Nitration of Aromatic Phenol derivatives differ from other Arimatic nitrations, since it works with dilluted HNO3 as well. A synthetic reagent equvivalent could also be the NH4NO3/H2SO4 in this case then. This is how we nitrated Phenol, Resorcinol and the Phloroglucinol. Excellent heattransfer due to the elevated Specific surface area / Reaction Volume ratio. -> This allows safer synthetic routines in highly exotermic reactions, just like nitration. Selectivity Control: Temperature ( Too low temperature would ‘freeze’ the nitration , too high may support oxidation -> dangerous) Approprietry chosen nitro source feed (Quantitative control: molar ratio of the nitro source to the aromatic reactant ). Nature of the nitro source (Qualitative control: Nitration with NH4NO3/H2SO4 is less accelerated, then HNO3/H2SO4 -> less chance for accelerating consecutive reactions, plus HNO3 does not trigger sidereactions , like oxidation) Chosen Reactor Length + Quench (Longer reactor-> higher chance of the consecutive reactions to proceed. Quench: Product mixture is poored on ice and thus the reaction is ‘freezed’, the compound precipitates )
The Problem Associated with the Swern oxidation from an industrial point of view is the formation of the ‘activated’ DMSO intermediate at low temperatures ( -50-60°C). The intermedier is not stable at or above -20°C, decomposing to afford Chloromethyl – Methyl – Sulfide. Having the ICFR utilized, we performed the Swern reaction at even -10°C , without experiencing any thioacetale byproduct formation ! In general, cryogenic synthetic techniques are pretty expansive games to play in industrial scale. Flow conditions, however, may also ease industrial applications. Besides Swern Oxidation, Lithiation and Diazotization is being investigated. Preliminary results are very promising !
Flow chemistry: A useful method for performing hazardous exothermic chemistry in a safer manner
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