pi technology update on microreactors · a. carlos-varaz, v. hessel, t. noel, q. wang chemsuschem...
TRANSCRIPT
Volker Hessel, [email protected]
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