Thales overview oct 2013
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Transcript of Thales overview oct 2013
Extending the Boundaries Of Organic Synthesis with Flow Chemistry
Heather Graehl, MS, MBA Director of Sales North America ThalesNano North America
San Diego Based
400+ Biotech Companies
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 conGnents. • 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?
What is flow chemistry?
• Performing a reacGon conGnuously, typically on small scale,
• through either a coil or fixed bed reactor.
OR
Pump Reactor CollecGon
Mixing (batch vs. flow)
Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds (suitable for fast reac6ons)
MiniaturizaGon: Enhanced temperature control Large surface/volume rate
• Microreactors have higher surface-‐to-‐volume raGo 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
KineGcs In Flow Reactors
• In a microfluidic device with a constant flow rate, the concentraGon of the reactant decays exponenGally with distance along the reactor.
• Thus Gme in a flask reactor equates with distance in a flow reactor
X
A
dX/dt > 0
dA/dt < 0
Reactants
Products
By-products
Traditional Batch Method
Gas inlet
Reactants
Products
By-products
Batch vs. Flow
Better surface interaction Controlled residence time Elimination of the products
Flow Method
H-Cube Pro™
Catalyst screening
Parameter scanning: effect of residence time to the conversion and selectivity
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
Selective aromatic nitro reduction
Increase and decrease of residence time on the catalyst cannot be performed in batch
Heating Control
Lower reaction volume. Closer and uniform temperature control
Outcome:
Safer chemistry. Lower possibility of exotherm.
Batch
Flow
Larger solvent volume. Lower temperature control.
Outcome:
More difficult reaction control. 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
Survey Conducted
Small scale: § Making processes safer § Accessing new chemistry
§ Speed in synthesis and analysis
§ AutomaGon
Large scale: § Making processes safer § Reproducibility-‐less batch to batch variaGon
§ SelecGvity
Why move to flow?
Reaction Line
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.
450°C, 100 bar (1450 psi) New chemistry capabilities. Chemistry in seconds. Milligram-kilo scale Solve Dead-end chemistry.
H-Cube Pro & Gas Module: Reagent gases
Phoenix Flow Reactor: Endothermic chemistry
IceCube: Exothermic Chemistry
H-Cube Catalysis Platform: Making hydrogenations safe, fast, and selective
H-Cube Pro Overview
• HPLC pumps continuous stream of solvent • Hydrogen generated from water electrolysis • Sample heated and passed through catalyst • Up to 150°C and 100 bar. (1 bar=14.5 psi)
Hydrogenation reactions: § Nitro Reduction § Nitrile reduction § Heterocycle Saturation § Double bond saturation § Protecting Group hydrogenolysis § Reductive Alkylation § Hydrogenolysis of dehydropyrimidones § Imine Reduction § Desulfurization
No More Hydrogen Cylinders
• Large cylinders contain 4360 litres of compressed H2
• They are a severe safety hazard • H-Cube doesn’t use gas cylinders • Only water • Clean • No transportation costs • Low energy • Safe • Just 2 mL H2 @ 1bar
Hydrogen generator cell § Solid Polymer Electrolyte
High-pressure regulating valves
Water separator, flow detector, bubble detector
Catalyst System - CatCart®
• Benefits • Safety • No filtration necessary • Enhanced phase mixing
• Over 100 heterogeneous and Immobilized homogeneous catalysts
10% Pd/C, PtO2, Rh, Ru on C, Al2O3 Raney Ni, Raney Co Pearlmans, Lindlars Catalyst Wilkinson's RhCl(TPP)3 Tetrakis(TPP)palladium Pd(II)EnCat BINAP 30
• Different sizes • 30x4mm • 70x4mm (longer residence time or scale up)
• Ability to pack your own CatCarts • CatCart Packer (with vacuum) • CatCart Closer (no vacuum)
New Software with H-Cube Pro
Timer Hydrogen Variability
Valve control Data saving Chemistry Guide
H-Cube Pro = higher throughput
2 cells for higher hydrogen production: 60 mL/min
H-Cube Pro: Higher temperature capability
H-Cube Pro: Selectivity with lower temp control
T (oC) p (bar) Flow rate (ml/min) Conversion (%) B Selectivity (%)
20 1, controlled 1 37 99 20 1, controlled 2 65 93 20 1, controlled 3 87 77
Solvent Conc. Temp. (°C) Pressure (bar)
Flow Rate (mL/min)
Product Distribution (%, GC-MS)
A B C EtOH 0.1 M 10 10 1 0 100 0
H-Cube
H-Cube Pro
Simple Validation Reactions (out of 5,000)
10% Pd/C, RT, 1 bar Yield: 86 - 89% Alternate reductions Ketone: Pt/C Aromatic: Ru/O2
Raney Ni, 70°C, 50 bar, 2M NH3 in MeOH, Yield: >85%
Simple Validation Reactions (out of 5,000)
10% Pd/C, 60˚C, 1 bar Yield: >90%
Batch reaction of {3-[(2-carbazol-9-yl-acetylamino)-methyl]-benzyl}-carbamic acid benzyl ester Reagent: H2, catalyst: 10% Pd/C, EtOH, 1 atm, Yield: 76 % Conn, M. Morgan; Deslongchamps, Ghislain; Mendoza, Javier de; Rebek, Julius; JACSAT; J. Am. Chem. Soc.; EN; 115; 9; 1993; 3548-3557.
Raney Ni, 80˚C, 80 bar Yield: 90%
Batch reference: Reagent: HCOONH4, catalyst: 10% Pd/C, solvent: MeOH, Reaction time: 30 min, 1 atm. Yield: 78 % Kaczmarek, Lukasz; Balicki, Roman; JPCCEM; J. Prakt. Chem/Chem-Ztg.; EN; 336; 8; 1994; 695-697
H-Cube® Reaction Examples
Batch: 200°C, 200 bar, 48 hours
Batch: 150°C, 80 bar, 3 days
Chemoselective hydrogenations
Selective reduction in presence of benzyl protected O or N 5% Pt/C, 75°C, 70 bar, 0,01M, ethanol,no byproduct Yield: 75%
Batch reference: Reagent: aq. NaBH4, Solvent: THF; 0°C, Yield: 76,1 % Nelson, Michael E.; Priestley, Nigel D.; JACSAT; J. Am.
Chem. Soc.; EN; 124; 12; 2002; 2894-2902
Route A: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 25°C. Yield: 80%
Route B: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 100°C. Yield: 85%
No batch reference
Selective Hydrogenations
Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 97% yield
Conditions: 1% Pt/C, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield
Conditions: Au/TiO2, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield
H-Cube® - Chemoselective hydrogenations
Ürge, L.et al. submitted for publication
Selective hydrogenation of the double-bond
Selective hydrogenation to afford oxime
Selective hydrogenation of the double-bond
Selective Hydrogenations
Conditions: 10% Pd/C, 70 bar, 0°C, residence time 16s Results: 100% conversion, 100% yield
Conditions: 1% Pt/C, 70 bar, 30°C, residence time 11-17s Results: 100% conversion, 100% yield
Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 100% yield
Ürge, L.et al. submitted for publication
H-Cube® - Chemoselective hydrogenations
Nitro group reduction in the presence of a halogen
Nitro group reduction in the presence of Cbz-group
Nitro group reduction without retro-Henry as a
side-reaction
Selective dehydrochlorination
Flow rate
(mL/min)
Pressure (bar) Temperature (oC)
Bubdet Catalyst Amount A (%)
Amount B (%)
Amount C (%)
Amount D (%)
1 20 (∆p:5 bar) 110 50 10% Pd/C 26.7% 61.5% - 7% 1 20 (∆p:3 bar) 110 50 1% Pd/C 61,90% 29,40% - 2,50% 1 20 (∆p:13
bar) 110 50 5% Rh/C 78.9% 5.1% - 9.2%
1 20 (∆p:10 bar)
110 50 5% Pd/C 26.7% 60.9% - 6.7%
1 20 (∆p:5 bar) 110 50 5% Pd/C(S) 25% 63.4% - 6.6%
Objective: Match similar selectivity of 60% but without additives of CsF, S, K2CO3 and PPh3
Partial saturation of heterocycles
Optimised reaction parameters: - H-Cube Pro - Temperature: 100oC - Pressure: 100 bar - Hydrogen amount: Maximum
Results:
• Generate new non-planar molecules from existing stocks. • New molecules have new Log P and other characteristics.
• Cheap • Clean • Quick • Only on H-Cube: High P + Selective control.
Flow rate (ml/min) Conversion % of A % of B % of C 0.3 100% 100 0 0 0.5 100% 92 8 0 1.0 100% 86 14 0
Deuteration
Substrate Product Deuterium content(%)
Isolated yield / %
99 99
97 98
93 97
96 98
96 99
Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374
H-Cube Autosampler™
Gilson 271 Liquid Handler § 402 single Syringe pump (10 mL) § Direct GX injector (Valco) § Low-mount fraction collection (Bio-Chem) § Septum-piercing needle § Static drain wash station § Tubes, connectors, fittings
Open vial collection Collection through probe (into closed vial)
H-Cube Midi™ reactor for scale-up
Parameters: - p= 1-100 bar - T=10-150°C - v=0.1-3 ml/min - c=0.01-0.1 M - H2 production = up to 60ml/min - CatCarts = 30x4mm or 70x4mm
Parameters: - p= 1-100 bar - T=25-150°C - v=5-25 ml/min - c=0.05-0.25 M - H2 production = up to 125ml/min - CatCarts = 90x9.5mm
Milligram to Gram Scale
Half Kilogram Scale
Expanding H-Cube Beyond Hydrogenation
Conversion: 90-95% (TLC) Purity: 70% (LC-MS) without work-up
Batch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °C Reference: (Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000; 8199-8202)
Suzuki-Miyaura C-C cross coupling:
Sample reactions
Br
N O 2 B
O H O H
N O 2 CatCart TM 70*4 mm Pd EnCat TM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min
+
Selective Suzuki coupling (Cl, Cl)
The condiGons were:
1 equivalent of 2,6-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid
ConcentraGon set to 0.02M
Solvent: Methanol
Base: NaOH
AnalyGcs: GC-‐MS
Flow rate (ml/min)
Pressure Temperature Catalyst Base
Result (bar) (oC) LC-‐MS, 220nm
0.8 20 100 Fibrecat 1007
(70mm) 3 ekv
Conversion: 82% SelecGvity: 48%
0.3 20 100 Fibrecat 1007
(70mm) 3 ekv
Conversion: 99% SelecGvity: 48%
0.8 20 100 Fibrecat 1035
2.5 ekv Conversion: 16%
(30mm) SelecGvity: 100%
0.8 20 100 Fibrecat 1029
(30mm) 2.5 ekv
Conversion: 18% SelecGvity: 100%
0.8 20 100 Fibrecat 1048
(30mm) 2.5 ekv
Conversion: 40% SelecGvity: 100%
0.8 20 100 10% Pd/C
2.5 ekv Conversion: 89%
(30mm) SelecGvity: 14%
0.5 20 50 Fibrecat 1048
2.5 ekv Conversion:17%
(30mm) SelecGvity: ~100%
0.5 20 100 Fibrecat 1048
2.5 ekv Conversion: 35%
(30mm) SelecGvity: ~100%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecGvity: 73%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecGvity: 80%
0.2 20 100 Fibrecat 1029
2.5 ekv Conversion: 12%
(30mm) SelecGvity: 100%
Purity (LCMS): 63%
Batch parameters: Pd(OAc)2, PPh3, TEA, DMF, 3 days, 110°C, yield: 70% Reference: J. Chem. Soc. Dalton Trans., 1998, 1461-1468 J. Chem. Soc. Dalton Trans., 1998, 1461-1468
Heck C-C cross coupling:
Sample reactions
CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M, 100oC, 1 bar, 0.2 ml/min.
Gas Module
• Versa6le: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.
• Fast: ReacGons with other gases complete in less than 10 minutes
• Powerful: Up to 100 bar capability.
• Robust: All high quality stainless steel parts.
• Simple: 3 bulon stand-‐alone control or via simple touch screen control on H-‐Cube Pro™.
Use of Gas Module Attached to the H-Cube Pro™
Gas Module HPLC pump H-Cube Pro™
Filter included Check valve included
Problems with Oxidation
Alcohol oxidation: Optimization
Pressure Temp. (oC) CatCart Conversion Selectivity
40 25 1 % Au/TiO2 0 – 40 65 1 % Au/TiO2 6.5 >85 40 25 1 % Au
/Fe2O3 0 – 40 65 1 % Au
/Fe2O3 12.7 0 40 25 5 % Ru
/Al2O3 2.8 ~100 40 65 5 % Ru
/Al2O3 3.6 ~100 100 65 5 % Ru
/Al2O3 2.7 ~100 100 100 5 % Ru
/Al2O3 8.5 ~100 100 140 5 % Ru
/Al2O3 15.5 ~100 100 65 1 % Au/TiO2 5.6 84 100 100 1 % Au/TiO2 47.2 93 100 140 1 % Au
/TiO2 ~100 93 100 65 1 % Au
/Fe2O3 4 0 100 100 1 % Au
/Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)
General conditions: H-Cube Pro with Gas Module, 50 mL/min oxygen gas, 1 mL/min liquid flow rate (0.05M in acetone, 20 mL sample volume), CatCart: 70mm., 1 % Au/TiO2 (cartridge: 70mm, THS 01639),
Batch ref.: Oxygen; perruthenate modified mesoporous silicate MCM-41 in toluene T=80°C; 24 h; Bleloch, Andrew; et al. Chemical Communications, 1999 , 8,1907 - 1908
Very fast addition of alcohol to gold surface. Alkoxide formation.
Aromatization of heterocycles
Reaction parameters were tested: - H-Cube Pro with and without GasModule - Oxidizing agent: Hydrogen-peroxide and Oxygen - Catalyst: MnO2, Amerlyst 36, Au/TiO2 - Solvent: Acetone/H2O2, Acetone - Temperature 60-150oC, pressure 20-50 bar, flow rate 1 ml/min, concentration: 0.05 mmol/ml
Oxidizing agent Solvent Catalyst
Temperature (oC)
Pressure (bar) Conversion Comment
MnO2 Acetone MnO2 60 20 82% Blockage aner 10 minutes
H2O2 Acetone -‐ H2O2
(4-‐1) Au/TiO2 70 20 68% aner 1 run 78% aner 2 run
H2O2 Acetone -‐ H2O2
(4-‐1) Au/TiO2 100 30 68% aner 1 run 98% aner 2 run
The catalyst was reacGvated with H2O2 between the runs.
O2 (10 ml/min) Acetone Au/TiO2 75 11 8%
O2 (10 ml/min) Acetone Au/TiO2 150 11 95%
Aner 10 minutes the conversion was dropped to
50%
O2 (50 ml/min) Acetone Au/TiO2 150 20 > 98%
Ø Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.01 M in THF Ø Catalyst: Polymer supported Pd(PPh3)4 Ø Reference test was managed on X-Cube Ø Reaction was repeated Ø Different gas flow rates were tested
Results
Aminocarbonylation
ReacGon HC-‐Pro with gas module (CO flow rate)
XC reference
10 ml/min
30 ml/min
60 ml/min
30 ml/min
30 ml/min
60 ml/min
60 ml/min
60 ml/min
Conversion % 60 65 79 66 62 79 79 82 0
Accessing New Molecules or Chemical Space
Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2963.
• 3000 potential bicyclic systems unmade • Many potential drug like scaffolds Why? • Chemists lack the tools to expand into new chemistry space to access these new compounds. • Time • Knowledge
The quest for novel heterocycles
• Standard benzannulation reaction • Good source of:
• Quinolines • Pyridopyrimidones • Naphthyridines
→ Important structural drug motifs
Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity • Solubility
W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
High T Chemistries – in Batch
• Replacement of diphenyl ether (b.p: 259°C) with THF (b.p.: 66 °C)
Cyclization conditions: a: 360 °C, 130 bar, 1.1 min b: 300 °C, 100 bar, 1.5 min c: 350 °C, 100 bar, 0.75 min
Pyridopyrimidinone Quinoline
No THF polymerization!
Batch conditions: 2 hours
Gould-Jacobs Reaction – in Flow
The nature of the substituents is critical because they increase or decrease the nucleophilicity of the ring: Electron donating groups increase yields, Electron withdrawing groups decrease yields.
50
Process exploration
• Meldrum’s acidic route to pyridopyrimidones and to hydroxyquinolines
Cyclization conditions: a: 300 °C, 160 bar, 0.6 min b: 300 °C, 100 bar, 0.6 min c: 360 °C, 100 bar, 1 min d: 350 °C, 130 bar, 4 min e: 300 °C, 100 bar, 1.5 min
Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743
New Scaffold Generation
5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
Phoenix Flow Reactor: High temperature synthesis
Powerful: Up to 450°C
Versatile: Heterogeneous and homogeneous capabilities.
Fast: Reactions in seconds or minutes.
Innovative: Validated procedure to generate novel bicyclic compounds
Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.
Phoenix loop-reactor possibilities
• Materials - sizes § Stainless steel (1 – 16 mL) –
up to 450oC and 100bar • Coil (1/16” 4-16 ml) • Short coil (1/16” 1-4ml) • Static mixer (3/8”, 32ml)
§ PTFE coil (4 – 16 ml) – up to 150oC or 20bar
§ Hastelloy (4 – 16 ml) – up to 450oC and 100bar
• Easy to recoil • Versatile
Phoenix packed bad reactor possibilities
• CatCart (30, 70 mm) – up to 250°C and 100 bar • MidiCart – up to 150°C and 100bar • Special high temperature cartridge – up to 450°C and 100bar
90 × 9.5 mm
Cartridge Volumes and Packing Type Volume Max. T/p (100 bar
unGl it is indicated otherwise)
Comment
H-‐Cube Pro Type CatCarts 30 mm 0.38 mL 250°C Packed by
ThalesNano 70 mm 0.76 mL 250°C Packed by
ThalesNano Phoenix Metal-‐Metal Sealing High T CatCarts
125 mm (1/4 SS id 3 mm) 0.9 mL 450 °C User can fill 125 mm (1/4 SS id 3.8 mm) 1.3 mL 450 °C User can fill 125 mm (1/2 SS id 9.4mm) 9 mL 450 °C User can fill, filters
are needed 250 mm (1/4 SS id 3mm) 1.8 mL 450 °C User can fill, filters
are needed 250 mm (1/4 SS id 3.8 mm) 2.6 mL 450 °C User can fill, filters
are needed 250 mm (1/2 SS id 9.4mm) 18 mL 450 °C User can fill, filters
are needed H-‐Cube Midi Type MidiCarts
MidiCart 7.6 mL 150 °C Packed by ThalesNano
Ring closure on aryl NH : key step • Mitsunobu reaction or traditional heating with T3P did not
furnish the bicyclic heterocycle. • Reaction proceeded smoothly in Phoenix reactor at 300oC with
65% yield despite requirement for the cis amide conformer in transition state.
Mitsunobu Reaction Application Note
N-Alkylation Application Note
RaNi 70mm 200C, 80bar 0.5ml/min
58
Reaction pathway using Raney-Ni catalyst
Advantages of Raney-Nickel: • Cheaper than Pd, Pt containing catalysts • Differently preactivated Raney-Ni catalyst can give more
flexibility – selectivity issues
But: Pyrophoric!
59
Optimizing the reaction conditions:
• 0.1M Indole solution in ethanol, RaNi 4200 Catalyst, GC-MS results
Reach higher selectivity: Protect the N-atom with TMS-Cl Result: 90% conversion with 80%
selectivity (300 °C, 100 bar, 0.5 mL/min,
isolated yield: 76.5%)
60
Alkylation of 2-methyl-indoline
The total amount of dialkylated products was 18%.
Alkylation coupled with dehydrogenation
61
Ring closuring of 2-methyl-indole with 1,3-butanediol
Ring closure is coupled with hydrogenation of double bond
Fischer-Indole Synthesis: Scale Out
cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003
In AcOH/2-propanol (3:1) (0.5M) 150 °C, 60 bars,
1.0 mL min-1 (4 min res. time) 88% isolated yield
Continuous Flow Results (4 mL or 16 mL Coil) Scale-up
200 °C, 75 bars, 5.0 mL min-1 (~3 min res. time)
96% isolated yield
25 g indole/hour
High temperature reactions
Conditions: p = 70 bar T = 270°C v = 0.4 mL/min c = 0.04 M (NMP) Result: 82% yield
Kappe, O. C. et al. Eur. J. Org. Chem., 2009, 9, 1321-1325.
X-Cube FlashTM – Kolbe Synthesis Conditions: p = 60 bar T = 180°C v = 4 mL/min Residence time: 440 s c = 0.49 M (H2O) Best result: 51% conversion
Kappe, O. et al. Chem. Eng. Technol. 2009, 32(11), 1-16.
X-Cube FlashTM – SNAr reaction
Versatile Catalysis Platform
• Reactions from 10-450C and 1-100bar (1450 psi) • Up to 13 different reagent gases • Heterogeneous or homogeneous catalysis
Fully Automated system now available
High Energy
Reac6ons
IceCube
Safe: Low reacGon volume, excellent temperature control, SW controlled – including many safety control points
Simple to use: easy to set up, default reactor structures, proper system construcGon
Powerful: Down to -‐50°C/-‐70°C, up to 80°C
Versa6le chemistry: Ozonolysis, nitraGon, lithiaGon, azide chemistry, diazoGzaGon
Versa6le reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops
Chemical resistance: Teflon weled parts
Mul6step reac6ons: 2 reacGon zones in 1 system Modular: OpGon for Ozone Module, more pumps
Size: Stackable to reduce footprint
Flexible and modular for variety of chemistry
• 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
• ConGnuous ozone producGon
• Controlled oxygen introducGon
• Max. 100 mL/min gas flow
• 14% Ozone producGon
Pump Module Ozone Module
ReacGon zones
First ReacGon Zone
Secondary ReacGon Zone
Right hand side: Water inlet and outlet
Reactor plate coiled with Teflon tube (1/16”)
Single or mulGstep reacGons
A
B C
A B
C
D
Pre-‐cooler/Mixer Reactor
-‐70-‐+80ºC
-‐70-‐+80ºC -‐30-‐+80ºC
Applica6ons: Azide, Lithia6on, ozonolysis, nitra6on, Swern oxida6on
Azide, nitra6on, Swern oxida6on
Ideal for reactive intermediates or quenching
Control – Graphical User Interface
Welcome screen of the IceCube
Ozonolysis set-‐up 3 pump – 2 reactor set-‐up
? Halogena6on
Nitra6on Azides
Mul6step reac6ons
Modular
Lithia6on
Ozonolysis
Swern Oxida6on
IdenGfied ApplicaGons
Why ozonolysis is neglected?
• Highly exothermic reacGon, high risk of explosion
• Normally requires low temperature: -‐78°C. • In addiGon, the batchwise accumulaGon of ozonide is associated again with risk of explosion
• There are alternaGve oxidizing agents/systems: • Sodium Periodate – Osmium Tetroxide (NaIO4-‐OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidaGon (CrO3, H2SO4)
• Swern oxidaGon • 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
Flow Ozonolysis of Styrenes
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lel.,
Oxida6on of alkynes
Oxida6on of amines to nitro groups
Flow Ozonolysis
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lel.,
Flow Ozonolysis Of Thioanisole
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lel.,
Batch reac6on: Max. -‐60°C to avoid side reacGon
In Flow:
Even at -‐10°C without side product formaGon
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
* Aner purificaGon
ApplicaGon Note: Swern OxidaGon
When compared to batch condiGons, IceCube can sGll control reacGons at warmer temperatures due to beler mixing and more efficient heat transfer.
DiazoGzaGon 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 aromaGc 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-‐sensiGve
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
NitraGon of AromaGc Alcohols
Pump A Pump B Temperature (oC)
Loop size (ml)
Conversion (%)
SelecGvity (%)
SoluGon Flow rate (ml/
min) SoluGon 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 invesGgaGng selecGvity at lower temperatures on IceCube
Coming soon…
• LithiaGon experiments (collaboraGons)
• FluorinaGon experiments (collaboraGons)
• Low temperature selecGve reacGons, not certainly from
exothermic nature
• Very low temperature experiments, where batch
condiGons required liquid nitrogen temperature or
below
Free Chemistry Services
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Low Temperature • reactive intermediates, selectivity, dangerous, exothermic chemistry
High Temperature & Pressures • dead end chemistry, flash heating, rearrangements, alkylations, reactions with gases (hydrogenation, oxidation, carbonylation), catalysis
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