The document discusses the use of real-time in situ Fourier transform infrared spectroscopy (FTIR) for kinetic investigation of organic synthesis reactions using a ReactIR flow cell. It provides examples of using the flow cell to monitor a palladium-catalyzed cross-coupling reaction in both continuous flow and batch modes. Reaction progress kinetic analysis of the cross-coupling revealed it to be zero-order in both reactants and first-order in the palladium catalyst, indicating the rate-limiting step is likely reductive elimination.

1. Recent Advances in Organic Synthesis
Using Real-Time in situ FTIR
Dominique Hebrault
Sr. Technology & Application
Consultant
Boston, August 22, 2010

2. Presentation Outline
 Introduction
 ReactIRTM Micro Flow Cell for Flow Chemistry
 Kinetic Investigation of a Pd-Catalyzed Cross-Coupling Reaction
 Conclusions

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
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4. …With Cutting-Edge Research Technologies
 Characterize Particles
 Analyze Reaction Chemistry
 Expand
Productivity  Data Capture and
Understanding

5. Recent Publications and Collaborations

6. Mid-IR Real-time Reaction Analysis

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. 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. 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
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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
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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. 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
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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)
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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. 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. 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.
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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
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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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Palladium-catalyzed cross-coupling reactions
What does all this mean?

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. 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. 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. Presentation Outline
 Introduction
 ReactIRTM Flow Cell for Continuous Processing Technologies
 Kinetic Investigation of a Pd-Catalyzed Cross-Coupling Reaction
 Conclusions

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
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