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

Email us at dominique.hebrault@mt.com

OR

autochem@mt.com

OR

Call us + 1.410.910.8500