Biomacromolecules 2001, 2, 223-232
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Biocompatible Polyester Macroligands: New Subunits for the Assembly of Star-Shaped Polymers with Luminescent and Cleavable Metal Cores Perry S. Corbin, Michael P. Webb, John E. McAlvin, and Cassandra L. Fraser* Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, Virginia 22904-4319 Received October 3, 2000; Revised Manuscript Received January 4, 2001
The synthesis of a series of star-shaped, biocompatible polyestersspolylactides (PLAs), polycaprolactones (PCLs), and various copolymer analoguesswith either labile iron(II) tris-bipyridyl or luminescent ruthenium(II) tris-bipyridyl cores is described.1 These polymers were readily assembled by a convergent, metal-templateassisted approach that entailed the synthesis of bipyridine (bpy) ligands incorporating PLA- and PCLcontaining arms and subsequent chelation of the “macroligands” to iron(II) or ruthenium(II). Specifically, the polyester macroligands bpyPLA2 and bpyPCL2 were prepared by a stannous octoate catalyzed ringopening polymerization of DL- or L-lactide and -caprolactone, using bis(hydroxymethyl)-2,2′-bipyridine as the initiator. Copolymers bpy(PCL-PLA)2 and bpy(PLA-PCL)2 were generated in an analogous manner using bpyPLA2 and bpyPCL2 as macroinitiators. Polymers with narrow molecular weight distributions and with molecular weights close to values expected based upon monomer/initiator loading were produced. The macroligands were subsequently chelated to iron(II) to afford six-armed, iron-core star polymers, which were characterized by UV-vis and 1H NMR spectroscopy. Estimated chelation efficiencies for formation of the star polymers (Mn calcd: 20-240 kDa) were high, as determined by UV-vis spectral analysis. Within the molecular weight range investigated, differential scanning calorimetry and thermogravimetric analysis revealed that the small amounts of metal in the polyester stars and differences in polymer architecture had little effect on the thermal properties of the PLA/PCL materials. However, thin films of the red-violet colored iron-core stars exhibited reversible, thermochromic bleaching. Solutions and films of the polymers also responded (with color loss) to a variety of chemical stimuli (e.g., acid, base, peroxides, ammonia), thus revealing potential for use in diverse sensing applications. Likewise, the polyester macroligands were chelated to ruthenium(II) to produce both linear and star-shaped polymers, which were characterized by UV-vis and 1H NMR spectral analysis. Molecular weights of the polymers were determined by gel permeation chromatography (Mn(MALLS): 6-30 kDa) with in-line, UV-vis diode-array detection, confirming the presence of the [Ru(bpy)3]2+ core in the eluting polymer fractions. As was the case with the corresponding iron-core polyesters, estimated chelation efficiencies were high. Introduction The design, synthesis, and study of metal-containing polymers have received considerable attention recently.2 This interest is due, in part, to the potential of metals to impart useful properties to polymeric materials, as well as to the prospect of using the well-defined coordination geometries of metal complexes to promote architectural diversity. Accordingly, we have approached the design of metalcontaining polymers by two different pathways. In the first, a metalloinitiation approach, a suitably functionalized metal complex serves as an initiator for living polymerizations and, thus, becomes the locus or end group of the resulting macromolecule.3-8 The second method, referred to as a “macroligand” chelation approach, entails the synthesis of polymer-containing ligands, which are subsequently coordinated to metals to generate linear and star-shaped polymers.3,9,10 Because the metal and ancillary ligands of such polymers can be modified along with the pendant side chains and end groups of the polymers (Figure 1), a virtual library
Figure 1. A schematic representation of a well-defined metalcentered polymer with its many variable components highlighted (adapted from ref 3).
of metal-containing macromolecules is envisioned. Moreover, the potential applications of metal-containing polymers are
10.1021/bm005621z CCC: $20.00 © 2001 American Chemical Society Published on Web 02/23/2001
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Figure 2. A schematic representation of a convergent, macroligand chelation approach to polymeric metal complexes.
far-reaching, and we anticipate that aptly tailored polymers will find use in a variety of biomedical applications, including sensing, imaging, surface modification, and targeted drug delivery.11 As a preliminary step toward such goals, we have incorporated biocompatible polymers into our synthetic arsenalsspecifically, polylactides (PLAs) and polycaprolactones (PCLs). In general, interest in PLAs, polyglycolides (PGAs), PCLs, and copolymers formed therefrom has steadily increased due to their successful employment as surgical sutures,12 orthopedic fixation devices,12 parenteral and microsphere-based drug-delivery vectors,13 and scaffolds for tissue engineering.14 Although efforts to improve the synthesis of these polyesters through catalyst development and initiator modification15,16 (single or multisite17,18) are ongoing, it, nonetheless, remains a challenge to modify and enhance the properties of the resulting materials. Thus, the prospect of incorporating metals into biocompatible polyesters is appealing and may afford biomaterials with “built-in” colorimetric, luminescent, paramagnetic, and radioactive response/tracer elements, as well as beneficial antibacterial, catalytic, and redox activity.2 Moreover, the architecture of a polymeric metal complex may be readily altered to control release of guests entrapped within these materials. And ligand dissociation, modulated by differences in the lability of metal complexes, provides a novel mechanism for triggered release. The synthesis of biodegradable PLA and PCL macroligands with low polydispersity indices (PDIs) is described herein. In short, homopolymeric macroligands were prepared by a tin(II)-catalyzed ring opening polymerization of DL- or L-lactide and -caprolactone using 4,4′-bis(hydroxymethyl)2,2′-bipyridine (1) as the initiator (Scheme 1). Likewise, copolymers were prepared using bpyPCL2 and bpyPLA2 as macroinitiators.19 The resulting macroligands were readily chelated to iron(II) to generate labile, violet-colored, sixarmed star polymers and to ruthenium(II), an “inert” metal, to generate red/orange-colored, luminescent, metal-containing stars (Figure 2). The effects of the metal core and polymer architecture upon the thermal properties of the polymers are discussed along with preliminary degradation studies. We anticipate that the modular, convergent approach to biocompatible, metal-containing macromolecules reported will facilitate their use in a variety of applications, including their use as analytical sensors. Experimental Section Materials. 3,6-Dimethyl-1,4-dioxane-2,5-dione (DL-lactide, Aldrich) and (3S)-cis-3,6-dimethyl-1,4-dioxane-2,5dione (L-lactide, Aldrich) were recrystallized twice from ethyl
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acetate and stored under nitrogen. -Caprolactone (Aldrich) was dried over CaH2 and distilled prior to use. Chloroform-d (CDCl3) was passed through a short plug of dry, activated (Brockman I) basic alumina prior to use. Glycolide (Polymer Science Corp.), tin(II) 2-ethylhexanoate (Sn(Oct)2, Aldrich), and all other reagents were used as received without further purification. Methods. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a General-Electric QE-300 instrument in CDCl3. 1H NMR spectra were referenced to the signal for residual protiochloroform at 7.260 ppm, and 13C NMR spectra were referenced to the chloroform signal at 77.0 ppm. 1H NMR coupling constants are given in hertz. UV-vis spectra were recorded on a Hewlett-Packard 8452A diode-array spectrophotometer in CHCl3 unless indicated otherwise, and fluorescence emission spectra were recorded on a Perkin-Elmer LS-50B luminescence spectrophotometer in CHCl3. IR spectra were obtained as thin films (prepared by evaporation of CH2Cl2 solutions) on a Nicolet Impact 400D FTIR spectrophotometer. Molecular weights were determined by gel permeation chromatography (GPC) (CHCl3, 25 °C, 1.0 mL/min) using multiangle laser light scattering (MALLS) (λmax ) 633 nm, 25 °C), refractive index (RI) (λmax ) 633 nm, 40 °C), and UV-vis, diode-array detection, unless indicated otherwise. Polymer Labs 5µ mixed-C columns along with Wyatt Technology Corp. (Optilab DSP interferometric refractometer, Dawn DSP laser photometer) and Hewlett-Packard instrumentation (series 1100 HPLC) and software (ASTRA) were used in GPC analysis. The incremental refractive indices (dn/dc values) of the homopolymeric macroligands bpyDLPLA2 (dn/dc ) 0.030 mL/g, Mw(MALLS) ) 9.8 kDa) and bpyPCL2 (dn/dc ) 0.056 mL/ g, Mw(MALLS) ) 10.0 kDa) were determined in microbatch mode using the aforementioned detectors. These values were used in determining the molecular weights of all PLA and PCL homopolymers, while dn/dc values for copolymers were estimated by a single injection method that assumed 100% mass recovery from the columns. Thermogravimetric analysis (TGA) was conducted using a TA Instruments TGA 2020 thermogravimetric analyzer over a temperature range from 40 to 900 °C with a heating/cooling rate of 10 °C/min. Differential scanning calorimetry (DSC) measurements were performed using a TA Instruments DSC 2920 modulated DSC. Analyses were carried out in modulated mode under a nitrogen atmosphere (amplitude ) (1 °C; period ) 60 s; heating rate ) 5 °C/min; range -10 to 210 °C or -10 to 100 °C). Reported values of thermal events are from the second heating cycle and the reversing heat flow curve unless indicated otherwise (Tg ) the midpoint of the change in the heat capacity; Tm reported as the peak maximum). Synthesis of the Polyester Macroligands. bpyDLPLA2. A representative procedure is provided. A dry, 25 mL Kontes flask was charged with 4,4′-bis(hydroxymethyl)-2,2′-bipyridine (25 mg, 0.12 mmol) and DL-lactide (834 mg, 5.79 mmol). The flask was evacuated, backfilled with nitrogen, sealed, and placed in an oil bath set at 130 °C to produce a homogeneous melt. A 24.0 mM solution of Sn(Oct)2 in hexanes (65 µL, 1.5 µmol) was added to the melt under a
Biocompatible Polyester Macroligands
nitrogen atmosphere, and the flask was resealed and heated at 130 °C for 2.5 h. The resulting clear, viscous mixture was cooled to room temperature and dissolved in THF (∼10 mL). The product was precipitated by dropwise addition of the THF solution to cold methanol (∼30 mL). The mixture was centrifuged, and the solid was recovered by decanting the supernatant liquor. The solid residue was precipitated a second time from THF/MeOH, washed with cold MeOH (∼10 mL), and dried in vacuo to provide the DLPLA (DLPLA ) DL-poly(lactic acid)) macroligand, bpyDLPLA2 (2a), as a colorless foam: 756 mg (88%). 1H NMR δ 8.67 (d, J ) 5.0, H-6, H-6′), 8.36 (s, H-3, H-3′), 7.28 (d, J ) 5.0, H-5, H-5′), 5.10-5.32 (m, CH, bpyCH2), 4.35 (m, RCH(CH3)OH), 1.52-1.62 (m, CH3) 1.49 (dd, RCH(CH3)OH). Mn(NMR) ) 7.7 kDa, Mw(MALLS) ) 9.8 kDa. IR 3504 cm-1 (OH), 1755 cm-1 (O-CdO). bpyLPLA2. LPLA (LPLA ) L-poly(lactic acid)) macroligands, bpyLPLA2 (2b), were synthesized from diol 1 and L-lactide using the procedure described for bpyDLPLA2, with the exception that high molecular weight polymers (>10 kDa) were precipitated from CH2Cl2/MeOH. Characterization data for a representative bpyLPLA2 sample is as follows: 1H NMR δ 8.76 (d, J ) 5.1, H-6, H-6′), 8.42 (s, H-3, H-3′), 7.38 (d, J ) 5.1, H-5, H-5′), 5.31 (s, bpyCH2), 5.16 (q, J ) 7.1, CH), 4.35 (q, J ) 7.1, RCH(CH3)OH), 1.57 (d, J ) 7.1, CH3), 1.49 (d, J ) 6.9, RCH(CH3)OH). Mn(NMR) ) 7.6 kDa, Mw(MALLS) ) 10.9 kDa. IR 3502 cm-1 (OH), 1750 cm-1 (O-CdO). bpyPCL2. PCL macroligands, bpyPCL2 (3), were synthesized from diol 1 and -caprolactone using the procedure described for bpyDLPLA2, with the exception that reactions were carried out at 110 °C, and polymers were precipitated from CHCl3/hexanes. Characterization data for a representative bpyPCL2 sample is as follows: 1H NMR δ 8.67 (d, J ) 5.0, H-6, H-6′), 8.38 (s, H-3, H-3′), 7.29 (d, J ) 5.0, H-5, H-5′), 5.21 (s, bpyCH2), 4.06 (t, J ) 6.6, RCO2CH2), 3.64 (m, CH2OH), 2.30 (t, J ) 7.3, CH2CO2R), 1.64 (m, CH2), 1.38 (m, CH2). Mn(NMR) ) 6.3 kDa, Mw(MALLS) ) 9.0 kDa. IR 3537 cm-1 (OH), 1728 cm-1 (O-CdO). bpy(DLPLA-PCL)2. The copolymeric macroligands 4, bpy(DLPLA-PCL)2, were synthesized from the macroinitiator bpyDLPLA2 and -caprolactone using the procedure described for bpyDLPLA2, with the exception that reactions were carried out at 110 °C. Characterization data for a representative bpy(DLPLA-PCL)2 sample prepared from bpyDLPLA2 (Mw(MALLS) ) 10.0 kDa) is as follows: 1H NMR δ 8.61 (d, J ) 4.6, H-6, H-6′), 8.31 (s, H-3, H-3′), 7.22 (d, J ) 4.6, H-5, H-5′), 5.00-5.23 (m, CH, bpyCH2), 4.07 (m, RCH(CH3)CO2CH2) 4.00 (t, J ) 6.6, RCO2CH2) 3.57 (t, J ) 6.5, CH2OH), 2.34 (m, CH2CO2CH(CH3)R), 2.25 (t, J ) 7.3, CH2CO2R), 1.45-1.65 (m, CH2, CH3), 1.38 (m, CH2). Mw(MALLS) ) 20.7 kDa. IR 3502 cm-1 (OH), 1732 cm-1 (O-CdO), 1756 cm-1 (O-CdO). bpy(PCL-DLPLA)2. The copolymeric macroligands 5, bpy(PCL-DLPLA)2, were synthesized from the macroinitiator bpyPCL2 (Mw(MALLS) ) 10.0 kDa) and DL-lactide using the procedure described for bpyDLPLA2, with the exception that polymers were precipitated from CH2Cl2/
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MeOH. Characterization data for a representative bpy(PCLDLPLA)2 sample prepared from bpyPCL2 (Mw(MALLS) ) 10.0 kDa) is as follows: 1H NMR δ 8.65 (d, J ) 5.0, H-6, H-6′), 8.36 (s, H-3, H-3′), 7.27 (d, J ) 5.0, H-5, H-5′), 5.085.26 (m, CH, bpyCH2), 4.32 (m, RCH(CH3)OH), 4.04 (t, J ) 6.7, RCO2CH2), 2.44 (t, J ) 7.3, CH2), 2.29 (t, J ) 7.5, CH2CO2R), 1.46-1.69 (m, CH2, CH3), 1.37 (m, CH2). Mw(MALLS) ) 16.9 kDa. IR 3503 cm-1 (OH), 1728 cm-1 (OCdO), 1755 cm-1 (O-CdO). Synthesis of Polymeric Iron(II) Complexes. [Fe(bpyDLPLA2)3]2+. A representative procedure is provided. A solution of bpyDLPLA2, 2a (Mw(MALLS) ) 24.3 kDa; 350 mg, 0.0158 mmol), in CH2Cl2 (7 mL) was added dropwise to a solution of Fe(NH4)2(SO4)2‚6H2O (2.2 mg, 0.0055 mmol) and NH4PF6 (93 mg, 0.570 mmol) in methanol (7 mL). The resulting mixture was stirred at room temperature under N2 for 5 min, and solvent was removed in vacuo. The crude product was dissolved in a minimal amount of CH2Cl2 (∼5 mL) and added dropwise to cold methanol (∼30 mL). The mixture was centrifuged, and the supernatant liquor was decanted. The resulting violet-red solid was washed with cold methanol (∼10 mL) and dried in vacuo to give the six-armed, iron-centered star polymer, [Fe(bpyDLPLA2)3]2+ (6a), as a dark purple foam: 275 mg (78%). 1H NMR δ 8.31-8.50 (bs, H-3, H-3′), 7.29-7.47 (bm, H-5, H-5′, H-6, H-6′), 5.105.32 (m, CH, bpyCH2), 4.35 (m, RCH(CH3)OH), 1.52-1.62 (m, CH3), 1.49 (dd, RCH(CH3)OH). UV-vis MLCT λmax() ) 531 nm (9470 M-1 cm-1). IR 3502 cm-1 (OH), 1761 cm-1 (O-CdO). [Fe(bpyLPLA2)3]2+. [Fe(bpyLPLA2)3]2+ samples, 6b, were synthesized from bpyLPLA2 and Fe(NH4)2(SO4)2‚6H2O using the procedure described for [Fe(bpyDLPLA2)3]2+. Characterization data for a representative [Fe(bpyLPLA2)3]2+ sample prepared from bpyLPLA2 (Mw(MALLS) ) 10.9 kDa) is as follows: 1H NMR δ 8.37 (s, H-3, H-3′), 7.3-7.4 (m, H-5, H-5′, H-6, H-6′), 5.40 (s, bpyCH2), 5.16 (q, J ) 7.1, CH), 4.35 (m, RCH(CH3)OH), 1.58 (d, J ) 6.9, CH3), 1.49 (d, J ) 6.9, RCH(CH3)OH). UV-vis MLCT λmax() ) 531 nm (9700 M-1 cm-1). IR 3502 cm-1 (OH), 1757 cm-1 (OCdO). [Fe(bpyPCL2)3]2+. [Fe(bpyPCL2)3]2+ samples, 7, were synthesized from bpyPCL2 and Fe(NH4)2(SO4)2‚6H2O using the procedure described for [Fe(bpyDLPLA2)3]2+. Characterization data for a representative [Fe(bpyPCL2)3]2+ sample prepared from bpyPCL2 (Mw(MALLS) ) 9.0 kDa) is as follows: 1H NMR δ 8.27 (s, H-3, H-3′), 7.3-7.5 (bm), 5.32 (s, bpyCH2), 4.06 (t, J ) 6.6, RCO2CH2), 3.65 (m, CH2OH), 2.31 (t, J ) 7.4, CH2CO2R), 1.65 (m, CH2) 1.39 (m, CH2). UV-vis MLCT λmax() ) 531 nm (9600 M-1 cm-1). IR 3544 cm-1 (OH), 1733 cm-1 (O-CdO). [Fe{bpy(DLPLA[Fe{bpy(DLPLA-PCL)2}3]2+. PCL)2}3]2+, 8, was synthesized from bpy(DLPLA-PCL)2 and Fe(NH4)2(SO4)2‚6H2O using the procedure described for [Fe(bpyDLPLA2)3]2+. Characterization data for a [Fe{bpy(DLPLA-PCL)2}3]2+ sample prepared from bpy(DLPLAPCL)2 (Mw(MALLS) ) 23.3 kDa) is as follows:20 1H NMR δ 8.69 (bm), 8.43 (bm), 7.32-7.48 (bm), 5.42 (s, bpyCH2), 5.06-5.37 (m, CH), 4.14 (m, CH(CH3)CO2CH2), 4.06 (t, J ) 6.8, RCO2CH2), 3.66 (m, CH2OH), 2.41 (m, CH2), 2.32
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(t, J ) 7.1, CH2CO2R), 1.49-1.76 (m, CH2, CH3), 1.40 (m, CH2). UV-vis MLCT λmax() ) 531 nm (10700 M-1 cm-1). IR 3502 cm-1 (OH), 1756 cm-1 (O-CdO). [Fe{bpy(PCL-DLPLA)2}3]2+. [Fe{bpy(PCL-DLPLA)2}3]2+ samples, 9, were synthesized from bpy(PCLDLPLA)2 using the procedure described for [Fe(bpyDLPLA2)3]2+. Characterization data for a representative [Fe{bpy(PCL-DLPLA)2}3]2+ sample prepared from bpy(PCLDLPLA)2 (Mw(MALLS) ) 15.4 kDa) is as follows:20 1H NMR δ 8.68 (bs), 8.21-8.46 (bm), 7.33-7.56 (bm), 5.055.30 (m, bpyCH2, CH), 4.34 (m, RCH(CH3)OH, 4.05 (t, J ) 6.5, RCO2CH2), 2.45 (m, CH2), 2.30 (t, J ) 6.9, CH2), 1.49-1.74 (m, CH2, CH3), 1.38 (m, CH2). UV-vis MLCT λmax() ) 529 nm (9650 M-1 cm-1). IR 3502 cm-1 (OH), 1756 cm-1 (O-CdO), 1734 cm-1 (O-CdO). Thin Film Preparation. Thin films of the iron-core star polymers were prepared by evaporating methylene chloride from polymer solutions (∼25 mg/mL) in vials (1 dram) and by evaporating methylene chloride from polymer solutions (∼80 mg/mL) deposited in a Teflon well (1.7 cm diameter Teflon disk with a 1.5 cm high detachable wall). In the latter case, free-standing films were readily obtained by drying the films in vacuo (15 h at ∼0.03 Torr) and carefully peeling the film off the Teflon support. Synthesis of Polymeric Ruthenium(II) Complexes with One Macroligand. [Ru(bpy)2(bpyDLPLA2)]2+. A representative procedure is provided. To a solution of Ru(bpy)2Cl2‚2H2O (17.6 mg, 33.8 µmol) in methanol (5 mL) was added AgPF6 (37.2 mg, 147 µmol). The resulting redcolored solution was heated at reflux under nitrogen for 5 h, filtered using a cannula to remove residual Ag salts, and concentrated in vacuo to give a red-colored solid. The solid was subsequently combined with bpyDLPLA2 (Mw(MALLS) ) 24.3 kDa; 149.5 mg, 6.76 µmol) and dissolved in DME (10 mL). The reaction mixture was heated at reflux under nitrogen for 1 day, cooled, cannula filtered, and concentrated in vacuo. The residue obtained was dissolved in CH2Cl2 (250 mL), passed through a plug of neutral alumina, and washed with H2O (2 × 150 mL). The organic layer was then concentrated in vacuo to provide the desired metal-centered linear polymer, [Ru(bpy)2(bpyDLPLA2)]2+ (10a), as an orange-colored film: 124 mg (74%). 1H NMR δ 8.43 (m, H-3, H-3′, H-3′′, H-3′′′), 8.02 (t, J ) 7.7, H-4′′, H-4′′′), 7.727.89 (m), 7.38-7.59 (m), 5.10-5.30 (m, CH, bpyCH2), 4.35 (m, RCH(CH3)OH), 1.56 (m, CH3). Mw(MALLS) ) 27.9 kDa. UV-vis MLCT λmax() ) 459 nm. IR 3503 cm-1 (OH), 1770 cm-1 (O-CdO). [Ru(bpy)2(bpyLPLA2)]2+. [Ru(bpy)2(bpyLPLA2)]2+ (10b) was synthesized from bpyLPLA2 (Mw(MALLS) ) 11.9 kDa) and Ru(bpy)2Cl2‚2H2O using the procedure described for [Ru(bpy)2(bpyLPLA2)]2+. Characterization data are as follows: 1H NMR δ 8.56 (m, H-3, H-3′, H-3′′, H-3′′′), 8.06 (t, J ) 6.7, H-4′′, H-4′′′), 7.74-7.91 (m), 7.42-7.61 (m), 5.45 (s, bpyCH2), 5.18 (q, J ) 7.0, CH), 4.37 (q, J ) 6.8, RCH(CH3)OH), 1.59 (d, J ) 7.1, CH3), 1.50 (d, J ) 6.9, RCH(CH3)OH). Mw(MALLS) ) 10.4 kDa. UV-vis MLCT λmax ) 457 nm. IR 3503 cm-1 (OH), 1761 cm-1 (O-CdO).
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[Ru(bpy)2(bpyPCL2)]2+. [Ru(bpy)2(bpyPCL2)]2+ (11) was synthesized from bpyPCL2 (Mw(MALLS) ) 9.0 kDa) and Ru(bpy)2Cl2‚2H2O using the procedure described for [Ru(bpy)2(bpyDLPLA2)]2+. Characterization data are as follows: 1H NMR δ 8.41 (d, J ) 8.5, H-3′′, H-3′′′), 8.35 (s, H-3, H-3′), 8.03 (m, H-4′′, H-4′′′), 7.75-7.89 (m), 7.437.61 (m), 5.32 (s, bpyCH2), 4.06 (t, J ) 6.6, RCO2CH2), 3.65 (t, J ) 6.6, CH2OH), 2.31 (t, J ) 7.3, CH2CO2R), 1.64 (m, CH2) 1.38 (m, CH2). Mw(MALLS) ) 9.2 kDa. UV-vis MLCT λmax ) 457 nm. IR 3543 cm-1 (OH), 1726 cm-1 (O-CdO). Synthesis of Polymeric Ruthenium(II) Complexes with Three Macroligands. [Ru(bpyDLPLA2)3]2+. A representative procedure is provided. A 6.2 mM solution of Ru(DMSO)4Cl2 was prepared in chloroform. A portion of this Ru(II) stock solution (500 µL, 3.1 µmol) was transferred to a flask containing bpyDLPLA2 (Mn(NMR) ) 7.7 kDa; 72.7 mg, 9.4 µmol) in DME (10 mL), and the resulting pale yellow mixture was heated at reflux under nitrogen for 2 days (Note: Color changes from yellow to purple). AgPF6 (40 mg, 0.158 mmol) was added to the dark purple reaction mixture, and the mixture was heated for an additional 24 h. Residual silver salts were subsequently removed by gravity filtration, and the orange-red filtrate was concentrated to dryness. The crude product was dissolved in THF (∼40 mL) and passed through a short plug of neutral alumina. Solvent was removed in vacuo, and the resulting residue was dissolved in CH2Cl2 (10 mL) and washed with H2O (2 × 25 mL). The organic solution was then concentrated in vacuo to afford the six-armed, ruthenium-centered star polymer 12 as an orange-colored solid:20 37 mg (50%). 1H NMR δ 8.69 (m), 8.40 (bm), 7.70 (bs), 7.42 (bs) 5.40 (s, bpyCH2), 5.105.28 (m, CH), 4.35 (m, RCH(CH3)OH); 1.51-1.62 (m, CH3). Mw vs polystyrene (PS) ) 23.9 kDa. UV-vis MLCT λmax ) 460 nm. IR 3502 cm (OH), 1755 cm-1 (O-CdO). [Ru(bpyPCL2)3]2+. [Ru(bpyPCL2)3]2+ (13) was synthesized from bpyPCL2 (Mn(NMR) ) 6.3 kDa) and Ru(DMSO)4Cl2 using the procedure described for [Ru(bpyDLPLA2)3]2+, with the exception that the crude product was not passed through a plug of neutral alumina prior to the aqueous wash. Characterization data are as follows: 1H NMR δ 8.27 (bs), 7.78 (m), 7.50 (m), 5.30 (s, bpyCH2), 4.06 (t, J ) 6.6, RCO2CH2), 3.64 (t, J ) 6.5, CH2OH), 2.30 (t, J ) 7.4, CH2CO2R), 1.65 (m, CH2) 1.39 (m, CH2). Mw(MALLS) ) 17.8 kDa. UV-vis MLCT λmax ) 462 nm. IR 3544 cm-1 (OH), 1725 cm-1 (OsCdO). [Ru{bpy(PCL-DLPLA)2}3]2+. [Ru{bpy(PCL-DLPLA)2}3]2+ (14) was synthesized from bpy(PCL-DLPLA)2 (Mn(NMR) ) 7.6 kDa) and Ru(DMSO)4Cl2 using the procedure described for [Ru(bpyDLPLA2)3]2+, with the exception that the crude product was not passed through a plug of neutral alumina prior to the aqueous wash. Characterization data are as follows:20 1H NMR δ 8.81 (bs), 8.30 (bs), 7.70-7.84 (bm), 7.52 (bs), 5.33 (s, bpyCH2), 5.125.29 (m, CH), 4.38 (m, RCH(CH3)OH), 4.15 (m, CH2), 4.08 (t, J ) 7.3, RCO2CH2), 2.47 (m, CH2), 2.33 (t, J ) 7.8, CH2CO2R), 1.52-1.76 (m, CH2, CH3), 1.40 (m, CH2).
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Biocompatible Polyester Macroligands Scheme 1
Table 1. A Summary of GPC Molecular Weights for Representative PLA and PCL Macroligands Mn(calcd) Mn polymer bpyDLPLA2
bpyLPLA2 bpyPCL2
bpy(PCL-DLPLA)2 bpy(DLPLA-PCL)2
Mw(PS) ) 25.4 kDa. UV-vis (CHCl3) λmax ) 462 nm. IR 3502 cm-1 (OH), 1756 cm-1 (O-CdO), 1733 (O-CdO). Results and Discussion Macroligand Synthesis. The synthesis of the PLA and PCL macroligands is outlined in Scheme 1. As mentioned above, reactions were carried out in bulk monomer using diol 1 as the initiator and Sn(Oct)2 as the catalyst (Scheme 1).17 The initiator was prepared according to the procedure of Beer and co-workers21 or via a more convenient route recently reported.22 When polymerizations were conducted with an initiator to catalyst loading, 1:Sn(Oct)2, of 75:1, polymers (2a, bpyDLPLA2; 2b bpyLPLA2; 3, bpyPCL2) were produced with low PDIs and molecular weights close to the targeted valuessfeatures characteristic of a controlled polymerization. Lactide polymerizations carried out with a monomer loading (lactide:1) of 50:1 were nearly complete (∼80% conversion) after 1 h. However, because the reaction mixtures became extremely viscous over the course of the polymerization, a reaction time of approximately 3 h was required for more complete monomer conversion (>95%). Reaction times for higher loadings of lactide and for caprolactone polymerizations generally ranged from 5 to 16 h, and yields of 70-98% were typical. A summary of GPC molecular weights for PLA and PCL macroligands determined using MALLS/RI detection is provided in Table 1. When using in-line UV-vis, diodearray detection, an absorbance characteristic of the π-π* transition of the bipyridyl moiety was associated with the GPC eluent peak. This observation implied that diol 1, indeed, served as the initiator in polymerizations. In contrast to polyoxazoline, polystyrene, and poly(methyl methacrylate) macroligands,4,6,9 the presence of the bipyridyl moiety in the aforementioned polyesters could be verified by 1H NMR spectroscopy (see Figure 4, vide infra) over a broad molecular weight range. Well-resolved, discrete peaks were observed for the bipyridine center as well as for the terminal methine of the polymer chains in spectra of the DLPLA and LPLA macroligands. Likewise, 1H NMR spectral analysis of the PCL macroligands revealed characteristic signals for
[M]/[1]a
(kDa)
(kDa)
Mw (kDa)b
PDI
50 100 160 315 620 50 100 200 30 50 100 150 600 30d 100f 100h 100j
7.4 14.6 23.3 45.6 89.8 7.4 14.6 29.0 3.6 5.9 11.6 17.3 68.7 7.7 21.7 28.3 19.2
7.6 (7.7)c 18.9 (13.8)c 22.1 46.6 79.8 8.5 (7.6)c 12.1 25.3 4.6 (3.4)c 8.5 (6.3)c 13.1 16.0 48.4 11.0e (7.6)c 16.1 27.0 19.1
10.0 20.4 24.3 50.5 84.9 10.9 12.5 26.9 6.7 9.0 15.4 16.8 59.5 15.4 16.9g 28.0i 20.7k
1.33 1.08 1.09 1.08 1.06 1.27 1.04 1.06 1.46 1.05 1.18 1.05 1.23 1.38 1.05 1.04 1.08
a Monomer to initiator loading. b Determined using MALLS/RI detection. The dn/dc values of the PLA and PCL macroligands were 0.030 and 0.056 mL/g, respectively, in chloroform. c Molecular weights given in parentheses were determined by 1H NMR spectral analysis. d Prepared using bpyPCL2 (Mn(NMR) ) 3.4 kDa) as the initiator. e Molecular weight estimated using dn/dc ) 0.040 mL/g. f Prepared using bpyPCL2 (Mn(NMR) ) 7.3 kDa) as the initiator. g dn/dc ) 0.044 mL/g. h Prepared using bpyPCL2 (Mn(MALLS) ) 13.9 kDa) as the initiator. i dn/dc ) 0.040 mL/g. j Prepared using bpyDLPLA2 (Mn(NMR) ) 7.7 kDa) as the initiator. k dn/dc ) 0.040 mL/g.
the bipyridine unit and adjacent methylene groups. The ratios of integration for the bipyridine signals and the terminal methine or methylene units of the macroligands were approximately 1:1, implying that diol 1 was the sole initiator for polymerization. 1 H NMR spectroscopy was also useful for determining the molecular weights of polymers prepared with low monomer loadings. Specifically, molecular weights were measured by comparing the integration of the main-chain methine (e.g., signal “e” in Figure 4) and methyl group signals in spectra of PLA macroligands and the methylene integration in spectra of PCL macroligands to that of their respective end groups (e.g., signal “e*” in Figure 4). This method is complementary to GPC/MALLS characterization, which is often not well-suited for the analysis of low molecular weight polymers. As expected, weights obtained by 1H NMR spectroscopy were in accord with those calculated based upon monomer-initiator loadings (Table 1).
In addition to homopolymeric macroligands, copolymers were prepared analogously using PLA and PCL macroligands
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Corbin et al.
Figure 3. (A) (left) GPC overlay (CHCl3) of a bpy(PCL-DLPLA)2 block copolymer (Mn(MALLS) ) 16.1 kDa) and the macroinitiator (Mn(NMR) ) 7.3 kDa) used in its preparation. (right) The carbonyl region of the 13C NMR spectrum (CDCl3) of bpy(PCL-DLPLA)2. (B) (left) GPC overlay of a bpy(DLPLA-PCL)2 copolymer (Mn(MALLS) ) 19.1 kDa) and the macroinitiator (Mn(NMR) ) 7.7 kDa) used in its preparation. (right) The carbonyl region of the 13C NMR spectrum (CDCl3) of bpy(DLPLA-PCL)2. Note: Tentative 13C NMR peak assignments were made in accordance with previous spectral assignments by Bero et al.23
as initiators (eqs 1 and 2). Representative GPC traces of copolymers 4 and 5, bpy(DLPLA-PCL)2 and bpy(PCLDLPLA)2, are shown in Figure 3. Comparison with the GPC traces of the respective macroinitiators revealed the expected shift to smaller elution volumes. When using bpyPCL2 as the initiator, 1H and 13C NMR spectral analysis supported the formation of bpy(PCL-DLPLA)2 block copolymers. Signals corresponding to CLL (C ) caprolactone, L ) lactide), LLC, LCL, and CLC sequences were not evident in 13C NMR spectra of bpy(PCL-DLPLA)2, demonstrating that transesterification was minimal (Figure 3).23 In contrast, NMR spectral analysis suggested that there was partial transesterification in caprolactone polymerizations using bpyDLPLA2 as the macroinitiator. Similar observations have been made previously in PLA-PCL copolymer syntheses.24,25 It has been speculated that the discriminate transesterification may arise from simple electronic and steric differences between lactyl and caproyl end groups that deem the caproyl end groups more nucleophilic.24 Despite increased sample heterogeneity, this reaction sequence, nonetheless, leads to an additional class of PCL-PLA macroligand. Synthesis and Characterization of Iron-Centered Polymers. The PCL and PLA macroligands were subsequently chelated to iron(II) to generate labile, metal-centered star polymers (6a, [Fe(bpyDLPLA2)3]2+; 6b, [Fe(bpyLPLA2)3]2+; 7, [Fe(bpyPCL2)3]2+; 8, [Fe{bpy(DLPLA-PCL)2}3]2+; 9, [Fe{bpy(PCL-DLPLA)2}3]2+). These homo- and copolymeric stars were prepared by stirring a solution of the macroligand with Fe(NH4)2(SO4)2 and NH4PF6 (eq 3),4 analogous to the synthesis of nonpolymeric iron(II) tris-
bipyridine complexes. Incidentally, chelation efficiencies were low when solutions of the macroligands and Fe(NH4)2(SO4)2 were stirred in the absence of NH4PF6. This intriguing observation is currently under investigation.
The lability of the red-violet polymeric complexes prohibited accurate molecular weight determination by GPC because the complexes partially fragmented during analysis.26 Similar observations have been made previously in studies of [Fe(bpy)3]2+-centered polyoxazolines.4 Thus, chelation efficiency was monitored by UV-vis and 1H NMR spectroscopy. The presence of a metal-to-ligand charge transfer (MLCT) band (λmax ) 531 nm) in UV-vis spectra of the polyesters in CHCl3 was indicative of the [Fe(bpy)3]2+ core. The molar extinction coefficients () of the bands were estimated using calculated molecular weights of the ironcore stars (Mn(calcd) ranging from 24 to 240 kDa) to determine concentration. These coefficients were close to
Biomacromolecules, Vol. 2, No. 1, 2001 229
Biocompatible Polyester Macroligands Table 2. Summary of UV-vis Data for Iron-Centered PLA and PCL Star-Shaped Polymers [Fe(bpyX2)3]2+ [Fe(bpyDLPLA2)3]2+
[Fe(bpyLPLA2)3]2+ [Fe(bpyPCL2)3]2+
[Fe{bpy(PCL-DLPLA)2}3]2+ [Fe{bpy(DLPLA-PCL)2}3]2+
Mn(calcd) (kDa)a
MLCT (M-1 cm-1)b
chelation effc
23.5 66.6 140.0 239.6 23.1 76.3 19.3 48.4 145.6 23.1 81.2 67.8
9300 9500 9640 7130 9700 9620 9600 8500 4700 9650 10300 10700
0.95 0.98 0.99 0.73 0.99 0.99 0.99 0.87 0.48 0.99 1.06 1.10
Calculated molecular weight of the complex including putative PF6counterions. b Molar absorptivity of the MLCT band (λmax ) 531 nm) of the complex. c The estimated chelation efficiency: MLCT[Fe(bpyX2)3]2+/ MLCT[Fe(bpy)3]2+. λmax[Fe(bpy)3]2+ in CH2Cl2 ) 525 nm, ) 9740 M-1 cm-1. a
Table 3. DSC Data for Bipyridyl-Centered Polyester Macroligands and Fe2+ Complexes Formed Therefrom polymer bpyDLPLA2
bpyLPLA2
bpyPCL2
bpyPGA2d bpy(PCL-DLPLA)2
bpy(DLPLA-PCL)2 [Fe(bpyDLPLA2)3]2+ [Fe(bpyLPLA2)3]2+ [Fe(bpyPCL2)3]2+ [Fe{bpy(PCL-DLPLA)2}3]2+ [Fe{bpy(DLPLA-PCL)2}3]2+
Mn (kDa)
Tg (°C)
7.7b 22.1 37.0 79.8 7.6b 12.1 25.3 3.4b 9.6 16.0 48.4
47 42 47 43 55 61 60 c c c c 38 c, e c, e c, e c, e 44 44 62 c c, e c, e c, e
7.6b 16.1 27.0 19.1 23.5 66.6 76.4 48.4 23.1 81.2 67.8
Tm (°C)
∆Hf (J/g)
151 163 170 48 56 58 58 215 39f 49 55 43
68 64 81 84 56 43 74 82 g g g g
167 54 38f 50 40f
62 38 g g g
Tdec (°C)a 214 296 324 342 244 277 282 260 277 292 374 253 209 220 304 260 309 333 335 368 320 341 331
a The onset temperature for decomposition determined by TGA. Determined by 1H NMR spectroscopy. c The Tg values of caprolactones are typically
