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1
Microwave Synthesis – An Introduction
While fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen
invented the burner in 1855 that the energy from this heat source could be applied to a
reaction vessel in a focused manner. The Bunsen burner was later superseded by the
isomantle, oil bath or hot plate as a source of applying heat to a chemical reaction. In
the past few years, heating chemical reactions by microwave energy has been an
increasingly popular theme in the scientific community. Since the first published
reports on the use of microwave irradiation to carry out organic chemical transfor-
mations by the groups of Gedye and Giguere/Majetich in 1986 [1], more than 3500
articles have been published in this fast moving and exciting field, today generally
referred to as microwave-assisted organic synthesis (MAOS) [2, 3]. In many of the
published examples, microwave heating has been shown to dramatically reduce
reaction times, increase product yields and enhance product purities by reducing
unwanted side reactions compared to conventional heating methods. The advantages
of this enabling technology have, more recently, also been exploited in the context of
multistep total synthesis [4] and medicinal chemistry/drug discovery [5], and have
additionally penetrated related fields such as polymer synthesis [6], material
sciences [7], nanotechnology [8] and biochemical processes [9]. The use of microwave
irradiation in chemistry has thus become such a popular technique in the scientific
community that it might be assumed that, in a few years, most chemists will probably
use microwave energy to heat chemical reactions on a laboratory scale. The statement
that, in principle, any chemical reaction that requires heat can be performed under
microwave conditions has today been generally accepted as a fact by the scientific
community.
The short reaction times provided by microwave synthesis make it ideal for rapid
reaction scouting and optimization of reaction conditions, allowing very rapid
progress through the hypotheses–experiment–results iterations, resulting in more
decision points per unit time. In order to fully benefit from microwave synthesis one
has to be prepared to fail in order to succeed. While failure could cost a few minutes,
success would gain many hours or even days. The speed at which multiple variations
of reaction conditions can be performed allows a morning discussion of What
should we try? to become an after lunch discussion of What were the results? Not
Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols
C. Oliver Kappe, Doris Dallinger, and S. Shaun Murphree
Copyright Ó 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 978-3-527-32097-4
, j 1 Microwave Synthesis – An Introduction
2
surprisingly, therefore, many scientists, both in academia and in industry, have
turned to microwave synthesis as a frontline methodology for their projects.
Arguably, the breakthrough in the field of MAOS on its way from laboratory
curiosity to standard practice started in the pharmaceutical industry around the year
2000. Medicinal chemists were among the first to fully realize the true power of this
enabling technology. Microwave synthesis has since been shown to be an invaluable
tool for medicinal chemistry and drug discovery applications since it often dramati-
cally reduces reaction times, typically from days or hours to minutes or even
seconds [5]. Many reaction parameters can therefore be evaluated in a few hours
to optimize the desired chemistry. Compound libraries can then be rapidly synthe-
sized in either a parallel or (automated) sequential format using microwave technol-
ogy [5]. In addition, microwave synthesis often allows the discovery of novel reaction
pathways, which serve to expand chemical space in general, and biologically-
relevant, medicinal chemistry space, in particular.
In the early days of microwave synthesis, experiments were typically carried out in
sealed Teflon or glass vessels in a domestic household microwave oven without any
temperature or pressure measurements [1]. Kitchen microwave ovens are not
designed for the rigors of laboratory usage: acids and solvents corrode the interiors
quickly and there are no safety controls. The results were often violent explosions due
to the rapid uncontrolled heating of organic solvents under closed vessel conditions.
In the 1990s several groups started to experiment with solvent-free microwave
chemistry (so-called dry-media reactions), which eliminated the danger of explo-
sions [10]. Here, the reagents were pre-adsorbed onto either a more or less microwave
transparent inorganic support (i.e., silica, alumina or clay) or a strongly absorbing one
(i.e., graphite), that additionally may have been doped with a catalyst or reagent.
Particularly in the beginning of MAOS, the solvent-free approach was very popular
since it allowed the safe use of domestic microwave ovens and standard open vessel
technology. While a large number of interesting transformations using dry-media
reactions have been published in the literature [10], technical difficulties relating to
non-uniform heating, mixing, and the precise determination of the reaction tem-
perature remained unsolved, in particular when scale-up issues needed to be
addressed.
Alternatively, microwave-assisted synthesis was, in the past, often carried out using
standard organic solvents under open vessel conditions. If solvents are heated by
microwave irradiation at atmospheric pressure in an open vessel, the boiling point of
the solvent typically limits the reaction temperature that can be achieved. In order to
nonetheless achieve high reaction rates, high-boiling microwave absorbing solvents
were frequently used in open-vessel microwave synthesis [11]. However, the use of
these solvents presented serious challenges during product isolation and recycling of
solvent. In addition, the risks associated with the flammability of organic solvents in a
microwave field and the lack of available dedicated microwave reactors allowing
adequate temperature and pressure control were major concerns. The initial slow
uptake of microwave technology in the late 1980s and 1990s has often been attributed
to its lack of controllability and reproducibility, coupled with a general lack of
understanding of the basics of microwave dielectric heating.
1
Microwave Synthesis – An Introduction
While fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen
invented the burner in 1855 that the energy from this heat source could be applied to a
reaction vessel in a focused manner. The Bunsen burner was later superseded by the
isomantle, oil bath or hot plate as a source of applying heat to a chemical reaction. In
the past few years, heating chemical reactions by microwave energy has been an
increasingly popular theme in the scientific community. Since the first published
reports on the use of microwave irradiation to carry out organic chemical transfor-
mations by the groups of Gedye and Giguere/Majetich in 1986 [1], more than 3500
articles have been published in this fast moving and exciting field, today generally
referred to as microwave-assisted organic synthesis (MAOS) [2, 3]. In many of the
published examples, microwave heating has been shown to dramatically reduce
reaction times, increase product yields and enhance product purities by reducing
unwanted side reactions compared to conventional heating methods. The advantages
of this enabling technology have, more recently, also been exploited in the context of
multistep total synthesis [4] and medicinal chemistry/drug discovery [5], and have
additionally penetrated related fields such as polymer synthesis [6], material
sciences [7], nanotechnology [8] and biochemical processes [9]. The use of microwave
irradiation in chemistry has thus become such a popular technique in the scientific
community that it might be assumed that, in a few years, most chemists will probably
use microwave energy to heat chemical reactions on a laboratory scale. The statement
that, in principle, any chemical reaction that requires heat can be performed under
microwave conditions has today been generally accepted as a fact by the scientific
community.
The short reaction times provided by microwave synthesis make it ideal for rapid
reaction scouting and optimization of reaction conditions, allowing very rapid
progress through the hypotheses–experiment–results iterations, resulting in more
decision points per unit time. In order to fully benefit from microwave synthesis one
has to be prepared to fail in order to succeed. While failure could cost a few minutes,
success would gain many hours or even days. The speed at which multiple variations
of reaction conditions can be performed allows a morning discussion of What
should we try? to become an after lunch discussion of What were the results? Not
Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols
C. Oliver Kappe, Doris Dallinger, and S. Shaun Murphree
Copyright Ó 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 978-3-527-32097-4
, j 1 Microwave Synthesis – An Introduction
2
surprisingly, therefore, many scientists, both in academia and in industry, have
turned to microwave synthesis as a frontline methodology for their projects.
Arguably, the breakthrough in the field of MAOS on its way from laboratory
curiosity to standard practice started in the pharmaceutical industry around the year
2000. Medicinal chemists were among the first to fully realize the true power of this
enabling technology. Microwave synthesis has since been shown to be an invaluable
tool for medicinal chemistry and drug discovery applications since it often dramati-
cally reduces reaction times, typically from days or hours to minutes or even
seconds [5]. Many reaction parameters can therefore be evaluated in a few hours
to optimize the desired chemistry. Compound libraries can then be rapidly synthe-
sized in either a parallel or (automated) sequential format using microwave technol-
ogy [5]. In addition, microwave synthesis often allows the discovery of novel reaction
pathways, which serve to expand chemical space in general, and biologically-
relevant, medicinal chemistry space, in particular.
In the early days of microwave synthesis, experiments were typically carried out in
sealed Teflon or glass vessels in a domestic household microwave oven without any
temperature or pressure measurements [1]. Kitchen microwave ovens are not
designed for the rigors of laboratory usage: acids and solvents corrode the interiors
quickly and there are no safety controls. The results were often violent explosions due
to the rapid uncontrolled heating of organic solvents under closed vessel conditions.
In the 1990s several groups started to experiment with solvent-free microwave
chemistry (so-called dry-media reactions), which eliminated the danger of explo-
sions [10]. Here, the reagents were pre-adsorbed onto either a more or less microwave
transparent inorganic support (i.e., silica, alumina or clay) or a strongly absorbing one
(i.e., graphite), that additionally may have been doped with a catalyst or reagent.
Particularly in the beginning of MAOS, the solvent-free approach was very popular
since it allowed the safe use of domestic microwave ovens and standard open vessel
technology. While a large number of interesting transformations using dry-media
reactions have been published in the literature [10], technical difficulties relating to
non-uniform heating, mixing, and the precise determination of the reaction tem-
perature remained unsolved, in particular when scale-up issues needed to be
addressed.
Alternatively, microwave-assisted synthesis was, in the past, often carried out using
standard organic solvents under open vessel conditions. If solvents are heated by
microwave irradiation at atmospheric pressure in an open vessel, the boiling point of
the solvent typically limits the reaction temperature that can be achieved. In order to
nonetheless achieve high reaction rates, high-boiling microwave absorbing solvents
were frequently used in open-vessel microwave synthesis [11]. However, the use of
these solvents presented serious challenges during product isolation and recycling of
solvent. In addition, the risks associated with the flammability of organic solvents in a
microwave field and the lack of available dedicated microwave reactors allowing
adequate temperature and pressure control were major concerns. The initial slow
uptake of microwave technology in the late 1980s and 1990s has often been attributed
to its lack of controllability and reproducibility, coupled with a general lack of
understanding of the basics of microwave dielectric heating.
