2014 Boston Flow Congress Presentation Heather Graehl
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Transcript of 2014 Boston Flow Congress Presentation Heather Graehl
Flow Chemistry: A useful method for performing hazardous chemistry in a safer manner
Heather Graehl, MS, MBA [email protected]
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?
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
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
Exothermic ReacQons
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
Endothermic ReacQons
Discovery Scale: ! Making processes safer ! Accessing new chemistry
! Speed in synthesis and workup
! AutomaQon
Process Scale: ! Making processes safer ! Reproducibility-‐less batch to batch variaQon
! SelecQvity ! Green
Why move to flow?
Survey Conducted
Where is flow chemistry applied best?
Exothermic Reactions • Very good temperature control • Accurate residence time control • Efficient mixing • Less chance for thermal run-away • Higher productivity per volume • High selectivity
Endothermic Reactions • Control over T, p and residence time • High selectivity • Accessing new chemistry • Higher productivity per volume • High atom efficiency
Reactions with gases
• Accurate gas flow regulation • Increased safety • Easy catalyst recycling • High selectivity • Higher productivity per volume
Scale up
• Increased safety • Higher productivity per volume • Selectivity • Reproducibility
150°C, 100 bar (1450 psi) H2, CO, O2, CO/H2, C2H4, CO2. Reactions in minutes. Minimal work-up.
-70 to +80C O3, Li, -N3, -NO2
Safe and simple to use. Multistep synthesis. 2 step independant T control. Coming: fluorinations, low T selectivity
450°C, 200 bar (2900 psi) New chemistry capabilities. Chemistry in seconds. Milligram-kilo scale Solve Dead-end chemistry. Heterocycle synthesis Supercritical Fluids
H-Cube Pro & Gas Module: Reagent gases
Phoenix Flow Reactor: Endothermic chemistry
IceCube: Exothermic Chemistry
Reactor Pla]orms
H-Cube Hydrogenation and Flow Catalysis Platform
• 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
Water Electrolysis
Hydrogen Tanks are Explosive and Severe Safety Hazard
Hydrogen generator cell ! Solid Polymer Electrolyte ! Single Cell output:
30ml/min hydrogen
High-pressure regulating valves
Water separator, flow detector, bubble detector
• 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
• 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
H-‐Cube Family
• 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
H-Cube®
H-Cube Pro™ H-Cube Mini™ H-Cube Midi™
Industry Hydrogenations and General Flow Platform
• Flow rate: 0,3-‐3 mL/min
• Temperature: 25°C to 100°C
• Pressure: 1-‐100 bar
• 30-‐70 mm CatCarts used
• Reusable drying CatCart applied
• 1 hydrogen cell
• Hydrogen producQon: 0 or 22 mL/min
• Small footprint, compact design
• Touch screen graphical user interface
• University teaching material ! Lab Manual ! Lecture Material ! Video
New H-‐Cube Mini for Academia
H-Cube Mini DryCart
• Installed with hundreds of H-Cubes • Flow Rates: 0.001 to 10ml/min • Stainless steel pump head
• Complaints • Loses prime frequently • Does not tolerate air bubbles • Difficult to maintain • Check valves are not robust • Poor performance at low flow rates, not advisable below 0.5ml/min
„Knauer Pumps are the achiles heel of the H-Cube” – H-Cube Customer
New ThalesNano Micro HPLC Pump
Knauer Smartline HPLC Pump
• New pump for H-Cube and Phoenix • Ruby Ball/Saphire Seat Check Valves • More accurate • Tolerates air bubbles • Self flushing compartment • Less often and easier maintenance • Stainless Steel
New ThalesNano Mirco HPLC Pump
• Versatile: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.
• Fast: Reactions with other gases complete in less than 10 minutes
• Powerful: Up to 100 bar capability.
• Robust: All high quality stainless steel parts.
• Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.
Gas Module
" Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.01 M in THF " Catalyst: Polymer supported Pd(PPh3)4 " Reaction was repeated " Different gas flow rates were tested
Observed reproducible conversion at each gas flow rate
CarbonylaQons
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
Powerful: Up to 450°C
Versatile: Heterogeneous and homogeneous capabilities.
Fast: Reactions in seconds or minutes.
Module for H-Cube Pro Use H-Cube’s HPLC pump
and backpressure regulator
Standalone Version Add our new 200 bar
backpressure regulator and Micro HPLC Pump
Safe – Software emergency shutoff and hardware pressure release valve
Phoenix Module or 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
• Standard benzannulation reaction • Good source of:
• Quinolines • Pyridopyrimidones • Naphthyridines
→ Important structural drug motifs
Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity
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
• 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
IceCube for
High Energy
Reac6ons
Halogena6on
Nitra6on Azides
Mul6step reac6ons
Reac6ve Intermediates
Lithia6on
Ozonolysis
Swern Oxida6on
IdenQfied ApplicaQons
• 2pcs rotary piston pumps, PeristalQc opQon
• 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
Welcome screen of the IceCube
Ozonolysis set-‐up 3 pump – 2 reactor set-‐up
Control Module
First Reac6on Zone Second Reac6on Zone
Water inlet and outlet
Reactor Plate • Aluminum blocks lined with teflon tubes • Easy to coil for desired pre-‐cooling and desired residence Qme amer mixing • Different mixers types available
A B
D
-‐70-‐+80ºC -‐30-‐+80ºC
C First Reac6on Zone Second Reac6on Zone
Cooling Module
A
B C
A B
C
D
Pre-‐cooler/Mixer Reactor
-‐70-‐+80ºC
-‐70-‐+80ºC -‐30-‐+80ºC
Ideal for reactive intermediates, quenching, or multistep reactions
Single or MulQ-‐Step ReacQons
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
• 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 • Ozonolysis is fast and atom efficient • Ease in Scale Up
Why Ozonolysis in Flow?
Oxida6on of alkynes
Oxida6on of amines to nitro groups
Flow Ozonolysis
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Leq.,
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
* Amer purificaQon
When compared to batch condiQons, IceCube can sQll control reacQons at warmer temperatures due to beqer mixing and more efficient heat transfer.
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
DioaziQzaQon
• 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!!
ANY QUESTIONS?