Thales Overview oct 2013 v3
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Extending the Boundaries Of Organic Synthesis with Flow Chemistry
Heather Graehl, MS, MBA Director of Sales North America ThalesNano 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.
• Based Budapest, Hungary • Market leader: 800 customer install base on 6 conFnents. • 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?
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What is flow chemistry?
• Performing a reacFon conFnuously, typically on small scale,
• through either a coil or fixed bed reactor.
OR
Pump Reactor CollecFon
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Mixing (batch vs. flow)
Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds (suitable for fast reac6ons)
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MiniaturizaFon: Enhanced temperature control Large surface/volume rate
• Microreactors have higher surface-‐to-‐volume raFo 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
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KineFcs In Flow Reactors
• In a microfluidic device with a constant flow rate, the concentraFon of the reactant decays exponenFally with distance along the reactor.
• Thus Fme in a flask reactor equates with distance in a flow reactor
X
A
dX/dt > 0
dA/dt < 0
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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™
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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
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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.
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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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Survey Conducted
Small scale: § Making processes safer § Accessing new chemistry
§ Speed in synthesis and analysis
§ AutomaFon
Large scale: § Making processes safer § Reproducibility-‐less batch to batch variaFon
§ SelecFvity
Why move to flow?
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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. 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
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H-Cube Catalysis Platform: Making hydrogenations safe, fast, and selective
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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
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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
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Hydrogen generator cell § Solid Polymer Electrolyte
High-pressure regulating valves
Water separator, flow detector, bubble detector
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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)
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New Software with H-Cube Pro
Timer Hydrogen Variability
Valve control Data saving Chemistry Guide
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H-Cube Pro = higher throughput
2 cells for higher hydrogen production: 60 mL/min
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H-Cube Pro: Higher temperature capability
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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
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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%
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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
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H-Cube® Reaction Examples
Batch: 200°C, 200 bar, 48 hours
Batch: 150°C, 80 bar, 3 days
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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
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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
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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
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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
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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
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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
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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)
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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
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Expanding H-Cube Beyond Hydrogenation
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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
+
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Selective Suzuki coupling (Cl, Cl)
The condiFons were:
1 equivalent of 2,6-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid
ConcentraFon set to 0.02M
Solvent: Methanol
Base: NaOH
AnalyFcs: 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% SelecFvity: 48%
0.3 20 100 Fibrecat 1007
(70mm) 3 ekv
Conversion: 99% SelecFvity: 48%
0.8 20 100 Fibrecat 1035
2.5 ekv Conversion: 16%
(30mm) SelecFvity: 100%
0.8 20 100 Fibrecat 1029
(30mm) 2.5 ekv
Conversion: 18% SelecFvity: 100%
0.8 20 100 Fibrecat 1048
(30mm) 2.5 ekv
Conversion: 40% SelecFvity: 100%
0.8 20 100 10% Pd/C
2.5 ekv Conversion: 89%
(30mm) SelecFvity: 14%
0.5 20 50 Fibrecat 1048
2.5 ekv Conversion:17%
(30mm) SelecFvity: ~100%
0.5 20 100 Fibrecat 1048
2.5 ekv Conversion: 35%
(30mm) SelecFvity: ~100%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecFvity: 73%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecFvity: 80%
0.2 20 100 Fibrecat 1029
2.5 ekv Conversion: 12%
(30mm) SelecFvity: 100%
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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.
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Gas Module
• Versa6le: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.
• Fast: ReacFons 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™.
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Use of Gas Module Attached to the H-Cube Pro™
Gas Module HPLC pump H-Cube Pro™
Filter included Check valve included
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Problems with Oxidation
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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.
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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 reacFvated 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%
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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
ReacFon 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
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Accessing New Molecules or Chemical Space
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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
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• 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
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• 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
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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.
49
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
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New Scaffold Generation
5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
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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™.
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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
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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
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Cartridge Volumes and Packing Type Volume Max. T/p (100 bar
unFl 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
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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
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N-Alkylation Application Note
RaNi 70mm 200C, 80bar 0.5ml/min
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57
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!
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58
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%)
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Alkylation of 2-methyl-indoline
The total amount of dialkylated products was 18%.
Alkylation coupled with dehydrogenation
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Ring closuring of 2-methyl-indole with 1,3-butanediol
Ring closure is coupled with hydrogenation of double bond
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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
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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
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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
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High Energy
Reac6ons
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IceCube
Safe: Low reacFon volume, excellent temperature control, SW controlled – including many safety control points
Simple to use: easy to set up, default reactor structures, proper system construcFon
Powerful: Down to -‐50°C/-‐70°C, up to 80°C
Versa6le chemistry: Ozonolysis, nitraFon, lithiaFon, azide chemistry, diazoFzaFon
Versa6le reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops
Chemical resistance: Teflon weled parts
Mul6step reac6ons: 2 reacFon zones in 1 system Modular: OpFon for Ozone Module, more pumps
Size: Stackable to reduce footprint
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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
• ConFnuous ozone producFon
• Controlled oxygen introducFon
• Max. 100 mL/min gas flow
• 14% Ozone producFon
Pump Module Ozone Module
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ReacFon zones
First ReacFon Zone
Secondary ReacFon Zone
Right hand side: Water inlet and outlet
Reactor plate coiled with Teflon tube (1/16”)
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Single or mulFstep reacFons
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
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Control – Graphical User Interface
Welcome screen of the IceCube
Ozonolysis set-‐up 3 pump – 2 reactor set-‐up
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? Halogena6on
Nitra6on Azides
Mul6step reac6ons
Modular
Lithia6on
Ozonolysis
Swern Oxida6on
IdenFfied ApplicaFons
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Why ozonolysis is neglected?
• Highly exothermic reacFon, high risk of explosion
• Normally requires low temperature: -‐78°C. • In addiFon, the batchwise accumulaFon of ozonide is associated again with risk of explosion
• There are alternaFve oxidizing agents/systems: • Sodium Periodate – Osmium Tetroxide (NaIO4-‐OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidaFon (CrO3, H2SO4)
• Swern oxidaFon • 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 and • triple 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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Flow Ozonolysis of Styrenes
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lel.,
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Oxida6on of alkynes
Oxida6on of amines to nitro groups
Flow Ozonolysis
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lel.,
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Flow Ozonolysis Of Thioanisole
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lel.,
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Batch reac6on: Max. -‐60°C to avoid side reacFon
In Flow:
Even at -‐10°C without side product formaFon
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 purificaFon
ApplicaFon Note: Swern OxidaFon
When compared to batch condiFons, IceCube can sFll control reacFons at warmer temperatures due to beler mixing and more efficient heat transfer.
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DiazoFzaFon 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 aromaFc 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-‐sensiFve
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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
NitraFon of AromaFc Alcohols
Pump A Pump B Temperature (oC)
Loop size (ml)
Conversion (%)
SelecFvity (%)
SoluFon Flow rate (ml/
min) SoluFon 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 invesFgaFng selecFvity at lower temperatures on IceCube
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Coming soon…
• LithiaFon experiments (collaboraFons)
• FluorinaFon experiments (collaboraFons)
• Low temperature selecFve reacFons, not certainly from
exothermic nature
• Very low temperature experiments, where batch
condiFons required liquid nitrogen temperature or
below
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Free Chemistry Services
Thalesnano has own chemistry team
We try to solve your challenging chemistry in flow
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
Email the group: [email protected]
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THANK YOU FOR YOUR ATTENTION!!
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