1. Flow Chemistry in Organic Synthesis Litterature Talk Filippo De Simone EPFL 6 June 2011 1

2. 2 1) Try to identify the limitations of flow chemistry 2) In witch context flow chemistry is advantageous?

3. Flow Chemistry Table of contents Introduction… from batch to flow Temperature, pressure, light… μW, induction, photochemistry Flow on supported catalysts… oxidation and reduction Solid Phase… mono- and multi-components Multi-steps flow synthesis… from easy to complex 3

4. Flow Chemistry Flow chemistry Small volume Low cost Short analysis time Microfluidics (10 -9 to 10 -18 L) Control of concentration in space/time Molecular analysis (GC, HPLC, CE) Molecular biologyBiodefenceMicroelectronics 1990 Microfluidic detector (for chemical and biological threats) (DARPA = Defense Advanced Research Projects Agency from US Department of Defense Academic interest DNA sequencing Microelectronics Technologies G. M. Whiteside, Nature, 2006, 442, 368. 4

5. Flow Chemistry  Superior heat and mass transfer rates (hight surface/volume ratio)  Easy scale up (bigger or multi columns)  Safe use of extreme pressures and temperatures  Precise control of conditions  Reduced chemical exposion and waste  Ideal for fast reactions, esothermic reactions, instable intermediate From batch to flow 5

6. Flow Chemistry Microfluidic (ø 10-500 μm) ● High heat transfer ● Efficient mixing ● Low flow capacity ● High pressure drop ● Tendency to block Microfluidic and Minifluidic Minifluidic (ø >0.5mm ) ● High flow capacity ● Low pressure drop ● No blocking ● Multigrams-multikilogram scale ● Packed reactors ● Lower heat transfer A. Kirschning, Chem. Comm, 2011, 4583. 6

7. Flow Chemistry A. Kirschning, Chem. Comm, 2011, 4583. Batch Volume Concentration Reaction time Reactor Volume Residence time Operation time Stoichiometry Concentration / Volumetric ratio Stoichiometry Concentration / Flow rate EtOH  AcOH Industrial batch processFlow microreactor Residence time (s)17603 Conversion (%)30/90>99 Reaction volume (cm 3 )29003 Throughput (cm 3 /h)59304300 Space-time yield (h -1 )0.7-2.0500 H.Lowe, Chem. Eng. Technol.,2005, 28, 267. From batch to flow 7

8. Flow Chemistry From batch to flow Heck reaction Side biaryl compound Formation of black Pd Insoluble ammonium salt G. C. Fu, JACS 2001, 123, 6989. S. L. Buchwald and K. F. Jensen, ACIE, 2010, 49, 7076. 8

9. Flow Chemistry Variable: Residence time Equivalents of alchene Concentration Catalyst loading Ph value Ionic strenght 140 μL 5 eq of alchene 6 gr of aryl chloride Yield 83% Process time 20 min Self optimization S. L. Buchwald and K. F. Jensen, ACIE, 2010, 49, 7076. From batch to flow Heck reaction 9

10. Flow Chemistry 7 mL 5 eq of alchene 26.9 g of product Yield 80% Process time 2 hours Scale up Concentration of alchene adjusted manually No feedback control Comparison with microscale S. L. Buchwald and K. F. Jensen, ACIE, 2010, 49, 7076. From batch to flow Heck reaction 10

11. Flow Chemistry High Temperature/Pressure Conditions C. O. Kappe, Eur. J. Org. Chem., 2009, 1321 Steal microreactor: Pressure up to 200 bar Temperature > 300°C Rapid heating and cooling Easily scale-up 11

12. Flow Chemistry Li, Y.; Padias, A. B.; Hall, H. K., Jr. J. Org. Chem. 1993, 58, 7049. High Temperature/Pressure Conditions T. N. Glasnov and C. O. Kappe, Eur. J. Org. Chem., 2009, 1321 12

13. Flow Chemistry High Temperature/Pressure Conditions Claisen rearrangement Indole Fisher synthesis S N Ar of inactivated Ar Newman-Kwart rearrangement T. N. Glasnov and C. O. Kappe, Eur. J. Org. Chem., 2009, 1321 13

14. Flow Chemistry Supercritical Conditions M. Poliakoff, Green Chem., 2008, 10, 98. C. O. Kappe, Eur. J. Org. Chem., 2009, 1321 14

15. Flow Chemistry Microwave-assisted synthesis C. O. Kappe, QSAR Comb. Sci., 2006, 25, 509. Dimroth rearrangement M. G. Organ, Chem. Eur. J., 2010, 16, 126 15

16. Flow Chemistry Inductively hated flow reactor 16

17. Flow Chemistry Inductively hated flow reactor A. Kirschning, Synlett, 2010, 2009. 17

18. Flow Chemistry A. Kirschning, Chem. Eur. J., 2010, 4372. Inductively hated flow reactor 18

19. Flow Chemistry A. Kirschning, Chem. Eur. J., 2011, 1884. Hydrogenolysis Reduction Reformatzky Inductively hated flow reactor 19

20. Flow Chemistry Inductively hated flow reactor Multi-component reactions Mannich Petasis MCR A. Kirschning, Chem. Eur. J., 2011, 1884. 20

21. Flow Chemistry Flow and photochemistry Mini flow condition 15 W black light (6x) Pyrex glass 61% yield 5.3 g (HPLC) 40 h of flow 20 min residence time Micro flow condition (10 mL) 15 W black light or LED Pyrex glass 71% yield mg scale, 0.05 mL/h 6-12 min residence time Micro flow 1000 μm width, 107 μm depth, 2.2 m length 0.2 mL volume Mini flow 1000 μm width, 500 μm depth, 0.5 m length 4 mL volume I. Ryu, Tetrahedron, 2009,65, 1593. Burton reaction 21

22. Flow Chemistry Fluorinated ethylpropylene [5 + 2] [2 + 2] Photocycloadditions M. B. Berry and K. I. Booker-Milburn, J. Org. Chem., 2005,70, 7558. Flow and photochemistry 22

23. Flow Chemistry Flow on supported catalysts S. Kobayashi, Science 2004, 304, 1305S. Kobayashi, ACIE 2009, 48, 4744 23

24. Flow Chemistry S. Kobayashi, Science 2004, 304, 1305S. Kobayashi, ACIE 2009, 48, 4744 Flow on supported catalysts 24

25. Flow Chemistry S. Kobayashi, Science 2004, 304, 1305 Hydrogenation Flow on supported catalysts 25

26. Flow Chemistry S. Kobayashi, ACIE 2009, 48, 4744 No loss of activity 99% conversion after 4 days Full conversion in flow Oxidation Flow on supported catalysts 26

27. Flow Chemistry Homogeneus surface Hight pressure drop avoided HPLC system used Wide functionalization PASSflow Polymer Assisted Solution-phase Synthesis A. Kirschning, ACIE, 2001, 3995. Flow synthesis throw solid phase reagents 27

28. Flow Chemistry A. Kirschning, ACIE, 2001, 3995. Flow synthesis throw solid phase reagents 28

29. Flow Chemistry Curtius Rearrangement Control of pore dimension Micro- and mini-flow system Easy to scale up Wide functionalization S. V. Ley, Org. Biomol. Chem., 2008, 1578. Flow synthesis throw solid phase reagents 29

30. Flow Chemistry - Exposure to hazards - Risk of shock/impact + Multiple usage + Easy regenaration S. V. Ley, Org. Biomol. Chem., 2008, 1578. Curtius Rearrangement Flow synthesis throw solid phase reagents 30

31. Flow Chemistry S. V. Ley, Org. Biomol. Chem., 2008, 1578. Curtius Rearrangement Flow synthesis throw solid phase reagents 31

32. Flow Chemistry J.-I. Yoshida, JACS, 2007, 129, 3046. Multi step flow synthesis 32 Li-halo exchange

33. Flow Chemistry J.-I. Yoshida, JACS, 2007, 129, 3046. Multi step flow synthesis 33

34. Flow Chemistry D. T. McQuade, ACIE, 2009, 48, 8547. Multi step flow synthesis 34

35. Flow Chemistry S. V. Ley, Chem. Commun., 2006, 2566. Multi step flow synthesis 35

36. Flow Chemistry T. Lectka, Org. Lett.,2005, 7, 3009. Multi step flow synthesis 36

37. Flow Chemistry Conclusion Flow chemistry high potential to improve synthesis process Flow chemistry: safe, time saving and easy scale up Progress needed in multi reactor assembly Collaboration between Chemists and Engineers are essential 37