Ice-Cube:
Low temperature flow
chemistry for enhanced safety
and selectivity
Heather Graehl, MS, MBA
Director of Sales Nor...
Who are we?

ThalesNano is a technology company that gives chemists
tools to perform novel, previously inaccessible chemis...
Customers (>800 worldwide)
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 (suitable
for fa...
Kinetics In Flow Reactors
In a microfluidic device with a constant flow rate, the
concentration of the reactant decays exp...
Miniaturization: Enhanced temperature control
Large surface/volume rate

Microreactors have higher surface-to-volume ratio...
Heating Control
Batch

Flow

- Larger solvent volume.
- Lower temperature control.

- Lower reaction volume.
- Closer and ...
Heating Control
Lithium Bromide Exchange
Batch

Flow

• Batch experiment shows temperature increase of 40°C.
• Flow shows ...
Industry perception

Why move to flow?
Small scale:
 Making processes safer
 Accessing new chemistry
 Speed in synthesi...
Low Temperature
Chemistry
IceCube
Safe: Low reaction volume, excellent
temperature control, SW controlled – including
many safety control points
Sim...
The IceCube family

Pump Module

• 2pcs rotary piston
pumps
• 2pcs 3-way inlet
valves
• Flow rate: 0.2 – 4.0
mL/min
• Max ...
Verstatility to access multiple working modes

A

C

B
-70-+80ºC
Reactor

Pre-cooler/Mixer

Potential Apps: Azide, nitrati...
Reaction zone cooling

Right hand side:
Water inlet and outlet
First Reaction
Zone

Secondary
Reaction Zone

Ideal for dan...
Control – Graphical User Interface
Seamless control of all the
modules on a touch screen
interface
For custom flow configu...
Main application areas
Exothermic Reactions
# of hits in sciencedirect.com

Ozonolysis
9 655

Azides

Nitration

89 718

2...
Why ozonolysis is neglected?
Highly exothermic reaction, high risk of explosion
Normally requires low temperature: -78°C.
...
What is ozonolysis?
Ozonolysis is a technique that cleaves double and
triple C-C bonds to form a C-O bond.
How does it work?

SM1 /
Reactant or
Solvent

Product or Waste

SM2 / Quench or
Solvent
Olefins using as masked terminal aldehydes/ alcohols
Synthesis of a Key intermediate for Indolizidine 215F

Biologically a...
Flow Ozonolysis of Styrenes

M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
Flow Ozonolysis
Oxidation of alkynes

Oxidation of amines to nitro groups

M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett...
Flow Ozonolysis Of Thioanisole

M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
Swern Oxidation on IceCube
0.45 M alcohol, 0.14 M
DMSO in DCM
0.94 mL/min

Batch reaction:
Max. -60°C to avoid side reacti...
Diazotization and azo-coupling in the IceCube

Aniline
HCl sol.

Pump A

NaNO2
sol.

Pump B

Entry

Pump C
Phenol
NaOH sol...
Safe reaction of azides using Ice-Cube

TKX50

• 2 Step Azide Reaction in flow
• No isolation of DAGL
• Significantly redu...
Novel scaffold synthesis from explosive intermediates
Nitration of Aromatic Alcohols

Currently investigating
selectivity ...
Coming soon…

• Lithiation experiments (collaborations)
• Fluorination experiments (collaborations)
• Low temperature sele...
Thank you for your attention!
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Ice-Cube: Low Temperature Flow Chemistry for Enhanced Safety and Selectivity

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ozonolysis, lithiations, nitrations, diazotation, swern oxidation, azide synthesis, reactive intermediates, exotherm, flow chemistry

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  • Safety departments are considering banning the use of ozonolysis.
  • Ozonolysis adds to the double or triple bond to form the molozonide. The molozonide is a very short lived species and quickly rearranges to form the trioxalane (ozonide).
    The ozonide is then reacted with another reagent to form either a ketone, aldehyde, alcohol, or carboxylic acid.
  • In addition to olefinic double bonds, the ozonolysis of the terminal C-C triple bond in 1,1- diphenylprop-2-yn-1-ol 5 (Scheme 1b) was also investigated. In our hands, the ozonolysis of propynol 5 inCHCl3 did not lead to the expected glycolic acid 616 but to diphenylketone 7 in 86% yield. The observed result can be rationalized by the presence of ozone in the reaction mixture, creating an oxidizing environment, able to rapidly decarboxylate the in situ formed glycolic acid, thereby forming diphenylketone 7 as observed previously by Hurd and Christ for similar substrates.17
    In another application of the continuous flowozonolysis concept, we attempted the oxidative transformation of octan-1-amine 8 (Scheme 1c) into the corresponding nitroalkane 10. Previous work by Bachman and Strawn has confirmed that primary amines of type 8 can be subjected to ozonolysis under batch conditions to provide nitroalkanes, 18 and the Jensen group has reported the oxidation 8 f 9 with O3 in a multichannel microreactor.8 Adopting operating conditions similar to those used during olefin ozonlysis, a 0.05 M EtOAc solution of octan-1-amine 8 was subjected to flow ozonolysis in the O-Cube at room temperature. Applying a 10% ozone concentration (∼3 equiv), complete consumption of the starting material was experienced, providing 1-nitrooctane 9 in 73%yield after a single pass through the instrument within 40 min.
  • The oxidation of thioanisole (10) appeared to be a somewhat more demanding process, as it has been found that aliphatic/ aromatic or aromatic/aromatic thioethers tend to react relatively slowly or not at all with ozone (thioesters).19 While the formation of the sulfoxide proceeds relatively slowly, the further oxidation step to the sulfone is known to be even more sluggish.19 Therefore, we investigated the oxidation behavior of thioanisole (10) with ozone under flow conditions. Initially, a 0.05Msolution of thioanisole (10) in methanol was processed at 25 C and 1 mL/min flowrate applying 5%O3 (1.0 equiv). Reductive quenching with 0.1 M NaBH4 in MeOH at 25 C followed by extractive workup provided sulfoxide 11 in 84% isolated product yield (Table 2, entry 1). In order to access sulfone 12 the reductive quench was replaced by an oxidative one (Table 2, entryies 2-8). Using NaIO4 as oxidative reagent at 25 C and 2 equiv of O3 in acetone, full conversion based on consumption of sulfide 10 was achieved at a 0.5mL/min flowrate in the ozonolysis step. Analysis (GC-MS) of the obtained reaction mixture showed predominant formation of sulfoxide 11 accompanied by 18% of the desired sulfone 12 (Table 2, entry 2). Lower temperatures and higher flow rates, as well as changing the oxidative reagent to 5 MH2O2 in water as solvent led to an improved sulfoxide/sulfone product distribution (Table 2, entries 3-5) providing up to 88% selectivity for sulfone 12.
    Ultimately, changing the reaction solvent to MeOH initially did not seem promising (Table 2, entry 6); however, after further optimization we were finally able to achieve quantitative conversion of thioanisole 10 into the desired sulfone 12.
    Under the optimized conditions for full conversion (Table 2, entry 8) a preparative experiment provided 87% isolated yield of sulfone 12 after a simple workup.
  • 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 )
  • Ice-Cube: Low Temperature Flow Chemistry for Enhanced Safety and Selectivity

    1. 1. Ice-Cube: Low temperature flow chemistry for enhanced safety and selectivity Heather Graehl, MS, MBA Director of Sales North America
    2. 2. Who are we? ThalesNano is a technology company that gives chemists tools to perform novel, previously inaccessible chemistry safer, faster, and simpler. Market leader: 800 customer install base on 6 continents. 33 employees with own chemistry team. 11 years old-most established flow reactor company. R&D Top 100 Award Winner.
    3. 3. Customers (>800 worldwide)
    4. 4. What is flow chemistry? Performing a reaction continuously, typically on small scale, through either a coil or fixed bed reactor. OR Pump Reactor Collection
    5. 5. Mixing (batch vs. flow) Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)
    6. 6. 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
    7. 7. 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 Flow Microreactors, ChemSusChem, 2010
    8. 8. Heating Control Batch Flow - Larger solvent volume. - Lower temperature control. - Lower reaction volume. - Closer and uniform temperature control Outcome: Outcome: -More difficult reaction control. - Higher possibility of exotherm. - Safer chemistry. - Lower possibility of exotherm.
    9. 9. 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
    10. 10. Industry perception Why move to flow? 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
    11. 11. Low Temperature Chemistry
    12. 12. IceCube Safe: Low reaction volume, excellent temperature control, SW controlled – including many safety control points Simple to use: easy to set up, default reactor structures, proper system construction Powerful: Down to -50°C/-70°C, up to 80°C Versatile chemistry: Ozonolysis, nitration, lithiation, azide chemistry, diazotization Versatile reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops Chemical resistance: Teflon wetted parts Modular: Option for Ozone Module, more pumps Size: Stackable to reduce footprint Multistep reactions: 2 reaction zones in 1 system
    13. 13. The IceCube family Pump Module • 2pcs rotary piston pumps • 2pcs 3-way inlet valves • Flow rate: 0.2 – 4.0 mL/min • Max pressure: 6.9 bar Cooling Module Ozone Module • Main reactor block temp: -70/50°C • Continuous ozone productio – +80°C • Controlled oxygen • Main reactor volume up to 8 mL introduction • Tubing: 1/16” or 1/8” OD PTFE • Max. 100 mL/min gas flow • Secondary reactor block temp.: - 30 – +80°C • 14% Ozone production • Secondary reactor volume up to 4 mL
    14. 14. Verstatility to access multiple working modes A C B -70-+80ºC Reactor Pre-cooler/Mixer Potential Apps: Azide, nitration, Swern oxidation C A B D -70-+80ºC -30-+80ºC Potential Apps: Azide, Lithiation, ozonolysis, nitration, Swern oxidation
    15. 15. Reaction zone cooling Right hand side: Water inlet and outlet First Reaction Zone Secondary Reaction Zone Ideal for dangerous/exotherm chemistry -Water (high specific heat) used in peltier cooler -Aluminum reactor plate has high thermal conductivity (205 W/mK) Reactor plate coiled with Teflon tube (1/16”)
    16. 16. Control – Graphical User Interface Seamless control of all the modules on a touch screen interface For custom flow configurations, flexible to allow control of each module on their own (pump, ozone generator, cooler) Welcome screen of the IceCube Ozonolysis set-up 3 pump – 2 reactor set-up
    17. 17. Main application areas Exothermic Reactions # of hits in sciencedirect.com Ozonolysis 9 655 Azides Nitration 89 718 26 701 Lithiation 9 432 ? Halogenation 9 653 Swern Oxidation 3 289 Multistep reactions Modular
    18. 18. 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.
    19. 19. What is ozonolysis? Ozonolysis is a technique that cleaves double and triple C-C bonds to form a C-O bond.
    20. 20. How does it work? SM1 / Reactant or Solvent Product or Waste SM2 / Quench or Solvent
    21. 21. Olefins using as masked terminal aldehydes/ alcohols Synthesis of a Key intermediate for Indolizidine 215F Biologically active natural product Oxandrolone, anabolic steroid used to promote weight gain following extensive surgery, chronic infection S. Van Ornum et al, Chem. Rev.106, 2990-3001 (2006)
    22. 22. Flow Ozonolysis of Styrenes M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
    23. 23. Flow Ozonolysis Oxidation of alkynes Oxidation of amines to nitro groups M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
    24. 24. Flow Ozonolysis Of Thioanisole M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
    25. 25. Swern Oxidation on IceCube 0.45 M alcohol, 0.14 M DMSO in DCM 0.94 mL/min Batch reaction: Max. -60°C to avoid side reaction In Flow: 0.45 M in DCM, 0.96 mL/min * After purification 3.6 M in MeOH, 0.76 mL/min Even at -10°C without side product formation When compared to batch conditions, IceCube can still control reactions at warmer temperatures due to better mixing and more efficient heat transfer.
    26. 26. Diazotization and azo-coupling in the IceCube Aniline HCl sol. Pump A NaNO2 sol. Pump B Entry Pump C Phenol NaOH sol. Vflow (ml/min) T (°C) τ (1. loop, τ (2. loop, min) min) 2.12 3.33 Isolated Yield (%) 1 A-B-C 0.4 0 2 0.9 0 0.94 1.48 91 3 0.6 0 1.42 2.22 85 4 0.9 10 0.94 1.48 85 5 1.5 10 0.56 0.88 86 6 1.5 15 0.56 0.88 98 7 1.2 15 0.71 1.11 84 8 1.8 15 0.47 0.74 86 91 • Most aromatic diazonium salts are not stable at temperatures above 5°C • Produces between 65 and 150 kJ/mole and is usually run industrially at sub-ambient temperatures • Diazonium salts decompose exothermically, producing between160 and 180 kJ/mole. • Many diazonium salts are shocksensitive
    27. 27. Safe reaction of azides using Ice-Cube TKX50 • 2 Step Azide Reaction in flow • No isolation of DAGL • Significantly reduced hazards
    28. 28. Novel scaffold synthesis from explosive intermediates Nitration of Aromatic Alcohols Currently investigating selectivity at lower temperatures on IceCube Pump A Solution ccHNO3 1.48g NH4NO3/15ml ccH2SO4 1.48g NH4NO3/15ml ccH2SO4 70% ccH2SO4 30% ccHNO3 70% ccH2SO4 30% ccHNO3 Flow rate (ml/min) 0.4 0.7 0.5 0.6 0.6 Pump B Flow rate Solution (ml/min) 1g PG/15ml ccH2SO4 0.4 1g PG/15ml ccH2SO4 0.5 1g PG/15ml ccH2SO4 0.5 1g PG/15ml ccH2SO4 0.5 1g PG/15ml ccH2SO4 0.5 Temperature Loop size Conversion (oC) (ml) (%) Selectivity (%) 5 - 10 7 100 0 (different products) 5 - 10 13 100 100 5 - 10 13 50 80 (20% dinitro) 5 - 10 13 (3 bar) 100 100 80 70 (30% dinitro and nitro) 5 - 10 13 (1 bar)
    29. 29. Coming soon… • Lithiation experiments (collaborations) • Fluorination experiments (collaborations) • Low temperature selective reactions, not certainly from exothermic nature • Very low temperature experiments, where batch conditions required liquid nitrogen temperature or below
    30. 30. Thank you for your attention!
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