Accelerating Your Synthesis with Flow Chemistry

Heather Graehl, MS, MBA

Director of Sales North America

ThalesNano North America

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 reaction continuously, typically on small scale, through either a coil or fixed bed reactor.

OR

PumpReactor Collection

What is flow chemistry?

• 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

Kinetics in Flow Reactors

Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)

Improved Mixing Compared to Batch

Improved mixing can lead to improved reaction times, especially with fixed bed reactors

Improved Mixing = Faster Rxn Time

• 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 FlowMicroreactors, ChemSusChem, 2010

Enhanced Temperature Control

Lower reaction volume. Closer and uniformtemperature control

Outcome:

Safer chemistry. Lower possibility of exotherm.

Batch

Flow

Larger solvent volume. Lower temperature control.

Outcome:

More difficult reaction control. Possibility of exotherm.

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

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

Enhanced Temperature Control

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Better surface interactionControlled residence timeElimination of the products

Flow Method

H-Cube Pro™

Selectivity – Residence Time Control

Catalyst screening

Parameter scanning: effect of residence time to the conversion and selectivity

0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2

85

90

95

100

105

110

Conversion Selectivity

%

Flow rate / mLmin-1

1% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzene

Catalyst 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

Conditions: 70 bar, EtOH, 25°C

Increase and decrease of residence time on the catalyst cannot be performed in batch

Selective Aromatic Nitro Reduction

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

Why move to flow?

Survey Conducted

150°C, 100 bar (1450 psi)

H2, CO, O2, CO/H2, C2H4, CO2.

Reactions in minutes.

Minimal work-up.

-70 - +80C

O3, Li, -N3, -NO2

Safe and simple to use.

Multistep synthesis.

2 step independant T control.

Coming: fluorinations, low T selectivity

450°C, 100 bar (1450 psi)

New chemistry capabilities.

Chemistry in seconds.

Milligram-kilo scale

Solve Dead-end chemistry.

Heterocycle synthesis

H-Cube Pro & Gas Module:

Reagent gases

Phoenix Flow Reactor:

Endothermic chemistry IceCube:

Exothermic Chemistry

Reactor Platforms

H-Cube Catalysis Platform: Making hydrogenations safe, fast, and selective

• 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)

NH

O2N

NH

NH2

Hydrogenation reactions:Nitro ReductionNitrile reductionHeterocycle SaturationDouble bond saturationProtecting Group hydrogenolysisReductive AlkylationHydrogenolysis of dehydropyrimidonesImine ReductionDesulfurization

H-Cube – How it Works

• Large cylinders contain 4360 litres of compressed H2

• They are a severe safety hazard• H-Cube doesn’t use gas cylinders• Only water• Clean• No transportation costs• Low energy• Safe

• Just 2 mL H2 @ 1bar

No more hydrogen cylinders!

Hydrogen generator cell Solid Polymer Electrolyte

High-pressure regulating valves

Water separator, flow detector, bubble detector

Water Electrolysis

•Benefits• Safety• No filtration necessary • Enhanced phase mixing

•Over 100 heterogeneous andImmobilized homogeneous catalysts

10% Pd/C, PtO2, Rh, Ru on C, Al2O3

Raney Ni, Raney CoPearlmans, Lindlars CatalystWilkinson's RhCl(TPP)3

Tetrakis(TPP)palladiumPd(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

10% Pd/C, RT, 1 barYield: 86 - 89%Alternate reductionsKetone: Pt/CAromatic: Ru/O2

Raney Ni, 70°C, 50 bar, 2M NH3 in MeOH, Yield: >85%

Simple Validation Reactions (out of 5,000)

10% Pd/C, 60˚C, 1 barYield: >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 barYield: 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

Simple Validation Reactions (out of 5,000)

N

O

OEt

Ar

NH

O

OEt

Ar

Acetic Acid

20% Pd(OH)2/C, 70 bar, 70oC

70% Yield, 5g

RuO2, 100 C

100 bar, 1 mL/min

99% Conversion

Batch: 200°C, 200 bar, 48 hours

Batch: 150°C, 80 bar, 3 days

Difficult Hydrogenatons

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

Selective Hydrogenations

NO2 NO2

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

O2N

O2N

NHO

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

Conditions: Au/TiO2, 70 bar, 30°C, residence time 17sResults: 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

Selective Hydrogenations

OO2N

Cl

OH2N

Cl

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

HN

OOO

OO2N HN

OOO

OH2N

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

O2N NO2

OHH2N NH2

OH

Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17sResults: 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

Selective Hydrogenations

Ar

F

F

Cl Ar

F

F

H Ar

F

H

H Ar

H

H

H

A B C D

Flow rate

(mL/min)

Pressure (bar)Temperature (oC)

Bubdet Catalyst Amount A (%)

Amount B (%)

Amount C (%)

Amount D (%)

1 20 (∆p:5 bar) 110 50 10% Pd/C 26.7% 61.5% - 7%1 20 (∆p:3 bar) 110 50 1% Pd/C 61,90% 29,40% - 2,50%1 20 (∆p:13

bar)110 50 5% Rh/C 78.9% 5.1% - 9.2%

1 20 (∆p:10 bar)

110 50 5% Pd/C 26.7% 60.9% - 6.7%

1 20 (∆p:5 bar) 110 50 5% Pd/C(S) 25% 63.4% - 6.6%

Objective: Match similar selectivity of 60% but without additives of CsF, S, K2CO3 and PPh3

Selective Dehydrochlorination

N

NO2

NH

NH2

PtO2

N

NH2

+

A B

NH

NH2

+

C

Optimised 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 00.5 100% 92 8 01.0 100% 86 14 0

Partial Saturation of Heterocycles

Chiral Phosphine-phosphoramidite ligands packed in CatCart

Asymmetric Hydrogenation

Substrate Product Deuterium content(%)

Isolated yield / %

99 99

97 98

93 97

96 98

96 99

PhPh Ph

Ph

D

D

Ph OMe

O

Ph OMe

OD

D

PhPhPh

PhD D

D D

NH

O

HN

O

Me

Me

HN

O

HN

O

Me

Me

D

D

HN

O

HN

O

Me

Me

HN

O

HN

O

Me

Me

D

D

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

Deuteration

•Original 2005 R&D100 award winner•20mg-10g/day•Ambient to 100°C•Limited H2 control: Full H2 mode (30ml/min), Controlled H2 mode, No H2

•Improved H-Cube•20mg-50g/day• -10°C to 150°C•H2 production variability from 0ml/min – 60ml/min•Reaction timer with auto switching valves•Software for logs, graphs, reaction guide, module control

•High throughput•Larger MidiCart Catalysts•20mg-500g/day•Ambient to 150°C•H2 production variability from 0ml/min – 125ml/min•Reaction timer with auto switching valves

Which H-Cube is best for me?

H-Cube Family

•Touch Screen Interface•Now can control hydrogen variability (0-60ml/min) for selectivity•Suggested reaction parameters for each functional group •Reaction Timer with automatic valve switching•Logs and graphs for viewing achieved reaction parameters

New Software with H-Cube Pro

0.7 M Solution in MeOHRaNi

30 °C, 100 bar1 mL/min

2 cells for higher hydrogen production: 60 mL/min

Compare to H-Cube SS where maximum concentration is 0.2M

100% conversion

H-Cube Pro = Higher Throughput

N

0.05 M EtOHPd/C

r.t., 30 bar1 mL/min

NH

CO2Et

CO2Et

NH

CO2Et0.05 M EtOHPd/C

100 °C, 100 bar1 mL/min

NH

CO2Et

+

50 : 50

NH

CO2Et

100 %

100 %

0.05 M EtOHPd/C

150 °C, 100 bar1 mL/min

H-Cube Pro

H-Cube

Ethyl Nicotinate

H-Cube Pro = Higher Temp Capability

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

+Conditions

A B C

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

H-Cube Pro – Lower Temp Selectivity

Parameters:- p= 1-100 bar- T=10-150°C- v=0.1-3 ml/min-c=0.01-0.1 M-H2 production = up to 60ml/min-CatCarts = 30x4mm or 70x4mm

Parameters:- p= 1-100 bar- T=25-150°C- v=5-25 ml/min-c=0.05-0.25 M-H2 production = up to 125ml/min-CatCarts = 90x9.5mm

Milligram to Gram Scale

Half Kilogram Scale

H-Cube Midi – Reactor for Scale Up

Gilson 271 Liquid Handler 402 single Syringe pump (10 mL) Direct GX injector (Valco) Low-mount fraction collection (Bio-Chem) Septum-piercing needle Static drain wash station Tubes, connectors, fittings

Open vial collectionCollection through probe (into closed vial)

H-Cube Autosampler

Expanding H-Cube Beyond Hydrogenation

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

Heck C-C cross coupling:

N

+

Br

NO2

NO2

N

CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M, 100oC, 1 bar, 0.2 ml/min.

Coupling Reactions

Conversion: 90-95% (TLC)

Purity: 70% (LC-MS) without work-up

Batch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °C

Reference:

(Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000; 8199-8202)

Suzuki-Miyaura C-C cross coupling:

Br

NO2

BOHOH

NO2

CatCartTM 70*4 mm Pd EnCatTM BINAP 30,2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min

+

Coupling Reactions

The conditions were:

1 equivalent of 2,6-dichloroquinoxaline with 1.2 equivalent of o-Tolylboronic acid

Concentration set to 0.02MSolvent: MethanolBase: NaOHAnalytics: GC-MS

N

N Cl

Cl

B

HO OH

N

N ClFlow rate (ml/min)

Pressure TemperatureCatalyst Base

Result

(bar) (oC) LC-MS, 220nm

0.8 20 100 Fibrecat 1007 (70mm) 3 ekv

Conversion: 82%Selectivity: 48%

0.3 20 100 Fibrecat 1007 (70mm) 3 ekv

Conversion: 99%Selectivity: 48%

0.8 20 100Fibrecat 1035

2.5 ekvConversion: 16%

(30mm) Selectivity: 100%

0.8 20 100 Fibrecat 1029 (30mm) 2.5 ekv

Conversion: 18%Selectivity: 100%

0.8 20 100 Fibrecat 1048 (30mm) 2.5 ekv

Conversion: 40%Selectivity: 100%

0.8 20 10010% Pd/C

2.5 ekvConversion: 89%

(30mm) Selectivity: 14%

0.5 20 50Fibrecat 1048

2.5 ekvConversion:17%

(30mm) Selectivity: ~100%

0.5 20 100Fibrecat 1048

2.5 ekvConversion: 35%

(30mm) Selectivity: ~100%

0.2 20 100Fibrecat 1007

2.5 ekvConversion: 93%

(70mm) Selectivity: 73%

0.2 20 100Fibrecat 1007

2.5 ekvConversion: 93%

(70mm) Selectivity: 80%

0.2 20 100Fibrecat 1029

2.5 ekvConversion: 12%

(30mm) Selectivity: 100%

Selective Coupling Reaction

• 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™.

Other Reagent Gases

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

Application 1: Carbonylation

Application 2: Green Oxidation

PressureTemp.

(oC) CatCart Conversion Selectivity

40 25 1 % Au/TiO2 0 –

40 65 1 % Au/TiO2 6.5 >85

40 251 %

Au/Fe2O3 0 –

40 651 %

Au/Fe2O3 12.7 0

40 255 %

Ru/Al2O3 2.8 ~100

40 655 %

Ru/Al2O3 3.6 ~100

100 655 %

Ru/Al2O3 2.7 ~100

100 1005 %

Ru/Al2O3 8.5 ~100

100 1405 %

Ru/Al2O3 15.5 ~100

100 65 1 % Au/TiO2 5.6 84

100 100 1 % Au/TiO2 47.2 93

100 1401 %

Au/TiO2 ~100 93

100 651 %

Au/Fe2O3 4 0

100 1001 %

Au/Fe2O3 31 7

OH O

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 tolueneT=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 Oxidation Optimization

NH

O2N

NH

O2N

Catalyst

Reaction 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 agent Solvent Catalyst

Temperature (oC)

Pressure (bar) Conversion Comment

MnO2 Acetone MnO2 60 20 82% Blockage after 10 minutes

H2O2

Acetone - H2O2 (4-1) Au/TiO2 70 20

68% after 1 run 78% after 2 run

H2O2

Acetone - H2O2 (4-1) Au/TiO2 100 30

68% after 1 run 98% after 2 run

The catalyst was reactivated with H2O2 between the runs.

O2 (10 ml/min) Acetone Au/TiO2 75 11 8%

O2 (10 ml/min) Acetone Au/TiO2 150 11 95%

After 10 minutes the conversion was dropped to

50%

O2 (50 ml/min) Acetone Au/TiO2 150 20 > 98%

Aromitization of Heterocycles

Accessing New

Molecules or

Chemical Space

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

The Quest for Novel Heterocycles

• Standard benzannulation reaction

• Good source of:

• Quinolines

• Pyridopyrimidones

• Naphthyridines

→ Important structural drug motifs

Disadvantages:

•Harsh conditions

•High b.p. solvents

•Selectivity

•Solubility

W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895

NH2

RO2C CO2R

OR''R'

+NH

R'

CO2RRO2C

Heat, -R''OH

R = alkylR' = alkyl, aryl, or HR" = alkyl or H

Heat

N R'

CO2R

OH

N R'

CO2H

OH

OH- Heat

methylenemalonic ester

CyclizationSaponification Decarboxylation

Condenzation

N R'

OH

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

Y

CO2Et

OEtX NH2

R

R'

X NH Y

R

CO2EtR'Batch Flow

1a-c 2a-c

3a-c

a: R=H, R'=H, X=N, Y=CO2Etb: R=H, R'=H, X=N, Y=CNc: R=H, R'=H, X=CH, Y=CN

+THF

3a (70%) 3b (75%) 3c (73%)

N

N

O

CO2EtN

N

O

CN

N

CN

OH

Gould Jacobs Reaction - Overview

The 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.

52

•Meldrum’s acidic route to pyridopyrimidones and to hydroxyquinolines

Meldrum-savCH(OEt)3

3a-eBatch Flow

1a-e 2a-e

a: R=H, R'=H, X=Nb: R=H, R'=H, X=N,c: R=F, R'=H, X=C(CH3)d: R=H, R'=CN, X=CHe: R=H, R'=OCH3, X=CH

in THF

R

N H 2X

RO

OO

O

NH

X

R' R'

3d (43%) 3e (60%)3a (89%) 3b (60%) 3c (62%)

O

NN

F

N

O

N

N

N

OHOH

NC

OHOH

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 min

Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743

Process Exploration

5 novel bicyclic scaffolds generated-fully characterized.

Many more to follow

New Scaffold Generation

Powerful: Up to 450°C

Versatile: Heterogeneous and homogeneous capabilities.

Fast: Reactions in seconds or minutes.

Innovative: Validated procedure to generate novel bicyclic compounds Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.

Phoenix Flow Reactor

• Choice of stainless steel, teflon, or Hastelloy

• Different length coils to vary residence time

• Easy to recoil

Phoenix Homogeneous Reactions

• 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 Reactions

HN

N

R

O

R

HO

HN

OR

HN R

Phoenix

T3P, 300C80 bar, THF

Ring closure on aryl NH : key step• Mitsunobu reaction or traditional heating with T3P did not

furnish the bicyclic heterocycle.• Reaction proceeded smoothly in Phoenix reactor at 300oC with

65% yield despite requirement for the cis amide conformer in transition state.

Mitsunobu Reaction not Possible in Batch

RaNi 70mm200C, 80bar0.5ml/min

N-Alkylation with RaNi CatCart

59

HN n-BuOH, 300 °C, 0.5 mL/min

RaNi, 100 bar

HN

HN

N

9.5%

5.5%

63.5%

The total amount of dialkylated products was 18%.

Alkylation coupled with dehydrogenation

Alkylation of 2-methyl-indone

60

HN

+

HO

N

HO

17%310 °C, 80 bar

RaNi, 0.3 mL/min

N

47%

Ring closure is coupled with hydrogenation of double bond

Ring closuring of 2-methyl-indole with 1,3-butanediol

Alkylation with Diol – Ring Closure

NHNH2

O

NH

+AcOH/2-propanol (3:1) (0.5 M)

200°C, 75 bar, 5.0 mL min-1

96 %

cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003

In AcOH/2-propanol (3:1) (0.5M)150 °C, 60 bars,

1.0 mL min-1 (4 min res. time) 88% isolated yield

Continuous Flow Results (4 mL or 16 mL Coil)

Scale-up 200 °C, 75 bars,

5.0 mL min-1 (~3 min res. time) 96% isolated yield

25 g indole/hour

Fischer-Indole Synthesis – Scale Out

Conditions:p = 70 barT = 270°Cv = 0.4 mL/minc = 0.04 M (NMP)Result: 82% yield

Kappe, O. C. et al. Eur. J. Org. Chem., 2009, 9, 1321-1325.

N Cl

+

O

NH

N N

O

X-Cube FlashTM – Kolbe Synthesis

OH

OH

+ KHCO3

H2OOH

OH

CO2H

Conditions:p = 60 barT = 180°Cv = 4 mL/minResidence time: 440 sc = 0.49 M (H2O)Best result: 51% conversion

Kappe, O. et al. Chem. Eng. Technol. 2009, 32(11), 1-16.

X-Cube FlashTM – SNAr reaction

Other High T/p Flow Reactions

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

Fully Automated system now available

Versatile Catalysis System

High EnergyReactions

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

Multistep reactions: 2 reaction zones in 1 systemModular: Option for Ozone Module or more pumps

Size: Stackable to reduce footprint

IceCube

First Reaction Zone Second Reaction Zone

Water inlet and outlet

Reactor Plate•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

AB

D

-70-+80ºC -30-+80ºC

CFirst Reaction Zone Second Reaction Zone

Reaction Zones

A

BC

AB

C

D

Pre-cooler/Mixer Reactor

-70-+80ºC

-70-+80ºC -30-+80ºC

Applications: Azide, Lithiation, ozonolysis, nitration, Swern oxidation

Azide, nitration, Swern oxidation

Ideal for reactive intermediates or quenching

Single or Multi-Step Reactions

Halogenation

NitrationAzides

Multistep reactions

Reactive Intermediates

Lithiation

Ozonolysis

Swern Oxidation

Identified Applications

Welcome screen of the IceCube

Ozonolysis set-up 3 pump – 2 reactor set-up

Touch Screen Interface

• 2pcs rotary piston pumps

• 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

• Continuous ozone production

• Controlled oxygen introduction

• Max. 100 mL/min gas flow

• 14% Ozone production

Pump Module Ozone Module

Modular for a Variety of Chemistry

Batch reaction:Max. -60°C to avoid side reaction

In Flow:

Even at -10°C without side product formation

0.45 M in DCM, 0.96 mL/min

0.45 M alcohol, 0.14 M DMSO in DCM0.94 mL/min

3.6 M in MeOH, 0.76 mL/min

* After purification

When compared to batch conditions, IceCube can still control reactions at warmer temperatures due to better mixing and more efficient heat transfer.

Application 1: Swern Oxidation

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

Flow Ozonolysis and Rebirth of O-Cube

• 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.

Why is Ozonolysis neglected?

SM1 / Reactant or Solvent

SM2 / Quench or Solvent

Product or Waste

IceCube Ozonolysis Setup

M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,

Flow Ozonolysis of Styrenes

Oxidation of alkynes

Oxidation of amines to nitro groups

Ph PhOH

+ O3

1. CHCl325 °C, 1 mL/min

2. 1.5 M H2O2/CHCl325 °C, 0.5 mL/min

HO

Ph

CO2H

Ph

O

Ph

Ph

86%

n-C8H17NH2 + O3

1. EtOAc25°C, 1 mL/min

2. 1.5 M H2O2/H2O25°C, 0.5 mL/min

n-C8H17NO2

73%

M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,

More Flow Ozonolysis

M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,

Flow Ozonolysis of Tioanisole

N

NN

N

NN

NN

OH

HO

N

N

OH

HO

Cl

Cl

NaN3/DMF N

N

OH

HO

N3

N3

1) HCl(g)/Et2O

2 H2O

+ NaCl

+ DMF

N

N

OH

HO

N3

N3

+ NaCl

+ DMF

+ NaCl

+ Me2NH

+ HCOOH2) H2O

• 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 3.33 912 0.9 0 0.94 1.48 913 0.6 0 1.42 2.22 854 0.9 10 0.94 1.48 855 1.5 10 0.56 0.88 866 1.5 15 0.56 0.88 987 1.2 15 0.71 1.11 848 1.8 15 0.47 0.74 86

NH2 N N+ Cl-NaNO2

HCl

O-

NaOH

N N

OH

AnilineHCl sol. Pump A

Pump BNaNO2 sol.

Pump C

Phenol NaOH sol. • Most aromatic diazonium salts

are not stable at temperaturesabove 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-sensitive

Dioazitization and azo coupling

Nitration of Aromatic Alcohols

OH OH

NO2

NO2

O2N

Phenol

Pump A Pump BTemperature

(oC)Loop size

(ml)Conversion

(%) Selectivity (%)Solution

Flow rate (ml/min) Solution

Flow rate (ml/min)

ccHNO3 0.41g PG/15ml

ccH2SO4 0.4 5 - 10 7 1000 (different products)

1.48g NH4NO3/15ml ccH2SO4 0.7

1g PG/15ml ccH2SO4 0.5 5 - 10 13 100 100

1.48g NH4NO3/15ml ccH2SO4 0.5

1g PG/15ml ccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)

70% ccH2SO4 30% ccHNO3 0.6

1g PG/15ml ccH2SO4 0.5 5 - 10 13 (3 bar) 100 100

70% ccH2SO4 30% ccHNO3 0.6

1g PG/15ml ccH2SO4 0.5 5 - 10 13 (1 bar) 80

70 (30% dinitro and nitro)

Currently investigating selectivity at lower temperatures on IceCube

Scaffolds from Explosive Intermediates

• 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

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, MBADirector of Sales North America

Based in sunny San Diegoheather.graehl@thalesnano.com

Onsite Demos & Seminars Available

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS?