Flow Chemistry: A useful method for performing hazardous chemistry in a safer manner

Heather Graehl, MS, MBA heather.graehl@thalesnano.com

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 heather.graehl@thalesnano.com

Onsite  Demos  &  Seminars  Available  

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS?