IceCube Overview Jan 2014

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  • Ozonolysis adds to the double or triple bond to form the molozonide. The molozonide is a very short lived species and quickly rearranges to form the trioxalane (ozonide).
    The ozonide is then reacted with another reagent to form either a ketone, aldehyde, alcohol, or carboxylic acid.
  • Safety departments are considering banning the use of ozonolysis.
  • In addition to olefinic double bonds, the ozonolysis of the terminal C-C triple bond in 1,1- diphenylprop-2-yn-1-ol 5 (Scheme 1b) was also investigated. In our hands, the ozonolysis of propynol 5 inCHCl3 did not lead to the expected glycolic acid 616 but to diphenylketone 7 in 86% yield. The observed result can be rationalized by the presence of ozone in the reaction mixture, creating an oxidizing environment, able to rapidly decarboxylate the in situ formed glycolic acid, thereby forming diphenylketone 7 as observed previously by Hurd and Christ for similar substrates.17
    In another application of the continuous flowozonolysis concept, we attempted the oxidative transformation of octan-1-amine 8 (Scheme 1c) into the corresponding nitroalkane 10. Previous work by Bachman and Strawn has confirmed that primary amines of type 8 can be subjected to ozonolysis under batch conditions to provide nitroalkanes, 18 and the Jensen group has reported the oxidation 8 f 9 with O3 in a multichannel microreactor.8 Adopting operating conditions similar to those used during olefin ozonlysis, a 0.05 M EtOAc solution of octan-1-amine 8 was subjected to flow ozonolysis in the O-Cube at room temperature. Applying a 10% ozone concentration (∼3 equiv), complete consumption of the starting material was experienced, providing 1-nitrooctane 9 in 73%yield after a single pass through the instrument within 40 min.
  • The oxidation of thioanisole (10) appeared to be a somewhat more demanding process, as it has been found that aliphatic/ aromatic or aromatic/aromatic thioethers tend to react relatively slowly or not at all with ozone (thioesters).19 While the formation of the sulfoxide proceeds relatively slowly, the further oxidation step to the sulfone is known to be even more sluggish.19 Therefore, we investigated the oxidation behavior of thioanisole (10) with ozone under flow conditions. Initially, a 0.05Msolution of thioanisole (10) in methanol was processed at 25 C and 1 mL/min flowrate applying 5%O3 (1.0 equiv). Reductive quenching with 0.1 M NaBH4 in MeOH at 25 C followed by extractive workup provided sulfoxide 11 in 84% isolated product yield (Table 2, entry 1). In order to access sulfone 12 the reductive quench was replaced by an oxidative one (Table 2, entryies 2-8). Using NaIO4 as oxidative reagent at 25 C and 2 equiv of O3 in acetone, full conversion based on consumption of sulfide 10 was achieved at a 0.5mL/min flowrate in the ozonolysis step. Analysis (GC-MS) of the obtained reaction mixture showed predominant formation of sulfoxide 11 accompanied by 18% of the desired sulfone 12 (Table 2, entry 2). Lower temperatures and higher flow rates, as well as changing the oxidative reagent to 5 MH2O2 in water as solvent led to an improved sulfoxide/sulfone product distribution (Table 2, entries 3-5) providing up to 88% selectivity for sulfone 12.
    Ultimately, changing the reaction solvent to MeOH initially did not seem promising (Table 2, entry 6); however, after further optimization we were finally able to achieve quantitative conversion of thioanisole 10 into the desired sulfone 12.
    Under the optimized conditions for full conversion (Table 2, entry 8) a preparative experiment provided 87% isolated yield of sulfone 12 after a simple workup.
  • Nitration of Aromatic Phenol derivatives differ from other Arimatic nitrations, since it works with dilluted HNO3 as well. A synthetic reagent equvivalent could also be the NH4NO3/H2SO4 in this case then. This is how we nitrated Phenol, Resorcinol and the Phloroglucinol.
    Excellent heattransfer due to the elevated Specific surface area / Reaction Volume ratio. -> This allows safer synthetic routines in highly exotermic reactions, just like nitration.
    Selectivity Control: Temperature ( Too low temperature would ‘freeze’ the nitration , too high may support oxidation -> dangerous)
    Approprietry chosen nitro source feed (Quantitative control: molar ratio of the nitro source to the aromatic reactant ).
    Nature of the nitro source (Qualitative control: Nitration with NH4NO3/H2SO4 is less accelerated, then HNO3/H2SO4 -> less chance for accelerating consecutive reactions, plus HNO3 does not trigger sidereactions , like oxidation) Chosen Reactor Length + Quench (Longer reactor-> higher chance of the consecutive reactions to proceed. Quench: Product mixture is poored on ice and thus the reaction is ‘freezed’, the compound precipitates )


  • 1. Accelerating Your Synthesis with Flow Chemistry Heather Graehl, MS, MBA Director of Sales North America ThalesNano North America
  • 2. 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.
  • 3. Customers •Flow Chemistry Market Leader •Over 800 customers worldwide
  • 4. What is flow chemistry?
  • 5. What is flow chemistry? Performing a reaction continuously, typically on small scale, through either a coil or fixed bed reactor. OR Pump Reactor Collection
  • 6. Kinetics in Flow Reactors • In a microfluidic device with a constant flow rate, the concentration of the reactant decays exponentially with distance along the reactor. • Thus time in a flask reactor equates with distance in a flow reactor X A dX/dt > 0 dA/dt < 0
  • 7. Improved Mixing Compared to Batch Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)
  • 8. Improved Mixing = Faster Rxn Time Improved mixing can lead to improved reaction times, especially with fixed bed reactors
  • 9. Enhanced Temperature Control • Microreactors have higher surface-to-volume ratio 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
  • 10. Enhanced Temperature 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.
  • 11. Enhanced Temperature Control Batch Heated Rxns • Safety concerns, especially in scale up • Microwave technology is fastest way of heating 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, continuously
  • 12. 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
  • 13. Selectivity – Residence Time Control Traditional Batch Method Flow Method Reactants Gas inlet H-Cube Pro™ By-products Better surface interaction Controlled residence time Elimination of the products By-products Reactants Products Products
  • 14. 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 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 1% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzene 110 105 100 Conditions: 70 bar, EtOH, 25°C % Catalyst 95 90 Conversion Selectivity 85 0,4 0,6 0,8 1,0 1,2 1,4 Flow rate / mLmin 1,6 -1 1,8 2,0 2,2
  • 15. Survey Conducted Why move to flow? Small scale:  Making processes safer  Accessing new chemistry  Speed in synthesis and analysis  Automation Large scale:  Making processes safer  Reproducibility-less batch to batch variation  Selectivity  Green
  • 16. Reactor Platforms 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. 450°C, 100 bar (1450 psi) New chemistry capabilities. Chemistry in seconds. Milligram-kilo scale Solve Dead-end chemistry. Heterocycle synthesis Reactions in minutes. Minimal work-up. IceCube: Exothermic Chemistry -70 - +80C O3, Li, -N3, -NO2 Safe and simple to use. Multistep synthesis. 2 step independant T control. Coming: fluorinations, low T selectivity
  • 17. High Energy Reactions
  • 18. IceCube Safe: Low reaction volume, excellent temperature control, SW controlled – including many safety control points Simple to use: easy to set up, default reactor structures, proper system construction Powerful: Down to -50°C/-70°C, up to 80°C Versatile chemistry: Ozonolysis, nitration, lithiation, azide chemistry, diazotization Versatile reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops High Chemical resistance: Teflon wetted parts Modular: Option for Ozone Module or more pumps Size: Stackable to reduce footprint Multistep reactions: 2 reaction zones in 1 system
  • 19. Reaction Zones Water inlet and outlet Reactor Plate First Reaction Zone Second Reaction Zone C First Reaction Zone •Aluminum stackable blocks •Teflon tubing for ease in addressing blocks •Easy to coil for desired pre-cooling and desired residence time after mixing •Different mixers types available Second Reaction Zone A B D -70-+80ºC -30-+80ºC
  • 20. Single or Multi-Step Reactions A C B -70-+80ºC Reactor Pre-cooler/Mixer Azide, nitration, Swern oxidation C A B D -70-+80ºC -30-+80ºC Applications: Azide, Lithiation, ozonolysis, nitration, Swern oxidation Ideal for reactive intermediates or quenching
  • 21. Identified Applications Ozonolysis Azides Nitration Lithiation Halogenation Multistep reactions Swern Oxidation Reactive Intermediates
  • 22. Touch Screen Interface Welcome screen of the IceCube Ozonolysis set-up 3 pump – 2 reactor set-up
  • 23. Modular for a 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 • Continuous ozone productio – +80°C • Controlled oxygen • Main reactor volume up to 8 mL introduction • Tubing: 1/16” or 1/8” OD PTFE • Max. 100 mL/min gas flow • Secondary reactor block temp.: - 30 – +80°C • 14% Ozone production • Secondary reactor volume up to 4 mL
  • 24. Application 1: Swern Oxidation 0.45 M alcohol, 0.14 M DMSO in DCM 0.94 mL/min Batch reaction: Max. -60°C to avoid side reaction In Flow: 0.45 M in DCM, 0.96 mL/min * After purification 3.6 M in MeOH, 0.76 mL/min Even at -10°C without side product formation When compared to batch conditions, IceCube can still control reactions at warmer temperatures due to better mixing and more efficient heat transfer.
  • 25. Flow Ozonolysis and Rebirth of O-Cube • Ozonolysis is a technique that cleaves double and • triple C-C bonds to form a C-O bond.
  • 26. Why is Ozonolysis neglected? • Highly exothermic reaction, high risk of explosion • Normally requires low temperature: -78°C. • In addition, the batchwise accumulation of ozonide is associated again with risk of explosion • There are alternative oxidizing agents/systems: • Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4) • Ru(VIII)O4 + NaIO4 • Jones oxidation (CrO3, H2SO4) • Swern oxidation • Most of the listed agents are toxic, difficult, and/or expensive to use.
  • 27. IceCube Ozonolysis Setup SM1 / Reactant or Solvent Product or Waste SM2 / Quench or Solvent
  • 28. Flow Ozonolysis of Styrenes M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
  • 29. More Flow Ozonolysis Oxidation of alkynes Oxidation of amines to nitro groups M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
  • 30. Flow Ozonolysis of Tioanisole M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
  • 31. Making Azide Chemistry Safer TKX50 • 2 Step Azide Reaction in flow • No isolation of DAGL • Significantly reduced hazards
  • 32. Dioazitization and azo coupling Aniline HCl sol. Pump A NaNO2 sol. Pump B Entry Pump C Phenol NaOH sol. Vflow (ml/min) T (°C) τ (1. loop, τ (2. loop, min) min) 2.12 3.33 Isolated Yield (%) 1 A-B-C 0.4 0 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 91 • Most aromatic 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 shocksensitive
  • 33. Scaffolds from Explosive Intermediates Nitration of Aromatic Alcohols Currently investigating selectivity at lower temperatures on IceCube Pump A Solution ccHNO3 1.48g NH4NO3/15ml ccH2SO4 1.48g NH4NO3/15ml ccH2SO4 70% ccH2SO4 30% ccHNO3 70% ccH2SO4 30% ccHNO3 Flow rate (ml/min) 0.4 0.7 0.5 0.6 0.6 Pump B Flow rate Solution (ml/min) 1g PG/15ml ccH2SO4 0.4 1g PG/15ml ccH2SO4 0.5 1g PG/15ml ccH2SO4 0.5 1g PG/15ml ccH2SO4 0.5 1g PG/15ml ccH2SO4 0.5 Temperature Loop size Conversion (oC) (ml) (%) Selectivity (%) 5 - 10 7 100 0 (different products) 5 - 10 13 100 100 5 - 10 13 50 80 (20% dinitro) 5 - 10 13 (3 bar) 100 100 80 70 (30% dinitro and nitro) 5 - 10 13 (1 bar)
  • 34. Coming soon… • Lithiation experiments (collaborations) • Fluorination experiments (collaborations) • Low temperature selective reactions, not necessarily exothermic nature • Very low temperature experiments, where batch conditions required liquid nitrogen temperature or below
  • 35. Free Chemistry Services 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.
  • 36. Onsite Demos & Seminars Available 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