Microwave-assisted organic syntheses: Microwave effect on intramolecular reactions-the Claisen rearrangement of allylphenyl ether and 1-allyloxy-4-methoxybenzene

Article abstract of DOI:10.1039/c5ra18039b

This article examined how and the possible effect microwaves may have on intramolecular reactions such as those of the Claisen-type rearrangement carried out in dimethyl sulfoxide (DMSO) solvent and in solvent-free, microwave irradiation conditions. For comparison, the reaction was also performed by conventional heating using an oil bath. 2-Allylphenol was synthesized from allylphenyl ether in DMSO solvent under stirring conditions as a model intramolecular reaction taking place via the Claisen rearrangement using a commercial microwave chemical apparatus together with conventional heating; no enhancement of the reaction occurred. To further examine the influence of microwave irradiation on Claisen rearrangement reactions, we also investigated the transformation of 1-allyloxy-4-methoxybenzene to 2-allyl-4-methoxyphenol under both solvent-free conditions (no stirring) and in DMSO medium; here also no reaction enhancement was observed. This notwithstanding, microwaves did impact the formation of a by-product formed in the latter reaction, which was identified by GC and GC/MS as 4-methoxyphenol, the yield of which was nearly fourfold greater (ca. 6%) under microwave irradiation than under oil-bath heating (ca. 1.5%). The latter suggests that under solvent-free conditions a microwave non-thermal effect influenced the formation of this by-product during the Claisen rearrangement process, contrary to the case where the reaction was performed in DMSO medium for which the yields were identical (ca. 2.5%), regardless of whether the reactant was microwave or oil-bath heated.

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Microwave-assisted organic syntheses: microwave
effect on intramolecular reactions – the Claisen
rearrangement of allylphenyl ether and 1-allyloxy-
4-methoxybenzene†
Cite this: RSC Adv., 2015, 5, 90272
a
Satoshi Horikoshi, Tomoki Watanabe,a Momoko Kamata,a Yumiko Suzukia
*
and Nick Serponeb
This article examined how and the possible effect microwaves may have on intramolecular reactions such
as those of the Claisen-type rearrangement carried out in dimethyl sulfoxide (DMSO) solvent and in solvent-
free, microwave irradiation conditions. For comparison, the reaction was also performed by conventional
heating using an oil bath. 2-Allylphenol was synthesized from allylphenyl ether in DMSO solvent under
stirring conditions as a model intramolecular reaction taking place via the Claisen rearrangement using
This article can be cited before page numbers have been issued, to do this please use: S. Horikoshi, T.
a commercial microwave chemical apparatus together with conventional heating; no enhancement of
Watanabe, M. Kamata, Y. Suzuki and N. Serpone, RSC Adv., 2015, DOI: 10.1039/C5RA18039B.
the reaction occurred. To further examine the influence of microwave irradiation on Claisen
rearrangement reactions, we also investigated the transformation of 1-allyloxy-4-methoxybenzene to 2-
allyl-4-methoxyphenol under both solvent-free conditions (no stirring) and in DMSO medium; here also
no reaction enhancement was observed. This notwithstanding, microwaves did impact the formation of
a by-product formed in the latter reaction, which was identified by GC and GC/MS as 4-methoxyphenol,
the yield of which was nearly fourfold greater (ca. 6%) under microwave irradiation than under oil-bath
Received 4th September 2015
Accepted 15th October 2015
heating (ca. 1.5%). The latter suggests that under solvent-free conditions a microwave non-thermal
effect influenced the formation of this by-product during the Claisen rearrangement process, contrary to
DOI: 10.1039/c5ra18039b
the case where the reaction was performed in DMSO medium for which the yields were identical (ca.
www.rsc.org/advances
2.5%), regardless of whether the reactant was microwave or oil-bath heated.
short times is not only ecofriendly but nancially attractive as
well.
Our studies in microwave-assisted chemistry have consis-
tently focused on how and what particular features of micro-
wave radiation impact syntheses, in general, and organic
syntheses involving intermolecular reactions, in particular.4–19
In this regard, in a previous study we investigated specic (non-
thermal) microwave effects that might have an impact on
organic syntheses by examining the synthesis of monoglyceryl-
1. Introduction
Microwave radiation has been used extensively as a heat source
in many organic syntheses since 2000,1 as a means of signi-
cantly accelerating processes, in general, and organic reactions,
in particular.2 However, in spite of this advantageous feature of
microwaves, a direct comparison with conventional heating is
neither straightforward nor simple because factors such as the
distribution of temperature3 and reactor types, among others, in
microwave heating are in most cases different from conven-
tional heating. A signicant advantage of microwaves is that
substrates can be heated directly in a short time thereby
avoiding the use of (organic) solvents. From the point of view of
industrial manufacturing and Green Chemistry, the use of
a technology that can deliver high yields of products in relatively
cetyldimethylammonium
chloride
from
3-chloro-1,2-
propanediol and N,N-dimethylhexadecylamine in 2-propanol
solvent, and under solvent-free conditions.18 No effects were
evident in homogeneous 2-propanol media under temperature
conditions identical to conventional heating; however, hetero-
geneous solvent-free conditions brought out non-insignicant
specic microwave effects as evidenced by variant product
yields: 62% by microwave irradiation versus 47% by conven-
tional heating (typically using an oil bath). This variance was
attributed to thermal conduction and localized hot spots
formed under microwave irradiation. The model proposed for
the solvent-free synthesis considered hydrophilic 3-chloro-1,2-
propanediol molecules forming preferentially H-bonded
aDepartment of Materials and Life Sciences, Faculty of Science and Technology, Sophia
University, 7-1 Kioicho, Chiyodaku, Tokyo 102-8554, Japan. E-mail: horikosi@sophia.
ac.jp; Fax: +81-3-3238-3361; Tel: +81-3-3238-4662
bPhotoGreen Laboratory, Dipartimento di Chimica, Universita di Pavia, via Taramelli
12, Pavia 27100, Italy
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra18039b
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domains (size, 2–20 mm) heated by microwaves and dispersed in presence of DMSO using frequency-precise (2.450000 GHz)
a sea of hydrophobic N,N-dimethylhexadecylamine molecules. microwaves emitted from a semiconductor generator combined
Moreover, the ionic liquid 1-butyl-3-methylimidazolium tetra- with a single-mode cavity. The latter process also yielded 4-
uoroborate, produced under solvent-free conditions, was ob- methoxyphenol in non-insignicant yields.
tained in high yields by microwave irradiation: 87% under 5.8
GHz microwave heating conditions versus 21% under conven-
2. Experimental setup
2.1 Microwave equipment with single-mode applicator and
tional heating.20 Evidently, the condition needed to observe
microwave specic phenomena in organic syntheses is that the
starting substrates have different large microwave absorption
features. That is, the microscopic dissimilar distribution of
temperature should enhance the collision frequency between
two different molecules.
semiconductor generator
The microwave irradiation setup with a single-mode TE103 cavity
(transverse electric 103 mode), schematically illustrated in
Fig. 1a, included a short plunger, an iris, a three-stub tuner,
a power monitor and an isolator. Continuous microwave radi-
ation was generated from a 2.450000 GHz microwave semi-
conductor generator (Fuji Electronic Industrial Co. Ltd.; GNU-
201AA; maximal power, 200 W). The resonance of the micro-
waves was adjusted with the iris and the plunger at 1.5 cycles.
Heating of the reactor contents was achieved by positioning the
quartz tube reactor in the single-mode microwave apparatus of
Fig. 1a and b at the position of maximal electric eld density (E
eld; Fig. 1a inset) within the waveguide. Temperatures of the
solutions were measured at 3 s intervals with an optical ber
thermometer (FL-2000, Anritsu Meter Co. Ltd.). The wavelength
of propagation of the microwaves in the TE103 mode within the
waveguide was 14.78 cm (estimated from eqn (3)):36
As part of our systematic studies then, the present study
focusses on the how microwave radiation might affect intra-
molecular reactions of the Claisen-type rearrangement. In this
regard, studies of microwave-assisted syntheses of naturally
occurring 1,4-benzoquinones and of bis-(3-allyl-4-hydroxyphenyl)
sulfone by the Claisen rearrangement process have been re-
ported by Davis et al. (reaction (1))21 and Yamamoto and
coworkers (reaction (2)),22 respectively, among several other
studies.23–34 In nearly all these studies, however, the interest
focused on the formation of the major product from the Claisen
rearrangement, as minor by-products are oen not reported or
otherwise noted.
lo
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
l ¼
(3)
2
1 ꢀ ðlo=2bÞ
(1)
where l is the wavelength in the waveguide; lo(2.45 GHz) (¼12.24
cm) is the wavelength in vacuum given by c/f, {c being the speed
of light, 2.9979 ꢁ 1010 cm sꢀ1, and f being the microwave
frequency 2.45 ꢁ 109 sꢀ1 for the 2.45 GHz microwaves used};
and b is the height of the waveguide, 10.92 cm (other dimen-
sions of the apparatus are singled out in Fig. 1b). The maximal
position of the E eld from the iris was located at 3/4 the
wavelength of the standing wave in the waveguide (namely at
11.09 cm).
(2)
The synthesis of 2-allyl-4-methoxyphenol by the Claisen
rearrangement process was examined by positioning the reactor
containing the initial substrate 1-allyloxy-4-methoxybenzene at
the maximal microwaves' E-eld density (Fig. 1a inset). The
microwave input power was ca. 170 W (without DMSO) and 46
W with DMSO present as the latter is a strong microwave
absorber. An electric eld monitor (Fuji Electronic Industrial
Co. Ltd.) was used to maintain the sample tube at the maximal
position of the E-eld density, as the reproducibility of such
experiments is oen diminished if such operations are
neglected. Under our conditions, no signicant positional
changes of the electric eld were needed on heating.
To enhance the heat effect of the microwaves in Claisen
rearrangements, a strong microwave absorbing solvent (e.g.,
water, alcohols) is typically used35 so that any direct effect
between reacting substrates and microwaves could not be
delineated. Accordingly, to assess the how and what effect
microwaves may have, if any, on intramolecular reactions, we
examined the synthesis of 2-allylphenol from the Claisen rear-
rangement of the corresponding allylphenyl ether in dimethyl
sulfoxide (DMSO) solvent, a strong microwave absorber solvent,
and using commercially available microwave chemical appara-
tuses. Further, the Claisen rearrangement of 1-allyloxy-4-
methoxybenzene to 2-allyl-4-methoxyphenol was investigated
under solvent-free, non-stirring conditions, as well as in the
2.2 Analytical methods and simulations
The yields of product(s) formed were determined by gas chro-
matographic analyses using a Shimadzu model 2014 FID-GC
(Restek Rtx-5 capillary column; helium was the carrier gas;
ꢀ1
ꢂ
ꢂ
column temperature, 100–280 C varied at 15 C min inter-
vals). Potential by-products that may form were identied by gas
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Fig. 1 (a) Details of the experimental setup and positioning of the samples in the single-mode microwave resonator; maximal position of the
electric field (E field) density. (b) Photograph of the single-mode microwave resonator and the 2.45 GHz semiconductor microwave generator.
Reproduced from ref. 36; Copyright 2012 by the International Microwave Power Institute.
chromatography/mass spectrometry techniques (GC/MS; Shi- and 120 min. The resulting product 2-allylphenol formed from
madzu model GCMS-QP2010 Ultra; Restek Rxi-5sil capillary the Claisen rearrangement process was subsequently washed
column; helium was the carrier gas). Dielectric constant and twice with toluene (5 mL), and its yield determined by gas
dielectric loss of the pure chemicals subjected to the 2.45 GHz chromatography in comparison with a standard 2-allylphenol
microwaves were measured with an Agilent Technologies 8720C sample from Wako Pure Chem. Co. The microwave apparatuses
Network Analyzer using a slim probe system. Unless otherwise with multimode applicators were the Milestone StartSYNTH
noted, proton NMR spectra were recorded in CD3Cl solvent with and Shikoku Instrumentation Co. Ltd. mReactor systems; in
a 400 MHz Bruker Avance DPX 400 NMR spectrometer; chem- both cases the reactor consisted of a two-neck quartz tube
ical shis are quoted in parts per million (ppm).
connected to a reux condenser. An Anton-Paar Monowave300
The RF model in the COMSOL multiphysics soware version microwave apparatus was also used albeit with a standard Pyrex
4.3a, based on a nite element method, was used for the closed reactor.
calculation and 3D simulation of the electromagnetic distribu-
tion, power density, and the temperature distribution under
microwave irradiation. The geometric model of the waveguide
reected the experimental setup used. The power density, or
power dissipated per unit volume, was calculated from the
electric eld strength using eqn (4):
2.4 Synthesis of the precursor ether 1-allyloxy-4-
methoxybenzene
The 1-allyloxy-4-methoxybenzene substrate was synthesized by
addition of 4-methoxyphenol (4 g; standard sample; purity >
99.0%; Tokyo Chemical Industry Co., Ltd.), potassium
carbonate (4 g), and allyl bromide (4 g) to an acetone (30 mL)
solution that was subsequently reuxed with oil-bath heating
for 3 days. Completion of the reaction was conrmed by thin
layer chromatographic techniques (TLC) using hexane as the
developing solvent. Potassium carbonate was removed by
ltration, aer which acetone was removed using a rotary
evaporator. The resulting residue was added to various water/
ethyl acetate aliquots (each 20 mL) in a separating funnel to
permit extraction of the organic layer. At this stage, any 4-
methoxyphenol le was removed by adding aqueous sodium
hydroxide (4 wt%), following which the small amount of water
was removed by addition of sodium sulfate (5 g). The mixture
was then ltered and the ethyl acetate removed from the ltrate
using a rotary evaporator. The residual sample was then treated
by ash chromatography on silica gel (230–400 mesh) in
hexane. The end point of product separation was conrmed by
TLC on aluminum-backed silica plates pre-coated with silica
2
00
~
P ¼ 2pf303 |E|
(4)
where f is the frequency, 30 the permittivity of free space (8.85
ꢁ 10ꢀ12 F mꢀ1), 300 is the dielectric loss factor, and E is the
electric eld strength (V mꢀ1). For the calculation, Maxwell's
equation and Fourier's energy balance equation were also used
(eqn (5)),
vT
vt
k
P
þ~v VT ¼
V2T þ
(5)
rCp
rCp
where r is the density (kg mꢀ3), Cp is the specic heat (J kgꢀ1 Kꢀ1),
k is the thermal conductivity (W m Kꢀ1), T is temperature (K), v
~
is the velocity vector (m sꢀ1), and P is the volumetric heat
(W mꢀ3).
2.3 Microwave-assisted synthesis of 2-allylphenol in DMSO
with commercial microwave equipment
The initial substrate allylphenyl ether (0.134 g; Wako Pure (0.2 mm); the plates were then developed using UV uorescence
Chem. Co) and DMSO solvent (5 mL) was placed in the reactor. and iodine. The synthesis yield of 1-allyloxy-4-methoxybenzene
The thermally driven reaction was then performed with micro- was 19%. A proton NMR spectrum of this product (see Fig. S-1
wave heating from commercial microwave equipment or heat- in ESI†) in CD3Cl revealed peaks at d (ppm) ¼ 3.775 (s, CH3,
ing from an oil bath at 180 ꢃ 1 ꢂC for reaction times of 30, 60, 3H), 4.48–4.52 (m, CH2, 2H), 5.29–5.50 (m, C]CH2, 2H), 6.03–
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6.16 (m, C]CH, 1H), 6.855–6.895 (m, ArH, 4H). These results
accord with those reported by Lin and coworkers.25
2.5 Microwave-assisted synthesis of 2-allyl-4-methoxyphenol
in a single-mode microwave system
The initial ethereal substrate 1-allyloxy-4-methoxybenzene (0.2
g) was placed in a quartz tube reactor (length: 20.0 cm; internal
diameter: 0.5 cm) and then heated either by microwave dielec-
ꢂ
tric heating or by oil-bath heating at 170 C under solvent-free
and non-stirring conditions for reaction times of 60, 120, and 240
min. The resulting product was washed twice with toluene (1
mL), and its yield also determined by gas chromatography. The
major product resulting from the Claisen rearrangement, 2-
allyl-4-methoxyphenol, was subsequently puried by vacuum
distillation, its purity being evidenced by gas chromatographic
analyses. The proton NMR spectrum (see Fig. S-2 in ESI†) of 2-
allyl-4-methoxyphenol in CD3Cl solvent showed peaks at
d (ppm) ¼ 3.38 (d, J ¼ 6.4 Hz, CH2, 2H), 3.76 (s, CH3, 3H), 4.62 (s,
OH, 1H), 5.13–5.20 (m, C]CH2, 2H), 5.95–6.01 (m, C]CH, 1H),
6.66–6.79 (m, ArH, 3H).
The microwave-assisted synthesis of 2-allyl-4-methoxyphenol
from the 1-allyloxy-4-methoxybenzene (0.2 g) precursor was also
investigated in DMSO solvent (5 mL) in a quartz reactor (length:
20.0 cm; internal diameter: 2.0 cm) in a single-mode microwave
system with the reactants heated to 170 ꢂC; the solution was
stirred using a micro-stirring bar. Subsequent to the work-up of
the reaction, the product was analyzed by the same techniques
as above.
Fig. 2 Chemical yields (%) of 2-allylphenol obtained from the Claisen
rearrangement of allylphenyl ether in DMSO solvent under stirring
conditions exposed to microwave heating using three different
commercial systems, and under oil-bath heating conditions;
temperature of reaction was 180 ꢃ 1 ꢂC.
single-mode microwave apparatus of Fig. 1 in which the micro-
waves irradiated directly the precursor allylphenyl ether under-
going the Claisen rearrangement. The microwave absorption
capacity of allylphenyl ether is fairly small (dielectric loss: 300
¼
r
0.363) relative to DMSO (300 ¼ 15.98) solvent, a strong microwave
r
absorber, so that microwave heating the initial substrate in the
absence of DMSO achieved temperatures no greater than 150 ꢂC.
In DMSO media, however, the microwaves heated DMSO pref-
erentially which, subsequent to heat transfer to allylphenyl ether,
ultimately led to the formation of 2-allylphenol. The microwaves
were thus used simply as a heat source in this process.
3. Results and discussion
3.1 Microwave-assisted synthesis of 2-allylphenol in DMSO
3.2 Microwave-assisted synthesis of 2-allyl-4-methoxyphenol
under solvent-free conditions
solvent
To improve the microwave absorption capacity of the starting
As a rst step in our query on the effect of microwaves on substrate, the precursor 1-allyloxy-4-methoxybenzene was
intramolecular reactions we carried out the synthesis of 2- synthesized and subsequently employed in the Claisen process
allylphenol via the Claisen rearrangement of allylphenyl ether in its conversion to 2-allyl-4-methoxyphenol utilizing the single-
in DMSO solvent using three commercial microwave chemical mode apparatus of Fig. 1 as the quantity obtained in the
apparatuses. The chemical yields of the resulting 2-allylphenol synthesis of this precursor was rather small. The use of
were 8.3% under microwave irradiation for 120 min using the commercial reactors and microwave apparatuses proved inad-
commercial Monowave300 and StartSYNTH systems (Fig. 1), equate in this case for such a small quantity and also because of
whereas the yields were 7.2% when using oil-bath heating and difficulties in measuring temperatures accurately. Solvent-free
the commercial mReactor system with microwave heating conditions precluded stirring during the reaction. Accord-
(Fig. 2). Although the synthesis was performed at the same ingly, the temperature distribution in neat 1-allyloxy-4-
microwave frequency (2.45 GHz; magnetron generator), the methoxybenzene was the rst step to examine under micro-
small difference in yields is likely due to the different types of wave heating.
reactors used. For instance, while a standard closed reactor was
The temperature distribution in the quartz reactor was
used in the Monowave300 apparatus, the reactor used for the determined by monitoring the temperature with an optical ber
StartSYNTH, mReactor and oil-bath heating consisted of a two- thermometer at the upper, at the center and at the lower
neck quartz tube connected to a reux condenser. In all cases portions of the reactor that contained the starting substrate (0.2
the reaction temperature was 180 ꢃ 1 ꢂC. No signicant g; liquid level, 15 mm; Fig. 3). At the lower part, the temperature
enhancement, if any, was observed when the reaction was was 170 ꢂC (usual measuring position), and 185 ꢂC and 178 ꢂC at
carried out under microwave heating relative to oil-bath the upper part and at the center, respectively. The 15 ꢂC
heating.
temperature variation between the upper and lower parts of the
To further explore the possible enhancing effect of micro- reactor was rather unexpected for such a little sample volume.
waves in an intramolecular reaction, we then performed the By comparison, under oil-bath heating the temperature distri-
synthesisof2-allylphenolundersolvent-freeconditionsusingthe bution was 170 ꢂC throughout the sample. Accordingly, oil-bath
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bath heating gave yields (empty circles) nearly identical to those
from microwave heating (full circles). Evidently, the synthesis of
2-allyl-4-methoxyphenol by the Claisen reaction is not enhanced
`
when using the microwave method vis-a-vis the conventional
method indicating that the microwave effect on the reaction is
strictly a thermal one, unlike intermolecular reactions wherein
non-thermal effects have been ascertained.4,6,9
The distribution of the electric eld inside the waveguide
was simulated by an analysis of the electromagnetic eld using
the RF model in the COMSOL multiphysics soware version
4.3a. The 1-allyloxy-4-methoxybenzene substrate was located at
the maximal electric eld position inside the waveguide, and
the microwave loss assessed. Results of the simulation are
presented in Fig. 5, which shows the microwave electric eld is
concentrated at the surface between the 1-allyloxy-4-
methoxybenzene sample and air. Therefore, the microwaves
(wavelength, ca. 14.78 cm) were concentrated mostly at the
microvolume sample, resulting in a distribution of temperature
within this microvolume.
Fig. 6 displays a photograph of various samples of 1-allyloxy-
4-methoxybenzene that were subsequently heated by the
microwaves (170–185 ꢂC) and conventionally by an oil bath (185
ꢂC) for 60, 120 and 180 min {note that because of difficulties in
detecting differences in color for such small samples by
photography, the samples were dissolved in 2 mL of toluene
solvent for better delineation}. With oil-bath heating, the color
of the solutions changed from nearly colorless to a light
brownish tinge, whereas under microwave heating the samples
turned from pale pink (at 60 min) to a more pronounced
reddish tinge aer 180 min. Gas chromatographic patterns
showed peaks with retention times at 8.095 min (1-allyloxy-4-
methoxybenzene), 8.967 min (2-allyl-4-methoxyphenol), and
a peak of an unknown substrate at 6.860 min at the completion
of the reaction. The latter peak increased with reaction time,
and was more intense under microwave heating than oil-bath
heating. An analysis of this unknown substrate by GC/MS
techniques revealed a mass signal at m/z ¼ 124.135, which
a library search of the GC/MS equipment identied it as per-
taining to 4-methoxyphenol that was subsequently further
Fig.
3 Temperature distribution of neat 1-allyloxy-4-methoxy-
benzene and neat DMSO solvent under microwave heating.
heating of the sample was also performed at the highest
temperature reached on microwave heating (185 C).
ꢂ
The temperature distribution observed upon microwave
heating a sample of neat 1-allyloxy-4-methoxybenzene required
170 W microwaves because microwave absorption by this
substrate was rather low (dielectric loss: 300 ¼ 0.827). Accord-
r
ingly, the temperature distribution of the strong microwave
absorber dimethyl sulfoxide (DMSO; 300 ¼ 15.98) solvent was
r
also examined in neat form (no other substrate present) with
the same microwave system; 42 W microwaves were needed to
ꢂ
bring pure DMSO solvent (alone) to 170 C at the lower part of
the reactor. From the data reported in Fig. 3, it is clear that the
temperature distribution inside the reactor showed a similar
tendency, though the extent of absorption of microwave radia-
tion for the sample changed. This infers that the temperature
distribution of the sample under microwave heating reected
the distribution of the microwaves' electric eld (see below).
The chemical yield of the Claisen rearrangement product 2-
allyl-4-methoxyphenol formed with oil-bath heating aer 4 h
under solvent-free conditions was 24% at 170 C (empty trian-
gles; Fig. 4), whereas the yield was 36% with microwave irradi-
ation at 170 ꢂC (full circles). The yield of product by the oil-bath
heating method at 185 C (full triangles, Fig. 4) was more than
twice the chemical yield observed at 170 C (empty triangles).
Interestingly, averaging the yields at 185 ꢂC and 170 ꢂC from oil-
ꢂ
ꢂ
ꢂ
Fig. 4 Chemical yields of 2-allyl-4-methoxyphenol obtained from the
Claisen rearrangement of 1-allyloxy-4-methoxybenzene under
solvent-free and non-stirring conditions exposed to microwave Fig. 5 Results of the simulation of the microwave electric field
heating (170–185 ꢂC) and to oil-bath heating at 185 ꢂC and 170 ꢂC; distribution in the waveguide containing 1-allyloxy-4-methoxy-
open circles indicate the average yield estimated from those at 185 ꢂC benzene in the quartz reactor located in the waveguide (inset image:
and 170 ꢂC.
loss distribution of the microwave electric field; same conditions).
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signicantly greater (threefold) under microwave irradiation
than under oil-bath heating. Formation of 4-methoxyphenol by
the microwave method seems to follow the formation of 2-allyl-
4-methoxyphenol, which infers that 4-methoxyphenol may have
been generated from a reaction involving the formation of 2-
allyl-4-methoxyphenol, a point discussed further below.
3.3 Microwave-assisted synthesis of 2-allyl-4-methoxyphenol
in DMSO solvent
To assess the inuence of a solvent on the chemical yields of 2-
allyl-4-methoxyphenol via the Claisen rearrangement of 1-
allyloxy-4-methoxyphenol, the reaction was also performed in
the presence of the strong microwave absorber DMSO solvent
under vigorous stirring conditions (mini-bar magnet). The
variance in the distribution of temperature was about 3 ꢂC
under these conditions. The solution was brought to a temper-
ature of 170 ꢂC using 46 W microwaves.
Fig. 6 Photograph of sample solutions of 1-allyloxy-4-methoxy-
benzene in toluene after reaction for 60, 120, 180 min when exposed
to microwave radiation (MW; T ¼ 170–185 ꢂC) and to oil-bath (OB; T ¼
185 ꢂC) heating.
conrmed by a GC/MS spectrum of a standard sample of 4-
methoxyphenol whose GC signal in toluene solvent also
occurred at a retention time of 6.860 min. The discoloration of
the solution was likely the result of air oxidation of the by-
The chemical yield data of 2-allyl-4-methoxyphenol produced
in DMSO media are summarized in Fig. 9a. There was little
variation – in fact negligible within experimental error –
between the yields from microwave heating and oil-bath heat-
ing under identical temperature conditions. The yields of the
by-product 4-methoxyphenol are reported in Fig. 9b. Aer 4 h of
product
4-methoxyphenol
toward
hydroquinone/
benzoquinone-type systems.
The chemical yields of 4-methoxyphenol produced as a by-
product in the synthesis of 2-allyl-4-methoxyphenol are
summarized in Fig. 7. Under microwave heating the yield was
5.9% aer 4 h of irradiation at a temperature of 170–185 ꢂC. By
contrast, the yield was 1.9% upon oil-bath heating at 185 ꢂC and
1.5% at 170 ꢂC; the yield at 200 ꢂC was 2.8%. Evidently,
microwave heating enhanced the formation of 4-methoxy-
phenol by nearly a factor of 3.5 compared to the average yield
(data of 185 ꢂC and 170 ꢂC) obtained from oil-bath heating.
The relationship between reaction temperature under
microwave heating and oil-bath heating with the percent yields
of 2-allyl-4-methoxyphenol and 4-methoxyphenol is reported in
Fig. 8a and b, respectively, for a reaction time of 3 h. There were
almost no changes in the yields of 2-allyl-4-methoxyphenol in
the temperature range 152–178 ꢂC under microwave and oil-
bath heating, indicating that microwaves had no effect on the
Claisen intramolecular reaction other than providing the
necessary thermal energy as provided by the more conventional
oil-bath heating method. Curiously, however, under identical
temperature conditions the yields of 4-methoxyphenol were
ꢂ
heating the yields at 170 C were 2.4% (microwave) and 2.3%
(oil bath), while under non-stirring conditions and microwave
irradiation the corresponding yield was unexpectedly 2.5% for
a temperature distribution of 183 ꢂC at the upper part of the
reactor and 170 ꢂC at the lower part. The small variance in
temperature had no inuence on the yields.
3.4 The Claisen rearrangement and formation of 4-
methoxyphenol
The thermal [3,3] sigmatropic reaction involving the Claisen
rearrangement of a substituted allyl aryl ether typically yields an
ortho-dienone species, which can then enolize readily to give an
ortho-allyphenol system (Scheme 1).25 However, when the rear-
rangement process occurs at an ortho position that bears
a substituent, a concomitant Cope rearrangement process can
take place that when followed by enolization leads to formation
of a para-allyphenol species. Such an arrangement is usually
irreversible in forming phenolic compounds (under thermody-
namic control) so that the ortho-Claisen species is typically the
major product.
Bagnell and co-workers reported that formation of phenol,
a by-product obtained subsequent to the microwave-assisted
synthesis of 2-allylphenol from allylphenyl ether via the
Claisen rearrangement, occurred on subjecting the allylphenol
in aqueous media to high temperature conditions (200 ꢂC).37
Although a small quantity of water was used in the present study
in several processes in the conversion of the 1-allyloxy-4-
methoxybenzene to 2-allyl-4-methoxyphenol, it is doubtful
that such a small quantity of water would have had a signicant
inuence on the overall Claisen process under the conditions
used. To test this inference, the 1-allyloxy-4-methoxybenzene
(0.2 g) was added to 0.1 mL of ion-exchanged water and then
heated by microwave irradiation for 4 h. The chemical yield of
Fig.
7 Percent chemical yields of 4-methoxyphenol by-product
under microwave heating at 170–185 ꢂC, and under oil-bath heating at
185 ꢂC, 170 ꢂC, and 200 ꢂC under non-stirring conditions and in
solvent-free media.
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Fig. 8 Temperature dependence of the chemical yields of (a) 2-allyl-4-methoxyphenol and (b) 4-methoxyphenol under microwave heating at
an average temperature of 152 ꢂC (145–158 ꢂC), 169 ꢂC (162–176 ꢂC) and 178 ꢂC (170–185 ꢂC), and under oil-bath heating at 152 ꢂC, 169 ꢂC, and
178 ꢂC under non-stirring conditions and in solvent-free media. Reaction time was 3 h.
4-methoxyphenol that formed under these conditions
decreased to 1.8%, indicating that the presence of water was not
at the origin of 4-methoxyphenol by the microwave heating
method. To test the latter assertion, 0.1 mL of acetic acid was
added to 0.2 g of 1-allyloxy-4-methoxybenzene in lieu of water.
The resulting solution was then exposed to microwave irradia-
tion for 4 h; no increase in the yield of formation of 4-methoxy-
phenol was observed.
Our presently available results permit proposing a possible
reaction pathway (Scheme 2) for the intramolecular rearrange-
ment of 1-allyloxy-4-methoxybenzene by the Claisen process,
which leads to formation of the major product 2-allyl-4-
methoxyphenol. However, unlike the events displayed in
Scheme 1, no Cope rearrangement is possible as the preferen-
tial para-position for rearrangement is blocked by the 4-
methoxy group. On the other hand, formation of 4-methoxy-
phenol could, in principle, occur via two possible routes.
Scheme 1 Claisen rearrangement processes for ally aryl ethers. After
ref. 25.
Route 1 might generate the by-product directly from 1-
allyloxy-4-methoxybenzene in line with reports that route 1
involving a catalyzed reaction38 or where the 1-allyloxy-4-
methoxybenzene ether is exposed to UV radiation (radical
To probe whether the 4-methoxyphenol occurred through
reactions39) leads to formation of 4-methoxyphenol during the
route 1 or route 2, we examined the synthesis of 2-allylphenol
Claisen process (photo-Claisen process39). However, neither of
using the corresponding allylphenyl ether by subjecting it to
these processes were relevant under our experimental condi-
both microwave and oil-bath heating. No formation of phenol
tions. The alternative route of forming 4-methoxyphenol might
occurred under both heating methods (Scheme 3) either
be during the attempted occurrence of the Cope rearrangement
through the occurrence of the Cope rearrangement process
(route 2).
Fig. 9 Percent chemical yields of (a) 2-allyl-4-methoxyphenol and (b) 4-methoxyphenol in DMSO solvent under microwave heating (MW) and
oil-bath (OB) heating at 170.0 (ꢃ1.5) ꢂC under stirring conditions. Yields from microwave heating without stirring are also reported albeit for the
temperature range 170–183 ꢂC.
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Scheme 2 Postulated mechanism of the synthesis of 2-allyl-4-methoxyphenol and 4-methoxyphenol.
methoxybenzene, was formed by reacting 4-methoxyphenol
with allyl bromide,21 it is not inconceivable that under micro-
wave heating (and to some extent oil-bath heating) a different
pathway involving the precursor might be taking place to yield
4-methoxyphenol concomitant with and/or subsequent to the
Claisen rearrangement process. Accordingly, the question as to
how 4-methoxyphenol formed will have to await further studies.
4. Summary
The question posed in this study was the how and what possible
effect(s), if any, did microwaves have on intramolecular reac-
tions such as those of the Claisen-type rearrangement carried
out in DMSO solvent or solvent-free, microwave irradiation
conditions, and with or without stirring. For the intramolecular
reaction occurring in the strong microwave absorbing solvent
Scheme 3 Proposed mechanism of the synthesis of phenol by the (DMSO), the microwaves heated the solvent rst that was
Claisen and Cope rearrangement of allylphenyl ether.
subsequently followed by the transfer of thermal energy from
the solvent to the starting substrate (reaction (6)). Microwave
radiation was used as the heat source for this process. However,
(similar to route 2), or through the direct involvement of the
allylphenyl ether (similar to route 1), especially under micro-
wave heating. Thus we conclude that formation of 4-methoxy-
phenol occurred by neither routes postulated in Scheme 2.
Nonetheless, to the extent that the precursor product to the
Claisen rearrangement examined herein, namely 1-allyloxy-4-
even if the microwaves had heated the starting substrate
directly, there was no enhancement of the reaction (reaction (7))
demonstrating that only microwave thermal effects were effec-
tive. Unlike intermolecular reactions, no microwave non-
thermal effects could be inferred in the intramolecular
Claisen rearrangement process.
(6)
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RSC Advances
13 S. Horikoshi, A. Osawa, M. Abe and N. Serpone, J. Phys.
Chem. C, 2011, 115, 23030.
14 S. Horikoshi, S. Sato, M. Abe and N. Serpone, Ultrason.
Sonochem., 2011, 18, 938.
15 S.HorikoshiandN. Serpone,Mini-Rev.Org.Chem., 2011,8, 299.
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T. Hirowatari, N.SerponeandM. Abe, J. OleoSci., 2011, 60, 375.
17 S. Horikoshi, A. Osawa, Y. Suttisawat, M. Abe and
N. Serpone, Org. Process Res. Dev., 2010, 14, 1461.
18 S. Horikoshi, M. Fukui, K. Tsuchiya, M. Abe and N. Serpone,
Chem. Phys. Lett., 2010, 491, 244.
19 S. Horikoshi, M. Abe, M. Kajitani and N. Serpone, Utilization
of 5.8 GHz microwaves in organic syntheses, Proc. GCMEA
2008 MAJIC, 1st Global Congress on Microwave Energy
Applications The New Flame for Humanity, Lake Biwa, Otsu,
Japan, August 4–8 2008.
20 S. Horikoshi, T. Hamamura, M. Kajitani, M. Yoshizawa-
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21 C. J. Davis, T. E. Hurst, A. M. Jacob and C. J. Moody, J. Org.
Chem., 2005, 70, 4414.
(7)
The above inferences notwithstanding, microwaves did have
an impact on the yields of the by-product identied as 4-
methoxyphenol. At 170 ꢂC, the yield of this by-product was
nearly fourfold greater (ca. 6%) under microwave irradiation
than under oil-bath heating (ca. 1.5%), which strongly suggests
that, under solvent-free conditions, microwave non-thermal
effect(s) were inuential during the various mechanistic steps
in the Claisen rearrangement of the initial substrate, at least in
those steps that led to the by-product. By contrast, the yields of
4-methoxyphenol in DMSO solvent media were identical (ca.
2.5%) regardless of whether the precursor substrate was
microwave or oil-bath heated.
22 T. Yamamoto, Y. Wada, H. Enokida, M. Fujimoto,
K. Nakamura and S. Yanagida, Green Chem., 2003, 5, 690.
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27 A. M. Jacob and C. J. Moody, Tetrahedron Lett., 2005, 46,
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Acknowledgements
We are grateful to the Japan Society for the Promotion of
Science (JSPS; Grant-in-aid for Scientic Research No. C-
25420820) for nancial support. We also thank Sophia Univer-
sity for a grant from the Sophia University-wide Collaborative
Research Fund to S. H. One of us (N. S.) is grateful to Prof. Albini
of the University of Pavia (Italy) for his continued hospitality
during the many winter semesters in his laboratory.
28 M. Mansha, Y. Abbas and N. Ullah, Synth. Commun., 2015,
45, 599.
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90280 | RSC Adv., 2015, 5, 90272–90280
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