Flow chemistry: A useful
method for performing
hazardous exothermic
chemistry in a safer manner
Richard Jones
Richard.jone...
What is flow chemistry?
Performing a reaction continuously, typically on small scale,
through either a coil or fixed bed r...
Mixing (batch vs. flow)
Flow reactors can achieve
homogeneous mixing and
uniform heating in
microseconds
(suitableforfastr...
Kinetics In Flow Reactors
• In a microfluidic device with aconstant flow rate, the
concentration of the reactant decaysexp...
Miniaturization: Enhanced temperature control
Largesurface/volumerate
• Microreactors have higher surface-to-volume ratio ...
Heating Control
Batch Flow
- Lower reaction volume.
- Closer and uniformtemperature control
Outcome:
- Safer chemistry.
- ...
Heating Control
Lithium Bromide Exchange
Batch
Flow
• Batch experiment shows temperature increase of 40 C.
• Flow shows li...
Reactants
Products
By-products
Traditional Batch Method
Gas inlet
Reactants
Products
By-products
Batch vs. Flow: Enhanced ...
Industry perception
Small scale:
 Making processes safer
 Accessing new chemistry
 Speed in synthesis and
analysis
 Au...
Hydrogenation
• Current hydrogenation processes have many
disadvantages:
 Need hydrogen cylinder-tough safety regulations
 Separate la...
•Benefits
• Safety
•No filtration necessary
•Enhanced phase mixing
Catalyst System-CatCart®
Aldoxim reduction
Aldehyde reduction
0
5
10
15
20
25
30
t/min
Flow
Batch
0
200
400
600
800
1000
1200
t/min
Alkylation Suzu...
Hydrogen generator cell
 Solid Polymer Electrolyte
High-pressure regulating
valves
Water separator, flow
detector, bubble...
H-Cube Pro Overview
• HPLC pumps continuous stream of solvent
• Hydrogen generated from water electrolysis
• Sample heated...
Conditions: 1% Pt/C, 70 bar, 100 C, residence time 17s
Results: 100% conversion, 100% yield
Nitro group reductions
Low Temperature
Chemistry
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 Or...
Why ozonolysis is neglected?
• Highly exothermic reaction, high risk of explosion
• Normally requires low temperature: -78...
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
OzoneModule:
generates O3from O2 100 mL/min, 10 % O3.
Pump Module – 2 Rotary Piston ...
Versatile: 2 options
A
B
C
A
B
C
D
Pre-cooler/Mixer Reactor
-70-+80ºC
-70-+80ºC -30-+80ºC
Potential Apps: Azide, Lithiatio...
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...
O-Cube™ – H-Cube®- ReactIR™
ozonolysis of decene
Ozonolysis Quenching with
H-Cube®
T = -30 ºC
CSM = 0.02 M (in EtOAc)
O3 e...
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...
Novel scaffold synthesis from explosive intermediates
Nitration of Aromatic Alcohols
Pump A Pump B Temperature
(o
C)
Loop ...
ThalesNano’s other cryogenic, continous flow applications
Swern Oxidation
Cryogenic operating conditions (< - 60 C), limit...
THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS
Booth 1422
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Flow chemistry: A useful method for performing hazardous exothermic chemistry in a safer manner

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  • 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. -&gt; 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 -&gt; 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 -&gt; less chance for accelerating consecutive reactions, plus HNO3 does not trigger sidereactions , like oxidation) Chosen Reactor Length + Quench (Longer reactor-&gt; 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

    1. 1. Flow chemistry: A useful method for performing hazardous exothermic chemistry in a safer manner Richard Jones Richard.jones@thalesnano.com
    2. 2. What is flow chemistry? Performing a reaction continuously, typically on small scale, through either a coil or fixed bed reactor. OR Pump Reactor Collection
    3. 3. Mixing (batch vs. flow) Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitableforfastreactions)
    4. 4. 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 flow reactor X A dX/dt> 0 dA/dt<0
    5. 5. Miniaturization: Enhanced temperature control Largesurface/volumerate • Microreactors have higher surface-to-volume ratio than macroreactors, heat transferoccurs rapidly in a flow microreactor, enabling precise temperature control. Yoshida, Green and Sustainable Chemical Synthesis Using Flow Microreactors, ChemSusChem, 2010
    6. 6. Heating Control Batch Flow - Lower reaction volume. - Closer and uniformtemperature control Outcome: - Safer chemistry. - Lower possibility of exotherm. - Larger solvent volume. - Lower temperature control. Outcome: -More difficult reaction control. - Higher possibility of exotherm.
    7. 7. 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
    8. 8. Reactants Products By-products Traditional Batch Method Gas inlet Reactants Products By-products Batch vs. Flow: Enhanced selectivity Low reactant concentration Elimination of the products Elution of gaseous by-product Flow Method
    9. 9. 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?
    10. 10. Hydrogenation
    11. 11. • 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
    12. 12. •Benefits • Safety •No filtration necessary •Enhanced phase mixing Catalyst System-CatCart®
    13. 13. Aldoxim reduction Aldehyde reduction 0 5 10 15 20 25 30 t/min Flow Batch 0 200 400 600 800 1000 1200 t/min Alkylation Suzuki-Miyaura Azide synthesis Sonogashira reaction Flow Batch Initial Experiments
    14. 14. Hydrogen generator cell  Solid Polymer Electrolyte High-pressure regulating valves Water separator, flow detector, bubble detector
    15. 15. 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) N H O2N N H NH2 H
    16. 16. Conditions: 1% Pt/C, 70 bar, 100 C, residence time 17s Results: 100% conversion, 100% yield Nitro group reductions
    17. 17. Low Temperature Chemistry
    18. 18. What is ozonolysis? Ozonolysis is a technique that cleaves double and triple C-C bonds to form a C-O bond.
    19. 19. 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
    20. 20. 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.
    21. 21. Ozonolysis in a 16–channel–microreactor (Wada, Jensen, MIT) Y Wada, K F. Jensen, Ind. Eng. Chem. Res. 2006, 45, 8036-8042
    22. 22. Set-up of the Ice Cube Modular System OzoneModule: generates O3from 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.
    23. 23. Versatile: 2 options A B C A B C D Pre-cooler/Mixer Reactor -70-+80ºC -70-+80ºC -30-+80ºC Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation
    24. 24. Quench Reactant
    25. 25. 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
    26. 26. O-Cube™ – H-Cube®- ReactIR™ ozonolysis of decene Ozonolysis Quenching with H-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. ThalesNano lab based chemistry-unpublished Ozonide eluted into cool vial under N2
    27. 27. 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 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+ Cl- NaNO2 HCl O- NaOH N N OH Aniline HCl sol. Pump A Pump BNaNO2 sol. Pump C Phenol NaOH sol.
    28. 28. Novel scaffold synthesis from explosive intermediates Nitration of Aromatic Alcohols Pump A Pump B Temperature (o C) Loop size (ml) Conversion (%) Selectivity (%) Solution Flow rate (ml/min) Solution Flow rate (ml/min) ccHNO3 0.4 1g PG/15ml ccH2SO4 0.4 5 - 10 7 100 0 (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)
    29. 29. 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 O DMSO, 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.
    30. 30. THANK YOU FOR YOUR ATTENTION!! ANY QUESTIONS Booth 1422
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