their their related related synthetic synthetic RROP RROP RROPRROP) methods.RROP) [99,100] [99,100] Some have have otheralso also been been AT-RROPs effectively effectively ofapplied applied CA or to to CKAobtain obtain typewell-defined well-defined monomers polymers polymers with with typicalwith ester ester linkages vinyl linkages monomers methods,(NM-RROP)(NM-RROP)methods, and and [97,98] applications[97,98] applications and and reversible onreversible on the the basis basisaddition-fragmentation addition-fragmentation of of a RROPa RROP approach. approach. chain chain transfer-mediated transfer-mediated RROP RROP (RAFT- (RAFT- have alsoinin the theTable been Tablebackbone. backbone. demonstrated2. 2.Summary Summary Table Table of2 of2 summarizes monomers, [summarizes74monomers,,88–96 ].polymer the polymer Accordingly,the monomers, monomers, structures structures polyme nitroxide-mediated, polyme,their their r related rstructures, relatedstructures, synthetic synthetic their their RROP methods, related methods,related (NM-RROP) synthetic and syntheticand [97,98] RROP)RROP)applications.applications. [99,100] [99,100] have have also also been been effectively effectively applied applied to to obtain obtain well-defined well-defined polymers polymers with with ester ester linkages linkages methods,methods, and and applications applications on on the the basis basis of of a RROPa RROP approach. approach. a a and reversibleinin the theTable Tablebackbone. backbone.Monomer(s) addition-fragmentationMonomer(s)2. 2.Summary Summary Table Table of2 of2 summarizes monomers, summarizesmonomers, Polymer Polymer chainStructure polymer theStructure polymerthe monomers, transfer-mediatedmonomers, structures structures Synthetic Synthetic polyme , polyme,their Methodtheir Method r related rstructures, RROP related structures, synthetic (RAFT-RROP)synthetic Applicationtheir Applicationtheir methods, related methods,related [synthetic99 and syntheticand,100 Ref Ref ] have also been effectivelyapplications.applications. applied to obtain well-defined polymers with ester linkages in the backbone. Table2 methods,methods,TableTable and 2.and 2. applicationsSummary applicationsSummary of of onmonomers, onmonomers, the the basis basis polymerof polymerof a RROPa RROP structures structuresapproach. approach., ,their their related related synthetic synthetic methods, methods, and and Monomer(s)Monomer(s) Polymer Polymer Structure Structure Synthetic Synthetic Method Method Application Application a a RefRef summarizesapplications.applications. the monomers, polymer structures, their related synthetic methods, and applications on TableTable 2. 2.Summary Summary of of monomers, monomers, polymer polymer structures structuresRROP, RROP,their their related related synthetic syntheticDegradableDegradable methods, methods, and and [65] [65] the basis of aMonomer(s) RROPMonomer(s) approach. Polymer Polymer Structure Structure Synthetic Synthetic Method Method Application Application a a RefRef applications.applications. Monomer(s)Monomer(s) Polymer Polymer Structure Structure Synthetic SyntheticRROPRROP Method Method ApplicationDegradable ApplicationDegradable a a [65]Ref[65]Ref Table 2. Summary of monomers, polymer structures, their related synthetic methods, and applications. Monomer(s)Monomer(s) Polymer Polymer Structure Structure Synthetic SyntheticRROPRROP Method Method ApplicationDegradable ApplicationDegradable a a [65][70]Ref[70][65]Ref Synthetic Monomer(s) Polymer Structure Application a Ref RROPMethodRROP DegradableDegradable [65][65] RROPRROP DegradableDegradable [70][70]

RROPRROPRROP Degradable DegradableDegradable [65][65] [65 ] RROPRROP DegradableDegradable [70][71][71][70]

RROPRROPRROP Degradable DegradableDegradable [70][70] [70 ] RROPRROP DegradableDegradable [71][71] RROPRROP DegradableDegradable [70][70] RROPRROPRROP Degradable DegradableDegradable [71][71] [71 ] RROPRROP DegradableDegradable [72][72]

RROPRROP DegradableDegradable [71][71]

RROPRROPRROP Degradable DegradableDegradable [72][72] [72 ] RROPRROP DegradableDegradable [71][71] DegradableDegradable & &FL FL b b Int.Int. J. Mol.J. Mol. Sci. Sci. 2020 2020, 21, 21, x, FORx FOR PEER PEER REVIEW REVIEW RROPRROP DegradableDegradable 9 [72]of9 [72] of18 18

Degradable & FL b RROPRROP AntibacterialDegradableAntibacterialDegradable [72][72] DegradableDegradableAntibacterial & &FL FL b b Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW RROPRROPRROP [75]9 [75]of [1875 ] Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW Degradable elastomer 9 of 18 RROPRROP DegradableDegradableDegradableDegradable elastomer elastomer [72][72] b b (viaDegradableDegradableAntibacterial post-modifications)Antibacterial & &FL FL

RROPRROP [75][75] (via(via post-modifications) post-modifications)b RROPRROP DegradableDegradableAntibacterialDegradableAntibacterialDegradable & &FL FL b [76][76] DegradableDegradable elastomer elastomer RROPRROP [75][75] DegradableDegradable & &FL FL b b DegradableDegradableAntibacterialAntibacterial elastomer elastomer RROPRROP (via(via post-modifications) post-modifications) DegradableDegradable [76] [76 ] RROPRROPRROP Degradable [75][76][75] AntibacterialAntibacterial (viaDegradable(viaDegradable post-modifications) post-modifications) elastomer elastomer RROPRROP [75][75]

(viaDegradable(viaDegradable post-modifications) post-modifications) elastomer elastomer AT-RROPAT-RROPAT-RROP Degradable DegradableDegradable [73][73] [73 ] (via(via post-modifications) post-modifications) a Specific applications reported in the study [75], or the degradabilityAT-RROP as the generalDegradable interest of the application.[73] a a AT-RROP Degradable [73] b FL: fluorescent. Specific Specific applications applications reported reported in in the the study study [75], [75], or or the the degradability degradability as as the the general general interest interest of of the the

application.application. b FL: b FL: fluorescent. fluorescent. a Specific applications reported in the study [75], or the degradability as the general interest of the 4. Synthesisa Specific of Degradable applications reported Polyesters in the bystudy Atom [75], or Transfer the degradability Radical as Polyadditionthe general interest (ATRPA) of the application. b FL: fluorescent. application. b FL: fluorescent. The normal ATRP and its derivative techniques [80] are based on atom transfer radical addition (ATRA) [101,102]. Recently, extensions of multi-step ATRA created a novel analog of aliphatic polyesters with functional groups on their polymer backbones that can be obtained through manipulation of the different activation/deactivation rate constants of the inimers (i.e., initiator and monomer). In 1997, preliminary research on the preparation of aliphatic polyesters through ATRP of AB-type inimers was reported by Matyjaszewski et al. [103,104]. The studies addressed the possibility of obtaining aliphatic polyesters during atom transfer-induced radical self-condensing vinyl polymerization (ATR-SCVP) of aliphatic ester type inimers. Through the ATR-SCVP of 2-((2-bromopropionyl)oxy)ethyl acrylate

Int. J. Mol. Sci. 2020, 21, 9581 9 of 17

(BPEA), topological (hyper)branched polymers comprising both aliphatic polyester and polyacrylates structures were attained. Later, Li et al. coined the term, “atom transfer radical polyaddition” (ATRPA), for the synthesis of perfect linear aliphatic polyesters. Scheme6 demonstrates the general mechanism of ATRPA, which provides perfect linear aliphatic polyesters (i.e., the R2 linkage comprising the ester group). The first example of perfect control ATRPA was demonstrated by Kamigaito et al. in 2007 [105]. Through the design of a specific AB type inimer (e.g., allyl 2-chloropropanoate) with a reactive C–Cl bond (i.e., site B), they developed a novel and radical polyaddition method perfectly controlled by transition metals. The specific inimer can be activated by a lower-oxidation state transition metal (e.g., Cu(I), Ru(II), Fe(II), etc.) to form a radical species (i.e., species 1) and react with a double bond (i.e., site A) of another inimer. More importantly, the newly formed single addition radical species (i.e., species 2) can be deactivated by a higher-oxidation state transition metal (e.g., Cu(II), Ru(III), Fe(III), etc.) to obtain a dimer that possesses extremely inactive pendant C–Cl bonds (i.e., site B’ on species 3). By perfectly and slowly repeating the single addition of inimers, linear aliphatic polyesters can be obtained [106,107]. Li et al. also designed an AB type inimer (i.e., (4-vinylbenzyl 2-bromo-2-isobutyrate (VBBiB)) [108] or AA/BB paired monomers, i.e., bis(styrenics)/bis(bromoisobutyrates) [109,110]. They made four critical breakthroughs on the basis of the ATRPA technique including: (i) controlling the topology from hyperbranched to linear polymers; (ii) improving the effectiveness of perfect-control ATRPA, i.e., polymerizations were reduced to a few days; (iii) rendering a variety of functional groups into the linear polymer backbone, i.e., diverse functional linkages between R1 and R2; and (iv) grafting different functional polymers onto the linear polymer backbone, i.e., through post-reactions of C–X bond. In polymerizations of VBBiB in anisole at 0 ◦C with a homogeneous catalyst system, for example, a step-growth trend was detected. At such a low temperature, high selectivity between the inactive B’ and active B sites can be retained, leading to the formation of linear aliphatic polyesters. In polymerizations of VBBiB in toluene at 0 ◦C with a heterogeneous catalyst system, the deactivation efficiency of the active B radical (chain-)ends was • insufficient,Int.which J. Mol. Sci. led 2020 to, 21 fast, x FOR conventional PEER REVIEW free radical polymerizations to produce linear 10 polymers of 17 with C–C as the backbones and bromoisobutyryl as the pendant groups. Polymerizations of VBBiB in anisole observed in the PVBBiB, which resulted in the formation of a five-membered-ring lactone structure at high temperatures(i.e., (5-(4-(bromomethyl)phenyl) (i.e., 20–60 ◦C)dihydro-3,3-dimethylfuran-2(3 with a homogeneous catalystH)-one)). system In the same resulted circumstances, in low selectivity between thethe PVBBPA inactive performed B’ and active as a stable B sites, type polyester. leading Eventually, to the formation post-click ofreactions branched were polymersapplied to through the mechanismobtain ofamphiphilic atom transfer-induced polymer brushes radical(i.e., alip self-condensinghatic polyesters as vinyl the polymerizationbackbone; hydrophilic (ATR-SCVP). Further, Kamigaitopoly(ethylene et al.glycol) and as Li the et al.grafting utilized chains). metal-catalyzed The novel polyesters intermolecular possess pH-sensitive radical polyadditions and to reversible thermoresponsive behaviors [110,113]. Therefore, the development of innovative ATRPAs design sequence-regulatedprovides an alternative vinyl strategy polymers for obtaining by exact f-APs. manipulation of functionality equivalents [102,107].

Scheme 6.SchemeGeneral 6. mechanismGeneral mechanism of transition of transition metal metal catalyzed catalyzed atom atom transfer transfer radical radical polyaddition polyaddition (ATRPA). (ATRPA).

Recently,5. Synthesis Huang of et al.Degradable [87,111, 112Polyesters] designed by Simultaneous a highly reactive Chain- AB and type Step-Growth inimer (i.e., Radical 4-vinylbenzyl 2-bromo-2-phenylacetatePolymerization (SCSRP) (VBBPA)), which significantly improved the reactivity for ATRPA (i.e., polymerizationsKamigaito were et al. developed reduced toanother a few novel hours) technique, but kept which high was similar selectivity, but different to obtain to ATRPA, linear aliphatic polyesters.for Therefore, simultaneous high chain- molecular and step-growth weight radical aliphatic polymerization polyesters (SCSRP) (Mw [114].= ca. As 26,000 shown and in SchemeMw/M n = 2.09) can be effectively7, a common obtained vinyl (i.e., in threemethyl hours. acrylate This (MA)) significant and an inimer improvement (i.e., compound was 1) are due both to present two factors: in (i) the the reaction mixture. Mediated by transition metal catalysts (e.g., Cu(I), Ru(II), Fe(II), etc.), the activation rate of the VBBPA initiating site is much faster than that of VBBiB (i.e., ka,VBBPA/ka,VBBiB = ca. resulting atom transfer reactions can effectively perform simultaneous ATRP (i.e., Path A) and ATRPA (i.e., Path B) mechanisms. The proper design of the inimer (i.e., compound 1) means that the branching reactions via the ATR-SCVP mechanism (i.e., Path D) can almost be suppressed. Eventually, novel polymer structures are obtained that are comprised of both polyvinyl and polyesters as the backbone (Mw = ca. 36,000 and Mw/Mn = 2.01). That is, the chemical structures obtained via the SCSRP of vinyls and effective inimers are similar to the copolymers obtained via the RROP of vinyls and CKAs. However, the CKA monomers have very poor reactivity toward copolymerization with vinyls, which limits the introduction of ester linkage into the polyvinyl backbones. Thus, copolymers with varying compositions of polyvinyl and polyester can be effectively attained via the SCSRP technique [115–117]. Zhu et al. [118] performed fast and effective SCSRP of MA and ABP (i.e., allyl 2-bromopropanoate) to obtain P(MA-co-ABP) copolymer (Mw = ca. 5100 and Mw/Mn = 1.78) with both a degradable ester group and an undegradable poly(acrylate) segment. They also identified the α-double bond at the copolymer chain end. Then, efficient thiol- ene click reactions of thiol-terminated PNIPAM (poly(N-isopropyl amide)) and double bond- terminated P(MA-co-ABP)s were performed. Serial novel block copolymers of PNIPAM-b-P(MA-co- ABP) were synthesized and these displayed thermoresponsive properties with lower critical solution temperatures (LCSTs: 34–37 °C). SCSRP successfully linked the undegradable polyvinyl (i.e., C–C linkages in the backbones) and the degradable polyester (i.e., ester groups in the backbones) to prepare functional and eco-friendly commodity plastics.

Int. J. Mol. Sci. 2020, 21, 9581 10 of 17

2 103 at 35 C), which results in highly reactive ATRPA; and (ii) the difference in the activation rate in × ◦ the C–X groups at the chain ends and the inactive C–X groups on the backbones is extremely large (i.e., k /k = ca. 3 104 at 35 C), which results in a highly selective a,C–X(PVBBPA end) a,C–X(PVBBPA backbone) × ◦ ATRPA. By tracing the ATRPAs of VBBiB and VBBPA, an interesting self-degrading behavior was observed in the PVBBiB, which resulted in the formation of a five-membered-ring lactone structure (i.e., (5-(4-(bromomethyl)phenyl)dihydro-3,3-dimethylfuran-2(3H)-one)). In the same circumstances, the PVBBPA performed as a stable type polyester. Eventually, post-click reactions were applied to obtain amphiphilic polymer brushes (i.e., aliphatic polyesters as the backbone; hydrophilic poly(ethylene glycol) as the grafting chains). The novel polyesters possess pH-sensitive and reversible thermoresponsive behaviors [110,113]. Therefore, the development of innovative ATRPAs provides an alternative strategy for obtaining f-APs.

5. Synthesis of Degradable Polyesters by Simultaneous Chain- and Step-Growth Radical Polymerization (SCSRP) Kamigaito et al. developed another novel technique, which was similar but different to ATRPA, for simultaneous chain- and step-growth radical polymerization (SCSRP) [114]. As shown in Scheme7, a common vinyl (i.e., methyl acrylate (MA)) and an inimer (i.e., compound 1) are both present in the reaction mixture. Mediated by transition metal catalysts (e.g., Cu(I), Ru(II), Fe(II), etc.), the resulting atom transfer reactions can effectively perform simultaneous ATRP (i.e., Path A) and ATRPA (i.e., Path B) mechanisms. The proper design of the inimer (i.e., compound 1) means that the branching reactions via the ATR-SCVP mechanism (i.e., Path D) can almost be suppressed. Eventually, novel polymer structures are obtained that are comprised of both polyvinyl and polyesters as the backbone (Mw = ca. 36,000 and Mw/Mn = 2.01). That is, the chemical structures obtained via the SCSRP of vinyls and effective inimers are similar to the copolymers obtained via the RROP of vinyls and CKAs. However, the CKA monomers have very poor reactivity toward copolymerization with vinyls, which limits the introduction of ester linkage into the polyvinyl backbones. Thus, copolymers with varying compositions of polyvinyl and polyester can be effectively attained via the SCSRP technique [115–117]. Zhu et al. [118] performed fast and effective SCSRP of MA and ABP (i.e., allyl 2-bromopropanoate) to obtain P(MA-co-ABP) copolymer (Mw = ca. 5100 and Mw/Mn = 1.78) with both a degradable ester group and an undegradable poly(acrylate) segment. They also identified the α-double bond at the copolymer chain end. Then, efficient thiol-ene click reactions of thiol-terminated PNIPAM (poly(N-isopropyl amide)) and double bond-terminated P(MA-co-ABP)s were performed. Serial novel block copolymers of PNIPAM-b-P(MA-co-ABP) were synthesized and these displayed thermoresponsive properties with lower critical solution temperatures (LCSTs: 34–37 ◦C). SCSRP successfully linked the undegradable polyvinyl (i.e., C–C linkages in the backbones) and the degradable polyester (i.e., ester groups in the backbones)Int. J. toMol. prepare Sci. 2020, 21 functional, x FOR PEER REVIEW and eco-friendly commodity plastics. 11 of 17

SchemeScheme 7. An exemplified7. An exemplified mechanism mechanism of simultaneous of simultan chain-eous and chain- step-growth and step-growth radical polymerization radical (SCSRP)polymerization of MA and inimer (SCSRP)1 [of96 MA]. and inimer 1 [96].

6. Conclusions and Outlook In this report, we first discussed the most recent novel synthetic methods for preparing functional polyesters. Then, recent topics of interest in regard to the synthesis of polyesters, including the use of bio-originated or “sustainable” monomers, organocatalyzed ROP for polyesters, and the efficient functionalization of polyesters are summarized. Finally, recent innovations in the polymer chemistry of RROP, ATRPA, and SCSRP methodologies have created a novel series of (bio)degradable and functional polyester-containing polymers. These novel functional polyesters have great potential for application in biomedical, biotechnology, nanomaterials, microelectronics as well as contributing to a circular economy, environmental protection, and agriculture. The development of degradable, especially biodegradable polymers with functional properties is becoming increasingly important. For example, the European Chemicals Agency recently announced a recommendation to restrict the amount of micro-plastic additives in products and there are other demands for environmental protection. Biodegradable polymers are excluded from these regulations; however, the polymers are required to reach degradability standards that are much stricter than in the past. The regulations regarding use of micro-plastics are also expected to be imposed on various (synthetic) polymer products. Therefore, polymers (as products and additives) with a wide range of functionality and sufficient value, which have low environmental impact and high (bio)degradability are highly desirable in the long run.

Author Contributions: C.-F.H. and Y.N. conceived the topic and sections. C.-C.W., C.-J.C., K.-Y.A.L. collected the literature and drew some figures. S.-T.L. drew some schemes and figures, and summarized the literature. Y.N., K.-Y.A.L., and C.-F.H. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding: The authors acknowledge the financial support from the Ministry of Science and Technology (MOST109-2221-E-005-071 and MOST108-2923-E-005-001-MY2), iCAST, and TCVGH-NCHU Joint Research Program.

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Vroman, I.; Tighzert, L. Biodegradable Polymers. Materials 2009, 2, 307–344. 2. Agarwal, S. Biodegradable Polymers: Present Opportunities and Challenges in Providing a Microplastic- Free Environment. Macromol. Chem. Phys. 2020, 221, 2000017. 3. DiCiccio, A.M.; Coates, G.W. Ring-Opening Copolymerization of Maleic Anhydride with Epoxides: A Chain-Growth Approach to Unsaturated Polyesters. J. Am. Chem. Soc. 2011, 133, 10724–10727.

Int. J. Mol. Sci. 2020, 21, 9581 11 of 17

6. Conclusions and Outlook In this report, we first discussed the most recent novel synthetic methods for preparing functional polyesters. Then, recent topics of interest in regard to the synthesis of polyesters, including the use of bio-originated or “sustainable” monomers, organocatalyzed ROP for polyesters, and the efficient functionalization of polyesters are summarized. Finally, recent innovations in the polymer chemistry of RROP, ATRPA, and SCSRP methodologies have created a novel series of (bio)degradable and functional polyester-containing polymers. These novel functional polyesters have great potential for application in biomedical, biotechnology, nanomaterials, microelectronics as well as contributing to a circular economy, environmental protection, and agriculture. The development of degradable, especially biodegradable polymers with functional properties is becoming increasingly important. For example, the European Chemicals Agency recently announced a recommendation to restrict the amount of micro-plastic additives in products and there are other demands for environmental protection. Biodegradable polymers are excluded from these regulations; however, the polymers are required to reach degradability standards that are much stricter than in the past. The regulations regarding use of micro-plastics are also expected to be imposed on various (synthetic) polymer products. Therefore, polymers (as products and additives) with a wide range of functionality and sufficient value, which have low environmental impact and high (bio)degradability are highly desirable in the long run.

Author Contributions: C.-F.H. and Y.N. conceived the topic and sections. C.-C.W., C.-J.C., K.-Y.A.L. collected the literature and drew some figures. S.-T.L. drew some schemes and figures, and summarized the literature. Y.N., K.-Y.A.L., and C.-F.H. wrote the paper. All authors have read and agreed to the published version of the manuscript. Funding: The authors acknowledge the financial support from the Ministry of Science and Technology (MOST109-2221-E-005-071 and MOST108-2923-E-005-001-MY2), iCAST, and TCVGH-NCHU Joint Research Program. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Vroman, I.; Tighzert, L. Biodegradable Polymers. Materials 2009, 2, 307–344. [CrossRef] 2. Agarwal, S. Biodegradable Polymers: Present Opportunities and Challenges in Providing a Microplastic-Free Environment. Macromol. Chem. Phys. 2020, 221, 2000017. [CrossRef] 3. DiCiccio, A.M.; Coates, G.W. Ring-Opening Copolymerization of Maleic Anhydride with Epoxides: A Chain-Growth Approach to Unsaturated Polyesters. J. Am. Chem. Soc. 2011, 133, 10724–10727. [CrossRef] 4. Jeske, R.C.; DiCiccio, A.M.; Coates, G.W. Alternating Copolymerization of Epoxides and Cyclic Anhydrides: An Improved Route to Aliphatic Polyesters. J. Am. Chem. Soc. 2007, 129, 11330–11331. [CrossRef] 5. Huijser, S.; HosseiniNejad, E.; Sablong, R.; de Jong, C.; Koning, C.E.; Duchateau, R. Ring-Opening Co- and

Terpolymerization of an Alicyclic Oxirane with Carboxylic Acid Anhydrides and CO2 in the Presence of Chromium Porphyrinato and Salen Catalysts. Macromolecules 2011, 44, 1132–1139. [CrossRef] 6. Deng, X.X.; Li, L.; Li, Z.L.; Lv, A.; Du, F.S.; Li, Z.C. Sequence Regulated Poly(ester-amide)s Based on Passerini Reaction. ACS Macro Letters 2012, 1, 1300–1303. [CrossRef] 7. Solleder, S.C.; Meier, M.A.R. Sequence Control in Polymer Chemistry through the Passerini Three-Component Reaction. Angew. Chem. Int. Ed. 2014, 53, 711–714. [CrossRef] 8. Kreye, O.; Toth, T.; Meier, M.A.R. Introducing Multicomponent Reactions to Polymer Science: Passerini Reactions of Renewable Monomers. J. Am. Chem. Soc. 2011, 133, 1790–1792. [CrossRef] 9. Ji, S.H.; Bruchmann, B.; Klok, H.A. Exploring the Scope of the Baylis-Hillman Reaction for the Synthesis of Side-Chain Functional Polyesters. Macromol. Chem. Phys. 2011, 212, 2612–2618. [CrossRef] 10. Ji, S.H.; Bruchmann, B.; Klok, H.A. Synthesis of Side-Chain Functional Polyesters via Baylis-Hillman Polymerization. Macromolecules 2011, 44, 5218–5226. [CrossRef] 11. Pastorino, L.; Pioli, F.; Zilli, M.; Converti, A.; Nicolini, C. Lipase-catalyzed degradation of poly(epsilon-caprolactone). Enzyme Microb. Technol. 2004, 35, 321–326. [CrossRef] Int. J. Mol. Sci. 2020, 21, 9581 12 of 17

12. Tsarevsky, N.V.; Matyjaszewski, K. Reversible Redox Cleavage/Coupling of Polystyrene with Disulfide or Thiol Groups Prepared by Atom Transfer Radical Polymerization. Macromolecules 2002, 35, 9009–9014. [CrossRef] 13. Li, C.M.; Madsen, J.; Armes, S.P.; Lewis, A.L. A New Class of Biochemically Degradable, Stimulus-Responsive Triblock Copolymer Gelators. Angew. Chem. Int. Ed. 2006, 45, 3510–3513. [CrossRef] 14. Liu, J.Q.; Tao, L.; Xu, J.T.; Jia, Z.F.; Boyer, C.; Davis, T.P.RAFT Controlled Synthesis of Six-armed Biodegradable Star Polymeric Architectures via a ‘Core-first’ methodology. Polymer 2009, 50, 4455–4463. [CrossRef] 15. Rikkou, M.D.; Loizou, E.; Porcar, L.; Butler, P.; Patrickios, C.S. Degradable Amphiphilic End-Linked Conetworks with Aqueous Degradation Rates Determined by Polymer Topology. Macromolecules 2009, 42, 9412–9421. [CrossRef] 16. Rikkou, M.D.; Patrickios, C.S. Well-defined networks with precisely located cleavable sites: Structure Optimization and Core Functionality Determination. Macromolecules 2008, 41, 5957–5959. [CrossRef] 17. Ge, Z.S.; Chen, D.Y.; Zhang, J.Y.; Rao, J.Y.; Yin, J.; Wang, D.; Wan, X.J.; Shi, W.F.; Liu, S.Y. Facile Synthesis of Dumbbell-shaped Dendritic-linear-dendritic Triblock Copolymer via Reversible Addition-Fragmentation Chain Transfer Polymerization. J. Polym. Sci. Part A 2007, 45, 1432–1445. [CrossRef] 18. You, Y.Z.; Hong, C.Y.; Wang, W.P.; Wang, P.H.; Lu, W.Q.; Pan, C.Y. A novel strategy to synthesize graft copolymers with controlled branch spacing length and defined grafting sites. Macromolecules 2004, 37, 7140–7145. [CrossRef] 19. Marquez, Y.; Franco, L.; Turon, P.; Rodriguez-Galan, A.; Puiggali, J. Study on the hydrolytic degradation of the segmented GL-b-[GL-co-TMC-co-CL]-b-GL copolymer with application as monofilar surgical suture. Polym. Degrad. Stab. 2013, 98, 2709–2721. [CrossRef] 20. Yang, L.Q.; Li, J.X.; Zhang, W.; Jin, Y.; Zhang, J.Z.; Liu, Y.; Yi, D.X.; Li, M.; Guo, J.; Gu, Z.W. The degradation of poly(trimethylene carbonate) implants: The role of molecular weight and enzymes. Polym. Degrad. Stab. 2015, 122, 77–87. [CrossRef] 21. Al Thaher, Y.; Latanza, S.; Perni, S.; Prokopovich, P.Role of poly-beta-amino-esters hydrolysis and electrostatic attraction in gentamicin release from layer-by-layer coatings. J. Colloid Interface Sci. 2018, 526, 35–42. [CrossRef] 22. Perni, S.; Prokopovich, P. Optimisation and feature selection of poly-beta-amino-ester as a drug delivery system for cartilage. J Mater Chem B 2020, 8, 5096–5108. [CrossRef] 23. Bracher, P.J.; Snyder, P.W.; Bohall, B.R.; Whitesides, G.M. The Relative Rates of Thiol-Thioester Exchange and Hydrolysis for Alkyl and Aryl Thioalkanoates in Water. Origins Life Evol B 2011, 41, 399–412. [CrossRef] 24. Aksakal, S.; Aksakal, R.; Becer, C.R. Thioester functional polymers. Polym. Chem. 2018, 9, 4507–4516. [CrossRef] 25. Syrett, J.A.; Becer, C.R.; Haddleton, D.M. Self-healing and self-mendable polymers. Polym. Chem. 2010, 1, 978–987. [CrossRef] 26. Syrett, J.A.; Mantovani, G.; Barton, W.R.S.; Price, D.; Haddleton, D.M. Self-healing polymers prepared via living radical polymerisation. Polym. Chem. 2010, 1, 102–106. [CrossRef] 27. Satoh, K.; Poelma, J.E.; Campos, L.M.; Stahl, B.; Hawker, C.J. A facile synthesis of clickable and acid-cleavable PEO for acid-degradable block copolymers. Polym. Chem. 2012, 3, 1890–1898. [CrossRef] 28. Johnson, J.A.; Baskin, J.M.; Bertozzi, C.R.; Koberstein, J.T.; Turro, N.J. Copper-free click chemistry for the in situ crosslinking of photodegradable star polymers. Chem. Commun. 2008, 44, 3064–3066. [CrossRef] 29. Schumers, J.M.; Gohy, J.F.; Fustin, C.A. A versatile strategy for the synthesis of block copolymers bearing a photocleavable junction. Polym. Chem. 2010, 1, 161–163. [CrossRef] 30. Johnson, J.A.; Lewis, D.R.; Az, D.D.D.U.; Finn, M.G.; Koberstein, J.T.; Turro, N.J. Synthesis of degradable model networks via ATRP and click chemistry. J. Am. Chem. Soc. 2006, 128, 6564–6565. [CrossRef] 31. Lofgren, A.; Albertsson, A.C.; Dubois, P.; Jerome, R. Recent Advances in Ring-Opening Polymerization of Lactones and Related-Compounds. J. Macromol. Sci. Rev. Macromol. Chem. Phys. 1995, C35, 379–418. [CrossRef] 32. Truong, T.T.; Thai, S.H.; Nguyen, H.T.; Vuong, V.D.; Nguyen, L.T.T. Synthesis of Allyl End-Block Functionalized Poly(epsilon-Caprolactone)s and Their Facile Post-Functionalization via Thiol-Ene Reaction. J. Polym. Sci. Part A 2017, 55, 928–939. [CrossRef] Int. J. Mol. Sci. 2020, 21, 9581 13 of 17

33. Mato, Y.; Honda, K.; Tajima, K.; Yamamoto, T.; Isono, T.; Satoh, T. A versatile synthetic strategy for macromolecular cages: Intramolecular consecutive cyclization of star-shaped polymers. Chem. Sci. 2019, 10, 440–446. [CrossRef] 34. Trollsas, M.; Hedrick, J.L.; Mecerreyes, D.; Dubois, P.; Jerome, R.; Ihre, H.; Hult, A. Highly functional branched and dendri-graft aliphatic polyesters through ring opening polymerization. Macromolecules 1998, 31, 2756–2763. [CrossRef] 35. Uhrich, K.E.; Cannizzaro, S.M.; Langer, R.S.; Shakesheff, K.M. Polymeric systems for controlled drug release. Chem. Rev. 1999, 99, 3181–3198. [CrossRef] 36. Albertsson, A.C.; Varma, I.K. Aliphatic polyesters: Synthesis, properties and applications. Adv. Polym. Sci. 2002, 157, 1–40. 37. Williams, C.K. Synthesis of functionalized biodegradable polyesters. Chem. Soc. Rev. 2007, 36, 1573–1580. [CrossRef] 38. Jerome, C.; Lecomte, P. Recent advances in the synthesis of aliphatic polyesters by ring-opening polymerization. Adv. Drug Deliver. Rev. 2008, 60, 1056–1076. [CrossRef] 39. Thomas, C.M. Stereocontrolled ring-opening polymerization of cyclic esters: Synthesis of new polyester microstructures. Chem. Soc. Rev. 2010, 39, 165–173. [CrossRef] 40. Tian, D.; Dubois, P.; Grandfils, C.; Jerome, R. Ring-opening polymerization of 1,4,8-trioxaspiro[4.6]- 9-undecanone: A new route to aliphatic polyesters bearing functional pendent groups. Macromolecules 1997, 30, 406–409. [CrossRef] 41. Lin, I.H.; Cheng, C.C.; Huang, C.W.; Liang, M.C.; Chen, J.K.; Ko, F.H.; Chu, C.W.; Huang, C.F.; Chang, F.C. Nucleobase-grafted polycaprolactones as reversible networks in a novel biocompatible material. RSC Adv. 2013, 3, 12598–12603. [CrossRef] 42. Parrish, B.; Breitenkamp, R.B.; Emrick, T. PEG- and peptide-grafted aliphatic polyesters by click chemistry. J. Am. Chem. Soc. 2005, 127, 7404–7410. [CrossRef][PubMed] 43. Al-Azemi, T.F.; Mohamod, A.A. Fluorinated epsilon-caprolactone: Synthesis and ring-opening polymerization of new alpha-fluoro-epsilon-caprolactone monomer. Polymer 2011, 52, 5431–5438. [CrossRef] 44. El Habnouni, S.; Darcos, V.; Coudane, J. Synthesis and Ring Opening Polymerization of a New Functional Lactone, alpha-Iodo-epsilon-caprolactone: A Novel Route to Functionalized Aliphatic Polyesters. Macromol. Rapid Commun. 2009, 30, 165–169. [CrossRef][PubMed] 45. Ligny, R.; Guillaume, S.M.; Carpentier, J.F. Yttrium-Mediated Ring-Opening Copolymerization of Oppositely Configurated 4-Alkoxymethylene-beta-Propiolactones: Effective Access to Highly Alternated Isotactic Functional PHAs. Chem. Eur. J. 2019, 25, 6412–6424. [CrossRef][PubMed] 46. Ligny, R.; Hanninen, M.M.; Guillaume, S.M.; Carpentier, J.F. Highly Syndiotactic or Isotactic Polyhydroxyalkanoates by Ligand-Controlled Yttrium-Catalyzed Stereoselective Ring-Opening Polymerization of Functional Racemic beta-Lactones. Angew. Chem. Int. Ed. 2017, 56, 10388–10393. [CrossRef] 47. Ligny, R.; Hanninen, M.M.; Guillaume, S.M.; Carpentier, J.F. Steric vs. electronic stereocontrol in syndio- or iso-selective ROP of functional chiral beta-lactones mediated by achiral yttrium-bisphenolate complexes. Chem. Commun. 2018, 54, 8024–8031. [CrossRef] 48. Shakaroun, R.M.; Jehan, P.; Alaaeddine, A.; Carpentier, J.F.; Guillaume, S.M. Organocatalyzed ring-opening polymerization (ROP) of functional beta-lactones: New insights into the ROP mechanism and poly(hydroxyalkanoate)s (PHAs) macromolecular structure. Polym. Chem. 2020, 11, 2640–2652. [CrossRef] 49. Jaffredo, C.G.; Chapurina, Y.; Kirillov, E.; Carpentier, J.F.; Guillaume, S.M. Highly Stereocontrolled Ring-Opening Polymerization of Racemic Alkyl beta-Malolactonates Mediated by Yttrium [Amino-alkoxy-bis(phenolate)] Complexes. Chem. Eur. J. 2016, 22, 7629–7641. [CrossRef] 50. Barouti, G.; Jaffredo, C.G.; Guillaume, S.M. Linear and three-arm star hydroxytelechelic poly(benzyl beta-malolactonate)s: A straightforward one-step synthesis through ring-opening polymerization. Polym. Chem. 2015, 6, 5851–5859. [CrossRef] 51. Jaffredo, C.G.; Carpentier, J.F.; Guillaume, S.M. Controlled ROP of beta-Butyrolactone Simply Mediated by Amidine, Guanidine, and Phosphazene Organocatalysts. Macromol. Rapid Commun. 2012, 33, 1938–1944. [CrossRef][PubMed] 52. Jaffredo, C.G.; Guillaume, S.M. Benzyl beta-malolactonate polymers: A long story with recent advances. Polym. Chem. 2014, 5, 4168–4194. [CrossRef] Int. J. Mol. Sci. 2020, 21, 9581 14 of 17

53. Mulzer, M.; Ellis, W.C.; Lobkovsky, E.B.; Coates, G.W. Enantioenriched beta-lactone and aldol-type products from regiodivergent carbonylation of racemic cis-epoxides. Chem. Sci. 2014, 5, 1928–1933. [CrossRef] 54. Kramer, J.W.; Treitler, D.S.; Dunn, E.W.; Castro, P.M.; Roisnel, T.; Thomas, C.M.; Coates, G.W. Polymerization of Enantiopure Monomers Using Syndiospecific Catalysts: A New Approach To Sequence Control in Polymer Synthesis. J. Am. Chem. Soc. 2009, 131, 16042. [CrossRef] 55. Fukushima, K. Poly(trimethylene carbonate)-based polymers engineered for biodegradable functional biomaterials. Biomater. Sci. 2016, 4, 9–24. [CrossRef] 56. Whiteoak, C.J.; Kielland, N.; Laserna, V.; Escudero-Adan, E.C.; Martin, E.; Kleij, A.W. A Powerful Aluminum Catalyst for the Synthesis of Highly Functional Organic Carbonates. J. Am. Chem. Soc. 2013, 135, 1228–1231. [CrossRef] 57. Dove, A.P. Organic Catalysis for Ring-Opening Polymerization. ACS Macro Lett. 2012, 1, 1409–1412. [CrossRef] 58. Stevens, D.M.; Rahalkar, A.; Spears, B.; Gilmore, K.; Douglas, E.; Muthukumar, M.; Harth, E. Semibranched polyglycidols as "fillers" in polycarbonate hydrogels to tune hydrophobic drug release. Polym. Chem. 2015, 6, 1096–1102. [CrossRef] 59. Gabirondo, E.; Sangroniz, A.; Etxeberria, A.; Torres-Giner, S.; Sardon, H. Poly(hydroxy acids) derived from the self-condensation of hydroxy acids: From polymerization to end-of-life options. Polym. Chem. 2020, 11, 4861–4874. [CrossRef] 60. Bailey, W.J.; Ni, Z.; Wu, S.R. Synthesis of Poly-Epsilon-Caprolactone Via a Free-Radical Mechanism—Free-Radical Ring-Opening Polymerization of 2-Methylene-1,3-Dioxepane. J. Polym. Sci. Part A 1982, 20, 3021–3030. 61. Bailey, W.J.; Ni, Z.; Wu, S.R. Free-Radical Ring-Opening Polymerization of 4,7-Dimethyl-2-Methylene-1,3-Dioxepane and "5,6-Benzo-2-Methylene-1,3-Dioxepane. Macromolecules 1982, 15, 711–714. [CrossRef] 62. Bailey, W.J.; Wu, S.R.; Ni, Z. Synthesis and Free-Radical Ring-Opening Polymerization of 2-Methylene-4-Phenyl-1,3-Dioxolane. Makromol. Chem. 1982, 183, 1913–1920. [CrossRef] 63. Bailey, W.J. Free-Radical Ring-Opening Polymerization. Polym. J. 1985, 171–190. 64. Bailey, W.J.; Chou, J.L.; Feng, P.Z.; Issari, B.; Kuruganti, V.; Zhou, L.L. Recent Advances in Free-Radical Ring-Opening Polymerization. J. Macromol. Sci. Chem. 1988, A25, 781–798. [CrossRef] 65. Sanda, F.; Takata, T.; Endo, T. Vinylcyclopropanone Cyclic Acetal Synthesis, Polymerization, Structure of the Polymer and Mechanism of the Polymerization. Macromolecules 1994, 27, 1099–1111. [CrossRef] 66. Okazaki, T.; Sanda, F.; Endo, T. Synthesis and Radical Ring-Opening Polymerization Behavior of Bifunctional Vinylcyclopropane Bearing a Spiroacetal Moiety. Macromolecules 1995, 28, 6026–6028. [CrossRef] 67. Sanda, F.; Endo, T. Radical ring-opening polymerization. J. Polym. Sci. Part A 2001, 39, 265–276. [CrossRef] 68. Evans, R.A.; Moad, G.; Rizzardo, E.; Thang, S.H. New Free-Radical Ring-Opening Acrylate Monomers. Macromolecules 1994, 27, 7935–7937. [CrossRef] 69. Fischer, H.; Radom, L. Factors Controlling the Addition of Carbon-Centered Radicals to Alkenes-An Experimental and Theoretical Perspective. Angew. Chem. Int. Ed. 2001, 40, 1340–1371. [CrossRef] 70. Roberts, G.E.; Coote, M.L.; Heuts, J.P.A.; Morris, L.M.; Davis, T.P. Radical Ring-Opening Copolymerization of 2-Methylene 1,3-Dioxepane and Methyl Methacrylate: Experiments Originally Designed To Probe the Origin of the Penultimate Unit Effect. Macromolecules 1999, 32, 1332–1340. [CrossRef] 71. Undin, J.; Illanes, T.; Finne-Wistrand, A.; Albertsson, A.-C. Random introduction of degradable linkages into functional vinyl polymers by radical ring-opening polymerization, tailored for soft tissue engineering. Polym. Chem. 2012, 3, 1260–1266. [CrossRef] 72. Hedir, G.G.; Bell, C.A.; O’Reilly, R.K.; Dove, A.P. Functional Degradable Polymers by Radical Ring-Opening Copolymerization of MDO and Vinyl Bromobutanoate: Synthesis, Degradability and Post-Polymerization Modification. Biomacromolecules 2015, 16, 2049–2058. [CrossRef][PubMed] 73. Chung, I.S.; Matyjaszewski, K. Synthesis of degradable poly(methyl methacrylate) via ATRP: Atom transfer radical ring-opening copolymerization of 5-methylene-2-phenyl-1,3-dioxolan-4-one and methyl methacrylate. Macromolecules 2003, 36, 2995–2998. [CrossRef] 74. Smith, Q.; Huang, J.Y.; Matyjaszewski, K.; Loo, Y.L. Controlled radical polymerization and copolymerization of 5-methylene-2-phenyl-1,3-dioxolan-4-one by ATRP. Macromolecules 2005, 38, 5581–5586. [CrossRef] Int. J. Mol. Sci. 2020, 21, 9581 15 of 17

75. Tardy, A.; Honoré, J.-C.; Tran, J.; Siri, D.; Delplace, V.; Bataille, I.; Letourneur, D.; Perrier, J.; Nicoletti, C.; Maresca, M.; et al. Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to Design Functional Polyesters. Angew. Chem. Int. Ed. 2017, 56, 16515–16520. [CrossRef][PubMed] 76. Hill, M.R.; Kubo, T.; Goodrich, S.L.; Figg, C.A.; Sumerlin, B.S. Alternating Radical Ring-Opening Polymerization of Cyclic Ketene Acetals: Access to Tunable and Functional Polyester Copolymers. Macromolecules 2018, 51, 5079–5084. [CrossRef] 77. Odian, G. Chapter 3. Radical chain polymerization. In Principles of Polymerization, 4th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2004. 78. Corrigan, N.; Jung, K.; Moad, G.; Hawker, C.J.; Matyjaszewski, K.; Boyer, C. Reversible-deactivation radical polymerization (Controlled/living radical polymerization): From discovery to materials design and applications. Prog. Polym. Sci. 2020, 111, 101311. [CrossRef] 79. Kamigaito, M.; Ando, T.; Sawamoto, M. Metal-catalyzed living radical polymerization. Chem. Rev. 2001, 101, 3689–3745. [CrossRef] 80. Matyjaszewski, K. Atom Transfer Radical Polymerization (ATRP): Current Status and Future Perspectives. Macromolecules 2012, 45, 4015–4039. [CrossRef] 81. Huang, C.-F.; Chen, W.-H.; Aimi, J.; Huang, Y.-S.; Venkatesan, S.; Chiang, Y.-W.; Huang, S.-H.; Kuo, S.-W.; Chen, T. Synthesis of Well-defined PCL-b-PnBA-b-PMMA ABC-type Triblock Copolymers: Toward the Construction of Nanostructures in Epoxy Thermosets. Polym. Chem. 2018, 9, 5644–5654. [CrossRef] 82. Huang, Y.-S.; Hsueh, H.-Y.; Aimi, J.; Chou, L.-C.; Lu, Y.-C.; Kuo, S.-W.; Wang, C.-C.; Chen, K.-Y.; Huang, C.-F. Effects of various Cu(0), Fe(0), and Proanthocyanidin Reducing Agents on Fe(III)-catalysed ATRP for the Synthesis of PMMA Block Copolymers and their Self-assembly Behaviours. Polym. Chem. 2020, 11, 5147–5155. [CrossRef] 83. Hawker, C.J.; Bosman, A.W.; Harth, E. New polymer synthesis by nitroxide mediated living radical polymerizations. Chem. Rev. 2001, 101, 3661–3688. [CrossRef][PubMed] 84. Moad, G.; Chong, Y.K.; Postma, A.; Rizzardo, E.; Thang, S.H. Advances in RAFT polymerization: The synthesis of polymers with defined end-groups. Polymer 2005, 46, 8458–8468. [CrossRef] 85. Huang, C.-F.; Nicolay, R.; Kwak, Y.; Chang, F.-C.; Matyjaszewski, K. Homopolymerization and Block Copolymerization of N-Vinylpyrrolidone by ATRP and RAFT with Haloxanthate Inifers. Macromolecules 2009, 42, 8198–8210. [CrossRef] 86. Huang, C.-F.; Hsieh, Y.-A.; Hsu, S.-C.; Matyjaszewski, K. Synthesis of Poly(N-vinyl carbazole)-based Block Copolymers by Sequential Polymerizations of RAFT-ATRP. Polymer 2014, 55, 6051–6057. [CrossRef] 87. Huang, Y.S.; Chen, J.K.; Kuo, S.W.; Hsieh, Y.A.; Yamamoto, S.; Nakanishi, J.; Huang, C.F. Synthesis of Poly(N-vinylpyrrolidone)-Based Polymer Bottlebrushes by ATRPA and RAFT Polymerization: Toward Drug Delivery Application. Polymers 2019, 11, 1079. [CrossRef] 88. Huang, J.Y.; Gil, R.; Matyjaszewski, K. Synthesis and characterization of copolymers of 5,6-benzo-2-methylene-1, 3-dioxepane and n-butyl acrylate. Polymer 2005, 46, 11698–11706. [CrossRef] 89. Siegwart, D.J.; Bencherif, S.A.; Srinivasan, A.; Hollinger, J.O.; Matyjaszewski, K. Synthesis, characterization, and in vitro cell culture viability of degradable poly(N-isopropylacrylamide-co-5,6-benzo- 2-methylene-1,3-dioxepane)-based polymers and crosslinked gels. J. Biomed. Mater. Res. Part A 2008, 87a, 345–358. [CrossRef] 90. Pan, C.Y.; Lou, X.D. "Living" free radical ring-opening polymerization of 2-methylene-4-phenyl-1,3-dioxolane by atom transfer radical polymerization. Macromol. Chem. Phys. 2000, 201, 1115–1120. [CrossRef] 91. Yuan, J.Y.; Pan, C.Y.; Tang, B.Z. "Living" free radical ring-opening polymerization of 5,6-benzo-2-methylene-1,3-dioxepane using the atom transfer radical polymerization method. Macromolecules 2001, 34, 211–214. [CrossRef] 92. Yuan, J.Y.; Pan, C.Y. Block copolymerization of 5,6-benzo-2-methylene-1,3-dioxepane with conventional vinyl monomers by ATRP method. Eur. Polym. J. 2002, 38, 1565–1571. [CrossRef] 93. Wickel, H.; Agarwal, S. Synthesis and characterization of copolymers of 5,6-benzo-2-methylene-1,3-dioxepane and styrene. Macromolecules 2003, 36, 6152–6159. [CrossRef] 94. Wickel, H.; Agarwal, S.; Greiner, A. Homopolymers and random copolymers of 5,6-benzo-2-methylene-1,3-dioxepane and methyl methacrylate: Structural characterization using 1D and 2D NMR. Macromolecules 2003, 36, 2397–2403. [CrossRef] Int. J. Mol. Sci. 2020, 21, 9581 16 of 17

95. Lutz, J.F.; Andrieu, J.; Uzgun, S.; Rudolph, C.; Agarwal, S. Biocompatible, thermoresponsive, and biodegradable: Simple preparation of "all-in-one" biorelevant polymers. Macromolecules 2007, 40, 8540–8543. [CrossRef] 96. Agarwal, S. Chemistry, chances and limitations of the radical ring-opening polymerization of cyclic ketene acetals for the synthesis of degradable polyesters. Polym. Chem. 2010, 1, 953–964. [CrossRef] 97. Tardy, A.; Delplace, V.; Siri, D.; Lefay, C.; Harrisson, S.; Pereira, B.D.A.; Charles, L.; Gigmes, D.; Nicolas, J.; Guillaneuf, Y. Scope and limitations of the nitroxide-mediated radical ring-opening polymerization of cyclic ketene acetals. Polym. Chem. 2013, 4, 4776–4787. [CrossRef] 98. Delplace, V.; Harrisson, S.; Tardy, A.; Gigmes, D.; Guillaneuf, Y.; Nicolas, J. Nitroxide-mediated radical ring-opening copolymerization: Chain-end investigation and block copolymer synthesis. Macromol. Rapid Commun. 2014, 35, 484–491. [CrossRef] 99. He, T.; Zou, Y.F.; Pan, C.Y. Controlled/"living" radical ring-opening polymerization of 5,6-benzo-2-methylene-1,3-dioxepane based on reversible addition-fragmentation chain transfer mechanism. Polym. J. 2002, 34, 138–143. [CrossRef] 100. Paulusse, J.M.J.; Amir, R.J.; Evans, R.A.; Hawker, C.J. Free Radical Polymers with Tunable and Selective Bio- and Chemical Degradability. J. Am. Chem. Soc. 2009, 131, 9805–9812. [CrossRef] 101. Minisci, F. Free-radical additions to olefins in the presence of redox systems. Acc. Chem. Res. 1975, 8, 165–171. [CrossRef] 102. Wang, C.H.; Song, Z.Y.; Deng, X.X.; Zhang, L.J.; Du, F.S.; Li, Z.C. Combination of ATRA and ATRC for the Synthesis of Periodic Vinyl Copolymers. Macromol. Rapid Commun. 2014, 35, 474–478. [CrossRef][PubMed] 103. Matyjaszewski, K.; Gaynor, S.G.; Kulfan, A.; Podwika, M. Preparation of hyperbranched polyacrylates by atom transfer radical polymerization. 1. Acrylic AB* monomers in “living” radical polymerizations. Macromolecules 1997, 30, 5192–5194. [CrossRef] 104. Yan, D.Y.; Muller, A.H.E.; Matyjaszewski, K. Molecular parameters of hyperbranched polymers made by self-condensing vinyl polymerization. 2. Degree of branching. Macromolecules 1997, 30, 7024–7033. [CrossRef] 105. Satoh, K.; Mizutani, M.; Kamigaito, M. Metal-catalyzed radical polyaddition as a novel polymer synthetic route. Chem. Commun. 2007, 43, 1260–1262. [CrossRef][PubMed] 106. Mizutani, M.; Satoh, K.; Kamigaito, M. Metal-Catalyzed Radical Polyaddition for Aliphatic Polyesters via Evolution of Atom Transfer Radical Addition into Step-Growth Polymerization. Macromolecules 2009, 42, 472–480. [CrossRef] 107. Satoh, K.; Ozawa, S.; Mizutani, M.; Nagai, K.; Kamigaito, M. Sequence-regulated vinyl copolymers by metal-catalysed step-growth radical polymerization. Nat. Commun. 2010, 1, 6. [CrossRef][PubMed] 108. Dong, B.T.; Dong, Y.Q.; Du, F.S.; Li, Z.C. Controlling Polymer Topology by Atom Transfer Radical Self-Condensing Vinyl Polymerization of p-(2-Bromoisobutyloylmethyl)styrene. Macromolecules 2010, 43, 8790–8798. [CrossRef] 109. Dong, B.T.; Li, Z.L.; Zhang, L.J.; Du, F.S.; Li, Z.C. Synthesis of linear functionalized polyesters by controlled atom transfer radical polyaddition reactions. Polym. Chem. 2012, 3, 2523–2530. [CrossRef] 110. Zhang, L.J.; Dong, B.T.; Du, F.S.; Li, Z.C. Degradable Thermoresponsive Polyesters by Atom Transfer Radical Polyaddition and Click Chemistry. Macromolecules 2012, 45, 8580–8587. [CrossRef] 111. Han, Y.M.; Chen, H.H.; Huang, C.F. Polymerization and degradation of aliphatic polyesters synthesized by atom transfer radical polyaddition. Polym. Chem. 2015, 6, 4565–4574. [CrossRef] 112. Huang, C.F.; Kuo, S.W.; Moravcikova, D.; Liao, J.C.; Han, Y.M.; Lee, T.H.; Wang, P.H.; Lee, R.H.; Tsiang, R.C.C.; II 0 Mosnacek, J. Effect of variations of (Cu X2)/L, surface area of Cu , solvent, and temperature on atom transfer radical polyaddition of 4-vinylbenzyl 2-bromo-2-isobutyrate inimers. RSC Adv. 2016, 6, 51816–51822. [CrossRef] 113. Lu, Y.C.; Chou, L.C.; Huang, C.F. Iron-catalysed atom transfer radical polyaddition for the synthesis and modification of novel aliphatic polyesters displaying lower critical solution temperature and pH-dependent release behaviors. Polym. Chem. 2019, 10, 3912–3921. [CrossRef] 114. Mizutani, M.; Satoh, K.; Kamigaito, M. Metal-Catalyzed Simultaneous Chain- and Step-Growth Radical Polymerization: Marriage of Vinyl Polymers and Polyesters. J. Am. Chem. Soc. 2010, 132, 7498–7507. [CrossRef][PubMed] Int. J. Mol. Sci. 2020, 21, 9581 17 of 17

115. Mizuntani, M.; Satoh, K.; Kamigaito, M. Degradable Poly(N-isopropylacrylamide) with Tunable Thermosensitivity by Simultaneous Chain- and Step-Growth Radical Polymerization. Macromolecules 2011, 44, 2382–2386. [CrossRef] 116. Mizutani, M.; Palermo, E.F.; Thoma, L.M.; Satoh, K.; Kamigaito, M.; Kuroda, K. Design and Synthesis of Self-Degradable Antibacterial Polymers by Simultaneous Chain- and Step-Growth Radical Copolymerization. Biomacromolecules 2012, 13, 1554–1563. [CrossRef][PubMed] 117. Mizutani, M.; Satoh, K.; Kamigaito, M. Construction of Vinyl Polymer and Polyester or Polyamide Units in a Single Polymer Chain via Metal-catalyzed Simultaneous Chain- and Step-growth Radical Polymerization of Various Monomers. Aust. J. Chem. 2014, 67, 544–554. [CrossRef] 118. Zhang, X.M.; Dou, H.Q.; Zhang, Z.B.; Zhang, W.; Zhu, X.L.; Zhu, J. Fast and effective copper(0)-mediated simultaneous chain- and step-growth radical polymerization at ambient temperature. J. Polym. Sci. Part A 2013, 51, 3907–3916. [CrossRef]

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).