14th bmos presentation
DESCRIPTION
Brasilian Meeting on Organic SynthesisTRANSCRIPT
Recent Advances in Organic Synthesis
using Real-Time In Situ FTIR Spectroscopy
Dominique Hebrault, Ph.D.
Brasilia, Sept. 1-5th 2011
Many Development & Collaboration Projects
Enhanced Development and Control of Continuous Processes
Kinetic Analysis in Rapid Development of New Processes
Agenda
On Adopting New Technologies…
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
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
Agenda
Continuous Chemistry - Analysis Challenges
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
Today: Limited availability of convenient,
specific, in-line monitoring techniques
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
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
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
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
ReactIRTM Flow Cell: An Analytical Accessory
for Continuous Flow Chemical Processing
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
In-Line FTIR Micro Flow Cell in the Laboratory
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
FlowIR: Flow chemistry and beyond…
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
Up to 60ºC
Spectral range 600-4000 cm-1
FlowIRTM: A New Plug-and-Play
Instrument for Flow Chemistry and
Beyond
Sensor (SiComp, DiComp)
and head
Small size, no purge, no
alignment, no liquid N2
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
Dispersion in the column causes
waste of chiral / expensive / toxic
material in multi-step sequences
Additional purification may be
required
Controlled addition of exact
stoichiometries of reagents leads to
a more efficient process
Accurate Control of Reagent Addition in Multi-step Process
Today: Manual pump (D) switch
on/on based on Mid-IR generated
dispersion curve (C: intermediate)
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
stoichiometries of reagents leads to
a more efficient process
Tomorrow: Automated pump (D) flow
rate automatically / proportionally
controlled based on Mid-IR
measured concentration (C)?
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
Let’s test it out...
4-chlorobenzophenone 3-methyl-4-nitroanisole
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
No ReactIR™ control
10 equiv toxic hydrazine
used
Visual observation used
to manually switch the
third pump
Extensive purification
required
... and now apply it to the formation of a pyrazole
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
Laboratory setup
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)
Summary
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
Agenda
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
Reaction Progress Kinetic Analysis (RPKA)
Blackmond, D. G.
Angew. Chemie Int. Ed. 2005, 44, 4302
Blackmond, D. G. et al.,
J. Org. Chem. 2006, 71, 4711
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. “Reaction Progress Kinetic Analysis”, Webinars, Part 1 (April 2010) and 2 (October 2010) available at www.mt.com
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
Experimental setup: ReactIRTM15, EasyMaxTM
EasyMaxTM with 2-
piece vessel and
overhead stirrer
Window and light to
see the reaction
mixture
ReactIR 15TM with
fiber optic probe
Real time data logging
on laptop
EasyMax touchpad: Intuitive
and powerful reaction control
2 days experiments
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
Amide formation - “Different Excess” conditions
1
2
4
3
5
[e] = 0.001 (1.1 eq Boc-L-t-Leu)
[e] = 0.005 (1.5 eq)
[e] = 0.01 (2 eq)
→ Intuitive and rapid input of IC IR data and reaction parameters in iC Kinetics
10
Amide formation: Model building
5
[e] = 0.001
[e] = 0.005
[e] = 0.01
6
7
→ iC Kinetics instantly choose (x,y) to obtain straight lines and overlay (3 kinetic trends)
→ Power law rate equation shows non-integer orders
Amide formation: Model evaluation
11
9
8
10
400 simulated conditions used to find optimum conditions out of only ≥ 2 experiments
Time to 90%
conversion
Current process conditions:
HO-Pro.HCl 9.9mM, Boc-L-t-Leu 11.3mM
(1.1 eq), 10˚C, ACN
[BOC-L-t-leucine]
[HO-Pro.HCl]
Amide formation: Model testing
The model predicts concentration evolution versus time, consistent with experiment data
HO-Pro.HCl 9.9mM,
Boc-L-t-Leu 15.4mM (1.5 eq), 10˚C, ACN
Time hh:mm:ss
HO-Pro.HCl
Molarity
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)
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
What do we mean with elementary reaction?
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
approximates
this form
Power law form Steady-state rate law
non-integer x and y
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
Amide formation: Temperature analysis
0ºC 10ºC
20ºC 30ºC
-10ºC
Straightforward comparison of kinetic profiles when changing reaction conditions
2nd Step: Temperature analysis, Arrhenius plot -10ºC to + 30ºC temperature range
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
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
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
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