IceCube Low Temperature Flow Chemistry v2

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 conCnents. 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 reacCon conCnuously, typically on small scale,

through either a coil or fixed bed reactor.

OR

Pump Reactor CollecCon

Mixing (batch vs. flow)

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

KineCcs In Flow Reactors

In a microfluidic device with a constant flow rate, the concentraCon of the reactant decays exponenCally with distance along the reactor.

Thus Cme in a flask reactor equates with distance in a flow reactor

X

A

dX/dt > 0

dA/dt < 0

MiniaturizaCon: Enhanced temperature control Large surface/volume rate

Microreactors have higher surface-‐to-‐volume raCo 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

HeaCng Control

Batch Flow

-‐ Lower reacCon volume. -‐ Closer and uniform temperature control

Outcome:

-‐ Safer chemistry. -‐ Lower possibility of exotherm.

-‐ Larger solvent volume. -‐ Lower temperature control.

Outcome:

-‐ More difficult reacCon control. -‐  Higher possibility of exotherm.

HeaCng Control

Lithium Bromide Exchange

Batch

Flow

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

Ref: Thomas Schwalbe and Gregor Wille, CPC Systems

Industry percepCon

Small scale: §  Making processes safer §  Accessing new chemistry

§  Speed in synthesis and analysis

§  AutomaCon

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

§  SelecCvity

Why move to flow?

Low Temperature

Chemistry

IceCube

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

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

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

Versa6le chemistry: Ozonolysis, nitraCon, lithiaCon, azide chemistry, diazoCzaCon

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

Chemical resistance: Teflon weied parts

Mul6step reac6ons: 2 reacCon zones in 1 system Modular: OpCon 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

•  ConCnuous ozone producCon

•  Controlled oxygen introducCon

•  Max. 100 mL/min gas flow

•  14% Ozone producCon

Pump Module Ozone Module

VerstaClity to access mulCple working modes

A

B C

A B

C

D

Pre-‐cooler/Mixer Reactor

-‐70-‐+80ºC

-‐70-‐+80ºC -‐30-‐+80ºC

Poten6al Apps: Azide, Lithia6on, ozonolysis, nitra6on, Swern oxida6on

Poten6al Apps: Azide, nitra6on, Swern oxida6on

ReacCon zone cooling

First ReacCon Zone

Secondary ReacCon 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)

? Halogena6on 9 653

Nitra6on 26 701

Azides 89 718

Mul6step reac6ons

Modular

Lithia6on 9 432

Ozonolysis 9 655

Swern Oxida6on 3 289

Exothermic ReacCons # of hits in sciencedirect.com

Main applicaCon areas

Why ozonolysis is neglected?

Highly exothermic reacCon, high risk of explosion

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

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

•  Ru(VIII)O4 + NaIO4

•  Jones oxidaCon (CrO3, H2SO4)

•  Swern oxidaCon 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

Olefins using as masked terminal aldehydes/ alcohols

Biologically acCve 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 weight gain following extensive surgery, chronic infecCon

Flow Ozonolysis of Styrenes

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

Oxida6on of alkynes

Oxida6on of amines to nitro groups

Flow Ozonolysis


Flow Ozonolysis Of Thioanisole


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

In Flow:

Even at -‐10°C without side product formaCon

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

* Axer purificaCon

Swern OxidaCon on IceCube

When compared to batch condiCons, IceCube can sCll control reacCons at warmer temperatures due to beier mixing and more efficient heat transfer.

DiazoCzaCon 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 aromaCc 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-‐sensiCve

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

NitraCon of AromaCc Alcohols

Pump A Pump B Temperature (oC)

Loop size (ml)

Conversion (%)

SelecCvity (%)

SoluCon Flow rate (ml/

min) SoluCon 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 invesCgaCng selecCvity at lower temperatures on IceCube

Coming soon…

•  LithiaCon experiments (collaboraCons)

•  FluorinaCon experiments (collaboraCons)

•  Low temperature selecCve reacCons, not certainly from

exothermic nature

•  Very low temperature experiments, where batch

condiCons required liquid nitrogen temperature or

below

Thank you for your aienCon!

IceCube Low Temperature Flow Chemistry v2

Business

enhanced safety

selectivity heather

low temperature flow