Use of pyrazoles as ligands greatly enhances the catalytic activity of titanium iso-propoxide for the ring-opening polymerization of l-lactide: a cooperation effect.

Using TiOiPr4 with a pyrazole ligand for one-pot LA polymerization improved catalytic activity compared with using TiOiPr4 only. At 60 °C, TiOiPr4 with furPz exhibited a higher catalytic activity (approximately 3-fold) than TiOiPr4. At room temperature, TiOiPr4 with BuPz exhibited a higher catalytic activity (approximately 17-fold) than TiOiPr4. High molecular mass PLA (M nGPC = 51 100, and Đ = 1.10) could be produced by using TiOiPr4 with furPz in melt polymerization ([TiOiPr4] : [furPz] = 1000 : 1 : 1 at 100 °C, 240 min). The crystal structure of MePz2Ti2OiPr7 revealed the cooperative activation between two Ti atoms during LA polymerization. This journal is © The Royal Society of Chemistry.

Introduction

Petrochemical plastics are extensively used in modern society; however, widely discarded plastic waste pollutes the environment continually[1-4] because bacteria cannot decompose it naturally within a short period. To accelerate the environmental degradation of polymers, biodegradable polylactide (PLA)[5-7] has been developed for creating a sustainable society. PLA-based biomaterials are used in various fields[8-18] because of their biocompatible[19,20] and permeable[21] physical properties. One of the methods of PLA synthesis is the Lewis acidic metal-catalyzed ring-opening polymerization (ROP) of cyclic esters.[22-31]

For biomaterials, metal residuals present in resulting PLA are a serious problem, and using catalysts with non-cytotoxic metals is a straightforward approach to solving this problem. Because of the non-cytotoxic property and strong Lewis acidity of titanium, Ti complexes[22,23,30-33] are commonly used catalysts in LA ROP. Numerous Ti complexes bearing various ligands such as calix[4]arene,[33,34] Schiff base,[35-39] salen,[40-42] salan,[43-46] phenolate,[47-50] aminophenolate,[51,52] benzotriazole phenolate,[53-55] phosphinophenolate,[56] thiophenolate,[57,58] bis-phenolate-N-heterocyclic carbene,[45] pyridonate,[59,60] and pyrrolide[61] have been reported to exhibit considerable catalytic activity or controllability, which is contributed by ligands. However, for most studies, focusing on materials is inconvenient, because the synthesis and purification of Ti catalysts are time-consuming processes. An efficient method of fabricating PLA without time-consuming Ti catalyst-base synthesis and purification is necessary. Herein, commercially available Ti alkoxides was also used catalysts for cyclic esters polymerization.[62-65] Recently, dinuclear Ti complexes[38] bearing hydrazine-bridging Schiff base ligands (Fig. 1) were reported to exhibit a high catalytic activity of LA polymerization because of the cooperation between two Ti atoms. Based on this study, if pyrazole is added to LA polymerization with titanium iso-propoxide (TiOiPr4) as a catalyst, bringing two Ti atoms close together to enable dinuclear cooperation is possible. Following this strategy, several pyrazole derivatives (Fig. 2) were added to LA polymerization with a TiOiPr4 catalyst to investigate dinuclear cooperation relative to the mixture of TiOiPr4 and pyrazole.

Fig. 1

Strategy of dinuclear Ti complexes in LA polymerization inspired by the literature.

Fig. 2

Pyrazole derivatives used in this study.

Experimental section

Chemicals

Standard Schlenk techniques and a N2-filled glovebox were used all over the isolation and treatment of all the compounds. Solvents, l-lactide (LA), and deuterated solvents were purified prior to use. LA, HPz, MePz, BuPz, PhPz, furPz, thioPz, Tz, pyPz, and MeOPz were purchased from Aldrich. ClPz[66] were prepared following literature procedures. 1H and 13C NMR spectra were recorded on a Varian Gemini 2000-200 (200 MHz for 1H and 50 MHz for 13C) spectrometer. Chemical shifts (in ppm) of 1H NMR spectra were referenced to tetramethylsilane (δ = 0 ppm) in CDCl3 as an internal standard, and chemical shifts of 13C NMR spectra were reported in ppm referenced to the center line of a triplet at 77.0 ppm of CDCl3. Microanalyses were performed using a Heraeus CHN-O-RAPID instrument. The gel permeation chromatography (GPC) measurements were performed on a Jasco PU-2080 PLUS HPLC pump system equipped with a differential Jasco RI-2031 PLUS refractive index detector using THF (HPLC grade) as an eluent (flow rate 1.0 mL min−1, at 40 °C). The chromatographic column was JORDI Gel DVB 10−3 Å, and the calibration curve was made by primary polystyrene standards to calculate molar masses of PLA. Values of Mn were obtained through gel permeation chromatography (GPC) times 0.58.

Synthesis of MePz2Ti2OiPr7

A mixture of MePz (0.96 g, 10 mmol) and TiOiPr4 (2.84 g, 10 mmol) in toluene (20 mL), was stirred at room temperature for 24 h. Volatile materials were removed under vacuum to give light yellow mud, and then hexane was transferred to be the suspension. The light-yellow powder was obtained after filtering, and was recrystallized in toluene to form the crystal. Yield: 1.15 g (33%). 1H NMR spectrum (CDCl3, 200 MHz, Fig. S1†) was complex, but it could be assigned that two β-Hs were at 5.59 and 5.43 ppm, and the methine protons of isopropyl oxide were at 4.92–4.28 ppm, and dimethyl groups of MePz were at 2.39 and 2.14 ppm.

Results and discussion

Polymerization of LA

Table 1 presents the conditions for optimizing LA polymerization by using a mixture of TiOiPr4 and thioPz as the catalyst. Entries 1–5 in Table 1 reveal that the 1 : 1 ratio of TiOiPr4 and thioPz ([LA] = 1 M, [TiOiPr4] = 10 mM) exhibited the fastest polymerization rate. When [LA] was increased to 2 M with 40 mM of [TiOiPr4], after 10 min, the conversion became 87%. Under this condition ([LA] = 2 M, [LA] : [TiOiPr4] : [thioPz] = 50 : 1 : 1 in 5 mL toluene), various pyrazole derivatives were used to analyze LA polymerization, and all pyrazole derivatives improved the catalytic activity of TiOiPr4, except pyPz and Tz in the following order: furPz > BuPz > PhPz > MeOPz > HPz > MePz = thioPz > ClPz > pyPz > Tz. Although MePz improved the catalytic activity of TiOiPr4, it provided low controllability (dispersity, Đ = 1.68). To solve this problem, the TiOiPr4 concentration was decreased from 20 to 13.4 mM, and the Đ value was decreased to 1.10. LA polymerization using TiOiPr4 (13.4 mM) as a catalyst with MePz was systematically investigated with the [LA]/[TiOiPr4] ratio ranging from 50 to 300 (entries 16–20). The results revealed that LA polymerization was controllable, confirmed by the linear relationship between [LA]0/[TiOiPr4] and Mn (Fig. 3). However, the controllability in the [LA]/[TiOiPr4] ratio of 300 (Đ = 1.49, entry 20 in Table 1) was low, and it may be ascribed to transesterification[67] because of the long polymerization time at 60 °C. Fig. 3 revealed that four isopropoxides of TiOiPr4 could be initiators to initiate LA. TiOiPr4 with thioPz exhibited a higher catalytic activity (3.5 folds) in LA polymerization than LH-TiOPr6 (entry 21)[38] did.

l-Lactide polymerization with the mixture of TiOiPr4 and pyrazole derivatives as catalysts in toluenea

Entry	Ligand (TiOiPr4 : L)	Time (min)	Conv.b (%)	M nGPC c (g mol−1)	M nNMR b (g mol−1)	Đ c	k obs (min−1)
1d	thioPz (1 : 0.5)	50	85	3900	3300	1.30	0.035
2d	thioPz (1 : 1)	45	86	4700	4600	1.51	0.036
3d	thioPz (1 : 2)	125	84	7000	6000	2.10	0.008
4d	thioPz (1 : 4)	220	99	7400	6500	2.02	0.013
5	thioPz (1 : 1)	10	87	2300	2200	1.27	0.232
6	L free	22	92	2100	1600	1.75	0.161
7	HPz (1 : 1)	8	88	2600	2100	1.31	0.285
8	MePz (1 : 1)	13	94	7100	4400	1.68	0.233
9	ClPz (1 : 1)	14	89	1900	1800	1.13	0.166
10	BuPz (1 : 1)	9	95	2100	1700	1.23	0.394
11	PhPz (1 : 1)	10	94	2500	2000	1.25	0.334
12	furPz (1 : 1)	5	86	2200	2100	1.23	0.418
13	pyPz (1 : 1)	15	88	2000	2200	1.18	0.152
14	MeOPz (1 : 1)	10	92	6500	3000	1.38	0.288
15	Tz (1 : 1)	20	87	1900	1800	1.12	0.120
16e	MePz (1 : 1)	16	88	1800	1700	1.10	—
17f	MePz (1 : 1)	25	89	3900	3600	1.27	—
18g	MePz (1 : 1)	24	80	5500	5200	1.27	—
19h	MePz (1 : 1)	45	87	8500	7900	1.32	—
20i	MePz (1 : 1)	95	90	13 100	12 500	1.49	—
21j	LH-TiOPr6[38]	50	89	3100	—	1.25	0.065

In general, the reaction was carried out in 5 mL toluene with [LA] = 2 M at 60 °C for LA polymerization ([LA] : [TiOiPr4] = 50 : 1).

The data were determined using 1H NMR analysis.

Values of Mn were corrected considering Mark–Houwink factor (0.58) from polystyrene standards in THF.

[LA] = 1 M, in 5 mL toluene, [LA] : [TiOiPr4] = 100 : 1.

[LA] : [TiOiPr4] : [MePz] = 50 : 1 : 1, [TiOiPr4] = 13.4 mM in toluene 15 mL.

[LA] : [TiOiPr4] : [MePz] = 100 : 1 : 1, [TiOiPr4] = 13.4 mM in toluene 15 mL.

[LA] : [TiOiPr4] : [MePz] = 150 : 1 : 1, [TiOiPr4] = 13.4 mM in toluene 15 mL.

[LA] : [TiOiPr4] : [MePz] = 200 : 1 : 1, [TiOiPr4] = 13.4 mM in toluene 15 mL.

[LA] : [TiOiPr4] : [MePz] = 300 : 1 : 1, [TiOiPr4] = 13.4 mM in toluene 15 mL.

[LA] : [LH-TiOPr6] = 100 : 1, [LA] = 2.0 mM in toluene 5 mL at 60 °C.

Fig. 3

Linear plot of various Mn with the supposed initiators and Mn against [LA]0 × conv./[TiOiPr4] (Table 1, entries 16–20).

A survey of LA ROP using Ti complexes as catalysts revealed that few Ti catalysts could polymerize LA at room temperature. Therefore, LA polymerization was conducted at room temperature (Table 2) to determine whether the addition of pyrazole ligands can enhance the catalytic ability of TiOiPr4 at room temperature. In addition, reducing the polymerization temperature may improve the controllability of Ti catalysts.

l-Lactide polymerization with the mixture of TiOiPr4 and pyrazole derivatives as catalysts in CH2Cl2 at room temperaturea

Entry	Ligand (TiOiPr4 : L)	Time (min)	Conv.b (%)	M nGPC c (g mol−1)	M nNMR b (g mol−1)	Đ c	k obs × 103 (min−1)
1	L free	4290	85	1600	1700	1.25	0.3
2	HPz	450	80	900	1000	1.12	3.0
3	MePz	1670	85	1300	1200	1.08	0.9
4	ClPz	720	85	1100	1200	1.08	2.0
5	BuPz	370	88	1100	1000	1.07	5.0
6	PhPz	1335	89	1400	1200	1.12	1.0
7	furPz	540	90	1000	1100	1.08	4.0
8	thioPz	660	84	1200	1200	1.08	2.0
9	pyPz	660	87	1000	1100	1.08	2.4
10	MeOPz	660	85	1200	1200	1.08	2.0
11	Tz	1670	87	1400	1300	1.11	0.7
12d	furPz	315	95	1400	1200	1.08	—
13e	furPz	310	88	1600	1500	1.09	—
14f	furPz	450	88	1800	1800	1.11
15g	furPz	510	89	2100	2200	1.27
16h	furPz	390	84	700	800	1.13	—
17i	+100 LA	895	92	1800	1900	1.09	—
18j	+100 LA	1495	83	2300	2200	1.16	—
19k	+100 LA	2000	72	2600	2600	1.14	—
20l	furPz	240	93	51 100	—	1.10
21m	L free	240	52	31 600	—	1.26

In general, the reaction was carried out in 2.5 mL CH2Cl2 with [LA] = 2 M at room temperature for LA polymerization ([LA] : [TiOiPr4] = 25 : 1).

The data were determined using 1H NMR analysis.

Values of Mn were corrected considering Mark–Houwink factor (0.58) from polystyrene standards in THF.

[LA] : [TiOiPr4] : [furPz] = 37.5 : 1 : 1, [TiOiPr4] = 0.08 M in 2.5 mL CH2Cl2.

[LA] : [TiOiPr4] : [furPz] = 43.75 : 1 : 1, [TiOiPr4] = 0.08 M in 2.5 mL CH2Cl2.

[LA] : [TiOiPr4] : [furPz] = 50 : 1 : 1, [TiOiPr4] = 0.08 M in 2.5 mL CH2Cl2.

[LA] : [TiOiPr4] : [furPz] = 62.5 : 1 : 1, [TiOiPr4] = 0.08 M in 2.5 mL CH2Cl2.

[LA] : [TiOiPr4] : [furPz] = 25 : 1 : 1, [TiOiPr4] = 0.08 M in 2.5 mL CDCl3.

After the conversion of the reaction (entry 16) was 84%, LA (0.72 g) was transferred into the solution.

After the conversion of the reaction (entry 17) was 92%, LA (0.72 g) was transferred into the solution.

After the conversion of the reaction (entry 17) was 83%, LA (0.72 g) was transferred into the solution.

[TiOiPr4] : [furPz] = 1000 : 1 : 1, melt reaction at 100 °C.

[LA] : [TiOiPr4] = 1000 : 1, melt reaction at 100 °C.

All pyrazole derivatives improved the catalytic activity of TiOiPr4 in the following order: BuPz > furPz > HPz > pyPz > ClPz = thioPz = MeOPz > PhPz > MePz > Tz (Table 2). In the CH2Cl2 solution, the pyrazole ligand provided the benefit of considerable improvement of the catalytic reaction. For example, kobs of TiOiPr4 with BuPz was 17 times higher than that of TiOiPr4, and kobs of TiOiPr4 with furPz was 13 times higher than that of TiOiPr4. In addition, the controllability of TiOiPr4 with all pyrazole derivatives was improved (Đ = 1.07–1.12). Although TiOiPr4 with BuPz revealed the highest polymerization rate, BuPz is overly expensive. Therefore, furPz was used as a ligand with TiOiPr4 as a catalyst to polymerize LA with various ratios of [LA]/[TiOiPr4] (entries 12–19, Table 2). The [LA]/[TiOiPr4] ratio from 37.5 to 62.5 was investigated, and the molecular mass (Mn) of PLA increased from 1400 to 2100. According to the solubility of LA in CH2Cl2, the limit of the [LA]/[TiOiPr4] ratio is 62.5 (1.80 g of LA in 2.5 mL CH2Cl2), and PLA with high molecular mass PLA cannot be synthesized by increasing the [LA]/[TiOiPr4] ratio.

To investigate the living property[68,69] of TiOiPr4 with the pyrazole ligand in LA polymerization, first, LA was polymerizated ([LA] : [TiOiPr4] : [furPz] = 100 : 4 : 4 in CDCl3, entry 16 in Table 2). After 390 min, the conversion was 84%, and 100 equivalents of LA were reloaded into the solution (entry 17 in Table 2). However, the polymerization time increased to 895 min with a 92% conversion. Subsequently, 100 equivalents of LA were reloaded into the solution (entry 18 in Table 2), and the polymerization rate decreased. After 1495 min, the conversion was 83%, and 100 equivalents of LA were reloaded into the solution (entry 19 in Table 2). The solution could not be stirred after 2000 min with a 72% conversion. The slower LA polymerization rate can be ascribed to the higher viscosity of the polymerizated solution. On the basis of the linear relationship between Mn and ([LA]0 × conv.)/[TiOiPr4] (entries 7, and 12–19 in Table 2 and Fig. 4), TiOiPr4 with the pyrazole ligand demonstrated a high controllability with narrow Đ for LA polymerization. To confirm that PLA with high molecular mass can be synthesized using TiOiPr4 with the pyrazole ligand, LA was polymerizated using TiOiPr4 with furPz ([LA] : [TiOiPr4] : [furPz] = 1000 : 1 : 1 at 100 °C without solvent, entry 20 in Table 2). After 240 min, the conversion was 93%, and PLA (Mn = 51 100, and Đ = 1.10) was obtained. Compared with LA polymerization using TiOiPr4 without furPz (240 min, conv. = 52%, Mn = 31 600, Đ = 1.26, entry 21 in Table 2), adding furPz to LA polymerization improved the polymerization rate and enhanced the controllability for producing PLA.

Fig. 4

Linear plots of Mnversus ([LA]0 × conv.)/[TiOiPr4]. Blue solid dots indicate Đs.

The 1H nuclear magnetic resonance (NMR) spectrum of PLA (entry 2 in Table 2 and Fig. 5) confirmed the presence of one isopropyl oxide group (peak a) and a hydroxyl chain end (peak c′), suggesting that initiation occurred through insertion of an isopropyl oxide into LA. The matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrum of PLA (entry 5 in Table 2 and Fig. 6) revealed the presence of isopropyl oxide group at the end of the PLA chain.

Fig. 5

1H NMR spectrum of PLA (entry 13 in Table 2).

Fig. 6

MALDI-TOF spectrum of PLA (entry 13 in Table 2).

Synthesis and characterization of MePz2Ti2OiPr7

To determine what was the real catalysis mechanism in the polymerization process, the reaction of MePz and TiOiPr4 (1 : 1) in toluene was investigated. Fig. 7 illustrates the crystal of MePz2Ti2OiPr7 (CCDC 1568213, Table S4†). However, the 1H NMR spectrum (Fig. S3†) revealed that MePz2Ti2OiPr7 was impure. The crystal data of MePz2Ti2OiPr7 indicated that the Ti–Ti distance was 3.2322(14) Å, which is slightly shorter than that of LBu-TiOPr6[38] distance (3.242 Å), and it implied the cooperative activation can occur in this system. To prove that MePz2Ti2OiPr7 is the real catalyst in LA polymerization, the crystal of impure MePz2Ti2OiPr7 was used as a catalyst in LA polymerization with the polymerization condition of entry 17 of Table 1 ([LA] : [MePz2Ti2OiPr7] = 100 : 0.5, [MePz2Ti2OiPr7] = 6.7 mM at 60 °C in 15 mL toluene). After 16 min, the conversion was 95% with Mn = 4900, Đ = 1.56, and kobs = 0.203 (min−1), and the results were similar to the results of entry 17 of Table 1 (conversion was 89% after 25 min).

Fig. 7

Molecular plot of MePz2Ti2OiPr7 with 20% probability ellipsoids (all hydrogen atoms were omitted for clarity).

Conclusions

Our strategy of using TiOiPr4 with pyrazole ligand for one-pot LA polymerization successfully improved the catalytic activity compared with using TiOiPr4 only. The crystal structure of MePz2Ti2OiPr7 revealed cooperative activation between two Ti atoms during LA polymerization. These results can provide a straightforward approach to synthesize PLA by using TiOiPr4 as a catalyst. In future, we intend to investigate the mechanism of LA polymerization.

Conflicts of interest

There are no conflicts to declare.