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Article

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

1
Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy and Division of Laboratory Medicine, Medical University of Warsaw, 1 Banacha St., Warsaw 02-097, Poland
2
Department of Organic Chemistry, Faculty of Materials Science and Design, Kazimierz Pulaski University of Technology and Humanities in Radom, Ul. Chrobrego 27, Radom 26-600, Poland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2015, 20(12), 21909-21923; https://doi.org/10.3390/molecules201219815
Received: 5 November 2015 / Revised: 23 November 2015 / Accepted: 30 November 2015 / Published: 8 December 2015
(This article belongs to the Section Organic Chemistry)

Abstract

:
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.

1. Introduction

Polymeric biomaterials (aliphatic polyesters, polyanhydrides, polyethers, polyamides, polyorthoesters or polyurethanes) signify one of the most interesting fields in current material chemistry. Among these materials, polylactide (PLA) is probably the most important biomedical polymer [1] and has previously been applied to the production of cell scaffolds, drug delivery systems (DDSs), sutures in tissue engineering and prostheses for tissue replacements [2,3,4,5,6,7,8].
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 (Mn), 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].
Zinc compounds are attractive catalytic systems because they combine high activity with relatively low toxicity [1,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. The carboxylates, halides, amino acid salts, alkoxides, phenoxy-diamine, bis(phenoxy diamine), phenoxy-imine, phenoxy imine amine, guanidinate, bis(phenoxy), calixarene and amino bis(pyrazolyl) complexes of zinc as initiators have been investigated [19,20,21,30,31,32,33,38,39]. Furthermore, the oxides have been used in ROP of rac-LA as heterogeneous catalysts [1,2].
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.

2. 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, Table 1, Table 2, Table 3 and Table 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.
Scheme 1. ROP of rac-LA in the presence of zinc-based catalytic systems.
Scheme 1. ROP of rac-LA in the presence of zinc-based catalytic systems.
Molecules 20 19815 g007
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 1H- or 13C-NMR and FT-IR studies (see the Experimental Section). The molecular weight and polydispersity of the synthesized polyesters were also determined.
Table 1. Ring-opening polymerization of rac-LA in toluene in the presence of ZnEt2/GAc catalytic system.
Table 1. Ring-opening polymerization of rac-LA in toluene in the presence of ZnEt2/GAc catalytic system.
EntryMolar Ratio [Zn]/[rac-LA]0Temp. (°C)Time (h)Yield a (%)Conv. b (%)Mn c (Da)PD cMC d (%)Mv e (Da)Mn f (Da)p2LiT
PLA 11/504016363925001.263280027000.702.860
PLA 21/504048444832001.48934002900--0.22
PLA 31/506016354020001.18324002100--0.19
PLA 41/506024434730001.541033003200--0.22
PLA 51/506048485233002.712234003100--0.57
PLA 61/508048586440003.393340003700--0.85
PLA 71/1004016283221001.49625002300--0.08
PLA 81/1004048394354001.56757005200--0.14
PLA 91/1006024384356001.63958005300--0.17
PLA 101/1006048434860002.491863006100--0.47
PLA 111/100806374152002.32655005000--0.36
PLA 121/1008016444759002.481762005800--0.41
PLA 131/1008024475266002.673066006200--0.49
PLA 141/1008048525768003.213971006400--0.76
a calculated by the weight method; b calculated from 1H-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; Mn corrected by a factor of ca. 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21 × 104 dL/g and α = 0.77) [42,43,44]; f determined by 1H-NMR; p2—coefficient of stereoselectivity calculated from the equation presented in [45]; T—transesterification coefficient [15]; Li = 2/pi—average length of lactyl units [46].
Table 2. Ring-opening polymerization of rac-LA in tetrahydrofuran and dichloromethane in the presence of ZnEt2/GAc catalytic system.
Table 2. Ring-opening polymerization of rac-LA in tetrahydrofuran and dichloromethane in the presence of ZnEt2/GAc catalytic system.
EntryMolar Ratio [Zn]0/[rac-LA]0MediumTemp. (°C)Time (h)Yield a (%)Conv. b (%)Mn c (Da)PD cMC d (%)Mv e (Da)Mn f (Da)p2LiT
PLA 151/50THF4016232616001.296180013000.633.170
PLA 161/50THF4048374125002.251327002100--0.33
PLA 171/50THF6048434729003.082932002600--0.64
PLA 181/100THF4048323645002.371147004300--0.26
PLA 191/100THF6048353847002.912449003800--0.59
PLA 201/50CH2Cl24024tracestraces--------
PLA 211/50CH2Cl24048212313002.861717001200--0.42
PLA 221/100CH2Cl24048161721002.321424002000--0.37
a calculated by the weight method; b calculated from 1H-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; Mn corrected by a factor of ca. 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21 × 104 dL/g and α = 0.77) [42,43,44]; f determined by 1H-NMR; p2—coefficient of stereoselectivity calculated from the equation presented in [45]; T—transesterification coefficient [15]; Li = 2/pi—average length of lactyl units [46].
Table 3. Ring-opening polymerization of rac-LA in toluene in the presence of ZnEt2/PGAc catalytic system.
Table 3. Ring-opening polymerization of rac-LA in toluene in the presence of ZnEt2/PGAc catalytic system.
EntryMolar Ratio [Zn]0/[rac-LA]0Temp. (°C)Time (h)Yield a (%)Conv. b (%)Mn c (Da)PD cMC d (%)Mv e [Da]Mn f [Da]p2LiT
PLA 231/504016394327001.192310029000.922.170
PLA 241/504048616945001.421148004200--0.13
PLA 251/506016535836001.283410039000.583.380
PLA 261/506024596541001.38744004300--0.05
PLA 271/506048687446002.361349004400--0.46
PLA 281/508048839157003.043159005200--0.74
PLA 291/1004016353948001.183530052000.902.220
PLA 301/1004048546177001.275810074000.722.770
PLA 311/1006016424657001.326620058000.603.330
PLA 321/1006024566279001.318830075000.613.280
PLA 331/1006048636887001.891689008500--0.38
PLA 341/100806545976001.39478007200--0.16
PLA 351/1008016626886001.481690008300--0.27
PLA 361/1008024677393002.062595009100--0.39
PLA 371/1008048758299002.473710,3009400--0.59
a calculated by the weight method; b calculated from 1H-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; Mn corrected by a factor of ca. 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21 × 104 dL/g and α = 0.77) [42,43,44]; f determined by 1H-NMR; p2—coefficient of stereoselectivity calculated from the equation presented in [45]; T—transesterification coefficient [15]; Li = 2/pi—average length of lactyl units [46].
Table 4. Ring-opening polymerization of rac-LA in tetrahydrofuran and dichloromethane in the presence of ZnEt2/PGAc catalytic system.
Table 4. Ring-opening polymerization of rac-LA in tetrahydrofuran and dichloromethane in the presence of ZnEt2/PGAc catalytic system.
EntryMolar ratio [Zn]0/[rac-LA]0MediumTemp. (°C)Time (h)Yield a (%)Conv. b (%)Mn c (Da)PD cMC d (%)Mv e [Da]Mn f [Da]p2LiT
PLA 381/50THF4016293120001.357230018000.712.820
PLA 391/50THF4048404629001.691833002600--0.19
PLA 401/50THF6048475133002.612237003100--0.49
PLA 411/100THF4048384151001.821257004700--0.07
PLA 421/100THF6048394455002.392656004900--0.44
PLA 431/50CH2Cl24016151712001.741815001100--0.27
PLA 441/50CH2Cl24048363924002.892926002100--0.53
PLA 451/100CH2Cl24048323442001.922347003800--0.38
a calculated by the weight method; b calculated from 1H-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; Mn corrected by a factor of ca 0.58 [41]; d MC (macrocyclic content) determined by MALDI TOF MS; e determined by viscosity method (K = 2.21 × 104 dL/g and α = 0.77) [42,43,44]; f determined by 1H-NMR; p2—coefficient of stereoselectivity calculated from the equation presented in [45]; T—transesterification coefficient [15]; Li = 2/pi—average length of lactyl units [46].
As shown in Table 1, Table 2, Table 3 and Table 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 ROP yield of the rac-LA process ranged from 16% to 58% for ZnEt2/GAc (Table 1 and Table 2) and from 15% to 83% for ZnEt2/PGAc catalytic systems (Table 3 and Table 4). Only in one case (PLA 20, Table 2) the polymeric product was obtained in a trace amount. It was found that this type of solvent had an essential influence on the process’ yield, that is, toluene was found to be an optimum polymerization medium. For ZnEt2/PGAc catalytic system, the yields of PLA were in the range of 35%–83% (medium—toluene, Table 3), 29%–47% (medium—THF, Table 4) and 15%–36% (medium—CH2Cl2, Table 4). In comparison, the yields of the ROP products of rac-LA catalyzed by ZnEt2/GAc ranged from 28% to 58% (medium—toluene, Table 1), 23%–43% (medium—THF, Table 2) and 0%–21% (medium—CH2Cl2, Table 2). Moreover, the ROP yields increased when the reaction temperature was raised from 40 to 80 °C. For example, PLAs were obtained with a high yield: 61% (PLA 24), 68% (PLA 27) and 83% yields (PLA 28), respectively (Table 3). The PLA yield tended to decrease with increasing of rac-LA/catalytic system molar ratio. For PLA 27, PLA 28, PLA 33 and PLA 37, the corresponding yield values were 68%, 83%, 63% and 75%, respectively (Table 3). The process yield also increased with the reaction time increasing. For example, PLAs were obtained with 53% (PLA 25, reaction time 16 h), 59% (PLA 26, reaction time 24 h) and 68% yields (PLA 27, reaction time 48 h), respectively (Table 3).
The molecular weight of PLAs was also dependent on the rac-LA/catalytic system molar ratio, reaction medium, temperature and reaction time (Table 1, Table 2, Table 3 and Table 4). The average molecular mass (Mn) values of PLA increased when the reaction time, reaction temperature and rac-LA/catalytic system molar ratio were increased. The Mn values of PLA determined by the GPC were in the range of 1200–9900 Da (ZnEt2/PGAc catalytic system, Table 3 and Table 4) and 1300–6800 Da (ZnEt2/GAc catalytic system, Table 1 and Table 2). When the process was carried out in the presence of a ZnEt2/PGAc catalytic system (where the molar ratio of catalyst to monomer was 1:100, reaction temp. 80 °C), the Mn 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 ZnEt2/GAc catalytic system was used, Mn 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 ZnEt2/PGAc catalytic system were generally characterized by a higher Mn when compared to the PLAs synthesized in the presence of ZnEt2/GAc. Moreover, when ROP was carried out in toluene, the synthesized PLAs were characterized by a higher Mn than that of PLAs synthesized in THF or CH2Cl2. The Mn values determined from GPC were comparable to the viscosity analysis results (Mv), as well as those of Mn calculated from 1H-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 ZnEt2/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 Table 1, Table 2, Table 3 and Table 4, trends of macrocyclization process during ROP of rac-LA in the presence of ZnEt2/PGAc were similar. The macrocyclic content (MC) for PLAs obtained in the presence of ZnEt2/PGAc catalytic system was low when compared to the MC of PLAs obtained in the presence of the ZnEt2/GAc catalytic system (Table 1, Table 2, Table 3 and Table 4). For PLA 23, PLA 1, PLA 29 and PLA 7, the corresponding MC values were 2%, 3%, 3% and 6%, respectively.
Figure 1. MALDI TOF MS spectrum of PLA obtained in the presence ZnEt2/PGAc catalytic system (PLA 26).
Figure 1. MALDI TOF MS spectrum of PLA obtained in the presence ZnEt2/PGAc catalytic system (PLA 26).
Molecules 20 19815 g001
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 1H-NMR and 13C-NMR spectra. The tetrad peaks in 1H-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 13C-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 1H- or 13C-NMR data using Bernoullian statistics [54].
T was calculated using the following equation:
T = (isi0isi)/(isi0 − 0.125)
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 pRR/RR = pSS/SS = p1. The probabilities of the enantiomer’s addition to the growing chain terminated with opposite enantiomers are equal pRR/SS = pSS/RR = p2 (because pRR/RR + pSS/RR = 1 and pSS/SS + pRR/SS = 1) [45].
It is therefore possible to calculate the intensity values of the individual sequences:
-
for tetrads
(iii) = p13 + 1.5p12p2 + 0.5p1p22
(iis) = (sii) = 0.5p12p2 + 0.5p1p22
(isi) = 0.5p12p2 + p1p22 + 0.5p23
(sis) = 0.5p1p22 + 0.5p23
-
for hexads
(iiiii) = p13 + 0.5p12p2
(iiiis) = (siiii) = (iisii) = 0.5p12p2
(iiisi) = (isiii) = 0.5p12p2 + 0.5p1p22
(iisis) = (siiis) = (sisii) = 0.5p1p22
(isisi) = 0.5p1p22 + 0.5p23
(sisis) = 0.5p23
The coefficient probabilities p1 and p2 were calculated from the above equations using the intensities of signals in the 13C-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 Figure 2 and Figure 3, when rac-LA was employed using a ZnEt2/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 ZnEt2/PGAc catalytic system (60 °C within 16 h, Table 3), the calculated coefficient of stereoselectivity p2 was 0.58 (PLA 25), whereas the average length of lactyl units Li = 3.38 (when no ss sequences were present in the polymer chain, this coefficient may be defined as p2 = 2/Li, where Li 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:
isotactic PLA (T = 0, p1 = 1, p2 = 0) ...SSSSSS... + ...RRRRRR...
“predominantly isotactic” PLA (T = 0, p1 = 0.5, p2 = 0.5, Li = 4) ...SSSRRRSSSSRRR...
“completely disyndiotactic” (heterotactic) PLA (T = 0, p1 = 0, p2 = 1, Li = 2) ...SSRRSSRRSSRR...
atactic PLA (T = 1) ...RRSSSRSRR... (Scheme 2) [46].
In the 13C-NMR spectra of PLA obtained in the presence of ZnEt2/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 (Figure 2 and Figure 3). In contrast, when ROP of rac-LA was carried out in the presence of ZnEt2/PGAc catalytic system at 40–80 °C within 48 h (Table 3), in the presence of ZnEt2/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 ZnEt2/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).
Figure 2. 13C-NMR spectra of “predominantly isotactic” PLA (methine region) (p2 = 0.58, PLA 25).
Figure 2. 13C-NMR spectra of “predominantly isotactic” PLA (methine region) (p2 = 0.58, PLA 25).
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Figure 3. 13C-NMR spectra of “predominantly isotactic” PLA (carbonyl region) (p2 = 0.58, PLA 25).
Figure 3. 13C-NMR spectra of “predominantly isotactic” PLA (carbonyl region) (p2 = 0.58, PLA 25).
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Figure 4. Homonuclear decoupled 1H-NMR spectra of the methine region of polylactide (PLA 14).
Figure 4. Homonuclear decoupled 1H-NMR spectra of the methine region of polylactide (PLA 14).
Molecules 20 19815 g004
Figure 5. 13C-NMR spectra of atactic PLA (methine region) (PLA 6).
Figure 5. 13C-NMR spectra of atactic PLA (methine region) (PLA 6).
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Scheme 2. The stereostructures of PLA.
Scheme 2. The stereostructures of PLA.
Molecules 20 19815 g008
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].
Figure 6. 13C-NMR spectra of disyndiotactic PLA (methine region) (p2 = 0.92, PLA 23).
Figure 6. 13C-NMR spectra of disyndiotactic PLA (methine region) (p2 = 0.92, PLA 23).
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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 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 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.
Scheme 3. The hypothetical mechanism of ROP of rac-LA in the presence of ZnEt2/GAc and ZnEt2/PGAc catalytic systems.
Scheme 3. The hypothetical mechanism of ROP of rac-LA in the presence of ZnEt2/GAc and ZnEt2/PGAc catalytic systems.
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3. Experimental Section

3.1. Materials

rac-Lactide (3,6-dimethyl-1,4-dioxane-2,5-dione, 99%, rac-LA) was purchased from Sigma-Aldrich Co. (Poznan, Poland) and further purified by crystallization from anhydrous toluene. Prior to use, the solvents (toluene, THF, CH2Cl2; Sigma-Aldrich, Co., Poznan, Poland) were dried over potassium or phosphorus pentoxide. Diethylzinc (ZnEt2, solution 15 wt % in toluene, Sigma-Aldrich, Co.), gallic acid (3,4,5-trihydroxybenzoic acid, GAc, 97.5%–102.5%, Sigma-Aldrich, Co.) and propyl gallate (3,4,5-trihydroxybenzoic acid propyl ester, PGAc, ≥98%, Sigma-Aldrich, Co.) were used as received from the manufacturer.

3.2. Synthesis of the Catalytic Systems

The diethylzinc/gallic acid (ZnEt2/GAc) and diethylzinc/propyl gallate (ZnEt2/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 ZnEt2 (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). The reactions were carried out for about 2 h [40].

3.3. Synthesis of Polylactide

The ROP of rac-LA was carried out in triplicate, in a glass tube in the presence of ZnEt2/GAc or ZnEt2/PGAc as catalysts. The required amount of monomer and ZnEt2/GAc or ZnEt2/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 CH2Cl2 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.

3.4. Spectroscopy Data

3.4.1. NMR Data

1H-NMR (CDCl3, δ, ppm): 5.10–5.25 (1H, q, -CH(CH3)-), 4.38 (1H, q, -CH(CH3)OH, end group), 1.50–1.60 (3H, d, -CH3);
13C-NMR (CDCl3, δ, ppm): 169.8 (-C(O)O-), 69.5 (-OC(O)CH(CH3)O-), 67.2(-OC(O)CH(CH3)OH, end group), 20.6 (-OC(O)CH(CH3)OH, end group), 17.1 (-OC(O)CH(CH3)O-);

3.4.2. FT-IR Data

(KBr, cm−1): 2997 (υasCH3), 2947 (υsCH3), 2882 (υCH), 1760 (υC=O), 1452 (δasCH3), 1348–1388 (δsCH3), 1368–1360 (δ1CH+δsCH3), 1315–1300 (δ2CH), 1270 (δCH + υCOC), 1215–1185 (υasCOC + rasCH3), 1130 (rasCH3), 1100–1090 (υsCOC), 1045 (υC-CH3), 960–950 (rCH3 + υCC), 875–860 (υC-COO), 760–740 (δC=O), 715–695 (γC=O), 515 (δ1C-CH3 + δCCO), 415 (δCCO), 350 (δ2C-CH3 + δCOC), 300–295 (δCOC + δ2C-CH3), 240 (τCC);

3.5. Measurements

The intrinsic viscosity of PLAs was determined in N,N-dimethylformamide (DMF) (at 30 °C) using a Stabinger Viscometer SVM 3000. The concentrations of the PLA solutions in DMF were as follow: 0.2%, 0.4%, 0.6%, 0.8% and 1%. The viscosity average molecular weight was calculated with the Mark–Houwink equation using the following constants: K = 2.21 × 104 dL/g and α = 0.77 [42,43,44].
Number-average molecular weight and polydispersity were determined by gel permeation chromatography (GPC). The GPC instrument (GPC Max + TDA 305, Viscotek) was equipped with Jordi DVB Mixed Bed columns (one guard and two analytical) at 30 °C in CH2Cl2 (HPLC grade, Sigma-Aldrich) and at a flow rate of 1 mL/min, with RI detection and calibration based on narrow PS standards (ReadyCal Set, Fluka). The results were processed with OmniSEC software (ver. 4.7. Houston, TX, USA).
MALDI-TOF mass spectra were performed in a linear mode using an ultrafleXtreme™ (Bruker Daltonics, Coventry, UK) mass spectrometer using a nitrogen gas laser and DCTB as a matrix. The PLA samples were dissolved in THF (5 mg/mL) and mixed with a solution of DCTB.
The polymerization products were characterized by means of 1H- or 13C-NMR (using Varian 300 MHz recorded, Palo Alto, CA, USA) in deuterated chloroform (CDCl3) at room temperature. FT-IR spectra (PerkinElmer, Waltham, MA, USA) were measured from KBr pellets.

4. Conclusions

In this study, we described for the first time the synthesis and characterization of polylactides obtained in the presence of two zinc-based catalytic systems. The biocompatible ZnEt2/GAc and ZnEt2/PGAc catalytic systems were shown to be effective for the coordination-insertion ring-opening polymerization of rac-lactide (rac-LA). Zinc catalytic systems were proven as promising catalysts not only for molecular weight control, but also for stereocontrol. It was found that when rac-LA was polymerized with ZnEt2/PGAc catalytic system (40 °C within 16–48 h or 60 °C within 16–24 h), the intermolecular transesterification process was not observed. Furthermore, “predominantly isotactic” PLA was obtained in these reaction conditions. In addition, when ROP of rac-LA was carried out in the presence of a ZnEt2/PGAc catalytic system (40 °C within 16 h), the microstructure of the examined polyester practically corresponds to “completely disyndiotactic” polymer. Efforts aimed at subsequent improvement of the stereocontrol of ROP of rac-LA in the presence of ZnEt2/GAc and ZnEt2/PGAc catalytic systems, as well as understanding the origin of isoselectivity and detailed reaction mechanisms, are currently underway in our laboratory.

Acknowledgments

This work was financially supported by National Science Centre of Poland (OPUS-5 research scheme, grant number DEC-2013/09/B/ST5/03480 entitled: “Elaboration of anti-cancer drug implantational delivery system immobilized on polymer matrix”). We would like to thank Piotr Goś from Medical University of Warsaw for the technical support. The authors are indebted to Andrzej Plichta (Warsaw University of Technology) for the GPC measurements, Monika Pisklak, Violetta Kowalska (Medical University of Warsaw) and Paweł Horeglad (Centre of New Technologies, University of Warsaw) for the spectroscopy measurements.

Author Contributions

The contributions of the respective authors are as follows: K.Ż., U.P., E.O. and M.S. gave the concept of work, synthesized and characterized products, interpreted the results, wrote the whole article, and made discussions and conclusions. All authors have contributed to, read and approved the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the synthesized compounds are available from the authors.

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MDPI and ACS Style

Żółtowska, K.; Piotrowska, U.; Oledzka, E.; Sobczak, M. Efficient Diethylzinc/Gallic Acid and Diethylzinc/Gallic Acid Ester Catalytic Systems for the Ring-Opening Polymerization of rac-Lactide. Molecules 2015, 20, 21909-21923. https://doi.org/10.3390/molecules201219815

AMA Style

Żółtowska K, Piotrowska U, Oledzka E, Sobczak M. Efficient Diethylzinc/Gallic Acid and Diethylzinc/Gallic Acid Ester Catalytic Systems for the Ring-Opening Polymerization of rac-Lactide. Molecules. 2015; 20(12):21909-21923. https://doi.org/10.3390/molecules201219815

Chicago/Turabian Style

Żółtowska, Karolina, Urszula Piotrowska, Ewa Oledzka, and Marcin Sobczak. 2015. "Efficient Diethylzinc/Gallic Acid and Diethylzinc/Gallic Acid Ester Catalytic Systems for the Ring-Opening Polymerization of rac-Lactide" Molecules 20, no. 12: 21909-21923. https://doi.org/10.3390/molecules201219815

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