Advantages of Continuous Flow Technology for Ionic

Advantages of Continuous Flow Technology for Ionic

Advantages of Continuous Flow Technology for
Ionic Liquid Chemistry
C. Oliver Kappe
Christian Doppler Laboratory for Microwave Chemistry (CDLMC)
and Institute of Chemistry, University of Graz
Heinrichstrasse 28, A-8010 Graz, Austria
[email protected]
www.maos.net
Microreactors/Flow Chemistry in Organic
Synthesis – Recent Books
Reviews on Microreactor/Flow Chemistry by:
Ley, Seeberger, Hessel, Jensen, Kirschning, Watts, Yoshida, Wirth, Roberge, Ryu, ....
1
Characteristics of Microreactor Chemistry
High Mixing Efficiency = Short Diffusion Paths
(Micromixing)
Diffusion time Reactor Size
0.5 ms
1 μm
0.05 s
10 μm
5s
100 μm
500 s
1 mm
MeO
OMe
+ CO2Me
N
Bu
batch or flow MeO
conditions
Bu
N
CO2 Me
OMe MeO
+
Bu
N
CO2 Me
OMe
CO2Me
-78 °C
OMe
OMe
batch:
T-mixer (500 μm):
MM1:
MM2 (25 μm):
37%
36%
50%
92%
OMe Bu
32%
31%
14%
4%
High
g Surface-To-Volume Ratio: Controlling
g Exothermic Reactions
O
Me
Me
O
H
Me
O
F2 /N2, HCOOH
5-10 °C
microreactor
Me
Me
O
F
Me
100% conv (91% yield)
Yoshida, J.-i. Flash Chemistry. Fast Organic Synthesis in
Microreactors, Wiley-VCH, 2008
Advantages of Microreactor/Continuous Flow
Chemistry
• Very efficient mixing of the reactants (micromixing)
• Rapid heat transfer and temperature control of the reaction system
• Control of residence/reaction times
• Automated reaction optimization – on the fly changes
• Multi step reactions in a continuous sequence
Microreactor Chip for
Flow Processing
• Immobilized catalysts/reagents
• Hazardous reagents/conditions
• Easy scale-up of a proven reaction by:
• increase of time
• reactor volume change
• parallel processing (numbering up)
• Automated purification possible by:
• solid phase scavenging
• chromatographic separation
• liquid/liquid extraction
• Integrated analytics and screening (lab-on-a-chip)
2
Industrial-Scale Use of Microreactors to
Produce Pharmaceuticals
Numbering Up Microreactors (DSM)
Naproxcinod (NicOx)
COX Inhibiting Nitric Oxide
COX-Inhibiting
Oxide-Donator
Donator (CINOD)
for Relief of Pain and Inflammation - Osteoarthritis
DSM - NicOx Collaboration
• nitration, neutralization and work-up in one flow step
• cleaner and higher yields as in batch process
• significantly lower waste generation
• >100 tons/year production scale
• “on hold” for FDA approval
96 reactors on 2 towers
Thayer, A. Chem. Eng. News 2009, 87 (March 16 issue), 17
Braune, S. et al. (DSM) Chem. Today 2009, 27(1), 26
Continuous Processing Top Priority For Green
Chemistry Research in Pharma
Jimenez-Gonzales, C. et al. Org. Process Res. Develop. 2011, 15, 900
3
Green and Sustainable Chemical Synthesis
Using Flow Chemistry
-
Improved product selectivity:
-
-
better control by fast heat and mass transfer
better kinetic control
Avoiding energy over-consuming
-
-
no cryogen cooling needed for lowtemperature reactions
Protecting-group-free synthesis
-
improved atom and step economy
Green and Sustainable Chemical Synthesis
Yoshida, J.-i.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4, 331
see also: Wiles, C.; Watts, P. Green Chem. 2012, 14, 38
Flow Ozonolysis (O-CubeTM Technology)
Schematic Diagram
www.thalesnano.com
Safety Features
¾ Ozone detector
¾ Temperature limit shutdown
¾ Pressure limit shutdown
temperature
flow rates
ozone conc.
-25 °C to rt
0.2- 2 mL/min
15 wt%
Irfan, M.; Glasnov, T. N.; Kappe, C. O.
Org. Lett. 2011, 13, 984
4
Synthesis of Ionic Liquids in Microreactors (1)
N
O
O S O
O
N +
Microreactor Set-Up
neat
+
N
N
_
EtSO4
microreactor
(< 100 °C)
50 °C
70 °C
7 mL/min
1.75 mm i.d.
6.7 mL volume
4.37 mm i.d.
13.8 mL volume
1 x 0.65 mm
x 125 mm channels
11 mL volume
600 x 600 μm
channels
Conversion: 98%
Productivity: 500 g/h
STY: 4 kg/m3s
Renken, A. et al. (EPFL, IMM, Solvent Innovation)
Chem. Eng. Process. 2007, 46, 840
Synthesis of Ionic Liquids in Microreactors (2)
N
N +
neat
Br
N
microreactor
(65-85 °C)
1.2 equiv
Microreactor Set-Up
+
N
_
Br
85 °C
8 mL/min
2.0 mm i.d.
3.0 mm i.d.
4.0 mm i.d.
6.0 mm i.d.
306 mL overall volume
450 μm
channels
Conversion: 97% (99% purity)
Residence time: 48 min
STY: 1.27 kg/Lh
Waterkamp, D. A. et al. (Uni Bremen, IoLiTec)
Green Chem. 2007, 9, 1084
5
Synthesis of Ionic Liquids in Microreactors (3)
N
N +
neat
Br
N
microreactor
(100-140 °C)
+
N
_
Br
Microreactor Set-Up
Set Up
1.7-3.3 mL/min
100-140 °C
45 μm
channels
NMR pure directly after
microreactor
Residence time: 5-10 min
Wilms, D. et. al. (Uni Mainz) Org. Proces Res.Develop. 2009, 13, 961
Flow Chemistry in High-Temperature/Pressure
Process Windows
• Very efficient mixing of the reactants (micromixing)
• Rapid heat transfer and temperature control of the reaction system
• High temperature/high pressure capability (back pressure regulation)
• Control of residence/reaction times
• Automated reaction optimization – on the fly changes
• Multi step reactions in a continuous sequence
• Immobilized catalysts/reagents
• Hazardous reagents/conditions
• Easy scale-up of a proven reaction by:
• increase of time
• reactor volume change
• parallel processing (numbering up)
• Automated purification possible by:
• solid phase scavenging
• chromatographic separation
• liquid/liquid extraction
• Integrated analytics and screening (lab-on-a-chip)
Tube/Capillary Reactor
for Flow Processing
(“Mesofluidic”)
6
Batch Microwave-Assisted Organic Synthesis
Characteristics of MW Heating
MeOH at 190 °C at 32 bar
p
35
30
200
25
T
150
20
15
100
10
50
P
5
0
Pressure [b
bar]
• direct energy transfer
• rapid dielectric heating (tan δ)
• volumetric heating
• superheating of solvents
(300 °C, 30 bar)
• fast cooling
Power [W]
Temperature [°C]
250
0
0
60
120
180
240
300
360
Time [s]
BUT: NOT SCALABLE IN
BATCH MODE!
Advantages
•
•
•
•
shortening reaction times
improving yields
cleaner reaction profiles
expanded reaction envelop
change product distributions
new reaction pathways
• …………..
• penetration depth (2.45 GHz)
• limitations in reactor design
• safety, cost, complexity
• magnetron power
• energy balance
Tutorial Review: Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127
Microwave Chemistry – From Laboratory
Curiosity to Standard Practice in 25 Years
Applications in Organic Synthesis
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Transition Metal Catalyzed C-X Bond
Formation
Other Metal-Mediated
Metal Mediated Processes
Metathesis, CH-Bond Activation
Cycloaddition Reactions
Rearrangements
Enantioselective Reactions
Organocatalysis, Biocatalysis
Radical Reactions
Oxidations, Reductions
Heterocycle Synthesis
Total Synthesis
Ionic Liquid Synthesis/Solvents
Solid- /Fluorous Phase Synthesis
Immobilized Reagents, Scavengers and
Catalysts
Solid Phase Peptide Synthesis
Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250
Kappe, C. O.; Stadler, A. “Microwaves in Organic and Medicinal Chemistry” Wiley-VCH, 2005 (2nd. Ed. 2012)
Kappe, C. O.; Dallinger, D. Mol. Diversity 2009, 13,71
7
Preparation of Ionic Liquids under
Microwave Conditions
Early Work
Westman, J. PCT Int. Appl. WO 0072956 (2000)
Namboodiri, V. V.; Varma, R. S. Chem. Commun. 2001, 643; Pure Appl. Chem. 2001, 73, 1309
Tetrahedron Lett. 2002, 43, 5381; Chem. Commun. 2002, 342
Khadilkar, B. M.; Rebeiro, G. L. Org. Proc. Res. Dev. 2002, 6, 826
Fraga-Dubreuil, J. et al. Org. Proc. Res. Dev. 2002, 6, 374
Recent Studies
R-X
N
Y
Z
R +
N
Y
MW, 80-210 °C, 6-20 min
0.05 - 2 mol scale
(open or closed vessel)
X
-
Z
R = alkyl
X = Cl, Br, or I
Z = NMe, S, CH
Y = CH, CMe, NMe
Deetlefs, M.; Seddon, K. R. Green Chem. 2003, 5, 181
SWOT Analysis: Deetlefs M.; Seddon, K. R. Green Chem. 2010, 12, 17
Review
Martinez-Palou, R. Mol. Diversity 2010, 14, 3
bmimBr Heating Behavior under Microwave Conditions
IR Versus FO Sensors
Heating Ionic Liquids
(100 °C Set Temp, IR + FO Probe)
Discover (CEM)
Internal Fiber-Optic Sensors
30 W max
250
250
OpS FO
N
+120
200
200
140
140
+
N
Br
_
100
100
150
150
80
80
CEM
CEM
IRIR
100
100
60
60
40
40
50
50
• Probe in immersion
well
• Fast response time
• Less dependent on
stirring efficiency
D. Obermayer
120
120
20
20
Power
Power
0
0
Power[W]
[W]
Power
• Measure surface
temperature of vessel
• Delay in response
• Extremely dependent
on stirring efficiency
Temperature[°C]
[°C]
Temperature
Initiator (Biotage)
External Infrared Sensors
00
50
50
100
100
150
150
200
200
0
0
250
250
Tim
Timee[s]
[s]
OpS FO
CEM IR
OpSens© Fiber Optic Probe
CEM Discover Standard Infrared Sensor
Org. Biomol. Chem. 2010, 8, 114
8
Simultaneous FO/IR Temperature Measurement
Monowave 300
FO/IR Dual Temperature Control
100 °C Set Temperature
Br
IR Control / FO Slave
(Set ramp time 2 min)
250
250
250
140
200
200
120
120
200
120
100
100
150
150
80
80
100
100
60
60
Power [W]
IR
IR
Power
Power
40
40
Temperature [°C
C]
Temperature [°C
C]
160
FO
FO
100
150
80
IR
100
60
Power
40
50
50
Power [W]
+35
_
FO Control / IR Slave
(Set ramp time 2 min)
160
160
140
140
+
N
N
50
20
20
20
00
0
00
00
100
100
200
200
300
300
0
0
400
400
100
200
300
400
Tim e [s]
Tim
Timee [s]
[s]
Org. Biomol. Chem. 2010, 8, 114
D. Obermayer
Microwave Synthesis of bmimBr –
Problems of Exothermicity and Absorptivity
FO Temperature Control, 100 °C Set Temp
(Monowave 300)
200
+50
140
180
FO
Temperature [°C]
140
IR
100
120
80
100
60
80
Image für prep run
40
N
160
120
N +
Power [W]
160
neat
Br
MW, 100°C, 10 min
1.02 eq
N
60
+
N
_
40
20
Br
20
Power
0
0
0
200
400
600
800
Tim e [s]
Microwave Absorptivity
bmimPF6
Temperature
25 °C
100 °C
200 °C
Tan δ
0.184
1.804
3.592
Solvent
EtOH
NMP
water
MeCN
THF
hexane
Tan δ (25 °C)
0.941
0.275
0.123
0.062
0.047
0.020
Robinson, J. et al. Phys. Chem. Chem. Phys. 2010, 12, 4750
9
Microwave Synthesis
of bmimBr in a Silicon Carbide Vessel
FO Temperature Control, 100 °C Set T
(Monowave 300)
N
N +
Br
neat
N
+
N
MW
_
Br
180
160
700
140
600
T (Pyrex)
120
500
100
400
T (SiC)
80
300
60
200
P (SiC)
P (Pyrex)
40
20
Power [W]
Temperature [°C]
800
100
0
0
0
60
120
180
240
300
360
420
480
540
600
660
Tim e [s]
Comparison of Thermal Effusivity for SiC, Pyrex and Steel
SiCa
Pyrex
18/8 Steel
125
1,2
30
Cp [J kg-1 K-1 10-3]
0,6
0,7
0,5
ρ [kg m-3 10-3]
3,10
2,23
8,02
1400
11000
Thermal conductivity
λ [W m-1 K-1]
Specific heat capacity
Density
Thermal effusivityb
e [J s-1/2 m-2 K-1]
15000
a SiC:Ekasic® F SSiC, ESK Ceramics. b Thermal effusivity e: [e = (kρc )0.5].
p
The Use of Ionic Liquids as Doping Agents in
Microwave Chemistry
Pyrazinone Diels-Alder Chemistry
Cl
Ph
N
O
N
O
conventional conditions:
PhCl, 135 °C, 1-2 days
solvent
O
Δ or MW
Ph
N
R = Cl
R = OH
O
N
R
Microwave conditions:
DCE, 160 °C, ca 1 h
DCE/IL 190 °C, 8 min
Temperature [°C]
Ionic-Liquid (IL) Doped Solvents
200
180
160
140
120
100
80
60
40
20
0
mmol IL in
2 mL DCE
0.300
Me
+
N
_
bmimPF6 =
N
PF6
0.150
0.070
Bu
0.035
heating profiles for bmimPF6-doped DCE (bp 80 °C)
0
E. Van der Eycken
100
200
300
Time [s]
400
500
0.000
600
J. Org. Chem. 2002, 67, 7904
10
Batch Microwave Versus
High-Temperature/Pressure Flow Chemistry
• Flash Heating (seconds?)
• High Pressures (< 30 bar)
• High Pressures (~200 bar)
• High Temperatures (< 300°C)
• High Temperatures (~350°C)
x Not Scaleable
• Directly Scaleable
x Explosions Possible
• Inherently Safe
HPLC
Pump A
M
• Flash Heating (~1 min)
P
Microreactor (Chip/Coil)
HPLC
Pump B
Microwave Reactor
((= Autoclave Reactor))
Can Microwave (Batch) Chemistry be Translated to Flow Conditions?
Short Reaction Times = Short Residence Times
Commercially Available “Mesofluidic“ Reactors for
(High Temperature/Pressure) Organic Synthesis
Labtrix
X-Cube Flash
www.thalesnano.com
www syrris com
www.syrris.com
www.chemtrix.com
Asia (Africa, FRX)
FlowStart Evo
www.futurechemistry.com
FlowSyn
www.uniqsis.com
R-Series
S
Flow
System
Propel
www.accendocorporation.com
MR Explorer Kit
www.vapourtec.co.uk
NanoTek
www.advion.com
Lonza FlowPlate
www.sigma-aldrich.com
http://www.ehrfeld.com
11
High-Temperature/Pressure Flow Reactor
(X-Cube Flash)
Stainless steel coil
(SX316L, 1000 μm i.d.)
www.thalesnano.com
Temperature
Pressure
Flow rates
Changeable size of reaction zone
4mL
Res. time [min]: 0.4 to 8
25-350 °C
50-180 bar
0.5-10 mL/min
4,8,16 mL
8mL
16mL
0.8 to 16
1.6 to 32
Razzaq, T.; Glasnov, T, N.; Kappe, C. O. Eur. J. Org. Chem. 2009, 1321; Chem. Eng. Technol. 2009, 32, 1702
Case Study of “Microwave-to-Flow”:
2-Methylbenzimidazole Formation
Kinetic Study (Batch/Microwave)
NH 2
O
+
NH 2
Temperature (°C)
25
60
100
130 (2 bar)
160 (4 bar)
200 (9 bar)
270 (29 bar)
OH
(excess)
neat (1 M)
N
rt-270 °C
N
H
t >99% conv (HPLC)
9 weeks
5 days
5h
30 min
10 min
3 min
“1 s“
k = A e-Ea/RT
Ea = 73.4 kJ mol-1
A = 3.1 x 108
12
Batch Microwave Scale-Up:
2-Methylbenzimidazole (250 °C, 4 s, 5 M)
MW instrument
Reaction volume
(mL)
Yield in g
(%)
Monowave 300
2.5
1.12 (85)
Masterwave BTR
630
300 (91)
Ramp/hold/cooling Overall processing
time (min)
time (min)
0.67/0.06/3.5
4.2
7/0 06/26
7/0.06/26
33
Heating Profiles
Temperatu
ure [°C]
300
250
T (Masterwave)
200
T (10 mL)
150
100
50
0
0
2
4
6
8
10
12
14 16 18
Time [min]
20
22
24
26
28
30
Converting Batch Microwave to Continuous
Processing (Process Intensification)
Benzimidazole Synthesis
NH 2
AcOH (1 M)
N
min-1
flow rate
270 °C, 70 bar, 8.0 mL
(4 mL coil, 30 s residence time)
NH 2
N
H
~50 g/hour
Pyrazole Synthesis
O
O
+
HN
Ph
NH2
1.1 equiv
EtOH (3 M), HCl (cat)
N
N
Ph
180 °C, 130 bar, 8.0 mL min-1 flow rate
(4 mL coil, 30 s residence time)
~225 g/hour
g
Diels-Alder Cycloaddition
+
2 equiv.
CN
toluene (2.2 M)
280 °C, 130 bar, 8.0 mL min-1 flowrate
(16 mL coil, 2 min residence time)
CN
~80.4 g/h
Damm, M.; Glasnov, T, N.; Kappe, C. O. Org. Process Res. Develop. 2010, 14, 215
13
High-Temperature/Pressure Flow Chemistry
Methylations with Dimethyl Carbonate
Dimethyl Carbonate (DMC) as Methylating Reagent
J. D. Holbrey,
y T. Yan
•
•
•
•
•
DMC considered as green methylation reagent
Replacement for toxic and hazardous dimethyl sulfate and methyl halides
Only CO2 and MeOH as byproducts
Environmentally benign, non-toxic, biodegradable, safe
No phosgene in the synthesis involved:
G. D. Short, M. S. Spencer 1985 EP0314668
Reviews: a) Y. Ono, Catal. Today 1997, 35, 15; b) S. Memoli, M. Selva, P. Tundo, Chemosphere 2001, 43, 115;
c) P. Tundo, M. Selva, Acc. Chem. Res. 2002, 35, 706; d) S. V. Chankeshwara, Synlett 2008, 624; e) F. Arico, P.
Tundo, Russ. Chem. Rev. 2010, 79, 479
Methylations with Dimethyl Carbonate (DMC)
DMC as Ambivalent Electrophile : Methoxycarbonylation vs Methylation
• Reactions promoted by base
• High T required for methylation
Reviews: a) Y. Ono, Catal. Today 1997, 35, 15; b) S. Memoli, M. Selva, P. Tundo, Chemosphere 2001, 43, 115;
c) P. Tundo, M. Selva, Acc. Chem. Res. 2002, 35, 706; d) S. V. Chankeshwara, Synlett 2008, 624; e) F. Arico, P.
Tundo, Russ. Chem. Rev. 2010, 79, 479
14
Ionic Liquid-Catalyzed N-Methylation of Indole
Under Microwave Batch Conditions
O
DMC:DMF (10:1)
IL catalyst
N
H
+
N
CH 3
MW, conditions
A
B
O
O-
O
N
N+
OCH3
I L Catal yst
IL reference (Bu3N + DMC): Holbrey, J. D. et al. Green Chem. 2010, 12, 407
Entry
Temp. [°C]
t [min]
1
3
5
7
8
9
10
11
13
90
130
170
210
230
230
230
230
230 (17 bar)
10
10
10
10
10
20
20
20
20
Catalyst
[mol%]
10
10
10
10
10
10
0
5
2
Conv.
[HPLC 215nm, %]
45
64
66
90
99
100
85
100
100
Selectivity [%]
A
B
0
45
0
64
15
51
79
11
98
1
100
0
6
79
100
0
100
0
Continuous Flow N-Methylation of Indole
Using Nearcritical/Supercritical DMC
DMC:DMF (10:1) (~1M)
Bu 3N (2 mol%)
N
H
285 °C, 150 bar, 1.3 mL/min
(3 min res. time, 4 mL coil)
N
CH 3
DMC critical point: Tc 275 °C, Pc 45 bar (bp. 90 °C)
In-Situ Generation of IL Catalyst
O
O
N
n -Bu3N
+ Me
O
O
DMC
Me
MeOH
MW, 160 °C, 10 h
O
ON+
IL Cat aly st
Holbrey, J. D. et al. Green Chem. 2010, 12, 407
15
Continuous Flow N-, O-, and S-Methylations
Using Nearcritical/Supercritical DMC
CH 3
N
H
98%
N
H
OH
OH
88%
87%
OH
90%
O2N
SH
H 3C
CH 3 93%
94%
F
N
SH
Conditions
•
•
•
•
52%
CH3
CO2 H
CH 3
93%
~0.9 M in DMC:DMF (10:1)
2 mol%
l% B
Bu3N
285 °C, 150 bar
~3 min res. time
CO 2H
86%
S
CO 2H
81%
Continuous-Flow High-T/p Methylations
Involving DMC
Methylations of Phenols
U. Tilstam,
Org. Process Res. Dev. 2012, 16, 1150
Methylation /Carboxylation of N-Methylimidazol
D. Breuch, H Löwe,
Green Process Synth. 2012, 1, 261
Methylation of 1-Pentanol in scCO2
D. N. Jumbam et al.,
J. Flow Chem. 2012, 1, 24
16
Ionic Liquids as Soluble Basic Catalysts
to Replace Inorganic Bases
Pd-Catalyzed Direct Arylation of Heterocycles (Fagnou)
Pd(OAc)2 , PCy3
PivOH, K 2CO3 , DMF
HetAr H
+
HetAr Br
1.1 equiv
HetAr
MW, 180 °C, 10-60 min
(CONV: 110 °C, 1.5-74 h)
HetAr
30 examples
(50-88%)
Optimization of Unsuccessful Examples
Br
H +
S
Pd(OAc) 2, ligand
PivOH (30 mol%), K 2CO3 (1.5 equiv)
solvent (0.5 M)
S
MW, 130-180 °C, 10-60 min
NO2
NO2
Entry
1 (lit)
2
3
……
xx
thiophene
(equiv)
1
1
1
Pd(OAc)2
(mol%)
2
2
2
Ligand (mol%)
Solvent
T (°C)
Conv (%)
DMA
DMA
DMA
Time
(min)
24 h
60
60
P(Cy)3·HBF4 (4)
P(Cy)3·HBF4 (4)
P(Cy)3·HBF4 (4)
110
130
180
<5
15
50
1.1
1
P(Cy)3 (2)
DMF
10
180
83 (75% yield)
J. Org. Chem. 2011, 76, 8138
M. Baghbanzadeh (with K. Bica, TU Vienna)
Our Drivers for Flow Chemistry
– Process Chemistry (Process Intensification)
SAFETY
Hazardous Chemistry
• Hydrogenation (H-Cube)
JCC 2005, 641; EJOC 2009, 1326
Review: CSC 2011, 300
• Ozonolysis
OL 2011, 984
• Hydrazoic Acid
SCALE-UP
“General”
General Organic Synthesis
• Transition-Metal Catalysis
ASC 2008, 717; CEJ 2009, 1001; ASC 2010, 3089
OL 2010, 2774; AJC 2011, 1522
• Multistep Target Synthesis
ASC 2010, 3089; OPRD 2011, 858; JOC 2011, 6657
Review: JHC 2011, 11
ACIE 2010, 7101; BJOC 2011, 503
CEJ 2011, 13146; JFC 2012, 8
• Peroxide/Ether
CEJ 2012, 6124
• Hydrazine/nano-Fe3O4
ACIE 2012, in press
High-T/p
High
T/p Process Windows
• Microwave-to-Flow
…………OPRD 2010, 215; EJOC 2009, 1321
Review: CEJ 2011, 11956
• High-T/p Flow Chemistry
………….CET 2009, 1702
Review: CAJ 2010, 1274
• Flow Microwave Processing
Review: MRC 2007, 395, GPS, 2012, 281
17
Mimicking Microwave Chemistry in
Conventionally Heated High T/p Flow Reactors
X-Cube Flash
(350 °C, 180 bar)
FlowSyn
(260 °C, 70 bar)
R-Series Flow
System
(250 °C
C, 200 bar)
Chem. Eur. J. 2011, 17, 11956
11956-11968
Continuous Flow Microwave Reactors
Pioneering Studies by Strauss (CSIRO, Australia)
Cablewski, T.; Faux, A. F.; Strauss, C. R. J. Org. Chem. 1994, 59, 3408
cf. Strauss, C. R.; Faux, A. F. Int. Pat. Appl. PCT/AU89/00437, 1989
Reviews: Glasnov, T. N.; Kappe, C. O. Macromol. Rapid Commun. 2007, 28, 395
Baxendale, I. R.; Hayward, J. J.; Ley, S. V. Comb. Chem. High Throughput Screening 2007, 10, 802
Singh, B. K.; Kaval, N.; Tomar, S.; Van der Eycken, E.; Parmar, V. S. Org. Process Res. Dev. 2008, 12, 468
18
Production Scale Continuous Flow
Microwave Reactor
Hybrid Reactor Equipment - General Setup for Continuous Processing
Clariant Unit:
- frequency:
2.45 GHz
- max power:
max 6 kW
Border Conditions for
Lab Use:
- max temp:
300°C
- max pressure:
70 bar
- max flow
20 l/h
Scale-Up to Production Scale in
Large Scale Microwave Flow Reactor
Process Intensification for Benzimidazole Synthesis
NH2
O
+
NH2
OH
(excess)
neat (5 M)
N
MW, 260 °C (25 bar)
5 L/h (42 s residence time)
N
H
25 mol/h
(3.65 kg/h = 86 kg/day)
• cylindrical ceramic flow tube (75 cm length, 10 mm i.d., 60 mL volume)
• single-mode microwave cavity (6 kW, 2.45 GHz)
• max temperature
t
t
300 °C,
°C max pressure 70 b
bar
• max flow rate 20 L/h
• extremely energy efficient
• advanced safety concept (TüV)
Morschhäuser, R. et al. Green Process. Synth. 2012, 1, 281
19
Scale-Up to Production Scale in
Large Scale Microwave Flow Reactor
Process Intensification for Organic Reactions
O
O
a)
OH +
C8 H17
H2N
neat
NMe 2
C8 H17
249 °C (35 bar)
b )
28 s (5.1 L/h)
(1.05 equiv)
N
H
NMe 2
b)
neat
MeO
OH
O
+
HNMe2
MeO
NMe2
246 °C (20 bar)
51 s (2.8 L/h)
(1.05 equiv)
O
c)
O
O
HO
+
OH
Me
HO
MeSO3 H (cat)
M
Me
HO
249 °C (27 bar)
27 s (5.3 L/h)
Me
O
Me
M
Me
Me
(2 equiv)
d)
OH
+
HO2C
NMP
O
O
225 °C (15 bar)
35 s (4.0 L/h)
N
N
CO2H
NH 2
(2.2 equiv)
Energy Efficiency
Single mode (lab use)
GHz
Overall
efficiency [%]
2.45
100%
from power plug
10-12% MW→heat transfer 40% transformation losses
Multi mode (lab use)
5-8%
2.45 GHz
30-40 % MW→heat transfer
40% transformation losses
20-25%
Hybrid resonator 2.45 GHz
90-95 % MW→heat transfer
40% transformation losses
Hybrid resonator 915 MHz
90-95 % MW→heat transfer
50-55%
70–75%
20% transformation losses
Moseley, J. D.; Kappe, C. O. Green Chemistry 2011, 13, 794
20
The Future of Continuous Manufacturing (1):
Container Plants Concept
The Future of Continuous Manufacturing (2):
“Factory of the Future”
Conventional Versus Process Intensified Plant
Naproxcinod (Nitronaproxen)
Non Steroidal Anti
Non-Steroidal
Anti-Inflammatory
Inflammator Drug
Dr g
(Not yet approved by the FDA)
DSM - NicOx Collaboration
• nitration, neutralization and work-up in one flow step
• cleaner and higher yields as in batch process
• from feasibility to large scale production in 18 month
• >100 tons/year production scale
EU FP7 Project: F3 (flexible, fast and future) Factory Initiative
(visualization by DSM)
21
Acknowledgements
Christian Doppler Laboratory for
Microwave Chemistry
A Public-Private-Partnership Initiative (2006-2013)
Dr. Toma N. Glasnov
Bernhard Gutmann
Tahseen Razzaq
David Obermayer
Benedikt Reichart
David Cantillo
Bartholomäus Pieber
Muhammad Irfan
The Journal of Flow Chemistry
Editor-in-Chief
C. Oliver Kappe
Associate Editors
Paul Watts,, Thomas Wirth,,
Ferenc Darvas, Claude De Bellefon,
Pete Licence
Regional Editors
Jun-ichi Yoshida, Volker Hessel
Aaron Beeler, Lixiong Zhang,
Rodrigo de Souza
Research Highlights Editor
T
Toma
N.
N Gl
Glasnov
Editorial Board
Andreas Kirschning, Peter Seeberger
Takehiko Kitamori, Andrew J. deMello
Brian Warrington
check out the issues online:
www.jflowchemistry.com
22
Microwave & Flow Chemistry Conference
20th – 23rd July 2013
Silverado Resort, Napa Valley, California
Chaired By: C. Oliver Kappe (University of Graz)
Nicholas Leadbeater (University of Connecticut)
Talk Deadline: 19th March 2013
Plenary Speakers Include: Roman Morschhaeuser (Clariant GmbH),
Peter Seeberger (Max‐Planck Institute), Jun‐Ichi Yoshida (Kyoto University), Timothy Jamison (MIT) & Timothy Braden (Eli Lilly and Company)
www.
.com
23