Thales nano reactor overview jan 2013
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  • 1. Accessing new chemical space with flow chemistryHeather Graehl, MS, MBADirector of Sales North America
  • 2. Agenda•  Company Background•  Intro to Flow Chemistry•  H-Cube Pro Overview•  Reaction Examples•  Gas Module for H-Cube Pro•  Phoenix Module for H-Cube Pro
  • 3. 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.  •  10  years  old-­‐most  established  flow  reactor  company.  •  33  employees  with  own  chemistry  team.  •  Headquarters  in  Budapest  •  R&D  Top  100  Award  Winner.
  • 4. Customers (>800 worldwide) §  20 out of 20 top pharmaceutical §  Top 3 agrochemical companies §  Petrochemical emerging
  • 5. Number of Publications on ThalesNano Instruments 142 in 7 years 20 18 16 14 2005 12 10 2006 8 2007 6 4 2008 2 2009 0 2010 2011
  • 6. What is flowchemistry?
  • 7. What is flow chemistry?Performing a reaction continuously by pumping fluid through a coil or fixed bed reactor. Coil/Glass Chip Column Homogeneous: Liquid-Liquid Homogeneous: Liquid-Liquid (inert column) Heterogeneous: Liquid-Solid Heterogeneous: Liquid-Solid-Gas
  • 8. 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.
  • 9. Heating ControlLithium 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
  • 10. 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-productsReactants Products Products
  • 11. 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 Wilkinsons 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)
  • 12. Other Advantages•  Fast Optimization §  Analytical sample after 5 min to change parameters•  Safety §  Generate H2 on demand, no tanks §  CatCart system ideal pyrophoric catalysts•  Automation•  Selectivity §  Residence time on catalyst controlled, not possible batch•  Speed §  Better mass transfer, high temp, high pressure §  Optimize for single pass 100% conversion for under 10min reactions
  • 13. IndustryPerspective
  • 14. The innovation gap
  • 15. Closing the Innovation Gap•  Companies are actively looking at new techniques to: §  Decrease reaction times → Faster to market §  Cut down on number steps→Lower cost §  Increase yields→Less purification downstream §  Reduce solvent/waste → Cost savings §  Re-examine industry wide untouchable chemistries→novel molecules→competitive edge•  Flow chemistry is one of these techniques being investigated.
  • 16. Survey  Conducted      Why  move  to  flow?  Small  scale:   Large  scale:   §  Making  processes  safer   §  Making  processes  safer   §  Accessing  new  chemistry   §  Reproducibility-­‐less  batch §  Speed  in  synthesis  and  to  batch  variaDon    analysis   §  SelecDvity   §  AutomaDon  
  • 17. Survey Conducted What chemistries are of interest? 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!
  • 18. Catalysis reactor: Modular: H-Cube Pro Phoenix Module 450°C Automated injection Novel heterocycles & collection. Optimization H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling H-Cube Midi Gas Module H2 Generation 12 Extra gases 150°C, 100 bar 100 bar Scale Up
  • 19. H-Cube Pro
  • 20. 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 (almost 1500 psi!)
  • 21. In Situ H2 ProductionNo more H2 Tanks or costly bomb roomsSafe hydrogenations up to 1450 PSI!!Hydrogen generator cells §  Solid Polymer ElectrolyteHigh-pressure regulating valvesWater separator, flow detector, bubble detectorNew on H-Cube Pro: •  Double H2 production •  Full H2 mode at any pressure up to 100bar!
  • 22. H-Cube Pro OverviewHydrogenation Reactions Reactions without H2 § Nitro Reduction No Modules § Nitrile reduction § Suzuki Reaction § Heterocycle Saturation § Heck Reaction § Double bond saturation § Catalysis § Protecting Group (homogeneous or hydrogenolysis heterogeneous) § Reductive Alkylation § Hydrogenolysis of With Adding Modules dehydropyrimidones § Carbonylation § Imine Reduction § Oxidation § Desulfurization § Diels Alder § Rearrangements § Supercritical fluids
  • 23. H-Cube Pro - Higher temperature capability
  • 24. Lower temperature capability-more selectiveH-Cube Conversion T (oC) p (bar) Flow rate (ml/min) B Selectivity (%) (%) 20 1, controlled 1 37 99 20 1, controlled 2 65 93 20 1, controlled 3 87 77H-Cube Pro Product Distribution (%, GC-MS) Pressure Flow Rate (mL/ Solvent Conc. Temp. (°C) (bar) min) A B C EtOH 0.1 M 10 10 1 0 100 0
  • 25. Simple Validation Reactions (out of 5,000) 10% Pd/C, RT, 1 bar Yield: 86 - 89% Raney Ni, 70°C, 50 bar, 2M NH3 in MeOH, Yield: >85%
  • 26. 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
  • 27. H-Cube® Reaction Examples Batch: 150°C, 80 bar, 3 days Batch: 200°C, 200 bar, 48 hours
  • 28. 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
  • 29. Hydrogenations in a simplified manner 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 oximeÜrge, L.et al. submitted for publication
  • 30. Hydrogenations in a simplified manner 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 Nitro group reduction in the presence of Cbz-group 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 Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 100% yieldÜrge, L.et al. submitted for publication
  • 31. Hydrogenations in a simplified manner H-Cube® - Dethionation Conditions: Raney Ni Full H2 mode T = 40°C v = 1 mL/min c = 0,012M (25 mL, MeCN) Result: Yield: 95%Kappe, O.C. et al. J. Comb. Chem., 2005, 7, 641-43 Conditions: H-Cube® - Formyl group reduction 10% Pd/C p = 40 bar T = 50°C v = 0.5 mL/min c = 10 mg/mL (MeOH) Result: Quantitative reaction (was used in the following reaction step without further purificationPorco, J.A. et al. Angew. Chem. Int. Ed., 2009, 48 (8), 1494-1497
  • 32. Deuteration Substrate Product Deuterium Isolated content(%) yield / % 99 99 97 98 93 97 96 98 96 99Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374
  • 33. Sample reactions Suzuki-Miyaura C-C cross coupling: NO 2 HO OH B + NO 2 CatCartTM 70*4 mm Pd EnCatTM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min BrConversion: 90-95% (TLC)Purity: 70% (LC-MS) without work-upBatch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °CReference:(Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000;8199-8202)
  • 34. Selective Suzuki coupling (Cl, Cl) Flow  rate  (ml/ Pressure   Temperature   Result   o Catalyst   Base   min)   (bar)   ( C)   LC-­‐MS,  220nm   Fibrecat  1007   Conversion:  82%   0.8   20   100   3  ekv   (70mm)   SelecDvity:  48%   Fibrecat  1007   Conversion:  99%   0.3   20   100   3  ekv   (70mm)   SelecDvity:  48%   Fibrecat  1035   Conversion:  16%   0.8   20   100   2.5  ekv   (30mm)   SelecDvity:  100%   0.8   The  condiDons  were:   1029   20   100   Fibrecat   2.5  ekv   Conversion:  18%   (30mm)   SelecDvity:  100%   0.8   20   1  equivalent  of  2,6-­‐dichloroquinoxaline  with 100   Fibrecat  1048   2.5  ekv   Conversion:  40%   (30mm)   SelecDvity:  100%    1.2  equivalent  of  o-­‐Tolylboronic  acid     10%  Pd/C   Conversion:  89%   0.8   20   100   2.5  ekv   ConcentraDon  set  to  0.02M   (30mm)   Fibrecat  1048   SelecDvity:  14%   Conversion:17%   0.5   20   50   2.5  ekv   Solvent:  Methanol   (30mm)   SelecDvity:  ~100%   Fibrecat  1048   Conversion:  35%   0.5   20   100   2.5  ekv   Base:  NaOH   (30mm)   SelecDvity:  ~100%   Fibrecat  1007   Conversion:  93%   0.2   20   100   2.5  ekv   AnalyDcs:  GC-­‐MS   (70mm)   SelecDvity:  73%   Fibrecat  1007   Conversion:  93%   0.2   20   100   2.5  ekv   (70mm)   SelecDvity:  80%   Fibrecat  1029   Conversion:  12%   0.2   20   100   2.5  ekv   (30mm)   SelecDvity:  100%  
  • 35. 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
  • 36. Sample reactions In-situ organic azide synthesis: Conversion: complete Purity (crude azide product): 95-100% (TLC) Batch reference: (Saxon, Eliana; Luckansky, Sarah J.; Hang, Howard C.; Yu, Chong; Lee, Sandy C.; Bertoyyi, Carolyn R.; J. Am. Chem. Soc. EN; 124; 5`; 2002; 14893-14902) Parameters: NaN3, DMF, 12 hours, 20 °C; Yield: 91%
  • 37. Faster OptimizationMonitor reaction progressafter 5 minutes!Temperature can be changed during the reaction50 reaction conditions canbe validated in a day.
  • 38. Example for fast optimization •  Batch reactions gave results after 4 hours! H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  • 39. Hydrogenation of diphenylacetylene, one day optimization, %f(T) •  [RuCl2(mTPPMS)2]/Molselect DEAE •  p(H2) = 30 bar, [S] = 0.1 M •  Solvent: toluene/ethanol 1/1 •  24 experiments, total operation time is one dayH. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  • 40. Hydrogenation of diphenylacetylene, one day optimization, %f(pressure) [RuCl2(mTPPMS)2]/Molselect DEAE T = 50 oC, [S] = 0.1 M Solvent: toluene/ethanol 1/1 26 experiments, total operation time is one dayH. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  • 41. University of Graz-Prof. Oliver Kappe Prof. Oliver Kappe, University of Graz, B. Desai, D. Dallinger, C. O. Kappe, Tetrahedron, 2006, 62, 4651-4664.
  • 42. Catalysis reactor: Modular: H-Cube Pro Phoenix Module 450°C Automated injection Novel heterocycles & collection. Optimization H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling H-Cube Midi Gas Module H2 Generation 12 Extra gases 150°C, 100 bar 100 bar Scale Up
  • 43. H-Cube Pro Modules Expanding Chemistry Capability of H-Cube and H-Cube Pro
  • 44. Gas Module
  • 45. 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  bubon  stand-­‐alone  control  or  via  simple   touch  screen  control  on  H-­‐Cube  Pro™.  
  • 46. Use of Gas Module Attached to the H-Cube Pro™ Gas Module HPLC pump H-Cube Pro™ Filter included Check valve included
  • 47. Alcohol oxidation: Optimization Temp. Pressure (oC) CatCart Conversion Selectivity 40 25 1 % Au/TiO2 0 – 40 65 1 % Au/TiO2 6.5 >85 1 % Au 40 25 /Fe2O3 0 –General conditions: H-Cube Pro with Gas Module, 1 % Au50 mL/min oxygen gas, 1 mL/min liquid flow rate 40 65 /Fe2O3 12.7 0(0.05M in acetone, 20 mL sample volume), 5 % RuCatCart: 70mm., 1 % Au/TiO2 (cartridge: 70mm, 40 25 /Al2O3 2.8 ~100THS 01639), 5 % Ru 40 65 /Al2O3 3.6 ~100 5 % Ru Very fast addition of alcohol to gold surface. 100 65 /Al2O3 2.7 ~100 Alkoxide formation. 5 % Ru 100 100 /Al2O3 8.5 ~100 5 % Ru 100 140 /Al2O3 15.5 ~100 100 65 1 % Au/TiO2 5.6 84 Batch ref.: Oxygen; perruthenate modified 100 100 1 % Au/TiO2 47.2 93 mesoporous silicate MCM-41 in toluene 1 % Au 100 140 /TiO2 ~100 93 T=80°C; 24 h; Bleloch, Andrew; et al. Chemical Communications, 1999 , 8,1907 - 1908 1 % Au 100 65 /Fe2O3 4 0 1 % Au 100 100 /Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)
  • 48. Aromatization of heterocyclesReaction 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   Temperature   Pressure   agent   Solvent   Catalyst   (oC)   (bar)   Conversion   Comment   MnO2   Acetone   MnO2   60   20   82%   Blockage  afer  10  minutes   Acetone  -­‐  H2O2   68%  afer  1  run   H2O2   (4-­‐1)   Au/TiO2   70   20   78%  afer  2  run   Acetone  -­‐  H2O2   68%  afer  1  run   The  catalyst  was  reacDvated   H2O2   (4-­‐1)   Au/TiO2   100   30   98%  afer  2  run   with  H2O2  between  the  runs.   O2  (10  ml/min)   Acetone   Au/TiO2   75   11   8%   Afer  10  minutes  the   conversion  was  dropped  to   O2  (10  ml/min)   Acetone   Au/TiO2   150   11   95%   50%   O2  (50  ml/min)   Acetone   Au/TiO2   150   20   >  98%  
  • 49. Aminocarbonylation 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 Results HC-­‐Pro  with  gas  module  (CO  flow  rate)   ReacDon   10 ml/ 30  ml/ 30  ml/ 30  ml/ 60  ml/ 60  ml/ 60  ml/ 60  ml/ min min   min   min   min   min   min   min   Conversion   %   60   65   62   66   79   79   79   82   Reproducible Conversion for Each Flow Rate
  • 50. Phoenix Module
  • 51. Phoenix Flow Reactor High Temperature Synthesis Powerful & New Parameter Space Up to 450°C, 100 bar Versatile: Cartridges for Heterogeneous and loops homogeneous capabilities. Fast: Reactions in seconds or minutes. Chemical Resistance: Stainless steel, Hastelloy, and teflon options Innovative: Validated procedure to generate novel bicyclic compounds Scale Up: Different size CatCarts, MidiCart, Loops Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.
  • 52. Catalyst Cartridges (Heterogenous Rxns)Type   Volume   Max.  T/p  (100  bar   Comment   unDl  it  is  indicated   otherwise)   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   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  
  • 53. Loop-Reactor Options (homogenous rxns)•  Control Residence/Rxn Time by Length/Volume of Coil.•  Materials and 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) •  Acidity limit §  Hastelloy (4 – 16 ml) – up to 450oC and 100bar •  Less sensitive to acid though more expensive than stainless steel §  PTFE coil (4 – 16 ml) – up to 150oC or 20bar•  Easy to recoil•  Versatile
  • 54. Places dedicated for connection of Phoenix 2. 1. 1.) reaction in the Phoenix Flow Reactor, followed by a reaction in the H-Cube Pro 2.) reaction in the H-Cube Pro, followed by a reaction in the Phoenix Flow Reactor i.) if inert CatCart is placed into the H-Cube Pro: reaction in the Phoenix Flow Reactor only ii.) engineering: forget about the H-Cube Pro CatCart place
  • 55. Back from Heat Exchanger To Heat ExchangerTo Heat ExchangerBack from Heat Exchanger Heat exchanger and release valve (140 bar)
  • 56. 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
  • 57. Our focus: 2 main cyclization routes • Gould-Jacobs-reaction • Meldrum’s acid variation 57 Curran, T.T. in Named reactions in Heterocyclic Chemistry; Li, J.-J., Corey, E. J. Eds. Wiley Interscience: New York, 2005, pp423-436
  • 58. Gould-Jacobs Cyclization Condensation Cyclization methylenemalonic ester Saponification Decarboxylation•  Standard benzannulation reaction Disadvantages:•  Good source of: • Harsh conditions •  Quinolines • High b.p. solvents •  Pyridopyrimidones • Selectivity •  Naphthyridines • Solubility•  Important structural drug motifs W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
  • 59. • Gould-Jacobs-reaction §  Replacement of diphenyl ether with THF 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 Batch conditions: 2 hours No THF polymerization! 59Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted for publishing)
  • 60. Pyrolysis of Meldrums Acid ketene•  Meldrum’s acid is more acidic than malonic ester=easier synthesis of adduct•  Decomposition needs no purification•  Lower temperature reactions
  • 61. 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 minThe 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. 61Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted for publishing)
  • 62. • Extension to the synthesis of naphthol and phenyl-substituted salicylic acid-derivatives• Formal mechanism: 62Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted)
  • 63. Thermal cyclisation of amino-flavon • Solution Phase Flow Thermolysis method 50% Yield 95% NMR purity In collaboration with the Patonay Group from Debrecen University 63
  • 64. Going supercritical:350°C<T>500°C
  • 65. Transesterification Conditions: 85% yield p = 180 bar T = 350°C Remark: little or no reaction below 200°C v = 0.5 mL/min c = 0.05 M (MeOH) Under supercritical conditions Esterification Conditions: MeOH and EtOH p = 120 bar 87% yield act as an acidic T = 300°C catalyst Remark: 3 passes v = 1.0 mL/min little or no reaction below 200°C c = 0.33 M (EtOH)Razzaq, T.;, Glasnov, T.N.; Kappe, O. C., Continuous-Flow Microreactor Chemistry under High-Temperature/Pressure Conditions,Eur. J. Org. Chem., 2009, 9, 1321-1325
  • 66. Esterification in supercritical methanol - Suppression of side reactions by increasing the pressure and flow rate - MeOH: Tcr = 239.4°C, pcr = 80.8 bar - Concentration: 0.05M Temp.  (°C)   Pressure  (bar)   Residence  7me  (sec)   Calc.  yield  (%)*   300   150   30   15   425   117   18   9   450   118   7,2   38   450   118   12   25   450   109   12   27   460   140   9   55   460   144   9   54   Rapid optimization 460   135   9   59   436   137   9   74   460   137   9   76   481   137   9   76   496   137   6,9   76   483   137   5   80   - Isolated yield 60%, NMR 98% 483   137   3,3   80   475   137   2,6   74   475   137   2,9   79  * By calibration curve, loop size 1.5 mL
  • 67. Thank you for your attention