Thales Overview oct 2013 v2
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Thales Overview oct 2013 v2 Thales Overview oct 2013 v2 Presentation Transcript

  • Extending the Boundaries Of Organic Synthesis with Flow Chemistry Heather Graehl, MS, MBA Director of Sales North America ThalesNano North America
  • I’m  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.   •  Based  Budapest,  Hungary   •  Market  leader:  800  customer  install  base  on  6  conJnents.   •  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  reacJon  conJnuously,  typically  on  small  scale,   •  through  either  a  coil  or  fixed  bed  reactor.   OR   Pump   Reactor   CollecJon  
  • Mixing  (batch  vs.  flow)   Flow  reactors  can  achieve   homogeneous  mixing  and  uniform   hea6ng  in  microseconds  (suitable   for  fast  reac6ons)  
  • MiniaturizaJon:  Enhanced  temperature  control     Large  surface/volume  rate   •  Microreactors  have  higher  surface-­‐to-­‐volume  raJo  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  
  • KineJcs  In  Flow  Reactors   •  In  a  microfluidic  device  with  a  constant  flow  rate,  the  concentraJon  of  the  reactant  decays  exponenJally  with  distance  along  the  reactor.     •  Thus  Jme  in  a  flask  reactor  equates  with  distance  in  a  flow  reactor   X   A   dX/dt  >  0     dA/dt  <  0    
  • Batch vs. Flow Traditional Batch Method Flow Method Reactants Gas inlet H-Cube Pro™ Better surface interaction Controlled residence time Elimination of the products By-products By-products Reactants Products Products
  • Selective aromatic nitro reduction Catalyst screening Parameter scanning: effect of residence time to the conversion and selectivity Increase and decrease of residence time on the catalyst cannot be performed in batch 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
  • Heating Control Batch Larger solvent volume. Lower temperature control. Outcome: More difficult reaction control. Possibility of exotherm. Flow Lower reaction volume. Closer and uniform temperature control Outcome: Safer chemistry. Lower 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      Why  move  to  flow?   Small  scale:   §  Making  processes  safer   §  Accessing  new  chemistry   §  Speed  in  synthesis  and  analysis   §  AutomaJon   Large  scale:   §  Making  processes  safer   §  Reproducibility-­‐less  batch  to  batch  variaJon   §  SelecJvity  
  • Reaction Line H-Cube Pro & Gas Module: Reagent gases Phoenix Flow Reactor: Endothermic chemistry 150°C, 100 bar (1450 psi) H2, CO, O2, CO/H2, C2H4, CO2. Reactions in minutes. Minimal work-up. 450°C, 100 bar (1450 psi) New chemistry capabilities. Chemistry in seconds. Milligram-kilo scale Solve Dead-end chemistry. IceCube: Exothermic Chemistry -70 - +80C O3, Li, -N3, -NO2 Safe and simple to use. Multistep synthesis. 2 step independant T control.
  • 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) 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 Valve control Hydrogen Variability 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 H-Cube 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 H-Cube Pro Solvent Conc. Temp. (°C) Pressure (bar) Flow Rate (mL/ min) Product Distribution (%, GC-MS) A EtOH 0.1 M 10 10 1 B C 0 100 0
  • 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: 150°C, 80 bar, 3 days Batch: 200°C, 200 bar, 48 hours
  • 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 H-Cube® - Chemoselective hydrogenations Selective hydrogenation of the double-bond 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 Selective hydrogenation of the double-bond Conditions: Au/TiO2, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield Selective hydrogenation to afford oxime Ürge, L.et al. submitted for publication
  • Selective Hydrogenations H-Cube® - Chemoselective hydrogenations Nitro group reduction in the presence of a halogen 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 Nitro group reduction without retro-Henry as a side-reaction Ürge, L.et al. submitted for publication Nitro group reduction in the presence of Cbz-group Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 100% yield
  • Selective dehydrochlorination Flow Pressure (bar) Temperatur Bubdet o rate e ( C) (mL/ min) 1 20 (∆p:5 bar) 110 50 1 20 (∆p:3 bar) 110 50 1 20 (∆p:13 110 50 bar) 1 20 (∆p:10 110 50 bar) 1 20 (∆p:5 bar) 110 50 Catalyst Amount Amount Amount Amount A (%) B (%) C (%) D (%) 10% Pd/C 1% Pd/C 5% Rh/C 26.7% 61.5% 61,90% 29,40% 78.9% 5.1% - 7% 2,50% 9.2% 5% Pd/C 26.7% 60.9% - 6.7% 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: 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   •  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.
  • Deuteration Substrate Product Isolated yield / % 99 99 97 98 93 97 96 98 96 Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374 Deuterium content(%) 99
  • 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 Open vial collection Static drain wash station Collection through probe (into closed vial) Tubes, connectors, fittings
  • H-Cube Midi™ reactor for scale-up Parameters: -  p= 1-100 bar -  T=10-150°C Milligram -  v=0.1-3 ml/min - c=0.01-0.1 M - H2 production = up to 60ml/min - CatCarts = 30x4mm or 70x4mm to Gram Scale Parameters: Half Kilogram -  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 Scale
  • Expanding H-Cube Beyond Hydrogenation
  • Sample reactions Suzuki-Miyaura C-C cross coupling: NO 2 HO B OH + Br NO 2 CatCartTM 70*4 mm Pd EnCatTM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min 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)
  • Selective Suzuki coupling (Cl, Cl) Flow  rate  (ml/ min)   0.8   0.3   0.8   0.8   0.8   0.8   0.5   0.5   0.2   0.2   0.2   Pressure   (bar)   Temperature   o ( C)   Catalyst   Fibrecat  1007   (70mm)   Fibrecat  1007   20   100   (70mm)   Fibrecat  1035   20   100   (30mm)   Fibrecat   The  condiJons  were:   1029   20   100   (30mm)   Fibrecat  1048   20   100   (30mm)   10%  Pd/C   20   100   (30mm)   Fibrecat  1048   20   50   (30mm)   Fibrecat  1048   20   100   (30mm)   Fibrecat  1007   20   100   (70mm)   Fibrecat  1007   20   100   (70mm)   Fibrecat  1029   20   100   (30mm)   20   100   Base   3  ekv   3  ekv   2.5  ekv   2.5  ekv   Result   LC-­‐MS,  220nm   Conversion:  82%   SelecJvity:  48%   Conversion:  99%   SelecJvity:  48%   Conversion:  16%   SelecJvity:  100%   Conversion:  18%   SelecJvity:  100%   Conversion:  40%   SelecJvity:  100%   Conversion:  89%   SelecJvity:  14%   Conversion:17%   SelecJvity:  ~100%   Conversion:  35%   SelecJvity:  ~100%   Conversion:  93%   SelecJvity:  73%   Conversion:  93%   SelecJvity:  80%   Conversion:  12%   SelecJvity:  100%   1  equivalent  of  2,6-­‐dichloroquinoxaline  with 2.5  ekv    1.2  equivalent  of  o-­‐Tolylboronic  acid     2.5  ekv   ConcentraJon  set  to  0.02M   2.5  ekv   Solvent:  Methanol   2.5  ekv   Base:  NaOH   2.5  ekv   AnalyJcs:  GC-­‐MS   2.5  ekv   2.5  ekv  
  • Sample reactions Heck C-C cross coupling: CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M, 100oC, 1 bar, 0.2 ml/min. 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
  • Gas  Module   •   Versa6le:     Compressed  Air,  O2,  CO,  C2H4,  SynGas,   CH4,  C2H6,  He,  N2,  N2O,  NO,  Ar.   •   Fast:     ReacJons  with  other  gases  complete  in   less  than  10  minutes   •   Powerful:     Up  to  100  bar  capability.   •   Robust:     All  high  quality  stainless  steel  parts.   •   Simple:     3  bumon  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 Filter included HPLC pump H-Cube Pro™ Check valve included
  • Problems with Oxidation
  • Alcohol oxidation: Optimization Pressure Selectivity 25 1 % Au/TiO2 0 – 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 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 Conversion 40 Very fast addition of alcohol to gold surface. Alkoxide formation. CatCart 40 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), Temp. (oC) 100 1 % Au /Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)
  • 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  aoer  10  minutes   H2O2   Acetone  -­‐  H2O2   (4-­‐1)   Au/TiO2   70   20   68%  aoer  1  run   78%  aoer  2  run   H2O2   Acetone  -­‐  H2O2   (4-­‐1)   Au/TiO2   100   30   68%  aoer  1  run   The  catalyst  was  reacJvated   98%  aoer  2  run   with  H2O2  between  the  runs.   O2  (10  ml/min)   Acetone   Au/TiO2   75   11   O2  (10  ml/min)   Acetone   Au/TiO2   150   11   95%   O2  (50  ml/min)   Acetone   Au/TiO2   150   20   >  98%   8%   Aoer  10  minutes  the   conversion  was  dropped  to   50%  
  • Aminocarbonylation Ø  Ø  Ø  Ø  Ø  Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.01 M in THF Catalyst: Polymer supported Pd(PPh3)4 Reference test was managed on X-Cube Reaction was repeated Different gas flow rates were tested Results ReacJon   Conversion   %   10  ml/ min   60   HC-­‐Pro  with  gas  module  (CO  flow  rate)   30  ml/ 60  ml/ 30  ml/ 30  ml/ 60  ml/ min   min   min   min   min   65   79   66   62   79   60  ml/ min   79   60  ml/ XC   min   reference   82   0  
  • Accessing New Molecules or Chemical Space
  • The quest for novel heterocycles 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
  • High T Chemistries – in Batch •  •  Standard benzannulation reaction Good source of: •  Quinolines •  Pyridopyrimidones •  Naphthyridines Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity • Solubility → Important structural drug motifs W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
  • Gould-Jacobs Reaction – in Flow • 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 No THF polymerization! Quinoline Batch conditions: 2 hours
  • 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 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. Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743 50
  • 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   30  mm     70  mm     125  mm  (1/4  SS  id  3  mm)   125  mm  (1/4  SS  id  3.8  mm)   125  mm  (1/2  SS  id  9.4mm)   Volume   Max.  T/p  (100  bar   unJl  it  is  indicated   otherwise)   H-­‐Cube  Pro  Type  CatCarts   0.38  mL   250°C   0.76  mL   250°C   Phoenix  Metal-­‐Metal  Sealing  High  T  CatCarts   0.9  mL   450  °C   1.3  mL   450  °C   9  mL   450  °C   250  mm  (1/4  SS  id  3mm)   1.8  mL   450  °C   250  mm  (1/4  SS  id  3.8  mm)   2.6  mL   450  °C   250  mm  (1/2  SS  id  9.4mm)   18  mL   450  °C   MidiCart   H-­‐Cube  Midi  Type  MidiCarts   7.6  mL   150  °C   Comment   Packed  by   ThalesNano   Packed  by   ThalesNano   User  can  fill   User  can  fill   User  can  fill,  filters   are  needed   User  can  fill,  filters   are  needed    User  can  fill,  filters   are  needed   User  can  fill,  filters   are  needed   Packed  by   ThalesNano  
  • Mitsunobu Reaction Application Note 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.
  • N-Alkylation Application Note RaNi 70mm 200C, 80bar 0.5ml/min
  • 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! 58
  • Optimizing the reaction conditions: 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%) •  0.1M Indole solution in ethanol, RaNi 4200 Catalyst, GC-MS results 59
  • Alkylation of 2-methyl-indoline Alkylation coupled with dehydrogenation The total amount of dialkylated products was 18%. 60
  • Ring closuring of 2-methyl-indole with 1,3-butanediol Ring closure is coupled with hydrogenation of double bond 61
  • Fischer-Indole Synthesis: Scale Out cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003 Continuous Flow Results (4 mL or 16 mL Coil) In AcOH/2-propanol (3:1) (0.5M) 150 °C, 60 bars, 1.0 mL min-1 (4 min res. time) 88% isolated yield Scale-up 25 g indole/hour 200 °C, 75 bars, 5.0 mL min-1 (~3 min res. time) 96% isolated yield
  • High temperature reactions X-Cube FlashTM – SNAr reaction 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.
  • 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  reacJon  volume,  excellent   temperature  control,  SW  controlled  –  including   many  safety  control  points   Simple  to  use:  easy  to  set  up,  default  reactor   structures,  proper  system  construcJon   Powerful:  Down  to  -­‐50°C/-­‐70°C,  up  to  80°C   Versa6le  chemistry:  Ozonolysis,  nitraJon,   lithiaJon,  azide  chemistry,  diazoJzaJon   Versa6le  reactors:  Teflon  loops  for  2  reactors   with  1/16”  and  1/8”  loops   Chemical  resistance:  Teflon  wemed  parts   Modular:  OpJon  for  Ozone  Module,   more  pumps   Size:  Stackable  to  reduce  footprint   Mul6step  reac6ons:  2  reacJon  zones  in  1  system  
  • Flexible  and  modular  for  variety  of  chemistry   Pump  Module   •   2pcs  rotary  piston   pumps     •   2pcs  3-­‐way  inlet   valves   •   Flow  rate:  0.2  –  4.0   mL/min   •   Max  pressure:  6.9   bar   Cooling  Module   Ozone  Module   •   Main  reactor  block  temp:    -­‐70/50°C   •   ConJnuous  ozone  producJon   –  +80°C     •   Controlled  oxygen   introducJon   •   Main  reactor  volume  up  to  8  mL   •   Tubing:  1/16”  or  1/8”  OD  PTFE   •   Max.  100  mL/min  gas  flow   •   Secondary  reactor  block  temp.:     -­‐  30  –  +80°C   •   14%  Ozone  producJon   •   Secondary  reactor  volume  up  to  4   mL  
  • ReacJon  zones   Right  hand  side:    Water  inlet  and  outlet   First   ReacJon   Zone   Secondary   ReacJon  Zone   Reactor  plate  coiled  with  Teflon  tube  (1/16”)  
  • Single  or  mulJstep  reacJons   A   C   B   -­‐70-­‐+80ºC   Reactor   Pre-­‐cooler/Mixer   Azide,  nitra6on,  Swern  oxida6on   C   A   B   D   -­‐70-­‐+80ºC   -­‐30-­‐+80ºC   Applica6ons:  Azide,  Lithia6on,  ozonolysis,  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  
  • IdenJfied  ApplicaJons   Ozonolysis   Azides   Nitra6on   Lithia6on   ?   Halogena6on   Swern  Oxida6on   Mul6step  reac6ons   Modular  
  • Why  ozonolysis  is  neglected?   •  Highly  exothermic  reacJon,  high  risk  of  explosion     •  Normally  requires  low  temperature:  -­‐78°C.   •  In  addiJon,  the  batchwise  accumulaJon  of  ozonide  is   associated  again  with  risk  of  explosion   •  There  are  alternaJve  oxidizing  agents/systems:   •  •  •  •  Sodium  Periodate  –  Osmium  Tetroxide  (NaIO4-­‐OsO4)   Ru(VIII)O4    +  NaIO4   Jones  oxidaJon  (CrO3,  H2SO4)   Swern  oxidaJon   •  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   Product  or  Waste   SM2  /  Quench  or   Solvent  
  • Flow  Ozonolysis  of  Styrenes   M.  Irfan,  T.  N.  Glasnov,  C.  O.  Kappe,  Org.  Lem.,  
  • Flow  Ozonolysis   Oxida6on  of  alkynes   Oxida6on  of  amines  to  nitro  groups   M.  Irfan,  T.  N.  Glasnov,  C.  O.  Kappe,  Org.  Lem.,  
  • Flow  Ozonolysis  Of  Thioanisole   M.  Irfan,  T.  N.  Glasnov,  C.  O.  Kappe,  Org.  Lem.,  
  • ApplicaJon  Note:  Swern  OxidaJon   0.45  M  alcohol,  0.14  M   DMSO  in  DCM   0.94  mL/min   Batch  reac6on:   Max.  -­‐60°C  to  avoid  side  reacJon   In  Flow:   0.45  M  in   DCM,  0.96   mL/min   *  Aoer  purificaJon   3.6  M  in   MeOH,   0.76  mL/ min   Even  at  -­‐10°C  without  side  product   formaJon   When  compared  to  batch  condiJons,   IceCube  can  sJll  control  reacJons  at   warmer  temperatures  due  to  bemer   mixing  and  more  efficient  heat   transfer.  
  • DiazoJzaJon  and  azo-­‐coupling  in  the  IceCube   Aniline   HCl  sol.   Pump  A   NaNO2     sol.   Pump  B   Entry   Vflow  (ml/min)   A  -­‐  B  -­‐  C   T  (°C)   1   2   0.4   0   2.12   3.33   91   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   Pump  C   Phenol     NaOH  sol.   τ  (1.  loop,   τ  (2.  loop,   min)   min)   Isolated   Yield  (%)   •  Most  aromaJc  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-­‐ sensiJve  
  • Safe reaction of azides using Ice-Cube TKX50 •  2 Step Azide Reaction in flow •  No isolation of DAGL •  Significantly reduced hazards
  • Novel  scaffold  synthesis  from  explosive  intermediates   NitraJon  of  AromaJc  Alcohols   Currently  invesJgaJng   selecJvity  at  lower   temperatures  on  IceCube   Pump  A   Flow  rate  (ml/ SoluJon   min)   ccHNO3   1.48g  NH4NO3/15ml   ccH2SO4   1.48g  NH4NO3/15ml   ccH2SO4   70%  ccH2SO4  30%   ccHNO3   70%  ccH2SO4  30%   ccHNO3   0.4   0.7   0.5   0.6   0.6   Pump  B   Temperature   Loop  size   Conversion   SelecJvity  (%)   Flow  rate  (ml/ (oC)   (ml)   (%)   SoluJon   min)   1g  PG/15ml   0  (different   0.4   5  -­‐  10   7   100   ccH2SO4   products)   1g  PG/15ml   0.5     5  -­‐  10   13   100   100   ccH2SO4   1g  PG/15ml   0.5     5  -­‐  10   13   50   80  (20%  dinitro)   ccH2SO4   1g  PG/15ml   0.5     5  -­‐  10   13  (3  bar)   100   100   ccH2SO4   1g  PG/15ml   70  (30%  dinitro   0.5     5  -­‐  10   13  (1  bar)   80   ccH2SO4   and  nitro)  
  • Coming  soon…   •  LithiaJon  experiments  (collaboraJons)   •  FluorinaJon  experiments  (collaboraJons)   •  Low  temperature  selecJve  reacJons,  not  certainly  from  exothermic  nature   •  Very  low  temperature  experiments,  where  batch  condiJons  required  liquid  nitrogen  temperature  or  below  
  • 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: askthechemist@thalesnano.com
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