Accelerating Your Synthesis with Flow Chemistry Heather Graehl, MS, MBA Director of Sales North America ThalesNano 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 reacQon conQnuously, typically on small scale, through either a coil or fixed bed reactor.
OR
Pump Reactor CollecQon
What is flow chemistry?
• In a microfluidic device with a constant flow rate, the concentraQon of the reactant decays exponenQally with distance along the reactor.
• Thus Qme in a flask reactor equates with distance in a flow reactor
X
A
dX/dt > 0
dA/dt < 0
KineQcs in Flow Reactors
Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds (suitable for fast reac6ons)
Improved Mixing Compared to Batch
Improved mixing can lead to improved reac6on 6mes, especially with fixed bed reactors
Improved Mixing = Faster Rxn Time
• Microreactors have higher surface-‐to-‐volume raQo 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
Enhanced Temperature 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.
Enhanced Temperature Control
Batch Heated Rxns • Safety concerns, especially in scale
up
• Microwave technology is fastest way of heaQng 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, conQnuously
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 interaction Controlled residence time Elimination of the products
Flow Method
H-Cube Pro™
SelecQvity – Residence Time Control
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
Increase and decrease of residence time on the catalyst cannot be performed in batch
SelecQve AromaQc Nitro ReducQon
Small scale: § Making processes safer § Accessing new chemistry
§ Speed in synthesis and workup
§ AutomaQon
Large scale: § Making processes safer § Reproducibility-‐less batch to batch variaQon
§ SelecQvity § 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 Pladorms
H-Cube Catalysis Platform: Making hydrogenations safe, fast, and selective
• 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
H-‐Cube – How it Works
Hydrogen generator cell § Solid Polymer Electrolyte
High-pressure regulating valves
Water separator, flow detector, bubble detector
Water Electrolysis
• 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)
Catalyst System -‐ CatCarts
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 ValidaQon ReacQons (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
Simple ValidaQon ReacQons (out of 5,000)
Batch: 200°C, 200 bar, 48 hours
Batch: 150°C, 80 bar, 3 days
Difficult Hydrogenatons
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
SelecQve HydrogenaQons
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
SelecQve HydrogenaQons
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
SelecQve HydrogenaQons
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
SelecQve DehydrochlorinaQon
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
ParQal SaturaQon of Heterocycles
Chiral Phosphine-phosphoramidite ligands packed in CatCart
Asymmetric HydrogenaQon
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
DeuteraQon
• Original 2005 R&D100 award winner • 20mg-10g/day • Ambient to 100°C • Limited H2 control: Full H2 mode (30ml/min), Controlled H2 mode, No H2
• Improved H-Cube • 20mg-50g/day • -10°C to 150°C • H2 production variability from 0ml/min – 60ml/min (selectivity!) • Reaction timer with auto switching valves • Software for logs, graphs, reaction guide, module control
• High throughput • Larger MidiCart Catalysts • 20mg-500g/day • Ambient to 150°C • H2 production variability from 0ml/min – 125ml/min • Reaction timer with auto switching valves
Which H-Cube is best for me?
H-‐Cube Family
• Touch Screen Interface • Now can control hydrogen variability (0-60ml/min) for selectivity • Suggested reaction parameters for each functional group • Reaction Timer with automatic valve switching • Logs and graphs for viewing achieved reaction parameters
New Sonware with H-‐Cube Pro
2 cells for higher hydrogen production: 60 mL/min
Compare to H-Cube SS where maximum concentration is 0.2M
100% conversion
H-‐Cube Pro = Higher Throughput
H-‐Cube Pro = Higher Temp Capability
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
H-‐Cube Pro = Lower Temp SelecQvity
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
H-‐Cube Midi – Reactor for Scale Up
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 Autosampler
Expanding H-Cube Beyond Hydrogenation
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:
CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M, 100oC, 1 bar, 0.2 ml/min.
Coupling ReacQons
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:
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
+
Coupling ReacQons
The condiQons were:
1 equivalent of 2,6-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid
ConcentraQon set to 0.02M
Solvent: Methanol
Base: NaOH
AnalyQcs: GC-‐MS
SelecQve Coupling ReacQon
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% SelecQvity: 48%
0.3 20 100 Fibrecat 1007
(70mm) 3 ekv Conversion: 99% SelecQvity: 48%
0.8 20 100 Fibrecat 1035
2.5 ekv Conversion: 16%
(30mm) SelecQvity: 100%
0.8 20 100 Fibrecat 1029
(30mm) 2.5 ekv Conversion: 18% SelecQvity: 100%
0.8 20 100 Fibrecat 1048
(30mm) 2.5 ekv Conversion: 40% SelecQvity: 100%
0.8 20 100 10% Pd/C
2.5 ekv Conversion: 89%
(30mm) SelecQvity: 14%
0.5 20 50 Fibrecat 1048
2.5 ekv Conversion:17%
(30mm) SelecQvity: ~100%
0.5 20 100 Fibrecat 1048
2.5 ekv Conversion: 35%
(30mm) SelecQvity: ~100%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecQvity: 73%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecQvity: 80%
0.2 20 100 Fibrecat 1029
2.5 ekv Conversion: 12%
(30mm) SelecQvity: 100%
SelecQve Coupling ReacQon 1 equivalent of 2,6
-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid
ConcentraQon set to 0.02M
Solvent: Methanol, Base: NaOH
AnalyQcs: GC-‐MS
• Versa6le: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.
• Fast: ReacQons with other gases complete in less than 10 minutes
• Powerful: Up to 100 bar capability.
• Robust: All high quality stainless steel parts.
• Simple: 3 buron stand-‐alone control or via simple touch screen control on H-‐Cube Pro™.
Other Reagent Gases
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 Reaction was repeated Ø Different gas flow rates were tested
Observed reproducible conversion at each gas flow rate
ApplicaQon 1: CarbonylaQon
ApplicaQon 2: Green OxidaQon
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.
Green OxidaQon OpQmizaQon
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 reacQvated 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%
AromiQzaQon of Heterocycles
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 Temp Chemistry – 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 ReacQon -‐ Overview
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.
52
• 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
Process ExploraQon
5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
New Scaffold GeneraQon
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 Flow Reactor
• Choice of stainless steel, teflon, or Hastelloy
• Different length coils to vary residence time
• Easy to recoil
Phoenix Homogeneous ReacQons
• Use same H-Cube Pro or Midi CatCarts
• Phoenix metal-metal Catcarts for >250°C reactions
Phoenix metal-metal CatCarts (125mm/250mm)
H-Cube Pro CatCarts (30 or 70mm)
Phoenix Heterogeneous ReacQons
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 ReacQon not Possible in Batch
RaNi 70mm 200C, 80bar 0.5ml/min
N-‐AlkylaQon with RaNi CatCart
59 The total amount of dialkylated products was 18%.
Alkylation coupled with dehydrogenation
AlkylaQon of 2-‐methyl-‐indone
60
Ring closure is coupled with hydrogenation of double bond
Ring closuring of 2-methyl-indole with 1,3-butanediol
AlkylaQon with Diol – Ring Closure
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
Fischer-‐Indole Synthesis – Scale Out
• Reactions from 10-450C and 1-100bar (1450 psi) • Up to 13 different reagent gases • Heterogeneous or homogeneous catalysis
Fully Automated system available
VersaQle Catalysis System
High Energy
Reac6ons
What is ozonolysis?
• Ozonolysis is a technique that cleaves double and triple C-C bonds to form a C-O bond.
• Currently neglected oxidation technique • Highly exothermic, ozonide accumulation is dangerous
Carboxylic Acid (oxidative work-up)
Aldehyde/Ketone (simple quenching)
Alcohol (reductive work-up)
Workup Determines Product
Synthesis of Indolizidine 215F
Other major drug syntheses featuring ozonolysis includes:
(+)-Artemisinin D,L-Camptothecin L-Isoxazolylalanine Prostaglandin endoperoxides.
Van Ornum, S.G., Champeau, R., Pariza, R., Chem. Rev. 2006, 106, 2990-3001
Ozonolysis in Industry
Why ozonolysis is neglected?
• Highly exothermic reacQon, high risk of explosion
• Normally requires low temperature: -‐78°C. • In addiQon, the batchwise accumulaQon of ozonide is associated again with risk of explosion
• There are alternaQve oxidizing agents/systems: • Sodium Periodate – Osmium Tetroxide (NaIO4-‐OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidaQon (CrO3, H2SO4)
• Swern oxidaQon • Most of the listed agents are toxic, difficult, and/or expensive to use.
• Highly effective oxidation • In line quenching of ozonide – SAFETY • Efficient cooling for exotherm control - SAFETY • The reactions typically go cleanly in high yield and
conversion with little by products • Gas is used as a reagent, so work up is less labor
intensive • Can be used in non-aqueous condition • Ozonolysis is fast and atom efficient • Ease in Scale Up
Why Ozonolysis in Flow?
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Ler.,
Flow Ozonolysis of Styrenes
Oxida6on of alkynes
Oxida6on of amines to nitro groups
Flow Ozonolysis
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Ler.,
Flow Ozonolysis Of Thioanisole
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Ler.,
Safe: Low reacQon volume, excellent temperature control, SW controlled – including many safety control points
Simple to use: easy to set up, default reactor structures, proper system construcQon
Powerful: Down to -‐50°C/-‐70°C, up to 80°C
Versa6le chemistry: Ozonolysis, nitraQon, lithiaQon, azide chemistry, diazoQzaQon
Versa6le reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops
High Chemical resistance: Teflon wered parts
Mul6step reac6ons: 2 reacQon zones in 1 system Modular: OpQon for Ozone Module or more pumps
Size: Stackable to reduce footprint
IceCube
Halogena6on
Nitra6on Azides
Mul6step reac6ons
Reac6ve Intermediates
Lithia6on
Ozonolysis
Swern Oxida6on
IdenQfied ApplicaQons
First Reac6on Zone Second Reac6on 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 Qme aner mixing • Different mixers types available
A B
D
-‐70-‐+80ºC -‐30-‐+80ºC
C First Reac6on Zone Second Reac6on Zone
ReacQon Zones
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
Single or MulQ-‐Step ReacQons
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
• ConQnuous ozone producQon
• Controlled oxygen introducQon
• Max. 100 mL/min gas flow
• 14% Ozone producQon
Pump Module Ozone Module
Modular for a Variety of Chemistry
Batch reac6on: Max. -‐60°C to avoid side reacQon
In Flow:
Even at -‐10°C without side product formaQon
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 purificaQon
When compared to batch condiQons, IceCube can sQll control reacQons at warmer temperatures due to berer mixing and more efficient heat transfer.
ApplicaQon Note 1: Swern OxidaQon
• 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 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 aromaQc 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-‐sensiQve
ApplicaQon Note 2: DioaziQzaQon
NitraQon of AromaQc Alcohols
Pump A Pump B Temperature (oC)
Loop size (ml)
Conversion (%)
SelecQvity (%)
SoluQon Flow rate (ml/
min) SoluQon 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 invesQgaQng selecQvity at lower temperatures on IceCube
Scaffolds from Explosive Intermediates
• LithiaQon experiments
• HalogenaQons/FluorinaQons
• Low temperature selecQve reacQons, not necessarily
exothermic nature
• EpoxidaQons
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, MBA Director of Sales North America
Based in sunny San Diego [email protected]
Onsite Demos & Seminars Available
THANK YOU FOR YOUR ATTENTION!!
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