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
Ice-Cube:Low temperature flow chemistry for enhanced safety and selectivity
Heather Graehl, MS, MBA
Director of Sales North America
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.
Customers (>800 worldwide)
What is flow chemistry?
Performing a reaction continuously, typically on small scale,through either a coil or fixed bed reactor.
OR
PumpReactor Collection
Mixing (batch vs. flow)
Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)
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
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
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.
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
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?
Low TemperatureChemistry
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
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
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
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)
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)
? 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
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.
What is ozonolysis?
Ozonolysis is a technique that cleaves double andtriple C-C bonds to form a C-O bond.
How does it work?
SM1 / Reactant or Solvent
SM2 / Quench or Solvent
Product or Waste
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
Flow Ozonolysis of Styrenes
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
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.,
Flow Ozonolysis Of Thioanisole
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
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.
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
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
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
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
Thank you for your attention!