Mikroreaktoren Microwave Vorlesung

7/21/2019 Mikroreaktoren Microwave Vorlesung

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Rainer Riedl 1

Masterstudiengang Chemistry for the Life Sciences

Modul: Small Active Molecules

Kurs: NewSynTech

New Synthetic Technologies HS 2014


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Rainer Riedl 2

Mikroreaktoren MikrowelleFestphasensynthese

Kombinatorische ChemieParallelsynthese

Warum neue Synthesetechnologien?

Molekulare Evolution

Biotransformationen Katalytische Antikrper

Ribozyme

Automatisierte Synthesen

Multikomponentenreaktionen Organokatalyse


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3

Mikroreaktoren

Rundkolben der Zukunft !?


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Rainer Riedl 4

Mikroreaktoren

Kontinuierliche Reaktionsfhrung

Miniaturisierung

Kurze Mischzeiten

Definierte Verweilzeiten

Sehr guter Wrmeaustausch, keine Hotspots

Einfaches Scale-up

Bessere Selektivitten und Ausbeuten


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Rainer Riedl 5

Ein praktisches Beispiel..

Medchem Approach

Traditioneller Scale-up.

Kontinuierliche Produktion.


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Rainer Riedl 6

Typische Mikroreaktoren


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Rainer Riedl 7

Mikroreaktoren aus Glas


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Rainer Riedl 8

Photolithographische Fabrikation vonMikroreaktoren

Chem. Soc. Rev., 2005, 34, 235-246.

Mikroreaktoren aus Glas

werden bevorzugt,

da chemisch weitgehend inert

visuelle Detektionsmethoden

sind mglich

Fabrikation ist etabliert

0.5m/min


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Rainer Riedl 9

Sind Mikroreaktoren wirklich mikro?

Science 206, 314, 430-431.

Mikroreaktoren an sich schon, aber der apparative Anhang nicht!

Autosampler, Pumpen, Mischungssystem, Detektionseinheit, Analyseeinheit

Beispiel einer vollautomatisierten 7-stufigen Synthese eines Naturstoffes


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Rainer Riedl 10

Mikroreaktoren

Es werden vielmals bessere Selektivitten und Ausbeuten

erreicht:

das Verstndnis von Reaktionsmechanismus und Kinetikist wichtig

per Design enges Temperatur- und Verweilzeitprofil

TMR

TBR

RK

E

A

B

C

B

B

B + C


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Rainer Riedl 12

Elektroosmotischer Fluss (EOF)

Keine Pumpen ntig

-> leichte Miniaturisierung

Chem. Soc. Rev., 2005, 34, 235-246.


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Rainer Riedl 13

Quelle: ChemFiles (Sigma-Aldrich) 2005, Vol. 5, Issue 7.

Beispiele fr Chemie in Mikroreaktoren


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Swern-Oxidation

Verstndnis von Reaktionsmechanismus definiert MR-Set-up

Kawaguchi et al.,Angew. Chem. 2005, 117, 2465-2468..


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Rainer Riedl 15

Pros and Cons

Schnelle, exotherme Reaktionen

Aggressive oder instabile Zwischenprodukte

Sehr gute Temperaturkontrolle von -40 bis 150 C

Erhhter Druck bis 100 bar mglich

Gasentwicklung fhrt zu verkrzter Reaktionszeit ist sonst aber

kein Problem

Grsste Einschrnkung: keine Feststoffe!


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Nchster Schritt:Lab on a Chip: Integration eines Mikroreaktors mitbiologischem Assay-System

Ideal fr Pharma:Kurze Reaktionszeiten

Geringe Substanzmengen

Keine Lagerung

bergang von Chemie zu Biologie wird eliminiert

Chem. Soc. Rev., 2005, 34, 235-246.


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Rainer Riedl

Weiterfhrende Literatur

Microreactors in Organic Synthesis and Catalysis, Wiley-VCH,

Ed. By T. Wirth, 2008.

Microreactors, Wiley-VCH, W. Ehrfeld, V. Hessel, H. Lwe,2005.


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Microwave Irradiation in Organic Synthesis:

The Bunsen burner of the 21st century!


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Rainer Riedl 19

Heating with Microwaves

Microwave irradiation is electromagnetic irradiation in the

frequency range of 0.3300 GHz. All domestic kitchen

microwave ovens and all dedicated microwave reactors for

chemical synthesis operate at a frequency of 2.45 GHz

(corresponding to a wavelength of 12.24 cm) to avoid

interference with telecommunication and cellular phonefrequencies. The energy of the microwave photon at this

frequency region (0.0016 eV) is too low to break chemical

bonds and is also lower than Brownian motion. It is therefore

clear that microwaves cannot induce chemical reactions.

Chimia 60 (2006) 308312.


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Rainer Riedl

Microwave Synthesizer

http://www.biotage.com

BiotageInitiator

Microwave Synthesizer

CEMs automated microwave

peptide synthesizer

http://www.cemmicrowave.co.uk


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Microwave-assisted organic synthesis (MAOS) inthe literature

Chimia 60 (2006) 308312.


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Pros and Cons

Pros:

Most importantly, microwave processing frequently leads to dramatically

reduced reaction times, higher yields, and cleaner reaction profiles. In

many cases the observed rate-enhancements may be simply a consequence

of the high reaction temperatures that can rapidly be obtained using this

non-classical heating method, or may result from the involvement of so-

called specific or non-thermal microwave effects.

An additional benefit of this technology is that the choice of solvent for a given

reaction is not governed by the boiling point (as in a conventional reflux

setup) but rather by the dielectric properties of the reaction medium which

can be easily tuned by e.g. addition of highly polar materials such as ionic

liquids.Chimia 60 (2006) 308312.


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Pros and Cons

Pros:

The temperature/pressure monitoring mechanisms of modern microwave

reactors allow for an excellent control of reaction parameters which generally

leads to more reproducible reaction conditions.

Because direct in core heating of the medium occurs, the overall process is

more energy efficient than classical oilbath heating.

Microwave heating can be rapidly adapted to a parallel or automatic

sequential processing format. In particular the latter technique allows for the

rapid testing of new ideas and high-speed optimization of reaction

conditions. The fact that a yes or no answer for a particular chemical

transformation can often be obtained within 5 to 10 min (as opposed to

several hours in a conventional protocol), has contributed significantly to the

acceptance of microwave chemistry both in industry and academia.

Chimia 60 (2006) 308312.


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Pros and Cons

Cons:

high equipment costs compared to conventional heating

equipment

MAOS has changed the world o f organic chemistry, and i t

wo uld be wise to embrace th is new technolog y or be lef t

lagging behind w i th convent ional heat ing methodolog ies.

Chimia 60 (2006) 308312.


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Doing MAOS

In open or closed vessels:

Open vessel: Boiling point limits reaction temperature

Closed vessel: Reaction temperatures above boiling point are

possible


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Traditional conductive heating versus heating with microwave

energy

Traditionally: Conductive heating

with external heat source

Slow and inefficient:

depends on thermal conductivity of vessel etc

MAOS: efficient internal heating

Direct coupling of microwave

energy with molecules

Reaction vessels are microwave

transparent (glass etc)


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Microwave versus oil-bath heating

Mol. Diversity 2003, 7, 293300; Biotage AB

Temperature profiles after 1 min of microwave irradiation

(left) and treatment in an oil bath (right).


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T/p/P profile of MAOS with state of the art equipment

Chimia 60 (2006) 308312.


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Energy Transfer in MAOS

When irradiated at microwave frequencies,

the dipoles or ions of the sample align in the

applied electric field.

As the applied field oscillates, the dipole or ion field

attempts to realign itself with the alternating electric

field and, in the process, energy is lost in the

form of heat through molecular friction.

Chimia 60 (2006) 308312.


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Solvents for MAOS

Chimia 60 (2006) 308312.

How about CCl4? Whats the dipole moment of CCl4?

Can you use it as solvent in MAOS?

The heating characteristics of a particular

material (i.e. a solvent) under microwaveirradiation conditions are dependent

on the dielectric properties of the material.

The ability of a specific substance to convert

electromagnetic energy into heat at a

given frequency and temperature is determined

by the so-called loss tangent tan .

The tangent loss factor is expressed as thequotient, tan = /, where is the dielectric

loss, indicative of the efficiency

with which electromagnetic radiation is

converted into heat, and is the dielectric

constant describing the ability of molecules

to be polarized by the electric field.


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Microwave effects: Non Thermal Microwave Effects

Classified as rate accelerations that cannot be rationalized by

either purely thermal/kinetic.

Essentially, non-thermal effects result from a proposed direct

interaction of the electric field with specific molecules.

It has been argued that the presence of an electric field leads to

orientation effects of dipolar molecules and hence changes the

pre-exponential factor A or the activation energy (entropy term) in

the Arrhenius equation.

Furthermore, a similar effect should be observed for polar reaction

mechanisms, where the polarity is increased going from the ground

state to the transition state, resulting in an enhancement of

reactivity by lowering of the activation energy. Chimia 60 (2006) 308312.


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MAOS Chemistry

Almost any type of synthetic transformation known today has been

evaluated under microwave conditions. These range from e.g.

Transition metal-catalyzed reactions,

rearrangements,

cycloadditions,

glycosylations

peptide couplings,multicomponent reactions,

free radical processes,

heterocyclic ring formations.

Microwave synthesis has been successfully integrated with other

technologies such as solid-phase synthesis,solid-supported reagents or catalysts,

and microreactor technology.

D. Bogdal, Microwave-Assisted Organic Synthesis, Elsevier, Amsterdam, 2005.


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Examples for MAOS

Tetrahedron 2002, 58, 31773183

Open vessel!!!


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Examples for MAOS


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Examples for MAOS

Tetrahedron 65 (2009) 33253355.

Documents

Mikroreaktoren Microwave Vorlesung