recent advances webinar part 8

Continuous Flow Chemistry

Recent Advances in Organic Chemistry

Part 8

Dom Hebrault, Ph.D.

Principal Technology and

Application Consultant

May 16th 2012

References cited in following case studies (4)

Continuous Flow Chemistry: Recent Advances in Organic Chemistry Part 7

Information Sharing Event:

- Continuous Flow Chemistry and Crystallization Development, New Brunswick, NJ,

September 2012

- Chemical and Crystallization Research & Development, Cambridge, MA, May 2012

Mettler Toledo articles & conference presentations: Chim. Oggi, White

Papers, FloHet, Flow Chemistry Congress, AIChE…

Other peer-reviewed scientific articles and references available on request

Background & Literature

Continuous Flow Production of Thermally

Unstable Intermediates in a Microreactor

with Inline IR-Analysis: Controlled

Vilsmeier−Haack

Introduction

Vilsmeier−Haack formylation hazardous

to scale-up: Unstable chloroiminium

intermediate

Enhanced safety in microreactors thanks

to better heat dissipation and smaller

volume

Flow Production of Unstable Intermediates

1- Formation of the VH-reagent

2- Arene oxidation – Iminium formation

3- Quench of iminium salt

A. M. W. van den Broek, J. R. Leliveld, R. Becker, M. M. E. Delville, P. J. Nieuwland, Kaspar Koch, F. P. J. T. Rutjes; FutureChemistry Holding BV,

Institute for Molecules and Materials, Radboud University Nijmegen; The Netherlands; Organic Process Research and Development, 2012, 16, 5,

934-938

FlowStart Evo

FutureChemistry

Vol. 92 μL, channel W 600 μm, D 500 μm, L 360 mm

Formation of the VH-reagent

At-line measurement required to prevent

partial conversion of POCl3: Pyrrole →

polymers → clogging

At-line UV unpractical because DMF

shows absorbance around 300 nm

Problem overcome using inline FlowIR


FlowIRTM` C-Cl

P-O-C

Rt 10 s

180 s



934-938

Formation of the VH-reagent

Plot [2] and [3] as a function of residence

time

Higher [3] level at Rt>100s possibly due

to higher [Cl-] resulting from counterion

degradation


IR 804 cm-1

IR 769 cm-1

2 3

2

3

Conclusions

VH formylation proved to be readily

conducted in flow microreactor system

FlowIR essential to solve at-line UV

limitations

Optimization of reaction time (180 s),

temperature (60 °C, molar ratio (1.5 eq.)

→ 5.98 g/h



934-938

A Microreactor System for High-Pressure

Continuous Flow Homogeneous Catalysis

Measurements

Introduction

Hydroformylation of alpha-olefins

commercially used to produce

aldehydes/alcohols

However, few and contradictory kinetics

data under relevant industrial conditions

(high P, T)

High-Pressure G/L Flow Homogeneous Catalysis

Microreactors for segmented flow for

1- Enhanced gas/liquid mass transfer

2- Isothermal operation → kinetics

Jaroslav Keybl and Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Ind. Eng. Chem. Res., 2011, 50, 11013–11022

Lab made silicon or Pyrex microreactor

Square channel 500 x 500 μm

Vol. 220 μl

1-octene

Toluene

100 °C, 30 b

Sampling issues resolved with inline

ATR-FTIR:

ReactIR 10 with DiComp DS Micro Flow

Cell; Vol. 50 μl


Sampling issues with GC

1- Volatile alkene → sample loss

2- Poor GC mass balance

3- Sampling reproducibility (carry-over)


& 910 cm-1



Up to 350 °C, 100 b

Rt: s to 15 min.

Teledyne Isco, 100DM

Teledyne Isco, Controller

Bronkhorst,

EL‐PRESS series

National

Instruments, v7.1

LabVIEW T° control

J‐Kem, Gemini‐K

GC

Teflon

ReactIR

Results

Confirm kinetic regime and analytical

mass balance

Detailed kinetic study using a non-linear

least square regression



ReactIR provided:

- Verification of proper operation

- Direct confirmation of steady state

after change of variable

- Real time component assay after

calibration

- Segmented G/L flow manageable

Automated Multi-trajectory Method for

Reaction Optimization in a Microfluidic

System using Online IR Analysis

Introduction

Production rate* of a Pall-Knorr reaction

maximized: Temperature (30–130°C),

time (2-30 min)

Continuous online infrared (IR)

monitoring

Automated Optimization using Microreactors

ReactIR provided benefits of:

- Low material requirement

- Inline conversion monitoring, steady

state reach for faster optimization

Jason S. Moore, Klavs F. Jensen; Department of Chemical Engineering, MIT, Cambridge, MA, USA, Org. Process Res. Dev. 2012, 16, 1409−1415

Paal –Knorr Reaction

Automation system

Data flow

Fluid flow

(Harvard)

IR spectrum of the Paal−Knorr reaction species

(solvent subtracted)


Goal:

- Compare performance of automated

optimization algorithms

- “Similar” optimum: T 130°C, t 4.5 min

- Large difference in number of runs (38

versus 126) and time required

Algorithm designed for

- Steps: 2°C, 1 min

- Single path to optimum

- Intelligently updating reaction conditions

based on inline analytics

- Automatically performing DOE towards

optimum

Optimum for each algorithm

Comparison of optimum reach for each algorithms

(number of runs, reaction conversion)

Steepest descent

Conjugate gradient

Armijo

conjugate

gradient



Conclusions:

- Pall-Knorr production rate maximized within

30–130°C, t 2-30 min

- Conjugate gradient with addition of Armijo-

type algorithm provides better optimization

efficiency

- Future development: Stoichiometry,

selectivity, impurity profile optimization ReactIR provided:

- Real time info about steady state reach

- Exportable data for feedback control →

dynamic experiment duration

- Non destructive analytical method and low

material requirement

- Total reaction mixture : No sampling, no

dilution

Production rate optimization strategies above 130°C

Production rate optimization using Armijo conjugate gradient


Continuous-flow catalytic asymmetric

hydrogenations: Reaction optimization

using FTIR inline analysis

Introduction

Microreactors setup coupled with ATR-FTIR

microflowcell (ReactIR)

Asymmetric hydrogenation of benzoxazines,

quinolines, quinoxalines, 3H-indoles with

Hantzsch dihydropyridine

Continuous Asymmetric Hydrogenation

ReactIR microflowcell benefits:

- More rapid screening of reaction para-

meters

- Faster reach of optimum reaction conditions

Magnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307

Commercial glass microreactor / In single glass reactor with inlets

Schematic of experimental setup and chemistry

Asym. ligand

Solvent: CHCl3


Method and results:

- Collection of reference spectra for solvent,

starting material, and reagents

- Optimum conditions after fast screening

thanks to real time analytics: T 60°C, t 20

min, flow rate 0.1 mL.min-1

Further reported investigations

- Scope

- Conditions optimization: Flow conditions,

catalyst loading, reagent Trend curve of product formation at different temperatures


IR spectra for substrate

consumption and

product formation at

different temperature


Conclusions:

- Microreactors setup coupled with ATR-FTIR

microflowcell (ReactIR)

- Inline real time analysis of the microreactor

reaction stream right at the outlet

- Faster, more precise feedback or reaction

mixture composition and component

concentration

- More rapid screening of reaction

parameters

- Faster reach of optimum reaction

conditions

- Ongoing development: automated

integration and feedback optimization of

reaction parameters


Continuous Preparation of Arylmagne-

sium Reagents in Flow with Inline IR

Monitoring

Introduction

Continuous flow reaction setup (Vapourtec

R2+) with inline ATR-FTIR FlowIR:

1. Grignard exchange

2. Coupling with carbonyl compounds

Comparison ATR-FTIR / GC / I2 titration

Preparation of Arylmagnesium in Flow

FlowIR benefits:

- Conversion, by-products in real time

- In situ determination of absolute concen-

tration after calibration

- Elucidation of mechanistic details

- Ensure / facilitate product high quality

- Faster optimization

Tobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, Steven V. Ley, Beilstein Org. Process Res. Dev. 2012, 16, 1102−1114

ATR-FTIR FlowIR instrument

Schematic of experimental setup and chemistry


Method and results:

- Collection of reference spectra

- Solvent subtraction from dataset

- Identify unique peaks

- Interpret changes

- Peak intensity versus Ar-X concentration

- Calibration

- Inline determination of concentration

- Further optimization: Accurately match

delivery of 3rd stream (vide infra) Mid-IR reference spectra for THF and Grignard reagent

Intensity of mid-IR peaks at different concentrations


Shift due to THF

coordination

1069 → 1043cm-1

913 → 894 cm-1

Aryl moiety

764, 711cm-1

Calibration curves


- Identify unique peaks for reaction

components

- Use 2nd derivative spectra as advanced

interpretation tool

- Trend component(s) of interest versus time

- Diffusion in the flow stream

- Timing and feed rate for 3rd stream

adjusted automatically and in real time to

mid-IR readout

- Screen of reaction parameters

- Scope (aryl halide, carbonyl derivative) Fingerprint region for solvent, starting material, (side)-products

Real time intensity of mid-IR peak of Grignard reagent


Toluene

ArMgX

767, 1043cm-1

Wurtz

side-product


IR spectra of iPrMgCl and iPrMgCl.LiCl complex

IR spectrum of Grignard reagent solution in toluene with THF


Role of LiCl/THF by IR spectroscopy

- Shift, intensity changes due to complex

Role of THF as solvent

- 1, 2, 4, 10 eq dry THF added to Grignard

reagent in toluene

- IR clearly indicates coordination of THF to

Mg in Grignard species

iPrMgCl

iPrMgCl.LiCl

With ReactIR, it became possible to:

- Ensure quality of Ar-MgX in solution, in situ

- Determine concentration of active

reagents, composition of reaction stream to

quickly optimize process

- Further used to monitor/optimize reaction

with carbonyl compounds

Acknowledgements

Institute for Molecules and Materials, Radboud University (The Netherlands)

- Pr. Floris P. J. T. Rutjes et al.

Department of Chemical Engineering, MIT (USA)

- Pr. Klavs Jensen, Dr. Jerry Keybl, Dr. Jason Moore

University of Cambridge, UK

- Pr. Steven V. Ley et al.

Department of Chemistry, Ludwig Maximilians-Universität München, Germany

- Pr. Paul Knochel et al.

Institute of Organic Chemistry, Aachen University, Germany

- Pr. Magnus Rueping et al.

Mettler Toledo Autochem

- Will Kowalchyk, Wes Walker, Paul Scholl (USA), Jon Goode (U.K.)