Microwave-induced electrostatic etching: Generation of highly reactive magnesium for application in Grignard reagent formation

Article abstract of DOI:10.1039/b926391h

A detailed study regarding the influence of microwave irradiation on the formation of a series of Grignard reagents in terms of rates and selectivities has revealed that these heterogeneous reactions may display a beneficial microwave effect. The interaction between microwaves and magnesium turnings generates violent electrostatic discharges. These discharges on magnesium lead to melting of the magnesium surface, thus generating highly active magnesium particles. As compared to conventional operation the microwave-induced discharges on the magnesium surface lead to considerably shorter initiation times for the insertion of magnesium in selected substrates (i.e. halothiophenes, halopyridines, octyl halides, and halobenzenes). Thermographic imaging and surface characterization by scanning electron microscopy showed that neither selective heating nor a "specific" microwave effect was causing the reduction in initiation times. This novel and straightforward initiation method eliminates the use of toxic and environmentally adverse initiators. Thus, this initiation method limits the formation of by-products. We clearly demonstrated that microwave irradiation enables fast Grignard reagent formation. Therefore, microwave technology is promising for process intensification of Grignard based coupling reactions.

Full text of DOI:10.1039/b926391h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Microwave-induced electrostatic etching: generation of highly reactive
magnesium for application in Grignard reagent formation†
a
a
b
a
Bastiaan H. P. van de Kruijs, Mark H. C. L. Dressen, Jan Meuldijk, Jef A. J. M. Vekemans and
Lumbertus A. Hulshof*
a
Received 9th December 2009, Accepted 1st February 2010
First published as an Advance Article on the web 1st March 2010
DOI: 10.1039/b926391h
A detailed study regarding the influence of microwave irradiation on the formation of a series of
Grignard reagents in terms of rates and selectivities has revealed that these heterogeneous reactions
may display a beneficial microwave effect. The interaction between microwaves and magnesium
turnings generates violent electrostatic discharges. These discharges on magnesium lead to melting of
the magnesium surface, thus generating highly active magnesium particles. As compared to
conventional operation the microwave-induced discharges on the magnesium surface lead to
considerably shorter initiation times for the insertion of magnesium in selected substrates (i.e.
halothiophenes, halopyridines, octyl halides, and halobenzenes). Thermographic imaging and surface
characterization by scanning electron microscopy showed that neither selective heating nor a “specific”
microwave effect was causing the reduction in initiation times. This novel and straightforward initiation
method eliminates the use of toxic and environmentally adverse initiators. Thus, this initiation method
limits the formation of by-products. We clearly demonstrated that microwave irradiation enables fast
Grignard reagent formation. Therefore, microwave technology is promising for process intensification
of Grignard based coupling reactions.
Introduction
the pressure was much higher than atmospheric which is not
advantageous when working on a larger scale. However, we were
the first to report the microwave-heated formation of these
1
The use of microwave heating in accelerating organic reactions
as compared to conventional heating techniques (referred to as
a positive microwave effect ) has attracted increased attention
of organic chemists over the past decade. A novel approach
to apply microwave technology in organometallic chemistry
4
reagents at atmospheric pressure and without using an initiator
2
(
e.g. iodine, dibromoethane.). It was demonstrated that microwave
3
heating can, for certain substrates, replace the initiators as an
initiation method. During irradiation in an inert argon atmosphere
violent blue arcing is observed (see Fig. 1). The mechanism of this
particular activation is, however, unknown which challenged us to
gain more insight in these arcing phenomena. Especially the role
of selective heating and the electrical discharges were studied in
detail. Also the applicability of the activation method was screened
for a series of substrates.
4
has been elaborated. Previously reported results teach that
heterogeneous reaction mixtures are most promising to show a
positive microwave effect. One of the most common and useful
heterogeneous organometallic reactions is the Grignard reagent
5
formation. Detailed studies on Grignard reagent formations have
6–9
been previously reported. Nevertheless, performing the reaction
can be difficult, the initiation times for the reaction are often
not reproducible, and may depend on the experimental skills
of the chemist. The reproducibility of the initiation step can be
10–14
improved by various techniques.
A relatively novel activation
method is the application of microwave irradiation. In literature
the formation of Grignard reagents by microwave irradiation in
sealed vessels at temperatures above the normal boiling points of
15–16
the solvents has been reported.
In these reported experiments
a
Eindhoven University of Technology, Department of Chemical Engineering
and Chemistry, Laboratory of Macromolecular and Organic Chemistry,
Applied Organic Chemistry, P.O Box 513, 5600 MB, Eindhoven, the
Netherlands. E-mail: L.A.Hulshof@tue.nl
b
Eindhoven University of Technology, Department of Chemical Engineering
and Chemistry, Process Development Group, P.O Box 513, 5600 MB,
Eindhoven, The Netherlands
†
This paper is part of an Organic & Biomolecular Chemistry web theme
Fig. 1 Violent blue arcing induced by irradiating magnesium turnings
with microwaves.
issue on enabling technologies for organic synthesis.
1
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Results and discussion
The influence of microwave irradiation on magnesium: is selective
heating the cause of the reduced initiation times?
It is obvious that microwave irradiation considerably reduces the
inhibition period of the initiation accompanying the Grignard
reagent formation. However, it is unclear whether selective heating
of the magnesium is the rationale of the reduction of the inhibition
period. In the first place, to get insight into the interaction of
magnesium with microwaves, heating experiments in the absence
of all reagents except magnesium and solvent were conducted.
Magnesium samples of different sizes were compared and the
temperature-time history was recorded, see Fig. 2.
Fig. 3 a Thermographic imaging: magnesium ribbon submerged in
THF. The dark rod in the upper left corner of the vessel is a tube supplying
argon above the solvent surface. The pale and diffuse half circle is the
ribbon submerged in THF. b Thermographic imaging: circular magnesium
ribbon in upright position partially above the gas/THF surface.
convection. In this temperature range no boiling of the solvent
occurs, thus eliminating the effect of preferred nucleation sites for
boiling on the magnesium surface. Fig. 3b shows a magnesium
ribbon partly above the THF surface. Surprisingly, the part of the
ribbon at the gas/THF surface displays no heating, as seen by the
darker color in the middle of the vessel. It can be concluded that
heating of the magnesium occurs in a layer at the magnesium/THF
boundary and is only observed for relatively large metal objects
Fig. 2 Temperature-time history of solvent (20 mL) and magnesium
samples of different sizes (0.2 g) under microwave irradiation (100 W).
(
Filled squares): THF, (open circles): THF and magnesium ribbon, (solid
line): THF and magnesium turnings, (dashed line): THF and magnesium
powder.
The results in Fig. 2 demonstrate that the size of the metal
particles strongly influences the heating rate of the mixture. A
magnesium ribbon submerged in THF showed rapid heating of the
mixture resulting in boiling at the surface of the ribbon. Arcing
was not observed. Magnesium turnings submerged in THF on
the other hand showed a heating pattern similar to that of pure
THF and substantial arcing. Also magnesium powder showed a
temperature-time history similar to that of pure THF. In this case
arcing was not observed. Hence, the appearance of the magnesium
plays a dominant role in the interaction of magnesium with
microwaves. The similar temperature-time history observed for
pure THF and the turnings in THF suggests that no significant
heat transfer from the magnesium particles to the solvent occurs.
These observations point to the absence of selective heating of
the magnesium turnings. To further detect any selective heating,
(
i.e. a ribbon). Therefore, selective heating of the magnesium
turnings is certainly not the origin of the decrease in initiation
time.
The influence of microwave irradiation on magnesium: electrical
discharges
The interaction of microwave irradiation with magnesium turnings
used for Grignard reagent formation causes charge generation
on the magnesium surface leading to a charge imbalance on the
surface of the magnesium. With large particles, such as ribbons, a
current on the metal is generated resulting into selective heating.
For smaller particles the charge is more or less trapped and released
by an electrical breakdown of the dielectric medium between two
opposite charged particles resulting into an arc. The possibility
that these electrical discharges give rise to the large decrease in
initiation and reaction time was further investigated using SEM
(scanning electron microscopy) and XPS (X-ray photoelectron
spectroscopy).
The arcing influences the surface of the magnesium dramatically
which is already noticeable by low magnification as shown in
Fig. 4. The microwave-heated turnings in THF were compared
with those treated by refluxing THF through oil-bath heating
to ensure exclusion of any solvent effects at the surface. The
impact area of the arcing is clearly visible in Fig. 4b. Fig. 5
17
thermographic imaging was applied. A camera was placed
above an open 6 cm diameter reaction tube to detect infrared
radiation emitted from a sample. The image was recorded by
transmission in an argon atmosphere. As expected the recording
of the microwave-irradiated magnesium turnings in THF did
not show selective heating. The thermographic images of the
irradiation of a magnesium ribbon are shown in Fig. 3a and
3
b. Fig. 3a depicts a magnesium ribbon submerged in THF
showing the selective heating of the ribbon. Note that THF is
not transparent for the wavelength used by this infrared camera
and the heating ring shown in the picture is a result of natural
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Fig. 4 SEM images of a magnesium turning treated in refluxing THF by a) oil-bath heating and b) microwave heating. The circles indicate the impact
area of the microwave-induced electrical discharges.
Fig. 5 SEM images of magnesium turnings after microwave irradiation: left: spherical objects that remain in the cavities of the surface after removal of
THF and right: impact area of the arc showing disruption of the magnesium surface and formation of cavities.
(
right) shows that the impact of the arcs on the surface causes
formation after prolonged arcing without traces of a reactive
organic halide. This may suggest that the arcing only facilitates
side reactions with the solvent. In the presence of reactive organic
halides, the formation of arcing-induced magnesium carbide from
the solvent is severely hampered. This observation, combined
with the fast oxidation observed for the spherical particles
after short exposure to air, stresses the reactive nature of the
magnesium produced by microwave-induced electrical discharges.
This reactive nature is mainly due to the high surface area to
volume ratio and lack of inhibiting magnesium oxide/hydroxide
layers.
a distortion of the magnesium surface. Probably this distortion
also influences the magnesium oxide/magnesium hydroxide layer.
A magnesium oxide/magnesium hydroxide layer is always present
on non-activated magnesium. This layer prevents an immedi-
ate reaction with organic halides. The etching causes metallic
18
0
magnesium (Mg ) to be exposed to the reactant. During the
investigation of the arcing phenomenon it was also discovered
that, when arcing is induced in the absence of a reactive organic
halide, the solvent becomes turbid. A black dispersion of small
magnesium particles is produced. The shape of the particles in
this dispersion is predominantly spherical, see Fig. 5 (left). The
formation of these spherical magnesium particles is induced by
the impact of high electrical currents, caused by the arc, at the
magnesium surface. These currents give rise to extremely high local
temperatures, which are not generated by the direct absorption
of microwave energy, and melting of the magnesium occurs. The
molten magnesium is transferred to the solvent phase and is
cooled almost instantaneously which leads to a preservation of
the spherical geometry that is adopted in the molten state. The
size of the produced particles varies between about 5 mm and
Application of microwave-induced electrical discharges in the
Grignard reagent formation
To demonstrate the applicability of microwave-induced electrical
discharges for the Grignard reagent formation a series of halo-
genated compounds was tested. The time-conversion histories
of the Grignard reagent formation was monitored by GC-MS
analyses of small aliquots quenched by saturated ammonium
chloride. For the determination of the yield of the Grignard
reagent a suitable consecutive reaction had to be performed.
A series of quenching reactions was evaluated. The ease of
purification and isolation of the product, the absence of ketone
corresponding to the produced alcohol accompanied by equimolar
amounts of benzyl alcohol by-products, and quantitative yields
5
0 mm, see Fig. 5 (left). The generation of this type of spherical
debris by electrical discharges in electrical discharge machining
(
never investigated. The results of the elemental analysis of these
particles by XPS showed a large degree of magnesium carbide
19
EDM) is known but the impact on synthetic chemistry was
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Table 1 Grignard reagent synthesis of selected substrates under microwave irradiation and conventional heating (oil bath), step 1, and subsequent
quenching reactions, step 2
Entry
R
X
Conditions step 1
Conditions step 2
Product (P)
1
2
3
4
2-Br
2-Br
2-Cl
2-Cl
A
B
A
B
C
C
C
C
5
6
7
8
2-Br
2-Br
2-Cl
2-Cl
A
B
A
B
D
D
D
D
9
1
3-Br
3-Br
A
B
D
D
0
1
1
Br
Br
A
B
E
C
1
2
1
1
3
4
I
I
A
B
C
C
1
1
5
6
n-C
n-C
8
8
H
H
17
17
Br
Br
A
B
C
C
n-C
n-C
8
8
H
H
17COOH
17COOH
1
1
7
8
n-C
n-C
8
8
H
H
17
17
Cl
Cl
A
B
C
C
n-C
n-C
8
8
H
H
17COOH
17COOH
◦
◦
◦
◦
A: oil-bath reflux (66 C), B: microwave, reflux (66 C), max power = 300 W, C: dry CO
2
, -78 C, D: benzaldehyde, 66 C, E: CS
2
, room temperature.
for the addition reaction, i.e. the Grignard reagent present reacts
quantitatively with the CO , made the reaction with carbon
dioxide the best choice for analyzing reactive Grignard reagents.
The maximum of 90% yield is due to the loss of starting
material during the Grignard reagent formation. The analogous
Table 2 depicts the initiation and reaction times with corre-
sponding yields for these reactions. The lower isolated yields
under microwave irradiation are mainly caused by a difficult layer
separation in the work-up procedure of the formed acid due to
residual magnesium carbide particles. The yields determined in the
crude reaction mixture were similar under both heating methods.
Further optimization of the work-up procedure may minimize
these losses.
2
reaction with CS was also almost completely selective and gave
2
an approximately 100% yield for the addition reaction of the
Grignard reagent. Relatively unreactive, or insoluble, Grignard
reagents, i.e. 3-halopyridine Grignard reagents, can be reacted
with benzaldehyde at reflux temperature showing moderate yields
and minor by-product formation. The undesired formation of
the ketone corresponding to the secondary alcohol together with
equimolar amounts of benzyl alcohol is clearly a consecutive
process that does not change the overall conclusions. Unstable
Grignard reagents, resulting from 2-halopyridine derivatives, tend
to polymerize into insoluble tars making the subsequent quench-
ing reaction redundant. Table 1 depicts a selection of substrates
that were subjected to microwave-induced arcing and conventional
heating to facilitate the synthesis of their corresponding Grignard
reagents.
4
The previously reported 2-halothiophenes are included in the
investigation for reference purposes. A large decrease in the
initiation time, compared to conventional heating, was observed
for 2-chlorothiophene and 2-bromothiophene (entries 1–4) when
the reaction was performed with microwave-induced electrical dis-
charges. Surprisingly, the formation of the Grignard reagent from
3-bromothiophene and 3-chlorothiophene failed using both heat-
ing methods, stressing the unreactive nature of the 3-position of
thiophene. When heating the reaction mixture of the halopyridines
(entries 5–10) the intensity of arcing under microwave irradiation
is less pronounced. This is mainly due to the higher dielectric
20
loss of the pyridine derivatives, ensuring a higher absorption of
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Table 2 Grignard reagent synthesis of selected substrates under mi-
crowave irradiation and conventional heating (oil bath), step 1, and
subsequent quenching reactions, step 2
activation and activation by electrical discharges is difficult to
quantify. Nevertheless, these same results clearly show that for
microwave irradiation the instantaneous initiation is consistent
and for conventional heating a scatter was observed, meaning
an increased reproducibility for these substrates with microwave
irradiation. The very exothermic reaction of the active substrates
with magnesium demands the drop-wise addition of these sub-
strates. The addition time governs the overall reaction time, thus
obscuring the influence of area enlargement of the magnesium by
electrical discharges on the reaction rate. Although no quantitative
distinction between conventional and microwave heating for the
reactive species can be made, the comparable yields for both
heating techniques make the application of microwave heating
for the production of Grignard reagents for the active substrates
feasible and increase the reproducibility. Therefore, it can be
concluded that microwave heating leads to a higher reproducibility
of the Grignard reaction than conventional heating.
Initiation time
step 1 (min)
Reaction time
step 1 (min)
e
f
Entry
Yield (%)
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
20
0–1
75
5
0–1
0
125
75
30
50
0–1
0
0–1
0
0–1
0
80
—
45
15
86
73
82
73
a
a
120
40
a
b
c
10
10
trace
trace
trace
trace
b
c
c
200
110
180
200
c
d
37 (8)
d
0
1
2
3
4
5
6
7
8
41 (19)
b
a
10
10
10
10
10
10
88
87
30
30
87
70
85
0
b
a
b
a
b
a
b
a
b
a
a
150
—
Conclusion
a
b
c
d
Isolated yield. Addition time of the substrate. Tar formation. Between
The use of metals in combination with microwave heating can
cause dramatic electrical discharges. The suppression of these
brackets: % of product representing ketone corresponding to the produced
e
alcohol accompanied by equimolar amounts of benzyl alcohol. Time at
f
21
which Grignard reagent starts to form. Time at complete conversion.
discharges has been a point of interest to expand the scope of
microwave heating in organic syntheses. The deliberate generation
of these discharges (with of course the due caution) gives rise to
effects that cannot be easily mimicked by other methods. One of
these effects is the generation of highly active magnesium that can
be directly used for the formation of Grignard reagents. Selective
heating of the metal during microwave irradiation does not occur
with magnesium turnings and is obviously not the origin of the
observed decrease in initiation time. The formation of highly active
magnesium spheres and the etching of the magnesium surface
resulting from the interaction of the microwaves with the metal
explain the large decrease in initiation times for selected substrates.
This novel and straightforward initiation method generates mag-
the microwave irradiation by the solvent/reagent mixture. The
higher absorption of the microwave irradiation by the solvent
leads to a diminished charge build-up at the magnesium surface.
The lower intensity of arcing for these substrates gives rise to a
smaller influence of microwave irradiation on the initiation time:
7
5 (entry 8) instead of 125 (entry 7) minutes for 2-chloropyridine.
The formation of the Grignard reagent from 3-bromopyridine
entries 9 and 10) is slightly retarded under microwave irradiation
(
indicating some competitive carbide formation reaction. The
influence of magnesium carbide formation is most clearly seen
from the Grignard reagent formation of n-octyl chloride (entries
22
nesium with a reactivity similar to that of Riekes magnesium
and eliminates the use of highly toxic and environmentally adverse
initiators and therefore limits the formation of by-products.
1
7 and 18). Although this substrate is reactive under conventional
heating conditions with an initiation time of 80 min, the reaction
does not occur with microwave irradiation. The formation of
magnesium carbide species from the activated magnesium is
believed to occur at a higher rate than the generation of Grignard
reagent for n-octyl chloride leading to an inhibiting layer on the
surface of the magnesium turnings. This layer causes the Grignard
formation reaction to be completely inhibited for n-octyl chloride
under microwave-induced electrical discharges. The formation
of magnesium carbide is a competitive process, rendering the
generation of very poorly reactive halides less probable. Short
exposure to microwave irradiation and subsequent transferring
the mixture to oil-bath heating (and therefore without additional
electrostatic discharges) gave comparable results as for oil-bath
heating only. The results in Table 2 demonstrate that 2-bromo-
pyridine (entries 5 and 6), bromobenzene (entries 11 and 12),
iodobenzene (entries 13 and 14) and n-octyl bromide (entries
Experimental section
All chemicals were purchased from Sigma-Aldrich and used as
received unless otherwise indicated. All presented results have
1
been reproduced. H-NMR spectra were measured in CDCl
3
with
Me Si as the internal standard. All reactions have been reproduced
4
at least two times.
Microwave heating
A commercially available, automated multimode microwave oven
MicroSynth from Milestone s.r.l. (Italy) was used. This oven
operates at 2.45 GHz and is temperature controlled by fiber-
optic sensor. To eliminate significant temperature distributions
the temperature was monitored by insertion of a calibrated fiber-
optic sensor in the reaction mixture while stirring properly. The
maximum power input could be adjusted between 0 and 1000
Watt.
1
5 and 16) are very reactive towards magnesium. The lower
yield for iodobenzene, under both heating methods, was mainly
caused by the insolubility of the formed Grignard reagent and
the formation of biphenyl. Due to the short initiation time of
the very reactive substrates a clear difference between thermal
1
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Thermal imaging
Additional irradiation with microwave energy (maximum power
input 200 W) was applied for 30–60 min. The solution of Grignard
reagent was separated from the remaining Mg with a syringe.
An infrared camera (FLIR Systems ThermaCAMTM P65) was
placed outside the cavity of the microwave unit and was focused
on an open vessel containing the THF/magnesium sample. The
images were recorded real time via IEEE-1394 FireWire DV-
output during irradiation. The mixture was covered with a blanket
of argon to ensure safety (no oxygen should be present during the
electrical discharges).
Grignard reagent formation of the relatively non-reactive substrates
under conventional heating (entries 3, 7, 9, 17, in Table 1)
Magnesium turnings (0.44 g, 18 mmol) and 2-chlorothiophene
(1.66 g, 14 mmol), dissolved in dry THF (10 mL, distilled from
˚
mol sieves 3 A), were introduced in an oven-dried 25 mL three
Scanning electron microscopy
neck round-bottomed flask under an argon atmosphere. The
◦
mixture was heated by a preheated oil bath (T = 85 C) to reflux.
SEM was performed on a Philips XL30 ESEM-FEG electron
microscope in the high-vacuum mode. The acceleration voltage
used was 5.0 kV. Samples were prepared by either placing a
droplet of a suspension of the particles in THF on an aluminium
stub followed by evaporation of the THF or by mounting the
particles with carbon tape on an aluminium stub. NOTE: The
activated magnesium may be pyrophoric and create a flare which
is hazardous to the eyes when exposed to air. Due caution should
always be taken in the handling of activated magnesium.
Additional heating was applied for 30–200 min. The solution of
Grignard reagent was separated from the remaining Mg with a
syringe.
Grignard reagent formation of the relatively non-reactive
substrates under microwave heating (entries 4, 8, 10, 18 in Table 1)
Magnesium turnings (0.44 g, 18 mmol) and 2-chlorothiophene
(
1.66 g, 14 mmol), dissolved in dry THF (10 mL, distilled from
˚
mol sieves 3 A), were introduced in an oven-dried 25 mL three neck
round-bottomed flask under an argon atmosphere. (Note: no oxy-
gen, or fire supporting oxygen rich compounds, should be present
upon the occurrence of the electrical discharges). The reaction
mixture was heated by microwave irradiation (maximum power
input 350 W) to reflux. Additional irradiation with microwaves
X-ray photoelectron spectroscopy
The XPS measurements are carried out with a Kratos AXIS
Ultra spectrometer, equipped with a monochromatic Al Ka X-ray
source and a delay-line detector (DLD). Spectra were obtained us-
ing the aluminium anode (Al Ka = 1486.6 eV) operating at 150 W.
For survey scans a constant pass energy of 160 eV was used and
for region scans a constant pass energy of 80 eV. The background
(
maximum power-input 200 W) was applied for 30–200 min. The
solution of Grignard reagent was separated from the remaining
Mg with a syringe.
-
9
pressure was 2 ¥ 10 mbar.
Quenching the Grignard reagents with CO
3, 14, 15, 16, 17, 18 in Table 1)
2
(entries 1, 2, 3, 4, 12,
Grignard reagent formation of the reactive substrates under
conventional heating (entries 1, 5, 11, 13, 15 in Table 1)
1
The solution of the Grignard reagent was added dropwise to an
excess of freshly prepared dry, solid CO (prepared by passing
sublimated CO over 3 stages of concentrated sulfuric acid and
depositing it in a liquid nitrogen cooled flask). After addition of
the reagent another layer of dry CO was deposited. The mixture
was slowly heated to room temperature in 15 min, acidified with
0 wt% HCl (10 mL) and extracted with toluene (3 ¥ 10 mL).
The organic layer was dried with MgSO , filtered and evaporated.
Magnesium turnings (0.44 g, 18 mmol) were introduced in an oven-
dried 25 mL three neck round-bottomed flask. 2-Bromothiophene
2
(
2.28 g, 14 mmol) was dissolved in dry THF (10 mL, distilled from
2
˚
mol sieves 3 A). A volume of 1 mL of the 2-bromothiophene
solution was added to the Mg in an argon atmosphere and the
2
◦
mixture was heated by a preheated oil bath (T = 85 C) to reflux.
1
As soon as initiation took place, the oil bath was lowered and the
remaining solution was added dropwise in 10 min to maintain a
gentle reflux. Additional heating with an oil bath was applied for
4
Optional purification method: the crude residue was dissolved in
toluene (15 mL) and extracted with 1.0 M KOH (2 ¥ 10 mL).
The aqueous layer was acidified with conc. HCl and extracted
3
0–60 min. The solution of Grignard reagent was separated from
the remaining Mg with a syringe.
with toluene. The toluene layer was dried with MgSO , filtered
4
1
Grignard reagent formation of the reactive substrates under
microwave heating (entries 2, 6, 12, 14, 16 in Table 1)
and evaporated yielding the pure product. Benzoic acid: H-NMR
(400 MHz, CDCl ) d 7.49 (m, 2H), 7.63 (m, 1H), 8.14 (m, 2H),
3
1
1
0
2
1.72 (s, 1H); Nonanoic acid: H-NMR (400 MHz, CDCl
3
) d
Magnesium turnings (0.44 g, 18 mmol) were introduced in an oven-
dried 25 mL three neck round-bottomed flask. 2-Bromothiophene
.88 (t, 3H), 1.25–1.30 (m, 12H), 1.63 (t, 2H), 10.63 (br s, 1H),
-Thiophenecarboxylic acid: H-NMR (400 MHz, CDCl ) d 7.1
1
3
(
2.28 g, 14 mmol) was dissolved in dry THF (10 mL, distilled from
(
dd, 1H), 7.90 (dd, 1H), 7.66 (dd, 1H), 9.76 (br s, 1H).
˚
mol sieves 3 A). A volume of 1 mL of the 2-bromothiophene
solution was added to the Mg in an argon atmosphere (Note:
no oxygen, or fire supporting oxygen rich compounds, should
be present upon the occurrence of the electrical discharges)
and irradiated with microwave energy (maximum power-input
Quenching the Grignard reagents with CS (entry 11 in Table 1)
2
The solution of the Grignard reagent was added dropwise at room
temperature to a flask containing a large excess of CS dissolved
2
˚
3
50 W) to reflux. As soon as initiation took place the remaining
solution was added dropwise in 10 min to maintain a gentle reflux
the microwave oven was in an OFF state during this period).
in THF (10 mL, distilled from mol sieves 3 A). The solution was
stirred for 1 h and subsequently acidified with 10 wt% HCl (10 mL)
and extracted with toluene (3 ¥ 10 mL). The organic layer was dried
(
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1
with MgSO
(
4
, filtered and evaporated. Benzodithio acid: H-NMR
2 A. de la Hoz, A. Diaz-Ortiz and A. Moreno, Chem. Soc. Rev., 2005,
3
4, 164.
400 MHz, CDCl ) d: 6.38 (br s, 1H) 7.40 (t, 2H), 7.60 (t, 1H),
3
3
(a) L. Perreux and A. Loupy, Tetrahedron, 2001, 57, 9199; (b) Mi-
crowaves in Organic and Medicinal Chemistry, C. O. Kappe, A. Stadler,
Wiley-VCH, Weinheim 2005.
8
.05 (d, 2H).
Quenching the Grignard reagent with benzaldehyde (entries 5, 6, 7,
, 9, 10 in Table 1)
4 M. H. C. L. Dressen, B. H. P. van de Kruijs, J. Meuldijk, J. A. J. M.
Vekemans and L. A. Hulshof, Org. Process Res. Dev., 2007, 11, 865.
8
5
6
7
8
V. Grignard, Compt. Rend., 1900, 130, 1322.
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The solution of the Grignard reagent was added dropwise to a flask
containing a two-fold molar excess of benzaldehyde dissolved in
˚
9 C. L. Hill, J. B. Vander Sande and G. M. Whitesides, J. Org. Chem.,
THF (10 mL, distilled from mol sieves 3 A) at reflux temperature.
1
980, 45, 1020.
The solution was stirred for 1 h and subsequently acidified with
1
0 K. V. Baker, J. M. Brown, N. Hughes, A. J. Skarnulis and A. Sexton,
saturated NH
The organic layer was dried with MgSO
4
Cl (10 mL) and extracted with toluene (3 ¥ 10 mL).
, filtered and evaporated.
Phenyl (2-pyridinyl)methanol: H-NMR (400 MHz, CDCl ) d:
.69(s, 1H), 5.74 (s,1H), 7.23–7.49 (m, 7H), 7.62 (td, 1H), 8.56 (d,
J. Org. Chem., 1991, 56, 698.
11 W. Oppolzer, E. P. Kundlg, P. M. Bishop and C. Perret, Tetrahedron
Lett., 1982, 23, 3901.
4
1
3
1
1
1
2 R. D. Rieke and S. E. Bales, J. Am. Chem. Soc., 1974, 96, 1775.
3 U. Tilstam and H. Weinmann, Org. Process Res. Dev., 2002, 6, 906.
4 J. L. Luche and J. C. Damiano, J. Am. Chem. Soc., 1980, 102, 7926.
4
1
8
1
1
H). Phenyl-(3-pyridyl)methanol: H-NMR (400 MHz, CDCl ) d:
.52 (d 1H), 8.37 (dd, 1H), 7.78 (dd, 1H) 7.20 (m, 5H), 7.15 (dd,
H), 5.82 (s, 1H), 4.7 (s, 1H) 3.15–4.36 (br s, 1H).
3
15 H. Gold, M. Larhed and P. Nilsson, Synlett., 2005, 10, 1596.
1
1
6 I. Mutule and E. Suna, Tetrahedron, 2005, 61, 11168.
7 S. Borrello, Thermography, Kirk-Othmer Encyclopedia of Chemical
Technology, 1998.
1
1
2
8 J. B. Abreu, J. E. Soto, A. Ashley-Facey, M. P. Soriaga, J. F. Garst and
J. L. Stickney, J. Colloid Interface Sci., 1998, 206, 247.
9 A. K. Khanra, L. C. Pathak and M. M. Godkhindi, J. Mater. Sci.,
Acknowledgements
The authors gratefully would like to thank SenterNovem for
funding this research. We wish to thank DSM Pharma Chemicals,
Geleen, The Netherlands and Syncom B.V., Groningen, The
Netherlands for their support. We are grateful to Jan Diepens
from the Architecture, Building and Planning department of
the Eindhoven University of Technology for placing the FLIR
ThermaCAMTM P65 at our disposal.
2
007, 42, 872.
0 The dielectric loss of the halopyridines is unknown. Therefore, an
estimation was done on the basis of unsubstituted pyridine which has a
dielectric constant of 13.25 and a loss tangent of 0.107 (for values see:
R. S. Holland and C. P. Smyth, J. Phys. Chem., 1955, 10, 1088). The
dielectric loss of substituted pyridines is assumed to be higher. This
assumption is based on the comparison of bromobenzene (dielectric
constant: 5.08 and loss tangent: 0.149), chlorobenzene (dielectric
constant: 5.5 and loss tangent: 1.016) and benzene (dielectric constant:
2
.284 and loss tangent: ~0). (For values see: F. H. Branin Jr. and C. P.
Smyt, J. Chem. Phys., 1952, 20, 1121).
1 A. G. Whittaker and D. M. P. Mingos, J. Chem. Soc., Dalton Trans.,
2000, 1521.
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694 | Org. Biomol. Chem., 2010, 8, 1688–1694
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