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

Email us at dominique.hebrault@mt.com

OR

autochem@mt.com

OR

Call us + 1.410.910.8500