Article pubs.acs.org/Macromolecules
Clickable Polylactic Acids by Fast Organocatalytic Ring-Opening Polymerization in Continuous Flow Sebastiaan A. van den Berg,† Han Zuilhof,*,†,‡ and Tom Wennekes*,†,§ †
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB, Wageningen, The Netherlands Department of Chemical and Materials Engineering, King Abdulaziz University, Jeddah, Saudi Arabia § Department of Chemical Biology and Drug Discovery and Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands ‡
S Supporting Information *
ABSTRACT: The use of microreactor technology for the ring-opening polymerization of L-lactide catalyzed by 1,5,7triazabicyclo[4.4.0]dec-5-ene allows for rapid optimization of reaction parameters (reaction temperature and residence time). At moderate catalyst loading, good control over the polymerization is demonstrated by high conversion of monomer (>95%) and low polydispersity (99.8%) were purified over aluminum oxide under argon using a Pure Solv 400 solvent purification system (Innovative Technology, Amesbury, MA). (3S)-cis-3,6-Dimethyl-1,4-dioxane-2,5-dione (L-lactide, Aldrich, 98%) was recrystallized twice from dry toluene and dried under vacuum. Benzoic acid (Sigma-Aldrich, 99.5%) was used as received. 1,5,7Triazabicyclo[4.4.0]dec-5-ene (TBD, Aldrich, 98%) is very moisture sensitive and was therefore stored in a glovebox under an argon atmosphere. 4-tert-Butylbenzyl alcohol, 1 (Aldrich, 98%), was stored on 4 Å mol sieves. ((1R,8S,9r)-Bicyclo[6.1.0]non-4-yn-9-yl)methanol (exo-BCN-alcohol 3)35 and 9-(azidomethyl)anthracene, 5, were prepared according to literature procedures.50 (4-(6-Methyl-1,2,4,5tetrazin-3-yl)phenyl)methanol (tetrazine 4) was prepared according to a literature procedure, 51 purified with dry column vacuum chromatography (heptane:ethyl acetate, 0%−60%, 5% increase in G
DOI: 10.1021/acs.macromol.5b02533 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules 1
of the glovebox, 2 mL of a solution of 4-tert-butylbenzyl alcohol solution (0.1 M, 0.164 g in 10 mL of DCM) and DCM was added to the 10 mL mark. A fresh monomer solution (1.6 M, 1.15 g in 5 mL of DCM) was prepared. 0.2 mL of each solution was added to oven-dried vials under a nitrogen flow. The temperature in the lab was 20 °C. After 3 s, 0.5 mL of a benzoic acid solution (0.2 M, 0.23 g in 10 mL of DCM) was added to quench the reaction. The solvent was removed by nitrogen flow. The conversion was measured using 1H NMR. To compare these results with flow, the same solutions were used in the microreactor setup. The temperature was set to 20 °C, the same as in the lab. After an equilibration time of 20 min, the output was collected and analyzed by 1H NMR after removal of solvent. L-Lactide Polymerization Initiated from BCN-Alcohol 3. As above, TBD (32 mg, 0.23 mmol) was weighed into a 10 mL volumetric flask inside the glovebox. To this flask was added exo-BCNalcohol 3 (28 mg, 0.19 mmol). The polymerization in the microreactor was performed as above. After obtaining optimal reaction conditions, the output of the microreactor was collected for 50 min to yield 152 mg BCN−PLA. L-Lactide Polymerization Initiated from Tetrazine-Alcohol 4. As above, TBD (27.0 mg, 0.19 mmol) was weighed into a 10 mL volumetric flask inside the glovebox. Under the above conditions (TBD and initiator in one flask), the tetrazine is not stable. Therefore, a new stock solution of L-lactide was made (1.15 g, 7.99 mmol) in 5 mL of distilled DCM. To this flask was added tetrazine-derived alcohol 4 (20 mg, 0.10 mmol). The polymerization in the microreactor was performed as above. After obtaining optimal reaction conditions, the output of the microreactor was collected for 50 min to yield 171 mg of tetrazine−PLA. SPAAC Reaction with Azidoanthracene and BCN−PLA. To 12 mg of BCN−PLA (0.001 mmol) in DCM (1 mL) was added 9(azidomethyl)anthracene 5 (5.5 mg, 0.024 mmol). This solution was stirred rt for 6 h. After this time, the polymer was precipitated twice in diethyl ether and isolated by centrifuge at 5000 rpm for 2 min. The resulting white precipitate was dried in vacuo and analyzed using GPC and 1H NMR. SPAAC Reaction with PEG-5000-N3 and BCN−PLA. In a GC vial was 27 mg of PEG-5000-N3 2 (0.0054 mmol). To this was added 1.0 mL of solution of BCN−PLA in DCM (0.005 mmol, Mn 28 000 g/ mol, PDI 1.24), and the resulting solution was stirred at rt. After 24 and 48 h, samples were taken and analyzed using GPC. SPAAC Reaction with N-Acetylgalactosamine Derivative 6 and BCN−PLA. To 12 mg of BCN−PLA (0.001 mmol) in hexafluoroisopropanol (0.5 mL) was added N-acetylgalactosamine derivative 6 (3.0 mg, 0.037 mmol). This solution was stirred at rt for 20 h. After this time, the suspension was filtered over cotton and precipitated into diethyl ether. After isolation by centrifugation (5000 rpm, 1 min), the resulting solid was redissolved in DCM and filtered again over cotton. The solvent was removed in vacuo, and the resulting polymer was analyzed using 1H NMR. Inverse Electron Demand Diels−Alder Reaction with Tetrazine−PLA and 5-Norbornene-2-carboxylic Acid. To 15 mg of purified tetrazine−PLA (0.0013 mmol) in 0.5 mL of DCM was added five drops of 5-norbornene-2-carboxylic acid (8). The resulting purple solution was kept at rt for 16 h. After this time, the solution had turned colorless. The polymer was precipitated twice from diethyl ether and analyzed by 1H NMR. Inverse Electron Demand Diels−Alder Reaction with Tetrazine−PLA and BCN−PLA. To 47 mg of tetrazine−PLA (0.004 mmol) was added 50 mg of BCN−PLA (0.004 mmol) and DCM (1 mL). The resulting purple solution was stirred at rt for 16 h, after which it was nearly colorless, purified by precipitation from diethyl ether, and analyzed with GPC and 1H NMR.
■
■
H NMR spectra of polymers and compounds, tabulated data of polymerization reactions, GPC traces, and selected graphs (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail
[email protected] (H.Z.). *E-mail
[email protected] (T.W.). Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work is supported by NanoNextNL (program 10C), a micro and nanotechnology consortium of the Government of The Netherlands and 130 partners, and The Netherlands Organization for Scientific Research (NWO VENI grant 722.011.006). The authors thank Dr. Jaime Garcia Hartjes for synthesizing and characterizing GalNAc derivative 6, Judith Firet for synthesis of BCN-alcohol 3, and Dr. Maarten Smulders for insightful discussions. The authors thank Henk Janssen and Xianwen Lou (TU/e, Eindhoven) for MALDIToF-MS measurements.
■
REFERENCES
(1) Wilms, D.; Klos, J.; Frey, H. Macromol. Chem. Phys. 2008, 209, 343−356. (2) Tonhauser, C.; Wilms, D.; Wurm, F.; Nicoletti, E. B.; Maskos, M.; Löwe, H.; Frey, H. Macromolecules 2010, 43, 5582−5588. (3) Iida, K.; Chastek, T. Q.; Beers, K. L.; Cavicchi, K. A.; Chun, J.; Fasolka, M. J. Lab Chip 2009, 9, 339−345. (4) Baeten, E.; Verbraeken, B.; Hoogenboom, R.; Junkers, T. Chem. Commun. (Cambridge, U. K.) 2015, 51, 11701−4. (5) Geyer, K.; Codee, J. D.; Seeberger, P. H. Chem. - Eur. J. 2006, 12, 8434−8442. (6) Tonhauser, C.; Natalello, A.; Löwe, H.; Frey, H. Macromolecules 2012, 45, 9551−9570. (7) Simón, L.; Goodman, J. M. J. Org. Chem. 2007, 72, 9656−9662. (8) Kiesewetter, M. K.; Scholten, M. D.; Kirn, N.; Weber, R. L.; Hedrick, J. L.; Waymouth, R. M. J. Org. Chem. 2009, 74, 9490−9496. (9) Hornung, C. H.; Guerrero-Sanchez, C.; Brasholz, M.; Saubern, S.; Chiefari, J.; Moad, G.; Rizzardo, E.; Thang, S. H. Org. Process Res. Dev. 2011, 15, 593−601. (10) Derboven, P.; Van Steenberge, P. H. M.; Vandenbergh, J.; Reyniers, M.-F.; Junkers, T.; D’Hooge, D. R.; Marin, G. B. Macromol. Rapid Commun. 2015, 36, 2149−2155. (11) Shen, Y.; Zhu, S. AIChE J. 2002, 48, 2609−2619. (12) Diehl, C.; Laurino, P.; Azzouz, N.; Seeberger, P. H. Macromolecules 2010, 43, 10311−10314. (13) Kundu, S.; Bhangale, A. S.; Wallace, W. E.; Flynn, K. M.; Guttman, C. M.; Gross, R. A.; Beers, K. L. J. Am. Chem. Soc. 2011, 133, 6006−11. (14) Natalello, A.; Morsbach, J.; Friedel, A.; Alkan, A.; Tonhauser, C.; Müller, A. H. E.; Frey, H. Org. Process Res. Dev. 2014, 18, 1408−1412. (15) Melker, A.; Fors, B. P.; Hawker, C. J.; Poelma, J. E. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2693−2698. (16) Leibfarth, F. A.; Johnson, J. A.; Jamison, T. F. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 10617−10622. (17) Jamshidian, M.; Tehrany, E. A.; Imran, M.; Jacquot, M.; Desobry, S. Compr. Rev. Food Sci. Food Saf. 2010, 9, 552−571. (18) Institute for Bioplastics and Biocomposites: Material share of biopolymer production capacity. http://ifbb.wp.hs-hannover.de/ downloads/content/Statistics/Market%20statistics/ P ro d u c ti o n % 2 0 c a p a c i t i e s / By % 20 m a t e r i a l % 2 0 t y p e / 2 0 1 3 / Material%20share%20of%20biopolymer%20production%20capaci ty%20sorted%20by%20material%20grade%202013.png (August 25, 2015).
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.5b02533. H
DOI: 10.1021/acs.macromol.5b02533 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules (19) Dove, A. P. ACS Macro Lett. 2012, 1, 1409−1412. (20) Lohmeijer, B. G. G.; Pratt, R. C.; Leibfarth, F.; Logan, J. W.; Long, D. A.; Dove, A. P.; Nederberg, F.; Choi, J.; Wade, C.; Waymouth, R. M.; Hedrick, J. L. Macromolecules 2006, 39, 8574− 8583. (21) Saito, T.; Aizawa, Y.; Tajima, K.; Isono, T.; Satoh, T. Polym. Chem. 2015, 6, 4374−4384. (22) Dove, A. P.; Li, H.; Pratt, R. C.; Lohmeijer, B. G. G.; Culkin, D. A.; Waymouth, R. M.; Hedrick, J. L. Chem. Commun. 2006, 2881− 2883. (23) Guillerm, B.; Lemaur, V.; Ernould, B.; Cornil, J.; Lazzaroni, R.; Gohy, J.-F.; Dubois, P.; Coulembier, O. RSC Adv. 2014, 4, 10028. (24) Jung, H.; Brummelhuis, N. t.; Yang, S. K.; Weck, M. Polym. Chem. 2013, 4, 2837. (25) Barker, I. A.; Hall, D. J.; Hansell, C. F.; Du Prez, F. E.; O’Reilly, R. K.; Dove, A. P. Macromol. Rapid Commun. 2011, 32, 1362−6. (26) Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2006, 128, 4556−4557. (27) Horn, H. W.; Jones, G. O.; Wei, D. S.; Fukushima, K.; Lecuyer, J. M.; Coady, D. J.; Hedrick, J. L.; Rice, J. E. J. Phys. Chem. A 2012, 116, 12389−12398. (28) Leibfarth, F. A.; Moreno, N.; Hawker, A. P.; Shand, J. D. J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 4814−4822. (29) Garcia Hartjes, J.; Bernardi, S.; Weijers, C. A. G. M.; Wennekes, T.; Gilbert, M.; Sansone, F.; Casnati, A.; Zuilhof, H. Org. Biomol. Chem. 2013, 11, 4340−4349. (30) Kallemeijn, W. W.; Witte, M. D.; Wennekes, T.; Aerts, J. M. F. G.; Derek, H. In Advances in Carbohydrate Chemistry and Biochemistry; Academic Press: 2014; Vol. 71, Chapter 4, pp 297−338. (31) Duval, F.; van Beek, T. A.; Zuilhof, H. Analyst 2015, 140, 6467− 6472. (32) Verrecchia, T.; Spenlehauer, G.; Bazile, D. V.; Murry-Brelier, A.; Archimbaud, Y.; Veillard, M. J. Controlled Release 1995, 36, 49−61. (33) Mackiewicz, N.; Nicolas, J.; Handké, N.; Noiray, M.; Mougin, J.; Daveu, C.; Lakkireddy, H. R.; Bazile, D.; Couvreur, P. Chem. Mater. 2014, 26, 1834−1847. (34) Lutz, J. F. Angew. Chem., Int. Ed. 2007, 46, 1018−25. (35) Dommerholt, J.; Schmidt, S.; Temming, R.; Hendriks, L. J.; Rutjes, F. P.; van Hest, J. C.; Lefeber, D. J.; Friedl, P.; van Delft, F. L. Angew. Chem., Int. Ed. 2010, 49, 9422−5. (36) Guo, J.; Chen, G.; Ning, X.; Wolfert, M. A.; Li, X.; Xu, B.; Boons, G. J. Chem. - Eur. J. 2010, 16, 13360−13366. (37) Zheng, J.; Liu, K.; Reneker, D. H.; Becker, M. L. J. Am. Chem. Soc. 2012, 134, 17274−7. (38) Ledin, P. A.; Kolishetti, N.; Hudlikar, M. S.; Boons, G. J. Chem. Eur. J. 2014, 20, 8753−8760. (39) Wang, S.; Yang, X.; Zhu, W.; Zou, L.; Zhang, K.; Chen, Y.; Xi, F. Polymer 2014, 55, 4812−4819. (40) Hansell, C. F.; Espeel, P.; Stamenovic, M. M.; Barker, I. A.; Dove, A. P.; Du Prez, F. E.; O’Reilly, R. K. J. Am. Chem. Soc. 2011, 133, 13828−31. (41) A residence time of 2 s is almost the fastest that this setup allows. Shorter residence times require higher flow rates that may damage the microreactor chip. (42) Duda, A.; Kowalski, A.; Libiszowski, J.; Penczek, S. Macromol. Symp. 2005, 224, 71−84. (43) Witzke, D. R.; Narayan, R.; Kolstad, J. J. Macromolecules 1997, 30, 7075−7085. (44) Micic, N.; Young, A.; Rosselgong, J.; Hornung, C. Processes 2014, 2, 58−70. (45) Martello, M. T.; Burns, A.; Hillmyer, M. ACS Macro Lett. 2012, 1, 131−135. (46) Tuba, R.; Grubbs, R. H. Polym. Chem. 2013, 4, 3959−3962. (47) Hong, M.; Chen, E. Y. X. Nat. Chem. 2016, 8, 42−49. (48) Knall, A.-C.; Slugovc, C. Chem. Soc. Rev. 2013, 42, 5131−42. (49) Karver, M. R.; Weissleder, R.; Hilderbrand, S. A. Bioconjugate Chem. 2011, 22, 2263−2270. (50) Tosic, O.; Mattay, J. Eur. J. Org. Chem. 2011, 2011, 371−376.
(51) Yang, J.; Karver, M. R.; Li, W.; Sahu, S.; Devaraj, N. K. Angew. Chem., Int. Ed. 2012, 51, 5222−5. (52) Mandal, S.; Sharma, N.; Mukhopadhyay, B. Synlett 2009, 2009, 3111−3114.
I
DOI: 10.1021/acs.macromol.5b02533 Macromolecules XXXX, XXX, XXX−XXX
