Ice-Cube:Low temperature flow chemistry for enhanced safety and selectivity

Heather Graehl, MS, MBA

Director of Sales North America

Who are we?

ThalesNano is a technology company that gives chemists tools to perform novel, previously inaccessible chemistry safer, faster, and simpler.

Market leader: 800 customer install base on 6 continents.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?

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

OR

PumpReactor Collection

Mixing (batch vs. flow)

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

Kinetics In Flow Reactors

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

Miniaturization: Enhanced temperature control Large surface/volume rate

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

Heating Control

Batch Flow

- Lower reaction volume. - Closer and uniform temperature control

Outcome:

- Safer chemistry.- Lower possibility of exotherm.

- Larger solvent volume. - Lower temperature control.

Outcome:

-More difficult reaction control. - Higher 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

Industry perception

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

Why move to flow?

Low TemperatureChemistry

IceCube

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

Chemical resistance: Teflon wetted parts

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

Size: Stackable to reduce footprint

The IceCube family

• 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

Verstatility to access multiple working modes

A

BC

AB

C

D

Pre-cooler/Mixer Reactor

-70-+80ºC

-70-+80ºC -30-+80ºC

Potential Apps: Azide, Lithiation, ozonolysis, nitration, Swern oxidation

Potential Apps: Azide, nitration, Swern oxidation

Reaction zone cooling

First Reaction Zone

Secondary Reaction Zone

Right hand side:Water inlet and outlet

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

Ideal for dangerous/exotherm chemistry

-Water (high specific heat) used in peltier cooler-Aluminum reactor plate has high thermal conductivity (205 W/mK)

Control – Graphical User Interface

Welcome screen of the IceCube

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

Seamless control of all the modules on a touch screen interface

For custom flow configurations, flexible to allow control of each module on their own (pump, ozone generator, cooler)

? Halogenation9 653

Nitration26 701

Azides89 718

Multistep reactions

Modular

Lithiation9 432

Ozonolysis9 655

Swern Oxidation3 289

Exothermic Reactions# of hits in sciencedirect.com

Main application areas

Why ozonolysis is neglected?

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 explosionThere 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.

What is ozonolysis?

Ozonolysis is a technique that cleaves double andtriple C-C bonds to form a C-O bond.

How does it work?

SM1 / Reactant or Solvent

SM2 / Quench or Solvent

Product or Waste

Olefins using as masked terminal aldehydes/ alcohols

Biologically active natural product

Synthesis of a Key intermediate for Indolizidine 215F

S. Van Ornum et al, Chem. Rev.106, 2990-3001 (2006)

Oxandrolone, anabolic steroid used to promote weightgain following extensive surgery, chronic infection

Flow Ozonolysis of Styrenes

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

Oxidation of alkynes

Oxidation of amines to nitro groups

Flow Ozonolysis

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.,

Flow Ozonolysis Of Thioanisole

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

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

Swern Oxidation on IceCube

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

Diazotization 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 3.33 912 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

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

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

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

Coming soon…

• Lithiation experiments (collaborations)

• Fluorination experiments (collaborations)

• Low temperature selective reactions, not certainly from

exothermic nature

• Very low temperature experiments, where batch

conditions required liquid nitrogen temperature or

below

Thank you for your attention!