flow chemistry: a useful method for performing hazardous exothermic chemistry in a safer manner

Flow chemistry: A useful

method for performing

hazardous exothermic

chemistry in a safer manner

Richard JonesRichard.jones@thalesnano.com

What is flow chemistry?

Performing a reaction continuously, typically on small scale,

through either a coil or fixed bed reactor.

OR

PumpReactor Collection

Mixing (batch vs. flow)

Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)

Kinetics In Flow Reactors

• In a microfluidic device with a constant flow rate, the concentration of the reactant decays exponentially with distance along the reactor.

• Thus time in a flask reactor equates with distance in a flow reactor

X

A

dX/dt > 0

dA/dt < 0

Miniaturization: Enhanced temperature control Large surface/volume rate

• Microreactors have higher surface-to-volume ratio than macroreactors, heat transfer occurs rapidly in a flow microreactor, enabling precise temperature control.

Yoshida, Green and Sustainable Chemical Synthesis Using FlowMicroreactors, ChemSusChem, 2010

Heating Control

Batch Flow

- Lower reaction volume. - Closer and uniform temperature control

Outcome:

- Safer chemistry.- Lower possibility of exotherm.

- Larger solvent volume. - Lower temperature control.

Outcome:

- More difficult reaction control. - Higher possibility of

exotherm.

Heating Control

Lithium Bromide Exchange

Batch

Flow

• Batch experiment shows temperature increase of 40°C.• Flow shows little increase in temperature.

Ref: Thomas Schwalbe and Gregor Wille, CPC Systems

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Batch vs. Flow: Enhanced selectivity

Low reactant concentrationElimination of the productsElution of gaseous by-product

Flow Method

Industry perception

Small scale: Making processes safer Accessing new chemistry Speed in synthesis and

analysis Automation

Large scale: Making processes safer Reproducibility-less batch

to batch variation Selectivity

Why move to flow?

Hydrogenation

• Current hydrogenation processes have many disadvantages:

Need hydrogen cylinder-tough safety regulations Separate laboratory needed! Time consuming and difficult to set up Catalyst addition and filtration is hazardous Parr has low temperature, low pressure capability Analytical sample obtained through invasive means. Mixing of 3 phases inefficient - poor reaction rates

• Benefits• Safety• No filtration necessary • Enhanced phase mixing

Catalyst System-CatCart®

Aldoxim reductionAldehyde reduction

0

5

10

15

20

25

30

t /m

in

Flow

Batch

0

200

400

600

800

1000

1200

t /

min

Alkylation Suzuki-Miyaura Azide synthesis Sonogashirareaction

Flow

Batch

Initial Experiments

Hydrogen generator cell Solid Polymer Electrolyte

High-pressure regulating valves

Water separator, flow detector, bubble detector

H-Cube Pro Overview

• HPLC pumps continuous stream of solvent • Hydrogen generated from water electrolysis• Sample heated and passed through catalyst• Up to 150°C and 100 bar. (1 bar=14.5 psi)

NH

O2N

NH

NH2

Hydrogenation reactions: Nitro Reduction Nitrile reduction Heterocycle Saturation Double bond saturation Protecting Group hydrogenolysis Reductive Alkylation Hydrogenolysis of dehydropyrimidones Imine Reduction Desulfurization

O2N NO2

OHH2N NH2

OH

Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17sResults: 100% conversion, 100% yield

Nitro group reductions

Low TemperatureChemistry

What is ozonolysis?

Ozonolysis is a technique that cleaves double and

triple C-C bonds to form a C-O bond.

Ozonolysis in Industry

Biologically active natural product

Synthesis of a Key intermediate for Indolizidine 215F

S. Van Ornum et al, Chem. Rev.106, 2990-3001 (2006)

Oxandrolone, anabolic steroid used to promote weightgain following extensive surgery, chronic infection

Why ozonolysis is neglected?

• Highly exothermic reaction, high risk of explosion • Normally requires low temperature: -78°C.• In addition, the batchwise accumulation of ozonide

is associated again with risk of explosion• There are alternative oxidizing agents/systems:

• Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4)

• Ru(VIII)O4 + NaIO4

• Jones oxidation (CrO3, H2SO4)

• Swern oxidation

• Most of the listed agents are toxic, difficult, and/or expensive to use.

Ozonolysis in a 16–channel–microreactor (Wada, Jensen, MIT)

Y Wada, K F. Jensen, Ind. Eng. Chem. Res. 2006, 45, 8036-8042

Set-up of the Ice Cube Modular System

Ozone Module: generates O3 from O2 100 mL/min, 10 % O3.

Pump Module – 2 Rotary Piston Pumps. Excellent chemical compatibility.

Reactor Module: 2 Stage reactor. -70°C-+80°C.Teflon tubing.

Versatile: 2 options

A

BC

AB

C

D

Pre-cooler/Mixer Reactor

-70-+80ºC

-70-+80ºC -30-+80ºC

Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation

Quench Reactant

T (°C) Solvent Vrea (ml/min)

vQuen (ml/min)

Quench c (M)

O3

(%)X (%) OH

(%)C=O(%)

RT Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 72 0 95

0 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 60 0 97

-20 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 65 0 97

RT Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 67 0 99

0 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 70 0 99

-20 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 63 0 99

Carbonyl is the productOther quenching agents for carbonyl production: PPh3, DMS

O

O

M=192 g/mol M=152 g/mol

OH

M=154g/mol

O-Cube™ – H-Cube® - ReactIR™ ozonolysis of decene

Ozonolysis Quenching withH-Cube®

T = -30 ºC

CSM = 0.02 M (in EtOAc)

O3 excess = 30 %

T = -30 ºC to r.t.

p = 1 bar

Cat: 10 % Pd/C

React IR™

O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.

H2 10%Pd/C

ThalesNano lab based chemistry-unpublished

Ozonide eluted into cool vial under N2

Diazotization and azo-coupling in Ice Cube

Vflow (ml/min)A - B - C

T (°C) τ (1. loop, min) τ (2. loop, min) Isolated Yield (%)

FM79-1 0.4 0 2.12 3.33 91FM79-2 0.9 0 0.94 1.48 91FM79-3 0.6 0 1.42 2.22 85FM79-4 0.9 10 0.94 1.48 85FM79-5 1.5 10 0.56 0.88 86FM79-6 1.5 15 0.56 0.88 98FM79-7 1.2 15 0.71 1.11 84FM79-8 1.8 15 0.47 0.74 86

NH2 N N+ Cl-NaNO2

HCl

O-

NaOH

N N

OH

AnilineHCl sol. Pump A

Pump BNaNO2 sol.

Pump C

Phenol NaOH sol.

Novel scaffold synthesis from explosive intermediates

Nitration of Aromatic Alcohols

OH OH

NO2

NO2

O2N

Phenol

Pump A Pump B Temperature (oC)

Loop size (ml)

Conversion (%) Selectivity (%)

SolutionFlow rate (ml/min) Solution

Flow rate (ml/min)

ccHNO3 0.41g PG/15ml

ccH2SO4 0.4 5 - 10 7 1000 (different products)

1.48g NH4NO3/15ml ccH2SO4 0.7

1g PG/15ml ccH2SO4 0.5 5 - 10 13 100 100

1.48g NH4NO3/15ml ccH2SO4 0.5

1g PG/15ml ccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)

70% ccH2SO4 30% ccHNO3 0.6

1g PG/15ml ccH2SO4 0.5 5 - 10 13 (3 bar) 100 100

70% ccH2SO4 30% ccHNO3 0.6

1g PG/15ml ccH2SO4 0.5 5 - 10 13 (1 bar) 80

70 (30% dinitro and nitro)

ThalesNano’s other cryogenic, continous flow applications

Swern Oxidation

Cryogenic operating conditions (< - 60°C), limit its utility for scale up operations in batch.

Temperature (°C) OAC Solution (ml/min) Alcohol and DMSO Solution (ml/min) Conversion (%) Selectivity (%)

-30 0.96 1.9 100% 100%

-20 0.96 1.9 100% 100%

-10 0.96 1.9 100% 100%

0 0.96 1.9 100% 60%

OH ODMSO, Oxalyl-Chloride

Quench: TEA

Ice-Cube Flow Reactor

Using TFAA as a DMSO activator seems to afford even higher temperatures.

No chloromethyl-methyl-sulfide production at higher Temps.

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS

Booth 1422