Magnesium Pyrazolyl-Indolyl Complexes as Catalysts for Ring-Opening Polymerization of L-Lactide

A series indole-based ligand precursors, PzRIndH (R = H, PzHIndH; R = Me, PzMeIndH; R = t-Bu, PztBuIndH; and R = Ph, PzPhIndH), have been synthesized via copper-catalyzed N-arylation (for PzHIndH) or the Bartoli indole synthesis (for PzMeIndH, PztBuIndH and PzPhIndH) reactions with moderate to high yield. Reactions of these ligand precursors with 0.7 equivalent of MgBu2 in THF (for 1) or hexane (for 2–4) afforded the bis-indolyl magnesium complexes 1–4, respectively. All the ligand precursors and related magnesium complexes have been characterized by NMR spectroscopy and elemental analyses. The molecular structure is reported for compound 1. These novel magnesium complexes demonstrate efficient catalytic activities for the ring-opening polymerization of L-lactide in the presence of alcohol.

Inova-600 (600 MHz) spectrometers (Agilent Technologies, Santa Clara, CA, USA) in chloroform-d or benzene-d 6 at room temperature unless stated otherwise and referenced internally to the residual solvent peak and reported as parts per million relative to tetramethylsilane.Elemental analyses were performed by an Elementar Vario ELIV instrument (Elementar, Hanau, Germany).The GPC measurements were performed in THF at 35 ˝C with a Waters 1515 isocratic HPLC pump, a Waters 2414 refractive index detector, and Waters styragel column (HR4E) (Waters, Milford, MA, USA).The number-average molecular weights (Mn) and molecular weight distributions (PDIs = Mw/Mn) were calculated using polystyrene as standard.

Crystal Structure Data
Crystals were grown from concentrated THF solution for 1, and isolated by filtration.Suitable crystals were mounted onto Mounted CryoLoop (HAMPTON RESEARCH, Aliso Viejo, CA, USA; size: 0.5-0.7 mm) using perfluoropolyether oil (Sigma-Aldrich, FOMBLIN Y) and cooled rapidly in a stream of cold nitrogen gas using an Oxford Cryosystems Cryostream unit.Diffraction data were collected at 100 K using an OxfordGemini S diffractometer (Oxford Diffraction Ltd., Abingdon, UK).Empirical absorption correction was based on spherical harmonics, implemented in the SCALE3 ABSPACK scaling algorithm from CrysAlis RED (Oxford Diffraction Ltd.).The space group determination was based on a check of the Laue symmetry and systematic absences and was confirmed using the structure solution.The structure was solved by direct methods using a SHELXTL package [41].All non-H atoms were located from successive Fourier maps, and hydrogen atoms were refined using a riding model.Anisotropic thermal parameters were used for all non-H atoms, and fixed isotropic parameters were used for H atoms.Some details of the data collection and refinement are given in Table 1.
CCDC reference number 1410371 for 1 contains the supplementary crystallographic data for this paper.These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 1957 Polymers 2015, 7, 1954-1964

Preparations of Ligand Precursors and Magnesium Complexes
There are various synthetic routes for the preparation of indole derivatives, such as Fischer indole synthesis [32], Bartoli indole synthesis [31] or Pd/Cu-catalyzed cyclization [42,43].Previously, we reported the preparation of indole bearing pendant functionalities using the Sonogashira reaction followed by Zn-mediated cyclization [28].In order to introduce pyrazolyl functionalities into indole molecules, copper-catalyzed N-arylation or the Bartoli indole synthesis are used to achieve this issue.The synthetic routes were shown in Scheme 1.The ligand precursor Pz H IndH was prepared via copper-catalyzed N-arylation reaction from 7-bromoindole with pyrazole [44].Related ligand precursors composed of pyrazolyl rings bound to carbazole at the 1-and 8-positions have recently been reported [45].The signal of -NH on 1 H NMR spectrum for indole Pz H IndH was observed at δ 10.37 ppm.The ligand precursors Pz Me IndH, Pz tBu IndH and Pz Ph IndH were prepared via the Bartoli indole synthesis from o-substituted nitrobenzenes with vinylmagnesium bromide [31].The signals of -NH on 1 H NMR spectra for indoles Pz Me IndH, Pz tBu IndH and Pz Ph IndH were observed at δ 9.70, 8.45, and 9.44 ppm, respectively.All the ligand precursors were characterized by elemental analyses as well.
Treatment of ligand precursors Pz R IndH with n Bu2Mg on the ratio of 1:0.7 by alkane elimination reaction in THF or hexane at room temperature affords the desired bis-indolyl magnesium complexes 1-4 in moderate yields, as shown in Scheme 1.For compound 1, the disappearance of the N-H signal of indole and the appearance of the coordinated THF are consistent with the proposed structure.Preparations of compounds 2-4 bearing the coordinated THF have been done in THF.However, the signals corresponding to coordinated THF disappeared after rinsing the crude products with hexane.For the convenience of separation, THF was used to prepare compound 1, whereas hexane was used to prepare compounds 2-4.The compounds 1-4 were all characterized by NMR spectroscopy as well as elemental analyses.
Suitable crystals for structure determination of 1 were obtained from concentrated THF solution.The molecular structure is depicted in Figure 1.Selected bond lengths and bond angles are summarized in Table 2.
Treatment of ligand precursors Pz R IndH with n Bu 2 Mg on the ratio of 1:0.7 by alkane elimination reaction in THF or hexane at room temperature affords the desired bis-indolyl magnesium complexes 1-4 in moderate yields, as shown in Scheme 1.For compound 1, the disappearance of the N-H signal of indole and the appearance of the coordinated THF are consistent with the proposed structure.Preparations of compounds 2-4 bearing the coordinated THF have been done in THF.However, the signals corresponding to coordinated THF disappeared after rinsing the crude products with hexane.For the convenience of separation, THF was used to prepare compound 1, whereas hexane was used to prepare compounds 2-4.The compounds 1-4 were all characterized by NMR spectroscopy as well as elemental analyses.
Suitable crystals for structure determination of 1 were obtained from concentrated THF solution.The molecular structure is depicted in Figure 1.Selected bond lengths and bond angles are summarized in Table 2.

Polymerization Studies
Since several magnesium complexes containing bis-indolyl ligands have demonstrated their catalytic activities towards the ROP of cyclic esters in the presence of alcohols [28], the homoleptic indolyl magnesium complexes reported here are expected to work as the catalysts for the ring opening polymerization.Representative results are collected in Table 3 for ROP of L-LA, respectively.
The polymerization of L-lactide using complexes 1-4 as catalyst precursors in the presence of alcohols is tested under a dry nitrogen atmosphere.Prescribed equivalent ratios on the catalyst precursor (0.025 mmol), L-LA and alcohol were introduced in 5.0 mL solvent at 0 °C for 1 min.After several trials on running polymerization with various solvents (dichloromethane, tetrahydrofuran or toluene) and alcohols (benzyl alcohol (BnOH), 2-propanol ( i PrOH) and 9-anthracenemethanol (9-AnOH)), the conditions were optimized to be toluene at 0 °C in the presence of 9-AnOH for the polymerization of L-LA (Table 1, Entries 1-5).However, only trace polymers were obtained from the blank tests in the absence of benzyl alcohol or 4 under the optimized conditions (Table 1, Entries 6-7).The same optimized conditions were applied to examine the catalytic activities of these catalysts with the reaction time extended to 5 min (Table 1, Entries 8-11).Only trace polymers obtained by using 1 as catalyst, this is consistent with the result demonstrated by magnesium bis-indolyl complex with pendant amine functionality and coordinated THF molecules [28].The bulkiness around the metal center caused by ligands and coordinated THF molecules might prevent the metal center from the coordination of monomers and alcohol.The catalytic activities exhibited by the other complexes without coordinated THF molecule seem to depend on the steric

Polymerization Studies
Since several magnesium complexes containing bis-indolyl ligands have demonstrated their catalytic activities towards the ROP of cyclic esters in the presence of alcohols [28], the homoleptic indolyl magnesium complexes reported here are expected to work as the catalysts for the ring opening polymerization.Representative results are collected in Table 3 for ROP of L-LA, respectively.
The polymerization of L-lactide using complexes 1-4 as catalyst precursors in the presence of alcohols is tested under a dry nitrogen atmosphere.Prescribed equivalent ratios on the catalyst precursor (0.025 mmol), L-LA and alcohol were introduced in 5.0 mL solvent at 0 ˝C for 1 min.After several trials on running polymerization with various solvents (dichloromethane, tetrahydrofuran or toluene) and alcohols (benzyl alcohol (BnOH), 2-propanol ( i PrOH) and 9-anthracenemethanol (9-AnOH)), the conditions were optimized to be toluene at 0 ˝C in the presence of 9-AnOH for the polymerization of L-LA (Table 1, Entries 1-5).However, only trace polymers were obtained from the blank tests in the absence of benzyl alcohol or 4 under the optimized conditions (Table 1, Entries 6-7).The same optimized conditions were applied to examine the catalytic activities of these catalysts with the reaction time extended to 5 min (Table 1, Entries 8-11).Only trace polymers obtained by using 1 as catalyst, this is consistent with the result demonstrated by magnesium bis-indolyl Polymers 2015, 7,[1954][1955][1956][1957][1958][1959][1960][1961][1962][1963][1964] complex with pendant amine functionality and coordinated THF molecules [28].The bulkiness around the metal center caused by ligands and coordinated THF molecules might prevent the metal center from the coordination of monomers and alcohol.The catalytic activities exhibited by the other complexes without coordinated THF molecule seem to depend on the steric hindrance resulting from the substituents on the pyrazolyl groups.The decreasing tendency of catalytic activity was found in the order 3 > 4 > 2. The catalytic activities were re-examined on the ratio of [L-LA] 0 /[Mg] 0 /[9-AnOH] 0 = 200/1/1 within 15 min.(Table 1, Entries 12-13).Complex 4 showed better activities than 3 with better controlled character.Therefore, complex 4 was subjected to exhibit the living character at 30 ˝C.The linear relationship between the number-average molecular weight (Mn) and the monomer-to-initiator ratio (range from 150 to 400) was demonstrated in Figure 2 (Table 1, Entries 14-19, PDIs = 1.22-1.39)with poor controlled character.1, Entries 12-13).Complex 4 showed better activities than 3 with better controlled character.Therefore, complex 4 was subjected to exhibit the living character at 30 °C.The linear relationship between the number-average molecular weight (Mn) and the monomer-to-initiator ratio (range from 150 to 400) was demonstrated in Figure 2 (Table 1, Entries 14-19, PDIs = 1.22-1.39)with poor controlled character.3).
The "immortal" character was examined using 2-4 equivalents 9-AnOH as chain transfer agent to produce polymers with reasonable Mn values (     3).
The "immortal" character was examined using 2-4 equivalents 9-AnOH as chain transfer agent to produce polymers with reasonable Mn values (Table 1, Entries 20-22, compared to entries 17, 15, and 14, respectively).The end group analysis is demonstrated by the 1 H NMR spectrum of polylactide (PLA-100) catalyzed by 4 in the presence of 9-AnOH, which is shown in Figure 3.
Peaks are assignable to the corresponding protons in the proposed structure.The mechanism might be similar to that reported on magnesium complexes bearing pendant indolyl ligand, indicating the active magnesium alkoxide species might form first, followed by the coordination-insertion mechanism [28].
Polymers 2015, 7, page-page 8 and 14, respectively).The end group analysis is demonstrated by the 1 H NMR spectrum of polylactide (PLA-100) catalyzed by 4 in the presence of 9-AnOH, which is shown in Figure 3.
Peaks are assignable to the corresponding protons in the proposed structure.The mechanism might be similar to that reported on magnesium complexes bearing pendant indolyl ligand, indicating the active magnesium alkoxide species might form first, followed by the coordination-insertion mechanism [28].

Conclusions
Four indole ligand precursors containing pendant pyrazolyl functionalities have been prepared.The novel magnesium bis-indolyl complexes 1-4 have been synthesized and fully characterized by NMR spectroscopic studies and elemental analyses.Due to the steric hindrance of ligands, only complex 1 bearing two coordinated THF molecules in cis-configuration has been synthesized and confirmed by single-crystal X-ray crystallography.However, the crowded environment around the metal center of 1 might prevent the coordination of monomers or alcohols and result in poor catalytic activities.Under optimized condition, complex 4 demonstrated both living and immortal characters but with poor PDIs values (1.20-1.42).Preliminary studies on fine-tuning modification of indole ligands with different substituents and their application in the synthesis of metal complexes are currently underway.

Conclusions
Four indole ligand precursors containing pendant pyrazolyl functionalities have been prepared.The novel magnesium bis-indolyl complexes 1-4 have been synthesized and fully characterized by NMR spectroscopic studies and elemental analyses.Due to the steric hindrance of ligands, only complex 1 bearing two coordinated THF molecules in cis-configuration has been synthesized and confirmed by single-crystal X-ray crystallography.However, the crowded environment around the metal center of 1 might prevent the coordination of monomers or alcohols and result in poor catalytic activities.Under optimized condition, complex 4 demonstrated both living and immortal characters but with poor PDIs values (1.20-1.42).Preliminary studies on fine-tuning modification of indole ligands with different substituents and their application in the synthesis of metal complexes are currently underway.

Scheme 1 .
Scheme 1. Synthetic routes for ligand precursors and magnesium complexes.

Figure 1 .
Figure 1.Molecular structure of 1. Hydrogen atoms are omitted for clarity.

Figure 1 .
Figure 1.Molecular structure of 1. Hydrogen atoms are omitted for clarity.

Figure 3 . 1 H
Figure 3. 1 H NMR spectrum of PLA-100 initiated by 4 in the presence of 9-AnOH in toluene at 0 °C.

Figure 3 . 1 H
Figure 3. 1 H NMR spectrum of PLA-100 initiated by 4 in the presence of 9-AnOH in toluene at 0 ˝C.

Table 1 .
Summary of crystal data for compound 1.

Table 3 .
Polymerization of L-LA using compounds 1-4 as catalysts in toluene if not otherwise stated.a

Table 3 .
Polymerization of L-LA using compounds 1-4 as catalysts in toluene if not otherwise stated.a