Microwave-enhanced radical reactions at ambient temperature Part 3: Highly selective radical synthesis of 3-cyclohexyl-1-phenyl-1-butanone in a microwave double cylindrical cooled reactor

Article abstract of DOI:10.1039/b810142f

The microwave-enhanced synthesis of 3-cyclohexyl-1-phenyl-1-butanone (CPB) from crotonophenone and iodocyclohexane in the presence of t-BuOOH and triethylborane was examined at ambient temperature and under reflux conditions in bulk solution using no less than four different synthetic protocols. Chemical yields of CPB (93 and 95%, respectively) obtained after 60 and 120 min under microwave dielectric heating coupled to a cooling system (MW/Cool protocol) for a reaction temperature of 20-24°C exceeded the yields from the reaction occurring at room temperature (24°C; no microwaves; 40% and 72%) for the same reaction times and temperature. The competitive radical reaction to produce CPB and a small amount of by-products generated from the thermally-induced synthesis by the non-selective radical reaction was restricted solely to the process occurring at ambient temperature (RT protocol), under microwave dielectric heating to reflux (MW protocol) and heating with an oil-bath also to reflux (Oil-bath protocol). By contrast, no by-products were generated or detected for the reaction taking place by the MW/Cool method. Comparison of product yields under conditions of identical temperature conditions must involve some specific microwave effect in the synthesis of the title compound. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2008.

Full text of DOI:10.1039/b810142f

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www.rsc.org/njc | New Journal of Chemistry
Microwave-enhanced radical reactions at ambient temperature Part 3:w
Highly selective radical synthesis of 3-cyclohexyl-1-phenyl-1-butanone
in a microwave double cylindrical cooled reactorz
Satoshi Horikoshi,*ab Junichi Tsuzuki,a Masatsugu Kajitani,a Masahiko Abec
and Nick Serpone*d
Received (in Gainesville, FL, USA) 17th June 2008, Accepted 6th August 2008
First published as an Advance Article on the web 15th September 2008
DOI: 10.1039/b810142f
The microwave-enhanced synthesis of 3-cyclohexyl-1-phenyl-1-butanone (CPB) from
crotonophenone and iodocyclohexane in the presence of t-BuOOH and triethylborane was
examined at ambient temperature and under reflux conditions in bulk solution using no less than
four different synthetic protocols. Chemical yields of CPB (93 and 95%, respectively) obtained
after 60 and 120 min under microwave dielectric heating coupled to a cooling system (MW/Cool
protocol) for a reaction temperature of 20–24 1C exceeded the yields from the reaction occurring
at room temperature (24 1C; no microwaves; 40% and 72%) for the same reaction times and
temperature. The competitive radical reaction to produce CPB and a small amount of by-
products generated from the thermally-induced synthesis by the non-selective radical reaction was
restricted solely to the process occurring at ambient temperature (RT protocol), under microwave
dielectric heating to reflux (MW protocol) and heating with an oil-bath also to reflux (Oil-bath
protocol). By contrast, no by-products were generated or detected for the reaction taking place by
the MW/Cool method. Comparison of product yields under conditions of identical temperature
conditions must involve some specific microwave effect in the synthesis of the title compound.
Interesting reports have also appeared about specific effects
of the microwave radiation1,3–5,7,10 that have been claimed to
result (i) from variations in activation parameters, (ii) from
1. Introduction
Utilization of microwave radiation as the heat source in
organic syntheses is no longer novel as microwave-assisted
enhanced molecular collisions, and (iii) probable highly loca-
organic syntheses have been reported in several excellent
recent reviews1–3 and books.4–8 Many of the studies reported
cesses. In this regard, some of the objectives of recent studies
lized hot spots by analogy with sonochemically assisted pro-
a decrease of reaction times that has been attributed to rapid
have focused on the causes of this increased efficiency through
heating induced by the microwaves (MW), and found to be
an examination of microwave thermal and non-thermal
effects11 and hot-spot effects.12 Despite the several inferences
more effective than conventional heating (typically with an oil-
bath). A recent tutorial review has summarized some of the
of non-thermal specific effects from the use of microwave
radiation in organic syntheses,1,3–5,7,10 Kappe and co-workers13
reactions examined up to 2008 in which microwave dielectric
heating has proved beneficial compared to the traditional way
of heating the reaction mixture.9
recently re-examined this issue using a dedicated reactor setup
that allowed internal reaction temperatures to be measured
accurately using fiber-optic probes (thermometers). They
a Department of Chemistry, Faculty of Science and Technology,
Sophia University, 7-1 Kioi-cho, Chiyoda-ku, Tokyo, 102-8554,
Japan. E-mail: horikosi@rs.noda.tus.ac.jp
concluded that rates are enhanced because of increased tem-
peratures attained by microwave dielectric heating and not by
microwave radiation field effects, as isolated product yields
and enantiomeric purities of products from both microwave
and conventional heating were identical. Apparently, studies
of non-thermal effects based on the use of infrared sensors
to measure reaction temperatures externally can lead to
misleading results owing to temperature gradients within
the reaction mixture because of field inhomogeneities in the
microwave cavity and inefficient magnetic agitation of
the reaction mixture.13
b Research Institute for Science and Technology, Tokyo University of
Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan
c Department of Pure and Applied Chemistry, Faculty of Science and
Technology, Tokyo University of Science, 2641 Yamazaki, Noda,
Chiba, 278-8510, Japan
d Dipartimento di Chimica Organica, Universita di Pavia, Via
Taramelli 10, Pavia, 27100, Italia. E-mail: nick.serpone@unipv.it;
nickser@alcor.concordia.ca
w Part 1: S. Horikoshi, M. Kajitani, N. Serpone, J. Photochem.
Photobiol., A. 2007, 188, 1–4; Part 2: S. Horikoshi, N. Ohmori, M.
Kajitani, N. Serpone, J. Photochem. Photobiol., A. 2007, 189, 374–379.
z Electronic supplementary information (ESI) available: (1) Gas chro-
matogram of the composition of products and reagents after 120 min
of reaction; (2) GC-MS mass spectral data of the species observed
in the gas chromatograms, and (3) proton NMR spectrum of the
major product obtained from the MW/Cool protocol. See DOI:
10.1039/b810142f
Simultaneous combination of cooling and microwave heat-
ing, in which care is taken to control microwave dielectric
heating through a cooling system, can lead to high product
yields by microwave dielectric heating under ambient tempera-
ture conditions.14 Along similar lines, the photoassisted TiO2
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degradation of the endocrine disruptor bisphenol-A was
significantly improved by microwave irradiation under cooling
conditions with temperatures measured by fiber-optic probes
and efficient magnetic stirring of the reaction mixtures.15
For the few reactions tested, combining microwave irradia-
tion with cooling to control the reaction temperature has thus
far proven advantageous, although the exact effect(s) of
cooling coupled to microwave heating remains somewhat
elusive requiring additional experimentation to establish a
library of reactions that may lead ultimately to delineate
factors that lead to improved yields and shorter reactions
times. In this regard, a few studies16 that examined microwave-
enhanced radical reactions ascribed improved product yields
and faster kinetics solely to microwave dielectric heating
effects. Toward a further understating of microwave effects
other than plain heating effects, we herein report the synthesis
of 3-cyclohexyl-1-phenyl-1-butanone (CPB) from a reaction
involving tert-butylhydroperoxide, triethylborane, iodocyclo-
hexane and crotonophenone in THF, a radical reaction that is
enhanced by microwave dielectric heating under ambient
temperature conditions. The microwave reactor used consisted
of an internal cooling system herein proposed as a simple
mono-modal experimental reactor.
Fig. 2 Cartoon illustrating the possible temperature distribution and
microwave irradiation situation that might make the difference in
efficiency between internal and external cooling conditions.
2. Experimental
2.1 Experimental setup of the microwave device
A three-pronged microwave double cylindrical cooling reactor
with a reflux condenser was located in the waveguide (see
Fig. 1). The reaction sample introduced into the reactor was
irradiated by continuous 2.45 GHz microwave radiation with
an IDX Inc. green-motif I microwave-type apparatus (mono-
modal microwave radiation system). The mono-mode reactor
provides a reliable homogeneity of the electric field (wave
focusing) and accurate control of temperature measured with
a fiber-optic probe, thus the possibility of operating under
temperature profiles otherwise identical in both kinds of
activation, namely microwave and conventional thermal acti-
vation.17 The coolant in the inner cold finger consisted of
hexane and dry-ice (solid CO2) grains. Note that hexane and
dry-ice grains absorb no microwave radiation, and control of
addition of the dry-ice achieved the desired solution tempera-
ture. Although internal heating of a reaction mixture was
described by Kappe and Stadler5 on the characterization of
microwave dielectric heating, irregular temperature zones in
the reacting solution due to internal heating and external
cooling (Fig. 2(a)) are not precluded. No such irregular
temperature zones are caused by internal cooling and micro-
wave heating, however (Fig. 2(b)). The advantage of internal
cooling rests in the prevention of condensation (Fig. 2(c) and
(d)) which can be generated on the reactor surface by cooling
the sample externally thereby resulting in a significant attenua-
tion of the microwave radiation reaching the reaction mixture
and causing a drop of reaction efficiency.
For a microwave applied power of 60 W, the temperature
could be easily controlled by addition of dry-ice grains as
measured by an optical fiber thermometer (FL-2000, Anritsu
Meter Co. Ltd.) and a k-type sheathed thermocouple. Varia-
tions in temperature readings at various positions in the
reactor with both probes were less than ca. ꢁ2 1C; no
temperature differences were evidenced within this error.
2.2 Synthesis of 3-cyclohexyl-1-phenyl-1-butanone (CPB)
A THF solution of triethylborane (2 mmol) was added
gradually under an inert argon atmosphere to a vigorously
magnetically stirred mixture comprised of iodocyclohexane
(1 mmol) and crotonophenone (2 mmol) in the cylindrical
Fig. 1 Details of the experimental setup with a three-pronged micro-
wave double cylindrical cooling reactor single mode system.
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reactor of Fig. 1, following which tert-butyl hydroperoxide
(70% aqueous solution; 1 mmol; t-BuOOH; CAUTIONy18)
was added slowly to the solution also under argon inert
conditions (reaction (1)).
ð1Þ
The synthesis of 3-cyclohexyl-1-phenyl-1-butanone (CPB)
was carried out using four different protocols: (a) application
of 60 W of microwave radiation while the solution was cooled
with dry-ice grains and hexane (MW/Cool); (b) conventional
microwave irradiation at a 60 W power level (MW); note that
the cold-finger contained only hexane to maintain reaction
conditions close to those of the MW/Cool method; (c) con-
ventional heating with an oil-bath (Oil-bath); and (d) synthesis
at room temperature with the mixture magnetically stirred
(RT). In all cases, reaction times for the syntheses were 60 and
120 min. Products were separated and purified by flash column
chromatography over silica gel-300; the eluent was a mixture
of dichloromethane and n-hexane (1 : 2 volume ratio).
Fig. 3 Graph illustrating the time needed for the solution to reach
maximal temperature.
MW/Cool method. For the MW protocol, the initial tempera-
ture was ca. 28 1C increasing rapidly under microwave
dielectric heating to reach 78 1C (reflux temperature) after
ca. 6 min. The corresponding profile of heating the solution by
the oil bath protocol was not very different (ca. 5 min) from
the MW protocol.
3.2 Synthesis and identification of products
The gas chromatogram of the products (Fig. S1a, ESIz) from
the synthesis of 3-cyclohexyl-1-phenyl-1-butanone obtained by
microwave dielectric heating the solution to reflux after
120 min (MW protocol) displays various peaks identified by
gas chromatographic methods: crotonophenone, 3-methyl-
1-phenyl-1-pentanone (by-product 1), 3-phenyl-4-hexen-3-ol
(by-product 2) and boranyl species (see below) with retention
times of 6.3, 7.1, 7.9 and 9.45–9.55 min, respectively. The
major product 3-cyclohexyl-1-phenyl-1-butanone eluted at a
retention time of 10.2 min. Identification of CPB and the
by-products was carried out by GC-MS mass spectral techni-
ques (Fig. S1b, ESIz). Except for the molecular mass peak, the
fragmentation patterns tended to be rather similar.
2.3 Characterization of 3-cyclohexyl-1-phenyl-1-butanone
(CPB) and by-products
The resulting major product 3-cyclohexyl-1-phenyl-1-buta-
none (CPB) and a small quantity of by-products (o ca. 5%;
except for the MW/Cool protocol—see below) were analyzed
by GC-MS techniques on a Shimadzu GC/MS Model QP5000
apparatus using an Ultra Alloy column (dimethylpolysiloxane
100%) obtained from Frontier Laboratory Ltd.; helium was
the carrier gas. Proton NMR spectra of the CPB product were
recorded on a JEOL 500-MHz spectrometer (Model LA500)
in CDCl3 solutions against TMS as the reference. Yields of the
major product were estimated by determining the actual mass
subsequent to the flash column chromatographic separa-
tion and purification and are based on the crotonophenone
reagent.
The proton NMR spectrum of the fraction of products
(Fig. S2, ESIz) obtained from the separation of products by
flash column chromatography is consistent with the major
product being 3-cyclohexyl-1-phenyl-1-butanone.
3. Results and discussion
3.3 Chemical yields of 3-cyclohexyl-1-phenyl-1-butanone (CPB)
3.1 Temperature–time profiles
Chemical yields of 3-cyclohexyl-1-phenyl-1-butanone obtained
under various experimental conditions are listed in Table 1. The
Temperature–time profiles for the sample solutions under the
MW, Oil-bath and MW/Cool protocols are reported in Fig. 3.
An initial solution temperature around 20–24 1C was main-
tained relatively constant by the hexane/dry-ice bath in the
Table 1 Chemical yields of 3-cyclohexyl-1-phenyl-1-butanone (CPB)
under various experimental conditions
Yield (%) after:
y tert-Butyl hydroperoxide is used as a free radical initiator over a
wide temperature range under appropriate redox initiation. It has a
high thermal stability compared to other organic peroxides and is one
of the safest of the organic peroxides. However, it is still a peroxide,
and as such under inappropriate conditions it can decompose explo-
sively. However, with proper handling it should cause no major
problem.18
Method
Reaction temperature (1C)
60 min
120 min
MW/Cool
MW
RT
20–24
93
56
40
27
95
53
72
31
78 (reflux)
24
78 (reflux)
Oil-bath
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yield of the major CPB product was nearly quantitative (93 and
95%) for the MW/Cool method, 56 and 53% for the MW
method, 40 and 72% for the RT method, and 27 and 31% for
the conventional heating method with an oil bath after 60 and
120 min of reaction time, respectively.
geometry (i.e. the steric factor p), thus the efficiency of the
encounters between reactants, and increasing the number of
collisions Z between reactant partners through a greater
diffusion of the reactants from their respective solvent cages.
Clearly, the most efficient synthesis of CPB occurred for
the coupled microwave heating/internal cooling system. The
rather unusual greater yields of CPB at room temperature
compared to the conventional heating method under reflux
with the oil-bath should also be noted. By comparison, the
yield obtained under reflux by the microwave dielectric heating
method (MW) was about 20–30% greater than by the con-
ventional heating method under otherwise identical tempera-
ture conditions. In this regard, we attribute the greater yield of
53–56% from the MW method to some specific microwave
effect. Most remarkable, however, are the greater yields of
CPB by the internal cooling/MW dielectric heating of the
reaction mixture (MW/Cool protocol).
3.4 Proposed steps in the synthesis of 3-cyclohexyl-1-phenyl-1-
butanone (CPB)
Four major steps involving radical events and likely implicated
in the synthesis of 3-cyclohexyl-1-phenyl-1-butanone are
suggested in Scheme 1. In Step 1, the initial stage is the
decomposition of the hydroperoxide t-BuOOH to tert-butyl
alcohol and oxygen21 through formation of hydroxyl and tert-
butoxy radicals by homolytic scission under microwave
dielectric heating or conventional heating,22 and photo-
chemically under typical laboratory conditions.21 The tert-
butoxyl radicals react with t-BuOOH to yield tert-butyl
alcohol and the tert-butyl peroxide radical which subsequently
dimerizes to the di-tert-butyl tetraoxide. Decomposition of the
latter yields molecular oxygen and the di-tert-butyl peroxide.23
In Step 2, molecular oxygen interacts with B of the triethyl-
borane structure releasing an ethyl radical,24 which
subsequently extracts the iodine from the C–I bond of iodo-
cyclohexane to yield ethyl iodide and cyclohexyl radicals in
Step 3. Dehalogenation of iodocyclohexane by ꢂOH radical
involvement from Step 1 is also not precluded in the formation
of the cyclohexyl radical. In Step 4, the cyclohexyl radical
subsequently adds to the position 3 of crotonophenone
assisted by triethylborane, which in this instance functions as
a Lewis acid. The ensuing carbon-centered radical at the
2-position then reacts with a hydrogen source, for example
t-BuOH (Step 1), to yield the 3-cyclohexyl-1-phenyl-1-buta-
none product and the di-tert-butyl peroxide. Note that
although addition of the cyclohexyl radical to position 2 is
also possible, the NMR results reported in Fig. S2 (ESIz) are
consistent with the 3-cyclohexyl-1-phenyl-1-butanone
product. No doubt other steps can also be envisaged that
would involve the various radicals and other species. Such
details were not the scope of the current study, however.
Nonetheless, quantification of the products and by-products
ꢂ
Earlier we reported that the concentration of OH radicals
generated from the photoassisted oxidation of water in TiO2
aqueous dispersions and monitored by electron spin resonance
(ESR) techniques under simultaneous irradiation by UV-light
and microwaves was significantly increased by irradiation with
microwaves relative to UV irradiation alone.19 By contrast, no
increase of ꢂOH radicals was obtained by conventional oil-
bath heating. Specific microwave radiation effects played a
non-insignificant role in this increase, although the exact
nature of such effects remained somewhat elusive. In the
present state of knowledge, we can only speculate on the root
cause(s) for such specific microwave effects that input on the
greater yields and faster kinetics relative to conventional
heating under otherwise identical temperature conditions. As
such we begin by considering the relationships that govern the
reaction kinetics (given by the rate constant, k) and the thermo-
dynamics of the reaction, namely the temperature dependence
of the rates, from transition state theory (eqn (2)) and from the
empirical Arrhenius equation (eqn (3)):20
k = (kT/h)exp(DS*/R)exp(ꢃDH*/RT)
k = pZ exp(ꢃDEa/RT)
(2)
(3)
where k is Boltzmann’s constant, T is absolute temperature, h
is Planck’s constant, DS* is the entropy of activation, DH* is
the enthalpy of activation, R is the gas constant, p is the steric
factor, Z is the total collision frequency, and Ea is the
activation energy; note that Ea E DH* for reactions in liquids
so that the pre-exponential factor pZ in eqn (3) is given
approximately by eqn (3):
pZ E (kT/h)exp(DS*/R)
(4)
Accordingly, the microwave radiation may affect one or more
of the above parameters to account for the enhanced reaction
kinetics and thus the yields; for example: (i) a decrease of the
activation energy Ea E DH* of the reaction through a greater
stabilization of the activated complex, particularly relevant for
polar reactants as they interact more effectively with the
microwave radiation field; and/or (ii) an increase in the
pre-exponential factor pZ through enhancing the encounter
Scheme 1 Some inferred steps in the overall synthesis of 3-cyclohexyl-1-
phenyl-1-butanone (CPB).
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after the 120-min reaction period infers that such other steps
were likely less significant, at least toward formation of the
major product.
Table 2 Chemical yields of 3-cyclohexyl-1-phenyl-1-butanone (CPB)
by the synthesis with and without t-BuOOH with the reactant solution
being purged with molecular oxygen
Method
Purging gas
Yield (%)
3.5 Effect of cooling coupled to microwave irradiation
MW/Cool
MW/Cool
O2
O2 (without t-BuOOH)
E100
E69
The radical events of Scheme 1 infer, among others, two likely
by-products in the synthesis of 3-cyclohexyl-1-phenyl-1-
butanone by microwave and conventional heating prior to
purification of the product(s) for the GC-MS analysis. The
concurrent formation of two of the by-products are the result
of addition of the generated ethyl radical at the 3-position of
the crotonophenone skeleton and at the 1-position to yield
by-products 1 and 2, respectively (see Scheme 2 and the
chromatogram in Fig. S1a, ESIz). To the extent that the mass
spectra (Fig. S1b, ESIz) of the species with retention times at
9.45 and 9.55 min are identical, we hypothesize that these two
chromatographic peaks (Fig. S1a, ESIz) correspond to the two
isomers constituting by-product 3, namely 2-diethylboranyl-1-
phenyl-1-butanone and 3-diethylboranyl-1-phenyl-1-butanone
that result from addition of the de-ethylated triethylborane
from Step 2 onto the olefinic bond positions of crotono-
phenone. Both the ethyl and hydroxyl radicals from Steps 1
and 2 can attack, albeit non-selectively, both crotonophenone
and iodocyclohexane reactants under heating by microwaves
(MW) and conventional heating (Oil-bath). For the MW/Cool
method, however, the exclusive synthesis of 3-cyclohexyl-
1-phenyl-1-butanone suggests selective attack of iodocyclo-
hexane by both ethyl and hydroxyl radicals to produce the
cyclohexyl radical. Evidently, the selectivity of the reaction
was improved under such cooling conditions for the MW/Cool
protocol,17 otherwise not evident for the other protocols.
conditions. These observations clearly indicate the key role
played by the t-BuOOH in the overall reaction. Moreover,
they also show the effect of cooling under microwave irradia-
tion in the selectivity of the radical reaction.
Summary
The synthesis yield of 3-cyclohexyl-1-phenyl-1-butanone by
microwave dielectric heating is improved for the radical reac-
tion under temperature conditions otherwise identical to those
of the conventional heating method and under close tempera-
ture control. The greater yields of the product observed for the
microwave-induced reaction over those obtained by conven-
tional heating for identical conditions of temperature likely
implicate some specific microwave effect(s), the nature of
which continues to be a subject of great debate. Cooling
coupled to microwave irradiation improved the selectivity of
the radical reaction toward a single major product without
losing the characteristic advantage(s) of the microwaves. The
non-selectivity of the chemical reaction by either conventional
or microwave dielectric heating alone could be attenuated by
cooling the reaction mixture while being microwave irradiated.
Acknowledgements
3.6 Influence of molecular oxygen
We are grateful to the Sophia University-wide Collaborative
Research Fund, the Foundation of Research for Promoting
Technological Seeds from the Japan Science and Technology
Agency to S. H. One of us (N. S.) is grateful to Prof. Albini
and his group for their gracious hospitality during his several
stays in Pavia during the winter semesters. We are also grateful
to one of the reviewers for pointing out some NMR features of
our major product from ChemNMR.
The influence of dissolved oxygen on the overall synthesis and
product yields was examined for 60-min irradiation by the
microwaves for solutions saturated with molecular oxygen.
Yields are reported in Table 2 for the case where both added
oxygen and oxygen produced in Step 1 of Scheme 1 was
present and for the case where only molecular oxygen was
added (no t-BuOOH used in this case). In the former case, the
chemical yield of 3-cyclohexyl-1-phenyl-1-butanone was ca.
100%, whereas a ca. 69% yield was obtained under the latter
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2262 | New J. Chem., 2008, 32, 2257–2262