Synthos 3000
Microwave Assisted
Organic Synthesis
Meanings & Model Applications
www.anton-paar.com
Contents
 What´s Microwave Assisted Organic Synthesis ?
 Why ? - Benefits of MAOS
 Instrumentation - Monomode vs. Multimode
 Getting Started
 Typical Applications
 Performance Verification - Model Applications
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MAOS
Microwave Assisted Organic Synthesis
Definition
“Preparation of a desired organic compound
from available starting materials via some
(multi-step) procedure, involving microwave
irradiation”
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Benefits of MW-Assisted Synthesis
 higher temperatures (superheating / sealed vessels)
 faster reactions, less byproducts, pure compounds
 absolute control over reaction parameters
 selective heating / activation of catalysts
 energy efficient, rapid energy transfer
 easy access to high pressure performance
 can do things that can´t be done conventionally
20
MeOH, 160 °C
200
15
150
10
100
5
50
0
0
60
120
180
240
Time (sec)
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300
0
360
Pressure (bar)
Temperature (°C)
Power (W)
250
Applicable Microwave Instrumentation
Single Mode
Instruments
Domestic MW Oven
MLS Ethos 1600
Emrys Liberator
Initiator
Mars-S
Multimode Batch Reactors
Discover
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Multimode vs. Monomode Cavities
Basic Technical Differences:
Multimode Cavity
Monomode (Single Mode) Cavity
antenna
sample
magnetron
Mode
stirrer
sample
Chaos
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Wave guide
magnetron
antenna
Standing Wave
A. Stadler, 2005
Multimode vs. Monomode Cavities
Practical Differences:
Multimode Cavity
Monomode (Single Mode) Cavity
 huge cavity
 large scale runs (5-1000 mL)
 simply applicable for scale-up
 high throughput by parallel synthesis
 field can be inhomogeneous
 lower power density
 high output power
 small scale experiments troublesome
 compact cavity
 small scale runs (0.5-50 mL)
 scale-up by flow-through technique
 throughput by automation
 highly homogeneous field
 high power density
 lower output power
 large scale runs time-consuming
Choice depends mainly on desired application (combichem, medchem,
process chemistry) and the scale, not on the chemistry !
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Getting Started
Initial Questions
 are solvent / reagents suitable for microwave irradiation
 what about thermal stability / decomposition
 expecting elaboration of pressure
 flash heating required
 fit limits of chemistry with equipment
 consider beneficial influence of selective heating
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Getting Started
General Hints:
 use polar solvents with thermal stability (ROH, MeCN, NMP...)
 apply small volumes unless reaction is optimized
 starting point 10 min @ 120 °C
 max. 30 min hold time
 increase temperature rather than time
 passive heating elements for improved energy transfer
 consider solvents changing their properties at higher temperatures
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Converting Conventional Protocols
Arrhenius Equation :
k = A*e
10
 Rule of thumb:
10° temperature increase
= 2-fold rate acceleration
–Ea/RT
80 °C
90 °C
100 °C
110 °C
120 °C
130 °C
140 °C
150 °C
160 °C
8h
4h
2h
1h
30 min
15 min
8 min
4 min
2 min
A. Stadler, 2005
Converting Conventional Protocols
Temp
20 °C
30 °C
40 °C
50 °C
60 °C
70 °C
80 °C
90 °C
100 °C
110 °C
120 °C
130 °C
140 °C
150 °C
160 °C
170 °C
180 °C
190 °C
200 °C
210 °C
220 °C
230 °C
240 °C
250 °C
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Time - change in color represents change in unit
1
2
4
6
8
12
24
48
30
1
2
3
4
6
12
24
15
30
1
1.5
2
3
6
12
8
15
30
45
1
1.5
3
6
4
8
15
23
30
45
1.5
3
2
4
8
11
15
23
45
1.5
56
2
4
6
8
11
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45
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56
2
3
4
6
11
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14
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56
1
2
3
6
11
7
14
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42
56
1
3
6
4
7
14
21
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42
1
3
2
4
7
11
14
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42
1
53
2
4
5
7
11
21
42
26
53
2
3
4
5
11
21
13
26
53
1
2
3
5
11
7
13
26
40
53
1
3
5
3
7
13
20
26
40
1
3
2
3
7
10
13
20
40
1
1
2
3
5
7
10
20
40
1
2
2
3
5
10
20
1
1
2
2
5
10
1
1
2
5
1
2
1
(h/ min / sec)
96
172
48
86
24
43
12
22
6
11
3
5
1.5
3
45
1
23
40
11
20
6
10
3
5
1
3
42
1
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9
3
5
1
2
40
1
20
35
10
18
5
9
2
4
e.g. a thermal reaction for
8h at 80°C works at
2 min at 160°C in the MW
©AstraZeneca,
A. Stadler, 2005
Macclesfield, UK
MAOS Applications
Principle Enhancement of...
• every thermal accelerated process
• time consuming experiments
• sealed vessel reactions
• conversion rates / product purity
Major Benefits
• super heating effect (solvents above their bp)
• powerful temperature/pressure conditions
• electronic parameter-control / unattended runs
• software-supported experiment documentation
MW make experimental work
more convenient
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Typical MAOS Applications
Solid Phase Synthesis
• significant rate enhancement (10 min vs. 48 h)
• less material strain of solid support
• reduction of reagent excess
Eur. J. Org. Chem. 2001, 919
Metal Catalysis
• decreased reaction time (10-30 min vs. > 24 h)
• reduced catalyst amount (environmentally friendly)
• simplified reaction mixtures
• improved purity of products
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Org. Lett. 2002, 3541
Typical MAOS Applications
J. Comb. Chem. 2001, 624
Focused Library Generation
• shortened optimization sequence (hours vs. days)
• automated reaction process, high throughput
• evident reduced over-all production time (days vs. weeks)
High Pressure Chemistry
• simplified use of pre-pressurized vessels
• reduced reaction times
• easy application of gaseous reagents
• excess of reagents minimized
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Org. Process Res. Dev. 2003, 707
Org. Biomol. Chem. 2004, 154
A. Stadler, 2005
Remarkable MAOS Applications
Metal Catalyzed Carbonylations
J. Comb. Chem. 2003, 350
Org. Lett. 2003, 4875
• ultra-fast chemistry (6-10 sec)
• utilizing solid CO-sources (not practicable conventionally)
• less catalyst needed
Reactions in Near Critical Water
Eur. J. Org. Chem. 2005, 3672
• chemistry at extreme conditions (>280°C, >60 bar)
• easy approach without toilsome accessories
• exact parameter control
• comprehensive safety features
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The Idea of MAOS
Changing Meanings of Microwave Instruments:
So far...
covering a niche in Organic Chemistry
to investigate new pathways
supporting the routine labwork
...and now:
 use MW instead of classic methods
 remove all other heating sources
 replace autoclaves
 powerful tool for all chemistries
in any scale
 develop / investigate / optimize
 produce the compounds
representing a valuable laboratory
equipment for various applications
from R&D to Production
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Synthos 3000
Scaling Up
Microwave Assisted
Organic Synthesis
www.anton-paar.com
Typical Operation Range
Method Development
 0.2 - 5.0 mL volume
 0.1 - 10 mmol scale
 5 - 30 min reaction time
 100 - 200 °C
 20 - 250 mg product
First Grade Synthesis
 > 5.0 mL volume
 > 10 mmol scale
 minimum reaction time
 optimized temperature
 100 - 1000 mg
 high throughput approach
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Reaction Optimization
 0.2 - 5.0 mL volume
 0.1 - 5 mmol scale
 1 - 30 min reaction time
 100 - 200 °C
 10 - 100 mg product
Batch Synthesis
 > 100 mL volume
 > 1 mol scale
 optimum time/temperature
conditions
 > 100 g product
 Need for proper Scale-Up techniques
A. Stadler, 2005
A Versatile and Modular Microwave
Platform System
 High performance rotors &
vessels
 Built-in magnetic stirrer
 Dual remote temperature
sensing
 Sophisticated accessories
IR
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Extended Operation Limits
Synthos
Main Experimental
Average
3000
Multimode
LimitsRange
Limits
120
H2O
MeOH
100
Pressure (bar)
EtOH
80
Acetone
MeCN
60
Ethylacetate
THF
40
Cyclohexane
DMF
20
DCM
0
0
20
40
60
80 100 120 140 160 180 200 220 240 260 280 300 320
Temperature (°C)
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Performance Verification
 Individual Scalability
• Protocol for 1 mmol should work for xxx mmol without
modifications
• Verified for various examples using Synthos 3000
Emrys
Synthos 3000
Biginelli
4 mmol: 52%
640 mmol: 48%
Heck
2 mmol: 78%
80 mmol: 79%
Kindler
4 mmol: 92 %
40 mmol: 90%
Negishi
1 mmol: 81 %
20 mmol: 77 %
Key publication: A. Stadler, B. Yousefi, D. Dallinger, P. Walla, E. Van der Eycken, N. Kaval, and C. O. Kappe
Organic Process Research & Development 2003, 707-716
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Performance Verification
 Homogeneity
• Parallel rotors should provide identical field distribution
at any position
• Proved by parallel Biginelli synthesis for Synthos 3000
NO2
O
T
120
O
Me
100
Temperature (°C)
NH
N
H
IR 1-8
Vessel 1
12.1 g
1400
Vessel 2
Vessel 3
Vessel 4
Vessel 5
Vessel 6
12.3 g
12.2 g
12.1 g
12.4 g
12.2 g
Vessel 7
12.5 g
Vessel 8
Total
12.3 g
98.1 g
1200
O
1000
Mol. Wt.: 319,31
80
1600
800
60
600
40
400
20
P
200
2520
2400
2280
2160
2040
1920
1800
1680
1560
1440
1320
1200
1080
960
840
720
600
480
360
240
120
0
0
0
Power (W)
140
Time (s)
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A. Stadler, 2005
47.3%
48.1%
47.8%
47.3%
48.5%
47.8%
48.9%
48.1%
48.0 %
Performance Verification
 Reproducibility
Repeating experiments must yield similar results
Verified with Heck Couplings in Rotor 8:
Exp. 1:
8x 20 mmol, homogeneous catalysis
Overall yield: 79%
NC
3-cyano cinnamic acid
Exp. 2:
8x 20 mmol, 4x homogeneous, 4x heterogeneous catalysis
Overall yield: 78%
Exp. 3:
8x 20 mmol, parallel synthesis, various substrates
Yield of model compound: 79%
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COOH
A. Stadler, 2005
Model Reactions
1) Biginelli Multicomponent Reaction
X
X
O
O
O
+
R
R1
H
O
NH2
H2N
O
EtOH/HCl
120 °C, 20 min
R
R1
NH
N
H
O
 effective multicomponent reaction
 optimized conditions tolerable to broad range of building blocks
 library generation in multi-gram scale (up to 80 mmol/vessel)
 16 different targets within one run
Org. Process Res. Dev. 2003, 707-716
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A. Stadler, 2005
Model Reactions
2) Kindler Thioamide Synthesis
Cl
Cl
S
H2N
HN
NMP
O
H
+ S8 +
F
140 °C, 10 min
F
 efficient synthesis of valuable building blocks
for biologically relevant heterocyclic scaffolds (40 mmol/vessel)
 significantly reduced reaction times
 unproblematic use of large amounts of elemental sulfur
 suitable reaction for library generation
Org. Process Res. Dev. 2003, 707-716
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Model Reactions
3) Heck Couplings
COOH
[Pd], TEA, MeCN
+
NC
Br
180 °C, 15 min
R
NC
COOH
R
a) R = H
b) R = F
 most important C-C bond forming reaction
 no interference of metal layer with microwaves
 parallel synthesis (20 mmol/vessel) with broad range of substrates
and varying catalysts
 unproblematic use of significant amounts of Pd catalyst (1 mol%)
Org. Process Res. Dev. 2003, 707-716
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A. Stadler, 2005
Model Reactions
4) Negishi Coupling
CN
CN
Br
PdCl2(PPh3)2, THF
+
H
ZnBr
H
160 °C, 1 min
O
O
 short reaction times even at larger scale (20 mmol/vessel)
 protection of sensitive reagents by inert gas flush
 use of dummy loads did not affect the reaction progress
Org. Process Res. Dev. 2003, 707-716
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A. Stadler, 2005
Model Reactions
5) Suzuki Cross-Coupling
Cl
Cl
F3C
Cl
Pd(OAc)2/PPh3
Et3N, DME/H2O
+
N
H
O
OMe
B(OH)2
OMe
F3C
150 °C, 30 min
N
H
O
 powerful general Suzuki protocol (4 mmol/vessel)
 suitable for parallel synthesis with various substrates
 efficient scaffold decoration for valuable building blocks
T. N. Glasnov, W. Stadlbauer, C. O. Kappe
J. Org. Chem. 2005, 3864-3870
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Model Reactions
6) Solid Phase Synthesis
Cl
MeNH2, H2O
150 °C, 5 min
N
H
Me
 efficient batch synthesis utilizing solid supports (5 g per vessel)
 non-adhesive PTFE-liners
 filtration unit for simplified work-up
 drastically enhanced reaction rates
 reduced thermal stress due to short reaction times
Org. Process Res. Dev. 2003, 707-716
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A. Stadler, 2005
Model Reactions
7) Diels-Alder Cycloaddition
Cl
Ph
N
O
N
Cl
C2H4 (7 bar), DCB
190 °C, 30 min
O
Cl
N
NaOH
70 °C, 30 min
Ph N
O
Cl
N
Ph N
OH
Cl
 simplified employing of gaseous reagents
 gas loading in assembled rotor
 individual pre-pressurizing
 parallel performance of pressurized reactions
 considerably reduced reaction times
N. Kaval , W. Dehaen , C. O. Kappe, E. Van der Eycken
Org. Biomol. Chem. 2004, 2, 154-156
Org. Process Res. Dev. 2003, 707-716
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Model Reactions
8) Near Critical Water Chemistry
O
O
R
H2O
OH
295 °C, 77 bar, 30-240min
7 mmol
R = OEt, NH2
 Ester/Amide Hydrolysis
 NCWC at temperatures >250°C and pressures >40 bar
 easily accessible with Rotor 8 SXQ80
 conditions can be maintained up to 4 hours
 enabling development of new reaction pathways
 Green Chemistry approach
J. M. Kremsner, C. O. Kappe
Eur. J. Org. Chem., 2005, 3672-3679
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Model Reactions
8) Near Critical Water Chemistry
NC
NC
Me
H2O
Me
295 °C, 77 bar, 20 min
Me
+
Me
 Diels-Alder Cycloaddition (7.6 mmol/vessel)
H
N
Me
O
NH2
+
Me
H2O
Me
Me
270 °C, 49 bar, 20 min
N
H
 Fischer Indole Synthesis (10 mmol/vessel)
Me
Me
OH
Me
OH Me
H2O
270 °C, 49 bar, 30 min
O
Me
Me
Me
Me
 Pinacol Rearrangement (3 mmol/vessel)
J. M. Kremsner, C. O. Kappe
Eur. J. Org. Chem., 2005, 3672-3679
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Summary
 Direct scalability up to 1 L reaction volume
 Parallel synthesis up to 48 derivatives in gram-scale
 Comprehensive performance verification
(scalability, homogeneity, reproducibility)
 Simultaneous pressure sensing
 Dual remote temperature measurement
(IR control & precise immersing temperature probe)
 Simplified access to special applications
(SPOS, gaseous reagents, sub-critical solvents, pre-pressurizing)
 Sophisticated accessories serving extraordinary reaction conditions
(quartz vessels, heating elements, gas-loading station, filtration unit, UV lamps)
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MAOS – Latest News
Comprehensive Review & MAOS Guide:
Kappe, C. Oliver / Stadler, Alexander
Microwaves in Organic and Medicinal Chemistry
Methods and Principles in Medicinal Chemistry (Volume 25)
• Microwave Theory
• Equipment Review
• Microwave Processing Techniques
• Getting started with Microwaves
• Comprehensive Literature Survey
1. Edition - June 2005
420 Pages, >400 References, Hardcover
ISBN 3-527-31210-2 - Wiley-VCH, Weinheim
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