Flow chemistry: A usefulmethod for performinghazardous chemistry in a safer mannerLászló Kocsislaszlo.kocsis@thalesnano.com

What is flow chemistry?

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

OR

PumpReactor Collection

Where is flow chemistry applied best?

Exothermic Reactions•Very good temperature control•Accurate residence time control•Efficient mixing•Less chance for thermal run-away•Higher productivity per volume•High selectivity

Endothermic Reactions

•Control over T, p and residence time•High selectivity•Accessing new chemistry•Higher productivity per volume•High atom efficiency

Reactions with gases

•Accurate gas flow regulation•Increased safety•Easy catalyst recycling•High selectivity•Higher productivity per volume

Scale up

•Increased safety•Higher productivity per volume•Selectivity•Reproducibility

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?

What is the issue with chemical space?

Region covered in a conventional laboratory

At ThalesNano

pressure / bar

Temperature / °C

100 200 300

Unexploited chemistry space

-100

0

100

200

300

400

500

• ThalesNano makes laboratory reactors that chemists use tocreate new drugs, new aromas, new chemicals, or newprocesses.

• We push the boundaries of science by giving chemists the tools to access novel chemistry at high temperatures and pressures safely and rapidly.

• We also make existing processes safer and more efficient.

Who we are, what we do?

Strategy

• Strategy: Solve chemical problems using flow

Dangerous exothermic reactions High temperature and pressure reactions Reactions with gases Highly selective reactions

Hydrogenation

• Current hydrogenation processes have many disadvantages:

Need hydrogen cylinder-tough safety regulations Separate laboratory needed! Time consuming and difficult to set up Catalyst addition and filtration is hazardous Parr has low temperature, low pressure capability Analytical sample obtained through invasive means. Mixing of 3 phases inefficient - poor reaction rates

Hydrogen generator cell Solid Polymer Electrolyte

High-pressure regulating valves

Water separator, flow detector, bubble detector

•Benefits• Safety• No filtration necessary • Enhanced phase mixing

Catalyst System-CatCart®

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)

NH

O2N

NH

NH2

Hydrogenation reactions:Nitro ReductionNitrile reductionHeterocycle SaturationDouble bond saturationProtecting Group hydrogenolysisReductive AlkylationHydrogenolysis of dehydropyrimidonesImine ReductionDesulfurization

Decomposition of High-Energy Materials

Flow rate(ml/min)

Pressure (bar)

Temperature(oC)

Catalyst Result

0.5 100 (∆p: 1) 100 5% Rh/C The starting material fully decomposed, the main product is the desired one. MW is 145g/mol

0.5 100 (∆p: 1) 100 RaNi The starting material fully decomposed, the main product is the selective nitro reduced benzene

derivative. MW is 139g/mol

0.5 100 (∆p: 1) 100 10% Pd/C The starting material fully decomposed, the main product is the selective nitro reduced benzene

derivative. MW is 139g/mol

OHNO2

NO2

O2NNH2

NH2

H2N

Molecular Weight: 229,10Molecular Weight: 145,20

OH

9 eqv. H2cat

NH2

NH2

H2NOH

Molecular Weight: 139,16

Reactions withtoxic gases

Toxic gasesCarbon monoxide:

Explosive limits: 12.5 – 74.2%

Conc: 1600ppm, death within

2 hours

Ammonia:

IDLH (Immediately Dangerous to Life and Health) is 300 ppm (NIOSH)

4

4 2

3 0

1

Carbonylation leading to esters

O

I

CO, DBUFibercat 1001

EtOH

O

OO Fibrecat 1001:Pd content [mmol/g]: 0.47, Load: mmol/catcart: 0.114.Void volume: 0.62 ml

Ethanolic solution: DBU: 1.1 eq., 4-iodo-anisole: 1.0 ekv, concentration: 0.1 M - 1.0 M

Concentration Liquid flow rate (mL/min)

Temperature (oC)

Gas flow rate

(ml/min)

Pressure (bar)

Pressure drop (bar)

Conversion(%)

Selectivity(%)

0.1 M 0.5 150 10 10 2 >99 >990.1 M 0.5 150 10 30 3 >99 >990.1 M 0.5 150 50 10 3 >99 >991 M 0.5 150 100 30 2 >99 >991 M 1 150 100 30 2 98.3 >99

Microwave reference from Nicholas Leadbeater’s lab (Org.Biomol.Chem. 2007, 65):Concentration: 0.1M, Pressure: 10 bar, Temperature: 125oC, Reaction time: 30 minConversion: 90%Flow reference from Nicholas Leadbeater’s lab (Org.Biomol.Chem. 2011, 6575):Concentration: 1M, Pressure: 17 bar, Temperature: 120oC Residence time: 120 minConversion: 98%

Paal-Knorr pyrole synthesis

T /oC Conversion (%)40 100

110 100

Phoenix with 4 ml loop60bar, 0.5 ml/min 0.1M hexanedione, 0.5 ml/min NH3 (4 min residence time)

Batch reference (Chem.Ber. 1885, 367):Temperature: 150oC, Reaction time: 120 min

Flow reference from Steve Ley’s lab (Org.Biomol.Chem. 2012, 5774):Pressure: 0.1M solution, Pressure: 3.5 bar, Temperature: 0oC for dissolving ammonia, than 110oCResidence time: 10 min on 0oC than 110 min on 110oCConversion: 100%

O

ONH

NH3MeOH

40-110oC

Low TemperatureChemistry

Set-up of the Ice Cube Modular System

Ozone Module: generates O3 from O2 100 mL/min, 10 % O3.

Pump Module – 2 Rotary Piston Pumps. Excellent chemical compatibility.

Reactor Module: 2 Stage reactor. -70°C-+80°C.Teflon tubing.

Versatile: 2 options

A

BC

AB

C

D

Pre-cooler/Mixer Reactor

-70-+80ºC

-70-+80ºC -30-+80ºC

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

? Halogenation

NitrationDiazotization

Swern oxidation Azide

Lithiation

Ozonolysis

Exothermic Reactions

What is ozonolysis?

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

• Market segments: • Pharmaceutical, Fine chemicals, Agrochemicals• Any organic chemistry synthesis segment.

R1

R3 R4

R2

R4

R2R1

R3

O O

O

OR

H

OR

OH

R

OH

O3

Ozonide

Ozonolysis in Industry

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

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 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.

Ozonolysis of decene

Y Wada, K F. Jensen, Ind. Eng. Chem. Res. 2006, 45, 8036-8042

Batch reference:

-78oC, DCM, NMMO as a quench. Yield: 88-94%

Tetrahedron, 2006, 10747

Ozonolysis in microreactor

Quench Reactant

Ice-Cube set-up

O-Cube™ – H-Cube® - ReactIR™ ozonolysis of decene

Ozonolysis Quenching withH-Cube®

T = -30 ºCCSM = 0.02 M (in EtOAc)

O3 excess = 30 %

T = -30 ºC to r.t.p = 1 barCat: 10 % Pd/C

React IR™

O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.

H2 10%Pd/C

ThalesNano lab based chemistry-unpublishedOzonide eluted into cool vial under N2

Equipment Conc. (M) Decene FR (ml/min)

Ozone FR (ml/min)

Quench FR (ml/min)

Conversion (%)

Temperature (oC)

O-Cube 0.02 1 20 0.2 97 -30

Ice-Cube 0.05

1

100 0,2

100

-40Ice-Cube 0.1 95

Ice-Cube 0.2 81

Ice-Cube 0.5 24

Ice-Cube 0.2 1 100 0

Ice-Cube 0.2 1 100

-20Ice-Cube 0.1 1.5 100

Ice-Cube 0.1 3 58

Ice-Cube 0.1 5 26

O-Cube – Ice Cube comparison

Dialdehyde Formation

T (°C) Solvent Vrea (ml/min)

vQuen (ml/min)

vO2 (ml/min)

Quench c (M)

O3

(%)X (%) 1

(%)2

(%)3

(%)

25 EtOAc 11 11 1010 PPh3 0.1 16 100 80 6 14

25 EtOAc 0.50.5 0.50.5 1010 PPh3 0.1 16 100 83 6 11

5 EtOAc 0.50.5 0.50.5 1010 PPh3 0.1 16 100 83 6 12

25 EtOAc 0.50.5 0.50.5 2020 PPh3 0.1 16 100 82 8 10

OO +

OH

O

O

OH+

EtOAc

O3, PPh31 2 3

ReferenceReference

Chem. Rev. 2006, 106, 2990-3001

Org. Proc. Res. Dev. 2003, 7, 155-160

40% conversion, T=-78°C

T=-78°C

Our resultsOur results

? Halogenation

NitrationDiazotization

Swern oxidation Azide

Lithiation

Ozonolysis

Exothermic Reactions

Diazonium salts and diazo coupling

NH2 N N+ Cl-NaNO2

HCl

O-

NaOH

N NOH

H2O

Cu2X2

RSH

OH

X

SR

• Most aromatic diazonium salts are not stable at temperatures above 5°C

• The synthesis reaction to prepare the diazonium salt is typically exothermic, producing between 65 and 150 kJ/mole and is usually run industrially at sub-ambient temperatures

• Diazonium salts decompose exothermically, producing between 160 and 180 kJ/mole

• Many diazonium salts are shock-sensitive

Azo dyes

• Azo dyes are synthetic colours that contain an azo group, -N=N-, as part of the structure. Azo groups do not occur naturally.

• Azo dyes account for approximately 60-70% of all dyes used in food and textile manufacture. 

• Azo des used in food: E102: Tartrazine, E107: Yellow 2G, E110: Sunset Yellow, E122: Azorubine, E123: Amaranth, E124: Ponceau 4R, E129: Allura Red, E151: Brilliant Black, E154: Brown FK, E155: Brown HT, E180 Lithol Rubine BK 

E102 : Tartrazine E122 : Azorubin E180 : Lithol Rubine BK

Diazotization and azo-coupling

Vflow (ml/min)A - B - C

T (°C) τ (1. loop, min) τ (2. loop, min) Isolated Yield (%)

FM79-1 0.4 0 2.12 3.33 91FM79-2 0.9 0 0.94 1.48 91FM79-3 0.6 0 1.42 2.22 85FM79-4 0.9 10 0.94 1.48 85FM79-5 1.5 10 0.56 0.88 86FM79-6 1.5 15 0.56 0.88 98FM79-7 1.2 15 0.71 1.11 84FM79-8 1.8 15 0.47 0.74 86

NH2 N N+ Cl-NaNO2

HCl

O-

NaOH

N NOH

AnilineHCl sol. Pump A

Pump BNaNO2 sol.

Pump C

Phenol NaOH sol.

Vflow (ml/min)A - B - C

T (°C) τ (1. loop, min) τ (2. loop, min) Isolated Yield (%)

FM81-1 0.6 0 1.42 2.22 77FM81-2 1.5 0 0.56 0.88 99FM81-3 1.5 15 0.56 0.88 99

NH2 N N+ Cl-NaNO2

HCl NaOH

N N

O-

OH

Advantages of diazotization in flow:

• safe handling of the diazonium salt• only small amount of diazonium is present at one time, determined by the size of the first loop (1.7 ml in our case)• Cooling is very effective, no danger of overheating and explosion• Diazotization can be driven safely > 5°C, if the residence time in the first loop is short enough• pH can be kept constant during the coupling• Residence time can be as low as 0.5-1 min, with concentrations similar to batch conditions (0.66M solutions)

Diazotization and azo-coupling

? Halogenation

NitrationDiazotization

Swern oxidation Azide

Lithiation

Ozonolysis

Exothermic Reactions

Nitration

Nitration is a general class of chemical process for the introduction of a nitro

group into an organic chemical compound.

Industrial use of nitro compounds:

• Drugs

• Explosives

• Solvents

• Plastics

• Rocket propellants

Hazards of nitrations:

• Highly exothermic

• Tends to be runaway

• Sideproducts are highly poisoning

• The products are explosives

OH OH

NO2

NO2

O2N

Phenol

Pump A Pump B Temperature (oC)

Loop size (ml)

Conversion (%) Selectivity (%)

SolutionFlow rate (ml/min) Solution

Flow rate (ml/min)

ccHNO3 0.41g Ph/15ml

ccH2SO4 0.4 5 - 10 7 1000 (different products)

1.48g NH4NO3/15ml ccH2SO4 0.7

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 100 100

1.48g NH4NO3/15ml ccH2SO4 0.5

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)

70% ccH2SO4 30% ccHNO3 0.6

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 (3 bar) 100 100

70% ccH2SO4 30% ccHNO3 0.6

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 (1 bar) 80

70 (30% dinitro and nitro)

Nitration of Aromatic Alcohols

Selective nitrations of aromatic alcohols

OH

Ice-Cube, 10°C

cc. H2SO4, 3.3eq HNO3

OHNO2

OH OHNO2

OHNO2

NO2 NO2

O2N+ + +

1 2 3 4SM

OHNO2O2N

NO25

+

Temperature (oC)

Residence time (min)

Composition of the product (%)

SM 1 2 3 4 5

10 5 7 80 1 7 5 0

10 1 9 56 24 5 4 0

10 0.5 10 49 28 6 5 0

10 0.25 10 50 29 5 4 0

10 0.1 13 57 19 6 5 0

0 0.5 19 48 22 6 4 0-10 0.5 22 45 22 7 4 0

? Halogenation

NitrationDiazotization

Swern oxidation Azide

Lithiation

Ozonolysis

Exothermic Reactions

Swern Oxidation

MethodResidence

time (tR1) [s] T [oC] Selectivity of cyclohexanone [%]

Microreactor2.4 -20 88

0.01 0 890.01 20 88

Flask -20 19 -70 83

If the temperature is not kept near -78°C, mixed thioacetals may result:

Chemistry-A European Journal 2008, 7450

Cryogenic operating conditions (< - 60°C), limit its utility for scale up operations in batch.

Temperature (°C) OAC Solution (ml/min) Alcohol and DMSO Solution (ml/min) Conversion (%) Selectivity (%)

-30 0.96 1.9 100% 100%

-20 0.96 1.9 100% 100%

-10 0.96 1.9 100% 100%

0 0.96 1.9 100% 60%

Using TFAA as a DMSO activator seems to afford even higher temperatures.

No chloromethyl-methyl-sulfide production at higher Temps.

Swern Oxidation

OH ODMSO, Oxalyl-Chloride

Quench: TEAIce-Cube Flow Reactor

? Halogenation

NitrationDiazotization

Swern oxidation Azide

Lithiation

Ozonolysis

Exothermic Reactions

Lithiation on Ice-Cube

Flow Rate (ml/min) Conversion (%) Selectivity (%)

0.8 100 60

0.5 98 71

0.3 100 75

T= 0oC; 1. loop: 1.7 ml; 2. loop: 4.0 ml

Br

O

BuLiO

O

OH

Conclusions

• Hazardous reactions can be managed in a safer manner using the flow methodology

• Better temperature control• Smaller amount of reactants• More efficient mixing

• Some exothermic reactions were shown as case studies

• Hydrogenation• Carbonylation• Ozonolysis• Diazotization• Nitration• Swen oxidation

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS?