Supramolecular Polylactides by the Cooperative Interaction of the End

Article pubs.acs.org/Macromolecules

Supramolecular Polylactides by the Cooperative Interaction of the End Groups and Stereocomplexation M. Brzeziński* and T. Biela* Department of Polymer Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 122, Lodz, Poland S Supporting Information *

ABSTRACT: The controlled ring-opening polymerization of L-lactide and D-lactide using 2-aminopyridine (AP), isocytosine (IC), uridine (U), and 2-ureido-4[1H]-pyrimidinone (UPyOH) initiators with stannous(II) octanoate as catalyst leads to polylactides (AP-PLA-OH, IC-PLA-OH, U-PLA-OH, and UPy-PLA-OH), which are capable of forming strong hydrogen bonds and consequently self-assemble. By means of “1H NMR titration”, the association constant (Ka) was determined for chosen model system composed of polylactides with uridine and aminopyridine end groups. The coupling reaction of UPyPLA-OH with diisocyanates was used to obtain PLLA and PDLA with UPy end groups on both sides of the chain: UPy-PLLAUPy and UPy-PDLA-UPy. The SEC analysis of the telechelic UPy-PLA-UPy revealed the presence of a supramolecular polymer with a high-molecular-weight fraction (Mn ≈ 70 000 g/mol) compared with the molar mass of the starting dimer (UPy-PLA-OH, Mn ≈ 7000 g/mol), which confirms the strong complementary interactions of the end groups. Moreover, the influence of the end groups of enantiomeric PLAs on their thermal properties and morphology was investigated. Additionally, the influence of the modified PLA enantiomers on the stereocomplexation phenomenon was analyzed. It was observed that stereocomplexes prepared from PLAs with UPy or U end groups on one chain end lead to the formation of microspheres during precipitation from N-methylpyrrolidone into methanol. The microscopic analysis of the telechelic UPy-PLLA-UPy/UPy-PDLA-UPy stereocomplex resulting from the precipitation from chloroform into methanol revealed a fibrous morphology. The probable mechanism of formation of the hierarchical structure of this stereocomplex material, which can be related to the specific geometry of the enantiomeric chains (mainly in a parallel arrangement), was proposed.

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INTRODUCTION Supramolecular chemistry refers to the construction of molecules that associate by noncovalent, complementary interactions, such as hydrogen bonds, van der Waals interactions, π−π interactions, and metal coordination.1 To obtain supramolecular aggregates that are held together by secondary interactions and not by covalent bonds, these interactions should be strong enough, highly directional, and reversible.2,3 The degree of polymerization (DP) of supramolecular polymers depends on the concentration of the supramolecular (oligomeric) components and the association constant (Ka), which is a function of the strength of the interactions between the difunctional monomer end groups located on both ends of the modified oligomer chains.3 PLA is an aliphatic polyester derived from renewable agricultural resources and is ultimately degradable under composting conditions. Because of this “green” feature, PLA is considered a promising candidate to replace traditional petroleum-based polymers4 with various applications in the textile industry, agriculture, medical devices, and bioplastic bags.5 Despite these advantages, many research groups are still looking for methods and ways of improving the physicochemical properties of PLA. One of these methods is the © XXXX American Chemical Society

functionalization of the PLA chain ends with groups that are able to self-assemble.6 Long et al.7 have synthesized supramolecular racemic PLA with complementary multiple hydrogen-bonding DNA base pair units for the first time. The association constant of this system, determined by 1H NMR titration and Benesi−Hildebrand analysis, was equal to 84 M−1. Equimolar mixtures of polylactides with adenine and thymine end groups exhibited higher solution viscosities than the same polymers without end group modifications.7 Supramolecular polymers usually have physicochemical properties similar to high-molecular-weight polymers at temperatures below the melting point. However, the lower melt viscosity, when secondary, reversible interactions are broken at an elevated temperature, is an important feature of these materials from the processing point of view.8 To obtain the desired end groups on the polymers, two methods are usually employed: polymer end group modification via postpolymerization or the use of initiators already bearing the targeted functional group. Scherman et al. used the Received: January 30, 2015 Revised: April 14, 2015

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DOI: 10.1021/acs.macromol.5b00208 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules UPy-functionalized initiator for the ROP of ε-caprolactone to obtain a polymer with UPy attached to the chain end.9 This method allows attaching the UPy group at exactly one terminus, in contrast to a postpolymerization route that is often used by several groups,10,11 where the full conversion of the original terminal end groups of PLA cannot be guaranteed. To obtain telechelic UPy-based supramolecular polyesters12 or polycarbonates,13 functionalization with UPy-synthons was implemented. The effectively increased mechanical properties for telechelic UPy-terminated supramolecular polylactide copolymers functionalized with the UPy-synthons were observed.14 The second and relatively easier method used for improving the properties of PLAs is stereocomplexation. 15 The interactions between the L- and D-lactide units of enantiomeric polylactides with opposite configuration affect several properties of PLA, most notably the melting temperature.16,17 Recently, we have shown that the combination of end group functionalization and stereocomplexation leads to materials with higher melting temperatures (∼50 °C) and unique morphologies.18 Stereocomplexes of enantiomeric linear polylactides with ionic liquid end groups precipitated in 1,4dioxane as uniform microspheres. Moreover, the spontaneous colloidal crystallization of the microspheres was observed after replacing one of the linear enantiomeric components of the stereocomplex on the six-arm star-shaped PLA.19 In this paper, we are demonstrating the introduction of end groups to polylactide chains by employing the ROP of lactides initiated with a small molecule bearing the desired functional end group, as depicted in Scheme 1. Both L- and D-polylactides,

oligomers, which remained in the reaction mixture as unreacted intermediates, ended with a supramolecular group from only one side of the chain, thus leading to a distortion of growth in the polymer chain length and these oligomers playing the role of “molecular chain stoppers”.24 Telechelic UPy-functionalized enantiomeric polylactides were obtained by the coupling reaction of the hydroxyl end group of UPy-PLA-OH with hexamethylene diisocyanate25, (Scheme 1), in contrast to the postpolymerization reaction of hydroxyl-functionalized polymers with UPy-synthons. Both mono- and telechelic UPy-functionalized enantiomeric PLAs were used for the stereocomplex preparation. The structure, self-assembly, physicochemical properties, and morphology of the obtained supramolecular PLAs and their stereocomplexes were analyzed using 1H NMR, size exclusion chromatography (SEC-MALLS) matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM).

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EXPERIMENTAL PART

Materials. Tin(II) octoate (2-ethylhexanoate) Sn(Oct)2 (commercial product from Sigma-Aldrich) was purified by two consecutive high-vacuum distillations at 140 °C/3 × 10−3 mbar. The purified Sn(Oct)2, stored on the vacuum line, was finally directly distributed into thin-walled vials or ampules equipped with break-seals and then sealed off and stored at −12 °C. D,D-Lactide (LA, from Boehringer Ingelheim, Germany) and L,L-lactide (99%, Purac, Netherlands) were consecutively crystallized from dry 2-propanol and toluene and purified just before use by sublimation in vacuo (10−3 mbar, 85 °C). Tetrahydrofuran (THF, POCH, Gliwice, Poland, 99%) was kept for several days over KOH pellets, filtered off, and refluxed over Na metal. Eventually, it was distilled, degassed, and stored over a liquid Na/K alloy, and it developed a blue color. N-Methyl-2-pyrrolidinone (MP, ACROS Organics, 99.5%) was distilled over CaH2 before use. Supramolecular initiators 2-aminopyridine (99%, Sigma-Aldrich), 2-amino-4-hydroxy-6-methylpyrimidine (99%, Sigma-Aldrich), and 2′,3′-O-isopropylidine−uridine (≥99% (HPLC), Sigma-Aldrich) were dried in vacuo (10−3 mbar, 85 °C) before use. Chloroform (CHCl3, POCh, Gliwice, Poland, pure p.a. grade) was distilled over P2O5 before use. 1,4-Dioxane (Chempur, pure) was purified by drying over calcium hydride, distillation (bp 100−102 °C), and treatment with sodium−potassium alloy. Methanol (POCH, Gliwice, Poland, pure p.a. grade), 5-amino-1-pentanol (95%, Sigma-Aldrich), 1,1′-carbonyldiimidazole (97%, Merck), and hexamethylene diisocyanate (98%, Sigma-Aldrich) were used as received. Synthesis of 6-Methyl-UPy-Imidazole. Synthesis of 2-(1imidazolycarbonylamino)-6-methyl-4[1H]-pyrimidinone. This compound was prepared as reported by Wong27 with a slight modification. 6-Methylisocytosine (5 g, 0.04 mol) was dissolved in dry N-methyl-2pyrrolidone because of the pure solubility of cytosine in other solvents. Then, 1,1′-carbonyldiimidazole (7 g, 0.043 mol) was added, and the mixture was stirred at 40−50 °C for 24 h. The suspension was cooled to 25 °C and filtered. The white solid was washed with acetone (3 × 20 mL) and dried in vacuo. The obtained compound (7.84 g, ∼100%) was used in the subsequent step without further purification. Synthesis of UPy-Initiator. Synthesis of 1-(5-hydroxypentyl)-3(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea. 6-Methyl-Upy-imidazole (7.29 g, 0.033 mol) and THF (20 mL) were stirred under a nitrogen atmosphere. 5-Amino-1-pentanol (7.8 g, 0.07 mol) and dry triethylamine (a few droplets) were added to the white suspension, and then the mixture was stirred at 60 °C for 24 h. The resulting turbid solution was diluted with THF (50 mL) to form a clear colorless solution. Then, the solution was washed with HCl (1 M), saturated NaHCO3 solution (30 mL), and saturated NaCl solution. The resulting white precipitate was filtered off, washed with hexane, and recrystallized from EtOH to afford 7.05 g (84%) of pure product.

Scheme 1. (A) Functional End Groups of PLA; (B) Scheme of Synthesis of UPy-PLA-OH and Telechelic UPy-PLA-UPy

functionalized with 2-aminopyridine (AP), isocytosine (IC), uridine (U) and 2-ureido-4[1H]-pyrimidinone (UPy), were obtained. This last group exhibits a high tendency to dimerization due to the quadruple hydrogen bonding sites.20,21 The self-association constant for this system is wellknown in different solvents: Kdim ≥ 107 M−1 in chloroform, 1 × 107 M−1 in chloroform saturated with water, and 6 × 108 M−1 in toluene.22 It is worth noting that the association constant and the concentration of the oligomeric components of aggregates in solution are the main parameters that influence the degree of polymerization (DP) of supramolecular polymers.23 Moreover, the presence of impurities in the supramolecular system is also important. The monofunctional B


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Macromolecules The white solid was dried overnight at 60 °C in vacuo. 1H NMR spectroscopy (CDCl3, δ): 13.20 (1H, s, UPy-amine), 11.79 (1H, s, ureido α to pyrimidinone), 9.91 (1H,s, ureido α to pyrimidinone), 5.86 (1H, s, UPy-aryl), 3.67 (2H, t, methylene α to ureido), 3.29 (2H, q methylene α to alcohol), 2.78 (1H, br s, alcohol), 2.23 (3H, s, 6methyl-UPy), 1.62−1.53 (6H, m, 3 × methylene). FT-IR (ATR): ν = 3390 (alcohol), 2936 (ureido N−H), 1698 cm−1 (ureido carbonyl). Ring-Opening Polymerization of L,L-Lactide and D,D-Lactide. The linear L-PLA and D-PLA enantiomeric (homochiral) polymers were synthesized according to the known procedure28,29 employing the ring-opening polymerization (ROP) of L,L- and D,D-lactides, respectively. L,L-Lactide or D,D-lactide monomers were polymerized in THF at 80 °C with Sn(Oct)2 and monofunctional initiators as components of the catalytic/initiating system. As an example of the process described polymerization initiated with UPy, and all other syntheses were carried out under identical conditions. A general procedure is described below. Polymerizing mixtures were prepared in sealed glass ampules using standard high-vacuum techniques. Sn(Oct)2 (1 mL of 0.25 mol L−1 solution in dry THF) and L,L-LA (5.79 g, 40 mmol) were transferred under vacuum into break-seals and sealed after freezing in liquid N2. The UPy-initiator (UPy-OH) (0.35 g, 1.37 mmol) was added to a thin-walled vial and dried under vacuum and then sealed after freezing in liquid N2. Break-seals containing the Sn(Oct)2/THF solution and LA monomer as well as the tube with the UPy-OH vial were sealed in the glass reaction vessel (∼35 mL). THF (26.8 mL) was distilled into the resulting reactor, which was then sealed off (in the case of isocytosine, polymerization was carried out in N-methylpyrrolidone). The break-seals of the vials were broken, and all the components were dissolved at room temperature. The ampule containing the reacting mixture was placed into a thermostat (80 °C) for approximately 24 h. The resulting polymer was dissolved in CHCl3 and precipitated into methanol, separated by filtration and washed several times with methanol. The mass of the vacuum-dried product was 4.63 g (80% yield). 1H NMR spectroscopy (CDCl3, δ): UPy-PLA-OH, δ =13.10 (1H, s, UPy-amine), 11.81 (1H, s, ureido α to pyrimidinone), 10.20 (1H,s, ureido α to pyrimidinone), 5.81 (1H, s, UPy-aryl), 5.14 (1H, q, polymer), 4.31 (1H, q, end group polymer), 4.12 (2H, t, methylene α to ureido), 3.29 (2H, q methylene α to alcohol), 2.78 (1H, br s, alcohol), 2.23 (3H, s, 6-methyl-UPy), 1.62− 1.53 (6H, m, 3 × methylene), 1.47 (3H, d, polymer). AP-PLA-OH, 1H NMR (CDCl3): δ = 8.45 (br s, 1H, NH aminopyridine), 8.26 (d, 1H, CHCH aminopyridine), 8.16 (d, 1H, CHCH aminopyridine), 7.71 (t, 1H, CHCH aminopyridine), 7.10 (t, 1H, CHCH aminopyridine), 5.16 (q, 1H, CH−CH3 polymer), 4.35 (q, 1H, CH−CH3 end group polymer), 1.67 (d, 3H, CH3 polymer) ppm. U-PLLA-OH, 1H NMR (CDCl3): δ = 8.25 (br s, 1H, NH uridine), 7.22 (d, 1H, CHCH uridine), 5.72 (d, 1H, N−CH⟨ sugar residue), 5.62 (d, 1H, CHCH uridine), 5.16 (q, 1H, CH−CH3 polymer), 5.03 (m, 2H, CH−CH sugar residue) 4.79 (q, 1H, sugar residue), 4.38 (dd, 1H, sugar residue), 4.35 (q, 1H, CH−CH3 end group polymer), 1.67 (d, 3H, CH3 polymer) ppm. IC-PLLA-OH, 1H NMR (CDCl3): δ = 5.98 (s, 1H, isocytosinearyl), 5.16 (q, 1H, CH−CH3 polymer), 4.35 (q, 1H, CH−CH3 end group polymer), 2.19 (s, 3H, 6-methylisocytosine) 1.67 (d, 3H, CH3 polymer) ppm. Coupling Reaction. The reaction of UPy-PLA-OH proceeded in the melted polymer (150 °C) under reduced pressure. The reaction mixture was purged with argon, and hexamethylene diisocyanate was added. The process then continued under reduced pressure. Afterward, the polymer was precipitated into methanol. UPy-PLLAUPy, 1H NMR (CDCl3): δ = 13.10 (b, 1H, UPy-amine), 11.81 (b, 1H, ureido α to pyrimidinone), 10.20 (b, 1H, ureido α to pyrimidinone), 5.81 (s, 1H, UPy-aryl), 5.14 (q, 1H, CH−CH3, polymer), 4.12 (2H, t, methylene α to ureido) 3.29 (q, 2H, methylene α to ester), 3.16 (q, 2H, CH2 urethane), 2.23 (s, 3H, 6-methyl-UPy), 1.47 (d, 3H, CH3, polymer) ppm. Preparation of Stereocomplex. The linear L-PLA and D-PLA (0.1 g) were dissolved separately in 2 mL of chloroform, 1,4-dioxane,

and N-methylpyrrolidone. In the case of chloroform and Nmethylpyrrolidone, the solutions were mixed together and stirred vigorously for at least 2 h at room temperature. Then, the resulting LPLA/D-PLA/CHCl3 (NMP) mixture was slowly precipitated into an excess of methanol. The fine precipitate of sc-PLA was filtrated and washed a few times with cold methanol and then dried under dynamic vacuum for 24 h. Equimolar amounts of enantiomeric polylactides were used to prepare the stereocomplexes in 1,4-dioxane. The solutions were mixed and (after short stirring) left at room temperature without stirring.23 The initially clear mixture became turbid after some time, and the stereocomplex started to precipitate. After 24 h, the supernatant was removed by decantation, and the solid was washed with three portions (1 mL each) of 1,4-dioxane and dried at room temperature under slight vacuum. Measurements. 1H NMR spectra were recorded in chloroform-d1 on a Bruker DRX500 spectrometer operating at 500 MHz. Traces of the nondeuterated chloroform were used as an internal standard. The number-average molecular weights Mn of the polymers were determined by gel permeation chromatography (GPC) using an Agilent Pump 1100 Series (preceded by an Agilent G1379A Degasser), equipped with a set of two PLGel 5 μ MIXED-C columns. A Wyatt Optilab Rex differential refractometer and a Dawn Eos (Wyatt Technology Corporation) laser photometer were used as detectors. Dichloromethane was used as eluent at a flow rate of 0.8 mL min−1 at room temperature. MALDI-TOF (matrix-assisted laser desorption/ ionization time-of-flight) measurements were performed with the Voyager Elite (PerSeptive Biosystems, Framingham, MA) time-offlight instrument equipped with a pulsed N2 laser (337 nm). Mass spectra were obtained in the linear mode with an accelerating voltage of 20 kV. Dithranol was used as matrix, LiCl as cationization agent, and THF as solvent. DSC analysis was performed under nitrogen at a heating and cooling rate of 10 °C/min on a DSC 2920 Modulated TA Instruments. Both the temperature and heat flow were calibrated with indium. FTIR spectra were measured with a Nicolet 6700 spectrometer equipped with a DGTS detector. Attenuated total reflectance (ATR) was used for IR measurements. The spectra were obtained by adding 64 scans at a 2 cm−1 resolution. Scanning electron microscopy (SEM) images were obtained with a Nova NanoSEM 230 instrument (FEI Co.) equipped with an SE detector at HV = 15 kV at low pressure (0.3 Torr) with a high-resolution Helix lens detector (resolution approximately 2 nm). The electron micrographs were recorded with a resolution of 1024 × 768. The samples were prepared with carbon adhesive tape and studied in a low-vacuum ambient without conductive layer.

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RESULTS AND DISCUSSION Synthesis and Characterization of Supramolecular PLAs. The polymerization method, initiation from a small molecule already bearing the desired end group (Scheme 1), ensures that all resulting polymer chains would be ended with AP, IC, U, and UPy groups (when the process is living). It is of note that the solubility of the initiator in the polymerization mixture is also an important parameter, especially for the control of the MW and the dispersity (Đ) of the synthesized polymers, and sometimes its improvement is required.15 In our study, THF was a suitable solvent for polymerization with the AP, U, and UPy initiators, whereas polymerization of the IC initiator proceeded in NMP. The initiators were perfectly soluble in the polymerization mixture (THF + LA or NMP + LA) at 80 °C. The molecular weight of the PLAs was close to the MW calculated from the [M]0/[I]0 ratio, and the dispersity (Đ) was low and in the range typically observed for the ROP of lactides with Sn(Oct)2 as a catalyst.30 Monomer-to-initiator ratios ([M0]/[I0]) were chosen to obtain polymers with low molecular weights (Mn ∼ 2000−4000 g/mol). The end group analysis and the determination of the C


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Macromolecules

Figure 1. 1H NMR spectra of PLA functionalized with ureidopyrimidinone UPy-PLA-OH.

Figure 2. MALDI-TOF spectrum of UPy-PLA-OH with exact m/z values and the number of lactide units in the oligomers. The m/z values correspond to adducts with H+ and Li+, respectively.

MW were carried out by means of 1H NMR by integrating the methine protons (HF) of the polymer end groups (one per chain) against the methine protons (HE) of the monomeric units in the main chain (Figure 1). The 1H NMR spectra of polylactides with other functional groups are shown in the Supporting Information (Figures S1−S3). To demonstrate that the supramolecular initiators have been incorporated in each of the PLA main chain, the MALDI-TOF MS analysis was employed. In the MALDI spectra of UPy-PLAOH, two populations of signals with even and odd numbers of

lactoyl units were found (Figure 2). The MALDI spectra of PLA with other functional end groups are shown in the Supporting Information (Figures S4−S6). The population with higher intensity ascribed to the desired polymer chains: for n = 32, UPy[O(O)CCH(CH3)]nOH, Li+ (m/z = 2566.34) and UPy[O(O)CCH(CH3)]nOH, H+ (m/z = 2559.82) clearly appear in the spectrum. These signals are separated from each other by 144.13, which corresponds to the molecular weight of a lactide unit. The second population of signals observed for macromolecules: for n = 31, UPy[O(O)D


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Macromolecules

Figure 3. (A) Change in chemical shift of the −NH protons of uridine with varying concentrations of AP-PLA-OH in the U-PLA-OH/AP-PLA-OH supramolecular aggregate. (B) Nonlinear relationship between the induced change in the uridine NH chemical shift and the solution concentration (Mn = 2700 g/mol ([U-PLLA-OH] = 2.0 mM, 27 °C). (C) Benesi−Hildebrand plots of U-PLA-OH/AP-PLA-OH association in CDCl3 (Mn = 2700 g/mol, [U-PLA-OH] = 2.0 mM, 25 °C).

CCH(CH3)]nOH, Li+ (m/z = 2493.56) and UPy[O(O)CCH(CH3)]nOH, H+ (m/z = 2487.88), which are separated from the main population by 72.065 (molecular weight of a lactoyl unit), indicates the presence of transesterification. This process involves the attack of the active sites of the carboxyl groups distributed along the PLA chain and leads to even and odd numbers of lactoyl units in the polymer chains.31 Determination of the Dimerization Constant Kdim for Supramolecular Model Systems. After precise characterization of the obtained PLAs, we investigated the aggregation of functional PLAs in solution by 1H NMR and SEC analysis. In supramolecular polymers, the degree of polymerization (DP) is determined by the strength of the end group interactions.11 Thus, two parameters of the supramolecular system are obviously important: the association constant (Ka) and the concentration of the supramolecular components. To determine the dimerization constant (Kdim), the “1H NMR titration” method is usually employed.32 However, this approach is only feasible when the Kdim is relatively low. It is related to the limitations of NMR analysis. Simply, for very large Kdim, the highest possible concentrations to follow the dissociation of supramolecular polymers are still too low to be observed in NMR. In this case, the determination of Kdim requires the introduction of fluorescent probes to the polymer chain, which allows the observation of the dissociation of supramolecular polymers at very low concentrations. Unfortunately, this

method is rather cumbersome and requires a very sophisticated synthesis.10 We decided to analyze the aggregation of the PLA model system functionalized with aminopyridine and uridine end groups. The Benesi−Hildebrand method was employed to calculate the Kdim from NMR titration data.32 Six solutions of the AP-PLA-OH/U-PLA-OH) were prepared, in which the UPLA-OH concentration was maintained constant (2 mM) while the AP-PLA-OH concentration was gradually increased from 0 to 16 mM. As a result, successive changes in the chemical shift of the uridine NH resonance were observed. An average uridine NH resonance (rather than two separate NH resonances) was observed due to the fast proton exchange between the associated AP-PLA-OH/U-PLA-OH complex and free APPLA-OH molecules.7,31 The plot of the changes in chemical shift versus AP-PLA-OH concentration has a nonlinear character (Figure 3). This type of curve confirmed the 1:1 stoichiometry of the PLA supramolecular complex.7 Moreover, the linear relationship in the double reciprocal of the association of HO-PLA-AP and HO-PLA-U also indicates the prevalence of a 1:1 HO-PLA-AP/HO-PLA-U complex in solution.33 Subsequently, the Benesi−Hildebrand analysis was used to calculate the association constant (Kdim) using the equations E


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Macromolecules K dim

supramolecular polylactide (only for high Ka) can be determined from the SEC only. Consistently, for diluted samples of polymer, the relationship between the hydrodynamic volume (which is a function of the elution volume) and the concentration is observed (see Figure 4). In Table 1, the increasing molecular weight of UPy-PLA-

AP‐PLA‐OH + U‐PLA‐OH XooooY AP‐PLA‐OH/U‐PLA‐OH (1)

1/Δδ = 1/(KKPTΔδmax[AP]) + 1/Δδmax

(2)

where Δδ = δAPU − δAP is the difference in chemical shift of the AP-PLA-OH/U-PLA−OH complex (δAPU) and uncomplexed AP-PLA-OH (δAP); [AP] is the concentration of AP-PLA-OH; Δδmax is the maximum change in chemical shift of the uridine NH protons corresponding to the complete formation of the associated complex as determined from Figure 3C. The Kdim that was calculated from the slope of the plot was 41.3 M−1 (Figure 3C). It is similar to the Kdim values typically observed for adenine−thymine base pair recognition.7 In the employed model, the self-association of AP and U end groups was omitted. Observation of PLA Aggregation Directly in SEC Analysis. A simple 1H NMR experiment was performed with varying concentrations of UPy functionalized PLA (from 1.72 to 5.17 mM) in the range applicable to this analysis. Changes in the chemical shifts of protons HA, HB, and HC as a function of concentration were not observed, indicating a rather strong association constant of the UPy end groups in this system. It is therefore clear that NMR spectroscopy is not adequate for Ka determination when dealing with very stable aggregates. To overcome this difficulty, an SEC analysis could be employed, as shown by Lou et al.,34 who used the SEC analysis as a powerful tool in the characterization of supramolecular assemblies. It is worth noting that the concentration of the analyzed polymer sample in SEC is at least 10 times lower than in the NMR analysis because of its dilution during the flow through the columns. It was shown that the shape of the chromatographic peak and the elution volume of the corresponding aggregates are strongly dependent on their association constant Ka. A sharp and well-defined chromatographic peak was observed for stable supramolecular complexes (with high Ka), whereas less stable complexes with lower Ka gave broadened and tailing peaks. The SEC measurements were performed in CH2Cl2, in which the UPy units are known to exhibit a high association constant,35 which means that it exists mainly in the dimerized form, as shown in Table 1. Thus, molar masses of twice the value obtained from 1H NMR were observed in SEC (for the highest concentrated sample). It is noteworthy that, in the case of supramolecular polymers, the molecular weight determined from 1H NMR is always that of a single oligomer unit and not of the entire aggregate. The actual total molar mass of the

Figure 4. Dependence of the location and the shape of chromatographic peaks of UPy-PLA-OH with concentration.

OH with increasing concentration is observed because relatively more supramolecular dimers could be dissociated at lower concentrations. In the case of PLA terminated with isocytosine end groups, that dependence is not observed because the IC groups interact significantly less with each other. Moreover, these oligomers appear almost exclusively in monomeric form in the SEC analysis even for relatively high concentrations, as shown in Table 1. Moreover, there is a characteristic dependence of the shape of the chromatographic peak on the concentration of a UPyPLA-OH polymer sample in the SEC analysis. Polymer samples of lower concentration appear as broadened and tailing peaks, whereas more concentrated samples produce sharp and welldefined peaks (Figure 4). The high concentration favors the formation of supramolecular complexes that can be seen in the SEC chromatograms. These observations strongly indicate that the Kdim of the UPy-PLA-OH system is really high. It is very likely that UPy-PLA-OH exists solely as a dimer in the solid state. Because of the strong self-association of the UPy moieties, polylactides decorated with the UPy group were chosen to prepare the telechelic polymers. To obtain enantiomeric polylactides modified with a UPy end group attached to both ends of the PLA chain, the coupling reaction of UPy-PLLA-OH and UPy-PDLA-OH with diisocyanate was performed, leading to UPy-PLLA-UPy and UPy-PDLA-UPy, respectively, as shown in Scheme 1. The details of the synthesis are described in the Experimental Part. The progress of the reaction was monitored in the 1H NMR spectra and SEC chromatograms. When the reaction was completed, the resonance signal derived from the

Table 1. Relationship between the Measured Molar Masses of Linear UPy-PLA-OH and IC-PLA-OH and the Concentration structure

concn [mM] (NMR)

concn [mM] (SEC)

Mn × 10−3 [g/mol] (NMRa)

Mn × 10−3 [g/mol] (SECb)

Mw/Mn (SEC)

HO-PLA-UPy HO-PLA-UPy HO-PLA-UPy HO-PLA-IC HO-PLA-IC HO-PLA-IC

1.72 3.44 5.17 1.19 2.38 3.57

0.17 0.34 0.52 0.12 0.24 0.36

2.5 2.5 2.5 4.2 4.2 4.2

3.7 6.6 7.6 3.5 3.7 3.9

1.10 1.09 1.21 1.30 1.24 1.41

a

Based on the integration of signals of CH groups in LA units within the chain (quartet centered at 5.14 ppm) and CH group in LA unit at the chain end terminated with AOH group (quartet centered at 4.33 ppm). bSEC with polylactide calibration. F


Article

Macromolecules terminal −CH−OH groups of the UPy-PLA-OH substrate at 4.35 ppm δ practically disappeared, and a new one appeared at 3.16 ppm, derived from the methylene groups of the coupling agent, diisocyanate (95% yield). The 1H NMR spectrum of the reaction product is shown in Figure 5. The peaks assigned to

The observed peak shape is the result of the overlap of the peak from the coupling reaction product (UPy-PLA-UPy) and those from its association to supramolecular PLA because the association is instantaneous and occurs simultaneously with the formation of UPy-PLA-UPy. Thus, the observed total SEC peak of the UPy-PLA-UPy covers a wide range of hydrodynamic volumes corresponding to the products of aggregation: dimer, trimer, tetramer, and higher oligomers up to supramolecular polymers with high molar masses, as shown in Figure 6. For example, aggregates that appear at elution volumes in the range of 13−14 mL reveal absolute molar masses equal to Mn ≈ 70 000 g/mol, as calculated with the MALLS detector. It is worth noting once again that the measurement of the UPy-PLA-UPy molar mass was made at very low concentrations (SEC conditions), which means that the aggregates may be largely dissociated and, as a consequence, their molar mass may be significantly reduced. Additionally, the determined molar mass of the resulting supramolecular aggregates is certainly also undervalued as a result of filtering, according to the procedure mentioned above. Cooperative Interactions of the PLA End Groups and Stereocomplexation. It was interesting to see the influence of end group interactions on the other type of supramolecular bonding−stereocomplexation. It was expected that the combination of those two types of supramolecular interactions should lead to materials with improved thermal stability and unique morphologies.23,24 Equimolar mixtures of functionalized enantiomers (both mono- and telechelic) were used to prepare two types of PLA stereocomplexes in three different solvents: chloroform, N-methyl-2-pyrrolidinone (NMP), and 1,4-dioxane. The solutions of the stereocomplex in CHCl3 and NMP were precipitated into methanol, and the mixture formed in 1,4dioxane was left in this solution at ambient temperature to precipitate. The detailed procedure of the preparation of the stereocomplexes is described in the Experimental Part. The formation of the stereocomplexes was confirmed by ATR FTIR spectroscopy (Figure S7, Supporting Information). The most characteristic changes occur in the 970−850 cm−1 region of the spectrum where a new band appears at 909 cm−1, which is characteristic of a β-helix in the stereocomplex. The band responsible for the α-helix vibrations of enantiomeric PLAs at 921 cm−1 completely disappeared after stereocomplexation.36 Moreover, in both mono- and telechelic UPy functionalized PLAs and their stereocomplexes, vibrations between 1700 and 1500 cm−1 from the keto form of the UPy end groups were observed.37 The thermal parameters and percentage of crystallinity of the obtained monofunctionalized polylactides and their stereocomplexes are shown in Table 2. The low-molecular-weight UPy-PLA-OH exhibits a high glass transition temperature, which confirms the strong complementary interactions between the UPy end groups. Yamauchi et al.38 have previously shown that polystyrene (PS) functionalized with UPy end groups exhibits a similar glass transition temperature (Tg) as the PS with hydroxyl end groups but with twice the molar mass. This result indicates that the polymers are strongly aggregated in the solid state, leading to the high rigidity of the polymer chains and, as a consequence, to a lower segmental mobility in the amorphous phase of the obtained supramolecular polymers. The melting temperature of PLA stereocomplexes with end groups able to form multiple hydrogen bonds is ∼60−70 °C higher than their enantiomeric components and higher than 50 °C for linear stereocomplexes

Figure 5. 1H NMR spectrum of telechelic polylactide functionalized ureidopyrimidinone end groups (UPy-PLA-UPy).

the UPy end groups in the telechelic UPy-PLA-UPy are broader than those of the PLA terminated with UPy on the one chain end. The main cause of this phenomenon is most probably the lower solubility of the telechelic UPy-PLA-UPy in CDCl3 and the increased viscosity of its solution as a result of aggregation. Thus, certain fractions of supramolecular PLA were apparently gradually separated from the solution to form a microgel, and parts of the microgel were removed from the analyzed system during routine filtration before the SEC analysis. Despite this, the peak in the SEC chromatograms related to the coupling product (UPy-PLA-UPy) was significantly shifted toward higher molar masses (higher hydrodynamic volumes) and became broad and asymmetric (Figure 6).

Figure 6. SEC chromatograms of polylactides UPy-PLA-OH and UPyPLA-UPy (before and after coupling reaction). G


Article

Macromolecules Table 2. Thermal Parameters Tg, + Tm and Enthalpies of Fusion (ΔHm) of Supramolecular Polylactides and Their Stereocomplexes (Molar Masses of PLAs in the Range 2000−5000 g/mol) structure

Tg [°C]

Tm [°C]

ΔHm [J/g]

Xca [%]

HO-PLLA-AP HO-PDLA-AP sc-PLA-AP HO-PLLA-U HO-PDLA-U sc-PLA-U HO-PLLA-IC HO-PDLA-IC sc-PLA-IC HO-PLLA-UPy HO-PDLA-UPy sc-PLA-UPy

56.9 50.7 52.3 50.6 52.8 53.9 46.4 56.6 51.8 57.6 61.4 67.6

155.2 151.3 214.9 121.8/131.2 140.7 195.1 148.9 137.4 203.9 118.7/130.8 121/132.1 200

57.3 61.4 100.5 53.2 62 91.6 60 58.1 89.4 47.6 54.2 67.8

62 66 71 57 67 64 64 62 63 51 58 48

configuration are also possible. The fraction of these irregular stereocomplexes can affect the structure and thermal properties of the total material. In the case of supramolecular UPy-PLLA-UPy and UPyPDLA-UPy stereocomplexation, the situation is much more complicated (Scheme 2B). There are three types of supramolecular interactions in the analyzed systems: end group interactions, stereocomplexation, and interaction of the selfassembled UPy/UPy or diisocyanate moieties in the complementary enantiomeric PLA chains leading to the stack structures. As mentioned above, the described supramolecular system is dynamic and reversible, and the formation of random copolymers such as ...LLDLD... during the preparation of the stereocomplex cannot be excluded. If the exchange of L and D segments is important, serious distortions in the regular structure of the resulting stereocomplex should occur. The existence of the other above-mentioned types of supramolecular interactions may compensate for incomplete stereocomplexation. Finally, despite these problems, the stereocomplex aggregates reveal the more effective cooperative interactions of enantiomeric chains that, in consequence, lead to higher thermal stability. Supramolecular PLA stereocomplexes have a degree of crystallization in the range of 48−71% (Table 2). The thermal properties of both mono- and telechelic UPy functionalized polylactides are collected in Table 3. Telechelic UPy-PLA-UPy exhibits lower glass transition and similar melting temperatures compared with UPy-PLA-OH in the first DSC heating run (Figure S8, Supporting Information). In the second heating run of UPy-PLA-UPy, only the glass transition was observed (neither cold crystallization nor melting transition was present). The standard rate of cooling and heating in the DSC analysis (10 °C/min) was probably too high, as the polymer crystallized and the final material was fully amorphous. A similar behavior for telechelic UPy-functionalized poly-ε-caprolactone17 (PCL) in the second heating run was observed. Moreover, polylactides are known to crystallize very slowly in the melt.41 Attaching “big” end groups, such as UPy, to oligomer chains most likely hinders the crystallization process additionally. In Figure 7, DSC traces of the stereocomplexes obtained from PLAs with mono- and telechelic-UPy functionalization are shown. The stereocomplexes of polylactide with a UPy group on one chain end exhibited an endothermic peak between 197 and 202 °C with a total enthalpy of fusion in the range of 69.5− 90.4 J/g (depending on the stereocomplexation solvent). For telechelic PLA functionalized with UPy end groups, the melting points are between 185 and 192 °C, and the enthalpy of fusion is also lower and in the range 49−69 J/g. In the second heating run of UPy-PLA-OH and UPy-PLA-UPy, the endotherms in the range 170−187 °C are related to the melting of the stereocomplex crystallites; however, lower temperatures (than in the first heating run) indicate that the crystallites prepared from solutions are more perfect than those from melted samples. Morphology of Supramolecular PLA Stereocomplexes. Using scanning electron microscopy (SEM), the morphology of all the obtained PLA stereocomplexes with different monofunctional groups and in different solvents was investigated. The importance of the stereocomplexation medium on their morphology is shown in Figure 8. A nonspecific morphology was observed for stereocomplexes

a

For calculation of the degree of crystallinity, two values were used: 93 and 142 J/g, which are the equilibrium enthalpies of fusion of PLA and sc-PLA, respectively.18

observed by Ikada et al.39 It is known that enantiomeric polylactide chains may interact in two geometrical ways because of their asymmetry: parallel or antiparallel. The calculated interaction energy in the stereocomplex is higher for the parallel PLA helices.40 The observed higher melting temperature is probably due to a combination of interactions of the enantiomeric helices and interactions of the UPy, U, AP, and IC end groups. The relatively strong hydrogen bonds in the end groups can preorganize the PLA chains before stereocomplex formation in the supramolecular dimers: LL and DD, as shown in Scheme 2. Scheme 2. Possible Mechanism of Formation of UPyModified Stereocomplexes of Different Morphology: (A) Dimer Stereocomplexation; (B) Supramolecular Polymer Stereocomplexation

Because the system is dynamic and reversible, the formation of LD dimers is also possible. Then, the dimers with opposite configurations form the stereocomplex aggregates LL/DD and LD/DL with parallel geometry only. The LL/LD and DD/LD stereocomplex aggregates with lower stability due to interaction with only the part of the PLA segments with opposite H


Article

Macromolecules

Table 3. Molar Masses, Dispersity, and Thermal Parameters of HO-PLA-UPy, UPy-PLA-UPy, and Their Stereocomplexes structure

Mn(SEC)

Mw/Mn(SEC)

Tga [°C] (1st run)

Tma [°C] (1st run)

ΔHm [J/g] (1st run)

Tga [°C] (2nd run)

Tma [°C] (2nd run)

ΔHm [J/g] (2nd run)

HO-PLLA-UPy HO-PDLA-UPy sc-UPy-PLA-OH (chloroform) sc-UPy-PLA-OH (pyrrolidone) sc-UPy-PLA-OH (dioxane) UPy-PLLA-UPy UPy-PDLA-UPy sc-UPy-PLA-UPy (chloroform) sc-UPy-PLA-UPy (pyrrolidone) sc-UPy-PLA-UPy (dioxane)

8490 7140

1.18 1.19

61.4 57.6

121/132.1 118.7/130.8 197.5

54.2 47.6 90.4

44.8 41 34.3

121.1/130.1 118.7/127 170.9

16.17 4.6 39.5

199.7

77.06

34.8

173.3

31.9

202

69.47

39.3

184.3

37.2

47.8 48.8 48.4

119.8/132.2 126 189.9

42.7 50.2 60.9

54.9 56.7 45.3

179.2

49

47.7

185.4/192.2

69

46

173.1/187.4

69.4

187.9

49.4

178

45.41

a

16750 15140

1.87 1.77

Heating and cooling rate equal to 10 °C/min.

Figure 7. DSC traces of UPy-PLA-OH, UPy-PLA-UPy, sc-UPy-PLAOH, and sc-UPy-PLA-UPy prepared in CHCl3 and precipitated into methanol.

Figure 8. SEM images of PLA stereocomplexes (A) sc-PLA-IC precipitating from 10% solution of 1,4-dioxane, (B) sc-PLA-U precipitated from N-methyl-2-pyrrolidinone to methanol, and (C, D) sc-PLA-UPy precipitated from N-methyl-2-pyrrolidinone to methanol.

formed by precipitation from chloroform to methanol (Figures S9B and S15A, Supporting Information). In 1,4-dioxane, the scPLA-IC precipitates in the form of poorly defined discoidal particles (Figure 8A). Only after precipitation of sc-PLA-U and sc-PLA-UPy from N-methyl-2-pyrrolidinone were spherical particles formed. However, the microspheres obtained from scPLA-U, with an average diameter of 3.5 μm, were not uniform. SEM images of the UPy-PLLA-OH/UPy-PDLA-OH stereocomplex precipitated from 10% solutions in N-methyl-2pyrrolidinone to methanol are shown in Figure 8C,D. This stereocomplex material precipitates in the form of microspheres with an apparently narrow size distribution. The diameter of the obtained microspheres was approximately 1 μm, which is much less than what we previously observed for stereocomplex microspheres composed of enantiomeric polylactides containing ionic end groups.23,24 Thus, to obtain stereocomplex spherical microparticles with controlled size distributions, the nature of the end groups and the kind of solvent from which the stereocomplex is precipitated should be taken into account. For stereocomplexes terminated with AP and IC end groups, the precipitation from N-methyl-2-pyrrolidinone to methanol

does not lead to the formation of microspheres. There is no flexible linker between the end groups able to form secondary interactions and the polymer chain, as in sc-PLA-U and sc-PLAUPy, where the end groups are linked to the PLA by a linker or sugar residue, which probably facilitates their interactions and promotes the specific preorganization of the macromolecules. It seems that the end groups directly linked to PLA (without a flexible linker) interact less efficiently due to the rigidity of the whole macromolecule, which hinders the specific adjustment of these functional groups. De Greef has shown that the length of the aliphatic linker between the UPy end group and the poly(butyl acrylate) main chain strongly affects the association constant42 which decreases by a factor of 103 when the UPy end group is attached by a short C2 spacer, in comparison with the typically used C6 spacer.43 Contrary to sc-UPy-PLA-OH, telechelic UPy-PLA-UPy in the NMP solvent precipitates into methanol in the form of poorly defined spherical particles (Figure S10, Supporting Information). However, after the precipitation of UPy-PLAUPy from chloroform to methanol, an interesting fibrous morphology was observed that is not present in any other I


Article

Macromolecules obtained stereocomplex. The fibers exhibit a broad size distribution ranging from 1 to 10 μm. Most probably, the formation of this structure is initiated by the formation of hydrogen bonds between single urea units, which subsequently allows for π−π interactions between the stacks of UPy end groups.44,45 This aggregation causes the phase separation of the UPy−urea moieties from the polymer backbone, which is the driving force of the nanofiber formation process.46 In our case, the fibrous structure (Figure 9A,B) has a

remarkable increase in the melting point is due to strong quadruple hydrogen bonding of the UPy end group, which probably favors parallel interactions in the stereocomplex. Moreover, it was demonstrated that the morphology of the obtained stereocomplexes strongly depends not only on the functionalization of PLA but also on the stereocomplexation medium. Monofunctionalized PLA usually forms microspherelike particles, whereas telechelic-functionalized PLA exhibits a fibrous structure. These polymers combine reversible weak interactions and strong hydrogen bonding. They are a new class of dynamic systems that can respond to external stimuli.

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ASSOCIATED CONTENT

S Supporting Information *

Figures S1−S16. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.macromol.5b00208.

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Figure 9. Morphology of sc-UPy-PLA-UPy during precipitation from chloroform to methanol.

AUTHOR INFORMATION

Corresponding Authors

*E-mail [email protected] (M.B.). *Email [email protected] (T.B.).

micrometer size. This high size is probably related to additional interactions in the initial step of aggregate formation, namely the stereocomplexation between enantiomeric PLAs, which leads to the formation of a very complex structure formed by hydrogen bonds between urea linkers, UPy end groups, and enantiomeric PLA chains.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work was financed by the National Science Center Poland Grant DEC-2013/09/B/ST5/03616. The authors thank Prof. Przemysław Kubisa for valuable comments and suggestions during the manuscript preparation.

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CONCLUSIONS To the best of our knowledge, PLA supramolecular systems in which two types of secondary interactions operate simultaneously: strong hydrogen bonds between complementary end groups of the polymer chain and weak, multicenter, nonclassical hydrogen bonds between enantiomeric PLA chains (stereocomplexation) were investigated for the first time. First of all, the successful synthesis of functionalized polylactides with end groups able to self-assemble has been demonstrated. Functionalized supramolecular initiators were used to ensure full control over the introduction of the desired end groups to the PLA chain end. The 1H NMR and MALDITOF analyses confirm that each polymer chain bears the desired end groups. Using the “NMR titration” method, the association constant was determined for the supramolecular model of PLAs bearing uridine and aminopyridine end groups. The obtained value (Kdim = 41.3 M−1) is within the same order of magnitude as the association constant of nucleobaseterminated PLAs. The SEC analysis conducted in CH2Cl2 revealed that UPy-PLA-OH occurs even in diluted solutions almost exclusively as a dimer. The coupling reaction was used to obtain UPy-PLA-UPy, and the SEC analysis in the same measurement conditions as for UPy-PLA-OH showed that this telechelic PLA is also substantially aggregated even under high dilution. The molar mass of the supramolecular PLA fraction determined for the part of the chromatographic peak at the lowest elution volume is equal to 70 000 g/mol. Furthermore, the relationship between the degree of aggregation and the shape of the chromatographic peaks for both types of modified PLAs was observed. This observation is unique, for supramolecular polymers and seems to be a good tool to confirm supramolecular binding. DSC experiments indicated that the thermal stability of polylactide stereocomplex could be greatly improved upon functionalization with UPy end groups. The

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Supramolecular Polylactides by the Cooperative Interaction of the End

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