ACS National Meeting Boston 2010

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ACS National Meeting Boston 2010

  1. 1. Recent Advances in Organic Synthesis Using Real-Time in situ FTIR Dominique Hebrault Sr. Technology & Application Consultant Boston, August 22, 2010
  2. 2. Presentation Outline  Introduction  ReactIRTM Micro Flow Cell for Flow Chemistry  Kinetic Investigation of a Pd-Catalyzed Cross-Coupling Reaction  Conclusions
  3. 3. Addressing Today’s Challenges… Early Phase Development Design and Process Scale-up and Development Manufacturing  Develop Compounds  Develop a Process  Establish Scalable  Provide Material  Safe Parameters  Establish Route  Robust  Reduce Batch Failures  Reduce Cycle Time 2
  4. 4. …With Cutting-Edge Research Technologies  Characterize Particles  Analyze Reaction Chemistry  Expand Productivity  Data Capture and Understanding
  5. 5. Recent Publications and Collaborations
  6. 6. Mid-IR Real-time Reaction Analysis
  7. 7. Mid-IR Real-time Reaction Analysis In-situ reaction results Absorbance Time  ConcIRTTM live  Peak height profiling  Quantitative model Component Spectra Component Profiles Relative concentration Absorbance or Time
  8. 8. Presentation Outline  Introduction  ReactIRTM Flow Cell for Continuous Processing Technologies  Kinetic Investigation of a Pd-Catalyzed Cross-Coupling Reaction  Conclusions Reference: Chemistry Today, 2009, Copyright Teknoscienze Publications, used by permission
  9. 9. CAMBRIDGE UNIVERSITY Introduction Chemical Laboratories Continuous flow chemistry – Advantages • Easier to precisely control reaction parameters, particularly temperature and mixing • Increased safety when dealing with hazardous reaction intermediates as only small amounts are generated at any one time • Improved reaction profile • In-line purification • High degrees of automation possible • Possibility of telescoping several steps [1] I. R. Baxendale, J. J. Hayward, S. Lanners, S. V. Ley and C. D. Smith, in Microreactors in Organic Synthesis and Catalysis, ed. T. Wirth, Wiley-VCH, Weinheim, 2008, ch. 4.2, pp. 84–122 8
  10. 10. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – technical details Chemical Laboratories MT ReactIRTM flow cell • Body: ReactIRTM 45m, fitted with a Mercury Cadmium Telluride (MCT) detector • Flow cell: Attenuated Total Reflectance (ATR) diamond or silicon sensor • Full infrared spectral region from 650 to 4000 cm 1 • Removable head (easy to be cleaned) • Head can be heated to 60 ºC and can stand pressures up to 30 bar • ¼-28 OmniFit connections for easy connection to continuous chemistry platforms • iC IR 4.0 software for system operation and data analysis 9
  11. 11. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories Heterocycle saturation • Coupling of the flow cell with the H-Cube Midi™: testing fast flow rates (>3 mL/min) , high dilutions (<0.1 mol/L), and application in a recycling process [4] (a) Moon, M. S.; Lee, S. H.; Cheong, C. S. Bull. Korean Chem. Soc. 2001, 22, 1167-1168. (b) Liljeblad, A.; Kavenius, H.-M.; Taehtinen, P.; Kanerva, L. T. Tetrahedron: Asymmetry 2007, 18, 181-191.(c) The H-Cube® and the H-Cube MidiTM by ThalesNano, Inc., Gázgyar u. 1-3, Budapest, Hungry H-1031. Website: www.thalesnano.com. 10
  12. 12. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories Heterocycle saturation • Concentration screen performed from 1 M – 0.01 M • Very low concentrations can be monitored using the solvent subtraction feature 11
  13. 13. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories Heterocycle saturation • Product formation and reagent consumption observed • Graph spiking due to experimental set-up • Monitoring multiple wavenumbers leads to same result • Potentially quantitative analysis possible (requires calibration procedures) 12
  14. 14. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories Hydrogenation of double bonds • Long term (16 h) experiment using the H-Cube® monitoring the decay of the substrate alkene band • Reaction seemed to be complete, but: 80 % conversion (1H NMR), probably due to the very low concentration of the reaction *5+ (a) Carter, C. F; Baxendale, I. R.; O’Brien, M.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, 4594-4597 (b) Carter, C. F.; Baxendale, I. R.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, submitted for publication. 13
  15. 15. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories BDA protection of halopropane diols • Using the IR flow cell for screening purposes • Changes in the intensity of the product peak with reaction temperature were observed • Consistent with batch screening (required five separate experiments!) *5+ (a) Carter, C. F; Baxendale, I. R.; O’Brien, M.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem.2009, 7, 4594-4597. (b) Carter, C. F.; Baxendale, I. R.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, submitted for publication. 14
  16. 16. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories Peptide coupling in batch mode • Monitoring batch processes using the IR flow cell by continuously withdrawing and returning 200 µL from the reaction mixture (5 mL) through the cell • Making use of the flow cell where the probe is less convenient [9] Kumarn, S.; Hoffmann, T.; Ley, S. V. unpublished results, University of Cambridge, 2010. 15
  17. 17. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories Peptide coupling in batch mode • Monitoring of reactive intermediate activated ester 28 is possible • Monitoring of different carbonyl bands is possible 16
  18. 18. CAMBRIDGE UNIVERSITY MT ReactIRTM flow cell – applications Chemical Laboratories Peptide coupling in batch mode • 3D analysis of the spectra greatly assists in the interpretation
  19. 19. CAMBRIDGE UNIVERSITY Conclusions Chemical Laboratories MT ReactIRTM 45m Flow Cell • Can we gain information about reactive intermediates? Yes, possibly the most interesting application for academic purposes, not many other ways to do this, could be used for mechanistic studies • Can it be used for screening? Yes, gives qualitative information, good for getting quick ideas; quantitative analyses possible • Can we monitor batch processes? Yes, with a withdraw and return procedure using conventional syringe pumps (small volumes) • What else could we use it for...? - Monitor compounds that are not UV active - Potential azide monitoring device [9] Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404
  20. 20. Presentation Outline  Introduction  ReactIRTM Flow Cell for Continuous Processing Technologies  Kinetic Investigation of a Pd-Catalyzed Cross-Coupling Reaction  Conclusions Reference: Arizona State University website, http://www.public.asu.edu/~laserweb/woodbury/classes/chm341/lecture_set7/Image275.gif
  21. 21. Articles on Reaction Progress Kinetic Analysis  Provides a full kinetic analysis from a minimum of two reaction progress experiments  Requires accurate in-situ method of data collection over the course of the reaction  Involves straightforward manipulation of the data to extract kinetic information Blackmond, D. G. Blackmond, D. G. et al., Angew. Chemie Int. Ed. 2005, 44, 4302 J. Org. Chem. 2006, 71, 4711
  22. 22. Software for Reaction Progress Data Analysis  iC KineticsTM for Reaction Progress Kinetic Analysis (RPKA) • Faster reaction optimization • Process robustness • Catalyst performance • Driving force analysis Temperature dependent models, simulation and optimization
  23. 23. Palladium-catalyzed cross-coupling reactions Investigation of an Efficient Palladium-Catalyzed C(sp)-C(sp) Cross-Coupling Reaction Using Phosphine-Olefin Ligand: Application and Mechanistic Aspects Use of in situ IR for preliminary kinetic  Introduction studies for mechanistic analysis Highly efficient method to synthesize unsymmetrical 1,3-diynes L1 Wei Shi, Yingdong Luo, Xiancai Luo, Lei Chao, Heng Zhang, Jian Wang, and Aiwen Lei; J. Am. Chem. Soc. 2008, 130, (44), 14713-14720; see also from Aiwen Lei et al: Org. Lett. 2008, 10, (13), 2661-2664 and Chemistry: A European Journal, 2009, 15, 3823-3829
  24. 24. Palladium-catalyzed cross-coupling reactions  Results Coupling monitoring by IR - Unique band for starting bromoalkyne and resulting 1,3-diynes Depletion of starting material and formation of product tracked by change of absorbance intensity Wei Shi, Yingdong Luo, Xiancai Luo, Lei Chao, Heng Zhang, Jian Wang, and Aiwen Lei; J. Am. Chem. Soc. 2008, 130, (44), 14713-14720
  25. 25. Palladium-catalyzed cross-coupling reactions Same excess experiment (IR measurement, GC calibration) Pd(dba)2 CuI Reaction A 0.41M 0.43M 0.006M 0.003M Reaction B 0.29M 0.31M 0.006M 0.003M Same 0.2M excess Unchanged 3.00E-04 Overlay: no catalyst deactivation 2.50E-04 [1c] = 0.29 M, [2g] = 0.31 M [1c] = 0.41 M, [2g] = 0.43 M Reaction rate (M/min) 2.00E-04 1.50E-04 1.00E-04 5.00E-05 Indicative of no product inhibition 0.00E+00 or catalyst deactivation 0 0.1 0.2 0.3 0.4 Concentration of 1c
  26. 26. Palladium-catalyzed cross-coupling reactions Different excess experiment overlay CuI (0.003M) + Pd(dba)2 (0.006M) (0.43M) 0.0006 Overlay gives order 0 in 1c 0.0005 [e] = 0.14 M 0.0004 [e] = 0.02 M Rate/[1g]0.03 [e] = -0.06 M 0.0003 Linear (Rate Eqn Prediction) 0.0002 0.0001 Straight lines give order 0 in 2g Indicative of zero-order in 0 1.15 1.2 1.25 1.3 1.35 1.4 both reactants [2g]-0.11
  27. 27. Palladium-catalyzed cross-coupling reactions Modeling and simulation in iC KineticsTM CuI + Pd(dba)2 • Power law rate equation gives rate constant and reaction orders • Simulation “time to 90% conversion” for design space approach
  28. 28. Palladium-catalyzed cross-coupling reactions What does all this mean?
  29. 29. Palladium-catalyzed cross-coupling reactions What does all this mean? 2 1 2 possible rate-limiting steps Source: Wei Shi, Yingdong Luo, Xiancai Luo, Lei Chao, Heng Zhang, Jian Wang, and Aiwen Lei; J. Am. Chem. Soc. 2008, 130, (44), 14713-14720
  30. 30. Palladium-catalyzed cross-coupling reactions  Further investigations - Reaction is first order in Pd(dba)2 loading - No dependence on copper salt loading - Reductive elimination is rate limiting although facilitated by L1 - Comparison of L1 with other ligands L1 Source: Wei Shi, Yingdong Luo, Xiancai Luo, Lei Chao, Heng Zhang, Jian Wang, and Aiwen Lei; J. Am. Chem. Soc. 2008, 130, (44), 14713-14720
  31. 31. Palladium-catalyzed cross-coupling reactions  Reaction Progress Kinetic Analysis - Graphical methodology aided by iCxKineticsTM - Provides a full kinetic analysis from a minimum of three reaction progress experiments - Continuous monitoring (e.g. ReactIRTM) facilitates RPKA - Demonstrated on the Pd-catalyzed preparation of 1,3-diynes: reaction orders and catalyst stability - Simulation for design space approach
  32. 32. Presentation Outline  Introduction  ReactIRTM Flow Cell for Continuous Processing Technologies  Kinetic Investigation of a Pd-Catalyzed Cross-Coupling Reaction  Conclusions
  33. 33. Acknowledgements  University of Cambridge, UK - Catherine F. Carter, Heiko Lange, and Pr. Steven V. Ley*  College of Chemistry and Molecular Sciences, Wuhan University, China - Wei Shi, Yingdong Luo, Xiancai Luo, Lei Chao, Heng Zhang, and Aiwen Lei*  Mettler Toledo Autochem - Jon G. Goode, Nigel L. Gaunt, Brian Wittkamp, and Jian Wang Email us at dominique.hebrault@mt.com OR autochem@mt.com OR Call us + 1.410.910.8500 32

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