Influence of polarity on the scalability and reproducibility of solvent-free microwave-assisted reactions

Article abstract of DOI:10.2174/138620711794474088

Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature control are generally considered as not reproducible, particularly when different instruments are used. For this reason, reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis (MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a reaction will be reproducible or not.

Full text of DOI:10.2174/138620711794474088

Combinatorial Chemistry & High Throughput Screening, 2011, 14, 109-116
109
Influence of Polarity on the Scalability and Reproducibility of Solvent-Free
Microwave-Assisted Reactions
Angel Díaz-Ortiz*,1, Antonio de la Hoz1, Jesús Alcázar2, José R. Carrillo1, María A. Herrero1,
Alberto Fontana2, Juan de M. Muñoz1, Pilar Prieto1 and Abel de Cózar1
1Dpto. Q. Orgánica, Q. Inorgánica y Bioquímica, Facultad Química, Universidad de Castilla-La Mancha, E-13071
Ciudad Real, Spain
2Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen-Cilag, S.A., Jarama s/n, E-45007
Toledo, Spain
Abstract: Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature
control are generally considered as not reproducible, particularly when different instruments are used. For this reason,
reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis
(MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the
scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been
translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of
these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using
temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a
reaction will be reproducible or not.
Keywords: Scalability, reproducibility, solvent-free reactions, microwave-assisted reactions.
INTRODUCTION
methodology was introduced twenty years ago, most
reactions were performed in domestic ovens without
appropriate temperature control. Most of these reactions
were performed in the absence of solvent for safety reasons.
The avoidance of solvents in organic synthesis leads to
clean, efficient and economical technologies (green
chemistry); safety is greatly increased, work-up is
considerably simplified, cost is reduced, increased amounts
of reactants can be used with the same equipment, and the
reactivity and sometimes the selectivity is enhanced without
dilution [1-4]. Thus, the absence of solvents coupled with the
high yields and short reaction times often associated with
reactions of this type make these procedures very attractive
in synthesis. It has been shown that solvent-free conditions
are especially applicable to microwave activation as
reactions can be carried out safely at atmospheric pressure in
the presence of significant amounts of products and avoiding
the use and recovery of considerable volumes of solvent [1-
4]. Furthermore, the use of microwave irradiation as a source
of heat has proven to be more energy efficient than the use of
traditional heating [5]. For this reason the combination of
solvent-free conditions and microwave irradiation has
attracted the interest of a large number of green chemists.
As a consequence, there is a plethora of interesting green
procedures that were originally carried out in domestic ovens
without appropriate temperature and pressure controls. These
reactions are generally considered as not reproducible,
particularly when a different scale or instrument was used,
and this has limited the application of such reactions [12,
13]. As a consequence, at present several journals do not
accept reports concerning reactions performed in domestic
ovens.
In recent years a number of reports have disclosed the
reproducibility of results between monomode and multimode
microwave instruments for solution chemistry [14-18]. Other
authors, such are Hamelin [19] and Loupy [20] have showed
how solvent-free reactions can be scale-up in monomode
apparatus (Synthewave 402 to Synthewave 1000), and very
recently Moseley [21] and Leadbeater [22] reported a
comparison of commercial microwave reactors and show
how different processing techniques can be used for scale-up
microwave-promoted reactions, respectively. However, to
the best of our knowledge, studies regarding reproducibility
of solvent-free reactions previously performed in domestic
ovens have not been described, although since 1986 to 1998
most of the microwave-assisted reactions -involving a lot of
interesting synthesis- was performed in these apparatus and
in these conditions.
Since 2000 the number of publications related to
Microwave-Assisted Organic Synthesis (MAOS) has
increased dramatically [6-11]. One of the reasons for the
increased interest in the use of microwave heating was the
introduction, at the dawn of the 21st Century, of dedicated
monomode and multimode instruments with appropriate
temperature and pressure controls, a development that allows
reproducibility of results. However, when the microwave
The polarity of the solvent is the most important
parameter to consider when microwave reactions are
performed in solution. Polar solvents directly absorb the
microwave radiation and the polarity of the substrate is
*Address correspondence to this author at the Dpto. Q. Orgánica, Q.
Inorgánica y Bioquímica, Facultad Química, Universidad de Castilla-La
Mancha, E-13071 Ciudad Real, Spain; Tel: +34 926295300; Fax: +34
926295318; E-mail: Angel.Diaz@uclm.es
1386-2073/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

110 Combinatorial Chemistry & High Throughput Screening, 2010, Vol. 14, No. 2
Díaz-Ortiz et al.
relatively unimportant. With non-polar solvents the
microwave radiation is absorbed by the substrates, but the
differences in absorption of the substrates are moderated by
the solvent, especially in dilute solution. In both cases, the
reaction temperature is limited by the solvent boiling point
and microwave-assisted reactions in solution are easily
controlled.
ketoximes [28] and oxidation of benzylic bromides to
aromatic aldehydes [29]. These microwave-assisted
processes were selected on the basis of their synthetic
importance and/or environmentally friendly characteristics.
Alkylation of benzotriazoles is performed in the absence of
any base or phase transfer catalyst simply by mixing the
reagents. Substituted ureas and thioureas have important
applications in agriculture, medicinal chemistry and
chemical transformations. Irradiation of ketoximes on
Montmorillonite K10 provides a dry and recyclable medium
to carry out a Beckmann rearrangement and avoids the use of
highly polluting strong acids. Oxidation of benzylic
bromides with pyridine N-oxide under microwaves in the
absence of solvent and base represents a useful and clean
synthetic process. These reactions can also be considered to
provide representative examples of a variety of conditions
reported in the literature.
In neat reactions, microwave radiation is again absorbed
by the substrates but there is no solvent to stabilize the
temperature. In this situation the nature of the substituents
and the polarity of the substrates influence the absorption of
microwave energy [23] and, as a consequence, the yield.
Moreover, in the absence of solvent the temperature is not
limited by the boiling point of the solvent. A process
involving highly polar reagents, intermediates or Transition
States can hardly be controlled under microwave irradiation.
Hence, it does not follow that a solvent-free reaction
previously performed in a domestic oven will be controllable
and reproducible in focused microwave reactors in a similar
way to reactions in solution, as the field density is very
different from one instrument to another [12, 13].
In each example we proceeded to compare the results
obtained in a monomode reactor Discover™ CEM with
those observed in the multimode microwave reactor
MultiSYNTH™ Milestone on increasing the amounts of
reagents. In each case, we have used reaction conditions
described in the original report, none optimization has been
performed in these reactions. In order to validate our results,
as well as to improve the synthetic utility of the reactions, we
chose substrates with different substituents and electron-
donating or electron-withdrawing groups, most of which
were not described in the original work. These compounds
cover a wide range of polarities and, as a consequence, of
microwave absorption.
The development of methodologies that allow
a
successful translation of useful synthetic processes from
domestic ovens to microwave reactors is of great importance
in order to update information and allow the application of a
considerable number of interesting reactions reported in the
early years that are, at this moment, overlooked as they are
considered as not reproducible. If this approach were applied
to solvent-free reactions these investigations would
constitute an interesting contribution to green chemistry
instrumentation and environmentally friendly processes.
RESULTS
Recently, we have shown for the first time that solvent-
free 1,3-dipolar cycloadditions of nitrile N-oxides with
nitriles, when carried out in a domestic oven [24], can be
reproduced, scaled up and parallelized in monomode and
multimode microwave reactors [25].
Alkylation of (1H)-Benzotriazoles
Following the procedure described by de la Hoz et al.
[26], irradiation of a mixture of (1H)-benzotriazole (1) (1
equiv.) and an alkyl bromide (2) (2 equiv.) in the absence of
any solvent for 4 min gave the alkylated benzotriazoles 3 and
4 (Scheme 1).
The objective of the work described here is to extend our
preliminary results to show whether solvent-free reactions
previously performed in
a
domestic oven, without
The results obtained with five different alkyl bromides,
including 2 new functionalities not represented in the
previous report, in monomode and multimode microwave
reactors using 3 mmol and 21 mmol scales, respectively,
were compared. These reactions were performed at 185ºC
for 4 min (see Table 1) - the same conditions employed in
the domestic oven in the original work. Reactions in the
multimode oven were performed in separate experiments due
to the different heating profiles of each mixture.
appropriate temperature and pressure controls, can be
reproduced and scaled up in controlled microwave
monomode and multimode reactors, and what parameters
may have an effect on reproducibility.
In order to achieve our aim, we studied four solvent-free
reactions that were previously carried out in domestic ovens.
These examples cover
transformations and, in contrast to the aforementioned
cycloaddition reaction, the polarity in the course of the
process increases and, as a consequence, it could be more
difficult to control. The reactions selected are: N-alkylation
of (1H)-benzotriazoles [26], condensation of anilines with
urea (or thiourea) [27], Beckmann rearrangement of
a
wide range of chemical
Condensation of Anilines with Urea or Thiourea
The anilines 5 were condensed with urea (6) (or thiourea,
7) in a domestic oven in 4 min to afford the diarylureas 8 (or
N
N
N
N
MW
N
N
R
N
R-Br
+
+
4 min
N
R
N
H
2
1
3
4
Scheme 1. Alkylation of (1H)-benzotriazole (1) with alkyl bromides (2).

Solvent-Free Microwave-Assisted Reactions
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 2 111
diarylthioureas) (Scheme 2) [27]. Purification of the products
was achieved simply by washing the crude reaction mixture
with water.
Beckmann Rearrangement of Ketoximes
Microwave irradiation in a domestic oven of ketoximes
with K-10 montmorillonite in dry media provides an
efficient method for the Beckmann rearrangement (Scheme
3) [28].
Table 1. Alkylation of (1H)-Benzotriazole (1) with Alkyl
Bromides 2a-e in a Monomode and a Multimode
Microwave Reactor at 185ºC for 4 min
In previous examples the scale up was performed in
separate experiments due to the different heating profiles of
Alkyl Bromide Yield (%) Monomodea,b
Yield (%) Multimodea,c
the mixtures. However, in this reaction the main absorption
and, hence, temperature is determined by the clay
(Montmorillonite K10). As a consequence, we carried out
five reactions in the multimode microwave oven at the same
time (see Table 3), which represents one of the first
examples of a combination of microwave parallel scale up
with green procedures.
n-C8H17Br
n-C16H33Br
81
63
83
10
25
78
60
81
10
27
Ph(CH2)3Br
EtO2C(CH2)5Br
PhO(CH2)4Br
Table 3. Beckmann Rearrangement of Ketoximes 9 in a
Monomode and Multimode Reactor at 150ºC
aYields were determined by HPLC by integration of peak areas using the pure product
as a standard.
bReactions performed on a 3 mmol scale.
cReactions performed on a 21 mmol scale.
Yield (%)
Yield (%)
R1
R2
Monomodea,c
Multimodeb,c
In order to study the translation and scalability of the
reaction, five reactions were performed at 180ºC, including
anilines with different substituents and thiourea, in both
monomode and multimode microwave ovens (Table 2). The
scale used in the latter instrument was 7 times larger than that
used in the monomode apparatus. As in the previous example,
reactions in the multimode oven were performed in separate
experiments. Only the last example in Table 2, involving aniline
+ thiourea, had been described in the original work, thus
increasing the general applicability of this reaction.
CH3
C6H5
C6H5
58
80
70
77
78
57
77d
67
74
77
C6H5
p-CH3OC6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3C6H4
o,p-CH3OC6H4 o,p-CH3OC6H4
aReactions performed with 0.3 g of ketoxime.
bReactions performed with 0.75 g of ketoxime.
cRatio ketoxime/K10 1:9 (w/w).
dTemperature-controlled reaction in the multimode apparatus.
Table 2. Condensation of Anilines 5a-d with Urea (6) or
Thiourea (7) in a Monomode and a Multimode
Microwave Reactor at 180ºC for 4 min
Oxidation of Benzylic Bromides with Pyridine N-Oxide
Yield (%)
Yield (%)
In 1996, Barbry et al. [29] described the oxidation of
benzylic bromides in the presence of pyridine N-oxide
without any solvent or base. These reactions took place in a
domestic oven to afford high yields of aromatic aldehydes
(Scheme 4).
Reaction
Monomodea,b
Multimodea,c
o-toluidine + urea
Aniline + urea
70
49
60
49
56
72
48
61
46
58
p-MeS-aniline + urea
m-Br-aniline + urea
Aniline + thiourea
However, all of our attempts to reproduce and control
this reaction using benzyl or p-nitrobenzyl bromide in
monomode or multimode microwave reactors failed. We
assessed a range of times, temperatures and powers
(including ramped conditions) but, unfortunately, we were
unable to control the process: the reaction temperature did
aIsolated yields.
bReactions performed on a 3 mmol scale.
cReactions performed on a 21 mmol scale.
X
X
MW
NH2
N
N
H
+
H
H2N
NH2
4 min
R
R
R
6, X = O
7, X = S
5
8
Scheme 2. Condensation of anilines 5 with urea (6) or thiourea (7).
O
R1
Montmorillonite K10
MW / 4 min
C
C
N
OH
R1
N
H
R2
R2
9
10
Scheme 3. Beckmann rearrangement of ketoximes 9.

112 Combinatorial Chemistry & High Throughput Screening, 2010, Vol. 14, No. 2
Díaz-Ortiz et al.
HBr
,
N
O
N
14
Br
N
MW
11
+
+
OCH2Ar
2 min
ArCH=O
ArCH2Br
13
12
15
Scheme 4. Oxidation of benzylic bromides 12.
not become stable but rose rapidly to give decomposition of
the products.
condensation were isolated from the crude reaction mixture
by washing with water; and (iii) amides obtained by
Beckmann rearrangement were purified by recrystallization
from ethanol.
DISCUSSION
As can be seen from the results in Tables 1-3, in the first
three reactions studied (where the reaction temperature is
easily controlled) the maximum difference in yield between
the two instruments in all the examples presented is 3%, with
the average difference being 2%. Similar behaviour was
observed in the 1,3-dipolar cycloaddition described
previously [25]. These results allow us to conclude that
solvent-free temperature-controlled reactions are absolutely
reproducible across monomode and multimode reactors.
As mentioned above, the reproducibility of microwave-
assisted reactions in solution has been unequivocally proved,
allowing the efficiency of microwave chemistry to be
combined with the productivity of the parallel approach [14-
18]. Other studies, involving scale-up of microwave-
promoted reactions -including solvent-free reactions- have
been also reported [19-22]. In the same way, we reported for
the first time that a solvent-free 1,3-dipolar cycloaddition
performed in a domestic oven can be reproduced in
monomode and multimode reactors [25]. We have now
studied four new solvent-free processes previously carried
out in a domestic oven, including substitution, condensation,
rearrangement and oxidation reactions. Since all of these
reactions have polar intermediate species, they show good
absorption of microwave radiation. Hence, the results
obtained in these five reactions can support a general
conclusion, since reproducibility of solvent-free reactions
previously reported in a domestic oven has not even been
published.
With the aim of explaining why the oxidations of
benzylic bromides are not temperature-controlled processes
under microwaves, we carried out a computational study of
this reaction and the aforementioned 1,3-dipolar
cycloaddition [25], which is easily controlled.
Computational Calculations
In this exploratory study, most of the calculations were
performed using the semi-empirical AM1 method available
in the AMPAC software [30]. This method gives reasonable
results for organic chemical reactivity studies [31].
Geometries of stationary points were determined by energy
minimizations with respect to all geometric parameters. All
reaction paths were determined by the fullchn process [30].
All Transition Structures (TS) of full reaction paths were
located by the chain method [32] and characterized by one
and only one negative eigenvalue of the Hessian matrix.
Furthermore, the corresponding vibration was found to be
associated with nuclear motions along the reaction
coordinate.
In an effort to prove the reproducibility of solvent-free
reactions carried out in a domestic oven, five substrates with
different substitution patterns were reacted in both
monomode
(Discover™
CEM)
and
multimode
(MultiSYNTH™ Milestone) microwave reactors. All of the
reactions were performed at the reaction temperatures
described in the original references for 4 min (except the
oxidation of benzylic bromides, for which the reaction time
was 2 min). Likewise, in order to demonstrate the scalability
of these reactions, the scale used in the multimode
instrument was seven times larger than that used in the
monomode apparatus. In the case of the Beckmann
rearrangement the scale was 2.5 times higher, but all of the
reactions were performed in parallel in a single experiment.
Moreover, if the reaction is performed using a solid support,
as exemplified in the Beckmann rearrangement, reactions
can be performed in parallel in the multimode oven; clearly
showing that it is possible to scale up in parallel solvent-free
reactions when heating profiles of individual reaction
mixtures are similar.
Solvent effects were estimated by means of the
AMSOL/SM5.2 model [33-35]. This model can be applied to
chemical reactions involving bond dissociation, thus full
solvent reaction paths were obtained with the fullchn
process. For semi-empirical calculations acetonitrile and
bromobenzene were chosen as the media.
Ab initio calculations were carried out using the
GAUSSIAN 03 [36] series of programs, with the standard 6-
31-G* basis set [37]. In order to include electron correlation
at a reasonable computational cost, Density Functional
Theory (DFT) [38, 39] was used. In this study, these
calculations were carried out by means of the three-
parameter functional developed by Becke [40-42], which is
usually denoted as B3LYP. All TS structures and minima
In addition to the environmentally friendly conditions
associated with solvent-free microwave irradiation, we wish
to emphasize that these reaction products were purified
following green procedures: (i) alkylation of benzotriazole
was analyzed by HPLC; (ii) diarylureas prepared by

Solvent-Free Microwave-Assisted Reactions
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 2 113
were fully characterized by harmonic analysis. Solvent
effects were estimated by means of polarization continuum
models (PCM) [43] using acetonitirle as the medium.
Loupy and Perreux [44] proposed that microwave effects
are due to the dipolar polarization phenomenon; the higher
the polarity of a molecule (such as the solvent) the more
pronounced the microwave effect when the rise in
temperature [45] is considered. In terms of reactivity and
kinetics, this effect depends of the mechanism, particularly
with regard to how the polarity of the system is altered
during the progress of the reaction. For this reason, in our
computational study the polarities of all species were
calculated.
In the first case studied, the reaction takes place through
a 1,3-dipolar cycloaddition between a nitrile N-oxide and a
nitrile (Scheme 5).
Fig. (1). Reaction profile for 3+2 cycloaddition in solution in
acetonitrile.
O
N
C
N
+
C
N
O
Ph
Ph
N
16
17
18
Scheme 5. 3+2 Cycloaddition of benzonitrile and benzonitrile N-oxide.
In principle, two possible reaction paths are conceivable:
the concerted and the stepwise mechanisms. The first
pathway proceeds in a suprafacial manner for both reactants
according to the thermally allowed [ꢀ2s + ꢀ4s] mechanism
[46, 47]. The second pathway consists of a second-order
nucleophilic addition of the 1,3-dipole over the dipolarophile
to yield a zwitterionic intermediate, whose ring closure leads
to the corresponding five-membered cycloadduct. Several
previous cases have shown that this process can involve
stepwise mechanisms [48-50]. In our case benzonitrile and
the benzonitrile oxide react through a stepwise mechanism.
The reaction profile is depicted in Fig. (1). Activation and
reaction energies in the gas phase and in solution are
collected in Table 4 and dipolar moments of all the
stationary points are given in Table 5.
With the aim of validating our method, we calculated the
reaction profile for this reaction with B3LYP/6-31G* and the
PCM solvent model. The energy values and dipolar moments
are collected in Tables 6 and 7.
Table 6. Activation Energies (ꢀEa, Kcal/mol) and Reaction
Energies (ꢀErxn, Kcal/mol)
ꢀEa1
ꢀEa2
ꢀErxn
Gas phase
19.30
19.95
7.51
8.43
-45.29
-44.27
Solution (acetonitrile)
Table 7. Dipole Moments (Debyes) of All Stationary Points
Table 4. Activation Energies (ꢀEa, Kcal/mol) and Reaction
Energies (ꢀErxn, Kcal/mol)
Reactants TS1
Int
TS2 Products
Gas phase
0.93
5.19
1.39
7.04
3.17
2.06
2.79
ꢀEa1
ꢀEa2
ꢀErxn
Solution (acetonitrile)
2.13 12.66 4.44
Gas phase
25.96
21.74
11.45
12.17
-10.26
-17.37
DFT and AM1 structures, reaction paths and dipolar
moments are similar. Therefore, B3LYP calculations
validate AM1 calculations for qualitative studies and AM1
calculations are sufficient to explain our experimental
results.
Solution (acetonitrile)
Table 5. Dipole Moments (Debyes) of all Stationary Points
Reactants TS1
Int
TS2 Products
The second reaction studied corresponds to an oxidation
of alkyl halides to carbonyl compounds [29, 51]. The
mechanism involves the formation of an N-benzyloxy
pyridinium bromide (13) and subsequent proton abstraction
to give the benzaldehyde (Scheme 4).
Gas phase
0.97
5.51
3.46
6.22
4.32
1.93
2.48
Solution (acetonitrile)
7.91 11.27 6.18
For this reaction the theoretical values of the dipolar
moments during the process show a maximum increase of
5.25 Debyes in the gas phase and 5.76 D in solution. The
intermediates have the highest polarity (Table 5).
This reaction could occur through SN1 or SN2
mechanisms. The reaction profiles for both processes are
depicted in Figs. (2, 3). Activation and reaction energies in
the gas phase and in solution are collected in Table 8 and

114 Combinatorial Chemistry & High Throughput Screening, 2010, Vol. 14, No. 2
Díaz-Ortiz et al.
dipolar moments of all the stationary points are shown in
Table 9.
ruled out the SN1 mechanism because this process possessed
higher activation energy than the SN2 pathway (Table 8). In
the SN2 mechanism the polarity of the system increased
markedly during the reaction (12.0 Debyes in the gas phase
and 19.97 Debyes in solution), in contrast to the 1,3-dipolar
cycloaddition. This fact can explain why the oxidation of
benzylic bromides with pyridine N-oxide is not
a
temperature-controlled process under microwave irradiation.
Moreover, if an SN1 mechanism is considered, the polarity
increase is even still higher (46.49 Debyes).
Reactions involving a moderate or medium increase in
polarity in the pathway from reactants to products are
relatively easy temperature-controlled processes under
microwave irradiation. In contrast, large increases in polarity
during the reaction path give rise to extreme absorptions of
microwave energy and make these processes more difficult
to control.
Fig. (2). SN2 reaction profile for the reaction between benzylic
bromide and pyridine N-oxide in solution in bromobenzene.
These results show that not all the reactions previously
performed in domestic ovens in the absence of solvent are
reproducible in single-mode or multimode microwave
reactors and could provide a criterion that assist to predict
the reproducibility.
CONCLUSIONS
In summary, the results of this work show that most
solvent-free reactions previously performed in a domestic
oven, without appropriate temperature control, can be
reproduced in both monomode and multimode microwave
instruments using temperature-controlled conditions. These
reactions can also be scaled up either singly or in parallel in
multimode instruments depending on the reaction procedure.
The range of transformations studied in this work shows that
scale up and reproducibility can be extended to other
solvent-free reactions when temperature is the parameter to
be controlled. We have also shown that, in solvent-free
conditions, temperature-controlled reactions can be
reproduced and scaled up regardless of the polarity.
Fig. (3). SN1 reaction profile for the reaction between benzylic
bromide and pyridine N-oxide in solution in bromobenzene.
Table 8. Activation Energies (ꢀEa, Kcal/mol) and Reaction
Energies (ꢀErxn, Kcal/mol)
ꢀEa
ꢀErxn
In addition, some solvent-free reactions in which polarity
undergoes a dramatic increase during the course of the
process may not be reproducible in dedicated microwave
reactors since the reaction temperature cannot be controlled.
These conclusions are in complete agreement with our initial
approach: in the absence of solvent there is no element to
limit the reaction temperature under microwave irradiation -
in contrast to solution reactions - and the process can be
controlled by the polarity of the reaction mixture.
SN2 Gas phase
67.25
50.53
57.59
-50.48
-49.47
-47.24
SN2 Solution (bromobenzene)
SN1 Solution (bromobenzene)
Table 9. Dipole Moments (Debyes) of All Stationary Points
Reactants
3.60
TS1
Int
TS2
Products
3.92
These conclusions represent a useful contribution to
microwave synthesis and green process research, as they enable
the advantages that modern microwave instrumentation offers to
be applied to synthetic transformations that have previously
been carried out in domestic ovens. Furthermore, these results
can provide a tool to predict the reproducibility of such
reactions. Nevertheless, the dependence of reproducibility with
polarity does not imply any non-thermal effect of the radiation
and it is independent of the classical heating results.
SN2 Gas phase
15.6
--
9.02
SN2 Solution
(bromobenzene)
5.05
19.98 25.02 23.81
22.74 52.04 24.88
5.00
SN1 Solution
(bromobenzene)
5.55
5.43
It is remarkable that in this process only the SN2
mechanism could be performed in the gas phase. In this case,
the intermediate was not computationally isolated because
the bromide ion is not solvated and is highly reactive. For
this reason, in the gas phase TS1 leads directly to TS2. We
EXPERIMENTAL
Monomode microwave irradiations were conducted using
a Discover® (CEM) focused microwave reactor. Multimode

Solvent-Free Microwave-Assisted Reactions
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 2 115
microwave irradiations were conducted in a MicroSYNTH
labstation multimode microwave oven (MILESTONE). Mps
were determined on a Gallenkamp apparatus and are
8.05 (d, 2 H, J = 8.4 Hz). 13C NMR (CDCl3) ꢀ (ppm) 26.4,
26.9, 47.2, 55.4, 109.1, 117.9, 120.1, 123.9, 126.4, 127.3,
132.8, 144.3, 145.9. ESI-HRMS C16H17N3O (M + H)+:
Calculated: 267.1372. Found: 267.1380.
1
uncorrected. NMR data were obtained at 500 MHz for H
and 125 MHz for 13C on a Varian Innova spectrometer using
CDCl3 as the solvent and TMS as an internal standard. High-
resolution mass spectra were recorded on an Agilent-
Micromass LCT Time of Flight mass spectrometer with
electrospray ionisation and a Lockmass device for mass
calibration. Column chromatography was performed using
230-400 mesh Merck type 60 silica gel. Yields were
determined using Hitachi L-7420 HPLC equipment fitted
with a Lichrospher® 100RP-18 (5 μm) column. Reagents
were purchased from commercial suppliers or prepared
according to literature procedures.
1,3-Bis(4-methylthiophenyl)urea (8c). M.p.: 232-233ºC.
1H NMR (DMSO-d6) ꢀ (ppm) 2.32 (s, 6 H), 7.21 (d, 2 H, J =
8.7 Hz), 7.41 (d, 2 H, J = 8.7 Hz), 8.65 (s, 2 H). 13C NMR
(DMSO-d6) ꢀ (ppm) 15.9, 118.8, 127.7, 130.8, 137.4, 152.4.
ESI-HRMS C15H16N2OS2 (M + H)+: Calculated: 304.0704.
Found: 304.0706.
ACKNOWLEDGEMENTS
Financial support from the DGICYT of Spain through
project CTQ2007-60037/BQU and from the Consejería de
Educación y Ciencia, JCCM through projects PBI08-025,
PCI08-0040 and PII2I09-0100 is gratefully acknowledged.
Alkylation of Benzotriazoles. General Procedure
A mixture of benzotriazole (1) (1 equiv.) and the
corresponding alkyl bromide (2) (2 equiv.) was irradiated at
185ºC for 4 min to obtain a mixture of the alkylated products
3 and 4. Yields were determined by HPLC using the pure
product as standard.
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Received: July 14, 2010
Revised: August 5, 2010
Accepted: August 7, 2010