Synthesis and Structural Characterization of Magnesium Drug

Oct 13, 2015 - (n) Gao , Y.; Dai , Z.; Zhang , J.; Ma , X.; Tang , N.; Wu , J. Inorg. Chem. 2014, 53, 716– 726 DOI: 10.1021/ic401459a. [ACS Full Tex...
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Synthesis and Structural Characterization of Magnesium Drug Complexes: Efficient Initiators for Forming Polylactide−Drug Conjugates Tomasz Han,† Rafał Petrus,‡ Dominik Bykowski,‡ Lucjan Jerzykiewicz,‡ and Piotr Sobota*,†,‡ †

Research & Development Centre Novasome, 5 Olsztyńska, 51-423 Wrocław, Poland Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie, 50-383 Wrocław, Poland

‡

S Supporting Information *

ABSTRACT: Five novel magnesium alkoxides supported by drug chelating agents pridinolum (PriOH = 1,1-diphenyl-3-(1piperidinyl)-1-propanol) and venlafaxinum (VenlOH = (RS)-1[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol) were successfully synthesized and characterized. Direct reaction of PriOH and VenlOH with MgBu2 (1:1) in toluene gives the dimeric compounds [Mg(μ,η2-OPri)nBu]2 (1) and [Mg(μ,η2VenlO)nBu]2 (2), respectively. Furthermore, the crystallization of an equimolar mixture of 1 and 2 in toluene yields heteroleptic magnesium complex [Mg(μ,η 2 -OVenl)(η 1 OPri)]2 (3). Moreover, reactions of 1 and 2 with 2 molar equivs of the corresponding drug−ligands give the homoleptic magnesium bis-alkoxides [Mg(μ,η2-OPri)(η1-OPri)]2 (4) and [Mg(μ,η2-OVenl)(η1-OVenl)]2 (5). The treatment of compound 1 with 2 equivs of VenlOH or 2 with 2 equivs of PriOH leads to the formation of 3. Complexes 1−5 were characterized by elemental analysis, nuclear magnetic resonance, and single crystal Xray diffraction (for 1−4). It was found that complexes 1−5 are efficient initiators of the ring-opening polymerization of L-LA, yielding PLA-OPri and PLA-OVenl conjugates, respectively. Moreover, the ring-opening polymerization of L-LA initiated by 3 led to the simultaneous generation of a blend of poly-L-lactide conjugates with end-capped VenlO and PriO groups.

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INTRODUCTION Over the recent decades there has been increasing interest in the conjugation of polymers with drugs to improve and modify their biopharmaceutical properties.1 Indeed, from a human healthcare perspective, numerous polymer−drug conjugates have been investigated. The possibility of linking a bioactive molecule to a macromolecular chain to make polymeric conjugated systems is applicable not only in drug delivery but also in fields such as tissue engineering, biosensors, affinity separations, enzymatic processes, and cell cultures.2 In studies related to these, popular synthetic polymers such as poly(ethylene glycol)3 and N-(2-hydroxylpropyl)methacrylamide4 are increasingly being used as biodegradable copolymers, especially with polylactide (PLA).5 The practice of synthesizing end-functionalized PLA is well established and has been widely explored. As early as 1994, Kricheldorf, and later in 2002 Stupp and colleagues, established that hydroxyl groups on vitamins, hormones, and drugs can be used to initiate the ring-opening polymerization (ROP) of lactide (LA) to produce end-functionalized PLA.6 Moreover, Cheng and colleagues have carried out detailed studies on the characterization of the PLA−drug conjugates obtained using magnesium and zinc complexes as initiators.7 The synthesis of drug−PLA conjugates has also been extensively developed by © XXXX American Chemical Society

our group. Recently, we reported on the interesting chemistry resulting from magnesium ligated by the drug pridinolum (PriOH), which forms a well-defined initiator [Mg(μ,η2OPri)(η1-OPri)]2 for the controlled polymerization of L-LA, leading to the formulation of PLA−pridinol conjugates.8 This process proceeds in the presence of metal-alkoxides (M-OR) via a coordination−insertion mechanism, whereby the metal center serves to activate the carbonyl group of the incoming LA molecules toward attack by the metal M-OR alkoxide group. This is followed by insertion of an LA molecule into the metalalkoxide bond with cleavage of the acyl-oxygen bond of the monomer.9 In this context, Mg-,10 Ca-,11 and Zn-alkoxides12 are very attractive initiators of the synthesis of biodegradable polymers that could be used in biomedical and environmental applications.13 In contrast to the well-studied Mg alkoxides, few examples of alkylmagnesium initiators have been reported as active singlesite catalysts for ROP. 14 The most broadly applied representations of this class of compounds are Grignard reagents, 15 alkylmagnesium alkoxides, 16 β-diketiminates (BDI),17 and tris(pyrazolyl)hydroborates.18 Various types of Received: February 20, 2015

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Organometallics Scheme 1. Synthesis of Magnesium Complexes 1, 2, 4, and 5

potential use in drug delivery and controlled-release applications.

polymerization mechanisms for LA, in the presence of the aforementioned alkylmagnesium initiators, have also been proposed in the literature.19−22 In this context, Sánchez-Barba reported on a series of alkylmagnesium heteroscorpionates, which initiated the rac- and L-LA polymerization process by nucleophilic attack of the alkyl group on the monomer.19 A similar course of polymerization reaction was also postulated by Chivers and Bochmann for magnesium BDI compounds and by Cui for complexes with N,O-bidentate pyridyl functionalized alkoxy ligands.20 Furthermore, Chisholm developed a mechanism for ROP of rac- and L-LA in the presence of alkylmagnesium β-diketiminates, based on initiation by βhydrogen atom transfer with the formation of the ring-opened lactide bound to the Mg center as an alkoxide and the elimination of 1-alkene.21 We also consider studies by Kricheldorf on the ROP of rac-, meso-, and L-LA in the presence of MgnBu2 and nBuMgCl, which suggest that the initiation process requires an acid−base proton transfer from the lactide to an alkyl group to generate a deprotonated lactide anion. This acts as a new active ligand in the ROP with the elimination of butane.22 We report herein on the preparation and characterization of new alkoxy-butylmagnesium complexes [Mg(μ,η2-OPri)nBu]2 (1) and [Mg(μ,η 2 -VenlO)n Bu]2 (2), where the drugs pridinolum (PriOH = 1,1-diphenyl-3-(1-piperidinyl)-1propanol) and venlafaxinum (VenlOH = (RS)-1-[2-dimethylamino-1(4-methoxyphenyl)-ethyl]cyclohexanol) are used as a muscle contraction agent and antidepressant, respectively.23 Furthermore, we have also examined the reactivity of 1−2 with 2 molar equivs of the corresponding drug−ligands. As a result of this study, we received new dimeric magnesium alkoxides [Mg(μ,η2OVenl)(η1-OPri)]2 (3), [Mg(μ,η2-OPri)(η1-OPri)]2 (4), and [Mg(μ,η2-OVenl)(η1-OVenl)]2 (5). Moreover, we found that synthesized complexes 1−5 are highly active initiators of the ROP of L-LA to give polymers terminated by a covalently attached drug molecule through ester linkers. These have

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RESULTS AND DISCUSSION

Synthesis and Characterization of Magnesium Complexes 1−5. As shown in Scheme 1, treatment of 1 equiv of hydroxyl ligands PriOH or VenlOH with 1 equiv of MgnBu2 under butane evolution in toluene affords new dimeric tetrahedral magnesium compounds [Mg(μ,η2-OPri)nBu]2 (1, 51%) and [Mg(μ,η2-VenlO)nBu]2 (2, 58%). Compounds 1 and 2 were isolated as colorless crystals, and they are readily soluble in hydrocarbons and THF. Their structures were confirmed by elemental analysis, X-ray crystallography, and nuclear magnetic resonance (NMR) spectroscopy [Supporting Information, Figures S3−S12]. The molecular structures of compounds 1 and 2 are shown in Figures 1 and 2, respectively. Selected bond distances and angles are given in the respective figure legends. Single-crystal X-ray diffraction (XRD) data reveal that both complexes in solid form are centrosymmetric dimers composed of two nBuMg(η2-OR) moieties bridged by alkoxy oxygen atoms O1 and O1i. In each case, these oxygen atoms are engaged in the formation of a central, planar four-membered Mg2(μ2-O)2 core structure, which is a common structural motif found in magnesium coordination chemistry.24 The positions of the nBu groups on the magnesium ions are anti with respect to the Mg2(μ2-O)2 ring. The Mg−O and Mg−N bond lengths are in the expected range for a four-coordinate Mg center.25 1 H NMR studies of 1 and 2 in C6D6 at room temperature show that as the reaction proceeds, disappearance of the OH signals of the ligands occurs along with the appearance of resonances for the protons of the n-butyl groups at the high field region. This is consistent with the structures proposed in Scheme 1. In addition, 1H−1H COSY and 1H−13C HSQC experiments show that all methylene protons of the OPri and OVenl ligands are diastereotopic. VT 1H NMR studies (from B

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in solution. Unlike other magnesium alkyls, compounds 1 and 2 remained thermally stable, even in a hot toluene solution. However, when we mixed together an equimolar amount of 1 and 2 in toluene we received, after 3 weeks of crystallization resulting from ligand redistribution, new heteroleptic magnesium complex [Mg(μ,η2-OVenl)(η1-OPri)]2 (3, 20%). Similar ligand exchange reactions that follow Schlenk equilibrium were observed previously for many magnesium alkyl systems.26 Therefore, it should be noted that in our study we used only compounds 1 and 2 that were directly synthesized, before physicochemical measurements were obtained or catalytic processes studied. Furthermore, we also examined the reactivity of 1 and 2 with corresponding drug−ligands. Results of these studies showed that the addition of 2 equivs of PriOH to a toluene solution of 1 or VenlOH to a solution of 2 leads to substitution of the −nBu groups by drug molecules with the formation of the alkoxide [Mg(μ,η2-OPri)(η1-OPri)]2 (4, 58%) or [Mg(μ,η2OVenl)(η1-OVenl)]2 (5, 85%) and the elimination of n-butane (Scheme 1). In the reactions of 1 with VenlOH or 2 with PriOH, we observed the formation of heteroleptic magnesium complex [Mg(μ,η2-OVenl)(η1-OPri)]2 (3, 50−59%), as shown in Scheme 2.

Figure 1. Molecular structure of [Mg(μ,η2-OPri)nBu]2 (1). Hydrogen atoms are omitted for clarity [symmetry code: (i) −x + 1, −y + 1, −z + 1]. Selected bond lengths (Å) and angles (deg): Mg1O1 2.005(2), Mg1O1i 1.980(2), Mg1N1 2.200(2), Mg1C21 1.490(2), O1 Mg1N1 92.69(6), O1Mg1O1i 85.40(6), O1Mg1C21 123.46(7), O1iMg1N1 109.52(7), O1iMg1C21 128.24(7), N1Mg1C21 110.56(8), and Mg1O1Mg1i 94.60(6).

Scheme 2. Synthesis of Heteroleptic Magnesium Complex 3

The X-ray structure determination of complexes 3 and 4 additionally revealed that −nBu groups present in 1 and 2 are replaced by terminal −OPri ligands, as shown in Figures 3 and 4. In both structures, the magnesium ions adopt a distorted tetrahedral geometry with O3N donor sets. The Mg atoms and the bridging alkoxide groups, similar to that for 1 and 2, are arranged in a Mg2(μ2-O)2 central core structure. The Mg−O bond lengths involved in the bridging alkoxo-oxygen groups are longer, by ca. 0.10−0.13 Å, than the bond distances involved in the terminal alkoxo donor sets. Similar geometric features were observed in the structures of [Mg(μ2-OR) (OR)(X)]2, where RO = 1,1-diphenylethoxide or triphenylsiloxide, and X = THF or py.27 Unfortunately, our attempts to grow single crystals of 5 for XRD analysis proved unsuccessful. However, based on

Figure 2. Molecular structure of [Mg(μ,η2-VenlO)nBu]2 (2). Hydrogen atoms are omitted for clarity [symmetry code: (i) −x + 2, −y, −z + 2]. Selected bond lengths (Å) and angles (deg) Mg1O1 1.972(2), Mg1O1i 1.962(2), Mg1N1 2.194(3), Mg1C31 2.129(3), O1 Mg1O1i 84.36(9), O1Mg1N1 90.13(9), O1Mg1C31 117.77(12), O1 i Mg1N1 113.48(10), O1 i Mg1C31 129.27(12), N1Mg1C31 111.53(12), and Mg1O1Mg1i 95.64(9).

−70 to +70 °C) in C7D8 do not introduce any structural changes and confirm that the dimeric structures are maintained C

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tional solvents. Therefore, NMR studies were performed using DMSO-D6. Because of the possibility of obtaining 3 by two alternative reactions, we decided to examine the selectivity of both using powder diffraction. Comparison of XRD patterns with the reference standards for pure 4 and 5 clearly shows that for both pathways complex 3 is the main product (Figure 5). The absence of distinctive peaks derived from homoleptic magnesium complexes also suggests that no disproportionation of 3 to the mixture of 4 and 5 was observed.

Figure 3. Molecular structure of [Mg(μ,η2-OVenl)(η1-OPri)]2· 2CH2Cl2 (3·2CH2Cl2). Hydrogen atoms and solvent molecules are omitted for clarity [symmetry code: (i) −x + 1, −y + 1, −z + 1]. Selected bond lengths (Å) and angles (deg): Mg1O1 1.960(4), Mg1O1i 1.958(4), Mg1N1 2.178(6), Mg1O3 1.839(4), O1 Mg1N1 90.33(19), O1Mg1O1i 83.70(18), O1Mg1O3 129.8(2), O1iMg1N1 118.9(2), O1iMg1O3 127.3(2), N1 Mg1O3 102.4(2), and Mg1O1Mg1i 96.30(18).

Figure 5. Comparison of XRD patterns of compound 3 obtained by reaction of 1 with 2 equivs of VenlOH or 2 with 2 equivs of PriOH. Reference standards of pure 4 and 5 are also shown.

Ring-Opening Polymerization of L-Lactide. The L-LA polymerization process was conducted in toluene using complexes 1 and 2 as initiators. The amount of compound used in each reaction was calculated on the basis of the number of Mg centers. Representative results from the L-LA polymerization processes are summarized in Table 1. The numberaverage molecular weight (Mn) and polydispersity index (PDI) values of the polymers were determined by size-exclusion chromatography with a multiangle laser light scattering detector (SEC-MALLS). The results of these studies demonstrate that the magnesium alkyls 1 and 2 initiated the rapid ROP of L-LA at room temperature and effectively provided an efficient method for the formation of PLA−drug conjugates. Analysis of the molecular weights of the obtained polymers shows that their values are higher than those calculated based on % monomer consumption (Table 1, entries 1−5). For example, when the ratio of L-LA:Mg was 20:1, compound 1 provided a polymer with a Mn value of 23 kDa, while compound 2 gave a polymer with a Mn value of 16 kDa, both with PDIs not exceeding 1.6 (Table 1, entries 1 and 4). The Mn values in these examples were seven and five times greater than those expected from reaction stoichiometries. To obtain information on the end-group, polymerizations were performed with a low monomer to Mg ratio (20:1), with these reactions studied by NMR and electrospray ionization mass spectrometry (ESI-MS). The 1H NMR study reveals that the −nBu moiety was not incorporated as the end group of the polymer chain. Moreover, the resonance signals derived from the hydroxymethine unit and the functional groups of the

Figure 4. Molecular structure of [Mg(μ,η2-OPri)(η1-OPri)]2·2C7H8 (4·2C7H8). Hydrogen atoms and solvent molecules are omitted for clarity [symmetry code: (i) −x + 1, y, −z + 1/2]. Selected bond lengths (Å) and angles (deg): Mg1O1 1.983(2), Mg1O1i 1.954(2), Mg1N1 2.183(2), Mg1O2 1.852(2), O1Mg1N1 93.83(7), O1Mg1O1i 82.04(6), O1Mg1O2 120.78(7), O1iMg1N1 116.70(7), O1 iMg1O2 119.66(7), N1 Mg1O2 116.16(7), and Mg1O1Mg1i 97.50(7).

spectroscopic studies for 5, and by analogy to 3 and 4, we suggest that the molecular structure of 5 has dimeric character. It should also be mentioned that the compounds 3−5, after isolation in crystalline form, are almost insoluble in convenD

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Organometallics Table 1. Polymerization of L-Lactidea entry

initiator

a

1 1 1 2 2 1 1 2 2 1 1 MgBu2 MgBu2 MgBu2 MgBu2 MgBu2 MgBu2 MgBu2 MgBu2 MgBu2 MgBu2

1 2a 3a 4a 5a 6a 7a 8a 9a 10a 11a 12b 13b 14b 15b 16b 17b 18b 19b 20b 21b

ROH

[L-LA]/[Mg]/[ROH]

t (min)

Mn (MALLS)c

Mw/Mnc

C (%)d

PriOH PriOH VenlOH VenlOH VenlOH VenlOH PriOH PriOH PriOH PriOH PriOH VenlOH VenlOH VenlOH VenlOH VenlOH

20/1/0 50/1/0 100/1/0 20/1/0 50/1/0 20/1/1 50/1/1 20/1/1 50/1/1 20/1/1 50/1/1 100/1/1 100/1/2 100/1/3 100/1/4 100/1/5 100/1/1 100/1/2 100/1/3 100/1/4 100/1/5

2 3 6 1 2 5 10 4 7 3 5 1 1 1 1 1 1 1 1 1 1

23000 32100 47100 16400 17300 4400 11800 10000 12100 12200 16100 59500 60400 57300 47000 50600 35200 34900 31500 39100 37300

1.58 1.66 1.71 1.63 1.54 1.37 1.21 1.34 1.41 1.85 1.61 1.38 1.36 1.34 1.37 1.34 1.51 1.42 1.52 1.41 1.31

96 95 99 99 98 98 94 99 98 99 99 97 98 97 98 98 98 99 99 99 99

a Polymerization conditions: [I]0 = 8.9 mM, 15 mL of toluene as solvent, temperature 25 °C, under N2 atmosphere. bPolymerization conditions: [MgBu2]0 = 4.0 mM, 25 mL of toluene as solvent, [L-LA]0 = 0.4 M, temperature 25 °C, under Ar atmosphere. cObtained from SEC analysis with MALLS detector. dObtained from 1H NMR analysis.

comparison with the above-mentioned results, we also conducted an L-LA polymerization process using compounds 1 and 2 in the presence of exogenous hydroxyl drugs of PriOH and VenlOH. These systems produce PLA polymer chains with a slightly improved (controlled) molecular weight distribution compared with that obtained in the polymerization initiated by complexes 1 and 2 (Table 1, entries 6−9). 1H NMR and ESIMS analyses of the resulting macromolecular chain ends obtained for an L-LA:Mg ratio of 20:1 reveal the formation of PLLA terminated by OPri (with 1) or OVenl groups (with 2). In these experiments, it is evident that dimeric magnesium bisalkoxide complexes are formed initially but that a direct comparison of the polymerization catalysis of both systems shows some differences. For example, we carried out the polymerization reaction with stoichiometries L-LA/Mg = 25 or 100, initiated by the combination 1 + PriOH or by 4. For the ratio LA/Mg = 100 and [Mg]0 = 3.5 mM, the results of both reactions are comparable: 91−96% monomer conversion was achieved after 1 min. Differences in the rate of polymerization have been seen for reactions with L-LA/Mg = 25 and [Mg]0 = 13.8 mM. For example, for 1 + PriOH, 96% monomer conversion was observed after 5 s, while for 4, 91% conversion was obtained after 45s. For a better understanding of the tested ROP of L-LA, we performed kinetic studies using 4 in order to establish the reaction order of monomer and initiator. The conversion of LLA ([L-LA]0 = 0.347 M) over time at various concentrations of 4 ([4]0 = 1.73, 2.31, 3.83, 6.90 mM) in toluene was monitored by 1H NMR. In each case, plots of (1/[L-LA]t − 1/[L-LA]0) versus time are linear, indicating that polymerization proceeds with a second-order dependence on monomer concentration (Figure S29). Thus, the rate of polymerization can be written as −d[L-LA]/dt = kapp[L-LA]2, where kapp = kp[4]n, kp is the propagation rate constant, and n is the order of the initiator. In order to determine the reaction order with respect to the

ligands indicate formation of linear polyesters terminated by drug molecules (Figures S19 and S21). ESI-MS analysis provides clear evidence of PriO− or VenlO− end group incorporation (Figures S20 and S22), which is consistent with a typical coordination−insertion polymerization mechanism. With a view to that mentioned in the Introduction regarding mechanisms of polymerization of LA using magnesium alkyls, we decided to attempt to explain what happened in the studied systems with −nBu groups during the polymerization process. For this purpose, we examined the reactions of the magnesium compounds 1−2 with 2 equivs of benzophenone or L-LA. The results of these studies showed that the reaction with Ph2CO proceeds with the β-hydrogen transfer resulting in the formation of 1-butene and an alkoxide ligand OCHPh2 (Figures S23 and S24). However, the reaction with L-LA is more complicated because there are two competing polymerization processes for the cyclic monomer initiated by the alkoxo-drug and 2-alkoxo-propanal group. The presence of the second group has been established on the basis of 1-butene evolution detected by 1H NMR (Figures S25 and S26), which is in agreement with Chisholm’s study.21 However, ESI-MS analysis of low molecular weight oligomers always confirms the presence of polyesters terminated by a covalently attached drug molecule through ester linkers. On the basis of the above results, we cannot exclude the fact that the high molecular PLAs are terminated by a 2-alkoxo-propanal group. It is also worth noting that both alkyl(alkoxy)magnesium initiators are very sensitive to the presence of hydroxyl impurities, such as water or lactic acid. Such impurities can cause substitution of the n-butyl group to release butane and form a polyester capped by the carboxylic end group. This is evident via 1H NMR and ESI-MS analyses (Figures S27−S28). There is currently a notable trend toward the use of alkylmagnesium compounds as precursors for the preparation of alkoxides for the ROP of cyclic esters.28 Therefore, for E

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Organometallics initiator, we plot ln(kapp) = ln(kp) + nln[4]. However, the nonlinear relationship means that we are unable to determine the values of n. The results of reactions for [4]0 = 1.73, 2.31, and 3.83 show that decreasing the initiator concentration increases the rate of polymerization. Therefore, based on the results of kinetic studies, as well as the determined Mn values that are significantly higher than those calculated from the reaction stoichiometry (Table 1), we have shown that the polymerization is carried out in an uncontrolled manner. This might be attributed to the impurities or aggregation of metal initiators on growing polymer chains. In order to improve control of the studied polymerization process, we decided to carry out additional reactions with the stoichiometry of [L-LA]/[Mg]/[ROH] = 100/1/1−5 using MgBu2 in combination with 1 to 5 equiv of ROH (where ROH = PriOH, VenlOH) to generate in situ the metal alkoxide initiators via alcoholysis. Results of these studies, presented in Table 1 (entries 12−21), show that increasing the amount of ROH does not increase control over the molecular weight. The SEC curves of the isolated PLLA samples were narrow and monomodal, and do not indicate any disturbance of the polymerization process. In the presence of PriOH, the molecular weight of the obtained polymers is in the range 47−60 kDa with PDIs 1.34−1.38. In the case of VenlOH, molecular weights of the polymers are lower than that for PriOH and range from 31−39 kDa with PDIs 1.31−1.51. Experiments with the stoichiometry of [L-LA]/[Mg]/[ROH] = 100/1/3−5 also show that hydroxyl ligands are not effective chain transfer agents during the polymerization process because of the resulting acidity and steric effects.29 Moreover, the following L-LA polymerizations, regardless of the initiator system used, synthesized in situ in the reaction of MgBu 2 with ROH (1:1−5), magnesium alkyls (1:1), magnesium bisalkoxides (1:2), or magnesium alkoxides in the presence of external ROH (1:3−5), show no control over the polymerization process. We also observed a large influence on the resulting molecular weight polyesters and PDIs from the method of used polymerization quenching. For example, for the reaction with stoichiometry L-LA/Mg = 100, the used HCl leads to a polymer with Mn = 47 kDa and PDI = 1.7, while the reaction stopped by air exposure and hexane precipitation yields a polymer with Mn = 60 kDa and PDI = 1.4. When VenlOH was used as an external agent to control alcoholysis of the n-butyl groups in 1 before polymerization was performed with an L-LA:Mg ratio of 20:1 (Table 1, entry 10), a polymer blend of PLLA-OVenl (75%) and PLLA-OPri (25%) was obtained, which was confirmed by NMR and ESI-MS, as shown in Figures 6 and 7. To better understand the reasons for the formation of the polymer blends, we conducted a series of polymerization reactions with stoichiometry [L-LA]/[Mg] = 20 initiated by magnesium alkoxides with different ratios of OPri/OVenl = 1.0/1.0, 1.2/0.8, 1.4/0.6, 1.6/0.4, and 1.8/0.2 synthesized in a reaction of MgBu2 with 2 equivs of ROH. The results of these studies demonstrate that OVenl is a more active initiating group than is OPri in the polymerization process. However, with an increase in reaction time we observe a slight increase in the amount of PLLA-OPri formed, likely as a result of partial depolymerization of PLLA via transestrification. It is also noted that drug tertiary ester end groups are unstable and easily hydrolyze to the alcohol and acid, e.g., they even react with humidity in the air. This was confirmed by ESI-

Figure 6. 1H NMR spectrum in CD2Cl2 of PriO-PLLA and VenlOPLLA blend oligomers. * is assigned to the signal of solvent CH2Cl2.

Figure 7. ESI-MS spectra of PriO-PLLA and VenlO-PLLA blend oligomers.

MS through measuring a sample left in air for a period of several days. Decomposition of polymer−drug conjugates with elimination of the drug molecules has also been observed during quenching polymerization by MeOH or HClaq (5%). On the basis of these observations, we decided to carry out an initial test release in DCl solution of the pharmacologically active substances obtained from the resulting polymeric matrices. The results of these studies showed that increasing the molar mass of the conjugate extended the drug-release time.

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CONCLUSIONS The reported results illustrate a new, simple, and efficient strategy for preparing a well-defined magnesium−drug initiator and its application in polymerization of L-LA to allow the formulation of PLA−drug conjugates. Moreover, we demonstrated that the drug molecules pridinolum and venlafaxinum may be used as versatile N,O-bifunctional supporting ligands as the initiating group for the synthesis of PLA−drug conjugates. This work also established an effective strategy for the synthesis of a blend PLLA−drug conjugate with end-capped VenlO and PriO groups. We believe that the current observations will be helpful for the design of new and efficient metal−drug compounds that can act as catalysts for the ROP of heterocyclic monomers. F

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Organometallics

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C48H66N2O2Mg2: C, 76.70; H, 8.85; N, 3.73. Found: C, 76.75; H, 8.91; N, 3.69. 1H NMR (500 MHz, C6D6): δ {7.90−7.70, 7.69−7.50 (m, ArH, 4H)}, 7.45 (m, ArH, 4H), 7.37 (t, J = 6.2 Hz, ArH, 4H), 7.20 (t, J = 6.2 Hz, ArH, 4H), {7.15−7.12, 7.09−7.03, 6.90 (m, ArH, 4H)}, {3.54 (m, CH2OPri, 2H), 1.68 (m, CH2OPri, 2H)}, {2.84 (dd, J = 12.1, 9.3 Hz, CH2OPri, 2H), 2.18 (dd, J = 12.1, 5.1 Hz, CH2OPri, 2H)}, {2.51 (m, CH2OPri, 2H), 1.27−1.19 (m, CH2OPri, 2H)}, {2.43 (m, CH2OPri, 2H), 1.92 (dd, J = 10.6, 4.9 Hz, CH2OPri, 2H)}, 1.80 (m, CH2nBu, 4H), 1.74 (m, CH2nBu, 4H), {1.52 (m, CH2OPri, 2H), 0.98 (m, CH2OPri, 2H)}, {1.35 (m, CH2OPri, 2H), 1.05 (m, CH2OPri, 2H)}, 1.31 (t, J = 5.7 Hz, CH3nBu, 6H), 0.76 (m, CH2OPri, 4H), −0.59 − −0.79 (m, Mg− CH2nBu, 4H). 13C NMR (125 MHz, C6D6): δ {155.8, 151.9, 151.0, 149.0 (Ar, 4C)}, {129.5, 128.7, 128.0, 127.5, 127.3, 126.9, 126.7, 126.5, 126.3 (ArH, 20C)},{80.1, 79.2, 78.8, 78.0 (C−O, 2C)}, {56.9, 56.2, 55.6, 55.3, 54.9, 52.9 (CH2OPri, 6C)}, {36.8 (CH2OPri, 2C)}, {33.6, 33.4, 33.2 (CH2nBu, 4C)}, {23.8, 23.6, 23.5 (CH2OPri, 6C)}, {14.8, 14.5, 13.9 (CH3nBu, 2C)}, {12.2, 11.4 (Mg−CH2nBu, 2C)}, {137.8, 129.3, 128.5, 125.6, 21.1 (Ar, ArH, CH3, toluene)}. Synthesis of [Mg(μ,η2-VenlO)nBu]2 (2). MgBu2 (6 mL, 6 mmol) was added dropwise to a solution of VenlOH (1.66 g, 5.99 mmol) in toluene (30 mL). The mixture was stirred at room temperature for 1 h. Then, the volume was reduced to 15 mL under vacuum. Single crystals for XRD analysis were obtained from the concentrated mother liquor at 5 °C. The crystals were filtered off, washed with hexane (3 × 10 mL), and dried under vacuum. Yield 1.25 g (58%). Anal. Calcd for C42H70N2O4Mg2: C, 70.49; H, 9.86; N, 3.91. Found: C, 71.45; H, 9.91; N, 3.89. 1H NMR (600 MHz, C6D6): δ {6.94, 6.89−6.70 (m, ArH, 8H)}, {3.62−3.41, 1.96, 1.86 (m, NCH2, 4H)}, 3.39−3.34 (s, OCH3, 6H), {3.13, 3.05, 2.89 (d, J = 11.7 Hz; d, J = 11.4 Hz; m; CH, 2H)}, {2.30, 2.26, 2.04 (s, NCH3, 12H)}, {2.23−2.13, 2.12, 1.76, 1.64, 1.47, 1.25, 1.13, 0.88 (m, CH2Cy, 20H)}, 1.88 (m, CH2nBu, 8H), 1.35 (t, J = 7.9 Hz, CH3nBu, 6H), {0.11−0.04, 0.03−0.05 (m, Mg−CH2nBu, 4H)}.13C NMR (151 MHz, C6D6) δ {159.1, 158.9, 158.8, 158.7 (Ar, 2C)}, {135.9, 135.5, 132.8 (Ar, 2C)}, {130.9, 130.4 (ArH, 4C)}, {113.8, 113.6 (ArH, 4C)}, {73.4, 73.3, 73.1, 73.0, 72.9, 72.8, 72.7 (C− O, 2C)}, {64.7, 63.3, 63.1 (NCH2, 2C)}, {56.9, 55.4, 55.1 (CH, 2C)}, {54.8 (OCH3, 2C)}, {49.0, 48.8, 48.7, 45.1, 44.9, 44.2, 44.3 (NCH3, 4C)}, {39.7, 39.3 (CH2Cy, 2C)}, {34.4, 34.3, 34.2 (CH2nBu, 2C)}, {33.0, 32.9, 32.7 (CH2nBu, 2C)}, {32.1, 31.9, 31.8, 30.2, 30.1, 29.9, 29.5, 29.2, 29.0, 26.1, 26.0, 25.9, 23.1, 22.3, 22.1, 21.4, 21.3 (CH2Cy, 8C)}, {15.0, 14.8, 14.7, 14.6, 14.5, 14.4, (CH3nBu, 2C)}, {9.4, 9.3, 8.9, 8.8, 8.4, 8.3 (Mg−CH2nBu, 2C)}, {137.8, 129.3, 128.5, 125.6, 21.1 (Ar, ArH, CH3, toluene)}. Synthesis of [Mg(μ,η2-OVenl)(η1-OPri)]2 (3). The synthesis of this compound was carried out in two different ways. In the first method, to a solution of 1 (2 g, 2.66 mmol) in toluene (80 mL), VenlOH (1.48 g, 5.33 mmol) was added. In the second method, PriOH (1.57 g, 5.32 mmol) was added to a solution of 2 (1.90 g, 2.66 mmol) in toluene (80 mL). Further proceedings in both synthesis methods were similar. The mixture was stirred at room temperature for 5 h. Then, the volume was reduced to 30 mL, and the white precipitate was filtered off, washed with hexane (5 × 20 mL), and dried under vacuum. The white solid was dissolved in dichloromethane (50 mL) and recrystallized to yield colorless crystals. Yield (a) 1.58 g (50%); (b) 1.87 g (59%). Anal. Calcd for C74H100N4O6Mg2: C, 74.67; H, 8.47; N, 4.71. Found: C, 74.70; H, 8.49; N, 4.67. 1H NMR (500 MHz, DMSO-D6): δ {7.76, 7.61, 7.46, 7.26, 7.18−7.07, 6.97, 6.80 (m, ArHOPri, 20H; m, ArHOVenl, 8H)}, 3.71 (s, OCH3OVenl, 6H), {2.94 (m, NCH2OVenl, 2H), 2.39 (m, NCH2OVenl, 2H; m, CH2OPri, 4H)}, 2.76 (m, CHOVenl, 2H), 2.32−2.20 (m, CH2OPri,12H), 2.12 (s, NCH3OVenl, 12H), 1.59−1.26 (m, CH2OPri, CH2OVenl, 26H), 1.15−0.85 (m, CH2OVenl, 6H). 13C NMR (125 MHz, DMSO-D6): δ 157.5 (ArOVenl, 2C), {155.9, 148.4 (ArOPri, 4C)}, 133.6 (ArOVenl, 2C), 130.2 (ArHOVenl, 4C), {127.8, 126.8, 126.2, 126.0, 125.5, 124.1 (ArHOPri, 20C)}, 112.9 (ArHOVenl, 4C), {77.3, 76.2 (C−OOPri, 2C)}, 72.2 (C−OOVenl, 2C), 60.2 (NCH2OVenl, 2C), {55.5, 54.8, 54.5, 53.9 (CH2OPri, 6C; OCH3OVenl, 2C)}, 51.6 (CHOVenl, 2C), 45.3 (NCH3OVenl, 4C), {37.0, 35.8, 32.8, 25.6, 24.3, 23.8, 21.2 (CH2OVenl, 10C; CH2OPri, 8C)}, {137.3, 128.9, 128.2, 125.3, 21.0 (Ar, ArH, CH3, toluene)}.

EXPERIMENTAL SECTION

Materials and Methods. All syntheses were performed under a dry nitrogen atmosphere using standard Schlenk techniques. Reagents were purified by standard methods: toluene, C6D6, and C7D8 were distilled over Na; CH2Cl2 was distilled over P2O5; DMSO-D6 was treated with CaH2 at 70 °C overnight and distilled under reduced pressure (repeated three times); L-LA was five-times recrystallized from toluene, sublimed, and kept over P2O5. All chemical reagents were purchased from commercial sources: L-LA and MgnBu2 solution 1.0 M in heptane (Aldrich, St Louis, MO, USA), PriOH (Padmavati Chemicals Pvt Ltd.), and VenlOH (S. Amit Specialty Chemicals Pvt. Ltd.), C6D6, C7D8, DMSO-D6, and CD2Cl2 (Cambridge Isotope Laboratories, Tewksbury, MA, USA). 1H, 13C, COSY, and HMQC NMR spectra were recorded at room temperature using Bruker Avance 500 and 600 MHz spectrometers. Chemical shifts are reported in ppm and referenced to the residual protons in deuterated solvents. Powder XRD experiments were performed using a Bruker D8 ADVANCE diffractometer equipped with a copper lamp (λCuKα = 1.5418 Å). Standard measurements were done for 2θ = 5−60° with the 2θ step 0.032° and 2.5 s counting time, under N2 atmosphere using a specimen holder for environmental sensitive materials. ESI-MS data were collected on a Bruker micrOTOF-Q mass spectrometer. Elemental analysis was determined on a PerkinElmer 2400 CHN Elemental Analyzer. SEC traces were recorded using an Agilent 1100 Series isocratic pump, a degasser, an autosampler thermostatic box for columns, and a set of TSK Gel columns (2 × PLGel 5 μm MIXED-C) at 30 °C. A Wyatt Optilab rEX interferometric refractometer and a MALLS DAWN EOS Laser Photometer (Wyatt Technology Corp., USA) were applied as detectors. Methylene chloride was used as the eluent, at a flow rate of 0.8 mL min−1. Mn and Mw/Mn were calculated from the experimental traces using a Wyatt ASTRA v 4.90.07 program. Pridinol (PriOH). 1H NMR (500 MHz, C6D6): δ 8.07 (s, OH, 1H), 7.70 (m, ArH, 4H), 7.21 (m, ArH, 4H), 7.06 (m, ArH, 2H), 2.22 (s, CH2, 4H), 2.03 (s, CH2, 4H), 1.32 (m, CH2, 4H), 1.12 (s, CH2, 2H). 13 C NMR (125 MHz, C6D6): δ 149.3 (Ar, 2C), 128.0 (ArH, 4C), 126.4 (ArH, 2C), 126.3 (ArH, 4C), 78.9 (C−OH, 1C), 55.9 (CH2, 1C), 54.4 (CH2, 2C), 36.0 (CH2, 1C), 26.2 (CH2, 2C), 24.3 (CH2, 1C). 1H NMR (500 MHz, DMSO-D6): δ 7.47 (m, ArH, 4H), 7.27 (m, ArH, 4H), 7.25 (s, OH, 1H), 7.15 (m, ArH, 2H), 2.39 (m, CH2, 2H), 2.28 (m, CH2, 6H), 1.48 (m, CH2, 4H), 1.37 (m, CH2, 2H). 13C NMR (125 MHz, DMSO-D6): δ 148.5 (Ar, 2C), 127.8 (ArH, 4C), 126.0 (ArH, 2C), 125.5 (ArH, 4C), 77.4 (C−OH, 1C), 54.8 (CH2, 1C), 53.9 (CH2, 2C), 35.8 (CH2, 1C), 25.6 (CH2, 2C), 23.8 (CH2, 1C). Venlafaxine (VenlOH). 1H NMR (500 MHz, C6D6): δ 6.95 (m, ArH, 2H), 6.78 (m, ArH, 2H), 6.32 (s, OH, 1H), 3.36 (s, OCH3, 3H), {3.11 (m, NCH2, 1H), 2.10 (dd, J = 12.4, 3.3 Hz, NCH2, 1H)}, 2.98 (dd, J = 12.4, 3.3 Hz, CH, 1H), {2.16 (m, CH2Cy, 2H), 1.61(m, CH2Cy, 1H),1.49 (m, CH2Cy, 1H)}, 1.97 (s, NCH3, 6H), {1.76 (m, CH2Cy, 2H), 1.39 (td, J = 13.0, 4.0 Hz, CH2Cy, 1H), 1.17 (td, J = 13.0, 4.0 Hz, CH2Cy, 1H)}, {1.67(m, CH2Cy, 1H), 0.93 (qt, J = 13.0, 3.7 Hz, CH2Cy, 1H)}. 13C NMR (125 MHz, C6D6): δ 158.9 (Ar, 1C), 133.4 (Ar, 1C), 130.5 (ArH, 2C), 113.7 (ArH, 2C), 74.0 (C−OH, 1C), 61.7 (NCH2, 1C), 54.7 (OCH3, 1C), 52.4 (CH, 1C), 45.3 (NCH3, 2C), {38.9, 32.0, 26.7, 22.2, 21.9 (CH2Cy, 5C)}. 1H NMR (500 MHz, DMSO-D6): δ 7.10 (d, J = 8.5 Hz, ArH, 2H), 6.80 (d, J = 8.5 Hz, ArH, 2H), 5.25 (s, OH, 1H), 3.71 (s, OCH3, 3H), {2.96 (dd, J = 12.4, 7.0 Hz,, NCH2, 1H), 2.40 (dd, J = 12.4, 7.0 Hz, 1H)}, 2.76 (t, J = 7.0 Hz, CH, 1H), 2.12 (s, NCH3, 6H), {1.61−1.48, 1.46−1.33, 1.30, 1.12, 1.02, 0.89 (m, CH2Cy, 10H)}. 13C NMR (125 MHz, DMSO-D6): δ 157.5 (Ar, 1C), 133.6 (Ar, 1C), 130.1 (ArH, 2C), 112.9 (ArH, 2C), 72.4 (C−OH, 1C), 60.3 (NCH2, 1C), 54.8 (OCH3, 1C), 51.7 (CH, 1C), 45.3 (NCH3, 2C), {37.1, 32.8, 25.6, 21.2 (CH2Cy, 5C)}. Synthesis of [Mg(μ,η2-PriO)nBu]2 (1). MgBu2 (6 mL, 6 mmol) was added dropwise to a solution of PriOH (1.77 g, 5.99 mmol) in toluene (30 mL). The mixture was stirred at room temperature for 1 h. Then, the volume was reduced to 15 mL under vacuum. Single crystals for XRD analysis were obtained from the concentrated mother liquor at 5 °C. The crystals were filtered off, washed with hexane (3 × 10 mL), and dried under vacuum. Yield 2.30 g (51%). Anal. Calcd for G

DOI: 10.1021/acs.organomet.5b00146 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Synthesis of [Mg(μ,η2-OPri)(η1-OPri)]2 (4). PriOH (1 g, 3.38 mmol) was added to a solution of 1 (1.27 g, 1.69 mmol) in toluene (80 mL). The mixture was stirred at room temperature for 3 h. Then, the volume was reduced to 60 mL. Single crystals for XRD analysis were obtained from the concentrated mother liquor at 2 °C. The crystals were filtered off, washed with hexane (3 × 20 mL), and dried under vacuum. Yield 1.21 g (58%). Anal. Calcd for C80H96N4O4Mg2: C, 78.36; H, 7.89; N, 4.57. Found: C, 78.47; H, 7.91; N, 4.57. 1H NMR (500 MHz, DMSO-D6): δ {7.78, 7.61, 7.47, 7.27, 7.12, 6.98, 6.86 (m, ArH, 40H)}, {2.39, 2.32−2.20, 1.52−1.40, 1.39−1.28 (m, CH2, 28H)}. 13C NMR (125 MHz, DMSO-D6): δ {157.1, 155.9, 148.4 (Ar, 8C)}, {127.8, 127.0, 126.8, 126.2, 126.0, 125.5, 124.1 (ArH, 40C)},{77.3, 77.1, 76.2 (C−O, 4C)}, {55.5, 54.8, 54.5, 53.9 (CH2, 12C)}, {41.2, 35.8 (CH2, 4C)}, {25.7, 24.3, 23.8 (CH2, 12C)}. Synthesis of [Mg(μ,η2-OVenl)(η1-OVenl)]2 (5). VenlOH (1 g, 3.60 mmol) was added dropwise to a solution of 2 (2.08 g, 1.8 mmol) in toluene (80 mL). The mixture was stirred at room temperature for 5 h. Then, the volume was reduced to 15 mL, and the white precipitate was filtered off, washed with hexane (5 × 20 mL), and dried under vacuum. Yield 1.77 g (85%). Anal. Calcd for C68H104N4O8Mg2: C, 70.76; H, 9.08; N, 4.85. Found: C, 70.88; H, 9.08; N, 4.83. 1H NMR (500 MHz, DMSO-D6): δ 7.10 (d, J = 6.2 Hz, ArH, 8H), 6.80 (d, J = 6.2 Hz, ArH, 8H), 3.72 (s, OCH3, 12H), {2.94, 2.41 (m, NCH2, 8H)}, 2.76 (m, CH, 4H), 2.12 (s, NCH3, 24H), {1.59−1.25, 1.17−0.84 (m, CH2Cy, 40H)}. 13C NMR (125 MHz, DMSO-D6): δ 157.5 (Ar, 4C), 133.6 (Ar, 4C), 130.2 (ArH, 8C), 112.9 (ArH, 8C), 72.2 (C−O, 4C), 60.2 (NCH2, 4C), 54.8 (OCH3, 4C), 51.6 (CH, 4C), 45.3 (NCH3, 8C), {37.0, 32.8, 25.6, 21.2 (CH2Cy, 20C)}. Polymerization Procedure. A typical polymerization procedure is exemplified by the synthesis of PLLA. To the solution of (a) 1 or 2 (0.133 mmol), (b) 1 or 2 (0.133 mmol), and ROH (PriOH or VenlOH, 0.266 mmol) in toluene (15 mL), 40, 100, or 200 [only for (a)] equivs of monomer in solid form were added (Table 1, entries 1− 11). For the L-LA polymerization studies using MgBu2 in combination with ROH (where ROH = PriOH and VenlOH) to the solution of LLA in 20 mL of toluene, the appropriate amounts of MgBu2 and ROH stirred for 30 min in 5 mL of toluene were added (Table 1, entries 12− 21; Table 2, entries 1−7). The reaction mixture was stirred for the

of one drop of acetic acid and 0.5 mL of hexane. The volatiles were removed in vacuo, and the solid residues were dissolved in C6D6 and analyzed by 1H NMR spectroscopy at room temperature. Crystallography. XRD data were collected at 100 K using a KUMA KM4 CCD κ-geometry diffractometer (ω scan technique) or at 140 K with an Xcalibur PX κ-geometry diffractometer (ω and φ scan technique).30 The experimental details and the crystal data are given in (Table S1). The structures were solved by direct methods and refined by full-matrix least-squares on F2 using the SHELXTL package.31 Nonhydrogen atoms were refined with anisotropic thermal parameters. All hydrogen atoms were positioned geometrically and added to the structure factor calculations but were not refined. The molecular graphics were created using Diamond, version 3.1e.32 Crystallographic data for the structural analyses reported in this article have also been deposited with the Cambridge Crystallographic Data Centre (CCDC), numbers CCDC 804613, 804614, 1419083, and 872926. Copies of the information may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax, + 44-1223-336033; e-mail, [email protected]; Web page, http://www.ccdc.cam.ac.uk).

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b00146. Crystallographic data for compounds 1−4 (CIF) NMR spectra of compounds 1−5, and 1H NMR and ESI-MS spectra of obtained polymers (PDF)

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t (min)

% PLLA-OPri

% PLLA-OVenlb

1.0/1.0 1.0/1.0 1.2/0.8 1.4/0.6 1.6/0.4 1.8/0.2 1.8/0.2

0.5 10 0.5 0.5 0.5 0.5 10

9(12) 22 15 18 34 44 55

91(88) 78 85 82 66 56 45

AUTHOR INFORMATION

Corresponding Author

*Tel: +48 71 375 73 06. Fax: +48 71 328 23 48. E-mail: piotr. [email protected]. Notes

The authors declare no competing financial interest.

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Table 2. Polymerization of L-Lactide by Magnesium Alkoxides with Different Ratios of OPri/OVenl Ligandsa OPri/OVenl

ASSOCIATED CONTENT

S Supporting Information *

ACKNOWLEDGMENTS We gratefully acknowledge support from the Wrocław Research Centre EIT+, under the project “Biotechnologies and advanced medical technologies − BioMed” (POIG.01.01.02-02-003/08), financed by the European Regional Development Fund (Operational Programme Innovative Economy, 1.1.2). The authors would like to express their gratitude to the National Science Centre (Grant 2014/B/ST5/01512) for financial support.

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a

Polymerization conditions: [Mg]0 = 13.9 mM, 25 mL of toluene as solvent, [L-LA]0 = 0.28 M, temperature 25 °C, under Ar atmosphere, [L-LA]/[Mg] = 20/1. bObtained from 1H NMR analysis by integration of signals from the −OVenl end group at ∼6.8 ppm relative to the signal at the −OPri end group at ∼7.4 ppm.

REFERENCES

(1) (a) Duncan, R. Nat. Rev. Drug Discovery 2003, 2, 347−360. (b) Duncan, R.; Vicent, M. J.; Greco, F.; Nicholson, R. I. Endocr.-Relat. Cancer 2005, 12, S189−S199. (2) (a) Wang, B.; Yuan, H.; Zhu, C.; Yang, Q.; Lv, F.; Liu, L.; Wang, S. Sci. Rep. 2012, 2, 766. (b) Pasut, G.; Veronese, F. M. Prog. Polym. Sci. 2007, 32, 933−961. (c) Larson, N.; Ghandehari, H. Chem. Mater. 2012, 24, 840−853. (d) Elvira, C.; Gallardo, A.; San Roman, J.; Cifuentes, A. Molecules 2005, 10, 114−125. (e) Yu, Y.; Chen, C.-K.; Law, W.-C.; Weinheimer, E.; Sengupta, S.; Prasad, P. N.; Cheng, C. Biomacromolecules 2014, 15, 524−532. (3) (a) Veronese, F. M.; Pasut, G. Drug Discovery Today 2005, 10, 1451−1458. (b) Knop, K.; Hoogenboom, R.; Fischer, D.; Schubert, U. S. Angew. Chem., Int. Ed. 2010, 49, 6288−6308. (c) Alconcel, S. N. S.; Baas, A. S.; Maynard, H. D. Polym. Chem. 2011, 2, 1442−1448. (d) Li, W.; Zhan, P.; De Clercq, E.; Lou, H.; Liu, X. Prog. Polym. Sci. 2013, 38, 421−444.

prescribed time. Conversion yield of PLAs was analyzed by 1H NMR spectroscopy. The mixture was than quenched by the addition of 5% HCl in CH2Cl2 (Table 1, entries 1−11) or annihilated by air exposure (Table 1, entries 12−21; Table 2, entries 1−7) and then both precipitated by hexane to give solid PLLA, which was filtered off and dried under vacuum. Kinetic Studies of L-LA Polymerization. A typical polymerization procedure was exemplified using complex 4 as an initiator. To a solution of L-LA (1g, 6.94 mmol) in 15 mL of toluene, various concentrations of 4 ([4]0 = 1.73, 2.31, 3.83, and 6.90 mM) in 5 mL of toluene were added. Aliquots (0.2 mL) were periodically withdrawn from the reaction mixture and quenched by air exposure and addition H

DOI: 10.1021/acs.organomet.5b00146 Organometallics XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.organomet.5b00146 Organometallics XXXX, XXX, XXX−XXX