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Mar 31, 2016 - (4), and 5-isocyanopent-1-yne (5) with 6-oxohexanoic acid in. CH2Cl2 generated PCL analogues (P1−P5) with different pendent groups ...
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Synthesis of Functional Polycaprolactones via Passerini Multicomponent Polymerization of 6‑Oxohexanoic Acid and Isocyanides Jian Zhang, Mei Zhang, Fu-Sheng Du, and Zi-Chen Li* Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Polymer Chemistry & Physics of Ministry of Education, Department of Polymer Science & Engineering, College of Chemistry and Molecular Engineering, Center for Soft Matter Science and Engineering, Peking University, Beijing 100871, China S Supporting Information *

ABSTRACT: We describe a straightforward strategy for a new family of functional polycaprolactones (PCL) via the Passerini multicomponent polymerization (P-MCP) of 6oxohexanoic acid and various isocyanides. Room temperature polymerization of tert-butyl isocyanide (1), 2,6-dimethylphenyl isocyanide (2), mOEG4 isocyanide (3), 5-isocyanopent-1-ene (4), and 5-isocyanopent-1-yne (5) with 6-oxohexanoic acid in CH2Cl2 generated PCL analogues (P1−P5) with different pendent groups amide-linked to the ε-position of PCL backbone. Furthermore, copolymerization of a mixture of isocyanides 1 and 3 in different molar ratios with 6oxohexanoic acid produced copolymers (P6−P9) with adjustable properties. To demonstrate the high versatility of this platform polymer, polymer P4 with pendent alkene group was further modified with glucose via the thiol−ene click reaction. The structures of these (co)polymers were confirmed by 1H NMR, 13C NMR, and matrix-assisted laser desorption ionization mass spectroscopy. The thermal properties of these (co)polymers were examined by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). All these polymers are amorphous with variable glass transition temperatures (Tg) depending on the side groups. For the copolymers, the dependence of Tgs on comonomer composition was well predicted by the Fox equation. Degradation of water-soluble polymer P3 in aqueous solutions was investigated by 1H NMR and SEC. It was revealed that P3 was stable in D2O or pD = 5.8 phosphate buffer (PB) up to 15 days, while it completely degraded in basic condition over a period of 6 h and in acidic condition over a period of 24 h. Interestingly, polymer P3 even degraded steadily in pD = 7.4 PB by a random hydrolysis mechanism. Two polymer samples were examined to be nontoxic. Thus, this novel class of PCL analogues can be easily engineered to tailor its material properties and degradation behavior and may have great potential as new degradable materials to meet biomedical applications.

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INTRODUCTION Aliphatic polyesters, owing to their biodegradability and biocompatibility, have gained widespread interest for their variable applications in biomedical fields.1−7 As one important member of the well-studied aliphatic polyester family, poly(εcaprolactone) (PCL) is an excellent material for tissue engineering and drug delivery.7−9 To expand the applications of PCL in different fields, synthesis of PCL with demanding functional side groups has received considerable attention over the past decades. These substituted PCLs exhibit tunable crystallinity, hydrophilicity, biodegradation, bioadhesion, and mechanical properties.10−12 Moreover, the pendant functional groups can be used for further conjugation of biomacromolecules and fluorescence probes.7,10,12 Ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) derivatives by either metal or organic catalyst is the prevailing method for these functionalized PCLs with predictable molecular weight, low polydispersity, and well-defined end-groups.11,13−15 In this context, the CL derivatives are usually generated by the © XXXX American Chemical Society

Baeyer−Villiger oxidation of the corresponding substituted cyclohexanone, and the substituents are in most cases located at the γ-, α-, or ε-position of the CL derivatives. Early substituted PCL examples were pioneered by the Jerome and Hedrick group,12,14−16 and many other examples were reported recently by other groups.17−31 Besides alkyl groups, many reactive groups, including hydroxyl, carboxylic acid, amino, azido, alkynyl, and alkenyl groups, have been introduced into PCL.7 However, a major drawback of this methodology is that it often requires several steps for the synthesis of functionalized CL monomers. When the functional groups are not compatible with the ROP catalysts, protection before polymerization and postpolymerization deprotection is necessary, and the deprotection should be very cautious to avoid possible degradation of the polymer backbone. Therefore, it is highly desirable to Received: January 14, 2016 Revised: March 21, 2016

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DOI: 10.1021/acs.macromol.6b00096 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

reference. Electrospray ionization mass spectroscopy (ESI-MS) was performed on a Bruker APEX-IV Fourier transform mass spectrometer in the positive ion mode. Matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF-MS) was conducted on a Bruker BIFLEX-III spectrometer equipped with a 337 nm nitrogen laser. α-Cyano-4-hydroxycinnamic acid was used as the matrix. Mass spectra were acquired in linear mode at an acceleration voltage of +19 kV. Size exclusion chromatography (SEC) was used to determine the number-average molecular weights (Mn) and Mw/Mn of the polymers using a Waters GPC equipped with a Waters 2414 refractive index detector, a Waters 1525 binary HPLC pump, and three Waters Styragel columns (1 × 104, 1 × 103, and 500 Å pore sizes). Tetrahydrofuran (THF) or dimethylformamide (DMF) was used as the mobile phase at a flow rate of 1 mL/min, and the column oven was set at 35 °C for THF or 50 °C for DMF. The calibration was performed using polystyrene standards, and the data were calculated with a Breeze 3.30 software. Thermal gravimetric analysis (TGA) was conducted on a Q600-SDT thermogravimetric analyzer (TA Co. Ltd.) at a heating rate of 10 °C/min under a nitrogen atmosphere of 100 mL/min. Differential scanning calorimetry (DSC) was performed on a Q100 differential scanning calorimeter at a heating rate of 10 °C/min under a nitrogen atmosphere of 50 mL/min. Data of the endothermic thermograms were recorded from the second scan and analyzed with a TA Universal Analysis software. Synthesis of 6-Oxohexanoic Acid.41 2-Hydroxycyclohexanone dimer (10.0 g, 43.9 mmol), sodium periodate (23.5 g, 109.6 mmol), THF (540 mL), and water (360 mL) was transferred into a 2 L roundbottom flask. The mixture was stirred at room temperature for 48 h. After that, the reaction mixture was diluted with ethyl acetate (800 mL), washed with brine (2 × 300 mL), dried, and concentrated by rotary evaporation. The obtained crude product was purified by silica flash column chromatography (eluted with ethyl acetate) to afford a white solid in 82% yield. The product was quickly transferred into a glass bottle and stored in N2 at −20 °C. 1H NMR (400 MHz, CDCl3, ppm): δ 11.71 (bs, 1H), 9.77 (s, 1H), 2.49 (t, J = 6.0 Hz, 2H), 2.39 (q, J = 6.6 Hz, 2H), 1.73−1.65 (m, 4H). 13C NMR (101 MHz, CDCl3, ppm): δ 202.2, 179.7, 43.4, 33.7, 24.0, 21.4. Synthesis of MOEG4-Isocyanide (3). 2-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}ethylamine (5.00 g, 24.2 mmol) was first transformed to the corresponding formamide (mOEG4-formamide) by refluxing with ethyl formate (100 mL) for 24 h, followed by removal of the solvent under reduced pressure. Then, to this raw material, triethylamine (4.85 g, 48.5 mmol) and 50 mL of CH2Cl2 were added, and the mixture was cooled in an ice bath, and then phosphorus(V) oxychloride (5.56 g, 36.3 mmol) in 50 mL of CH2Cl2 was added dropwise within 3 h. The mixture was stirred for another 2 h before K2CO3 (20% aq, w/w, 50 mL) was added to quench the reaction. The aqueous layer was extracted with 2 × 30 mL CH2Cl2, and the combined organic phase was dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica column chromatography eluted with ethyl acetate to afford a pale yellow oil as the final product in 68% yield. 1H NMR (400 MHz, CDCl3, ppm): δ 3.74−3.64 (m, 12H), 3.60−3.54 (m, 4H), 3.38 (s, 3H). 13C NMR (101 MHz, CDCl3, ppm): δ 157.20 (t), 71.92, 70.85, 70.80−70.41 (m), 68.66, 59.03, 41.75 (t). MS (ESI): [M + Na+] calcd: 240.1212; found: 240.1206. Synthesis of 5-Isocyanopent-1-ene (4).42,43 5-Bromo-1-pentene (11.6 g, 78.0 mmol), 15-crown-5 (1.7 g, 7.8 mmol), sodium diformylamide (8.9 g, 0.94 mmol), and sodium iodide (0.35 g, 2.3 mmol) were dissolved in 200 mL of acetonitrile in a 500 mL roundbottom flask. The mixture was refluxed overnight before filtration of the salts and rotary evaporation of acetonitrile. Afterward, 100 mL of methanol and KOH (0.22 g, 3.9 mmol) was added, and the mixture was stirred at room temperature for 20 min. After removal of methanol under reduced pressure, 100 mL of ethyl acetate was added, and the organic phase was washed with brine, combined, and dried. N-(4Pentenyl)formamide was obtained as yellow oil in 82% yield after complete removal of ethyl acetate. 1H NMR (400 MHz, CDCl3, ppm) as 4:1 mixture of rotamers: δ 8.10 (s, 1H), 7.97 (d, J = 12.0 Hz, 1H, rotamers), 6.25 (s, 1H), 5.74 (ddt, J = 20.5, 10.2, 6.7 Hz, 1H), 5.04−

develop other simple methodology for the synthesis of functionalized PCLs with tunable properties. Passerini three-component reaction (Passerini-3CR) of an aldehyde, a carboxylic acid, and an isocyanide is a highly efficient and atom-economic reaction to provide α-acyloxycarboxamide in a one-pot fashion.32 This reaction has recently been introduced into polymer science for the synthesis of functional polymers.33−35 In particular, using two components as bifunctional compounds and the other as a monofunctional component, a new stepwise Passerini multicomponent polymerization (P-MCP) (the A2 + B2 + C approach) has been developed as a simple and straightforward method for functional polymers. In this P-MCP, compound C plays a key role as a linking agent and offering functional side groups. This P-MCP has been used by Meier’s group and our group to prepare linear functional polyesters, poly(ester−amide)s, and polyamides.36−38 Furthermore, this P-MCP was extended to the AB + C system to get functional polyesters with more unified repeating units. Using an oxocarboxylic acid and an isocyanide afforded functionalized polyesters.39,40 These polyesters contain side functional groups amide-linked to the polyester backbone. These previous works promoted us to apply the same methodology for the more straightforward and versatile synthesis of functionalized PCL in a one-pot fashion. Herein, we reported the first synthesis of a family of εsubstituted PCLs by the P-MCP of 6-oxohexanoic acid and various isocyanides, the functional groups of which are originated from the isocyanides and amide-linked to the PCL backbone (Scheme 1). Since the ε-position of this type of PCL Scheme 1. Functional Poly(caprolactone)s via the P-MCP

has an electron-withdrawing amide substituent, we are also interested in revealing the structural effects on the thermal and degradation properties of these substituted PCLs.

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EXPERIMENTAL SECTION

Materials. The following reagents were used as received: 5-bromo1-pentene (95%, TCI, Shanghai), sodium diformylamide (97%, TCI, Shanghai), tert-butyl isocyanide (1, 98%, J&K), 2,6-dimethylphenyl isocyanide (2, Alfa Aesar), 2-hydroxycyclohexanone dimer (90+%, Alfa Aesar), 5-chloro-1-pentyne (98%, Alfa Aesar), 2-dimethoxy-2-phenylacetophenone (DMPA, 99%, Acros), 2,3,4,6-tetra-O-acetyl-1-thiol-β-Dglucopyranose (TG, 97%, Sigma-Aldrich), 2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethylamine (mOEG4-NH2, 99%, Biomatrik), PVA (Aldrich, Mw: 13 000−23 000, 87−89% hydrolyzed), PEI (Aldrich, average Mw ∼ 25 000 as measured by LS, branched), and poly(ethylene glycol) monomethyl ether with molecular weight of 2000 (Fluka) were used as received. All other chemicals were purchased from Beijing Chem. Reagent Co., Ltd. Measurements and Characterizations. 1H NMR and 13C NMR spectra were recorded in CDCl3, DMSO-d6, or D2O on a Bruker ARX400 spectrometer with tetramethylsilane (TMS) as the internal B

DOI: 10.1021/acs.macromol.6b00096 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Scheme 2. Synthesis of 6-Oxohexanoic Acid and the Functional Isocyanidesa

Reagents and conditions: (i) NaIO4, THF/H2O, rt, 24 h; (ii) ethyl formate, reflux, 30 h; (iii) POCl3, NEt3, CH2Cl2, 0 °C to rt; (iv) sodium diformamide, NaI, CH3CN, reflux, 36 h; aq KOH in methanol, 20 min; (v) TsCl, tri-n-octylamine.

a

10H), 3.52−3.57 (m, 4H), 3.46 (m, 2H), 3.38 (s, 3H), 2.40 (t, J = 7.5 Hz, 2H), 1.84 (m, 2H), 1.66 (m, 2H), 1.41 (m, 2H). Mn = 14.8 kDa, Mw/Mn = 1.44. P4: 6-Oxohexanoic acid (125 mg, 0.96 mmol) and isocyanide 4 (110 mg, 1.15 mmol) in 0.5 mL of CH2Cl2, 74% yield. 1H NMR (400 MHz, CDCl3, ppm): δ 6.40 (s, 1H), 5.79 (ddt, J = 17.2, 13.1, 6.6 Hz, 1H), 5.13 (s, 1H), 5.01 (dd, J = 17.6, 14.0 Hz, 2H), 3.26 (m, 2H), 2.38 (m, 2H), 2.08 (dd, J = 13.8, 6.9 Hz, 2H), 1.94−1.54 (m, 4H), 1.47− 1.32 (m, 2H). Mn = 7.8 kDa, Mw/Mn = 1.28. P5: 6-Oxohexanoic acid (135 mg, 1.04 mmol) and isocyanide 5 (116 mg, 1.25 mmol) in 0.5 mL of CH2Cl2, 83% yield. 1H NMR (400 MHz, CDCl3, ppm): δ 6.59 (s, 1H), 5.13 (s, 1H), 3.38 (m, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.24 (td, J = 6.8, 2.3 Hz, 2H), 2.03 (s, 1H), 1.95− 1.60 (m, 6H), 1.41 (m, 2H). Mn = 11.2 kDa, Mw/Mn = 1.35. Copolymers P6, P7, P8, and P9 were prepared in a similar manner starting from 6-oxohexanoic acid and a mixture of two isocyanides, 1 and 3. Total amount of isocyanides (1 + 3) was 1.2 equiv to 6oxohexanoic acid, and the feed molar ratios of 1 to 3 were 1:2, 1:3, 1:7, and 1:10 for polymers from P6 to P9, respectively. P6: 6-Oxohexanoic acid (142 mg, 1.09 mmol), isocyanide 1 (37 mg, 0.44 mmol), and isocyanide 3 (189 mg, 0.87 mmol) in 0.5 mL of CH2Cl2, 87% yield. 1H NMR (400 MHz, CDCl3, ppm): δ 6.62 (s, 2H), 5.92 (s, 1H), 5.11 (s, 2H), 5.01 (s, 1H), 3.60−3.68 (m, 10H), 3.55 (m, 4H), 3.46 (m, 2H), 3.38 (s, 3H), 2.45−2.35 (m, 2H), 1.84 (m, 2H), 1.65 (m, 2H), 1.45−1.34 (m, 11H). Mn = 15.1 kDa, Mw/Mn = 1.55. P7: 6-Oxohexanoic acid (135 mg, 1.04 mmol), isocyanide 1 (26 mg, 0.31 mmol), and isocyanide 3 (202 mg, 0.93 mmol) in 0.5 mL of CH2Cl2, 85% yield. Mn = 13.2 kDa, Mw/Mn = 1.48. P8: 6-Oxohexanoic acid (122 mg, 0.94 mmol), isocyanide 1 (12 mg, 0.14 mmol), and isocyanide 3 (215 mg, 0.99 mmol) in 0.5 mL of CH2Cl2, 90% yield. Mn = 12.8 kDa, Mw/Mn = 1.44. P9: 6-Oxohexanoic acid (145 mg, 1.12 mmol), isocyanide 1 (10 mg, 0.12 mmol), and isocyanide 3 (265 mg, 1.22 mmol) in 0.5 mL of CH2Cl2, 85% yield. Mn = 11.3 kDa, Mw/Mn = 1.48. Thiol−Ene Postmodification of P4 with TG. Polymer P4 (22 mg, 0.098 mmol alkenyl groups), TG (72 mg, 0.20 mmol), DMPA (4.5 mg, 0.018 mmol), and CH2Cl2 (2 mL) were added into a 5 mL round-bottom flask. The mixture was stirred under 365 nm UV lamp at room temperature for 24 h and then precipitated into diethyl ether (20 mL). A white solid (P4-TG) was obtained in 61% yield after vacuum dryness. Mn = 8.5 kDa, Mw/Mn = 1.34. Degradation of P3 in Aqueous Solution. Polymer P3 (Mn = 13.4 kDa, Mw/Mn = 1.45, 10 mg) was separately dissolved in D2O (600 μL), DCl solution (in D2O, 2 wt %, 600 μL), and NaOD solution (in D2O, 2 wt %, 600 μL) and then transferred into three NMR tubes incubated at 37 °C. 1H NMR measurements were conducted at different time to follow the scission of the main chain ester bonds. For

4.91 (m, 2H), 3.14−3.28 (m, 2H), 2.11−2.00 (m, 2H), 1.63−1.54 (m, 2H). 13C NMR (101 MHz, CDCl3, ppm): δ 164.77, 161.38, 137.50, 137.05, 115.81, 115.34, 41.04, 37.62, 30.96, 30.36, 30.09, 28.57. N-(4-Pentenyl)formamide (1.90 g, 16.8 mmol), tri-n-octylamine (11.93 g, 33.7 mmol), and p-tosyl chloride (6.43 g, 33.7 mmol) were transferred into a 25 mL round-bottom flask and heated under stirring to 80 °C within 1 h. 5-Isocyanopent-1-ene (4) can be distilled out under reduced pressure in 28% yield. 1H NMR (400 MHz, CDCl3, ppm): δ 5.76 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.14−5.03 (m, 2H), 3.44−3.36 (m, 2H), 2.22 (q, J = 7.1 Hz, 2H), 1.78 (m, 2H). 13C NMR (101 MHz, CDCl3, ppm): δ 156.02 (t), 136.08, 116.53, 40.74 (t), 30.17, 28.14. Synthesis of 5-Isocyanopent-1-yne (5). The synthesis of N-(4pentynyl)formamide is conducted in a similar way to the synthesis of N-(4-pentenyl)formamide, starting from 5-chloro-1-pentyne. A pale yellow oil was obtained as the pure product in 88% yield. 1H NMR (400 MHz, CDCl3, ppm) as 4:1 mixture of rotamers: δ 8.18 (s, 1H), 8.08 (d, J = 11.9 Hz, 1H, rotamers), 6.35 (s, 1H), 3.46−3.36 (m, 2H), 2.32−2.25 (m, 2H), 2.05−2.00 (m, 2H), 1.82−1.73 (m, 2H). 13C NMR (101 MHz, CDCl3, ppm) as 4:1 mixture of rotamers: δ 164.89, 161.52, 83.18, 82.46, 69.87, 69.32, 40.32, 37.20, 29.30, 27.93, 15.98, 15.31. 5-Isocyanopent-1-yne (5) was obtained in 25% yield from N-(4pentynyl)formamide following the same protocol as for the synthesis of compound 4. 1H NMR (400 MHz, CDCl3, ppm): δ 3.59−3.53 (m, 2H), 2.40 (td, J = 6.8, 2.7 Hz, 2H), 2.02 (t, J = 2.7 Hz, 1H), 1.94−1.86 (m, 2H). 13C NMR (101 MHz, CDCl3, ppm): δ 156.74 (t), 81.59, 70.02, 40.21 (t), 27.84, 15.43. Passerini Multicomponent Polymerization and Copolymerization. Take the synthesis of P1 as an example. 6-Oxohexanoic acid (144 mg, 1.11 mmol), 1 (110 mg, 1.33 mmol), and 0.6 mL of CH2Cl2 were sequentially transferred into a 25 mL Schlenk flask. The mixture was degassed by three freeze−pump−thaw cycles and stirred under N2 atmosphere at room temperature for 48 h. After precipitating the polymer solution into diethyl ether three times and dried under vacuum, P1 was recovered in 82% yield as a white solid. 1H NMR (400 MHz, CDCl3, ppm): δ 5.98 (s, 1H), 5.03 (s, 1H), 2.49−2.30 (m, 2H), 1.91−1.76 (m, 2H), 1.68 (s, 2H), 1.47−1.25 (m, 11H). Mn = 15.2 kDa, Mw/Mn = 1.36. P2, P3, P4, and P5 Were Synthesized Following the Same Protocols as P1. P2: 6-Oxohexanoic acid (140 mg, 1.08 mmol) and isocyanide 2 (170 mg, 1.30 mmol) in 0.5 mL of CH2Cl2, 77% yield. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.38 (s, 1H), 7.04 (s, 3H), 4.98 (s, 1H), 2.43 (m, 2H), 2.09 (s, 6H), 1.84 (m, 2H), 1.59 (m, 2H), 1.46 (m, 2H). Mn = 30.1 kDa, Mw/Mn = 1.87. P3: 6-Oxohexanoic acid (132 mg, 1.02 mmol) and isocyanide 3 (272 mg, 1.25 mmol) in 0.5 mL of CH2Cl2, 86% yield. 1H NMR (400 MHz, CDCl3, ppm): δ 6.61 (s, 1H), 5.12 (s, 1H), 3.60−3.68 (m, C

DOI: 10.1021/acs.macromol.6b00096 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. 1H and 13C NMR spectra of 6-oxohexanoic acid and P1 in CDCl3. the degradation of polymer P3 in phosphate buffer, polymer P3 (15 mg) was separately dissolved in 600 μL of deuterated phosphate buffer (0.10 M) at pD = 7.4, 5.8, and 8.4 and then transferred into three NMR tubes. The tube was incubated at 37 °C. The 1H NMR spectrum was recorded at specific time point. At the same time, 50 μL of the solution was taken out, followed by solvent removal, and applied for SEC measurement. Preparation of P1 Nanoparticles by Single Emulsion Method. The o/w single emulsion approach was applied for the preparation of the nanoparticles of P1 according to a reported procedure.44,45 Briefly, P1 (6 mg) was thoroughly dissolved in DCM (300 μL). This solution was added to a PVA solution (3 mL, 1% w/w in PB, pH = 7.4) and emulsified by sonicating for 60 s in an ice bath using a probe sonicator (JY96-II) with an output setting of 5 and a duty cycle of 50%. After removing DCM by stirring for 2 h at 35 °C, the nanoparticles were stored at 4 °C. Cytotoxicity Assay. PEG (Mw = 2000) and PEI dissolved in PB (50 mM, pH 7.4) were used as the negative and positive controls, respectively. P1 nanoparticles were used as above prepared, and P3 was directly dissolved in PB solutions. CCK-8 assay was used to assess the cytotoxicity of the samples to LO2 cells. The cells were seeded in the 96-well plates and incubated at 37 °C with 5% CO2 humidified atmosphere for 24 h. Then, 10 μL of the sample solutions with specific concentrations was added to each well; the cells were cultured for another 24 h and subjected to CCK-8 assay. The absorbance of the solution in each well was detected on a microplate reader at 450 nm. Cell viability (%) was defined as (Asample/Acontrol) × 100. The data were obtained in triplicate.

removal of the solvent, 6-oxohexanoic acid was stored in a N2 atmosphere at −20 °C. It is also very helpful to add a little antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT) in 6oxohexanoic acid to prevent it from oxidation. Since BHT does not interfere with the polymerization procedure, it was not removed before conducting the following polymerization. The isocyanides used in this work were synthesized by the known procedures upon dehydration from their corresponding formamide precursors which were prepared from halides and primary amines. The mOEG4 isocyanide 3 is prepared from the corresponding formamide (obtained upon reacting the commercial available amine with ethyl formate) using POCl3 as the dehydrant. For isocyanides 4 and 5, we initially tried to synthesize the corresponding amines, but they turned out to be very difficult to purify. Finally, we successfully synthesized the corresponding formamides by the SN2 transformation from the corresponding halides with sodium diformamide (Scheme 2).42 In accordance with the literature, it was found that the formamides obtained are composed of two rotamers as confirmed by the 1H NMR and 13C NMR spectra (Figure S1). The reason is that partial electron donation of the nitrogen atom to the carbonyl renders the nature of the C−N bond more akin to a double bond, decreasing the rotation of the C− N bond. The dehydration was carried out with p-tosyl chloride at high temperature, and the low boiling nature of isocyanides 4 and 5 allowed them to be distilled out under reduced pressure.43 The isocyanides 4 and 5 are not as stable upon storage as isocyanides 1, 2, and 3. Therefore, they were used as freshly prepared. The structures of isocyanides 3−5 were confirmed by 1H NMR and 13C NMR (Figure S2). Passerini Multicomponent Polymerization. Through the P-MCP of the AB-type monomer 6-oxohexanoic acid and isocyanides (C), we can easily prepare functional PCLs in a one-pot “AB + C” polymerization process (Scheme 1). Altering the isocyanides can afford different PCL analogues with the functional groups amide-linked to the ε-position of PCL backbone. In line with our previous results,39 polymerizations were performed in CH2Cl2 at room temperature. Since the isocyanide is the connecting component in the P-MCP, a moderate excess (20% excess) of isocyanide is needed to drive 6-oxohexanoic acid to complete consumption and get polymers

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RESULTS AND DISCUSSION Monomer Synthesis. The key monomer in this work is 6oxohexanoic acid, which was easily synthesized by oxidation of the commercial 1,2-diol-like 2-hydroxycyclohexanone dimer with sodium periodate according to a literature method (Scheme 2).41 The 1H NMR and 13C NMR spectra confirm the monomer structure (Figure 1). During the work-up, we found that the monomer was prone to oxidation. Once upon exposure to air, it quickly converted to adipic acid. Because of the step-growth nature of the P-MCP methodology, to obtain high molecular weight polymers, it is critical to prevent the oxidation of 6-oxohexanoic acid. Thus, the purification process, including washing with brine, drying, and the flash chromatography, should be carried out as fast as possible to minimize the contact of 6-oxohexanoic acid with air. After purification and D

DOI: 10.1021/acs.macromol.6b00096 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Table 1. Results of P-MCPa

with high molecular weight. Compared with the “A2 + B2 + C” MCP system, in an “AB + C” step-growth polymerization system, the rigorous requirement of stoichiometric balance of the carboxylic acid and aldehyde group is intrinsically established in 6-oxohexanoic acid. We also optimized several polymerization parameters by the polymerization of 6-oxohexanoic acid and tert-butyl isocyanide 1 (Table S1, Figure S3). As expected, higher monomer concentration and longer polymerization time favored both polymer yields and the molecular weights. Although running the polymerization for 96 h furnished polymers with a slightly higher molecular weight (Table S1, entries 2 and 3), we have ultimately established the protocol of P-MCP to be at 2 M for 48 h in CH2Cl2. After precipitating the polymer solution in diethyl ether, polymer 1 (85% yield) with a Mn = 15.2 kDa and a Mw/Mn = 1.36 was recovered. The relative low yield was because of the formation of low molecular weight cyclic oligomers which had been removed by precipitation (Table S1, entries 3 and 4). Indeed, after evaporating the remaining filtrate, ESI-MS of the residue revealed the existence of oligomeric cyclic species (Figure S4). The structure of P1 was characterized by 1H NMR, 13C NMR, and MALDI-TOF-MS (Figures 1 and 2). The proton

polymer

monomers

P1 P2 P3 P4 P5 P6 P7 P8 P9 P4-TG

M M M M M M M M M

+ + + + + + + + +

1 2 3 4 5 1 1 1 1

+ + + +

3g 3g 3g 3g

Mnb (kDa)

Mw/Mnb

yieldc (%)

Tdd (°C)

Tge (°C)

15.2 30.1f 14.8 7.8 11.2 15.1 13.2 12.8 11.3 8.5

1.36 1.87 1.44 1.28 1.35 1.55 1.48 1.44 1.48 1.34

82 77 86 74 83 87 85 90 85 61

315 303 316 291 310 320 324 319 318 178

58.4 115.6 −31.4 13.9 22.6 −11.1 −17.5 −25.9 −28.8 60.9

a Polymerizations are performed in CH2Cl2 at room temperature for 48 h, M = 6-oxohexanoic acid, [M] = 2 M. The isocyanides are fed 1.2 equiv to M. bDetermined by SEC with THF as eluent (1 mL/min, 35 °C) using polystyrene calibration. cCalculated based on polymers recovered after precipitation. dDetermined by TGA, 10 °C/min scan rate. Td is defined as the temperature when 5% weight loss occurs. e Determined by DSC, 10 °C/min scan rate. Values are recorded from the second scan data. fDetermined by SEC with DMF as eluent (1 mL/min, 50 °C) using polystyrene calibration. gFor copolymers P6− P9, the ratios of 1 to 3 are 1:2, 1:3, 1:7, and 1:10, respectively.

chloroform, and THF. Indeed, during the polymerization, P2 precipitated from the CH2Cl2 solution after about 12 h. Therefore, P2 was obtained in a slightly low yield, and the NMR and SEC characterizations were conducted in DMSO-d6 and DMF, respectively. Water-soluble P3 was obtained in 86% yield with isocyanide 3. Alkenyl and alkynyl side groups were introduced to PCL by the P-MCP with 4 and 5, respectively. All the 1H NMR and 13C NMR spectra are consistent with the expected structures of P2−P5 (Figures S5−S8). Besides, the MALDI-TOF-MS spectra of P2−P5 also confirmed their structural integrity and the existence of two topological species, i.e., linear and cyclic (Figures S9−S12). As indicated in SEC traces, all these polymers are with moderate to high molecular weights (Table 1, Figure S13), demonstrating the high efficiency and good functional tolerance of this P-MCP methodology. P1, P2, and P3 have relatively higher molecular weights, suggesting that isocyanides 1, 2, and 3 have higher reactivity toward Passerini reaction. Alkenyl-functionalized P4 and alkynyl-functionalized P5 have moderate molecular weights, which might be due to the relatively unstable nature of isocyanides 4 and 5. To further realize the structural diversity and tailor the polymer properties, copolymerization through the P-MCPs of 6-oxohexanoic acid and a mixture of 1 and 3 in different molar ratios were carried out (Table 1, P6−P9). Copolymers with high molecular weights were obtained as confirmed by SEC (Figure S13). The structures of copolymers P6−P9 were identified by 1H NMR spectra (Figure S14). Peaks a and c correspond to the repeating units bearing OEG side groups, while peaks b and d correspond to that bearing tert-butyl side groups. The copolymer compositions are calculated from the average of ratios b/a or d/c. Slight discrepancy between the feed ratios and copolymer compositions exists as a result of the different reactivity between the two isocyanides; tert-butyl isocyanide 1 appears to be more reactive than mOEG4isocyanide 3. Thiol−Ene Postmodification. The pendant alkenyl groups of P4 can be further modified by thiol−ene click reaction. Thus, the postmodification of P4 with a thiol−glucose was conducted

Figure 2. MALDI-TOF-MS spectrum of polymer P1.

signals a and g of P1 are the characteristic peaks generated in Passerini reaction. The MALDI-TOF-MS spectrum of P1 displays two series of peaks, both separated by intervals of 213 Da which corresponds to the molar mass of the repeating unit of P1 (213.3 Da). These two series of peaks can be assigned to linear and cyclic polymeric species, respectively. Thus, via the P-MCP of 6-oxohexanoic acid and 1, we provide the first example of PCL analogues with the amide-linked side group at the ε-position. To expand the scope of this polymerization and get more PCL analogues with different side groups, we conducted the PMCP of 6-oxohexanoic acid with isocyanides 2, 3, 4, and 5 under similar conditions (Table 1). Owing to the rigid phenyl side groups and the amide linkage to the PCL backbone, P2 shows poor solubility in common solvents like CH2Cl2, E

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Figure 3. TGA thermograms of polymers.

Figure 4. DSC thermograms of polymer.

Figure 5. (a) SEC traces and (c) 1H NMR spectra of P3 monitored during degradation in pD = 7.4 deuterated PB at 37 °C. Ed denotes the percentage of ester bond cleavage. (b) Degradation product in PB.

pendant alkenes or alkynes.48 In the second stage, these polymers suffered from catastrophic decomposition. The modified polymer sample P4-TG exhibits significantly lower decomposition temperature compared with the unmodified P4, probably owing to its labile thiol−ether linkages. In contrast to semicrystalline PCL which has a melting peak around 60 °C, these PCL analogues do not show melting peaks in the DSC thermograms (Figure 4 and Table 1), probably because the introduction of side groups disrupts the backbone packing. Polymer P1 has a Tg of 58.4 °C. For polymer P2 with a rigid aromatic side group, it exhibits a Tg as high as 115.6 °C. By contrast, P3 has a Tg of −31.4 °C due to its pendent flexible

by the radical-mediated thiol−ene click chemistry to afford P4TG.46,47 The signals of the alkenyl protons completely disappeared after modification, as suggested by 1H NMR (Figure S15), which confirmed the complete addition of TG onto the pendant alkenyls. As expected, the SEC traces of P4TG shifted to a shorter elution time as compared with that of P4 (Figure S16). Thermal Properties of the Polymers. Most of these PCL analogues start to decompose around 300 °C when the pyrolysis of polyester backbones takes place (Figure 3, Table 1). P4 and P5 display a two-stage weight loss. The first stage shows only a slight weight loss, suggesting the pyrolysis of F

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Figure 6. MALDI-TOF-MS of P3 degraded in pD = 7.4 deuterated PB after 25 days at 37 °C.

OEG segments. P4-TG has a Tg around 60 °C, much higher than that of the unmodified P4 (13.9 °C), owing to the bulky rigid glucose group. For copolymers P6−P9, more OEG contents decrease the Tg and more tert-butyl contents increase the Tg. Therefore, the Tg of these copolymers can be finely tuned by varying the ratios of the two isocyanides, 1 and 3. The Tg of a copolymer is described by the Fox equation49

repeating units, and it can thus be estimated by the integrals of peak c to that of peak a (Ed = Ic/(Ic + Ia)). After 16 days, the Ed reached 10%, and it reached 15% after 25 days. As shown in SEC, the molecular weight of P3 drastically decreased while only a low percentage of ester bond cleavage occurred; hence, we suppose that the degradation may follow a random ester hydrolysis. The MALDI-TOF-MS spectrum of the degradation product clearly shows two types of species, which further supports our speculation (Figure 6). Generally, aliphatic polyesters hydrolyzed very slowly in neutral phosphate buffer, but in our PCL analogues, the ester bond was formed by a secondary alcohol linked with an electron-accepting amide group; this structural difference may account for the hydrolysis even in neutral phosphate buffer. Similar results have been observed in a recent report on the hydrolysis of water-soluble polycarbonate.50 The polycarbonate containing a side carboxylic group can also be degraded in pH 7.4 PB prepared in D2O solvent. We have also investigated the degradation of P3 in PBs with pD = 5.8 and 8.4. At pD = 5.8, the hydrolysis of main chain ester bonds rarely happened and the decrease of molecular weight over 2 weeks was very slow, as observed in both 1H NMR spectra and SEC traces (Figures S20 and S21). However, at pD = 8.4, a gradual decrease of molecular weight with incubation time was observed, concomitant with the increase of ester bond cleavage (Figures S22 and S23). The timedependent extent of degradation and molecular weight at three pDs was plotted and compared (Figures S24 and S25), which confirmed that P3 degraded faster in alkaline conditions than in acidic ones. Cytotoxicity of Polymers P1 and P3. It is important to ensure the biocompatibility of functional PCLs since they are usually used in biomedical applications. Therefore, we measured the cytotoxicity of polymers P1 and P3. As shown in Figure 7, both P1 and P3 do not exhibit toxicity to LO2 cells over a range of polymer concentration, indicating good cytocompatibility of P1 and P3. This result falls within our expectation because the excellent biocompatibility of PCL is well-known.9

wP1/TgP1 + wP3/TgP3 = 1/Tg

where wP1 and wP3 are the weight fractions of both repeating units. Using the measured Tg for the “homopolymer” P1 and P3, and upon converting to Kelvin scale (331.6 and 241.8 K, repectively, Table 1), the calculated Tg values for the copolymers P6−P9 are −11.8, −17.8, −25.0, and −26.9 °C, which match the experimental data very well (−11.1, −17.5, −25.9, and −28.8 °C, Table 1). The Tgs of all these polymer samples span a wide temperature range of roughly 150 °C, demonstrating the profound influence of side groups on the segment mobility of PCLs. Degradation of Polymer P3 in Aqueous Solution. Polymer P3 is water-soluble, enabling us to study its degradation in aqueous solution. P3 was stable up to 15 days in D2O at 37 °C as confirmed by both 1H NMR and SEC (Figures S17 and S18). As expected, in aqueous acid and alkaline conditions, P3 was not stable and hydrolyzed quickly. For example, in DCl (2 wt % in D2O) at 37 °C, about 50% of the main chain ester bond had been hydrolyzed over 6 h, and complete hydrolysis was observed in 24 h. The hydrolysis of P3 in NaOD (2 wt % in D2O) was even faster, and after 6 h, the hydrolysis degradation was complete as demonstrated by 1H NMR (Figure S19). This shows that P3 is more susceptible to degradation in alkaline conditions than in acidic ones. Interestingly, when P3 was dissolved in pH 7.4 phosphate buffer (PB) prepared in D2O solvent and incubated at 37 °C, we also observed the degradation by both NMR and SEC (Figure 5). In the time-dependent SEC traces (Figure 5a), a gradual decrease of polymer molecular weights with incubation time was observed over a 25 day period. This indicates the ester bonds had been broken with the formation of two oligomers with the end groups being hydroxyl group or carboxylate group (Figure 5b). Peak c corresponds to the methine protons adjacent to the hydroxyl groups, and peak d corresponds to the methylene protons adjacent to the carboxylate group, both of them are generated from the direct ester hydrolysis. The extent of degradation (Ed) is defined as the percentage of the degraded

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CONCLUSIONS We have demonstrated a facile straightforward strategy for the preparation of a novel class of diversely functionalized PCL analogues via the P-MCP of 6-oxohexanoic acid and different isocyanides. We have also illustrated the versatility of this new G

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(5) Hillmyer, M. A.; Tolman, W. B. Aliphatic Polyester Block Polymers: Renewable, Degradable, and Sustainable. Acc. Chem. Res. 2014, 47, 2390. (6) Yu, Y.; Zou, J.; Cheng, C. Synthesis and biomedical applications of functional poly(alpha-hydroxyl acid)s. Polym. Chem. 2014, 5, 5854. (7) Rainbolt, E. A.; Washington, K. E.; Biewer, M. C.; Stefan, M. C. Recent developments in micellar drug carriers featuring substituted poly(epsilon-caprolactone)s. Polym. Chem. 2015, 6, 2369. (8) Place, E. S.; George, J. H.; Williams, C. K.; Stevens, M. M. Synthetic polymer scaffolds for tissue engineering. Chem. Soc. Rev. 2009, 38, 1139. (9) Woodruff, M. A.; Hutmacher, D. W. The return of a forgotten polymer-Polycaprolactone in the 21st century. Prog. Polym. Sci. 2010, 35, 1217. (10) Hao, J.; Rainbolt, E. A.; Washington, K.; Biewer, M. C.; Stefan, M. C. Synthesis of Functionalized Poly(caprolactone)s and Their Application as Micellar Drug Delivery Systems. Curr. Org. Chem. 2013, 17, 930. (11) Labet, M.; Thielemans, W. Synthesis of polycaprolactone: a review. Chem. Soc. Rev. 2009, 38, 3484. (12) Seyednejad, H.; Ghassemi, A. H.; van Nostrum, C. F.; Vermonden, T.; Hennink, W. E. Functional aliphatic polyesters for biomedical and pharmaceutical applications. J. Controlled Release 2011, 152, 168. (13) Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.; Lohmeijer, B. G. G.; Hedrick, J. L. Organocatalytic ring-opening polymerization. Chem. Rev. 2007, 107, 5813. (14) Coulembier, O.; Degee, P.; Hedrick, J. L.; Dubois, P. From controlled ring-opening polymerization to biodegradable aliphatic polyester: Especially poly(beta-malic acid) derivatives. Prog. Polym. Sci. 2006, 31, 723. (15) Pounder, R. J.; Dove, A. P. Towards poly(ester) nanoparticles: recent advances in the synthesis of functional poly(ester)s by ringopening polymerization. Polym. Chem. 2010, 1, 260. (16) Lecomte, P.; Riva, R.; Schmeits, S.; Rieger, J.; Van Butsele, K.; Jerome, C.; Jerome, R. New prospects for the grafting of functional groups onto aliphatic polyesters. Ring-opening polymerization of alpha- or gamma-substituted epsilon-caprolactone followed by chemical derivatization of the substituents. Macromol. Symp. 2006, 240, 157. (17) El Habnouni, S.; Blanquer, S.; Darcos, V.; Coudane, J. Aminated PCL-Based Copolymers by Chemical Modification of Poly(alphaiodo-epsilon-caprolactone-co- epsilon-caprolactone). J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 6104. (18) Darcos, V.; El Habnouni, S.; Nottelet, B.; El Ghzaoui, A.; Coudane, J. Well-defined PCL-graft-PDMAEMA prepared by ringopening polymerisation and click chemistry. Polym. Chem. 2010, 1, 280. (19) El Habnouni, S.; Nottelet, B.; Darcos, V.; Porsio, B.; Lemaire, L.; Franconi, F.; Garric, X.; Coudane, J. MRI-Visible Poly(epsiloncaprolactone) with Controlled Contrast Agent Ratios for Enhanced Visualization in Temporary Imaging Applications. Biomacromolecules 2013, 14, 3626. (20) Cheng, Y.; Hao, J.; Lee, L. A.; Biewer, M. C.; Wang, Q.; Stefan, M. C. Thermally Controlled Release of Anticancer Drug from SelfAssembled gamma-Substituted Amphiphilic Poly(epsilon-caprolactone) Micellar Nanoparticles. Biomacromolecules 2012, 13, 2163. (21) Hao, J.; Cheng, Y.; Ranatunga, R. J. K. U.; Senevirathne, S.; Biewer, M. C.; Nielsen, S. O.; Wang, Q.; Stefan, M. C. A Combined Experimental and Computational Study of the Substituent Effect on Micellar Behavior of gamma-Substituted Thermoresponsive Amphiphilic Poly(epsilon-caprolactone)s. Macromolecules 2013, 46, 4829. (22) Senevirathne, S. A.; Boonsith, S.; Oupicky, D.; Biewera, M. C.; Stefan, M. C. Synthesis and characterization of valproic acid ester prodrug micelles via an amphiphilic polycaprolactone block copolymer design. Polym. Chem. 2015, 6, 2386. (23) Rainbolt, E. A.; Miller, J. B.; Washington, K. E.; Senevirathne, S. A.; Biewer, M. C.; Siegwart, D. J.; Stefan, M. C. Fine-tuning

Figure 7. LO2 cell viability measured by CCK-8 assay.

polymerization platform by thiol−ene postmodification and copolymerization of a mixture of isocyanides with 6oxohexanoic acid. These polymers are all amorphous materials with a wide spectrum of Tgs depending on the side groups and copolymer composition. The water-soluble mOEG-functionalized PCL was found to be stable in deuterated water or pD = 5.8 PB, it degraded quickly in strong alkaline or acidic conditions. Interestingly, even in neutral phosphate buffer solution, this polymer degraded steadily in a random hydrolysis fashion. Two representative polymer samples exhibited no cytotoxicity. Therefore, this work not only provides a facile strategy toward new PCL analogues with tunable properties but also expands the scope of degradable polyesters available for biomedical applications.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b00096. Figures S1−S25 and Table S1 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected]; Tel +86-10-6275-5543; Fax +86-106275-1708 (Z.-C.L.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is financially supported by National Natural Science Foundation of China (No. 21225416 and 21534001). REFERENCES

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