Inductive heating with magnetic materials inside flow reactors

Article abstract of DOI:10.1002/chem.201002291

Superparamagnetic nanoparticles coated with silica gel or alternatively steel beads are new fixed-bed materials for flow reactors that efficiently heat reaction mixtures in an inductive field under flow conditions. The scope and limitations of these novel heating materials are investigated in comparison with conventional and microwave heating. The results suggest that inductive heating can be compared to microwave heating with respect to rate acceleration. It is also demonstrated that a very large diversity of different reactions can be performed under flow conditions by using inductively heated flow reactors. These include transfer hydrogenations, heterocyclic condensations, pericyclic reactions, organometallic reactions, multicomponent reactions, reductive cyclizations, homogeneous and heterogeneous transition-metal catalysis. Silica-coated iron oxide nanoparticles are stable under many chemical conditions and the silica shell could be utilized for further functionalization with Pd nanoparticles, rendering catalytically active heatable iron oxide particles.

Full text of DOI:10.1002/chem.201002291

DOI: 10.1002/chem.201002291
Inductive Heating with Magnetic Materials inside Flow Reactors
[
a]
Sascha Ceylan, Ludovic Coutable, Jens Wegner, and Andreas Kirschning*
Abstract: Superparamagnetic nanopar-
ticles coated with silica gel or alterna-
tively steel beads are new fixed-bed
materials for flow reactors that effi-
ciently heat reaction mixtures in an in-
ductive field under flow conditions.
The scope and limitations of these
novel heating materials are investigat-
ed in comparison with conventional
and microwave heating. The results
suggest that inductive heating can be
compared to microwave heating with
respect to rate acceleration. It is also
demonstrated that a very large diversi-
ty of different reactions can be per-
formed under flow conditions by using
inductively heated flow reactors. These
hetero AHCTUNTGERNNUNcG yclic condensations, pericyclic
reactions, organometallic reactions,
multicomponent reactions, reductive
cyclizations, homogeneous and hetero-
geneous
transition-metal
catalysis.
include
transfer
hydrogenations,
Silica-coated iron oxide nanoparticles
are stable under many chemical condi-
tions and the silica shell could be uti-
lized for further functionalization with
Pd nanoparticles, rendering catalytical-
ly active heatable iron oxide particles.
Keywords: flow chemistry · induc-
tive heating · microreactors · multi-
component reactions
catalysis
·
organo-
Introduction
the microstructured flow device. Therefore, heating has
been combined with high pressure to achieve sufficiently
[3]
Synthesis under flow conditions using micro- or mesofluidic
reactors has become a very active field of research in aca-
large rates. Heating with microwave irradiation is a direct
method for heating the reactor from inside, as long as all
the other reactor materials chosen are microwave transpar-
[1]
demic and industrial research. The use of microstructured
flow reactors is one attractive technique, among other ena-
bling technologies, which have had a fundamental impact
[4]
ent. However, the technical setup, as well as safety issues
associated with microwaves, has hampered their broad ap-
plication in flow systems so far.
[2]
upon how chemists perform synthesis currently. They in-
clude techniques such as nonconventional heating tech-
niques of which microwave irradiation is a very prominent
one, solid-phase assistance, nonclassical solvents, and new
reactor designs just to list the most important ones. In short
they help to carry out synthesis, including multistep synthe-
sis, faster and to perform workups more efficiently. Efficient
heating of reactants is a key issue when conducting synthesis
in mesofluidic reactors because heating has to proceed very
rapidly when reactions are carried out continuously at high
flow rates. Conventional heating using an external oven,
which is based on heat transfer by convection, is often too
slow to effectively heat the stream of reactants that enters
Recently, we disclosed the first examples of inductively
heated mesofluidic reactors using ferromagnetic materials
like magnetic nanoparticles 1 as the heating media. Heating
of continuous reactions is achieved by using an external in-
ductor that generates a high or medium frequency field
[5]
(Figure 1). In our preliminary report, we found that this
new heating enabling technology is ideally suited to being
combined with flow processes using flow reactors. In fact,
magnetic nanoparticles have gained considerable interest
lately due to their magnetic properties, which allow their re-
[6]
moval from a reaction mixture with a magnet. However,
the important property of heating these materials in an elec-
tromagnetic field has been completely overlooked by syn-
thetic chemists. This phenomenon relies on magnetic induc-
tive hyperthermia, which is based on the fact that loss of
magnetic hysteresis creates heat (Nꢀel relaxation), when
magnetic nanoparticles are exposed to a constantly changing
[
a] S. Ceylan, Dr. L. Coutable, J. Wegner, Prof. Dr. A. Kirschning
Institut fꢁr Organische Chemie and Zentrum
fꢁr Biomolekulare Wirkstoffe (BMWZ)
Leibniz Universitꢂt Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
Fax : (+49) 511-762-3011
[7]
magnetic field.
superparamagnetism. Furthermore, a very strong rapidly al-
This phenomenon is also termed
AHCTUNGTRENNUNG
E-mail: andreas.kirschning@oci.uni-hannover.de
ternating magnetic field induces eddy currents on any con-
ductive material placed in the vicinity of that field that are
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem201002291.
1884
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Chem. Eur. J. 2011, 17, 1884 – 1893

FULL PAPER
Figure 2. Heating profiles of different nano and macroscopic ferromag-
netic materials. Used power output refers to the percentage of the power
provided by the magnetic field that is being transferred into the ferro-
magnetic material to be heated, 1000% is therefore the maximum; ^ =1,
&
=MnFe O , ~ =Bayferrox, ꢄ=Fe powder.
2 4
higher power output, silica-coated 1 is superior to all other
particles. Bayferrox behaved in a similar manner to 1 in the
electromagnetic field, however at a lower level. Pure iron
powder was heated up only moderately in a medium-fre-
quency field. Besides the good heating performance of 1 this
material features a number of additional advantages. The
silica shell renders these particles robust enough against
many chemicals and it paves the way to heterogenize re-
agents or catalysts on its surface (see above). It needs to be
stressed that not only the composition of the material has an
impact on the heating profile, but also the shape and parti-
cle size of the material. Therefore, we generally carried out
our studies with particles of comparable size. Additionally, it
has to be pointed out that although we call our materials
nanoparticles we observed agglomeration of 1 under the re-
action conditions, creating clusters of individual nanoparti-
cles. This is a beneficial process because alternatively the
particles would easily be washed out under the convective
flow conditions. Still, the silica shell in 1 keeps the superpar-
amagnetic nuclei apart so that the magnetic properties are
unaltered.
Figure 1. Superparamagnetic core-shell nanoparticles 1 (schematic draw-
ing of 1 and TEM micrographs) and experimental setup for either circu-
lar or continuous operation.
also able to heat the metal by induction. This happens to a
lesser extent with magnetic materials, which mainly produce
heat through the so-called hysteresis effect.
Overall, nanoparticles 1 are ideally suited to being incor-
porated into flow devices and have several advantages, in-
cluding the following: 1) a simple setup; 2) only the super-
paramagnetic particles are the initial source for heating,
which occurs inside the reactor; 3) nanoparticles can be su-
perheated (above 5008C); and 4) minimal safety issues. Usu-
ally, these materials were incorporated inside a flow reactor
made of glass and encased with an inductor.
Herein, we demonstrate the broad synthetic applicability
of inductive heating in continuous flow systems. For this pur-
pose we studied a diverse number of reactions and show
that appropriate reactor design can pave the way to perform
reactions under high pressure/high temperature conditions.
Furthermore, we disclose alternative materials that are suit-
able for inductive heating and compare them with superpar-
amagnetic nanoparticles, such as 1.
Nanoparticles based on iron or manganese are not the
only materials that can be heated in an inductive field. Since
conductivity is a requirement for these materials in principal
ferromagnetic metals should also heat in an inductive field.
Therefore, we studied noncorrosive steel beads that differed
in size (0.8–4.8 mm diameter, Figure 3) and hence could also
serve as packed-bed material in microstructured flow reac-
tors.
Results and Discussion
As previously described, the investigations on the heating
profiles of different materials were carried out inside a glass
Choice of inductively heatable material: We first investigat-
ed several magnetic nanoparticles, some of which are de-
signed as core/shell particles, with respect to their heating
properties in a medium frequency magnetic field (25 kHz;
[5,9,10a]
reactor using an external pyrometer.
The steel beads
responded almost proportionally to the power of the exter-
nal electromagnetic field. The largest beads reached highest
temperatures well above 3508C (Figure 4). However, beads
with a diameter below 0.4 mm responded sluggishly and
heat formation was not very pronounced. Although the
heating profile of the larger steel beads would encourage
their use, we did not employ them in our studies. A fixed
bed composed of large steel beads results in larger open
[8]
Figure 2). The heating experiments were first conducted
with the dry powder inside a glass reactor and by employing
an external pyrometer. At low power, the data reveal that
manganese ferrite nanoparticles are particularly well affect-
ed by the external magnetic field compared with MAGSILI-
CA (1), Bayferrox (synthetic a-Fe O ), and iron powder. At
3
4
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1885

A. Kirschning et al.
Reactors: Principally, we utilized two different reactor mate-
rials: glass and PEEK (polyether ether ketone). These mate-
rials do not heat up in an inductive field. The glass reactors
consisted of simple glass tubes equipped with screw caps
and Kalrez gaskets. The advantages of this design are the
low cost, easy adjustability of the reactor diameters, and the
simple setup. However, a disadvantage of these reactors is
that the gaskets are only tight up to a pressure of approxi-
mately 3–5 bar. However, in flow synthesis it is often benefi-
cial to apply temperatures above the boiling point of the sol-
vent, which can be exploited to accelerate reactions. Under
these conditions a backpressure regulator has to be included
into the flow system. We found that tailor made PEEK reac-
tors are ideal components for carrying out high tempera-
ture–high pressure reactions. PEEK is a high performance
polymer that resists high temperature and pressure and that
is inert to most common chemicals and solvents. Further-
more, it can easily be processed for the manufacturing of
many different reactor designs. We equipped these reactors
with screw caps also made of PEEK and with Kalrez gaskets
so that the reactor could directly be attached to HPLC fit-
tings. Those reactors can at least withstand pressures of up
to 20 bar and temperatures of up to 2208C without signifi-
cant decrease in stability (Figure 1). Still, it needs to be kept
in mind that compared with glass PEEK is an expensive ma-
terial.
Figure 3. Steel beads with a diameter of 0.8 mm.
The dimensions of our standard glass and PEEK reactors
are 12 cm in length with an internal diameter of 8.5 mm.
The void volume (left for the fluid) of the reactor packed
with 1 is approximately 4 mL (Figure 5). In addition to these
Figure 4. Heating profiles of ferromagnetic steel beads of various diame-
ter (1) in an inductive field; 1=2.0 (^), 5.0 (
), 0.8 mm (~).
&
spaces between them, which in turn leads to poorer heat
transfer into the stream of reactants and hence to reduced
reaction kinetics. Therefore, we commonly employed steel
beads with a diameter of 0.8 mm, which turned out to be an
ideal compromise between efficient heating and a high sur-
face-to-heat-transfer ratio. It should be noted that copper
[10b]
can also serve as heatable fixed-bed material.
Ferromagnetic nanopowders like 1 and other heating
media, such as steel beads, can be regarded to be comple-
mentary to each other and should be individually chosen for
a given reaction. Importantly, the silica surface in 1 can be
functionalized, which is a property that steel beads lack. In
contrast, the silanol groups on the outer silica shell that
allow for further functionalization can, in some cases, inter-
fere with reagents rendering them inactive. This drawback
does not occur with steel beads. The silica shell also causes
problems in reactions in which protic solvents are required,
especially at very low or very high pH values. Under these
conditions, the nanoparticles may be destroyed or blockage
of the flow system is observed. Steel beads heat up very effi-
ciently and hot spots may occur on their surface, which may
cause destruction of sensitive substrates or reagents. We
found that in those cases the application of 1 gave better re-
sults. It has to be noted that from a monetary point of view
steel beads with a diameter of 0.8 mm do not have any ad-
vantage compared with 1.
Figure 5. Examples of microstructured flow reactors: a) glass reactor,
b) PEEK reactor, c) PEEK reactor encased with the inductor.
standard reactors we utilized smaller glass reactors (12 cm
length and 5.0 mm internal diameter and 12 cm length and
3.0 mm internal diameter), as well as larger PEEK reactors
(31 cm length and 20 mm internal diameter) in combination
with the appropriate inductors. Reactions could be operated
in a circular or alternatively in a continuous mode. Com-
monly, we optimized reaction parameters (concentration of
reactants, flow rates, induction parameters for heating) to
achieve full conversion in a single pass.
Inductors/generators: The inductors and generators were de-
veloped to serve our purpose (see the Acknowledgements
1886
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Inductive Heating with Magnetic Materials inside Flow Reactors
and the Experimental Section) by specifically being adjusted
FULL PAPER
pared with the measured bulk temperatures. This effect has
[11]
[14]
to the whole system. The small-sized inductors are suited
to accommodate small flow reactors and are commonly air
cooled (Figure 5). In the case of the larger reactors the in-
ductors had to be water cooled. They are constructed of fer-
rite cores and are encased in an epoxide resin. The genera-
tors are connected to a medium-frequency transformer that
is also water cooled. The power that is transferred into the
heatable material by magnetic induction is determined by
the frequency applied and the modulation of the electric
pulse (output power or ppm). For smaller particles a high
frequency had to be chosen, whereas for larger particles
previously been described in another context. Therefore,
this result indicates that inductive heating with superpara-
magnetic particles, such as 1, is not only a new principal
heating technology for synthesis, but is also a competitive
technique for fast and efficient heating in the batch mode.
Furthermore, the preliminary results demonstrated that it is
comparable to microwave heating. Removal of the magnetic
material was achieved either by applying a magnet or by
simple filtration and the heating material can immediately
be reused after washing with an organic solvent like toluene
or CH Cl and drying.
2
2
(
e.g., steel beads) a lower frequency turned out to be benefi-
cial. Therefore, we set a certain frequency for every heating
media and modified the output power for adjusting the tem-
perature.
Reactions: Herein, we provide a broad scope of different re-
actions (transfer hydrogenations, heterocyclic condensations,
pericyclic reactions, organometallic reactions, multicompo-
nent reactions, reductive cyclizations, homogeneous and het-
erogeneous transition-metal catalysis), many of which have
never been reported under flow conditions, to demonstrate
the general utility of this heating technique in combination
with flow synthesis and thereby providing information on
the chemical stability of silica coated superparamagnetic
nanoparticles like 1 under very different reaction conditions.
For comparison reasons, the reactions were also performed
in the batch mode using conventional heating.
Comparison studies in the batch mode: To compare the in-
ductive heating concept with well-established heating meth-
ods we chose a set of experiments in which we conducted a
high-temperature sigmatropic Claisen rearrangement of ally-
laryl ether 2 to phenol 3 (Scheme 1) under batch mode con-
Transfer hydrogenations: We first investigated several prin-
cipal thermal reactions under flow conditions for which in-
ductive heating had to serve as the thermal energy source.
In many cases conditions reported for batch reactions had
to be modified and optimized to guarantee homogeneous
conditions throughout the flow process. Transfer hydrogena-
tions of various functional groups have occasionally been
[15]
employed in flow applications.
Under inductive heating
conditions with 1 in the presence of Pd (10%) on charcoal
as the packed bed, transfer hydrogenations of benzyl ethers
Scheme 1. Comparison between conventional heating (external oil bath),
microwave (mw) irradiation, and inductive heating under batch-mode
conditions.
4
and 5, nitroarenes 8 and 9, alkene 12, and alkyne 14 pro-
ceeded smoothly to give the corresponding reaction prod-
ucts 6, 7, 10, 11, 13, and 15 under continuous flow conditions
in good to excellent yields. Cyclohexene/EtOH was used as
the reductant (Scheme 2) and a standard glass reactor with a
void volume of 4 mL was used.
ditions employing all three heating techniques, that is, oil
bath, microwave irradiation, and inductive heating. From
[12]
our synthetic studies on geldanamycin we knew that the
chosen reaction only proceeds with moderate yield, a pre-
requisite for a comparison study. The experiments were con-
ducted in a closed vessel because the applied temperature of
Typically, flow rates were chosen between 0.2 to
À1
0.5 mLmin to guarantee complete transformation in one
pass. From these flow rates residence times inside the reac-
À1
tor were calculated to be between 8 (0.5 mLmin ) and
À1 [16]
2008C is well above the boiling point of toluene. In the oil
20 min (0.2 mLmin ). Yields were comparable or better
bath only 17% of the product was isolated after 2 h, where-
as microwave heating gave 38% of the product. In the mi-
crowave experiment SiC had to be added to the reaction
mixture because toluene does not sufficiently absorb micro-
wave irradiation. Inductive heating in the presence of 1
afforded the rearranged product 3 in 39% yield after
to those that were obtained under batch conditions. More
importantly, the reaction time was minimized dramatically,
which can be attributed to the close contact of the palladium
catalyst with the reactants and the high local concentration
of the catalyst. Additionally, we cannot exclude the fact that
the superparamagnetic nanoparticles could have a higher
local temperature than the temperature measured for the
fluid (hot-spot effect). It must be noted that the same reac-
tor was repeatedly used for different hydrogenations with-
out loss of heating efficiency which exemplifies the thermal
[13]
120 min. The difference in conversion comparing micro-
wave-assisted and inductive heating with conductive heating
can be explained by the expected higher local temperature
on the surface of the MAGSILICA and SiC particles com-
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1887

A. Kirschning et al.
[18]
et al. had to be further optimized for the flow system. The
,4-dihydro-2-methyl-3-oxo-2H-benzoxazines 18 and 19,
3
formed by reaction of ethyl 2-bromopropionate and 2-ami-
nophenols 16 and 17, were isolated in 80 and 82% yield, re-
spectively. For comparison reasons, the batch mode reac-
tions, conducted under the same conditions, afforded the
heterocycles in slightly higher yields. As a second example
[19]
we chose the Friedlꢂnder synthesis of quinoline 22 from
-aminoacetophenone (20) and 4-bromoacetophenone (21).
2
Instead of acidic conditions we had to conduct the reaction
under basic conditions (KOH in EtOH) because the materi-
al of the pumps employed would not withstand the acidic
conditions. Gratifyingly, we found that quinoline 22 was gen-
erated in very high yield under batch conditions. Under flow
conditions full conversion was observed, but we only isolat-
ed the product in a moderate yield of 67%. The concentra-
tion of the base is high during the reaction (in comparative
experiments with less equivalents of base only low conver-
sions were observed), which may cause partial decomposi-
tion of the fixed bed material.
Pericyclic reactions: Next, we investigated different pericy-
[20]
clic reactions,
such as Diels–Alder cycloadditions
(
Scheme 4a and b), the Alder-ene reaction (Scheme 4c), and
a decarboxylation (Scheme 4d) using 1 or steel beads as the
Scheme 2. Continuous (single pass) flow transfer hydrogenations with in-
ductive heating (yields of the isolated products are reported).
and chemical stability of the fixed bed under the conditions
employed.
Heterocyclic condensations: Another group of important re-
actions are heterocyclizations, most of which are condensa-
tions. In Scheme 3 some representative examples for the
continuous flow synthesis of heterocycles are depicted. The
first one concerns the synthesis of 2H-1,4-benzoxazin-3-
(
4H)-ones, a scaffold frequently found in biologically active
[17]
compounds.
The batch mode protocol, reported by Dai
Scheme 4. Continuous (single pass) flow pericyclic reactions (yields of
the isolated products are reported); brsm=based on recovered starting
material.
Scheme 3. Continuous (single pass) flow synthesis of heterocycles by con-
densation reactions (yields of the isolated products are reported).
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Inductive Heating with Magnetic Materials inside Flow Reactors
FULL PAPER
fixed-bed materials. The cycloaddition of anthracene (23)
with maleic anhydride (24) was carried out in a mixture of
fairly complex. Typically, three sometimes four different
building blocks are mixed and heated to achieve full conver-
sion. These reactions have found broad application in the
parallel high-throughput preparation of potential drug can-
anisole/DMF to solubilize the reactants. The flow rate was
À1
0
.2 mLmin , which equals a residence time of about 20 min
[16]
[29]
inside the reactor.
The cycloadduct 25 was isolated in
didates. As representative examples, we selected the Bigi-
[30]
[31]
[32]
7
5% yield, along with a small portion of unreacted anthra-
nelli,
Mannich,
and Petasis
reactions. Experiments
[21]
cene (12%). The continuous flow experiment gave signifi-
cantly better results than the corresponding reaction under
batch conditions. In the second example, a solution of 3-for-
mylchromone (26) and n-butyl vinyl ether (27) in DMF was
pumped through a MAGSILICA-filled reactor at a flow
were conducted under continuous flow conditions by using 1
or steel beads as inductively heated fixed-bed materials
(Scheme 6). For the Biginelli reaction, we encountered a sol-
[33]
ubility issue for urea (38) and products 41 and 42. This
problem was overcome by using a mixture of polyethylene
glycol PEG-200 and DMF. The 3,4-dihydropyrimidin-2-ones
41 and 42 were formed in moderate to good yields with
À1
rate of 0.1 mLmin affording the endo and exo cycload-
ducts 28a and 28b isolated in good yield and in a ratio of
2.4:1. The batch experiment gave the cycloadducts 28a and
2
8b in a similar yield and with a diastereoisomeric ratio
[22]
(
d.r.) of 3.5:1. This series of pericyclic reactions was com-
pleted with the Alder-ene reaction of b-pinene (29) with di-
[23]
ethyl mesoxalate (30). When MAGSILICA 1 was used as
heating material, the adduct 31 was isolated in 52% yield.
When steel beads were used instead, the yield increased to
64%. This result indicates that in selected cases steel beads
are a good alternative to superparamagnetic particles such
as 1. The corresponding batch Alder-ene experiment gave
product 31 in lower yield (40%). Finally, we performed the
decarboxylation of allylmalonic acid (32) under flow condi-
tions to yield pent-4-enoic acid (33) in 78% yield
À1
[24]
(
0.2 mLmin ; residence time 20 min).
In a comparative
batch experiment full conversion of the substrate was
reached after 1.5 h to give the isolated product in 85%
yield. Pleasingly, simple aqueous workup and subsequent re-
moval of the solvent gave pure 33.
Organometallic reactions: We further extended our studies
to an organometallic reaction, the Reformatzky reaction,
using
Zn as an
additional
fixed-bed material
[25,26]
(
Scheme 5).
Acetophenone (34) and 2-bromopropanoic
ethyl ester (35) were coupled to give 36 under continuous
flow conditions with in situ formation of the intermediate
[27]
organozinc species.
In a comparative experiment in the
flask, compound 36 was formed in only 35% yield. These
results show that 1 can be employed in the presence of a
metal and an organometallic species.
Scheme 5. Continuous (single pass) flow organometallic reactions (yields
of the isolated products are reported).
Multicomponent (MCP) reactions: A particularly attractive
application for performing synthesis in microstructured flow
[28]
devices are multicomponent (MCP) reactions. These reac-
tions rapidly provide products that are structurally already
Scheme 6. Continuous (single pass) flow multicomponent reactions
(yields of the isolated products are reported).
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1889

A. Kirschning et al.
para-toluenesulfonic acid (PTSA) as the catalyst. Batch-
mode reactions under the same conditions afforded the
products 41 and 42 in comparable yields (58 and 54%, re-
spectively). We also evaluated the asymmetric three-compo-
nent Mannich reaction, catalyzed by (S)-proline. Several
groups showed that organocatalyzed reactions can be ther-
mally accelerated, without compromising on the enantiocon-
[
34]
trol.
formaldehyde (44), and aniline (45) in DMSO, containing
Consequently, a solution of cyclohexanone (43),
1
6
0 mol% of (S)-proline, was pumped through the reactor at
58C. A flow rate of 0.07 mLmin , which equals a resi-
À1
dence time of 60 min led to the b-aminoketone 46 in 85%
yield with 88% enantiomeric excess (ee). The same reaction
in a flask gave a lower yield but slightly higher enantioselec-
tivity (64% yield and 92% ee). Next, we studied the Petasis
Scheme 7. Reductive cyclizations (single pass) in flow using PEEK reac-
tors (yields of the isolated products are given).
[35]
or boronic Mannich reaction. Glyoxalic acid (48) and sali-
cylic aldehyde (51), respectively, were reacted with morpho-
line (47) and para-methoxyphenyl boronic acid (49). The re-
action was conducted in 1-propanol with moderate heating
and in both cases the desired products 50 and 52, respective-
ly, were obtained in excellent yields (98 and 93%). When
the Petasis reaction was carried out under batch mode con-
ditions, the products 50 and 52 were formed in lower yields
toluene (3:1) through a MAGSILICA-filled reactor at
1498C. Dihydrobenzoxazine 60 was isolated in 52% yield,
[38]
which is close to the reported literature value.
Again,
when higher, as well as lower, temperatures were applied
the yield decreased in both cases. Higher temperatures led
to decomposition of the starting material and lower temper-
atures led to a decrease in conversion at the given flow rate.
Importantly, the latter reaction was performed under high
pressure and high temperature conditions at 100 psi back
pressure.
(
77 and 87%, respectively).
Apart from these well-established multicomponent reac-
tions,
we
also
investigated
the
synthesis
of
furo[3’,4’:5,6]pyridoACHTUNGTRENNUNG
reaction. This nitrogen-containing tetracycle was synthe-
[2,3-d]pyrimidine in a three-component
[36]
sized by passing a solution of para-chlorobenzaldehyde (53),
Homogeneous transition-metal catalysis: An important
indandione (54), and 2,6-diaminopyrimidin-4
A
H
U
G
R
N
N
(3H)-one (55)
group of transformations that often requires heat are transi-
[39]
in wet DMF through a reactor filled with MAGSILICA (1)
at 1008C. Under these reaction conditions, full conversion
could be achieved and the pure product 56 (87% yield)
crystallized upon addition of water. The corresponding
batch reaction employing the same reaction conditions af-
forded 56 only after an extended reaction time of 3 h in
tion-metal-catalyzed CÀC and CÀX coupling reactions. As
illustrative examples, we investigated the palladium-cata-
lyzed tandem synthesis of benzofuran 63 and phenylindole
65 (Scheme 8). Gratifyingly, these palladium- catalyzed reac-
tions were not affected or inhibited by the inductively
heated MAGSILICA particles. Thus, 2-phenyl benzofuran
(63) was obtained by a continuous Sonogashira–Hagihara
70% yield.
coupling cyclization sequence in
manner. For this reaction a solution of the starting materi-
a
straightforward
[40]
Reductive cyclizations: An alternative way to access nitro-
gen-containing heterocycles is by reductive cyclization of ni-
troarenes using phosphite as a reductant. Although these re-
actions are postulated to proceed via highly reactive arylni-
trene and arylnitroso intermediates, they could smoothly be
conducted under inductive heating conditions in the flow
mode (Scheme 7). Thus, aminopyridylpyrazole 57 could be
converted into betaine 58 under flow conditions at 1498C by
using steel beads inside a PEEK reactor. If higher tempera-
tures were employed, complete decomposition of the start-
[37]
ing material was encountered.
The literature protocol
could not be used, because of solubility issues. Thus, the re-
action had to be carried out in a mixture of triethylphos-
phite and DMF 3:1, instead. When the reaction was repeat-
ed under the same conditions in the batch mode the product
was formed in slightly higher yield (50%); however, no
starting material could be recovered. The synthesis of dihy-
drobenzoxazine 60 was achieved by passing allyl 2-nitrophe-
nylether 59 dissolved in a mixture of triethylphosphite and
Scheme 8. Pd-catalyzed tandem reactions with inductive heating (yields
of the isolated products are given).
1890
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Chem. Eur. J. 2011, 17, 1884 – 1893

Inductive Heating with Magnetic Materials inside Flow Reactors
FULL PAPER
als and reagents was passed through a glass reactor filled
with steal beads at 1108C. Pleasingly, under the conditions
employed (tetrabutylammonium acetate (TBAA; 2 equiv),
PdCl2 (1 mol%), N-methylpyrrolidone (NMP; 0.33m),
1108C, 2 h) the flow setup allowed us to improve the yield
and reaction time compared with the batch procedure. Al-
though 2-phenyl benzofuran (63) could be synthesized in a
tandem reaction, 2-phenylindole (65) had to be prepared
from an advanced intermediate, the substituted aniline 64,
in a single step by directing a stream of the reaction mixture
through a MAGSILICA-filled glass reactor at 808C. For full
conversion, the literature batch procedure had to be opti-
mized to guarantee homogeneity throughout the process.
The solvent system was changed from dichloroethane to a
mixture of dichloroethane and DMF and instead of PdCl2/
Scheme 10. Selected examples of Pd-catalyzed cross-coupling reactions
with Pd-doped MAGSILICA 67 (yields of the isolated products are
given).
[41]
reduced or even erased. To prove this hypothesis and to as-
certain that the products are not contaminated we measured
the leaching of iron into solution under inductive heating
conditions. MAGSILICA 1 was heated at 80 and 1208C
inside the microstructured flow reactor in different common
solvents. The system was flushed with the solvent for 20 min
FeCl ·6H O, [(MeCN) Pd] ACHTUNGTRENNNU(G BF ) /FeCl ·6H O was employed.
4 2 3 2
3
2
4
Interestingly, this catalytic system only afforded indole 65 in
5
7
0% yield under batch conditions, but under flow conditions
0% of the product was formed in a shorter reaction time.
À1
at a flow rate of 0.1 mLmin after which time a sample was
Heterogeneous transition-metal catalysis: With these results
collected. This sample was treated with nitric acid and ana-
lyzed by ICP-OES (inductively coupled plasma optical emis-
sion spectroscopy) (Table 1). The amount of iron released
into the solution was found to be very low and close to the
bottom limit of the sensitivity range (0.1 ppm). Only in the
case of PEG we encountered a significant degree of leaching
in hand we initiated a program to immobilize the palladium
[5]
species on the silica shell of our nanomaterial 1. We found
that palladium particles obtained by reductive precipitation
of ammonium-bound tetrachloropalladate gave nanoparti-
cles 67 (Scheme 9). Based on our earlier studies of doping
(
Table 1, entry 4), which is likely to be associated with the
[43]
excellent metal-chelating properties of PEG.
Table 1. Leaching experiments for 1 in different solvents.
Entry
Solvent
Fe amount
at 808C [ppm]
Fe amount
at 1208C [ppm]
[
a]
[a]
1
2
3
4
5
dodecane
toluene
DMF
PEG
ethanol
0.15
0.15
0.17
5.49
0.15
0.46
0.11
0.34
2.65
0.25
[
a] Determination of Fe content by ICP-OES analysis (Æ0.003; 2%)
0
Scheme 9. Preparation of magnetic nanoparticles 67 doped with Pd .
These results clearly demonstrate that the silica shell in 1
Merrifield-type ion-exchange resins with Pd nanoparti-
serves as good protection for the iron oxide core, which is
further supported by the fact that fixed beds made of 1 can
be reused for several dozen reactions without a decrease or
loss of the heating performance by electromagnetic induc-
tion. Typically, the reactor was washed after each experi-
ment with an appropriate solvent to remove any remaining
traces before the system could be preflushed with the sol-
vent required for the next reaction. Thus, we never had to
clear the reactor in between different runs.
[
42,15]
cles
we first transformed the silica shell in 1 and created
superparamagnetic core-shell nanoparticles 66 that showed
ion-exchange properties. We used these Pd-doped particles
6
7 in Suzuki–Miyaura and Heck reactions (Scheme 10). In
these reactions only a little leaching of palladium was found
inductively coupled plasma mass spectrometry (ICP-MS)
analysis indicated 34 ppm for Suzuki–Miyaura reactions and
00 ppm for Heck reactions) and the same catalyst could be
(
1
reused for more than 3 times without a decrease in activity.
Leaching experiments: An important feature of 1 is the
silica shell, which should chemically protect the magnetite/
maghemite core. Furthermore, the shell is expected to sup-
press agglomeration of the Fe O /Fe O particles. If this hap-
Conclusion
We described the inductive heating of silica-coated super-
paramagnetic nanoparticles, as well as steel beads, inside mi-
crostructured nanoparticles and the use of this flow system
2
3
3
4
pens, superparamagnetic and heating properties would be
Chem. Eur. J. 2011, 17, 1884 – 1893
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1891

A. Kirschning et al.
in organic synthesis. Clearly, a very diverse number of chem-
ical reactions can be conducted in a flow mode, so that this
new heating concept can be regarded to be of general utility
and importance. In addition, we showed that the silica coat-
ing covering and protecting the Fe O nanoparticles can be
niz Universitꢂt Hannover) is gratefully acknowledged for the ICP-OES
analyses to measure the degree of iron leaching. We thank Dr. C. Friese
(
PIT, Plasma-Induction-Technology, Dꢁsseldorf) for helpful discussions
and K. Poscharny for experimental support.
3
4
further modified with catalytically active palladium. From
our experience, the technical setup is much simpler than cor-
responding microwave devices when performing chemistry
under flow conditions. Also, leaching of metal species is
minimal and in-line scavengers can be applied if necessary.
Furthermore, the reactor concept is simple and can be
adapted to other flow systems too. In view of the dramatic
increase in interest for flow chemistry we believe that this
new heating technology has future prospects both in aca-
demia and industry.
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Experimental Section
1
General methods: H NMR spectra were recorded at 400 MHz with a
1
3
Bruker AVS-400 spectrometer. C NMR spectra were recorded at
1
7
00 MHz with a Bruker AVS-400. Mass spectra (EI) were obtained at
0 eV with a type VG Autospec apparatus (Micromass) or with a type
LCT (ESI) (Micromass). Analytical TLC was performed using precoated
silica gel 60 F254 plates (Merck, Darmstadt), and the spots were visualized
2 4
with UV light at 254 nm or by staining with H SO /4-methoxybenzalde-
hyde in ethanol. Flash column chromatography was performed on Merck
silica gel 60 (230–400 mesh). The inductor was constructed by IFF
GmbH (Ismaning, Germany). Pumps were obtained from Knauer GmbH
Berlin, Germany). MAGSILICA 1 was provided by EVONIK Degussa
GmbH (Essen, Germany). Steel beads (0.8 mm, 2.0 mm and 4.8 mm)
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Acknowledgements
This work was supported by the Fonds der Chemischen Industrie. We
thank Henkel AG & KGaA (Dꢁsseldorf, Germany), EVONIK Degussa
GmbH (Essen, Germany), and IFF GmbH (Mꢁnchen, Germany) for fi-
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1892
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ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 1884 – 1893

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FULL PAPER
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Published online: January 7, 2011
Chem. Eur. J. 2011, 17, 1884 – 1893
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1893