Enhanced Development and Control of Continuous Processes Flow Chemistry Congress April 2011
Enhanced Development and Control of
Continuous Processes
Flow Chemistry Congress
April 2011
On Adopting New Technologies…
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
Continuous Flow Chemistry - Analysis Challenges
ReactIR™ In Situ IR Spectroscopy
Accurate Addition of Reagent in Multi-step Segmented Flow Processing
Agenda
Continuous Chemistry - Analysis Challenges
Chemical information
- Continuous reaction monitoring highly desirable versus traditional sampling
for offline analysis (TLC, LCMS, UV, etc.)
→ Stability of reactive intermediates
→ Rapid optimization procedures
Technical knowledge
- Dispersion and diffusion are unavoidable side effects of continuous flow –
must be characterized, especially for multistep reaction sequences
Broader development of flow chemistry limited by the
availability of convenient, specific, in-line monitoring
techniques, especially when dealing with multistep
sequences
Monitor Chemistry In Situ, Under Reaction Conditions
- Non-destructive
- Hazardous, air sensitive or unstable reaction species (ozonolysis, azides etc)
- Extremes in temperature or pressure
Real-Time Analysis, “Movie” of the reaction
- Track instantaneous concentration changes (trends, endpoint, conversion)
- Minimize time delay in receiving analytical results
Determine Reaction Kinetics, Mechanism and Pathway
- Monitor key species as a function of reaction parameters
- Track changes in structure and functional groups
In-Line IR Monitoring
Continuous Flow Chemistry - Analysis Challenges
ReactIR™ In Situ IR Spectroscopy
Accurate Addition of Reagent in Multi-step Segmented Flow Processing
Agenda
ReactIRTM Micro Flow Cell
A New Analytical Tool 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
Why ATR for in situ monitoring
applications?
No interference from bubbles,
solid, mixing, etc.
Selective information on the
liquid phase
High chemical resistance
1st R-Br addition
Initiation2nd R-Br addition
ReactIR™ - In Situ Infrared Spectroscopy
Grignard formation
ATR-FTIR
Continuous Flow Chemistry - Analysis Challenges
ReactIR™ In Situ IR Spectroscopy
Accurate Addition of Reagent in Multi-step Segmented Flow Processing
Agenda
Dispersion of the reaction “plug” is
an issue, especially when
performing multi-step sequences
Controlled addition of exact
stoichiometries of reagents to a
product stream is desirable but
challenging
Poor control is wasteful
(chiral/expensive/toxic material
used in excess)
→ Additional purification
Accurate Control of Reagent Addition in Multi-step Process
Today: Mid-IR generates dispersion
curve (intermediate) used to
manually switch the pump on
Dispersion of the reaction “plug” is
an issue, especially when
performing multi-step sequences
Controlled addition of exact
stoichiometries of reagents to a
product stream is desirable but
challenging
Poor control is wasteful
(chiral/expensive/toxic material
used in excess)
→ Additional purification
Accurate Control of Reagent Addition in Multi-step Process
Tomorrow: Can Mid-IR information
be automatically converted into a
flow rate → Third stream dispensed
proportionally to concentration?
nequiv. = desired number of equivalents
nstream = flow rate of output process
fA = absorption coefficient of I in reaction solvent
A = IR absorbance of I
cD = concentration of standard solution of reactant
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
Flow Rate = ((1× 0.25 × 2210)/0.0833) × A
= 6630 × A
LabView multiplies 4-chlorobenzophenone peak height in real time by 6630
→ flow rate in mL/min
Concentration / M
Ab
sorb
ance
/ A
.U.
Can We Add a Third Stream with Accurate 1:1 Stoichiometry?
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
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
Laboratory setup
In-line infra-red spectroscopy with ReactIR™ DS Micro Flow Cell:
Provides highly molecular-specific chemical information instantaneously
Enables the flow rate of a pump to be controlled in real-time as a function of
the concentration of a component
ReactIR™ DS Micro Flow Cell can be used with a range of different scale flow
reactors:
- Microscale - 10mL (Future Chemistry)
- Meso scale flow reactors (Uniqsis, Vapourtec)
- Large kilo lab flow reactors (Alfa Laval)
Summary
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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