Flow chemistry: A useful
method for performing
chemistry in a safer manner
What is flow chemistry?
Performing a reaction continuously, typically on small scale,
through either a coil or fixed bed reactor.
Mixing (batch vs. flow)
Flow reactors can achieve
homogeneous mixing and
uniform heating in
Kinetics In Flow Reactors
• In a microfluidic device with aconstant flow rate, the
concentration of the reactant decaysexponentially with
distance along the reactor.
• Thus time in aflask reactor equates with distance in a
Miniaturization: Enhanced temperature control
• Microreactors have higher surface-to-volume ratio than macroreactors, heat
transferoccurs rapidly in a flow microreactor, enabling precise temperature
Yoshida, Green and Sustainable Chemical Synthesis Using Flow
Microreactors, ChemSusChem, 2010
- Lower reaction volume.
- Closer and uniformtemperature control
- Safer chemistry.
- Lower possibility of exotherm.
- Larger solvent volume.
- Lower temperature control.
-More difficult reaction control.
- Higher possibility of exotherm.
Lithium Bromide Exchange
• Batch experiment shows temperature increase of 40 C.
• Flow shows little increase in temperature.
Ref: Thomas Schwalbe and Gregor Wille, CPC Systems
Traditional Batch Method
Batch vs. Flow: Enhanced selectivity
Low reactant concentration
Elimination of the products
Elution of gaseous by-product
Making processes safer
Accessing new chemistry
Speed in synthesis and
Making processes safer
to batch variation
Why move to flow?
• Current hydrogenation processes have many
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
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)
Conditions: 1% Pt/C, 70 bar, 100 C, residence time 17s
Results: 100% conversion, 100% yield
Nitro group reductions
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 weight
gain 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,
Y Wada, K F. Jensen, Ind. Eng. Chem. Res. 2006, 45, 8036-8042
Set-up of the Ice Cube Modular System
generates O3from O2 100 mL/min, 10 % O3.
Pump Module – 2 Rotary Piston Pumps.
Excellent chemical compatibility.
2 Stage reactor. -70 C-+80 C.
Versatile: 2 options
Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation
O-Cube™ – H-Cube®- ReactIR™
ozonolysis of decene
Ozonolysis Quenching with
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
O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International
Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.
ThalesNano lab based
Ozonide eluted into cool vial under N2
Diazotization and azo-coupling in Ice Cube
A - B - C
T (°C) τ (1. loop, min) τ(2. loop, min) Isolated Yield
FM79-1 0.4 0 2.12 3.33 91
FM79-2 0.9 0 0.94 1.48 91
FM79-3 0.6 0 1.42 2.22 85
FM79-4 0.9 10 0.94 1.48 85
FM79-5 1.5 10 0.56 0.88 86
FM79-6 1.5 15 0.56 0.88 98
FM79-7 1.2 15 0.71 1.11 84
FM79-8 1.8 15 0.47 0.74 86
NH2 N N+
HCl sol. Pump A