icecube low temperature flow chemistry v2
TRANSCRIPT
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 conCnents. 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 reacCon conCnuously, typically on small scale,
through either a coil or fixed bed reactor.
OR
Pump Reactor CollecCon
Mixing (batch vs. flow)
Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds (suitable for fast reac6ons)
KineCcs In Flow Reactors
In a microfluidic device with a constant flow rate, the concentraCon of the reactant decays exponenCally with distance along the reactor.
Thus Cme in a flask reactor equates with distance in a flow reactor
X
A
dX/dt > 0
dA/dt < 0
MiniaturizaCon: Enhanced temperature control Large surface/volume rate
Microreactors have higher surface-‐to-‐volume raCo 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
HeaCng Control
Batch Flow
-‐ Lower reacCon volume. -‐ Closer and uniform temperature control
Outcome:
-‐ Safer chemistry. -‐ Lower possibility of exotherm.
-‐ Larger solvent volume. -‐ Lower temperature control.
Outcome:
-‐ More difficult reacCon control. -‐ Higher possibility of exotherm.
HeaCng Control
Lithium Bromide Exchange
Batch
Flow
• Batch experiment shows temperature increase of 40°C. • Flow shows liile increase in temperature.
Ref: Thomas Schwalbe and Gregor Wille, CPC Systems
Industry percepCon
Small scale: § Making processes safer § Accessing new chemistry
§ Speed in synthesis and analysis
§ AutomaCon
Large scale: § Making processes safer § Reproducibility-‐less batch to batch variaCon
§ SelecCvity
Why move to flow?
Low Temperature
Chemistry
IceCube
Safe: Low reacCon volume, excellent temperature control, SW controlled – including many safety control points
Simple to use: easy to set up, default reactor structures, proper system construcCon
Powerful: Down to -‐50°C/-‐70°C, up to 80°C
Versa6le chemistry: Ozonolysis, nitraCon, lithiaCon, azide chemistry, diazoCzaCon
Versa6le reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops
Chemical resistance: Teflon weied parts
Mul6step reac6ons: 2 reacCon zones in 1 system Modular: OpCon 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
• ConCnuous ozone producCon
• Controlled oxygen introducCon
• Max. 100 mL/min gas flow
• 14% Ozone producCon
Pump Module Ozone Module
VerstaClity to access mulCple working modes
A
B C
A B
C
D
Pre-‐cooler/Mixer Reactor
-‐70-‐+80ºC
-‐70-‐+80ºC -‐30-‐+80ºC
Poten6al Apps: Azide, Lithia6on, ozonolysis, nitra6on, Swern oxida6on
Poten6al Apps: Azide, nitra6on, Swern oxida6on
ReacCon zone cooling
First ReacCon Zone
Secondary ReacCon 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)
? Halogena6on 9 653
Nitra6on 26 701
Azides 89 718
Mul6step reac6ons
Modular
Lithia6on 9 432
Ozonolysis 9 655
Swern Oxida6on 3 289
Exothermic ReacCons # of hits in sciencedirect.com
Main applicaCon areas
Why ozonolysis is neglected?
Highly exothermic reacCon, high risk of explosion
Normally requires low temperature: -‐78°C. In addiCon, the batchwise accumulaCon of ozonide is associated again with risk of explosion
There are alternaCve oxidizing agents/systems: • Sodium Periodate – Osmium Tetroxide (NaIO4-‐OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidaCon (CrO3, H2SO4)
• Swern oxidaCon Most of the listed agents are toxic, difficult, and/or expensive to use.
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
SM2 / Quench or Solvent
Product or Waste
Olefins using as masked terminal aldehydes/ alcohols
Biologically acCve 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 infecCon
Flow Ozonolysis of Styrenes
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lei.,
Oxida6on of alkynes
Oxida6on of amines to nitro groups
Flow Ozonolysis
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lei.,
Flow Ozonolysis Of Thioanisole
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lei.,
Batch reac6on: Max. -‐60°C to avoid side reacCon
In Flow:
Even at -‐10°C without side product formaCon
0.45 M in DCM, 0.96 mL/min
0.45 M alcohol, 0.14 M DMSO in DCM 0.94 mL/min
3.6 M in MeOH, 0.76 mL/min
* Axer purificaCon
Swern OxidaCon on IceCube
When compared to batch condiCons, IceCube can sCll control reacCons at warmer temperatures due to beier mixing and more efficient heat transfer.
DiazoCzaCon 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 91
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
Aniline HCl sol. Pump A
Pump B NaNO2 sol.
Pump C
Phenol NaOH sol. • Most aromaCc 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 shock-‐sensiCve
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
NitraCon of AromaCc Alcohols
Pump A Pump B Temperature (oC)
Loop size (ml)
Conversion (%)
SelecCvity (%)
SoluCon Flow rate (ml/
min) SoluCon 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)
Currently invesCgaCng selecCvity at lower temperatures on IceCube
Coming soon…
• LithiaCon experiments (collaboraCons)
• FluorinaCon experiments (collaboraCons)
• Low temperature selecCve reacCons, not certainly from
exothermic nature
• Very low temperature experiments, where batch
condiCons required liquid nitrogen temperature or
below
Thank you for your aienCon!