IceCube Overview Jan 2014
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Accelerating Your Synthesis with Flow Chemistry Heather Graehl, MS, MBA Director of Sales North America
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Transcript of IceCube Overview Jan 2014
Accelerating Your Synthesis with Flow Chemistry
Heather Graehl, MS, MBADirector of Sales North AmericaThalesNano North America
Who are we?
• ThalesNano is a technology company that gives chemists tools to perform novel, previously inaccessible chemistry safer, faster, and simpler.
• Based Budapest, Hungary• 33 employees with own chemistry team.• 11 years old-most established flow reactor company.• R&D Top 100 Award Winner.
•Flow Chemistry Market Leader•Over 800 customers worldwide
Customers
What is flow
chemistry?
Performing a reaction continuously, typically on small scale, through either a coil or fixed bed reactor.
OR
PumpReactor Collection
What is flow chemistry?
• 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
Kinetics in Flow Reactors
Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)
Improved Mixing Compared to Batch
Improved mixing can lead to improved reaction times, especially with fixed bed reactors
Improved Mixing = Faster Rxn Time
• 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
Enhanced Temperature Control
Lower reaction volume. Closer and uniformtemperature control
Outcome:
Safer chemistry. Lower possibility of exotherm.
Batch
Flow
Larger solvent volume. Lower temperature control.
Outcome:
More difficult reaction control. Possibility of exotherm.
Enhanced Temperature Control
Batch Heated Rxns• Safety concerns, especially in scale
up• Microwave technology is fastest
way of heating solvent in batch
Flow Chemistry Heated Rxns• Flow mimics microwave’s rapid
heat transfer• Solvent is not limited to dipole• Higher pressures and
temperatures possible• High pressures allow use of low
boiling point solvents for easy workup
• Safety improvement as small amount is reacted, continuously
Enhanced Temperature Control
Exothermic Chemistry – LiBr Exchange
• Batch experiment shows temperature increase of 40°C.• Flow shows little increase in temperature.
Ref: Thomas Schwalbe and Gregor Wille, CPC Systems
Enhanced Temperature Control
Reactants
Products
By-products
Traditional Batch Method
Gas inlet
Reactants
Products
By-products
Better surface interactionControlled residence timeElimination of the products
Flow Method
H-Cube Pro™
Selectivity – Residence Time Control
Catalyst screening
Parameter scanning: effect of residence time to the conversion and selectivity
0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2
85
90
95
100
105
110
Conversion Selectivity
%
Flow rate / mLmin-1
1% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzene
Catalyst Flow rate / mL/min
Residence time / sec
Conc. / mol/dm3
Conv. / %
Sel. / %
IrO2 2 9 0,2 52 69
Re2O7 2 9 0,2 53 73
(10%Rh 1% Pd)/C
2 9 0,2 79 60
RuO2
(activated)2 9 0,2 100 100
1 18 0,2 100 99
0,5 36 0,2 100 98
Ru black 2 9 0,2 100 83
1% Pt/C doped with Vanadium
2 9 0,2 100 96
1 18 0,2 100 93
0,5 36 0,2 100 84
Conditions: 70 bar, EtOH, 25°C
Increase and decrease of residence time on the catalyst cannot be performed in batch
Selective Aromatic Nitro Reduction
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 Green
Why move to flow?
Survey Conducted
150°C, 100 bar (1450 psi)
H2, CO, O2, CO/H2, C2H4, CO2.
Reactions in minutes.
Minimal work-up.
-70 - +80C
O3, Li, -N3, -NO2
Safe and simple to use.
Multistep synthesis.
2 step independant T control.
Coming: fluorinations, low T selectivity
450°C, 100 bar (1450 psi)
New chemistry capabilities.
Chemistry in seconds.
Milligram-kilo scale
Solve Dead-end chemistry.
Heterocycle synthesis
H-Cube Pro & Gas Module:
Reagent gases
Phoenix Flow Reactor:
Endothermic chemistry IceCube:
Exothermic Chemistry
Reactor Platforms
High EnergyReactions
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
High Chemical resistance: Teflon wetted parts
Multistep reactions: 2 reaction zones in 1 systemModular: Option for Ozone Module or more pumps
Size: Stackable to reduce footprint
IceCube
First Reaction Zone Second Reaction Zone
Water inlet and outlet
Reactor Plate•Aluminum stackable blocks•Teflon tubing for ease in addressing blocks•Easy to coil for desired pre-cooling and desired residence time after mixing•Different mixers types available
AB
D
-70-+80ºC -30-+80ºC
CFirst Reaction Zone Second Reaction Zone
Reaction Zones
A
BC
AB
C
D
Pre-cooler/Mixer Reactor
-70-+80ºC
-70-+80ºC -30-+80ºC
Applications: Azide, Lithiation, ozonolysis, nitration, Swern oxidation
Azide, nitration, Swern oxidation
Ideal for reactive intermediates or quenching
Single or Multi-Step Reactions
Halogenation
NitrationAzides
Multistep reactions
Reactive Intermediates
Lithiation
Ozonolysis
Swern Oxidation
Identified Applications
Welcome screen of the IceCube
Ozonolysis set-up 3 pump – 2 reactor set-up
Touch Screen Interface
• 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
Modular for a Variety of Chemistry
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
When compared to batch conditions, IceCube can still control reactions at warmer temperatures due to better mixing and more efficient heat transfer.
Application 1: Swern Oxidation
• Ozonolysis is a technique that cleaves double and• triple C-C bonds to form a C-O bond.
Flow Ozonolysis and Rebirth of O-Cube
• 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.
Why is Ozonolysis neglected?
SM1 / Reactant or Solvent
SM2 / Quench or Solvent
Product or Waste
IceCube Ozonolysis Setup
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
Flow Ozonolysis of Styrenes
Oxidation of alkynes
Oxidation of amines to nitro groups
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.,
More Flow Ozonolysis
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
Flow Ozonolysis of Tioanisole
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
• 2 Step Azide Reaction in flow• No isolation of DAGL• Significantly reduced hazards
TKX50
Making Azide Chemistry Safer
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
Dioazitization and azo coupling
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
Scaffolds from Explosive Intermediates
• Lithiation experiments (collaborations)
• Fluorination experiments (collaborations)
• Low temperature selective reactions, not necessarily
exothermic nature
• Very low temperature experiments, where batch
conditions required liquid nitrogen temperature or
below
Coming soon…
Our chemistry team is full of flow chemistry and catalysis experts
We aim to solve your challenging chemistry in flow!
Phoenix Flow Reactor - High temperature and pressure reactor for novel heterocycle and compound synthesis (up to 450C)
H-Cube Pro and Gas Module - for gas reagent chemistry from hydrogenation to oxidation
IceCube - for low temperature and high energy reactions
Free chemistry services on Thalesnano flow platforms for up to a week. No strings attached.
Ship us your compound or visit our labs in Budapest, Hungary. CDAs and NDAs are approved quickly.
Free Chemistry Services
We can visit your site for chemistry demos and seminars. Impress your colleagues and bring flow chemistry to your lab.
Phoenix Flow Reactor - High temperature and pressure reactor for novel heterocycle and compound synthesis (up to 450C)
H-Cube Pro and Gas Module - for gas reagent chemistry from hydrogenation to oxidation
H-Cube Midi – scale up H-Cube for 10-500g/day hydrogenations
IceCube - for low temperature and high energy reactions
Heather Graehl, MS, MBADirector of Sales North America
Based in sunny San [email protected]
Onsite Demos & Seminars Available
THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS?
