Efficient Diethylzinc/Gallic Acid and Diethylzinc/Gallic Acid Ester Catalytic Systems for the Ring-Opening Polymerization of rac-Lactide

Polylactide (PLA) represents one of the most promising biomedical polymers due to its biodegradability, bioresorbability and good biocompatibility. This work highlights the synthesis and characterization of PLAs using novel diethylzinc/gallic acid (ZnEt2/GAc) and diethylzinc/propyl gallate (ZnEt2/PGAc) catalytic systems that are safe for human body. The results of the ring-opening polymerization (ROP) of rac-lactide (rac-LA) in the presence of zinc-based catalytic systems have shown that, depending on the reaction conditions, “predominantly isotactic”, disyndiotactic or atactic PLA can be obtained. Therefore, the controlled and stereoselective ROP of rac-LA is discussed in detail in this paper.

Two methods for PLA preparation are commonly known: the polycondensation of lactic acid and the ring-opening polymerization (ROP) of lactide (LA) [1]. The polycondensation process is hampered by the typical limitations of step polymerization, whereas ROP of LA can be initiated by metal complexes and organic compounds or enzymes, both with and without alcohol [1,[9][10][11][12].
Metal complexes are desirable because they can give rise to controlled polymerizations and can therefore yield materials with a well-defined number-average molecular weight (M n ), as well as a narrow polydispersity index (PD) [1,13]. These initiators are metal alkoxide or amide coordination compounds (sometimes formed in situ), which are particularly useful because of their selectivity, rate and lack of side reactions. However, metal residues are undesirable for medical or pharmaceutical applications and in these cases, a low toxicity organocatalytic or enzyme catalytic systems are favorable [1].
There are two primary mechanisms for the ROP of LA: the coordination insertion mechanism for metal complexes and the activated monomer mechanism for organo/cationic initiators [1,13]. The key initiator or catalyst parameters are polymerization control, rate and stereocontrol. Stereocontrol is an important parameter, because the PLA's tacticity influences its properties (e.g., isotactic PLA is crystalline, whereas atactic PLA is amorphous). PLA tacticity is dependent on both the type of LA and the selected initiator or catalyst [14][15][16].
During initiator selection, the biocompatibility and toxicity of the initiator or catalytic system are important issues, especially in the case of medical or pharmaceutical applications. In general, the metal-based initiators or catalysts remain in the macromolecule and during degradation, are likely to be converted into an oxide or hydroxide. For example, some Sn-, Zn-or Zr-based initiator/catalyst systems are generally considered non-toxic [1,13].
The development of reproducible and efficient DDS requires fine tailoring of the properties of the applied PLA. The microstructure of PLA (isotactic, syndiotactic, heterotactic and atactic) influences the kinetics of the biodegradation process [1,[13][14][15][16].
In our recent study, we found catalytic systems composed of diethylzinc/gallic acid (ZnEt 2 /GAc) and diethylzinc/propyl gallate (ZnEt 2 /PGAc), synthesized for the first time, to be quite effective in the ROP of ε-caprolactone (CL). Polymerization in bulk at 40-80˝C produced poly(ε-caprolactone) (PCL) with a high yield (ca. 100% in some cases). Most importantly, when the ROP of CL was carried out in the presence of ZnEt 2 /PGAc catalytic system at 40-60˝C within 48 h or at 80˝C within 6 h, no macrocyclic products were formed [40].
However, the ring-opening homopolymerization of rac-LA alongside the application of the above-mentioned Zn-catalytic systems has not previously been studied. Therefore, in this work, the effects of temperature, reaction time and Zn-catalytic system dosage on the ROP of rac-LA were examined in detail. We believe that the produced PLAs, which had a well-defined microstructure, can be practically applied as "long", "medium" or "short term" DDSs.

Results and Discussion
Catalytic systems were obtained in the reaction of ZnEt 2 with natural GAc (or PGAc) at a molar ratio of 3:1. rac-LA polymerizations in the presence of ZnEt 2 /GAc or ZnEt 2 /PGAc catalytic systems were carried out at zinc to monomer molar ratio of 1:50 or 1:100 at 40-80˝C (Scheme 1, Tables 1-4). Toluene, tetrahydrofuran or dichloromethane were used as a reaction medium. The effects of the reaction medium, temperature and reaction time on the monomer conversion, product molecular weight, as well as the microstructure of the synthesized polyesters were investigated.
Molecules 2015, 20, page-page 2 There are two primary mechanisms for the ROP of LA: the coordination insertion mechanism for metal complexes and the activated monomer mechanism for organo/cationic initiators [1,13]. The key initiator or catalyst parameters are polymerization control, rate and stereocontrol. Stereocontrol is an important parameter, because the PLA's tacticity influences its properties (e.g., isotactic PLA is crystalline, whereas atactic PLA is amorphous). PLA tacticity is dependent on both the type of LA and the selected initiator or catalyst [14][15][16].
During initiator selection, the biocompatibility and toxicity of the initiator or catalytic system are important issues, especially in the case of medical or pharmaceutical applications. In general, the metal-based initiators or catalysts remain in the macromolecule and during degradation, are likely to be converted into an oxide or hydroxide. For example, some Sn-, Zn-or Zr-based initiator/catalyst systems are generally considered non-toxic [1,13].
The development of reproducible and efficient DDS requires fine tailoring of the properties of the applied PLA. The microstructure of PLA (isotactic, syndiotactic, heterotactic and atactic) influences the kinetics of the biodegradation process [1,[13][14][15][16].
In our recent study, we found catalytic systems composed of diethylzinc/gallic acid (ZnEt2/GAc) and diethylzinc/propyl gallate (ZnEt2/PGAc), synthesized for the first time, to be quite effective in the ROP of ε-caprolactone (CL). Polymerization in bulk at 40-80 °C produced poly(ε-caprolactone) (PCL) with a high yield (ca. 100% in some cases). Most importantly, when the ROP of CL was carried out in the presence of ZnEt2/PGAc catalytic system at 40-60 °C within 48 h or at 80 °C within 6 h, no macrocyclic products were formed [40].
However, the ring-opening homopolymerization of rac-LA alongside the application of the above-mentioned Zn-catalytic systems has not previously been studied. Therefore, in this work, the effects of temperature, reaction time and Zn-catalytic system dosage on the ROP of rac-LA were examined in detail. We believe that the produced PLAs, which had a well-defined microstructure, can be practically applied as "long", "medium" or "short term" DDSs.

Results and Discussion
Catalytic systems were obtained in the reaction of ZnEt2 with natural GAc (or PGAc) at a molar ratio of 3:1. rac-LA polymerizations in the presence of ZnEt2/GAc or ZnEt2/PGAc catalytic systems were carried out at zinc to monomer molar ratio of 1:50 or 1:100 at 40-80 °C (Scheme 1, Tables 1-4). Toluene, tetrahydrofuran or dichloromethane were used as a reaction medium. The effects of the reaction medium, temperature and reaction time on the monomer conversion, product molecular weight, as well as the microstructure of the synthesized polyesters were investigated. We found that ROP of rac-LA produced PLAs terminated with hydroxyl chain end groups under these conditions. The chemical structures of the obtained PLAs were confirmed by 1 H-or 13 C-NMR and FT-IR studies (see the Experimental Section). The molecular weight and polydispersity of the synthesized polyesters were also determined. We found that ROP of rac-LA produced PLAs terminated with hydroxyl chain end groups under these conditions. The chemical structures of the obtained PLAs were confirmed by 1 H-or 13 C-NMR and FT-IR studies (see the Experimental Section). The molecular weight and polydispersity of the synthesized polyesters were also determined. a calculated by the weight method; b calculated from 1 H-NMR analysis (spectra of a crude reaction mixture; the conversion has been calculated by the integration of the characteristic signal of the monomer (δ = 5.03 ppm) and the polymer chain (ranged from δ = 5.13 to 5.18 ppm)); c determined by GPC; M n corrected by a factor of ca. 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21ˆ10´4 dL/g and α = 0.77) [42][43][44]; f determined by 1 H-NMR; p 2 -coefficient of stereoselectivity calculated from the equation presented in [45]; T-transesterification coefficient [15]; L i = 2/p i -average length of lactyl units [46]. a calculated by the weight method; b calculated from 1 H-NMR analysis (spectra of a crude reaction mixture; the conversion has been calculated by the integration of the characteristic signal of the monomer (δ = 5.03 ppm) and the polymer chain (ranged from δ = 5.13 to 5.18 ppm)); c determined by GPC; M n corrected by a factor of ca. 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21ˆ10´4 dL/g and α = 0.77) [42][43][44]; f determined by 1 H-NMR; p 2 -coefficient of stereoselectivity calculated from the equation presented in [45]; T-transesterification coefficient [15]; L i = 2/p i -average length of lactyl units [46]. Table 3. Ring-opening polymerization of rac-LA in toluene in the presence of ZnEt 2 /PGAc catalytic system. a calculated by the weight method; b calculated from 1 H-NMR analysis (spectra of a crude reaction mixture; the conversion has been calculated by the integration of the characteristic signal of the monomer (δ = 5.03 ppm) and the polymer chain (ranged from δ = 5.13 to 5.18 ppm)); c determined by GPC; M n corrected by a factor of ca. 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21ˆ10´4 dL/g and α = 0.77) [42][43][44]; f determined by 1 H-NMR; p 2 -coefficient of stereoselectivity calculated from the equation presented in [45]; T-transesterification coefficient [15]; L i = 2/p i -average length of lactyl units [46]. a calculated by the weight method; b calculated from 1 H-NMR analysis (spectra of a crude reaction mixture; the conversion has been calculated by the integration of the characteristic signal of the monomer (δ = 5.03 ppm) and the polymer chain (ranged from δ = 5.13 to 5.18 ppm)); c determined by GPC; M n corrected by a factor of ca 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21ˆ10´4 dL/g and α = 0.77) [42][43][44]; f determined by 1 H-NMR; p 2 -coefficient of stereoselectivity calculated from the equation presented in [45]; T-transesterification coefficient [15]; L i = 2/p i -average length of lactyl units [46]. Tables 1-4 the yield of the ROP process was dependent on the rac-LA/catalytic system's molar ratio, reaction medium, temperature and reaction time.
The molecular weight of PLAs was also dependent on the rac-LA/catalytic system molar ratio, reaction medium, temperature and reaction time (Tables 1-4). The average molecular mass (M n ) values of PLA increased when the reaction time, reaction temperature and rac-LA/catalytic system molar ratio were increased. The M n values of PLA determined by the GPC were in the range of 1200-9900 Da (ZnEt 2 /PGAc catalytic system, Tables 3 and 4) and 1300-6800 Da (ZnEt 2 /GAc catalytic system, Tables 1 and 2). When the process was carried out in the presence of a ZnEt 2 /PGAc catalytic system (where the molar ratio of catalyst to monomer was 1:100, reaction temp. 80˝C), the M n results were: 9900 Da for PCL 37 (reaction time 48 h), 9300 Da for PLA 36 (reaction time 24 h) and 8600 Da for PLA 35 (reaction time 16 h) ( Table 3). In comparison, when the ZnEt 2 /GAc catalytic system was used, M n results were 6800 Da for PLA 14 (reaction time 48 h), 6600 Da for PLA 13 (reaction time 24 h) and 5900 Da for PLA 12 (reaction time 16 h), respectively ( Table 1).
As was shown, the PLAs obtained in the presence of ZnEt 2 /PGAc catalytic system were generally characterized by a higher M n when compared to the PLAs synthesized in the presence of ZnEt 2 /GAc. Moreover, when ROP was carried out in toluene, the synthesized PLAs were characterized by a higher M n than that of PLAs synthesized in THF or CH 2 Cl 2 . The M n values determined from GPC were comparable to the viscosity analysis results (M v ), as well as those of M n calculated from 1 H-NMR.
As is known, in the MALDI-TOF MS spectra of PLA, two populations of chains can be observed (the even number and the odd number of lactyl units). An odd number of lactyl units shows that the PLA chain undergoes intra-and intermolecular transesterification. In our results, the MALDI-TOF MS spectra of the synthesized PLAs comprise two or three series of peaks (Figure 1). The primary series (I) corresponded to PLA macromolecule terminated with a hydroxyl group and a hydrogen atom (residual mass: ca. 41 Da, Na + adduct). The third series of peaks (III) also corresponded to PLA molecules terminated with a hydroxyl group and hydrogen atom (residual mass: ca. 57 Da, K + adduct). The second series of peaks, which had low intensity (almost unnoticeable) (II), corresponded to cyclic molecules (residual mass: ca. 23 Da, Na + adduct). The content of this population was determined on the basis of the intensity ratio of the peaks for linear and cyclic PLA. As was shown, the content of cyclic products generally increased with increasing of the temperature and polymerization time. In our previous paper, we reported that when ROP of CL was carried out in the presence of ZnEt 2 /PGAc catalytic system at 40-60˝C within 48 h or at 80˝C within 6 h, macrocyclic products did not formed [40]. As shown in Tables 1-4  In summary, our results clearly show that ZnEt2/PGAc is a more effective catalytic system for the promotion of the polymerization of rac-LA, compared to ZnEt2/GAc. The rac-LA monomer had almost completely been consumed in the presence of ZnEt2/PGAc within 48 h at 80 °C (Table 3, PLA 28, conversion 91%). In comparison, the maximum conversion for ROP of rac-LA catalyzed by ZnEt2/GAc was 64% in the same reaction condition (Table 1, PLA 6). The same trend was observed in our previous experiments concerning ROP of CL in the presence of ZnEt2/PGAc or ZnEt2/GAc catalytic systems. This likely demonstrates that only -OZn-active species are formed in the first case (ZnEt2/PGAc) whereas in the second case (ZnEt2/GAc), -COOZn-species are also formed [40].
It has been established that the physico-chemical, biological and biodegradation properties of PLA are dramatically dependent on the stereochemistry of PLA. Although zinc compounds have been extensively studied, these are the highest stereoselectivity, achieved by zinc-based catalysts from rac-LA to date [47][48][49][50][51][52][53].
The microstructure of the PLA was evaluated by homonuclear-decoupled 1 H-NMR and 13 C-NMR spectra. The tetrad peaks in 1 H-NMR spectra were assigned as noted in the literature [49]. Tetrads (for the methine carbon) or hexads (for the carbonyl carbon) distribution were also observed in the 13 C-NMR [45].
The literature notes that when an intermolecular transesterification process does not occur during polymerization, the carbonyl carbon region exhibits several lines that correspond to 11 hexads, resulting from a pair addition of enantiomers of LA. When the transesterification process occurs, new lines can be observed in the spectrum of carbonyl region as a combination of 21 hexads containing ss segment [45]. Moreover, when intermolecular transesterification process do not occur during polymerization, the resonanse lines due to iss, sss and ssi tetrads are not observed in the methine region [45][46][47][48][49][50][51][52][53][54][55][56].
The values of transesterification coefficient (T) were calculated from the proportion of iss tetrad in 1 H-or 13 C-NMR data using Bernoullian statistics [54].
T was calculated using the following equation: The experimental isi relative weight can essentially vary from 0.125 (random linkage of lactyl units) to 0.25 (Bernoullian addition of pairs). It is known that T values varying from 0 to 1 and in a stereoselective process the upper limit related to the isi tetrad relative weights is higher [11]. In summary, our results clearly show that ZnEt 2 /PGAc is a more effective catalytic system for the promotion of the polymerization of rac-LA, compared to ZnEt 2 /GAc. The rac-LA monomer had almost completely been consumed in the presence of ZnEt 2 /PGAc within 48 h at 80˝C (Table 3, PLA 28, conversion 91%). In comparison, the maximum conversion for ROP of rac-LA catalyzed by ZnEt 2 /GAc was 64% in the same reaction condition (Table 1, PLA 6). The same trend was observed in our previous experiments concerning ROP of CL in the presence of ZnEt 2 /PGAc or ZnEt 2 /GAc catalytic systems. This likely demonstrates that only -OZn-active species are formed in the first case (ZnEt 2 /PGAc) whereas in the second case (ZnEt 2 /GAc), -COOZn-species are also formed [40].
It has been established that the physico-chemical, biological and biodegradation properties of PLA are dramatically dependent on the stereochemistry of PLA. Although zinc compounds have been extensively studied, these are the highest stereoselectivity, achieved by zinc-based catalysts from rac-LA to date [47][48][49][50][51][52][53].
The microstructure of the PLA was evaluated by homonuclear-decoupled 1 H-NMR and 13 C-NMR spectra. The tetrad peaks in 1 H-NMR spectra were assigned as noted in the literature [49]. Tetrads (for the methine carbon) or hexads (for the carbonyl carbon) distribution were also observed in the 13 C-NMR [45].
The literature notes that when an intermolecular transesterification process does not occur during polymerization, the carbonyl carbon region exhibits several lines that correspond to 11 hexads, resulting from a pair addition of enantiomers of LA. When the transesterification process occurs, new lines can be observed in the spectrum of carbonyl region as a combination of 21 hexads containing ss segment [45]. Moreover, when intermolecular transesterification process do not occur during polymerization, the resonanse lines due to iss, sss and ssi tetrads are not observed in the methine region [45][46][47][48][49][50][51][52][53][54][55][56].
The values of transesterification coefficient (T) were calculated from the proportion of iss tetrad in 1 H-or 13 C-NMR data using Bernoullian statistics [54].
T was calculated using the following equation: T " pisi 0´i siq{pisi 0´0 .125q (1) The experimental isi relative weight can essentially vary from 0.125 (random linkage of lactyl units) to 0.25 (Bernoullian addition of pairs). It is known that T values varying from 0 to 1 and in a stereoselective process the upper limit related to the isi tetrad relative weights is higher [11].
In our study, a racemic mixture of LA was polymerized (for the ratio of enantiomers, k = 1). It is possible to assume that the probabilities of the enantiomer addition to the growing chain terminated with the same enantiomer are equal p RR/RR = p SS/SS = p 1 . The probabilities of the enantiomer's addition to the growing chain terminated with opposite enantiomers are equal p RR/SS = p SS/RR = p 2 (because p RR/RR + p SS/RR = 1 and p SS/SS + p RR/SS = 1) [45].

(11)
The coefficient probabilities p 1 and p 2 were calculated from the above equations using the intensities of signals in the 13 C-NMR spectrum [45]. In this work, the influence of the types of catalytic systems, as well as the reaction time and temperature on the chain microstructure was investigated.
As shown in Table 3 and Figures 2 and 3 when rac-LA was employed using a ZnEt 2 /PGAc catalytic system (40˝C within 16-48 h or 60˝C within 16-24 h), the intermolecular transesterification process was not observed (T = 0). For example, for a polyester obtained in the presence of ZnEt 2 /PGAc catalytic system (60˝C within 16 h, Table 3), the calculated coefficient of stereoselectivity p 2 was 0.58 (PLA 25), whereas the average length of lactyl units L i = 3.38 (when no ss sequences were present in the polymer chain, this coefficient may be defined as p 2 = 2/L i , where L i is the average length of the isotactic microblocks). In our research, the "predominantly isotactic" PLA (PLA 25) was obtained in the conditions stated above. As is commonly known, the ROP process of rac-LA enables the following to form: In the 13 C-NMR spectra of PLA obtained in the presence of ZnEt 2 /PGAc catalytic system (40˝C within 16-48 h or 60˝C within 16-24 h), no lines due to tetrads and hexads containing the ss sequences were present (Figures 2 and 3). In contrast, when ROP of rac-LA was carried out in the presence of ZnEt 2 /PGAc catalytic system at 40-80˝C within 48 h (Table 3), in the presence of ZnEt 2 /GAc catalytic system at 40˝C within 24-48 h, or at 60-80˝C within 6-48 h (Table 1), the intermolecular transesterification process was observed (T ‰ 0). As noted, the values of T generally increased with increasing of the temperature and polymerization time. For example, the T was 0.13 (temp. process 40˝C), 0.46 (temp. process 60˝C), 0.74 (temp. process 80˝C) for PLA 24, PLA 27 and PLA 28, respectively. Furthermore, when ROP of rac-LA was carried out at, e.g., 80˝C within 48 h (the presence of ZnEt 2 /GAc catalytic system), stereocontrol was not observed and an atactic material was obtained (Table 1, PLA 14, Figure 4). The analysis of the intensities of the lines due to tetrads and the calculated transesterification coefficient T = 0.85 indicated strong intermolecular transesterification of PLA chain (e.g., PLA 6), that in consequence leads to the formation of the atactic polymer ( Figure 5).
Molecules 2015, 20, page-page transesterification coefficient T = 0.85 indicated strong intermolecular transesterification of PLA chain (e.g., PLA 6), that in consequence leads to the formation of the atactic polymer ( Figure 5).         It is worth noting that, when ROP of rac-LA was carried out in the presence of a ZnEt2/PGAc catalytic system at 40 °C within 16 h, the microstructure of the examined polyester almost corresponded to a "completely disyndiotactic" polymer (PLA 23, PLA 29) (Table 3, Figure 6). In this instance, the values of p2 were roughly 0.92 and 0.90. During the reaction progress, the transesterification process tended to reduce the chain's microstructure regularity. An analogous trend was observed by Bero when ROP of rac-LA was carried out in the presence of lithium tert-butoxide [55]. It is worth noting that, when ROP of rac-LA was carried out in the presence of a ZnEt2/PGAc catalytic system at 40 °C within 16 h, the microstructure of the examined polyester almost corresponded to a "completely disyndiotactic" polymer (PLA 23, PLA 29) (Table 3, Figure 6). In this instance, the values of p2 were roughly 0.92 and 0.90. During the reaction progress, the transesterification process tended to reduce the chain's microstructure regularity. An analogous trend was observed by Bero when ROP of rac-LA was carried out in the presence of lithium tert-butoxide [55]. It is worth noting that, when ROP of rac-LA was carried out in the presence of a ZnEt 2 /PGAc catalytic system at 40˝C within 16 h, the microstructure of the examined polyester almost corresponded to a "completely disyndiotactic" polymer (PLA 23, PLA 29) (Table 3, Figure 6). In this instance, the values of p 2 were roughly 0.92 and 0.90. During the reaction progress, the transesterification process tended to reduce the chain's microstructure regularity. An analogous trend was observed by Bero when ROP of rac-LA was carried out in the presence of lithium tert-butoxide [55].
catalytic system at 40 °C within 16 h, the microstructure of the examined polyester almost corresponded to a "completely disyndiotactic" polymer (PLA 23, PLA 29) (Table 3, Figure 6). In this instance, the values of p2 were roughly 0.92 and 0.90. During the reaction progress, the transesterification process tended to reduce the chain's microstructure regularity. An analogous trend was observed by Bero when ROP of rac-LA was carried out in the presence of lithium tert-butoxide [55]. The results of ROP of rac-LA in the presence of ZnEt2/PGAc have also demonstrated that, depending on the conditions, "predominantly isotactic", disyndiotactic or atactic PLA can be obtained. It is also worth noting that, when the process was carried out in the presence of a ZnEt2/PGAc catalytic system (40 °C within 16-48 h or 60 °C within 16-24 h), intermolecular transesterification was not observed. Generally, we can find that when the temperature and the reaction time have been increased, the The results of ROP of rac-LA in the presence of ZnEt 2 /PGAc have also demonstrated that, depending on the conditions, "predominantly isotactic", disyndiotactic or atactic PLA can be obtained. It is also worth noting that, when the process was carried out in the presence of a ZnEt 2 /PGAc catalytic system (40˝C within 16-48 h or 60˝C within 16-24 h), intermolecular transesterification was not observed. Generally, we can find that when the temperature and the reaction time have been increased, the microstructure of obtained PLA has been changed in the following way: disyndiotactic, "predominantly isotactic" and "completely atactic".
We assume that ROP of rac-LA catalyzed by ZnEt 2 /GAc or ZnEt 2 /PGAc probably follows a coordination-insertion mechanism. The acidic metal center loosely binds and activates the lactide to attack by the -ZnO-group. The intermediate undergoes acyl bond cleavage of the lactide ring to generate a -ZnO-species and a growing chain end capped with an ester group (Scheme 3). However, it is difficult to obtain molecular zinc complexes (from the reaction of ZnEt 2 with GAc or PGAc), due to the strong association tendency of the products in the reaction medium [40]. However, the relevant kinetic and mechanistic studies are underway and will be presented in our next paper.
We assume that ROP of rac-LA catalyzed by ZnEt2/GAc or ZnEt2/PGAc probably follows a coordination-insertion mechanism. The acidic metal center loosely binds and activates the lactide to attack by the -ZnO-group. The intermediate undergoes acyl bond cleavage of the lactide ring to generate a -ZnO-species and a growing chain end capped with an ester group (Scheme 3). However, it is difficult to obtain molecular zinc complexes (from the reaction of ZnEt2 with GAc or PGAc), due to the strong association tendency of the products in the reaction medium [40]. However, the relevant kinetic and mechanistic studies are underway and will be presented in our next paper.

Synthesis of the Catalytic Systems
The diethylzinc/gallic acid (ZnEt 2 /GAc) and diethylzinc/propyl gallate (ZnEt 2 /PGAc) catalytic systems were prepared each time in an argon atmosphere at room temperature immediately before reaction. The synthesis of catalytic systems was carried out in three-necked, 100 mL round-bottomed flasks. Each glass vessel was equipped with a magnetic stirrer. The flasks contained a mixture of ZnEt 2 (0.0177 mol) and GAc (or PGAc) (0.0059 mol) at a molar ratio of 3 to 1 and toluene as a solvent (35 mL

Synthesis of Polylactide
The ROP of rac-LA was carried out in triplicate, in a glass tube in the presence of ZnEt 2 /GAc or ZnEt 2 /PGAc as catalysts. The required amount of monomer and ZnEt 2 /GAc or ZnEt 2 /PGAc was placed in a 10 mL glass ampoule in an argon atmosphere. The reaction vessel was then kept standing in a thermostated oil bath at 40, 60 or 80˝C for 6 to 48 h. When the reaction time was completed, the cold reaction product was dissolved in CH 2 Cl 2 and precipitated from distilled water with diluted hydrochloric acid (5% aqueous solution). The organic phase was separated, washed with distilled water and dried in a vacuum for 2 to 3 days.