thales overview oct 2013 v3

Extending the Boundaries Of Organic 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 •  Market leader: 800 customer install base on 6 conFnents. •  33 employees with own chemistry team.

•  11 years old-‐most established flow reactor company. •  R&D Top 100 Award Winner.

Customers (>800 worldwide)

What is flow chemistry?

What is flow chemistry?

•  Performing a reacFon conFnuously, typically on small scale,

•  through either a coil or fixed bed reactor.

OR

Pump Reactor CollecFon

Mixing (batch vs. flow)

Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds (suitable for fast reac6ons)

MiniaturizaFon: Enhanced temperature control Large surface/volume rate

•  Microreactors have higher surface-‐to-‐volume raFo 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

KineFcs In Flow Reactors

•  In a microfluidic device with a constant flow rate, the concentraFon of the reactant decays exponenFally with distance along the reactor.

•  Thus Fme in a flask reactor equates with distance in a flow reactor

X

A

dX/dt > 0

dA/dt < 0

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Batch vs. Flow

Better surface interaction Controlled residence time Elimination of the products

Flow Method

H-Cube Pro™

Catalyst screening

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

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

Selective aromatic nitro reduction

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

Heating Control

Lower reaction volume. Closer and uniform temperature control

Outcome:

Safer chemistry. Lower possibility of exotherm.

Batch

Flow

Larger solvent volume. Lower temperature control.

Outcome:

More difficult reaction control. Possibility of exotherm.

Heating Control

Lithium Bromide Exchange

Batch

Flow

•  Batch experiment shows temperature increase of 40°C. •  Flow shows little increase in temperature.

Ref: Thomas Schwalbe and Gregor Wille, CPC Systems

Survey Conducted

Small scale: §  Making processes safer §  Accessing new chemistry

§  Speed in synthesis and analysis

§  AutomaFon

Large scale: §  Making processes safer §  Reproducibility-‐less batch to batch variaFon

§  SelecFvity

Why move to flow?

Reaction Line

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

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

H-Cube Pro Overview

•  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

No More Hydrogen Cylinders

•  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

Hydrogen generator cell §  Solid Polymer Electrolyte

High-pressure regulating valves

Water separator, flow detector, bubble detector

Catalyst System - CatCart®

• 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)

New Software with H-Cube Pro

Timer Hydrogen Variability

Valve control Data saving Chemistry Guide

H-Cube Pro = higher throughput

2 cells for higher hydrogen production: 60 mL/min

H-Cube Pro: Higher temperature capability

H-Cube Pro: Selectivity with lower temp control

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

Simple Validation Reactions (out of 5,000)

10% Pd/C, RT, 1 bar Yield: 86 - 89% Alternate reductions Ketone: Pt/C Aromatic: 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 bar Yield: >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 bar Yield: 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

H-Cube® Reaction Examples

Batch: 200°C, 200 bar, 48 hours

Batch: 150°C, 80 bar, 3 days

Chemoselective hydrogenations

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

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

Selective Hydrogenations

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

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

Selective dehydrochlorination

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

Partial saturation of heterocycles

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 0 0.5 100% 92 8 0 1.0 100% 86 14 0

Deuteration

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

H-Cube Autosampler™

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 collection Collection through probe (into closed vial)

H-Cube Midi™ reactor for scale-up

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

Expanding H-Cube Beyond Hydrogenation

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:

Sample reactions

Br

N O 2 B

O H O H

N O 2 CatCart TM 70*4 mm Pd EnCat TM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min

+

Selective Suzuki coupling (Cl, Cl)

The condiFons were:

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

ConcentraFon set to 0.02M

Solvent: Methanol

Base: NaOH

AnalyFcs: GC-‐MS

Flow rate (ml/min)

Pressure Temperature Catalyst Base

Result (bar) (oC) LC-‐MS, 220nm

0.8 20 100 Fibrecat 1007

(70mm) 3 ekv

Conversion: 82% SelecFvity: 48%

0.3 20 100 Fibrecat 1007

(70mm) 3 ekv


0.8 20 100 Fibrecat 1035

2.5 ekv Conversion: 16%

(30mm) SelecFvity: 100%

0.8 20 100 Fibrecat 1029

(30mm) 2.5 ekv


0.8 20 100 Fibrecat 1048

(30mm) 2.5 ekv


0.8 20 100 10% Pd/C



0.5 20 50 Fibrecat 1048

2.5 ekv Conversion:17%

(30mm) SelecFvity: ~100%

0.5 20 100 Fibrecat 1048


(30mm) SelecFvity: ~100%

0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1029



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:

Sample reactions

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

Gas Module

•  Versa6le: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.

•  Fast: ReacFons with other gases complete in less than 10 minutes

•  Powerful: Up to 100 bar capability.

•  Robust: All high quality stainless steel parts.

•  Simple: 3 bulon stand-‐alone control or via simple touch screen control on H-‐Cube Pro™.

Use of Gas Module Attached to the H-Cube Pro™

Gas Module HPLC pump H-Cube Pro™

Filter included Check valve included

Problems with Oxidation

Alcohol oxidation: Optimization

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.

Aromatization of heterocycles

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 aner 10 minutes

H2O2 Acetone -‐ H2O2

(4-‐1) Au/TiO2 70 20 68% aner 1 run 78% aner 2 run

H2O2 Acetone -‐ H2O2

(4-‐1) Au/TiO2 100 30 68% aner 1 run 98% aner 2 run

The catalyst was reacFvated 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%

Aner 10 minutes the conversion was dropped to

50%

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

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  Reference test was managed on X-Cube Ø  Reaction was repeated Ø  Different gas flow rates were tested

Results

Aminocarbonylation

ReacFon HC-‐Pro with gas module (CO flow rate)

XC reference

10 ml/min

30 ml/min

60 ml/min

30 ml/min

30 ml/min

60 ml/min

60 ml/min

60 ml/min

Conversion % 60 65 79 66 62 79 79 82 0

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

High T Chemistries – 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 Reaction – in Flow

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.

49

Process exploration

• Meldrum’s acidic route to pyridopyrimidones and to hydroxyquinolines

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

New Scaffold Generation

5 novel bicyclic scaffolds generated-fully characterized. Many more to follow

Phoenix Flow Reactor: High temperature synthesis

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 loop-reactor possibilities

•  Materials - sizes §  Stainless steel (1 – 16 mL) –

up to 450oC and 100bar •  Coil (1/16” 4-16 ml) •  Short coil (1/16” 1-4ml) •  Static mixer (3/8”, 32ml)

§  PTFE coil (4 – 16 ml) – up to 150oC or 20bar

§  Hastelloy (4 – 16 ml) – up to 450oC and 100bar

•  Easy to recoil •  Versatile

Phoenix packed bad reactor possibilities

• CatCart (30, 70 mm) – up to 250°C and 100 bar •  MidiCart – up to 150°C and 100bar •  Special high temperature cartridge – up to 450°C and 100bar

90 × 9.5 mm

Cartridge Volumes and Packing Type Volume Max. T/p (100 bar

unFl it is indicated otherwise)

Comment

H-‐Cube Pro Type CatCarts 30 mm 0.38 mL 250°C Packed by

ThalesNano 70 mm 0.76 mL 250°C Packed by

ThalesNano Phoenix Metal-‐Metal Sealing High T CatCarts

125 mm (1/4 SS id 3 mm) 0.9 mL 450 °C User can fill 125 mm (1/4 SS id 3.8 mm) 1.3 mL 450 °C User can fill 125 mm (1/2 SS id 9.4mm) 9 mL 450 °C User can fill, filters

are needed 250 mm (1/4 SS id 3mm) 1.8 mL 450 °C User can fill, filters

are needed 250 mm (1/4 SS id 3.8 mm) 2.6 mL 450 °C User can fill, filters

are needed 250 mm (1/2 SS id 9.4mm) 18 mL 450 °C User can fill, filters

are needed H-‐Cube Midi Type MidiCarts

MidiCart 7.6 mL 150 °C Packed by ThalesNano

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 Application Note

N-Alkylation Application Note

RaNi 70mm 200C, 80bar 0.5ml/min

57

Reaction pathway using Raney-Ni catalyst

Advantages of Raney-Nickel: •  Cheaper than Pd, Pt containing catalysts •  Differently preactivated Raney-Ni catalyst can give more

flexibility – selectivity issues

But: Pyrophoric!

58

Optimizing the reaction conditions:

•  0.1M Indole solution in ethanol, RaNi 4200 Catalyst, GC-MS results

Reach higher selectivity: Protect the N-atom with TMS-Cl Result: 90% conversion with 80%

selectivity (300 °C, 100 bar, 0.5 mL/min,

isolated yield: 76.5%)

59

Alkylation of 2-methyl-indoline

The total amount of dialkylated products was 18%.

Alkylation coupled with dehydrogenation

60

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

Ring closure is coupled with hydrogenation of double bond

Fischer-Indole Synthesis: Scale Out

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

High temperature reactions

Conditions: p = 70 bar T = 270°C v = 0.4 mL/min c = 0.04 M (NMP) Result: 82% yield

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

X-Cube FlashTM – Kolbe Synthesis Conditions: p = 60 bar T = 180°C v = 4 mL/min Residence time: 440 s c = 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

Versatile Catalysis Platform

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

Fully Automated system now available

High Energy

Reac6ons

IceCube

Safe: Low reacFon volume, excellent temperature control, SW controlled – including many safety control points

Simple to use: easy to set up, default reactor structures, proper system construcFon

Powerful: Down to -‐50°C/-‐70°C, up to 80°C

Versa6le chemistry: Ozonolysis, nitraFon, lithiaFon, azide chemistry, diazoFzaFon

Versa6le reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops

Chemical resistance: Teflon weled parts

Mul6step reac6ons: 2 reacFon zones in 1 system Modular: OpFon for Ozone Module, more pumps

Size: Stackable to reduce footprint

Flexible and modular for variety of chemistry

•  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

•  ConFnuous ozone producFon

•  Controlled oxygen introducFon

•  Max. 100 mL/min gas flow

•  14% Ozone producFon

Pump Module Ozone Module

ReacFon zones

First ReacFon Zone

Secondary ReacFon Zone

Right hand side: Water inlet and outlet

Reactor plate coiled with Teflon tube (1/16”)

Single or mulFstep reacFons

A

B C

A B

C

D

Pre-‐cooler/Mixer Reactor

-‐70-‐+80ºC

-‐70-‐+80ºC -‐30-‐+80ºC

Applica6ons: Azide, Lithia6on, ozonolysis, nitra6on, Swern oxida6on

Azide, nitra6on, Swern oxida6on

Ideal for reactive intermediates or quenching

Control – Graphical User Interface

Welcome screen of the IceCube

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

? Halogena6on

Nitra6on Azides

Mul6step reac6ons

Modular

Lithia6on

Ozonolysis

Swern Oxida6on

IdenFfied ApplicaFons

Why ozonolysis is neglected?

•  Highly exothermic reacFon, high risk of explosion

•  Normally requires low temperature: -‐78°C. •  In addiFon, the batchwise accumulaFon of ozonide is associated again with risk of explosion

•  There are alternaFve oxidizing agents/systems: •  Sodium Periodate – Osmium Tetroxide (NaIO4-‐OsO4)

•  Ru(VIII)O4 + NaIO4

•  Jones oxidaFon (CrO3, H2SO4)

•  Swern oxidaFon •  Most of the listed agents are toxic, difficult, and/or expensive to use.

What is ozonolysis?

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

How does it work?

SM1 / Reactant or Solvent

SM2 / Quench or Solvent

Product or Waste

Flow Ozonolysis of Styrenes

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

Oxida6on of alkynes

Oxida6on of amines to nitro groups

Flow Ozonolysis


Flow Ozonolysis Of Thioanisole


Batch reac6on: Max. -‐60°C to avoid side reacFon

In Flow:

Even at -‐10°C without side product formaFon

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

* Aner purificaFon

ApplicaFon Note: Swern OxidaFon

When compared to batch condiFons, IceCube can sFll control reacFons at warmer temperatures due to beler mixing and more efficient heat transfer.

DiazoFzaFon and azo-‐coupling in the IceCube

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 aromaFc 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-‐sensiFve

Safe reaction of azides using Ice-Cube

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

TKX50

Novel scaffold synthesis from explosive intermediates

NitraFon of AromaFc Alcohols

Pump A Pump B Temperature (oC)

Loop size (ml)

Conversion (%)

SelecFvity (%)

SoluFon Flow rate (ml/

min) SoluFon Flow rate (ml/

min)

ccHNO3 0.4 1g PG/15ml ccH2SO4 0.4 5 -‐ 10 7 100

0 (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 invesFgaFng selecFvity at lower temperatures on IceCube

Coming soon…

•  LithiaFon experiments (collaboraFons)

•  FluorinaFon experiments (collaboraFons)

•  Low temperature selecFve reacFons, not certainly from

exothermic nature

•  Very low temperature experiments, where batch

condiFons required liquid nitrogen temperature or

below

Free Chemistry Services

Thalesnano has own chemistry team

We try to solve your challenging chemistry in flow

Low Temperature • reactive intermediates, selectivity, dangerous, exothermic chemistry

High Temperature & Pressures • dead end chemistry, flash heating, rearrangements, alkylations, reactions with gases (hydrogenation, oxidation, carbonylation), catalysis

Email the group: [email protected]

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS

thales overview oct 2013 v3

Technology