Ice-Cube: Low Temperature Flow Chemistry for Enhanced Safety and Selectivity
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Transcript of Ice-Cube: Low Temperature Flow Chemistry for Enhanced Safety and Selectivity
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Ice-Cube:Low temperature flow chemistry for enhanced safety and selectivity
Heather Graehl, MS, MBA
Director of Sales North America
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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.
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Customers (>800 worldwide)
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What is flow chemistry?
Performing a reaction continuously, typically on small scale,through either a coil or fixed bed reactor.
OR
PumpReactor Collection
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Mixing (batch vs. flow)
Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)
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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
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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
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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.
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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
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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?
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Low TemperatureChemistry
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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
Multistep reactions: 2 reaction zones in 1 systemModular: Option for Ozone Module, more pumps
Size: Stackable to reduce footprint
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The IceCube family
• 2pcs rotary piston pumps
• 2pcs 3-way inlet valves
• Flow rate: 0.2 – 4.0 mL/min
• Max pressure: 6.9 bar
• Main reactor block temp: -70/50°C – +80°C
• Main reactor volume up to 8 mL
• Tubing: 1/16” or 1/8” OD PTFE
• Secondary reactor block temp.: - 30 – +80°C
• Secondary reactor volume up to 4 mL
Cooling Module
• Continuous ozone production
• Controlled oxygen introduction
• Max. 100 mL/min gas flow
• 14% Ozone production
Pump Module Ozone Module
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Verstatility to access multiple working modes
A
BC
AB
C
D
Pre-cooler/Mixer Reactor
-70-+80ºC
-70-+80ºC -30-+80ºC
Potential Apps: Azide, Lithiation, ozonolysis, nitration, Swern oxidation
Potential Apps: Azide, nitration, Swern oxidation
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Reaction zone cooling
First Reaction Zone
Secondary Reaction Zone
Right hand side:Water inlet and outlet
Reactor plate coiled with Teflon tube (1/16”)
Ideal for dangerous/exotherm chemistry
-Water (high specific heat) used in peltier cooler-Aluminum reactor plate has high thermal conductivity (205 W/mK)
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Control – Graphical User Interface
Welcome screen of the IceCube
Ozonolysis set-up 3 pump – 2 reactor set-up
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)
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? Halogenation9 653
Nitration26 701
Azides89 718
Multistep reactions
Modular
Lithiation9 432
Ozonolysis9 655
Swern Oxidation3 289
Exothermic Reactions# of hits in sciencedirect.com
Main application areas
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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 explosionThere 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.
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What is ozonolysis?
Ozonolysis is a technique that cleaves double andtriple C-C bonds to form a C-O bond.
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How does it work?
SM1 / Reactant or Solvent
SM2 / Quench or Solvent
Product or Waste
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Olefins using as masked terminal aldehydes/ alcohols
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
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Flow Ozonolysis of Styrenes
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
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Oxidation of alkynes
Oxidation of amines to nitro groups
Flow Ozonolysis
Ph PhOH
+ O3
1. CHCl325 °C, 1 mL/min
2. 1.5 M H2O2/CHCl325 °C, 0.5 mL/min
HO
Ph
CO2H
Ph
O
Ph
Ph
86%
n-C8H17NH2 + O3
1. EtOAc25°C, 1 mL/min
2. 1.5 M H2O2/H2O25°C, 0.5 mL/min
n-C8H17NO2
73%
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
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Flow Ozonolysis Of Thioanisole
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
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Batch reaction:Max. -60°C to avoid side reaction
In Flow:
Even at -10°C without side product formation
0.45 M in DCM, 0.96 mL/min
0.45 M alcohol, 0.14 M DMSO in DCM0.94 mL/min
3.6 M in MeOH, 0.76 mL/min
* After purification
Swern Oxidation on IceCube
When compared to batch conditions, IceCube can still control reactions at warmer temperatures due to better mixing and more efficient heat transfer.
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Diazotization and azo-coupling in the IceCube
Entry Vflow (ml/min)
A - B - C
T (°C) τ (1. loop, min)
τ (2. loop,
min)
Isolated Yield (%)
1 0.4 0 2.12 3.33 912 0.9 0 0.94 1.48 913 0.6 0 1.42 2.22 854 0.9 10 0.94 1.48 855 1.5 10 0.56 0.88 866 1.5 15 0.56 0.88 987 1.2 15 0.71 1.11 848 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. • Most aromatic diazonium salts
are not stable at temperaturesabove 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 shock-sensitive
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N
NN
N
NN
NN
OH
HO
N
N
OH
HO
Cl
Cl
NaN3/DMF N
N
OH
HO
N3
N3
1) HCl(g)/Et2O
2 H2O
+ NaCl
+ DMF
N
N
OH
HO
N3
N3
+ NaCl
+ DMF
+ NaCl
+ Me2NH
+ HCOOH2) H2O
Safe reaction of azides using Ice-Cube
• 2 Step Azide Reaction in flow• No isolation of DAGL• Significantly reduced hazards
TKX50
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Novel scaffold synthesis from explosive intermediates
Nitration of Aromatic Alcohols
OH OH
NO2
NO2
O2N
Phenol
Pump A Pump BTemperature
(oC)Loop size
(ml)Conversion
(%) Selectivity (%)Solution
Flow 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)
Currently investigating selectivity at lower temperatures on IceCube
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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
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Thank you for your attention!