Thales overview jan 2014

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 reacQon conQnuously, typically on small scale, through either a coil or fixed bed reactor.

OR

Pump Reactor CollecQon

What is flow chemistry?

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

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

X

A

dX/dt > 0

dA/dt < 0

KineQcs in Flow Reactors

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

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.


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


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


Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Better surface interaction Controlled residence time Elimination of the products

Flow Method

H-Cube Pro™

SelecQvity – Residence Time Control

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

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

SelecQve AromaQc Nitro ReducQon

Small scale: §  Making processes safer §  Accessing new chemistry

§  Speed in synthesis and analysis

§  AutomaQon

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

§  SelecQvity §  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 Pladorms

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)

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

•  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 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

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 ValidaQon ReacQons (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

Simple ValidaQon ReacQons (out of 5,000)

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

SelecQve HydrogenaQons

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


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


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

SelecQve DehydrochlorinaQon

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

ParQal SaturaQon of Heterocycles

Chiral Phosphine-phosphoramidite ligands packed in CatCart

Asymmetric HydrogenaQon

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

DeuteraQon

• 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 (selectivity!) • 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 Sooware with H-‐Cube Pro

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

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

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 SelecQvity

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 collection Collection 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:

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

Coupling ReacQons

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

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

+

Coupling ReacQons

The condiQons were:

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

ConcentraQon set to 0.02M

Solvent: Methanol

Base: NaOH

AnalyQcs: GC-‐MS

SelecQve Coupling ReacQon

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% SelecQvity: 48%

0.3 20 100 Fibrecat 1007

(70mm) 3 ekv Conversion: 99% SelecQvity: 48%

0.8 20 100 Fibrecat 1035

2.5 ekv Conversion: 16%

(30mm) SelecQvity: 100%

0.8 20 100 Fibrecat 1029

(30mm) 2.5 ekv Conversion: 18% SelecQvity: 100%

0.8 20 100 Fibrecat 1048

(30mm) 2.5 ekv Conversion: 40% SelecQvity: 100%

0.8 20 100 10% Pd/C



0.5 20 50 Fibrecat 1048

2.5 ekv Conversion:17%

(30mm) SelecQvity: ~100%

0.5 20 100 Fibrecat 1048


(30mm) SelecQvity: ~100%

0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1029



SelecQve Coupling ReacQon 1 equivalent of 2,6

-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid

ConcentraQon set to 0.02M

Solvent: Methanol, Base: NaOH

AnalyQcs: GC-‐MS

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

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

•  Powerful: Up to 100 bar capability.

•  Robust: All high quality stainless steel parts.

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

Other Reagent Gases

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

ApplicaQon 1: CarbonylaQon

ApplicaQon 2: Green OxidaQon

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

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 aoer 10 minutes

H2O2 Acetone -‐ H2O2

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

H2O2 Acetone -‐ H2O2

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

The catalyst was reacQvated 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%

Aoer 10 minutes the conversion was dropped to

50%

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

AromiQzaQon 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

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

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.

53

• 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

Process ExploraQon

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

New Scaffold GeneraQon

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 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

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 ReacQon not Possible in Batch

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

N-‐AlkylaQon with RaNi CatCart

60 The total amount of dialkylated products was 18%.

Alkylation coupled with dehydrogenation

AlkylaQon of 2-‐methyl-‐indone

61

Ring closure is coupled with hydrogenation of double bond

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

AlkylaQon with Diol – Ring Closure

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 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

Other High T/p Flow ReacQons

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

Fully Automated system now available

VersaQle Catalysis System

High Energy

Reac6ons

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

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

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

Versa6le chemistry: Ozonolysis, nitraQon, lithiaQon, azide chemistry, diazoQzaQon

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

High Chemical resistance: Teflon wesed parts

Mul6step reac6ons: 2 reacQon zones in 1 system Modular: OpQon for Ozone Module or more pumps

Size: Stackable to reduce footprint

IceCube

First Reac6on Zone Second Reac6on 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 Qme aoer mixing • Different mixers types available

A B

D

-‐70-‐+80ºC -‐30-‐+80ºC

C First Reac6on Zone Second Reac6on Zone

ReacQon Zones

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

Single or MulQ-‐Step ReacQons

Halogena6on

Nitra6on Azides

Mul6step reac6ons

Reac6ve Intermediates

Lithia6on

Ozonolysis

Swern Oxida6on

IdenQfied ApplicaQons

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

•  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

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

* Aoer purificaQon

When compared to batch condiQons, IceCube can sQll control reacQons at warmer temperatures due to beser mixing and more efficient heat transfer.

ApplicaQon 1: Swern OxidaQon

•  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 reacQon, high risk of explosion

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

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

•  Ru(VIII)O4 + NaIO4

•  Jones oxidaQon (CrO3, H2SO4)

•  Swern oxidaQon •  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. Les.,

Flow Ozonolysis of Styrenes

Oxida6on of alkynes

Oxida6on of amines to nitro groups


More Flow Ozonolysis


Flow Ozonolysis of Tioanisole

•  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 and azo coupling

NitraQon of AromaQc Alcohols

Pump A Pump B Temperature (oC)

Loop size (ml)

Conversion (%)

SelecQvity (%)

SoluQon Flow rate (ml/

min) SoluQon 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 invesQgaQng selecQvity at lower temperatures on IceCube

Scaffolds from Explosive Intermediates

•  LithiaQon experiments (collaboraQons)

•  FluorinaQon experiments (collaboraQons)

•  Low temperature selecQve reacQons, not necessarily

exothermic nature

•  Very low temperature experiments, where batch

condiQons 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, MBA Director of Sales North America

Based in sunny San Diego [email protected]

Onsite Demos & Seminars Available

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS?

Thales overview jan 2014

Documents

flow chemistry heather