Brasilian Meeting on Organic Synthesis

1. Recent Advances in Organic Synthesis
using Real-Time In Situ FTIR Spectroscopy
Dominique Hebrault, Ph.D.
Brasilia, Sept. 1-5th 2011

2. Many Development & Collaboration Projects

3. Agenda
 Enhanced Development and Control of Continuous Processes
 Kinetic Analysis in Rapid Development of New Processes

4. On Adopting New Technologies…
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications

5. Agenda
 Enhanced Development and Control of Continuous Processes
- Continuous Flow Chemistry - Analysis Challenges
- ReactIR™ In Situ IR Spectroscopy
- Accurate Addition of Reagent in Multi-Step Flow Processing
 Kinetic Analysis in Rapid Development of New Processes

6. Continuous Chemistry - Analysis Challenges
Today: Limited availability of convenient,
specific, in-line monitoring techniques
 Chemical information
- Continuous reaction monitoring superior to traditional sampling for offline
analysis (TLC, LCMS, UV, etc.)
→ Stability of reactive intermediates
→ Rapid optimization procedures
 Technical knowledge
- Dispersion and diffusion: Side effects of continuous flow – must be
characterized

7. Agenda
 Enhanced Development and Control of Continuous Processes
- Continuous Flow Chemistry - Analysis Challenges
- ReactIR™ In Situ IR Spectroscopy
- Accurate Addition of Reagent in Multi-Step Flow Processing
 Kinetic Analysis in Rapid Development of New Processes

8. In-Line IR Monitoring
 Monitor Chemistry In Situ, Under Reaction Conditions
- Non-destructive
- Hazardous, air sensitive or unstable reaction species (ozonolysis, azides etc)
- Extremes in temperature or pressure

9. In-Line IR Monitoring
 Real-Time Analysis, “Movie” of the reaction
- Track instantaneous concentration changes (trends, endpoint, conversion)
- Minimize time delay in receiving analytical results

10. In-Line IR Monitoring
 Determine Reaction Kinetics, Mechanism and Pathway
- Monitor key species as a function of reaction parameters
- Track changes in structure and functional groups

11. In-Line FTIR Micro Flow Cell in the Laboratory
ReactIRTM Flow Cell: An Analytical Accessory
for Continuous Flow Chemical Processing
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
-40 → 120ºC
Wetted parts: HC276, Diamond, (Silicon) & Gold
Multiplexing
Spectral range 600-4000 cm-1
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

12. FlowIR: Flow chemistry and beyond…
FlowIRTM: A New Plug-and-Play
Instrument for Flow Chemistry and
Beyond
Sensor (SiComp, DiComp)
and head
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
Up to 60ºC
Small size, no purge, no
Spectral range 600-4000 cm-1 alignment, no liquid N2

13. Agenda
 Enhanced Development and Control of Continuous Processes
- Continuous Flow Chemistry - Analysis Challenges
- ReactIR™ In Situ IR Spectroscopy
- Accurate Addition of Reagent in Multi-Step Flow Processing
 Kinetic Analysis in Rapid Development of New Processes

14. Accurate Control of Reagent Addition in Multi-step Process
 Dispersion in the column causes
waste of chiral / expensive / toxic
material in multi-step sequences
 Additional purification may be
required
 Controlled addition of exact
 Today: Manual pump (D) switch
stoichiometries of reagents leads to on/on based on Mid-IR generated
dispersion curve (C: intermediate)
a more efficient process

15. Accurate Control of Reagent Addition in Multi-step Process
 Dispersion in the column causes
waste of chiral / expensive / toxic
material in multi-step sequences
 Additional purification may be
required
 Controlled addition of exact
 Tomorrow: Automated pump (D) flow
stoichiometries of reagents leads to rate automatically / proportionally
controlled based on Mid-IR
a more efficient process
measured concentration (C)?

16. Let’s test it out...
4-chlorobenzophenone 3-methyl-4-nitroanisole
 3-Methyl-4-nitroanisole successfully added with 1:1
stoichiometry for >97% of the material
 Limitation towards the end of dispersion curves because
of inaccuracy of piston pumps at very low flow rates
H. Lange, C. F. Carter, M. D. Hopkin, A. Burke, J. G. Goode, I. R. Baxendale and S. V. Ley, Chem. Sci. 2011, 2, 765-769

17. ... and now apply it to the formation of a pyrazole
No ReactIR™ control
 10 equiv toxic hydrazine
used
 Visual observation used
to manually switch the
third pump
 Extensive purification
required
With ReactIR™ control
 Toxic hydrazine ↓ to 3 equiv.
 Reaction temperature ↓ to
80ºC to avoid polymerisation
of terminal acetylene
 Higher purity and colourless
pyrazole now obtained
 Plug of silica gel added →
chromatographic separation
with IR detection
H. Lange, C. F. Carter, M. D. Hopkin, A. Burke, J. G. Goode, I. R. Baxendale and S. V. Ley, Chem. Sci. 2011, 2, 765-769

18. Laboratory setup

19. Summary
In-line IR spectroscopy with ReactIR™ DS Micro Flow Cell:
 Provides highly molecular-specific information instantaneously
 Pump flow rate controlled in real-time as a function of [intermediate]
Used with a range of flow reactors:
 Micro scale - 10mL (Future Chemistry)
 Meso scale flow reactors (Uniqsis, Vapourtec)
 Large kilo lab flow reactors (Alfa Laval)

20. Agenda
 Enhanced Development and Control of Continuous Processes-on
Kinetic Analysis in Rapid Development of New Processes
- Early-on kinetic analysis today
- Case study: Dipeptide coupling

21. Agenda
 Enhanced Development and Control of Continuous Processes
 Kinetic Analysis in Rapid Development of New Processes
- Early-on kinetic analysis today
- Case study: Dipeptide coupling

22. Reaction Progress Kinetic Analysis (RPKA)
Leverages the extensive data available from accurate in situ monitoring
Provides a full kinetic analysis from a minimum of two reaction progress experiments
 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
Blackmond, D. G. “Reaction Progress Kinetic Analysis”, Webinars, Part 1 (April 2010) and 2 (October 2010) available at www.mt.com

23. Agenda
 Enhanced Development and Control of Continuous Processes
 Kinetic Analysis in Rapid Development of New Processes
- Early-on kinetic analysis today
- Case study: Dipeptide coupling

24. Experimental setup: ReactIRTM15, EasyMaxTM
ReactIR 15TM with
fiber optic probe 2 days experiments
Real time data logging
on laptop
Window and light to
see the reaction
mixture
EasyMaxTM with 2-
piece vessel and EasyMax touchpad: Intuitive
overhead stirrer and powerful reaction control

25. Agenda
 Enhanced Development and Control of Continuous Processes
 Kinetic Analysis in Rapid Development of New Processes
- Early-on kinetic analysis today
- Case study: Dipeptide coupling
Model development: “different excess” strategy
Temperature analysis

26. Amide formation - “Different Excess” conditions
1
2
4
5
[e] = 0.001 (1.1 eq Boc-L-t-Leu)
[e] = 0.005 (1.5 eq)
[e] = 0.01 (2 eq)
3
10
→ Intuitive and rapid input of IC IR data and reaction parameters in iC Kinetics

27. Amide formation: Model building
7
6
5
[e] = 0.001
[e] = 0.005
[e] = 0.01
→ iC Kinetics instantly choose (x,y) to obtain straight lines and overlay (3 kinetic trends)
→ Power law rate equation shows non-integer orders

28. Amide formation: Model evaluation
8
9
10 Current process conditions:
Time to 90% HO-Pro.HCl 9.9mM, Boc-L-t-Leu 11.3mM 11
conversion (1.1 eq), 10˚C, ACN
[HO-Pro.HCl]
[BOC-L-t-leucine]
400 simulated conditions used to find optimum conditions out of only ≥ 2 experiments

29. Amide formation: Model testing
HO-Pro.HCl 9.9mM, HO-Pro.HCl
Boc-L-t-Leu 15.4mM (1.5 eq), 10˚C, ACN Molarity
Time hh:mm:ss
The model predicts concentration evolution versus time, consistent with experiment data

30. What have we learned so far?
 Validation of ATR-FTIR (ReactIR-ConcIRT) for real time monitoring, kinetic
trends confirmed by EasyMax heat flow
 Fast, prelim. kinetic investigation and modeling in 2-4 experiments (R2 0.99)
 Partial orders in activated anhydride and amide (0.78 and 0.69, k =
0.0115M-1.s-1). Power law rate equation more complex than for an
elementary reaction (intermediate steps, equilibria)
 Kinetic model (“different excess”) predicts concentration evolution versus
time. Prediction confirmed with experimental data
 Outcome: 400 simulated experimental conditions and rates → Find optimum
process operating conditions (cycle time, robustness, yield, cost, safety)

31. What do we mean with elementary reaction?
 “An elementary reaction is a chemical reaction in which one or more of
the chemical species react directly to form products in a single reaction
step and with a single transition state”
 Organocatalytic reaction
Steady-state reaction rate law
more complex than for an
elementary reaction
Blackmond, D. G. “Reaction Progress Kinetic Analysis”, Webinars, Part 1 (April 2010) and 2 (October 2010) available at www.mt.com

32. What do we mean with elementary reaction?
Power law form Steady-state rate law
approximates
non-integer x and y
this form
 IC Kinetics provides the power law form without the need to describe
each individual elementary reaction
 No need to know or describe reaction mechanism
 (k’, x, y) → driving force analysis

33. Agenda
 Enhanced Development and Control of Continuous Processes
 Kinetic Analysis in Rapid Development of New Processes
- Early-on kinetic analysis today
- Case study: Dipeptide coupling
Model development: “different excess” strategy
Temperature analysis

34. Amide formation: Temperature analysis
-10ºC
10ºC
30ºC 0ºC
20ºC
Straightforward comparison of kinetic profiles when changing reaction conditions

35. 2nd Step: Temperature analysis, Arrhenius plot
-10ºC to + 30ºC temperature range

36. What have we learned?
 Temperature dependent model developed across -10ºC → +30ºC
 Adequate to excellent fit (R2 ≤ 0.998)
 Activation energy: 27.5 kJ/mol (most chemical reactions: 10-50 kJ/mol)
 Rate of reaction approx. doubles for each 10 K when Ea = 50 kJ/mol; xx1.5
for each 10 K increase when Ea = 27 kJ/mol
 This particular amide bond formation is more complex than for an
elementary reaction (intermediate steps, equilibria), as shown by power law
rate equation → Careful data interpretation

37. So what?
 Guide experimental approach towards maximizing information
 No calibration needed, no dedicated experiments, real time reaction
monitoring ideal
 Allows chemists to gain faster, improved insight into synthetic reaction and
mechanism
 Speeds up research process and reaction optimization (duration,
robustness, yield, safety, cost)
 Reduce number of experiments, complement DOE methodology
 No requirement for extensive kinetic knowledge or experience

38. Acknowledgements
 University of Cambridge, UK
- Catherine F. Carter, Heiko Lange, Mark D. Hopkin, Ian R. Baxendale, Pr.
Steven V. Ley*
 Mettler Toledo Autochem
- Jon G. Goode, Adrian Burke
Email us at dominique.hebrault@mt.com
OR
autochem@mt.com
OR
Call us + 1.410.910.8500