Thalesnano Overview Aug 2013
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Thalesnano Overview Aug 2013

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Thalesnano Overview Aug 2013 Thalesnano Overview Aug 2013 Presentation Transcript

  • Extending the Boundaries Of Organic 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.   •  Market  leader:  800  customer  install  base  on  6  conDnents.   •  33  employees  with  own  chemistry  team.   •  10  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 reaction continuously, typically on small scale, through either a coil or fixed bed reactor.
  • 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
  • Industry Perspective
  • Survey  Conducted   Small  scale:   §  Making  processes  safer   §  Accessing  new  chemistry   §  Speed  in  synthesis  and  analysis   §  AutomaDon   Large  scale:   §  Making  processes  safer   §  Reproducibility-­‐less  batch  to  batch  variaDon   §  SelecDvity      Why  move  to  flow?  
  • Survey Conducted What chemistries? Difficult to perform chemistries • Low temperature exothermic reactions • Reactions with gases • Very slow reactions or unaccessible chemistry • Reactions with selectivity issues Approx. 30% of reactions!
  • What  are  our  drivers?   •  ThalesNano  is  specialized  on  designing  reactors  around  specific  chemistries  where  reacDons  in  flow  would  be  highly  beneficial   Exothermic Reactions • Safety • New chemistry • Simplicity Endothermic Reactions • New chemistry • Speed • Green Reactions with gases • Safety • Simplicity • Speed • Green Scale up • Safety • Selectivity • Reproducibility • Speed
  • 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
  • Catalysis reactor: Modular: H-Cube Pro H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling Gas Module 12 Extra gases 100 bar Phoenix Module 450°C Novel heterocycles Automated injection & collection. Optimization H-Cube Midi H2 Generation 150°C, 100 bar Scale Up
  • H-Cube Pro
  • 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) Hydro § N § N § H § D § P § R § H § I § D
  • 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)Temperatur e ( o C) 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
  • 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 NO2 B OHOH NO2 CatCartTM 70*4 mm Pd EnCatTM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min +
  • Selective Suzuki coupling (Cl, Cl) The  condiDons  were:   1  equivalent  of  2,6-­‐dichloroquinoxaline  with  1.2  equivalent  of  o-­‐Tolylboronic  acid     ConcentraDon  set  to  0.02M   Solvent:  Methanol   Base:  NaOH   AnalyDcs:  GC-­‐MS   Flow  rate  (ml/ min)   Pressure   Temperature   Catalyst   Base   Result   (bar)   ( o C)   LC-­‐MS,  220nm   0.8   20   100   Fibrecat  1007   (70mm)   3  ekv   Conversion:  82%   SelecDvity:  48%   0.3   20   100   Fibrecat  1007   (70mm)   3  ekv   Conversion:  99%   SelecDvity:  48%   0.8   20   100   Fibrecat  1035   2.5  ekv   Conversion:  16%   (30mm)   SelecDvity:  100%   0.8   20   100   Fibrecat  1029   (30mm)   2.5  ekv   Conversion:  18%   SelecDvity:  100%   0.8   20   100   Fibrecat  1048   (30mm)   2.5  ekv   Conversion:  40%   SelecDvity:  100%   0.8   20   100   10%  Pd/C   2.5  ekv   Conversion:  89%   (30mm)   SelecDvity:  14%   0.5   20   50   Fibrecat  1048   2.5  ekv   Conversion:17%   (30mm)   SelecDvity:  ~100%   0.5   20   100   Fibrecat  1048   2.5  ekv   Conversion:  35%   (30mm)   SelecDvity:  ~100%   0.2   20   100   Fibrecat  1007   2.5  ekv   Conversion:  93%   (70mm)   SelecDvity:  73%   0.2   20   100   Fibrecat  1007   2.5  ekv   Conversion:  93%   (70mm)   SelecDvity:  80%   0.2   20   100   Fibrecat  1029   2.5  ekv   Conversion:  12%   (30mm)   SelecDvity:  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.
  • Catalysis reactor: Modular: H-Cube Pro H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling Gas Module 12 Extra gases 100 bar Phoenix Module 450°C Novel heterocycles Automated injection & collection. Optimization H-Cube Midi H2 Generation 150°C, 100 bar Scale Up
  • Gas  Module   •   Versa7le:     Compressed  Air,  O2,  CO,  C2H4,  SynGas,   CH4,  C2H6,  He,  N2,  N2O,  NO,  Ar.   •   Fast:     ReacDons  with  other  gases  complete  in   less  than  10  minutes   •   Powerful:     Up  to  100  bar  capability.   •   Robust:     All  high  quality  stainless  steel  parts.   •   Simple:     3  budon  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  ager  10  minutes   H2O2   Acetone  -­‐  H2O2   (4-­‐1)   Au/TiO2   70   20   68%  ager  1  run   78%  ager  2  run   H2O2   Acetone  -­‐  H2O2   (4-­‐1)   Au/TiO2   100   30   68%  ager  1  run   98%  ager  2  run   The  catalyst  was  reacDvated   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%   Ager  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 ReacDon   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™.
  • 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
  • N-Alkylation Reaction RaNi 70mm 200C, 80bar 0.5ml/min
  • 55 C-H Activation •  Objectives: to find a cheap and green alternative of performing 1 step alkylation reaction via C-H activation. •  Relevance: used for generation of novel compounds, via C-H activation untouched positions on rings can be activated. •  Main problems: •  strong bond between carbon and hydrogen atoms •  Multistep reaction •  Require expensive metal catalysts (Pd, Pt) •  Selectivity is an issue •  Results: form another C-C or C-X bond at a position not favored by conventional alkylation methods
  • 56 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!
  • 57 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%)
  • 58 Alkylation of 2-methyl-indoline The total amount of dialkylated products was 18%. Alkylation coupled with dehydrogenation
  • 59 Ring closuring of 2-methyl-indole with 1,3-butanediol Ring closure is coupled with hydrogenation of double bond
  • Diels Alder • Diels-Alder reactions usually require long reaction times. • This reaction time could be reduced to 5 minutes at 250°C using toluene. • .Product isolated in near quantitative yield. • Reaction also possible using lower boiling solvents (MeCN, THF, DME) with same result using higher pressures (200 bar).
  • 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
  • High  Energy   Reac7ons  
  • Ice Cube Modules Ozone Module generate O3 from O2 100 mL/min, 15 % O3 Cooled Reactor Module – teflon tube on peltier coolers; -70°C. Pump Module – Peristaltic or Gear Pump Optional: 1 or 2
  • Versa7le:  2  op7ons   A B C A B C D Pre-cooler/Mixer Reactor -70-+80ºC -70-+80ºC -30-+80ºC Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation
  • Safe reaction of azides using Ice-Cube •  2 Step Azide Reaction in flow •  No isolation of DAGL •  Significantly reduced hazards TKX50
  • Ozone concentration critical! Reaction parameters: Flow rate = 0,7 ml/min Quench flow rate = 1,4 ml/min O3 flow rate = 17,5 ml/min (~2 eq.) T = -5 oC cEugenol = 0,05 M cNaBH4 = 0,05 M Solvent = EtOH Results: Conversion = 100 % misolated = 326,2 mg mmax. yield = 504 mg Isolated yield = 65 % Purity of isolated product = 98 % *
  • Nitration in flow Pump  A   Pump  B   Temperature   (o C)   Loop  size   (ml)   Conversion   (%)   SelecDvity  (%)   SoluDon   Flow  rate  (ml/ min)   SoluDon   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)   Batch reference: 30ml ccH2SO4, 1g PG, 1.48g NH4NO3, 5-10oC 10 min, Conversion: 91%
  • Flow  University   •  PracDcal  Lab  Manual   •  PresentaDon  tutorial   •  Background  notes   •  EducaDonal  Videos   q In  English   q In  Mandarin  Chinese   q SubDtled  
  • THANK YOU FOR YOUR ATTENTION!! ANY QUESTIONS