acs national meeting boston 2010

Recent Advances in Organic Synthesis

Using Real-Time in situ FTIR

Dominique Hebrault

Sr. Technology & Application

Consultant

Boston, August 22, 2010

Introduction

ReactIRTM Micro Flow Cell for Flow Chemistry

Kinetic Investigation of a Pd-Catalyzed Cross-Coupling Reaction

Conclusions

Presentation Outline

Scale-up and

Manufacturing

Establish Scalable

Parameters

Reduce Batch Failures

Reduce Cycle Time

Design and Process

Development

Develop a Process

Safe

Robust

Addressing Today’s Challenges…

2

Early Phase Development

Develop Compounds

Provide Material

Establish Route

Analyze Reaction Chemistry

Expand

Productivity

Characterize Particles

Data Capture and

Understanding

…With Cutting-Edge Research Technologies

Recent Publications and Collaborations

Mid-IR Real-time Reaction Analysis

Component Spectra Component Profiles

In-situ reaction results

ConcIRTTM live

Peak height profiling

Quantitative model

Mid-IR Real-time Reaction Analysis

Time

Ab

so

rba

nce

or

Rela

tive c

oncentr

ation

Time

Absorb

ance

Introduction

ReactIRTM Flow Cell for Continuous Processing Technologies


Conclusions


Reference: Chemistry Today, 2009, Copyright Teknoscienze Publications, used by permission

CAMBRIDGE UNIVERSITY

Chemical Laboratories

8

Introduction

[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

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



9

MT ReactIRTM flow cell – technical details

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



10

MT ReactIRTM flow cell – applications

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: Asymmetry2007, 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.



11



• Concentration screen performed from 1 M – 0.01 M

• Very low concentrations can be monitored using the solvent subtraction feature



12



• 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)



13


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.



14


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.



15


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.



16



• Monitoring of reactive intermediate activated ester 28 is possible

• Monitoring of different carbonyl bands is possible




• 3D analysis of the spectra greatly assists in the interpretation




Conclusions

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

Introduction



Conclusions


Reference: Arizona State University website, http://www.public.asu.edu/~laserweb/woodbury/classes/chm341/lecture_set7/Image275.gif

http://www.public.asu.edu/~laserweb/woodbury/classes/chm341/lecture_set7/Image275.gif

Articles on Reaction Progress Kinetic Analysis

Blackmond, D. G.

Angew. Chemie Int. Ed. 2005, 44, 4302

Blackmond, D. G. et al.,

J. Org. Chem. 2006, 71, 4711

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

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

Investigation of an Efficient

Palladium-Catalyzed C(sp)-C(sp)

Cross-Coupling Reaction Using

Phosphine-Olefin Ligand:

Application and Mechanistic Aspects

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

Palladium-catalyzed cross-coupling reactions

Introduction

Highly efficient method to synthesize

unsymmetrical 1,3-diynes

L1

Use of in situ IR for preliminary kinetic

studies for mechanistic analysis

Wei Shi, Yingdong Luo, Xiancai Luo, Lei Chao, Heng Zhang, Jian Wang, and Aiwen Lei; J. Am. Chem. Soc. 2008, 130, (44), 14713-14720


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


Same excess experiment (IR measurement, GC calibration)

Reaction A 0.41M 0.43M 0.006M 0.003M

Reaction B 0.29M 0.31M 0.006M 0.003M

Pd(dba)2 CuI

UnchangedSame 0.2M excess

Indicative of no product inhibition

or catalyst deactivation0.00E+00

5.00E-05

1.00E-04

1.50E-04

2.00E-04

2.50E-04

3.00E-04

0 0.1 0.2 0.3 0.4

Rea

ctio

n r

ate

(M/m

in)

Concentration of 1c

[1c] = 0.29 M, [2g] = 0.31 M

[1c] = 0.41 M, [2g] = 0.43 M

Overlay:

no catalyst deactivation


Different excess experiment overlay

CuI

Indicative of zero-order in

both reactants

(0.43M)

(0.006M)

(0.003M)+

Pd(dba)2

0

0.0001

0.0002

0.0003

0.0004

0.0005

0.0006

1.15 1.2 1.25 1.3 1.35 1.4

Rat

e/[1

g]0.

03

[2g]-0.11

[e] = 0.14 M

[e] = 0.02 M

[e] = -0.06 M

Linear (Rate Eqn Prediction)

Overlay gives order 0 in 1c

Straight lines give order 0 in 2g


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


What does all this mean?

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


What does all this mean?

1

2

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


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


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

Introduction



Conclusions


3232

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

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acs national meeting boston 2010

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