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Future trends in microwave synthesis

This article discusses the current status of microwave organic chemistry and briefly explains how the technology
evolved to this point. Several trends in the technology and where it is likely to go in the future are also discussed.
These trends include the way in which chemists think about microwave energy, the current method of use and the
hardware presently available. Some of the future trends explored are microwave use in relation to materials
synthesis, bioscience applications, scale up and flow chemistry.

The beginning of microwaves in

synthetic chemistry
Microwave energy began to be applied to organic
chemistry reactions in the mid-1980s [1,2] .
The initial work was performed in kitchen
microwaves or in multiple-mode systems
with 50100-ml pressure vessels, which were
designed for acid-digestion applications. The
problems with performing chemistry in a
kitchen microwave are reproducibility and
safety; there is no temperature control or stirring, there are limitations to the power that can
be applied and the placement of the reaction
vessel in the cavity is critically important. The
multimode systems, although capable of temperature measurement, stirring and running at
elevated pressures, struggle with sample size.
Typically, you need to run a total sample size
of 20ml or more in these systems. It was not
until around 2000 that single-mode reactors,
which were designed for smaller samples, began
to emerge in the market. A single-mode cavity
is a smaller cavity design that allows a standing
wave to be propagated in the cavity, resulting
in a single mode of high microwave intensity.
These cavities must be designed specifically to
stay in tune with the load in the microwave
cavity. One of the tricks of microwave cavity
design is that, as the sample in the microwave
cavity changes, so does the field. So, the cavity
has to be allowed to adjust to different samples
in order to ensure that the sample is in the
region of high microwave intensity. This also
addresses the issue of reproducibility. It ensures
that if the same reaction is run in a single-mode
cavity multiple times, the reaction yield will
remain fairly consistent. An additional benefit
of the smaller, single-mode cavities is that the
footprint of the entire system is much smaller

and weighs less than a multimode system, which

is more amenable to a synthetic chemistry laboratory, even allowing the microwave to reside in
the fume hood.
Initially, the main advantage of microwaves
was thought to be in combination with pressure vessels, where microwave energy was used to
quickly drive a reaction mixture to elevated temperatures and hold it at these temperatures; however, it appears that microwaves actually offer
an advantage beyond that, in the application of
the energy itself. Applying energy to the system
directly and instantaneously provides the molecules in the reaction mixture with the energy
needed to react and form chemical bonds, thus,
the bulk temperature is a side product involving
the entire reaction mixture rising to an elevated
energy level. More microwave users have begun
to think of the technology as an efficient way
to apply energy directly into a system instead of
simply a way to heat things rapidly. This shows
benefits for chemistries performed at reflux, as
well as chemistries carried out in pressure vessels.
The advantage of being able to run an open vessel is that it applies to a broader range of chemistries for the medicinal chemist and is less of a
change from what they are doing conventionally.
It also allows the evolution of gaseous products
and operation at larger scales.

10.4155/FMC.09.133 2010 Future Science Ltd

Future Med. Chem. (2010) 2(2), 151155

Michael J Collins Jr
CEM Corporation, PO Box200,
Matthews, NC, USA
Tel.: +1 704 821 7015
Fax: +1 704 821 8710
E-mail: michael.collins_jr@
cem.com

Microwaves

explained
An important topic to address here is how
microwave energy works, because that has a
bearing on the future direction of the technology. Microwave energy is spectrum in the
same way as visible light, infrared irradiation
and UV irradiation. Microwaves occupy the
region of the spectrum from approximately
300300,000 MHz, just lower in quantum
ISSN 1756-8919

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Commentary | Collins
energy than infrared irradiation. This means
that microwave energy does not have the quantum energy necessary to make or break chemical bonds. There is not even sufficient quantum energy in microwaves to rotate or vibrate
chemical bonds, the energy simply causes molecules to attempt to orient along their dipole
moment with the electric field. Since the electric field oscillates billions of times persecond,
the molecule is in constant motion, attempting
to align with the field. This motion causes friction, which translates into heat or an increase
in temperature around this molecule that is
quickly dissipated in the bulk solution. In the
case of ions, any ions present in solution will
move through the solution based on the orientation of the electric field and, again, since this
is in constant fluctuation, the ion is moving
in constantly changing directions through the
solution, causing a local temperature rise due
to friction. Another interesting phenomenon is
that microwave energy induces electron movement in metals, which causes rapid heating.
Traditionally, metals are thought to be incompatible with microwave energy; however, this is
not true of all cases. This electron movement
in metals is what causes arcing in some cases
when the electrons jump a gap from one metal
surface to another. There are ways to prevent
the arcing of metals in a microwave cavity, such
as ensuring that the metals are in solution the
liquid provides an insulator between the metal
surfaces making it less likely that electrons will
jump the gap. Using these unique properties of
metals can actually be to a chemists advantage
in microwave chemistry. For metal-catalyzed
reactions, a metal catalyst can be used in a soluble form or as an insoluble metal to drastically
enhance reaction rates and product yields. This
is due to the fact that the surface of the catalyst,
where the reaction occurs, is superheated, thus,
essentially, you have supercharged your catalyst. This is one of the main reasons why palladium-catalyzed coupling reactions have been
explored so extensively in the microwave. These
mechanisms help illustrate that the advantages
seen when using microwave synthesizers really
boil down to the fact that microwaves allow
energy to be transferred rapidly and specifically and that the application of the energy
can be turned on and off instantaneously
(Figures 1&2) . The reasons for the speculation
that microwave energy is doing something other
than what is achievable conventionally are that
the reactions seem to follow unusual kinetics or
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Future Med. Chem. (2010) 2(2)

the results of the chemistry are different. This

is likely because the measured bulk temperature of the reaction mixture is not indicative
of the instantaneous molecular temperatures
that are driving the reaction. If you use these
instantaneous temperatures as the temperatures
driving the reaction, the kinetics of the reaction
can usually be shown to be the same for both
conventional and microwave methods. The reason for unusual results likely occurs because
the bulk reaction mixture is not exposed to the
elevated temperatures for extended amounts
of time. Essentially, with microwave energy
you can achieve the temperatures needed to
cause chemical conversion without the conditions that cause molecular degradation. This
can allow chemistries to take place that will
not react or will only occur minimally under
conventional conditions.
Where

is microwave acceptance today?

A reasonable estimate is that microwave synthesizers can be found in 1520% of organic chemistry laboratories and they are usually a shared
resource for everyone in that laboratory. Of the
chemists who actually use the microwave, there
is a dichotomy: those who use microwave as a
last resort to see if they can make impossible
reactions happen and those who use it on a daily
basis for a large percentage of the reactions they
attempt. We have seen, and are seeing, a movement of chemists from the first category to the
latter, which is encouraging for the acceptance
of microwaves into the everyday workflow of
the organic chemist. In addition to this trend, a
higher percentage of microwave users are using
laboratory-grade instruments, which improves
the repeatability of their results, as evidenced
by the increasing number of microwave publications each year. In addition, there is quite
a number of books and review articles on the
topic of microwave chemistry [317] .
Where

are things going?

The presence of microwaves in chemistry
laboratories is increasing, but there are still
a few roadblocks preventing the dramatic
expansionusage.
The first of these is ease of use. Part of this
is the perception many chemists have of microwaves as being difficult to use and requiring
a specialist; part of this is that the systems
themselves must become easier to operate.
Microwave systems will never find themselves
in every fume hood or even every laboratory if
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Future trends in microwave synthesis

they require a microwave specialist to use them.
They must be easy enough to operate that any
chemist in the laboratory, even if he or she has
never used a microwave before, can work out
how to run the system and what parameters to
enter for a reaction, within 5min of walking
up to the system. Really, using microwaves is
no more difficult than that. It is very similar
to using a hotplate, only it is a more efficient
way to apply the energy. The chemistry follows
the same basic rules as on a hotplate. It just
may be that the temperatures and the times
are different because, at a molecular level,
the reactants are exposed instantaneously to
highertemperatures.
The second factor that will determine the
future success of microwave systems is the hardware. Although there are currently good systems
available for laboratory work, the price of these
instruments is anywhere from US$10,000 to
US$50,000. In order to make systems available for every fume hood, the US$5000 barrier
must be broken, meaning that a system must be
developed costing the user less than US$5000
to put in his or her laboratory. The footprint
of this system would have to be approximately
the same as a hotplate with temperature control
and it would have to be as simple to use as a
hotplate. The availability of a system like this,
which has been talked about in the industry
for quite some time, would increase the use of
microwavesdramatically.
A third factor in the acceptance of the technology is the comfort level chemists have with
microwave energy. One trend that is occurring
is a dramatic increase in the usage of microwave
energy at the graduate research level, which
creates familiarity with the technology that
extends into their professional career. Over the
past decade, we have seen researchers who are
starting their careers at pharmaceutical or biotechnology companies or as young professors,
telling their new employers that they need a
microwave for their research just as they would
a rotary evaporator. To them, it is no more difficult to use than a hotplate, and provides many
more possibilities. We see them use it as a first
resource in their chemistry and without any
hesitation or uncertainty, due to their familiarity with the technology. An extension of this is
that, now, universities and colleges have begun to
incorporate microwaves into their undergraduate
organic chemistry teaching laboratories. To assist
teaching, there are now manuals available that
contain preconstructed and tested microwave
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| Commentary

Future Med. Chem Future Science Group (2010)

Figure1. Conventional heating. The temperature on the outside surface is

greater than the internal temperature. Energy is transferred via
thermalconduction.

experiments. By being exposed to a technology

at this early stage in their careers, young chemists
develop a real understanding of the technology
and become comfortable with it. In some cases,
they help to remind us how uncomplicated the
technology really is. In addition to the exposure they are getting to a new technology, there
is an additional benefit for young chemists in
using microwaves in their teaching laboratories.
Since the reactions are so fast (530min even

Reactantsolvent
mixture (absorbs
microwave energy)
Vessel wall is
transparent to
microwave energy
Localized
superheating

Future Med. Chem Future Science Group (2010)

Figure2. Microwave heating. The vessel wall is transparent to microwave

energy. Since the energy is transferred kinetically, localized superheating occurs
and the reactant mixture absorbs microwave energy.

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Commentary | Collins
for difficult reactions), they can perform reactions that were previously too difficult and therefore required too much time to run in a 23-h
laboratory period. Who would have thought of
running DielsAlder reactions, multistep reactions, SNArs or Suzuki couplings in Organic
Laboratory 101? But are these not the reactions
we run in the real world?
Areas

of future exploration
There are a few things that are likely to occur
with microwave technology in the next few
years. First is the advancement of microwaves
into new areas such as materials science and biochemistry. Second is the future role of microwave in flow and scale-up chemistries. Third,
and finally, is the evolution of the ways in which
microwaves are used.
Microwaves offer some unique advantages
to materials synthesis. Owing to the ability of
microwaves to interact directly with the sample and to turn on and off quickly, the particle
growth of these materials is much more controlled and uniform, which results in an improvement in the desired property of these materials.
There is only a small number of researchers using
microwave synthesizers in this field currently,
but they are seeing remarkable results. This will
most likely lead to an increased adoption rate of
the technology over the next few years.
Another trend that is occurring is the use of
microwaves in biochemistry. This helps illustrate
the real advantage of the technology. Most biomolecules are fairly temperature-sensitive and
will lose their biological function if exposed to
elevated temperatures for extended periods of
time; however, there are a lot of biochemical
interactions that are slow or difficult to occur. For
temperature-stable small molecules, the solution
would typically be to apply heat to promote the
reaction, but this is less feasible in the bio world.
Microwaves, however, fit this need perfectly. They
are able to push biochemical interactions to occur
without the high bulk temperatures that would
cause loss of activity or degradation. This helps
to show that the great advantage of microwave
energy is efficient energy transfer rather than
a method to rapidly heat a solution to elevated
temperatures. Think of a microwave as a scalpel
compared with a sledgehammer. This property is
what has caused a tremendous amount of acceptance in areas including peptides and proteomics.
The challenge in this field is on the instrument
providers to deliver the right hardware to the
market for these different applications.
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Future Med. Chem. (2010) 2(2)

Flow chemistry is now emerging as an area

of interest and with it is the desire to couple
flow with microwave energy. Although it is an
interesting field and there are many examples of
very good chemistries being performed in a flow
microwave, it remains to be seen whether flow
will be adopted more broadly in the medicinal
chemistry world. Organic chemists have been
mixing things in pots for over 100 years, and
moving from batch to flow, although technically feasible, would require a significant concerted movement. The eventual role of flow
in a field where the chemistries are varied and
constantly changing is unclear, so it remains to
be seen where microwaves will fit in this area.
One of the main questions asked about microwaves is related to scale up; when will scale-up
systems be available for microwaves? Currently,
there are microwave systems to address scale up
to the kilogram level, but off-the-shelf systems are not available for larger scales. There
are several industrial microwave companies that
specialize in large-scale microwave systems, but
most of these systems are developed for applications other than bulk chemical processing,
such as curing, drying and food processing,
for example. The problem with developing a
scale-up microwave system for bulk chemical
processing is that you start to question the
advantage of microwave. In some of the current applications where scale-up microwaves are
applied, there are clear advantages to using a
microwave; however, for bulk heating of a large
vat of chemicals to drive a reaction, microwave
energy may not be the way to go. Even continuous flow on that scale has its issues, such as the
handling of solids, residence time in the microwave field versus throughput and dealing with
elevated pressures. The application of microwave energy on the research scale demonstrates
clear advantages to conventional heating, but
it is unclear whether microwaves will ever find
their way into the manufacturing facilities. As
more chemical reactions are run in a microwave as a primary method, this will push the
microwave scale-up discussion to the forefront
and solutions will have to be found. It may be
that microwave energy is only the solution in
certain cases and, in these cases, the solution
may be a custom design versus an off-the-shelf
system that will find broad acceptance across
the board in manufacturing plants.
A decade from now, a microwave will not be
uncommon or unique in a chemistry laboratory.
It will be much like having a hotplate or a
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Future trends in microwave synthesis

rotary evaporator in your laboratory. The units
will be small, almost unnoticeable, but they
will be used every day for a majority of the
chemistry performed in order to allow rapid
reactions and push the boundaries of chemistries that will afford good results. The technology will open up new synthetic pathways and
allow the use of more environmentally friendly
solvents. It will yield cleaner products that
will not require as much purification. In addition, the scientists using this equipment will
understand how to apply this technology to
their workflow, but they will not be microwave

| Commentary

specialists. Microwaves will simply be another

tool in their standard toolkit, much like thin
layerchromatography.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.

Executive summary

Microwave energy is a safe and efficient method of rapidly performing organic synthesis.

Microwave energy enables chemists to instantaneously heat their reactants, allowing chemistries to proceed much more rapidly and
with fewer side reactions than conventional methods.

Acceptance of microwave technology for the laboratory is growing.

The perception of microwave energy as difficult to work with must be overcome in order for the technology to grow, but with the use
of microwave synthesis in undergraduate teaching laboratories, many chemists are becoming familiar with the equipment early on.

The use of microwave energy in materials synthesis and biochemistry will grow, but it remains to be seen if it is the right technology for
scale-up or flow chemistry.

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