Accelerating Your Synthesis with Flow Chemistry

Heather Graehl, MS, MBADirector of Sales North AmericaThalesNano 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

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?