1. Continuous Flow Chemistry
Recent Advances in Organic Chemistry
Part 8
Dom Hebrault, Ph.D.
Principal Technology and
Application Consultant
May 16th 2012

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. Flow Production of Unstable Intermediates
Vol. 92 μL, channel W 600 μm, D 500 μm, L 360 mm
Continuous Flow Production of Thermally
Unstable Intermediates in a Microreactor
with Inline IR-Analysis: Controlled
Vilsmeier−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
FutureChemistry
A. 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. 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 s
A. 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. 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/h
A. 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. High-Pressure G/L Flow Homogeneous Catalysis
A Microreactor System for High-Pressure
Continuous Flow Homogeneous Catalysis Lab made silicon or Pyrex microreactor
Square channel 500 x 500 μm
Measurements 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 for
1-octene 1- Enhanced gas/liquid mass transfer
2- Isothermal operation → kinetics
Jaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022

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 μl
Jaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022

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 series
Jaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022

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 manageable
Jaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022

10. Automated Optimization using Microreactors
Fluid flow
Automated Multi-trajectory Method for
Reaction 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 optimization
Jason S. Moore, Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Org. Process Res. Dev. 2012, 16, 1409−1415

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) optimum
Jason S. Moore, Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Org. Process Res. Dev. 2012, 16, 1409−1415

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 dilution
Jason S. Moore, Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Org. Process Res. Dev. 2012, 16, 1409−1415

13. Continuous Asymmetric Hydrogenation
Continuous-flow catalytic asymmetric Asym. ligand
hydrogenations: Reaction optimization
using 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 conditions
Commercial glass microreactor / In single glass reactor with inlets
Magnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307

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, reagent
Magnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307

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 parameters
Magnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307

16. Preparation of Arylmagnesium in Flow
Continuous Preparation of Arylmagne-
sium Reagents in Flow with Inline IR
Monitoring
 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 optimization
Tobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114

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 reagent
Tobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114

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. 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 compounds
Tobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114

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.)