Volker Hessel, v.hessel@tue.nl

A. Anastasopoulou, B. Patil

Eindhoven University of Technology

Department of Chemical Engineering and Chemistry

Micro Flow Chemistry and Process Technology

Spring Session PINNL 2013, Amersfoort, ISPT – 9 April 2013

PI Technology Update on Microreactors

CONTENTS

• New media (books, journals, …)

• New scientific trends / challenges (lab level)

–waiting for industrial uptake

• New commercial devices / services

• New applications (commercial-test level) reflecting industrial uptake

• New reports about industrials uses

New = 2010-2013 (preferably)

Flashlights (30 min) on …

MEDIA: PAPERS, JOURNALS, AND BOOKS,

0

200

400

600

800

1000

1200

2002 2006 2010 2014

Year

Pu

bli

cati

on

nu

mb

er Microreactors

Flow Chemistry

Chemistry / Chem Eng: 250,000 papers (2012)

Media

AU NANOCATALYSTS SHAPING

A)

B) C)

Duraiswamy S, Khan S. Small 5 (2009) 2828–2834.

Bullen C, Latter M,

D’Alonzo N, Willis

G, Raston C. Chem.

Commun. 2011, 47,

4123–4125.

Au Nanorods

Trends / Challenges

NANOPARTICLE

SUPERSTRUCTURES

Tetrahedron-like Au superclusters

PMS-NPs Supraballs

Nagaki A, Takabayashi N, Moriwaki Y, Yoshida J. Flash. Chem. Eur. J. 2012, 18, 11871 – 11875.

Köhler J, Wagner J, Albert J. J.

Mater. Chem. 2005, 15, 1924-1930.

GOLD NANOCATALYSIS IN FLOW

Gross E, Liu J, Toste F, Somorjai G. Nature Chemistry 4 (2012) 947-952.

IN-SITU GENERATION OF INSTABLE,

HIGHLY ACTIVE CATALYSTS

Jamal F, Jean-Sebastien G, Mael P,

Edmond P, Christian R. Microsyst.

Technol. 18 (2012) 151–158.

NON-POLYMERIZATION

POLYMER DROPLETS

Polymersomes

Silk protein microspheres

Wrinkled polystyrene surfaces by

evaporation of n-hexadecanol

D. N. Breslauer, S. J. Muller, L. P. Lee,

Biomacromolecules 11 (2010) 643.

S. Liu, R. Deng, W. Li, J. Zhu, Adv. Functional Mat. 22 (2012) 1692.

H. C. Shum, Y. Zhao, S.-H. Kim, D. A. Weitz,

Angewandte Chemie 123 (2011) 1686.

V. Hessel, C. Serra, T. Ono et al., Macromol. React. Eng. (2013) accepted.

Lipid-polymer and lipid quantum dot nanoparticles

Meloxicam nanoparticles in poloxamer

LIFE SCIENCES –

DRUG-LOADED NANOPARTICLES

R. Karnik et al.,

Nano letters 8

(2008) 2906.

S. Dev, K. S. Iyer, C.

L. Raston, Lab on a

chip 11 (2011) 3214

N. Anton et al., Soft

Matter 8 (2012) 10628.

Nanodisperse copolymer encapsulates

HOST-GUEST SYSTEMS

Two-step, three-component

formation of the cucurbit[8]uril

ternary complex in water with

methyl viologen and naphthol

J. Zhang et al., Science 335 (2012) 690.

Pressurized high-T

capillaries

Propel

Coflore

Flowsyn

X-Cube Flash Asia 320

R Series

FLOW CHEMISTRY: COMMERCIALIZATION & ORGANIZATION

NOVEL PROCESS WINDOWS

2nd and 3rd INTENSIFICATION FIELDS

HUISGEN CYCLOADDITION–

TEMPERATURE INFLUENCE

0

10

20

30

40

50

60

70

80

90

100

140 160 180 200

69 % 74 %

91 % 78 %

H N

MR

Yie

ld [

%]

Temperature [ºC]

Reaction Conditions

Flow Rate 10μL/min

ζ (min) 10

Solvent NMP

Cu(CH4CN)4BF4 2.50 mol%

Alkyne M 0.23

Azide M 0.23

A. Carlos-Varaz, V. Hessel, T. Noel, Q. Wang ChemSusChem 5, 9 (2012) 1703-1707.

High-T

Solvent

CLAISEN REARRANGEMENT

- SOLVENT

0

10

20

30

40

50

60

70

80

90

100

220 240 260 280 300

Yie

ld [%

]

Temperature [˚C]

High-T

T. Noel, V. Hessel et al. Tetrahedron 69, 14 (2013) 2885-2890. J.P. McMullen , K.F. Jensen, Org.

Process Res. Dev. 15, 2 (2011) 398–407.

Process automation

a-Amino alcohols /

Threonine Aldolase

Transesterification /

Lipase (Antarctica)

Gluconic acid /

Glucose Oxidase

REACTIONS INVESTIGATED IN

ENZYMATIC MICROREACTORS

Indirect method

IMMOBILIZATION PROCEDURES

Direct method

Nanosprings

Eupergit

GPTMS method

H. Fu, I. Dencic, V. Hessel et al. Chem. Eng. J. 207-208 (2012) 564-576

Amount of enzymes: Flow: 146 g L-1 vs. Batch: 2.4 g L-1

0

0.2

0.4

0.6

0.8

1

0 10 20 30 40 50 60 70 80 90 100

Co

nve

rsio

n (

-)

Time (min)

(■) Flow reactor; molar ratio: 1 : 2

(▲) Batch reactor; molar ratio: 1 : 5

Productivity: 1.9 g/l 2.86 ml/h; 5 mol/l

FLOW vs. BATCH – LIPASE-NOVOZYM 435

ENZYMATIC MICROREACTOR

I. Dencic, S. van Veen, M. de Croon, J. Meuldijk, V. Hessel et al. Ind. Eng. Res. Dev. (2012) accepted

Cyclohexane

KA Oil

Cyclohexene

Adipic Acid

DIRECT ROUTES –

ADIPIC ACID

-

Flow process design

needs reaction design

V. Hessel, I. Vural Gursel, Q. Wang, T. Noel, J. Lang, Chem. Eng. Tech. 35 (2012) 1184

V. Hessel, I. Vural Gursel, Q. Wang, T. Noel, J. Lang, Chem. Ing. Tech. 84 (2012) 660

I. Vural Gursel, V. Hessel, Q. Wang, T. Noel, J. Lang, Green Proc. Synt. 4 (2012) 315

Process integration

Organic phase

Aqueous phase

Syringe pump

Syringe pump

Products

Glass

window

Oil Bath

Thermo-couple

InletOutlet

Inlet

Outlet

T-mixer

0

32.9

42

49.5

42.5

31

0

10

20

30

40

50

60

60 70 80 90 100 110 120

Temperature (℃)

Yie

ld

of

ad

ipic

acid

(%

)

Oxidising agent, solvent,

Co-catalyst, PT catalyst,

n(H2O2): n(cyclohexene):

n(Na2WO4): n(PTC)=440:100:6:6

50% H2O2, c(H+) = 1.27mol/l

ADIPIC ACID - PROCESS CONDITIONS

FOR BEST CURRENT YIELD

M. Shang, T. Noël, Q. Wang, V. Hessel, Chem. Eng. Technol. (2013) accepted

PHOTO-RADICAL REACTION USING A

COMPACT LIGHT SOURCE

Barton nitrite photolysis of a steroidal

compound

Key intermediate for the synthesis of

myriceric acid A

A.Sugimoto, T. Fukuyama, Y.Sumino, M. Takagi,

I. Ryu, Tetrahedron 65 (2009) 1593–1598.

SUPERCRITICAL PROCESSING: PHOTO-

OXIDATION USING 1O2 IN scF-CO2

R.A. Bourne, X. Han, M. Poliakoff, M.W. George,

Angew. Chem. 121 (2009) 5426-5429.

Aqueous

Phase

Organic

Phase

EDTA (aq)

NMP

Cu

* The European Agency for Evaluation of

Medicinal Products, London, UK, 2002.

Almost complete phase separation

EtOAc

Triazole

Cu?? Syrris, Flexx

module

15 ppm in API is allowed.

A. Carlos-Varaz, V. Hessel, T. Noel, Q. Wang

ChemSusChem 5, 9 (2012) 1703-1707.

3-STAGED Cu EXTRACTION IN FLOW

Extraction Stage Residual Copper

start 3156 ppm

1 159 ± 9 ppm

2 97 ± 3 ppm

3 14 ± 1 ppm

MICRODESTILLATION/-

RECTIFICATION

Capillary forces and

segmented flow

Central and Coriolis forces

2,2-dimethylbutane/2-methyl-2-

butene (50:50)

6.6 stages with a distillation time

of only 0.13 seconds per stage. Single-stage distillation

of methanol-toluene

o-/p-xylol, stage number

of 12; HETS of 1.08 cm

Microrectification

device

R.L. Hartman, K.F. Jensen, Lab

Chip 9 (2009) 2495-2507.

J.M. MacInnes, J. Ortiz-Osorio, P.J.

Jordan, G.H. Priestman, R.W.K. Allen,

Chem. Eng. J. 159 (2010) 159-169.

A. Ziogas, G. Kolb, H.-J. Kost,

V. Hessel: Chem. Ing. Techn.

83 (2011) 465-478.

CRYSTALLIZATION: CaCO3 FORMATION

http://chiron.no/pdf/syrris/Syrris_FRX_7_

Control_of_Crystallization.pdf

Microreactor 7.5 s

Microreactor 3.0 s

Batch

Holistic Process Papers’ “The whole is more than

the sum of its parts"

Aristotle (Αριστοτέλης)

FULL-CHAIN, HOLISTIC VIEWPOINT

Holistic Route Selection

DOW paper; Leng et al. OPRD (2012)

dx.doi.org/10.1021/op200264t

http://www.ace.gsk.com/GSM

/Background.aspx

MULTISTEP SYNTHESIS OF HIGHLY

COMPLEX MOLECULES IN FLOW

S. V. Ley Chem. Rec. 12 (2012) 378-390.

• With use of immobilized reagents, scavengers and catalysts

• Many examples reported such as casein kinase I inhibitors, imatinib and oxomaritidine

Oxomaritidine

Grossamide

Process integration

PROCESS DESIGN OF THE TRADITIONAL

TWO-STEP & NEW ONE-STEP PROCESS

Process integration ‘2-Step’

‘Direct’

V. Hessel, I. Vural Gursel, Q. Wang, T. Noel, J. Lang, Chem. Eng. Tech. 35 (2012) 1184

V. Hessel, I. Vural Gursel, Q. Wang, T. Noel, J. Lang, Chem. Ing. Tech. 84 (2012) 660

327 €/genzyme

7321 €/genzyme

225 €/genzyme

I. Dencic, V. Hessel, M.H.J.M. de Croon, J. Meuldijk, C.W.J.

van der Doelen, K. Koch ChemSusChem 5 (2012) 232-245

I. Dencic, J. Meuldijk, M.H.J.M. de Croon, V. Hessel J. Flow Chem. 1, 1 (2011) 13-23

COSTS ENZYME IMMOBILIZATION

Evotrainer advantageous for fine-chemical and pharma production

Bulk-chemical not profitable at this low production rate

Cash-Flow Analysis for Container / Flow

PAGE 29

Pharmaceutical

Fine-chemical

Bulk-chemical

2,4-dihydroxybenzoic acid

adipic acid

naproxen

All in flow

ca. 25%

I. Vural Gursel, V. Hessel, Q. Wang, T. Noel, J. Lang, Green Proc. Synth. 1, 4 (2012) 315

DIRECT ROUTE – LCA FOOTPRINT

1. AP: acidification potential (average European)

2. GWP 20a: climate change in 20 years

3. EP: Eutrophication potential (average European)

4. FAETP 20a: freshwater aquatic ecotoxicity in 20 years

5. HTP 20a: human toxicity in 20 years

6. Land Use

7. Malodours Air

8. MAETP 20a: marine aquatic ecotoxicity in 20 years

9. High NOx Photochemical oxidant creation potential

10. Depletion of abiotic resources

11. TAETP 20a: Terrestrial ecotoxicity in 20 years Database: Ecoinvent. Source: CML2001

Q. Wang, I. Vural Gursel, M.

Shang, V. Hessel, Energy

Environm. Sci. (2013) submitted

D. Kralisch, V. Hessel, E. Santacesaria et al. ChemSusChem 5, 2 (2011) 300-311.

EX-ANTE SELECTION OF PI

PROCESS SCENARIOS

HEAT INTEGRATION – PINCH ANALYSIS

Direct Route

I. Vural Gursel, Q. Wang, T. Noel, V. Hessel, Ind. Eng. Chem. Res. (2013) submitted

C O N F I D E N T I A L

Plantrix Industrial

Flow Reactor

Rolling

MASS MANUFACTURING TECHNIQUES AND

PILOT MICRO REACTORS – HEAT EXCHANGERS

Equipment / Services

Department of Chemical Engineering and Chemistry

Microwave assisted microreactor – ArrheniusOneTM

• Developed by WaveCraft, Sweden;

• Improved efficiency - reactions rates accelerated by a factor of 10

to 1000

• Immediate scale-up - allow for rapid scale-up to multi-kg quantities

• Faster work-up of final product - rapid and dynamic optimization

of reaction conditions

http://www.wavecraft.se/Pages/CF_MAOStechnology.aspx

PHOTO-RADICAL REACTION USING A

COMPACT LIGHT SOURCE

Automated flow photo synthesis

Alternative light source, UV-LED (365

nm, 35mW, 48 pieces), which emits

light at only the wavelength required

for this reactiond similar to black

light, albeit lower in energy (1.7 W).

Department of Chemical Engineering and Chemistry

Micro photo reactor

• Developed in collaboration with ;

• Heterogeneous sensitized, photo catalyzed and photo chemically initiated

reactions.

• From microliter to milliliter capacity

• Sources of irradiation: VUV, UV, VIS

http://www.uv-consulting.de/english/products/photochemistry/microphotoreactor/mikrophoptreaktoren.html

MEMBRANE AND TUBE-IN-

TUBE MICROREACTORS

INTEGRATED (MULTI-INJECTION) MICROFLUIDIC

SYSTEMS FOR PARTICLE SYNTHESIS

Multi-step cascaded

solid processing by microfluidics

Winterton et al., J. Nanoparticle Res. 2008,10, 893

Wagner et al., Chem. Eng. J. 2008,135, S104

Shestopalov et al.,Lab Chip 2004, 4 ,316

Wang et al., Chem. Commun. 2004, 48

Paclawski et al., Colloids & Surfaces A. 2012, online

Eder et al. Cryst. Growth Des. 2012, 12, 4733

E. Shahbazali, V. Hessel, Nanotechnology Reviews (2013) submitted.

CONTAINER PLANT FOR F3

FACTORY AT INVITE FACILITY

Process Equipment Container (PEC) Process Equipment Assembly (PEA)

Docking Station PEC – BASF/Polymer

PEC – Bayer/Pharma

Bringing the NPW + Container

to Industrial Production

© 14.04.2013

NPW industrially

achieved

A new continuous, fast

safe process

PDI (flow): 1.04

Residence time [s]

Mo

lecu

lar

weig

ht

Experiment

Simulation

CONTAINER PLANTS

– POTENTIAL FOR COST REDUCTION?

Lower interest rates

Faster time to market

(“50% idea”)

Wo

rkfl

ow

Ba

sed

on

Mo

du

lar

Co

mp

on

en

ts Process Selection

Modular Assembly Planning

Preassembling Modules

Short Field Installation

Start-up

Optimal Configuration Selection

More efficient embedding of

smart production technologies

Standardized infrastructure: fixed,

small-serial manufacturing costs

Risk depends on capacity risk [%] > risk [%]

NPV ECV

cash

time risk [%]

Compactness

Department of Chemical Engineering and Chemistry

Technology-Provider Applications

1) Plantrix® Industrial Flow Reactor (Chemtrix)

Applications

• Biocatalysis reactions

• Heterocycle Synthesis

• Strecker Reactions

• C-C Bond Forming Reactions

• Electroorganic Synthesis

• Amide Bond Forming Reactions

• Esterification Reactions

http://www.chemtrix.com/img/downloads/Plantrix.pdf

2) Asia flow chemistry system (Syrris)

Applications

• MOM deprotection using solid supported tosic acid, Lipase catalyzed esterification

• Knoevenagel condensation using solid supported piperidine,

• Copper catalyzed Azide-Alkyne cycloaddition, Benzylation of alcohols using solid supported DMAP,

• Acylation of alcohols using solid supported DMAP

http://syrris.com/applications/flow-chemistry-reactions

• Heterogeneous

Chemistry

• Radiochemistry

• Reactor Volume Range:

2.9 ml- 5lt.

• Operating Temperature

up to 1500°C

• Operating Pressure up

to 25 bar for T<100°C

Techn. Applications

Department of Chemical Engineering and Chemistry

3) X-Cube™ Flow Reactor ( Thales-Nano)

Applications

• Heterogeneously catalyzed reactions

• Heck and Suzuki Reaction

• Ruthenium-Based Olefin Metathesis Catalysts

• Reductive Amination of Ketones

http://www.thalesnano.com/products/x-cube

4) FlowStart Evo Microreactor (FutureChemistry)

Applications

• Selective α-ketone bromination, Paal-Knorr pyrrole synthesis

• Synthesis of azides from amines, Swern-Moffatt

• Nitration of anisole, Wittig Reaction, Grignard reaction

• Synthesis of silver nanoparticles

http://www.futurechemistry.com/news.html

Technology-Provider Applications (II)

Department of Chemical Engineering and Chemistry

Chemtrix

• DSM and Chemtrix collaborated for continuous flow

chemistry to provide sustainable equipment for

pharmaceutical industry (February 20, 2013).

FutureChemistry

• Joins microfluidic NMR project for medical diagnosis

http://www.wavecraft.se/Pages/CF_MAOStechnology.aspx

Microreactors for schools

Flow Chemistry Course

Technology-Provider Applications (III)

Department of Chemical Engineering and Chemistry

Selective nitration for pharmaceutical production (2009)

DSM and Corning collaborated to develop and pilot a new process to perform a

selective nitration for pharmaceutical production under cGMP conditions

• highly efficient process, which was quickly and easily transferred from the

laboratory to production without scale-up procedure

• 100 kg/h which corresponds to approximately 800 tons per year

Sascha braune, peter pöchlauer, raf reintjens, stefan steinhofer, marc winter, olivier lobet, roland guidat, pierre woehl, celine guermeur, 2009. Selective nitration in a microreactor for pharmaceutical production under cGMP conditions,

Chemistry Today, vol 27 n 1, January-February

Real-life Applications

5-SUBSTITUTED 1H-TETRAZOLES FROM

NITRILES AND HYDRAZOIC ACID

B. Gutmann, J.-P. Roduit, D. Roberge, C. Oliver Kappe, Angew. Chem. 122 (2010) 7255 –7259

• Microwave optimisation strategy – sealed vessels

• In-situ generation of toxic and explosive HN3

• Use of extreme temperatures

• Change from hours‘ to minutes‘ reaction time

• Catalyst-free method; benign solvents; inexpensive NaN3

• Atom economy; environmental friendly

COMBINED AZIDE FORMATION AND STAUDINGER

HYDRATION PERFORMED AT SIGMA ALDRICH

• Production capacity in two subsequent glass microreactors

exceeds 1 kg per day with a yield of 60%

• Work-up and isolation of the potentially hazardous intermediate

SAFE KILOGRAM-SCALE O2 OXIDATION

PERFORMED AT ELI LILLY & Co

X. Ye, M. D. Johnson, T. Diao, et al. Green Chem. 12 (2010) 1180–1186

FLOW vs. BATCH – LIPASE-NOVOZYM 435

ENZYMATIC MICROREACTOR

P. Tambarussi Baraldi, V. Hessel, Green Process. Synth. 1, 2 (2012) 149-168.

Efaproxiral

Depression treatment

Rimonabant

Anti-obesity drug Hypertension treatment

Metropolol

Indacaterol

Beta-adrenoceptor agonist

Ciproflaxocin

Gyrase inhibitor

VeGA FUEL CELL-MICROREFORMER

SYSTEM FOR LEISURE VEHICLES

GTL MICROCHANNEL

DEMONSTRATION PLANTS

Department of Chemical Engineering and Chemistry

Compact GTL plant (2012)

Based on microchannel process technology

Developed jointly by CompactGTL and Petrobras and

successfully tested in January 2012.

Capacity of 200,000 scf/day

http://compactgtl.com/about/petrobras-commercial-demonstration-plant/

Brazil Pilot Plant

FLOATING PRODUCTION, STORAGE

AND OFFLOADING (FPSO) UNIT

FPSO Firenze moored at Hellenic Shipyards, 2007

FPSO Firenze moored at Hellenic Shipyards, 2007

5.25 trillion cubic feet

(tcf) of associated gas -

equivalent of 27% of US

gas consumption - was

flared in 2004

http://en.wikipedia.org/wiki/Floating_

production_storage_and_offloading

Petrobras: Brazilian national oil company and the largest company in Latin America

Toyo Engineering: global engineering, procurement and construction company

MODEC: the world’s second largest owner/supplier of FPSOs to the oil industry

Kobe Steel, Ltd.: one of Japan’s leading steel makers will manufacture the microreactors

Circular FPSO Sevan

Voyageur moored at Nymo

yard at Evdehaven, Norway