1. Rapid Carbanionic and Oxyanionic Polymerizations Transferred to Continuous Microfluidic Systems: Recent Results and Perspectives Holger Frey Adrian Natalello, Jan Morsbach, Andreas Friedel, Christoph Tonhauser, Daniel Wilms University of Mainz Institute of Organic and Macromolecular Chemistry Duesbergweg 10-14 55099 Mainz, Germany December 4, 2014, Paris

2. 2 Hessel, V.; Serra, C.; Löwe, H.; Hadziioannou, G. Chem. Ing. Tech. 2005, 77, 1693. Polymerization „Reactors“

3. 3 Review Articles D. Wilms, J. Klos, H. Frey, Macromol. Chem. Phys. 2008, 209(4), 343-356. C. Tonhauser, A. Natalello, H. Löwe, H. Frey, Macromolecules 2012, 45, 9551-9570.

4. 4 Outline Carbanionic / Oxyanionic Polymerization in Continuous Flow Living Carbanionic Polymerization: Introduction Use of Micromixing Devices for Carbanionic Polymerization End-Functional Polymers Synthesis of Block Copolymers by Carbanionic Polymerization Controlled Polydispersity via Microfluidic Strategies Oxyanionic Polymerization in Microfluidic Devices Conclusion and Perspectives

5. 5  Micromixer: Fast Mixing, Excellent Heat Dissipation, Continuous  Problems: Mixing, Heat Dissipation, Sensitivity, Reaction Times ? Living Carbanionic Polymerization Characteristics: Precise Control over Molecular Weight (via M/I), Low Polydispersity Mostly Rapid Polymerization, even at Low Temperatures Living Character  Various Macromolecular Architectures Inherently Sensitive to Impurities Commonly Highly Exothermic Living Anions “on Tap“ SIMM-V2 HP-IMM

6. Polymerization in Continuous Flow Tonhauser, C.; Natalello, A.; Löwe, H.; Frey, H. Macromolecules. 2012, 45 (25), 9551–9570. Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Angew. Chem. Int. Ed. 2004, 43, 406-446. Wilms, D.; Klos, J.; Frey, H. Macromol. Chem. Phys. 2008, 209, 343-356. Wurm, F.; Wilms, D.; Klos, J.; Löwe, H.; Frey, H. Macromol. Chem. Phys. 2008, 209, 1106-1114. 6 Effective mixing High surface-to- volume ratio Small internal volume High chemical and mechanical resistance

7. Multilamination Mixing Device 7 ParameterSIMM-V2 Mixing principlesMulti-lamination Size (L x B x H) / mm30 x 40 x 30 Temperature / °C-40 – 220 Pressure stability / bar100 Inner volume / µL8 Slit Interdigital Micromixers: Laminar Mixing

8. 8 Living Anionic Polymerization of Styrene High Rate Constants (Dependent on Solvent, Temperature, Concentration) Wurm, F.; Wilms, D.; Klos, J.; Löwe, H.; Frey, H. Macromol. Chem. Phys. 2008, 209, 1106 1.Solvent: Cyclohexane  Non-Polar Reaction Medium

9. 9 Carbanionic Polymerization in Non-Polar Medium SampleM n (theor.) M n (SEC) M w /M n (SEC) PS-15005701.25 PS-22,0003,0001.09 PS-33,0003,3001.10 PS-46,0008,0001.08 PS-520,00024,0001.11 PS-630,00032,0001.21 SEC (THF) RI Detection Flow Rates: 1 – 3.5 mL/min Residence Times:40 – 120 s Narrow Molecular Weight Distribution Convenient Adjustment of Molecular Weight at Varying Flow Rate Ratios

10. 10 Carbanionic Polymerization in Non-Polar Medium SampleM n (theor.) M n (SEC) M w /M n (SEC) PS-15005701.25 PS-22,0003,0001.09 PS-33,0003,3001.10 PS-46,0008,0001.08 PS-520,00024,0001.11 PS-630,00032,0001.21 1 H-NMR (CDCl 3 ) MALDI-ToF MS Full Conversion (NMR spectroscopy) Quantitative Functionalization (MALDI-ToF-MS)

11. 11 Solvent: THF  Polar Reaction Medium Extremely Fast Kinetics; Control in Conventional Set-Up Only Possible at Low Temperature Fast Mixing and Excellent Heat Transfer in the Microstructured Reaction Device Permit Continuous Synthesis of Well-Defined Polystyrenes at 25°C Carbanionic Polymerization in Polar Medium

12. 12 Polar Medium (THF): Room Temperature (!) Sample M n (theor.) M n (SEC) M w /M n (SEC) PS-7 2,000 1,7001.28 PS-8 3,000 2,3001.14 PS-9 4,000 3,6001.11 PS-10 5,000 6,4001.10 PS-11 6,000 6,9001.09 PS-12 10,000 10,5001.14 PS-13 12,000 11,3001.09 PS-14 15,000 17,0001.10 PS-15 40,000 42,2001.24 PS-16 60,000 71,0001.25 SEC (THF) RI Detection Flow Rates: 0.8 – 2.6 mL/min Residence Times:1.6 – 5.0 s

13. 13 Conventional Approach vs. Micromixing Molecular WeightsBroad Range Polydispersity≤ 1.05Mostly ≤ 1.15 Temperature ≤ - 60°C in Polar Solvents≥ 25 °C Reaction TimesHoursSeconds Versatility One Sample/Experiment Several Samples/Experiment Living Carbanionic Polymerization of Styrenic Monomers: Batch Reactor vs. Microstructured Reactor

14. 14 Versatile Synthesis of End-Functional Polymers Conventional Access to End-Functional Polymers via Carbanionic Polymerization Termination Agents: Chlorosilane, Diphenylethlene (DPE) and Epoxides Epoxide Derivatives  Quantitative Functionalization (Quirk et al.) EEGE (Ethoxy Ethyl Glycidyl Ether) Quirk, R. et al. Macromol. Symp. 2000, 161, 37-44. Quirk, P. R.; Gomochak, D. L. Rubber Chem. Technol. 2003, 76, 812.

15. 15 Synthesis of End-Functional Polystyrene Termination in Supplementary T-Junction Continuous Flow Process: Polymerisation-Termination Sequence Rapid and Quantitative Functionalization End-Functionalization of Polystyrene in THF (Polar Medium)

16. 16 Synthesis of End-Functional Polystyrene SampleM n (theor.) M n (SEC) M w /M n (SEC) PS-171,900 1.15 PS-182,9003,0001.14 PS-194,3003,9001.14 PS-204,5006,4001.18 PS-217,50017,0001.35 SEC (THF) RI Detection Flow Rates: 0.5 – 1.5 mL/min Residence Times:5 – 15 s

17. 17 Synthesis of End-Functional Polystyrene SampleM n (theor.) M n (SEC) M w /M n (SEC) PS-171,900 1.15 PS-182,9003,0001.14 PS-194,3003,9001.14 PS-204,5006,4001.18 PS-217,50017,0001.35 Flow Rates: 0.5 – 1.5 mL/min Residence Times:5 – 15 s MALDI-ToF MS

18. C. Tonhauser, D. Wilms, F. Wurm, E. Berger-Nicoletti, M. Maskos, H. Löwe, H. Frey, Macromolecules 2010, 43, 5582-5588 Functional Termination

19. 19 Synthesis of End-Functional Polystyrene Release of Hydroxyl Groups by Acidic Hydrolysis Semi-Continuous Approach to Hydroxy Functional Polymers Facile Access to Precursors for Complex Macromolecular Architectures (Blockcopolymers, Miktoarm Star Polymers)

20. 20 Synthesis of Block Copolymers SampleS:t-BuOSM n (theor.) M n (SEC) M n (MALLS) M w /M n (MALLS) PS-170:203,6003,7004,2001.21 PS-185:51,4001,3001,5001.18 PS-1910:51,900 2,1001.22 PS-2022:124,4004,8004,7001.17 PS-2180:3013,60013,10013,6001.15 PS-22200:2525,30024,70025,6001.14

21. Change Mixing Pattern: Turbulent Mixing 21 4-Way Jet Mixing Device Initiator Monomer Polymer

22. Polymerization in Continuous Flow 22 Sample Total Flow / mL/min M n (GPC) / g∙mol -1 PDI PS-782 2001.09 PS-894 7001.08 PS-10732 2001.08 PS-11842 5001.08 PS-141074 2001.05 PS-1511104 2001.04 PS-1612148 7001.04 Sample Total Flow / mL/min M n (GPC) / g∙mol -1 PDI P2VP-8101 8001.16 P2VP-1083 5001.17 P2VP-1176 4001.19 P2VP-121014 3001.15 P2VP-131118 7001.17 P2VP-141149 3001.12 P2VP-151096 0001.05 Styrene in THF sec-BuLi in hexane 2-Vinyl pyridine in THF sec-BuLi in benzene

23. Comparison Polymerization in Continuous Flow Natalello, A.; Morsbach, J.; Friedel, A.; Alkan, A.; Tonhauser, C.; Müller, A. H.E., Frey, H.; Org. Process Res. Develop., 2014, dx.doi.org/10.1021/op500149t 23 CharacteristicsBatch Multi- lamination Jet mixing EffortHighMiddleLow Side reactionDifficult to avoidNo Molecular weights Broad range 70 000 10 000 150 000 100 000 PDI< 1.10 1.09 – 1.28 1.19 – 1.26 1.04 – 1.10 1.05 – 1.19 Temperature≤ - 78°CRT VersatilityOne sampleSeveral samples PS and P2VP

24. C. Serra et al., LAB ON A CHIP, 2008, 8,1682-1687 DOI: 10.1039/b803885f Influence of Mixing on Polydispersity 24

25. 25 Control of Polydispersity by Microreactor Influence of PDI on polymer properties Common mindset: “monodisperse polymers are good; polydisperse are bad” 1 Mainly theoretical investigations but only a few experimental contributions 2 Most experimental studies are based on mixing of several polymer samples 3 Key issue: No controllable parameter to tailor polydispersity is available (1) Lynd N A, Meuler A J, Hillmyer M A. Polydispersity and block copolymer self-assembly. Progress in Polymer Science 2008; 33; 875-893. (2) Leibler L. Theory of microphase seperation in block copolymers. Macromolecules 1980;13:1602-17. (3) Noro A, Cho D, Takano A, Matsushita Y. Effect of molecular weight distribution on microphase seperated structures from block copolymers. Macromolecules 2005;38;4371-6.

26. M I T Mixer Carbanionic polymerization Controlled living carbanionic polymerization  Well defined polymer architectures  Very narrow mass distributions possible (PDI < 1.10)  Linear dependence of the achieved molecular weights D P = [M]/[I] Pump 1: Monomer/Solvent Flow rate: x Pump 2: Initiator/Solvent Flow rate: y Pump 3: Termination reagent Mixing device Microreactor setup

27. M I T Mixer sampleM max (GPC, g mol -1 )PDIflow rate (ml s -1 ) PS03-0134031,158,0 PS03-0235861,168,0 PS03-0332831,227,0 PS03-0432331,226,2 PS03-0532621,225,4 PS03-0632061,264,8 PS03-0731291,294,2 PS03-0831621,283,6 PS03-0931111,343,2 PS03-1034531,332,8 PS03-1130891,452,4 PS03-1231971,562,0 PS03-1331761,681,6 PS03-1431931,751,2 PS03-1533871,830,8 sampleM max (GPC, g mol -1 )PDIflow rate (ml s -1 ) PS03-0134031,158,0 PS03-0235861,168,0 PS03-0332831,227,0 PS03-0432331,226,2 PS03-0532621,225,4 PS03-0632061,264,8 PS03-0731291,294,2 PS03-0831621,283,6 PS03-0931111,343,2 PS03-1034531,332,8 PS03-1130891,452,4 PS03-1231971,562,0 PS03-1331761,681,6 PS03-1431931,751,2 PS03-1533871,830,8 PS03-1633991,950,4 PS03-1734842,210,3 sampleM max (GPC, g mol -1 )PDIflow rate (ml s -1 ) PS03-0134031,158,0 PS03-0235861,168,0 PS03-0332831,227,0 PS03-0432331,226,2 PS03-0532621,225,4 PS03-0632061,264,8 PS03-0731291,294,2 PS03-0831621,283,6 PS03-0931111,343,2 PS03-1034531,332,8 PS03-1130891,452,4 sampleM max (GPC, g mol -1 )PDIflow rate (ml s -1 ) PS03-0134031,158,0 PS03-0235861,168,0 PS03-0332831,227,0 PS03-0432331,226,2 PS03-0532621,225,4 PS03-0632061,264,8 sampleM max (GPC, g mol -1 )PDIflow rate (ml s -1 ) PS03-0134031,158,0 sample M max (GPC, g mol -1 )PDIflow rate (ml s -1 ) PS03-0134031,158,0 PS03-0235861,168,0 PS03-0332831,227,0 PS03-0432331,226,2 PS03-0532621,225,4 PS03-0632061,264,8 PS03-0731291,294,2 PS03-0831621,283,6 PS03-0931111,343,2 PS03-1034531,332,8 PS03-1130891,452,4 PS03-1231971,562,0 PS03-1331761,681,6 PS03-1431931,751,2 PS03-1533871,830,8 PS03-1633991,950,4 PS03-1734842,210,3 Turbulent mixing device – point of broadening Flow rate/ ml min -1

28. + 104 g/mol M I T Mixer Carbanions are still living: -> Quantitative functionalization (MALDI-ToF) total flow = 0.8 ml/min PDI (MALDI) = 1.10 total flow = 3.0 ml/min PDI (MALDI) = 1.09 total flow = 4.0 ml/min PDI (MALDI) = 1.07 total flow = 6.0 ml/min PDI (MALDI) = 1.06 total flow = 10.0 ml/min PDI (MALDI) = 1.05

29. Summar y Systematic influence on the PDI of a polymerization at constant molecular weights achieved System can be transferred to other polymer systems Analysis how the properties are influenced are in progress Quantitative functionalized polymers enables further investigations of block copolymer behavior Jan Morsbach PhD student M I T Mixe r

30. 30 Hyperbranched Polymers & Microreactors

31. M n ~ 750 g/mol M w /M n = 1.6 T = 120°C Continuous flow Throughput: 1 – 5 ml/min Reaction time: several minutes SEC analysis (DMF) Hyperbranched Polyglycerol: Target M n = 1,000 g/mol D. Wilms, J. Nieberle, J. Klos, H. Löwe, H. Frey, Chem. Eng. Technol. 2007, 30(11), 1519-1524.

32. 1 H-NMR analysis M n = 1,100 g/mol DP n = 16 Initiator core Repeat units Hydroxyl groups Methanol-d 4 Hyperbranched Polyglycerol: Target M n = 1,000 g/mol

33.  MALDI-ToF analysis Confirmation of initiator core incorporation Complete core incorporation (Independent of flow rates) 14 Hyperbranched Polyglycerol: Initiator attachment?

34. SampleTarget M n [g/mol] Flow Rate Monomer [ml/min] Flow Rate Initiator [ml/min] Molar Ratio Initiator:Monomer M n ( 1 H-NMR) PG-11,0000,8711 : 10,71100 PG-21,0001,7421 : 10,71300 PG-31,0002,172,51 : 10,71600 Hyperbranched Polyglycerol: Variation of Flow Rates SEC analysis (DMF) D. Wilms, J. Nieberle, J. Klos, H. Löwe, H. Frey, Chem. Eng. Technol. 2007, 30(11), 1519-1524.

35. SampleTarget M n [g/mol] Flow Rate Monomer [ml/min] Flow Rate Initiator [ml/min] Molar Ratio Initiator:Monomer M n ( 1 H-NMR) PG-41,0000,8711 : 10,71100 PG - -51,0200,9111 : 12,01600 PG-61,1001,9721 : 13,01200 PG-72,0001,8111 : 25,03200 Isolation by Dialysis M n ~ 150,000 g/mol M w /M n ~ 1.1 (PS Standards) SEC analysis (DMF) 16 Hyperbranched Polyglycerol: Variation of Flow Rates

36. 36 Conclusion & Perspectives Polymer Synthesis in Microreactors: Carbanionic and Oxyanionic Techniques Efficient Continuous Flow Process for Living Carbanionic Polymerization Facile and Fast Processes Serve to Optimize Reaction Parameters Convenient Molecular Weight Adjustment Tailoring of the Polydispersity of Living Polymer Cabanions Quantitative Implementation of Various End-Groups at Polymers Facile Extension to Complex Polymer Architectures (Star Polymers, Block Copolymers)

37. 37 Conclusion & Perspectives Pending Questions Unprecedented Polymer Structures? Kinetic Control of Polymerization of Metastable Monomers? (Example: Vinyl Alcohol) Gradients, One-Step Block Copolymer Syntheses, Architectures by versatile multi-microfluidic systems

38. 38 Acknowledgments Prof. Holger Löwe Michael Maskos Elena Berger-Nicoletti Monika Schmelzer POLYMAT Institut für Mikrotechnik Mainz

39. 39 Conclusion & Perspectives Pending Questions Unprecedented Polymer Structures? Kinetic Control of Polymerization of Metastable Monomers? (Example: Vinyl Alcohol) Gradients, One-Step Block Copolymer Syntheses, Architectures by versatile multi-microfluidic systems

40. 40 Multilamination Flow Pattern Hydrodynamic Focusing Jet Formation in the Slit-Shaped Interdigital Micromixer Hessel, V. et al. AIChE Journal 2003, 49, (3), 566-577. Löb, P. et al. Chemical Engineering Science 2006, 61, (9), 2959-2967. Micromixer Inlay Mulitlamination Flow Pattern Method of Operation