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Rainer Riedl 1

Masterstudiengang Chemistry for the Life Sciences


Modul: Small Active Molecules
Kurs: NewSynTech


New Synthetic Technologies HS 2014
Rainer Riedl 2
Mikroreaktoren Mikrowelle Festphasensynthese
Kombinatorische Chemie Parallelsynthese
Warum neue Synthesetechnologien?
Molekulare Evolution
Biotransformationen Katalytische Antikrper
Ribozyme
Automatisierte Synthesen
Multikomponentenreaktionen Organokatalyse
3
Mikroreaktoren

Rundkolben der Zukunft !?
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Mikroreaktoren
Kontinuierliche Reaktionsfhrung
Miniaturisierung
Kurze Mischzeiten
Definierte Verweilzeiten
Sehr guter Wrmeaustausch, keine Hotspots
Einfaches Scale-up
Bessere Selektivitten und Ausbeuten

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Ein praktisches Beispiel..
Medchem Approach
Traditioneller Scale-up.
Kontinuierliche Produktion.
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Typische Mikroreaktoren
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Mikroreaktoren aus Glas
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Photolithographische Fabrikation von
Mikroreaktoren
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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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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Mikroreaktoren
Es werden vielmals bessere Selektivitten und Ausbeuten
erreicht:
das Verstndnis von Reaktionsmechanismus und Kinetik
ist wichtig
per Design enges Temperatur- und Verweilzeitprofil

T
MR
T
BR
RK
E
A
B
C
B
B
B + C
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Apparativer Aufbau
Genereller Set-up
2 Pumpen (HPLC oder Spritzenpumpen)
Mikroreaktor mit Verweilzeitmodul
Temperierung: Kryostat/Wrmebad und/oder integrierter
Wrmetauscher
T/P-Sensoren, Steuerung
Mikroreaktoren
T P
T P
T T
Verweilzeitmodul
Heiz/Khlbad
PC-Steuerung der Pumpen und Heiz/Khlbad
T- und P-Messung
Wrmetauscher
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Elektroosmotischer Fluss (EOF)
Keine Pumpen ntig
-> leichte Miniaturisierung
Chem. Soc. Rev., 2005, 34, 235-246.
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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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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 mit
biologischem 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.
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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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 phone
frequencies. 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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Microwave Synthesizer
http://www.biotage.com
Biotage

Initiator
Microwave Synthesizer
CEMs automated microwave
peptide synthesizer
http://www.cemmicrowave.co.uk
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Microwave-assisted organic synthesis (MAOS) in
the 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 of organic chemistry, and it
would be wise to embrace this new technology or be left
lagging behind with conventional heating methodologies.
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, 293 300; 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 CCl
4
? Whats the dipole moment of CCl
4
?
Can you use it as solvent in MAOS?
The heating characteristics of a particular
material (i.e. a solvent) under microwave
irradiation 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 the
quotient, 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: Thermal effects
In the early days: Different outcome of MAOS experiments compared to
conventional heating -> non thermal / specific microwave effects?
Low reproducibility of experiments due to equipment!
Temperature profiles of MOAS and conventional heating are different!
Reviewing the present literature: In the majority of cases the reason for the
observed rate enhancements is a purely thermal/kinetic effect, i.e. a
consequence of the high reaction temperatures that can rapidly be attained
when irradiating polar materials in a microwave field. Methanol, can be
rapidly superheated to temperatures >100C in excess of its boiling point
when irradiated under sealed vessel microwave conditions.
Chimia 60 (2006) 308312.
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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, 3177 3183
Open vessel!!!
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Examples for MAOS
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Examples for MAOS
Tetrahedron 65 (2009) 33253355.