Recent Advances Webinar Part 8

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Recent Advances Webinar Part 8

  1. 1. Continuous Flow ChemistryRecent Advances in Organic Chemistry Part 8 Dom Hebrault, Ph.D. Principal Technology and Application Consultant May 16th 2012
  2. 2. Background & Literature References cited in following case studies (4) Continuous Flow Chemistry: Recent Advances in Organic Chemistry Part 7 Information Sharing Event: - Continuous Flow Chemistry and Crystallization Development, New Brunswick, NJ, September 2012 - Chemical and Crystallization Research & Development, Cambridge, MA, May 2012 Mettler Toledo articles & conference presentations: Chim. Oggi, White Papers, FloHet, Flow Chemistry Congress, AIChE… Other peer-reviewed scientific articles and references available on request
  3. 3. Flow Production of Unstable Intermediates Vol. 92 μL, channel W 600 μm, D 500 μm, L 360 mmContinuous Flow Production of ThermallyUnstable Intermediates in a Microreactorwith Inline IR-Analysis: ControlledVilsmeier−Haack  Introduction Vilsmeier−Haack formylation hazardous to scale-up: Unstable chloroiminium intermediate 1- Formation of the VH-reagent Enhanced safety in microreactors thanks 2- Arene oxidation – Iminium formation to better heat dissipation and smaller volume 3- Quench of iminium salt FlowStart Evo FutureChemistryA. M. W. van den Broek, J. R. Leliveld, R. Becker, M. M. E. Delville, P. J. Nieuwland, Kaspar Koch, F. P. J. T. Rutjes; FutureChemistry Holding BV,Institute for Molecules and Materials, Radboud University Nijmegen; The Netherlands; Organic Process Research and Development, 2012, 16, 5,934-938
  4. 4. Flow Production of Unstable Intermediates  Formation of the VH-reagent At-line measurement required to prevent partial conversion of POCl3: Pyrrole → polymers → clogging At-line UV unpractical because DMF shows absorbance around 300 nm Problem overcome using inline FlowIR P-O-C Rt 10 s C-Cl FlowIRTM` 180 sA. M. W. van den Broek, J. R. Leliveld, R. Becker, M. M. E. Delville, P. J. Nieuwland, Kaspar Koch, F. P. J. T. Rutjes; FutureChemistry Holding BV,Institute for Molecules and Materials, Radboud University Nijmegen; The Netherlands; Organic Process Research and Development, 2012, 16, 5,934-938
  5. 5. Flow Production of Unstable Intermediates  Formation of the VH-reagent Plot [2] and [3] as a function of residence time Higher [3] level at Rt>100s possibly due to higher [Cl-] resulting from counterion 2 3 degradation  Conclusions IR 769 cm-1 VH formylation proved to be readily IR 804 cm-1 conducted in flow microreactor system 2 FlowIR essential to solve at-line UV limitations 3 Optimization of reaction time (180 s), temperature (60 °C, molar ratio (1.5 eq.) → 5.98 g/hA. M. W. van den Broek, J. R. Leliveld, R. Becker, M. M. E. Delville, P. J. Nieuwland, Kaspar Koch, F. P. J. T. Rutjes; FutureChemistry Holding BV,Institute for Molecules and Materials, Radboud University Nijmegen; The Netherlands; Organic Process Research and Development, 2012, 16, 5,934-938
  6. 6. High-Pressure G/L Flow Homogeneous CatalysisA Microreactor System for High-PressureContinuous Flow Homogeneous Catalysis Lab made silicon or Pyrex microreactor Square channel 500 x 500 μmMeasurements Vol. 220 μl  Introduction Hydroformylation of alpha-olefins commercially used to produce aldehydes/alcohols However, few and contradictory kinetics data under relevant industrial conditions (high P, T) Toluene 100 °C, 30 b Microreactors for segmented flow for1-octene 1- Enhanced gas/liquid mass transfer 2- Isothermal operation → kineticsJaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022
  7. 7. High-Pressure G/L Flow Homogeneous Catalysis Sampling issues with GC 1- Volatile alkene → sample loss & 910 cm-1 2- Poor GC mass balance 3- Sampling reproducibility (carry-over) Sampling issues resolved with inline ATR-FTIR: ReactIR 10 with DiComp DS Micro Flow Cell; Vol. 50 μlJaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022
  8. 8. High-Pressure G/L Flow Homogeneous Catalysis National T° control Instruments, v7.1 J‐Kem, Gemini‐K LabVIEW ReactIR GC Teflon Teledyne Isco, 100DM Up to 350 °C, 100 b Bronkhorst, Teledyne Isco, Controller Rt: s to 15 min. EL‐PRESS seriesJaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022
  9. 9. High-Pressure G/L Flow Homogeneous Catalysis  Results Confirm kinetic regime and analytical mass balance Detailed kinetic study using a non-linear least square regression ReactIR provided: - Verification of proper operation - Direct confirmation of steady state after change of variable - Real time component assay after calibration - Segmented G/L flow manageableJaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022
  10. 10. Automated Optimization using Microreactors Fluid flowAutomated Multi-trajectory Method forReaction Optimization in a Microfluidic (Harvard)System using Online IR Analysis  Introduction Production rate* of a Pall-Knorr reaction Data flow maximized: Temperature (30–130°C), time (2-30 min) Continuous online infrared (IR) monitoring Automation system Paal –Knorr Reaction ReactIR provided benefits of: - Low material requirement - Inline conversion monitoring, steady state reach for faster optimizationJason S. Moore, Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Org. Process Res. Dev. 2012, 16, 1409−1415
  11. 11. Automated Optimization using Microreactors Goal: - Compare performance of automated optimization algorithms - “Similar” optimum: T 130°C, t 4.5 min - Large difference in number of runs (38 versus 126) and time required Optimum for each algorithm IR spectrum of the Paal−Knorr reaction species Armijo (solvent subtracted) conjugate Conjugate gradient gradient Algorithm designed for Steepest descent - Steps: 2°C, 1 min - Single path to optimum - Intelligently updating reaction conditions based on inline analytics - Automatically performing DOE towards Comparison of optimum reach for each algorithms (number of runs, reaction conversion) optimumJason S. Moore, Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Org. Process Res. Dev. 2012, 16, 1409−1415
  12. 12. Automated Optimization using Microreactors Conclusions: - Pall-Knorr production rate maximized within 30–130°C, t 2-30 min - Conjugate gradient with addition of Armijo- type algorithm provides better optimization efficiency - Future development: Stoichiometry, Production rate optimization strategies above 130°C selectivity, impurity profile optimization ReactIR provided: - Real time info about steady state reach - Exportable data for feedback control → dynamic experiment duration - Non destructive analytical method and low material requirement - Total reaction mixture : No sampling, no Production rate optimization using Armijo conjugate gradient dilutionJason S. Moore, Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Org. Process Res. Dev. 2012, 16, 1409−1415
  13. 13. Continuous Asymmetric HydrogenationContinuous-flow catalytic asymmetric Asym. ligandhydrogenations: Reaction optimizationusing FTIR inline analysis  Introduction Microreactors setup coupled with ATR-FTIR microflowcell (ReactIR) Asymmetric hydrogenation of benzoxazines, quinolines, quinoxalines, 3H-indoles with Solvent: CHCl3 Hantzsch dihydropyridine Schematic of experimental setup and chemistry ReactIR microflowcell benefits: - More rapid screening of reaction para- meters - Faster reach of optimum reaction conditionsCommercial glass microreactor / In single glass reactor with inletsMagnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307
  14. 14. Continuous Asymmetric Hydrogenation IR spectra for substrate consumption and Method and results: product formation at different temperature - Collection of reference spectra for solvent, starting material, and reagents - Optimum conditions after fast screening thanks to real time analytics: T 60°C, t 20 min, flow rate 0.1 mL.min-1 Further reported investigations - Scope - Conditions optimization: Flow conditions, Trend curve of product formation at different temperatures catalyst loading, reagentMagnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307
  15. 15. Continuous Asymmetric Hydrogenation Conclusions: - Microreactors setup coupled with ATR-FTIR microflowcell (ReactIR) - Inline real time analysis of the microreactor reaction stream right at the outlet - Faster, more precise feedback or reaction mixture composition and component concentration - More rapid screening of reaction parameters - Faster reach of optimum reaction conditions - Ongoing development: automated integration and feedback optimization of reaction parametersMagnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307
  16. 16. Preparation of Arylmagnesium in FlowContinuous Preparation of Arylmagne-sium Reagents in Flow with Inline IRMonitoring  Introduction Continuous flow reaction setup (Vapourtec R2+) with inline ATR-FTIR FlowIR: 1. Grignard exchange Schematic of experimental setup and chemistry 2. Coupling with carbonyl compounds FlowIR benefits: Comparison ATR-FTIR / GC / I2 titration - Conversion, by-products in real time - In situ determination of absolute concen- tration after calibration - Elucidation of mechanistic details - Ensure / facilitate product high quality ATR-FTIR FlowIR instrument - Faster optimizationTobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114
  17. 17. Preparation of Arylmagnesium in Flow Calibration curves Method and results: - Collection of reference spectra Aryl moiety 764, 711cm-1 - Solvent subtraction from dataset - Identify unique peaks - Interpret changes Shift due to THF coordination 1069 → 1043cm-1 913 → 894 cm-1 Intensity of mid-IR peaks at different concentrations - Peak intensity versus Ar-X concentration - Calibration - Inline determination of concentration - Further optimization: Accurately match delivery of 3rd stream (vide infra) Mid-IR reference spectra for THF and Grignard reagentTobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114
  18. 18. Preparation of Arylmagnesium in Flow - Identify unique peaks for reaction components - Use 2nd derivative spectra as advanced interpretation tool - Trend component(s) of interest versus time ArMgX Real time intensity of mid-IR peak of Grignard reagent 767, 1043cm-1 Wurtz Toluene side-product - Diffusion in the flow stream - Timing and feed rate for 3rd stream adjusted automatically and in real time to mid-IR readout - Screen of reaction parameters Fingerprint region for solvent, starting material, (side)-products - Scope (aryl halide, carbonyl derivative)Tobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114
  19. 19. Preparation of Arylmagnesium in Flow Role of LiCl/THF by IR spectroscopy - Shift, intensity changes due to complex Role of THF as solvent - 1, 2, 4, 10 eq dry THF added to Grignard reagent in toluene - IR clearly indicates coordination of THF to Mg in Grignard species IR spectrum of Grignard reagent solution in toluene with THF iPrMgCl.LiCl With ReactIR, it became possible to: iPrMgCl - Ensure quality of Ar-MgX in solution, in situ - Determine concentration of active reagents, composition of reaction stream to quickly optimize process - Further used to monitor/optimize reaction IR spectra of iPrMgCl and iPrMgCl.LiCl complex with carbonyl compoundsTobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114
  20. 20. Acknowledgements Institute for Molecules and Materials, Radboud University (The Netherlands) - Pr. Floris P. J. T. Rutjes et al. Department of Chemical Engineering, MIT (USA) - Pr. Klavs Jensen, Dr. Jerry Keybl, Dr. Jason Moore University of Cambridge, UK - Pr. Steven V. Ley et al. Department of Chemistry, Ludwig Maximilians-Universität München, Germany - Pr. Paul Knochel et al. Institute of Organic Chemistry, Aachen University, Germany - Pr. Magnus Rueping et al. Mettler Toledo Autochem - Will Kowalchyk, Wes Walker, Paul Scholl (USA), Jon Goode (U.K.)

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