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.  

•  Flow  Chemistry  Experience:  12  years  •  R&D  100  award  winning  instrument    •  Based  Budapest,  Hungary  •  33  employees  with  R&D  labs,  chemists,  and  engineers  

• Flow  Chemistry  Market  Leader  • Over  800  customers  worldwide  

Customers  

What is flow chemistry?

Performing  a  reacRon  conRnuously,  through  either  a  coil  or  fixed  bed  reactor.  

OR  

Pump  Reactor  

CollecRon  

What  is  flow  chemistry?  

Flow  reactors  can  achieve  homogeneous  mixing  and  uniform  hea6ng  in  microseconds  

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  raRo  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  ReacRons  

Batch  Heated  Rxns  •  Safety  concerns,  especially  in  scale  

up  •  Microwave  technology  is  fastest  

way  of  heaRng  solvent  in  batch  

Flow  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,  conRnuously  

   

Endothermic  ReacRons  

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

Safe High Energy Reactions

Lithiation Ozonolysis

Nitration

-70 – + 80°C Inert Conditions

2 Reaction Zones Fast Optimization

Reactions with Gases Made

Simple

Hydrogenation Oxidation

Carbonylation

150°C,100 bar mg - Half a Kilo

13 Gases No Catalyst Handling

Synthesize Novel Compounds

Heterocycles C-H activation

Catalyst screening

450°C, 100 bar Microwave Scale Up Homogeneous and

Heterogeneous

Untapped Chemical Space

Cyclization Molecule cleavage

Free radicals

Vacuum to 400 bar RT to 1000°C

New Synthesis Routes Clean

H-Cube Hydrogenation and Flow Catalysis Platform

H-­‐Cube  Family  

H-Cube®

H-Cube Pro™ H-Cube Mini™ H-Cube Midi™

Industry Hydrogenations and General Flow 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 – fast reaction times

• 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

• Pack your own with CatCart Packer

Catalyst  System  -­‐  CatCarts  

NO2 NO2

Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 97% yield

O2N

O2N

NHO

Conditions: 1% Pt/C, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield

Conditions: Au/TiO2, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield

H-Cube® - Chemoselective hydrogenations

Ürge, L.et al. submitted for publication

Selective hydrogenation of the double-bond

Selective hydrogenation to afford oxime

Selective hydrogenation of the double-bond

SelecRve  HydrogenaRons  

OO2N

Cl

OH2N

Cl

Conditions: 10% Pd/C, 70 bar, 0°C, residence time 16s Results: 100% conversion, 100% yield

HN

OOO

OO2NHN

OOO

OH2N

Conditions: 1% Pt/C, 70 bar, 30°C, residence time 11-17s Results: 100% conversion, 100% yield

O2N NO2OH

H2N NH2OH

Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 100% yield

Ürge, L.et al. submitted for publication

H-Cube® - Chemoselective hydrogenations

Nitro group reduction in the presence of a halogen

Nitro group reduction in the presence of Cbz-group

Nitro group reduction without retro-Henry as a

side-reaction

SelecRve  HydrogenaRons  

H-Cube: <5min Batch: 200°C, 200 bar, 48 hours

H-Cube: <5 min Batch: 150°C, 80 bar, 3 days

Difficult  Hydrogenatons  

10% Pd/C, 0.05M, EtOH, RT, 30 bar

10% Pt/C, 0.05 M EtOAc 100 °C, 100 bar

85% yield 92% yield

Partial or Full Reduction in <5min

N

NO2

NH

NH2PtO2

N

NH2

+

A BNH

NH2

+

COptimised reaction parameters: -  H-Cube Pro -  Temperature: 100oC -  Pressure: 100 bar -  Hydrogen amount: Maximum

Results: •  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.

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  

ParRal  SaturaRon  of  Heterocycles  

Radiochemistry  applicaRon  

•  Model reaction:

18F t1/2 = 109.8 min

5 min

92% 90%

3 min

1 cartridge used 15 times – no degradation

Including purification 40 min process time

S. Liang, T. Collier, B. Rotstein, R. Lewis, M. Steck, and N. Vasdev.; Chem. Com., 2013; 49 (78); 8755 – 8757.

Harvard Medical School, Massachusetts General Hospital and Northeastern University

Positron emission tomography

Chiral Phosphine-phosphoramidite ligands packed in CatCart

Asymmetric  HydrogenaRon  

Substrate Product Deuterium content(%)

Isolated yield / %

99 99

97 98

93 97

96 98

96 99

Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374

DeuteraRon  

New  Sohware  on  H-­‐Cube  Pro  Timer Hydrogen Variability

Valve control Data saving Chemistry Guide

Increased  ProducRon  and  Delivery  of  H2  

2 hydrogen cells for higher hydrogen production: 60 mL/min

New hydrogen delivery algorithm •  No more “controlled mode” (7% of 30ml/min) •  Full H2 at at all pressures (100% 60ml/min) •  Hydrogen control from 0-100% of 60ml/min

12g / hour!

H-­‐Cube  Pro:  Higher  temperature  

H-­‐Cube  Pro:  SelecRvity  with  lower  temp    

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

Solvent Conc. Temp. (°C) Pressure (bar)

Flow Rate (mL/min)

Product Distribution (%, GC-MS)

A B C EtOH 0.1 M 10 10 1 0 100 0

H-Cube

H-Cube Pro

• 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  

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

Observed reproducible conversion at each gas flow rate

CarbonylaRons  

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  OxidaRon  OpRmizaRon  

Powerful: Up to 450°C Versatile: Heterogeneous and homogeneous capabilities. Fast: Reactions in seconds or minutes. Safe – Software emergency shutoff and hardware pressure release valve

Phoenix  Flow  Reactor  

Standalone Version Module Version Includes HPLC Pump and 200bar Valve Module

Requires HPLC Pump and BP Regulator from existing Thales Reactor (H-Cube, X-Cube, etc)

Phoenix metal-metal CatCarts (125mm/250mm)

Max T 450°C+

H-Cube Pro CatCarts (30 or 70mm) Max T 250°C

Phoenix  Heterogeneous  ReacRons  

•  Choice of stainless steel, teflon, or Hastelloy

•  Different length coils to vary residence time

•  Easy to recoil

Phoenix  Homogeneous  ReacRons  

8ml loop w/ SS tubing

8ml loop holder

SnAr in Flow – Rapid Optimization

Simplex  optimalization  

pointTemperature

Flow  Rate  mL/min

Equivalent Yield

1 180 0.5 1 402 200 0.5 2 603 200 1 2 354 220 1 2 505 250 1 2 806 250 1 4 807 250 0.7 2 888 270 0.5 2 999 250 0.5 2 98  

Loop: 4 mL, concentration: 0.2M, residence time: 8 min

Simplex  optimalization  

pointTemperature

Flow  Rate  mL/min

Equivalent Yield

1 200 1 8 252 250 1 12 403 250 0.7 12 564 280 0.7 12 605 320 0.6 16 806 350 0.5 16 867 350 0.5 19 99

Loop:16 mL,concentration:0.05M, residence time: 32 min

CN

F F

NH

NMP + 6 %MeOH

CN

F N

2 eq.

CN

N N

NH

8-19eq.

NMP

•  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  ReacRon  -­‐  Overview  

Merck & Phoenix Flow Reactor

• Optimal temperature at 220C • Des methyl quinoline ester observed

• Reactions from 10-450C and 1-100bar (1450 psi) • Up to 13 different reagent gases • Heterogeneous or homogeneous catalysis

Fully Automated system available

VersaRle  Flow  Chemistry  Plalorm  

IceCube  for    High  Energy  Reac6ons  

Halogena6on  

Nitra6on  Azides  

Mul6step  reac6ons  

Reac6ve  Intermediates  

Lithia6on  

Ozonolysis  

Swern  Oxida6on  

IdenRfied  ApplicaRons  

Set-up of the Ice Cube Modular System

Ozone Module: generates O3 from O2 100 mL/min, 14 % O3.

Pump Module – 2 Rotary Piston Pumps. Excellent chemical compatibility. Automation in progress.

Reactor Module: 2 Stage reactor. -70°C-+80°C. Teflon tubing.

A B

C

D -70-+80ºC -30-+80ºC

Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation Teflon tubing for cheap and easy blockage removal.

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  Rme  aher  mixing  • Different  mixers  types  available  

A  B  

D  

-­‐70-­‐+80ºC   -­‐30-­‐+80ºC  

C  First  Reac6on  Zone   Second  Reac6on  Zone  

Cooling  Module  

What is ozonolysis?

•  Ozonolysis is a technique that cleaves double and •  triple C-C bonds to form a C-O bond.

•  Safety problems: §  Control of temperature. §  Explosive decomposition

R1

R3 R4

R2

R4

R2R1

R3

O O

O

OR

H

OR

OH

R

OH

O3

Ozonide

Flow Ozonolysis

O3(g)  

Alkene   Alcohol,  Alehyde,  Ketone  0ºC   -­‐0ºC  

Quench  First  Reac6on  Zone   Second  Reac6on  Zone  

•  No ozonide is isolated •  Exotherm controlled •  Not just for Alkenes

§  Alkynes §  Amine §  Thiols

Org Let 2011 Vol. 13, No. 5 984–987

Multistep Flow with Unconventional Quench

Ozonolysis Quenching with H-Cube®

T = -30 ºC CSM = 0.02 M (in EtOAc) O3 excess = 30 %

T = -30 ºC to r.t. p = 1 bar Cat: 10 % Pd/C

Mettler Flow IR™

O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.

ThalesNano lab based chemistry-unpublished Ozonide eluted into cool vial under N2

Batch  reac6on:  Max.  -­‐60°C  to  avoid  side  reacRon    In  Flow:            Even  at  -­‐10°C  without  side  product  formaRon  

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  

*  Aher  purificaRon  

When  compared  to  batch  condiRons,  IceCube  can  sRll  control  reacRons  at  warmer  temperatures  due  to  beser  mixing  and  more  efficient  heat  transfer.  

Swern  OxidaRon  

•  2 Step Azide Reaction in flow •  No isolation of DAGL •  Significantly reduced hazards

TKX50

Making  Azide  Chemistry  Safer  

Diazonium salts and diazo coupling

•  Most aromatic diazonium salts are not stable at temperatures above 5°C

•  The synthesis reaction to prepare the diazonium salt is typically exothermic, producing between 65 and 150 kJ/mole and is usually run industrially at sub-ambient temperatures

•  Diazonium salts decompose exothermically, producing between 160 and 180 kJ/mole

•  Many diazonium salts are shock-sensitive

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  aromaRc  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-­‐sensiRve  

DioaziRzaRon  

•  Reagent: BuLi

•  Set-up: 3 pumps, 2 reactors. •  Requires N2 atmosphere in the input vial. •  It’s not necessary to cool the system down to -78 °C.

LithiaRon  

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?