www.anton-paar.com

Microwave Synthesis Microwave Synthesis

@ Anton Paar@ Anton Paar

2

A Success Story

of more than 85 Years

1922 The one-man business Anton Paar is founded

1957 Production of Kratky small-angle X-ray scattering camera

1963 † Anton Paar; Ulrich Santner joins the company

1967Presentation of the first digital density meter based on the

oscillating U-tube principle

1997 Dr. Friedrich Santner becomes CEO

2004 New ownership: The charitable Santner Foundation

2010 Establishment of the 13th subsidiary, AP Switzerland AG

3

Dipolar Rotation Ionic Conduction

� Dipoles align in Electromagnetic Field

� Rotation � Friction

� Heat transfer

� Effectiveness is a function of

Dipole moment

� Ions oscillate in Electromagnetic Field

� Rapid movement � Friction

� Heat Transfer

� Effectiveness is a function of

Concentration

Microwave-Mediated Heating Process

� direct „in-core“ heating (generated from within the sample)

� Interaction with MW determined by Loss Tangent ����tan � � �� � �� � �� � �‘‘ ��������‘����

= Measure for conversion of electromagnetic energy into heat

4

Loss Tangents of Different Solvents

(2.45 GHz, 20 °C)

“High“ (> 0.5)

Solvent tan ����

ethylene glycol 1.350

EtOH 0.941

DMSO 0.825

2-propanol 0.799

formic acid 0.722

MeOH 0.659

nitrobenzene 0.589

1-butanol 0.571

“Medium“ (0.1-0.5)

Solvent tan ����

2-butanol 0.447

dichlorobenzene 0.280

NMP 0.275

acetic acid 0.174

DMF 0.161

dichloroethane 0.127

water 0.123

chlorobenzene 0.101

“Low“ (< 0.1)

Solvent tan ����

chloroform 0.091

MeCN 0.062

EtOAc 0.059

acetone 0.054

THF 0.047

DCM 0.042

toluene 0.040

hexane 0.020

from “Microwave Synthesis“, Hayes, B., CEM Publishing, Matthews, NC, 2002 Chapter 2

Loss tangent, tan ����

� defines ability of materials to convert electromagnetic energy into heat energy

at given frequency and temperature

5

Conventional Heating by Conduction

� Conductive heat

� Heating by convection current

� Slow and energy inefficient process

Temperature on the outside surface is far higher than the real internal temperature

6

”Direct” Heating by Microwave Irradiation

Inverted temperature gradients !

� Solvent/reagent absorbs MW energy

� Vessel wall transparent to MW

� Direct in-core heating

� Instant on-off

7

Boiling over night

0

100

200

300

0 150 300 450 600 750 900

Time [s]

Power [W

]Temperature [°C]

0

10

20

30

Pressure [bar]

Controlled reactions within a few minutes

Benefits of MW-Assisted Synthesis

8

Arrhenius Equation :

k = A*e –Ea/RT

� Rule of thumb:

10 °C temperature increase

= 2-fold rate acceleration

Increasing temperature

Decreasing reaction time

2 min4 min8 min15 min30 min1 h2 h4 h8 h

160 °C150 °C140 °C130 °C120 °C110 °C100 °C90 °C80 °C

Benefits of MW-Assisted Synthesis

9

Benefits of MW-Assisted Synthesis

� Energy efficient direct “in core heating”, rapid energy transfer

� no temperature gradients (possibility of wall effects excluded)

� Enhanced temperatures, rapid superheating of solvents in sealed vessels

� easy access to high pressures (autoclave-like)

� Faster reactions, higher yields (less byproducts), pure compounds

� Rapid reaction screening and optimization of conditions

� ideally suited for automation and parallel synthesis

� Selective heating (activation of catalysts), specific effects

� Excellent control over reaction parameters (instant on/off)

10

1986 first relevant publications

“The Use of Microwave Ovens for Rapid Organic Synthesis”

Gedye, R. N. et al. (Laurentian University, Canada)

Tetrahedron Lett. 1986, 27, 279.

“Application of Commercial Microwave Ovens to Organic Synthesis”

Giguere, R. J. (Mercer Univ) and Majetich, G. (Univ Georgia)

Tetrahedron Lett. 1986, 27, 4945.

up to 1000 fold rate increases for several reactions reported !

Earlier Patent Literature

“Carrying Out Chemical Reactions Using Microwave Energy”

Vanderhoff, J. W. (Dow Chem Co), US 3,432,413 (1969)

see also: US 4,210,593 (1981), DE 3,018,321 (1981)

Microwaves in Organic Synthesis

11

© C.O. Kappe, CDLMC, University Graz

Cumulative: 5500 Publications

0

100

200

300

400

500

600

198619

8719

8819

8919

9019

9119

9219

9319

9419

9519

9619

9719

9819

9920

0020

0120

0220

0320

0420

0520

06

Annual Number of Publications Domestic Microwave Ovens

Dedicated Instruments for

Organic Synthesis

70020

0720

08

Publications on MAOS

12

Dedicated Reactors

Advantages

� Maximum safety (explosion proof)

� Easy access to high pressure performance

(autoclave-like)

� Excellent control over reaction parameters

(temperature, pressure, power)

� Ideally suited for automation /

parallel synthesis

� Stirring (homogeneous temperature

distribution)

� Highly reproducible results

� Continuous power output

0

100

200

300

0 150 300 450 600 750 900

Time [s]

Power [W

]Temperature [°C

]

0

10

20

30

Pressure [bar]

13

Instrumentation

Monowave 300

Multimode Batch ReactorsMonomode Reactor

Masterwave BTR

Synthos 3000

14

Monomode vs. Multimode

Monomode

vs.

Multimode

15

Monomode Cavity

Multimode vs. Monomode Cavities

Standing Wave

Chaos

Multimode Cavity

antenna

magnetron

Mode

stirrer

sample

One or two magnetrons create microwave

irradiation, which is directed into the cavity through

a waveguide and distributed by a mode stirrer.

Microwaves are reflected from the walls thus

interacting with the sample in a chaotic manner.

The microwave energy is created by a single

magnetron and directed through a waveguide

to the sample.

antenna

magnetron sample

Wave guide

16

Practical Differences:

� Huge cavity

� Large scale runs (5-1000 mL)

� Simply applicable for scale-up

� High throughput by parallel synthesis

� Lower field density

� High output power

� Small scale experiments cumbersome

� Compact cavity

� Small scale runs (0.5-30 mL)

� Only limited Scale-up possible

� Throughput by automation

� High field density

� Lower output power

� Large scale runs time-consuming

The choice depends mainly on individual applications (screening,

optimization, special applications), the required reaction conditions

(pressure, temperature) and the reaction scale!

Multimode Cavity Monomode (Single mode) Cavity

Multimode vs. Monomode Cavities

www.anton-paar.com

Dedicated Microwave Dedicated Microwave

ReactorsReactors

18

Dedicated Reactors – Small scale

Monowave 300

19

Monowave 300 - General Features

� IR temperature sensor (up to 300 °C)

� Swiveling cover with pressure sensor (up to 30 bar)

� 850 W magnetron & compact design

� utmost field density

� effective heating of poor microwave absorbers

� Compressed air cooling

� magnetic stirring

� 2x USB port, ethernet connection

Single-mode Microwave Synthesis Reactor

Options:

� Fiber Optic Sensor

� Autosampler MAS 24

20

Monowave 300 - Vial types

� Standard borosilicate glass (G4, G10, G30)

� Durable snap caps

� PTFE-coated silicone septa

� Standard stir bars applicable

� Sustainable items

Standard Reaction Containers

6-20 ml

2-6 ml

0.5-2 ml

21

� 10 mL SiC vessel for special applications

� Rapid heating of non-absorbing solvents

� Resistant to fluorine chemistry

� Unlimited reusability

� Standard stir bars applicable

High-Performance Silicon Carbide Vessel (C10)

Monowave 300 – Vial types

2-6 ml

SiC vessel

Pyrex vial

5 mL toluene

22

Monowave 300 – Temperature Control

Air in

Air out

IR Channel

IR-Sensor

0

50

100

150

200

250

300

0 200 400 600 800 1000 1200

Temperature [°C]

23

Dedicated Reactors – Scale up

Masterwave Bench Top Reactor

24

Masterwave BTR – General Features

� 1700 W microwave output power

� Reaction conditions up to 250 °C, 30 bar

� 1 L PTFE vessel (up to 750 mL operation volume)

� Rising PT100 temperature sensor

� Sliding cover comprising pressure sensor

� Automatically adjustable integrated agitator

� Independent stirring regime

� Embedded cooling system

� 2x USB port & Ethernet connection

� Adequate safety measures

� Optional Remote Control (VNC)

Masterwave BTR

25

Screenshots

Masterwave BTRMonowave 300

26

Dedicated Reactors – Parallel Synthesis

Synthos 3000

27

General Features

� simultaneous IR and internal

temperature monitoring

� Built-in cooling unit

� up to 300 °C AND 80 bar

� high safety standards

� inbuilt display

� external magnetic keyboard

� instant data export

� modular platform

� 1400 W unpulsed microwave output power (2 magnetrons)

28

Versatile and Modular Platform System

Scale-Up and High Performance

Synthos 3000� 48 positions

� 6-25 mL

� 200 °C

20 bar

� 8 positions

� 6-60 mL

� 300 °C

80 bar

� 16 positions

� 6-60 mL

� 240 °C

40 bar

29

Combinatorial Chemistry

� different matrixes

� individual filling volumes (0.02 mL – 3 mL)

� up to 200 °C and up to 20 bar

� standard glassware applicable

5x4

6x4

8x6

30

Microwaves in Pharmaceutical Industry

Parallel

synthesis

Synthos 3000

Batch Synthesis

Masterwave BTR

iterateNo

YesReaction

scouting

Biological

screening

Produce

library

Synthesize

building

blocks

Validate

methods

Plan &

design

library

Scale up

to 20 g

Scale up

to 1 kg

plan

synthesize

purify

analyze

Sequential

Synthesis

Monowave 300

+ MAS 24

www.anton-paar.com

Application ExamplesApplication Examples

32

Model Applications

Reference publication: M. Damm, T. N. Glasnov, C.O. Kappe, Org. Process Res. Dev. 2010, 215-224

1 sec29 bar270 °C

3 min9 bar200 °C

10 min4 bar160 °C

1 h2 bar130 °C

3 daysatm60 °C

9 weeksatm25 °C

Hold TimePressureTemperatureMicrowaves

� Effective way to reach

extreme conditions

� Tremendous decrease of

process time

� Convenient handling

Drugs - Synthesis of Heterocycles

� Microwave reactors used in industrial research facilities and universities

� Time equals money!

� Example Synthesis:

MeCOOH

MW, 270 °C, 1 s

NH2

NH2NH

N

Me

33

H2SO4, EtOH80 °C, over night

OEt

OF3C

EtO2C

NHNH2

NO2

HCl

NO2

NN

EtO2CCF3

NH2

NN

EtO2CCF3

NH

NN

EtO2CCF3

Cl

Cl

Cl

O

H2, Pd/C, EtOAcRT, 2h

BOP, DIEA, DMFRT, over night

Drugs - Synthesis of Heterocycles

� Microwave reactors used in industrial research facilities and universities

� Time equals money!

� Example Synthesis:

Glasnov, T. N.; Groschner, K.; Kappe, C. O. ChemMedChem 2009, 4, 1816-1818

EtOHMW, 160 °C, 2 min

Conv.: 82 %MW: 81 %

cyclohexene, Pd/C, EtOHMW, 160 °C, 2 min

Conv.: 87 %MW: 92 %

PCl3, MeCNMW, 150 °C, 5 min

HO Cl

Cl

Cl

O

Conv.: 35 %MW: 76 %

Overall:Conv.: 25 % in 2 daysMW: 57 % in 40 min

Model Applications

34

Y

DMA

MW, 250 °C, 30 min

Y N

NH

O

X

R

+ R-CHO

MW, 200 °C, 30 min

X

NH2

O

OH Me O Me

OO

NH4OAc

Y N

NH

O

X

Me

X = H, Cl, OMeY = CH, NR = (het)aryl, alkyl

Drugs - Synthesis of Heterocycles

� Microwave reactors used in industrial research facilities and universities

� Time equals money!

� Example Synthesis:

Baghbanzadeh, M. et al. J. Comb Chem. 2009, 11, 676-684

39 different compoundsprocessed within ~2 h

yields: 25-82 %

� Parallel reactions for ultra fast

reaction screening

� utmost efficiency

� Completely similar conditions

in each vial

� Easy automation

Model Applications

35

Model Applications

N

N O

Cl

Ph

ClN

N

Ph

Cl

Cl

ONaOH

NN

Ph

Cl

OH

OC2H4 (7 bar), DCB

190 °C, 30 min 70 °C, 30 min

� simplified application of ethylene gas

� individual pre-pressurization

� parallel processing of pressurized reactions

� convenient and safe setup

N. Kaval , W. Dehaen , C. O. Kappe, E. Van der Eycken

Org. Biomol. Chem. 2004, 2, 154-156

� Diels-Alder Cycloaddition

Gaseous Reagents

Synthos 3000

36

Model Applications

Near Critical Water Chemistry

� NCWC at temperatures >250°C and pressures >40 bar

� Convenient access to extreme conditions

� Conditions can be maintained up to 4 hours

� Green Chemistry approach

J. M. Kremsner, C. O. Kappe

Eur. J. Org. Chem., 2005, 3672-3679

R

O

H2OOH

O

295 °C, 77 bar, 30-240min

7 mmol

R = OEt, NH2

� Ester/Amide Hydrolysis

Synthos 3000

37

Model Appliactions

Microwaves

J. M. Kremsner, M. Rack, C. Pilger, C. O. Kappe, Tetrahedron Lett. 2009, 50, 3665

A silicon carbide vessel is chemically inert

and allows applications where glass

material will be destroyed.

Fluorinations� Fluorinated compounds often show biological activities

� Special fluorination agents simplify the introduction of fluorine into certain

groups of molecules

� Example: Cl Cl

TREAT-HF

MW, 200 °C, 5 min

F F

38

Model Appliactions

B. Gutmann et al. Chem. Eur. J. 2010, 12182

D. Obermayer, B. Gutmann, C. O. Kappe Angew. Chem. Int. Ed. 2009, 48, 8321

Silicon carbide

� Fluorinations, hydroxide solutions

� Microwave transparent solvents

SiC vessel

Pyrex vial

� Basic investigations (MW effects)

pyrex vial

SiC vessel

� Controll of thermal runaways

39

J. M. Kremsner, C. O. Kappe,

J. Org. Chem. 2006, 4651-4658

20

40

60

80

100

120

140

160

180

200

0 60 120 180 240 300 360

Time [s]

Tem

pera

ture

[°C

]

pure solvent

Solvent + HE10 x 10 mL

Model Applications

99% conversion

99% conversion

� Diels Alder Cycloaddition

� Claisen Rearrangement

Toluene

MW, 250 °C, 20 min

Me

Me

CN Me

Me

+

CN

Toluene

MW, 240 °C, 90 min

O OH

40

MicrowavesMicrowave irradiation (in combination with effective stirring) ensures an ideal and

homogeneous environment for the growth of nanocrystals.

� Convenient, accurate and reproducible

Model Applications

Nanotechnology� Nanocrystals have special structures providing unique properties

� Size, shape and dimensionality highly affect the properties of nanomaterials

� Upon only slightly changing environment parameters, the crystal growth can be

completely different!

A. Pein et al. G. Trimmel, Inorg. Chem. 2011, 50, 193

41

Model Applications

Polymer Synthesis

� Plastics is everywhere � synthesis is of high importance!

� Viscous solutions � preparative challenge (agitiation, temperature monitoring)

IR

internal

J. Rigolini, B. Grassl, S. Reynaud, L. Billon J. Polym. Sci., Part A: Polym. Chem. 2010, 5775

Microwaves

Dual temperature monitoring can visualize the reaction progress.

42

Model Applications

� 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

R

R1

O

O

HO

X

H2N

NH2

O

NH

NHR

O

R1 O

X

+

EtOH/HCl

120 °C, 20 min

Org. Process Res. Dev. 2003, 707-716

� Biginelli Cyclocondensation

Drugs - Synthesis of Heterocycles

43

Model Appliactions

Scale-up� Without possibility of scale-up � limited application in industries

� Once a reaction has been optimized, large scale production

becomes an issue

� Example:

NC

X

Ni-cat., K3PO4, toluene

MW, 180 °C, 10 min

NC

Me

Me B(OH)2

X = OCONEt2, OSO2NMe2 85 - 90 %

Microwaves

M. Baghbanzadeh, C. Pilger, C. O. Kappe, J. Org. Chem. 2011, 76, 1507

� Accurate temperature monitoring is the key to

successful method transfer.

� 1000 fold scale-up is not an issue

(kilogram production)

44

Recommendation for Beginners and

Advanced Microwave Chemists

Kappe, C. Oliver / Stadler, Alexander

Microwaves in Organic and Medicinal ChemistryMethods and Principles in Medicinal Chemistry (Volume 25)

1. Edition - June 2005

420 Pages, >400 References, Hardcover

ISBN 3-527-31210-2 - Wiley-VCH, Weinheim

� Microwave Theory

� Equipment Review

� Microwave Processing Techniques

� Getting started with Microwaves

� Comprehensive Literature Survey

“...this is now the seminal text for chemists using MW on

laboratory scale. I can warmly recommend this book,

and would expect it to end up on the shelves in most

synthetic organic laboratories.”Spargo, P. L. Org. Process Res. Develop. 2005, 9, 697