Use of a scientific microwave apparatus for rapid optimization of reaction conditions in a monomode function and then substrate screening in a multimode function

Article abstract of DOI:10.1016/j.tet.2007.04.074

Recently, a new apparatus has become available, which aims to bring together in one unit the advantages of a monomode and a multimode microwave device. We have assessed the applicability of the apparatus toward rapid optimization of reaction conditions in a monomode function and then substrate screening in a multimode function. We have also probed the effects of differences in microwave absorptivity of reaction mixtures on the product conversions in screening multiple substrates simultaneously in a multimode microwave apparatus. We find that when the microwave absorptivity of a reaction mixture is dictated by the solvent, there is little effect on the heating profile of varying the substrate in a screening run. However, this is not the case when reactions involving non-microwave absorbant solvents are used. In this case the characteristics of the substrate can affect significantly the outcome of the reaction.

Full text of DOI:10.1016/j.tet.2007.04.074

Tetrahedron 63 (2007) 6764–6773
Use of a scientific microwave apparatus for rapid optimization
of reaction conditions in a monomode function and then
substrate screening in a multimode function
*
Nicholas E. Leadbeater and Jason R. Schmink
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA
Received 6 March 2007; revised 11 April 2007; accepted 23 April 2007
Available online 4 May 2007
Abstract—Recently, a new apparatus has become available, which aims to bring together in one unit the advantages of a monomode and
a multimode microwave device. We have assessed the applicability of the apparatus toward rapid optimization of reaction conditions in
a monomode function and then substrate screening in a multimode function. We have also probed the effects of differences in microwave
absorptivity of reaction mixtures on the product conversions in screening multiple substrates simultaneously in a multimode microwave ap-
paratus. We find that when the microwave absorptivity of a reaction mixture is dictated by the solvent, there is little effect on the heating profile
of varying the substrate in a screening run. However, this is not the case when reactions involving non-microwave absorbant solvents are used.
In this case the characteristics of the substrate can affect significantly the outcome of the reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
into the cavity they will move around and bounce off the
walls. They generate pockets of high energy and low energy
as the moving waves either reinforce or cancel out each
other. This means that the microwave field in the microwave
cavity is not uniform. The microwave field can be homoge-
nized either by ensuring that the dimensions of the cavity
avoid whole-number multiples of the microwave full or half
wavelength. Also, some means must be employed to
physically disrupt any standing waves that may form as a
consequence of items placed in the cavity. This is best
performed with a mechanical mode stirrer, typically a peri-
odically moving metal vane that continuously changes the
instantaneous field pattern inside the cavity.
By using microwave heating it is often possible to enhance
the rate of reactions and improve product yields.1,2 Much
of the early microwave-promoted synthesis was performed
using domestic (household) microwave apparatus. As well as
being inherently unsafe due to the fact that a domestic micro-
wave apparatus is not designed for synthetic chemistry, it can
be hard to measure temperature accurately and there can be
issues with reproducibility. With the advent of scientific mi-
crowave apparatus many of these problems have been over-
come. There are two main classes of scientific microwave
apparatus used by synthetic chemists. Monomode micro-
wave units have been used with great success for small-scale
reactions using sealed glass tubes up to a working volume of
approximately 20 mL or open round-bottom flasks to a vol-
ume of up to 125 mL. Multimode apparatus has been used
for scaling up reactions as well as performing chemistry in
multiple vessels. The biggest difference between the two
types of apparatus is the size of the microwave cavity. In
monomode units, the cavity is small since it is designed for
the length of only one wave (mode). By placing the sample
in the middle of the cavity it can be irradiated constantly with
microwave energy. Using a monomode apparatus, it is pos-
sible to heat samples of as little as 0.2 mL very effectively.
Multimode cavities are larger and as the microwaves come
While it is possible to translate chemistry developed in
monomode apparatus to a multimode microwave with the
objective of either scaling up a synthesis or else performing
multiple reactions in a carousel,2c,3 the chemist must be in
possession of two separate units. Recently, a new apparatus
has become available, which claims to bring together in one
unit the advantages of a monomode and a multimode micro-
wave device. In this report we present three different chem-
istries performed in this new unit. We discuss the feasibility
for rapid optimization of conditions in a single reaction ves-
sel before either running multiple reactions or else perform-
ing the chemistry on a larger scale in the same unit. As well
as showing the applicability of the apparatus we also discuss
in general terms some important considerations that need to
be taken into account when preparing small libraries of com-
pounds in a multimode microwave cavity.
* Corresponding author. Tel.: +1 860 486 5076; fax: +1 860 486 2981;
e-mail: nicholas.leadbeater@uconn.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.074

N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
6765
2. Results and discussion
2.1. Description of the apparatus
The MultiSynth apparatus is a single-magnetron system with
a variable output power of up to 800 W, controlled via a
microprocessor (Fig. 1). The microwave cavity measures
26.5ꢀ24.5ꢀ20.0 cm. Direct temperature monitoring and
control is possible via a fiber-optic probe inserted into one
reaction vessel. Contact-less temperature monitoring and
control is possible for all vessels using an infrared sensor
located in the cavity wall. Reaction vessels are mechanically
shaken during the course of the reaction to ensure agitation
of reaction mixtures. A range of reaction vessels can be used
with the apparatus. For small-scale reactions (0.25–5 mL),
the reagents are placed into a glass tube, this in turn being
placed into a protective Teflon sleeve and sealed with a
screw-top fitted with a ceramic thermowell. The Teflon
sleeve is spring loaded at the bottom such that when the top
is screwed down, the spring is compressed, holding the ves-
sel in tight contact with the top. In the monomode function,
the vessel in its protective sleeve is placed in a holder
(Fig. 2). The internal temperature can be measured by
Figure 3. The MultiSynth apparatus in the multimode function.
placing a fiber-optic probe into the thermowell. While there
is no direct pressure measurement, the spring mechanism in
the Teflon vessel covers ensures a pre-calibrated pressure
point of 20 bar is not exceeded. In the case of overpressure
the system automatically releases the pressure and the vials
are resealed. Reaction parameters (temperature, microwave
power, and desired time) are programmed into a controller
unit and the progress of the experiment can be monitored
as it runs. If necessary, parameters can be modified during the
course of the reaction. When processing samples in parallel,
the software utilizes the fiber-optic sensor in the control ves-
sel and the continuous stream of data from the contact-less
infrared temperature sensor to display individual tempera-
ture profiles for the complete collection of vessels. This pro-
vides detailed information on reaction conditions for each
processed sample. To move from single to parallel process-
ing in the multimode function, up to 12 vessels in their pro-
tective sleeves can be placed into a 12-place holder (Fig. 3).
One of the vessels acts as the control and onto this is secured
the screw-top fitted with a ceramic thermowell for internal
temperature measurement. For larger scale parallel reac-
tions, up to six PEEK vessels of working volume 10–35 mL
can be used, again it being possible to measure the internal
temperature of only one vessel. At the end of a reaction, ves-
sels can be cooled by passing compressed air over them in
the cavity.
Figure 1. The MultiSynth apparatus used in this study.
2.2. Suzuki coupling reactions
The Suzuki reaction (palladium-catalyzed cross coupling of
aryl halides with boronic acids) is used extensively for the
selective construction of carbon–carbon bonds, in particular
for the formation of biaryls.4 As the biaryl motif is found in
a range of pharmaceuticals, herbicides, and natural products,
as well as in conducting polymers and liquid crystalline ma-
terials, development of improved conditions for the Suzuki
reaction has received much recent attention. In our group
we have focused considerable effort on development of pro-
tocols for performing the reaction in water as a solvent in
conjunction with microwave heating.5–8 Since we are very
familiar with the Suzuki coupling on a variety of scales we
decided to use it as a baseline for our assessment of the
MultiSynth unit. Results are shown in Table 1.
Figure 2. The MultiSynth apparatus in the monomode function.

6766
N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
Br
B(OH)2
[Pd]
+
MW, H2O / EtOH,
Na2CO3
R
R
Our previous experience using monomode apparatus had
shown that the reaction can be performed using low loadings
of ligandless palladium sources. Working in a 1: 1 water/eth-
anol mix as solvent, heating the reaction mixture to 150 ꢁC,
and holding at this temperature for 5 min proved sufficient
Table 1. Microwave-promoted Suzuki coupling reactions between aryl
Figure 4. Heating profile for the coupling of 4-bromoacetophenone and
phenylboronic acid.
bromides and phenylboronic acida
Entry
1
Aryl halide
COMe
Conditions
A
Product yield/%
99
for the coupling of a range of aryl bromide substrates. Using
the MultiSynth in the monomode format we first performed
the Suzuki coupling of 4-bromoacetophenone with phenyl-
boronic acid. Working on a 1 mmol scale and using
0.1 mol % Pd as catalyst, we heated the reaction mixture to
150 ꢁC over the period of 2 min and held it at this temperature
for 5 min. A 99% conversion to the desired product was
obtained (Table 1, entry 1). We screened three other aryl bro-
mide substrates using the same reaction conditions and again
obtained good conversions to the desired biaryl products
(Table 1, entries 2–4). The heating profile for the coupling of
4-bromoacetophenone and phenylboronic acid is shown in
Figure 4. It can be seen that the IR and internal (fiber optic)
temperature profiles closely track each other during the
course of the reaction.
Br
2
A
A
A
B
B
B
B
C
C
C
C
C
99
98
96
99
98
98
97
99
98
97
97
85
Br
OMe
NH2
3
Br
4
Br
COMe
5
Br
6
Br
We next moved to the multimode function and, using the 12-
position rotor, ran all four of our aryl bromide substrates in
triplicate (i.e., three tubes for each of the four substrates).
We used identical reaction conditions with the exception of
the time taken to reach the target temperature, which was ex-
tended from 2 to 3 min. The product conversions obtained
correlated very well to those obtained for the substrates
using the monomode function showing that, in this case,
translation to the multimode function was possible with no
deleterious effect (Table 1, entries 5–8). The composite heat-
ing profiles for the reactions are shown in Figure 5. When
looking at the temperature plots of the 12 reaction vessels
measured using the IR sensor in the apparatus the first obser-
vations are that there is significant noise and that they all
read a significantly lower value than the internal fiber-optic
OMe
NH2
7
Br
Br
8
COMe
9
Br
10
11
12
13
Br
OMe
NH2
Br
Br
Br
Br
14
C
97
Conditions A: 1 mmol scale, 0.1 mol % Pd(OAc)2, monomode function,
2 min ramp to 150 ꢁC, and 5 min hold at this temperature.
Conditions B: 3ꢀ1 mmol, 0.1 mol % Pd(OAc)2, multimode function in
12-position rotor, 3 min ramp to 150 ꢁC, and 5 min hold at this temperature.
Conditions C: 10 mmol, 0.05 mol % Pd(OAc)2, multimode function in
6-position rotor, 5 min ramp to 150 ꢁC, and 5 min hold at this temperature.
a
Reactions were run in a sealed tube using a 1:1 stoichiometric ratio of aryl
halide to phenylboronic acid and a 1:1 volume ratio of water/ethanol as
solvent.
Figure 5. Composite heating profiles for the Suzuki coupling reactions run
in the 12-position rotor.

N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
6767
device placed in one of the vessels. Both of these factors can
be attributed to the means by which the IR probe measures
the temperature. In essence it takes a shot of every vessel
each time it rotates around the cavity in the carousel. If the
point at which the shot is taken varies even slightly then
some significant noise would be expected. In addition, while
rotating, the carousel is also being agitated in a lateral mo-
tion in order to ensure efficient mixing of the vessel contents.
This adds to the issue of measuring the temperature of all 12
vessels accurately. However, we know from the product con-
versions obtained from each vessel that the contents were at
the necessary bulk temperature to ensure effective coupling.
1 M phenacyl bromide in acetone, 1.3 equiv phenol, 2 equiv
potassium carbonate as base, heating to 130 ꢁC and holding
at this temperature for 20 min. This led to a quantitative con-
version to the desired product. Decreasing the reaction tem-
perature or quantity of base had a significantly deleterious
effect on the product conversion. Reducing the reaction
time from 20 to 10 min led to a slight reduction in product
conversion.
With optimized conditions in hand, we screened twelve phe-
nols in the reaction using the 12-position rotor. The phenols
screened and product conversions obtained are shown in
Table 2. The fiber-optic probe for internal temperature mea-
surement was placed into the vessel containing phenol and
thus it was this vessel that was used to control the microwave
power input. The temperature of all 12 vessels was moni-
tored using the external IR sensor. The heating profiles for
all the reaction vessels are shown in Figure 6. There is a clear
variation in the temperature measured across the 12 vessels.
Some vessels reach a significantly higher temperature than
Another point for consideration is that in these reactions, the
solvent mixture used (water/ethanol) is significantly micro-
wave absorbent. Since the quantities of substrates used are
small in comparison to the volume of solvent, variation in
their microwave absorptivity would not be expected to im-
pact the heating profile considerably. This is seen when look-
ing at the temperature plots of the 12 reaction vessels
measured using the IR sensor in the apparatus, all of them
being relatively closely bunched to one another.
Table 2. Microwave-promoted Williamson ether synthesis between
phenacyl bromide and a range of phenolsa
We wanted to scale up the reaction and so performed the
chemistry using the multimode function but in larger vessels.
Using the six-position rotor, we screened six aryl bromide
substrates working on the 10 mmol scale in 100 mL capacity
vessels, allowing us to make gram quantities of biaryls. We
knew from previous scale-up experience that it was possible
to reduce the catalyst loading when moving up in scale
in sealed vessels. Thus, we used a palladium loading of
0.05 mol %, heated the mixtures to 150 ꢁC over the period of
5 min and then holding them at this temperature for 5 min.
Product conversions again correlated very well to those
obtained for the substrates using the monomode function
(Table 1, entries 9–14).
Entry
Phenol
Conversion/%
No additive 0.25 mmol TBAB
OH
1
2
3
88
97
96
92
91
63
OH
OH
OH
4
5
6
7
97
99
98
dec
91
92
82
dec
MeO
Br
2.3. Williamson ether synthesis
OH
We next wanted to probe a reaction in which one of the com-
ponents was heterogeneous and also where the effects of
microwave absorptivity of substrates can begin to be probed.
We chose the Williamson ether synthesis as our first test
case. This reaction is typically carried out in refluxing ace-
tone for 2–4 h using potassium carbonate as a base.9 We
wanted to study this reaction using microwave heating.10
Since acetone is not particularly microwave absorbent, func-
tionality on the substrates could have a significant effect on
the heating profile of the reaction mixture. Also, since potas-
sium carbonate is only sparingly soluble in acetone, efficient
agitation of the reaction mixture would be important. We
decided to focus our attention on the reaction of phenacyl
bromide (a-bromoacetophenone) with a range of phenols
with different electronic properties.
OH
F
OH
OHC
C9H19
OH
8
52
99
79
16
69
31
OH
9
Cl
Cl
OH
10
OH
O
11
Mixture
Mixture
Mixture
Mixture
O
OH
OH
O
OH
Br
MW
acetone, K2CO3
+
12
R
R
OH
a
Reactions were run in a sealed tube using 2 mmol phenyacylbromide,
1.3 equiv phenolic substrate, and 2 equiv K2CO3. The temperature was
ramped to 130 ꢁC over the period of 2 min and held there for 20 min.
We first optimized the reaction on the 2 mmol scale using
phenol as substrate and found that optimal conditions were

6768
N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
We find that the profiles for the 12 vessels are now more sim-
ilar to one another and all are 25–35 ꢁC below the internal
temperature measured in the reference vessel using the fi-
ber-optic probe. Conversions to the desired products are in
some cases similar to those in the absence of the additive
but a deleterious effect of using the additive is observed
with several substrates. These differences could be attributed
back to the original heating profiles where, in fact, some re-
action mixtures were heated to greater than or less than the
target temperature. This may have had a positive effect on
the product yield in that our optimal conditions determined
for phenol may not be the optimal conditions for every sub-
strate screened.
Figure 6. Composite heating profiles for the etherification reactions run in
the 12-position rotor.
2.4. Michael addition of anilines to alkenes
the 130 ꢁC set and some fall considerably short of the target
temperature, even taking into account the 20–30 ꢁC differ-
ence expected between the fiber optic and IR temperature
profiles. This shows that the microwave absorptivity of the
phenolic substrate has a significant effect on the heating
characteristics of the contents of a particular reaction vessel.
We have recently reported the rapid, simple, microwave-pro-
moted synthesis of N-aryl functionalized b-amino esters us-
ing a Michael addition protocol.14 Reactions are performed
neat at 200 ꢁC for 20 min and are catalyzed by acetic acid.
We wanted to use this as part of our current study since, be-
ing a solvent-free protocol, any effects due to differences in
microwave absorptivity between reagents, or indeed prod-
ucts, would be exacerbated. In addition, this chemistry is
highly temperature dependent. Insufficient heating leads to
very poor yields and too much heating leads to side-product
formation and decomposition.
In the combinatorial chemistry field, an approach used by
chemists to ensure even heating of multiple vessels in a mi-
crowave field has been to use a solid heating element such as
silicon carbide or Weflon, a proprietary mixture of carbon
and fluoropolymer, which are both excellent absorbers of
microwaves.11,12 To overcome the temperature differential
from vessel to vessel we see in our etherification reactions,
we decided to re-run them but this time with the addition
of 0.25 mmol tetrabutylammonium bromide (TBAB) to
each. The TBAB, because it is charged, will interact very
strongly with the microwave irradiation and we predicted
this would outweigh any effects from variations in the ab-
sorption characteristics of the phenolic substrates. A similar
approach of adding ionic compounds to nonpolar reaction
mixtures has been used previously to ensure efficient heating
when using microwave irradiation.13 In our case, although
the reaction mixtures were heated effectively without an
additive, we wanted to moderate the heating so as to main-
tain a similar bulk temperature in each of our 12 vessels.
The heating profiles obtained in the presence of the TBAB
additive are shown in Figure 7.
O
H
NH2
N
OMe
MW, 200 °C, 20 min
AcOH
OMe
+
O
R
R
Our previous experiments were performed using a dedicated
monomode microwave apparatus. To determine whether
moving from that to the MultiSynth apparatus required re-
optimization of reaction conditions, we initially focused at-
tention on the acid-catalyzed addition of aniline to methyl
acrylate. Working on a 15 mmol scale, heating a 1:1 mixture
of the substrates with 10 mol % acetic acid at 200 ꢁC for
20 min resulted in a 80% yield of the desired product, this
correlating well with that obtained using the monomode ap-
paratus in our previous studies. Using the 12-place carousel
we performed the reaction between aniline and methyl
acrylate in 10 separate reaction vessels to probe the vessel-
to-vessel reproducibility of the apparatus in the multimode
format. We obtained an average conversion of 82% with
a standard deviation of 3% conversion. With our conditions
in hand we next turned our attention to screening six
aniline substrates in the reaction with methyl acrylate
using the 12-place carousel using the multimode configura-
tion. Each substrate was run in duplicate on the rotor with us
choosing aniline, p-toluidine, N-ethylaniline, 2,6-dimethyl-
aniline, m-anisidine, and p-anisidine. The results are shown
in Table 3.
It is immediately apparent that the yields obtained using the
multimode configuration differ from those of our previous
report using a monomode microwave apparatus. With the
Figure 7. Composite heating profiles for the etherification reactions run in
the 12-position rotor with the addition of TBAB.

N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
Table 3. Microwave-promoted Michael addition of anilines to a,b-unsaturated alkenesa
6769
Entry
Aniline
NH2
Product
Conversion (MultiSynth)/%
Conversion (monomode)/%b
81
H
N
1
77
CO2Me
CO2Me
H
N
NH2
2
3
87
26
79
43
H
N
N
CO2Me
CO2Me
H
N
NH2
4
5
12
29
79
H
N
MeO
MeO
NH2
MeO
MeO
dec
CO2Me
H
N
NH2
CO2Me
6
dec
70
a
Reactions were run in a sealed tube using 15 mmol aniline, 15 mmol methyl acrylate, and 1.5 mmol acetic acid. The temperature was ramped to 200 ꢁC over
the period of 10 min and held there for 20 min.
Results from previous report. Reactions performed individually in a dedicated monomode apparatus [Ref. 14].
b
exception of p-toluidine (Table 3, entry 2) the product yields
In our previous investigation using the monomode appara-
tus, because the reactions were run individually, the heating
profiles were much more similar, the target temperature be-
ing reached and not exceeded in each case. To probe in more
detail the variation in heating across the anilines studied we
turned to a monomode apparatus (CEM Discover). We ran
the reaction between aniline and methyl acrylate using an
initial microwave power of 100 W. The reaction mixture took
almost 5 min to reach the target temperature of 200 ꢁC
(Fig. 9). After holding at this temperature for 20 min, we
cooled the reaction mixture down to room temperature.
We then exposed the same reaction mixture to the same
reaction conditions (i.e., microwave heating of 100 W to
are lower than those from the monomode experiments. The
heating profiles for all the reaction vessels in the run using
the multimode apparatus are shown in Figure 8. As in the
case of the etherification reaction, there is a clear variation
in the temperature measured across the 12 vessels. Indeed in
this case the effect is even greater. Some vessels reach in
excess of 250 ꢁC and some fall considerably short of the
target temperature of 200 ꢁC, even taking into account
the 20–30 ꢁC difference expected between the fiber optic
and IR temperature profiles. At first glance this suggests
that the microwave absorptivity of the aniline substrate
has a significant effect on the heating characteristics of the
contents of the vessel. The fact that we see lower yields in
most cases when running the reactions in the multimode
apparatus corroborates this. The data suggest that either
the reaction mixtures did not reach temperature (N-ethyl-
aniline, 2,6-dimethylaniline; Table 3 entries 3 and 4) or
else were overheated (m-anisidine, p-anisidine; Table 3
entries 5 and 6).
Figure 8. Composite heating profiles for the Michael addition reactions run
in the 12-position rotor.
Figure 9. Heating profile for the reaction between aniline and methyl
acrylate using an initial microwave power of 100 W.

6770
N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
Table 4. Probing effects in the microwave-promoted Michael addition of anilines to a,b-unsaturated alkenesa
Entry
Aniline
Conversion (%)
in trial 1b
Conversion (%)
in trial 2c
Conversion (%)
in trial 3d
Conversion
(monomode)e/%
NH2
1
2
77
26
66
22
50
12
81
43
H
N
NH2
3
4
12
10
7
29
MeO
NH2
dec
516
60
41
79
—
Average microwave power delivered by magnetron
339
264
a
Reactions were run in a sealed tube using 15 mmol aniline, 15 mmol methyl acrylate, and 1.5 mmol acetic acid. The temperature was ramped to 200 ꢁC over
the period of 10 min and held there for 20 min.
Control vessel containing aniline.
Control vessel containing 2,6-dimethylaniline.
Control vessel containing m-anisidine.
Results from previous report. Reactions performed individually in a dedicated monomode apparatus [Ref. 14].
b
c
d
e
200 ꢁC) and found that the target temperature was reached in
m-anisidine, presumably because the reaction is rapid
and the product generated absorbs microwave radiation
very rapidly leading to overheating. When the control vessel
is 2,6-dimethylaniline a good yield of product is obtained
with m-anisidine, the lower microwave power allowing for
efficient heating but not overheating. When the control
vessels contain m-anisidine itself, a 41% conversion is
obtained.
less than 2 min (Fig. 9). This suggests that the product is
significantly more microwave absorbent than the starting
mixture of aniline and methyl acrylate. Therefore, in the
multimode run, it could well be that the rate of heating is dic-
tated not only by the microwave absorptivity of the starting
aniline but also by the product. As a consequence, even if the
aniline used was not microwave absorbent but was highly re-
active, rapid heating could still be possible, this coming
about from the high microwave absorptivity of the product
being formed.
In an attempt to unify the heating profiles of the different
anilines and negate effects from variation of the control
vessel, we took a similar approach as in the etherification
reactions. The reactions were run using 0.25 mmol tetra-
butylammonium acetate (TBAOAc) as an additive. This has
the desired effects and the yields obtained are more closely
parallel to those obtained in the monomode apparatus. The
heating profiles are shown in Figure 10 and the product
conversions in Table 5. Each aniline substrate was run in du-
plicate to probe the vessel to vessel uniformity in terms of
product conversion obtained and the results obtained show
consistency.
Our results show that when performing a screening
experiment using a range of substrates in a multimode
microwave apparatus, a key parameter for consideration is
into which vessel the fiber-optic probe should be placed,
i.e., which vessel should be the control. To determine the
effects of this we ran a version of our aniline screen three
times having as the control a vessel containing either aniline
(trial 1), 2,6-dimethylaniline (trial 2) or m-anisidine (trial 3).
We determined not only the product conversion obtained
in each trial but also the average microwave power delivered
by the magnetron. Our results are shown in Table 4. When
aniline is used as the control vessel, an average microwave
power of 516 W is delivered by the magnetron during the
course of the run to reach and maintain the target tempera-
ture of 200 ꢁC. This decreases to 339 W in the case of 2,6-
dimethylaniline as the control and to 264 W in the case of
m-anisidine. Thus there is clearly a significant difference
depending on which vessel is used as the control. As the
microwave power delivered decreases so does the product
conversion in the case of aniline, N-ethylaniline, and 2,6-di-
methylaniline (Table 4, entries 1–3). This can be attributed
to the fact that as the microwave power decreases so the
temperature attained in these vessels decreases also. As
already discussed, insufficient heating leads to poorer
yields. The case of m-anisidine is particularly interesting
(Table 4, entry 4). When the control vessel contains
aniline, decomposition is observed in the vessels containing
Figure 10. Composite heating profiles for the Michael addition reactions
run in the 12-position rotor with the addition of TBAOAc.

N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
6771
Table 5. Microwave-promoted Michael addition of anilines to a,b-unsatu-
rated alkenes using 0.25 mmol TBAOAc as an additivea
4. Experimental
4.1. General experimental
Entry
Aniline
Conversion
Conversion
(monomode)/%
(MultiSynth)b/%
Reactions were performed using a Milestone MultiSynth mi-
crowave apparatus or, in the case of the two monomode heat-
ing experiments discussed in the Michael addition case
study, a CEM Discover unit. The former is discussed in de-
tail in Section 2 and for information on the latter the reader is
directed to previous reports in the literature. All reagents
were obtained from commercial suppliers and used without
further purification. The palladium stock solution used in the
Suzuki coupling experiments was elemental Pd in 20% HCl;
Concentration 1000 mg/mL; J.T. Baker cat. no. 5772-04. 1H
and 13C NMR spectra were recorded at 293 K on a 400 MHz
Bruker Avance spectrometer.
NH2
1
2
82/83
77/75
81c
79c
NH2
H
N
3
4
5
28/27
18/16
43c
29c
NH2
NH2
66/67
69/71
64
4.2. Suzuki coupling of 4-bromoacetophenone and
phenylboronic acid using the monomode function
F
NH2
6
70c
MeO
In a 10-mL glass tube were placed 4-bromoacetophenone
(1.0 mmol, 199.0 mg), phenylboronic acid (1.1 mmol,
134 mg), Na2CO3 (3.7 mmol, 390 mg), 1000 mg/mL palla-
dium solution in HCl (0.2500 mL, 0.0024 mmol Pd), ethanol
(1 mL), and deionized water (1 mL). The glass tube was
placed in a Teflon outer jacket and secured with a Teflon
top containing a ceramic thermo well. A fiber-optic probe
was placed into the thermal well and the reaction vessel
placed into the holder in the microwave cavity. The micro-
wave apparatus was set to ‘monomode irradiation’ function
and the sample was irradiated with the maximum power
needed to reach 150 ꢁC in 2 min at which point the temper-
ature was held constant for an additional 5 min. The reaction
vessel was agitated in an elliptical motion while undergoing
microwave irradiation, the agitation being set to 50% of
maximum. After allowing the mixture to cool to room
temperature, the reaction vessel was opened and the
contents poured over 15 mL deionized water. The organic
material was extracted using ethyl acetate (3ꢀ20 mL), the
organic washings combined and dried over MgSO4, the ethyl
acetate removed under vacuum leaving the crude product,
which was characterized by comparison of NMR data
a
Reactions were run in a sealed tube using 15 mmol aniline, 15 mmol
methyl acrylate and 1.5 mmol acetic acid. The temperature was ramped
to 200 ꢁC over the period of 6 min and held there for 20 min.
Reactions performed in duplicate.
Results from previous report. Reactions performed individually in a dedi-
cated monomode apparatus [Ref. 14].
b
c
3. Summary
The objective of this study was twofold. Firstly, we wanted
to assess the applicability of the MultiSynth apparatus
towards rapid optimization of reaction conditions in a mono-
mode function and then substrate screening in a multimode
function. Secondly, we wanted to probe the effects of differ-
ences in microwave absorptivity of reaction mixtures on the
product conversions in screening multiple substrates simul-
taneously in a multimode microwave apparatus. We find that
the apparatus is a useful tool for performing reactions in
a single vessel and then moving to multiple vessels. Unsur-
prisingly, the efficiency of heating reaction mixtures is de-
pendent on the microwave absorptivity of the reagents and
solvent used. We do however find that this effect is more
marked when using the MultiSynth than with other mono-
mode apparatus. Discussion of this will form the basis of
a later article. Our results show that when the microwave
absorptivity of a reaction mixture is dictated by the solvent,
there is little effect on the heating profile of varying the
substrate in a screening run. However, this is not the
case when reactions involving non-microwave absorbant
solvents are used. In this case the characteristics of
the substrate can affect significantly the outcome of the
reaction. This effect is further marked when a reaction is
performed solvent-free. Another parameter for consider-
ation when performing a screening experiment using a
range of substrates in a multimode microwave apparatus is
into which vessel the fiber-optic probe should be placed
and thus is used as the control. We find that effects of uneven
heating of substrates and variation of the control vessel
can be mollified by adding a small quantity of a highly
microwave absorbent material to each reaction vessel in
a screening set.
1
with that in the literature. H NMR (CDCl3): d 7.90 (d,
2H, J¼7.3 Hz), 7.50 (t, 1H, J¼7.4 Hz), 7.40 (t, 2H,
J¼7.3 Hz), 7.20 (t, 2H, J¼7.6 Hz), 7.90 (t, 3H, J¼7.8 Hz),
5.18 (s, 2H).
4.3. Suzuki couplings of aryl bromides and phenylbor-
onic acid using the multimode function on the 1 mmol
scale
In a 10-mL glass tube were placed 4-bromoacetophenone
(1.0 mmol, 199.0 mg), phenylboronic acid (1.1 mmol,
134 mg), Na2SO4 (3.7 mmol, 390 mg), 1000 mg/mL palla-
dium solution in HCl (0.2500 mL, 0.0024 mmol Pd), ethanol
(1 mL), and deionized water (1 mL). The glass tube was
placed in a Teflon outer jacket and secured with a Teflon
top containing a ceramic thermowell. Eleven other vessels
with variously substituted aryl bromide substrates were sim-
ilarly prepared, these being secured with a Teflon top but
with no thermal well. All the vessels were loaded onto
a 12-place rotor within the microwave cavity. The fiber-optic
probe was placed into the reaction vessel containing the

6772
N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
thermal well. The vessels were irradiated using the ‘multi-
mode irradiation’ function with the maximum power needed
to reach 150 ꢁC in 2 min at which point the temperature was
held constant for an additional 5 min. Additionally, while
under irradiation, the samples were set to oscillate 360ꢁ in
a clockwise–counterclockwise fashion while being agitated
in a horizontal motion, the agitation being set to 50% of
maximum. After allowing the reaction mixtures to cool to
room temperature, they were opened and the products iso-
lated and characterized in an identical manner to the case
of the single reaction experiment.
dried over MgSO4. The ether was removed under vacuum
leaving the crude product, which was characterized by com-
parison of NMR data with that in the literature. H NMR
1
(CDCl3):
d
7.90 (d, 2H, J¼7.3 Hz), 7.50 (t, 1H,
J¼7.4 Hz), 7.40 (t, 2H, J¼7.3 Hz), 7.20 (t, 2H, J¼7.6 Hz),
6.90 (t, 3H, J¼7.8 Hz), 5.18 (s, 2H).
4.6. Etherification of phenols with phenacyl bromide
using the multimode function
In a 10-mL glass tube were placed a-bromoacetophenone
(2.0 mmol, 199.0 mg), K2CO3 (4.0 mmol, 550.0 mg), phe-
nol (2.6 mmol, 245.0 mg), and acetone (2 mL). The glass
tube was placed in a Teflon outer jacket and secured with
a Teflon top containing a ceramic thermowell. Eleven other
vessels with variously substituted phenol substrates were
similarly prepared, these being secured with a Teflon top
but with no thermal well. All the vessels were loaded onto
a 12-place rotor within the microwave cavity. The fiber-optic
probe was placed into the reaction containing the thermal
well. The vessels were irradiated using the ‘multimode irra-
diation’ function with the maximum power needed to reach
130 ꢁC in 5 min at which point the temperature was held
constant for an additional 20 min. Additionally, while under
irradiation, the samples were set to oscillate 360ꢁ in a clock-
wise–counterclockwise fashion while being agitated in a hor-
izontal motion, the agitation being set to 50% of maximum.
After allowing the reaction mixtures to cool to room temper-
ature, they were opened and the products isolated and char-
acterized in an identical manner to the case of the single
reaction experiment.
4.4. Suzuki couplings of aryl bromides and phenyl-
boronic acid using the multimode function on the
10 mmol scale
In a 75-mL capacity Teflon tube were placed 4-bromoaceto-
phenone (10.0 mmol, 1.990 g), phenylboronic acid
(10.0 mmol, 1.2330 g), Na2CO3 (12.0 mmol, 1.272 g),
1000 mg/mL palladium solution in HCl (1.2500 mL,
0.012 mmol Pd), 10.0 mL ethanol, and 8.75 mL deionized
water. The 80-mL tube was placed into an outer protective
jacket secured with a screw-top containing a ceramic ther-
mowell. Eleven other vessels with variously substituted
aryl bromide substrates were similarly prepared, these being
secured with a Teflon top but with no thermal well. All
the vessels were loaded onto a 6-place rotor within the
microwave cavity. The fiber-optic probe was placed into
the reaction mixture containing the 4-bromoacetophenone.
The vessels were irradiated using the ‘multimode irradia-
tion’ function with the maximum power needed to reach
150 ꢁC in 5 min at which point the temperature was held
constant for an additional 5 min. Additionally, while under
irradiation, the samples were set to oscillate 360ꢁ in a
clockwise–counterclockwise fashion while being agitated
in a horizontal motion, the agitation being set to 50% of
maximum. After allowing the reaction mixtures to cool to
room temperature, they were opened and the products iso-
lated and characterized in an identical manner to the case
of the single reaction experiment.
4.7. Etherification of phenols with phenacyl bromide
using the multimode function and with the
addition of TBAB
A 125 mM stock solution of tetrabutylammonium bromide
(TBAB) (3.75 mmol, 1.210 g in 30 mL acetone) was pre-
pared. The reaction vessels were loaded and heated in an
identical manner to the case of the analogous experiments
above, substituting this stock solution (2 mL) for the pure
acetone (equating to 0.25 mmol TBAB per vessel).
4.5. Etherification of phenol with phenacyl bromide
using the monomode function
4.8. Reaction of aniline with methyl acrylate
using the monomode function
In a 10-mL glass tube were placed a-bromoacetophenone
(2.0 mmol, 199.0 mg), K2CO3 (4.0 mmol, 550.0 mg), phe-
nol (2.6 mmol, 245.0 mg), and acetone (2 mL). The glass
tube was placed in a Teflon outer jacket and secured with
a Teflon top containing a ceramic thermowell. A fiber-optic
probe was placed into the thermal well and the reaction ves-
sel placed into the holder in the microwave cavity. The mi-
crowave apparatus was set to ‘monomode irradiation’
function and the sample was irradiated with the maximum
power needed to reach 130 ꢁC in 5 min at which point the
temperature was held constant for an additional 20 min.
The reaction vessel was agitated in an elliptical motion while
undergoing microwave irradiation, the agitation being set to
50% of maximum. After allowing the mixture to cool to
room temperature, the reaction vessel was opened and the
contents poured over 15 mL deionized water. The organic
material was extracted using diethyl ether (3ꢀ20 mL), the
organic washings combined, washed twice with 2.0 M
NaOH solution (2ꢀ10 mL), washed with brine, and then
In a 10-mL glass tube were placed aniline (15.0 mmol,
1.395 g, 1.360 mL), methyl acrylate (15.0 mmol, 1.290 g,
1.350 mL), and acetic acid (1.5 mmol, 0.090 g, 0.086 mL).
The glass tube was placed in a Teflon outer jacket and
secured with a Teflon top containing a ceramic thermowell.
A fiber-optic probe was placed into the thermal well and the
reaction vessel placed into the holder in the microwave
cavity. The microwave apparatus was set to ‘monomode
irradiation’ function and the sample was irradiated with the
maximum power needed to reach 200 ꢁC in 10 min at which
point the temperature was held constant for an additional
20 min. The reaction vessel was agitated in an elliptical mo-
tion while undergoing microwave irradiation, the agitation
being set to 50% of maximum. After allowing the mixture
to cool to room temperature, the crude product was charac-
terized by comparison of NMR data with that in the litera-
1
ture. H NMR (CDCl3): d 7.18 (t, 2H, J¼7.5 Hz), 6.70

N. E. Leadbeater, J. R. Schmink / Tetrahedron 63 (2007) 6764–6773
6773
Medicinal Chemistry; Wiley-VCH: Weinhiem, 2005; (c)
€
Microwave-Assisted Organic Synthesis; Lidstrom, P., Tierney,
(t, 1H, J¼7.3 Hz), 6.62 (d, 2H, J¼7.7 Hz), 4.00 (br, 1H),
3.70 (s, 3H), 3.46 (t, 2H, J¼6.4 Hz), 2.63 (t, 2H, J¼6.4 Hz).
J. P., Eds.; Blackwell: Oxford, 2005.
2. For recent reviews, see: (a) Kappe, C. O. Angew. Chem., Int. Ed.
2004, 43, 6250; (b) Larhed, M.; Moberg, C.; Hallberg, A. Acc.
4.9. Reaction of anilines with methyl acrylate
using the multimode function
€
Chem. Res. 2002, 35, 717; (c) Lidstrom, P.; Tierney, J. P.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
3. For an example of translation from monomode to multimode,
see: (a) Perio, B.; Dozias, M.-J.; Hamelin, J. Org. Process
Res. Dev. 1998, 2, 428; (b) Cleophax, J.; Liagre, M.; Loupy,
A.; Petit, A. Org. Process Res. Dev. 2000, 4, 498.
The glass tube was placed in a Teflon outer jacket and se-
cured with a Teflon top containing a ceramic thermowell.
Eleven other vessels with variously substituted aniline
substrates (a total of two vessels each of six anilines) were
similarly prepared, these being secured with a Teflon top
but with no thermal well. All the vessels were loaded onto
a 12-place rotor within the microwave cavity. The fiber-optic
probe was placed into the reaction containing the thermal
well. The vessels were irradiated using the ‘multimode irra-
diation’ function with the maximum power needed to reach
200 ꢁC in 10 min at which point the temperature was held
constant for an additional 20 min. Additionally, while under
irradiation, the samples were set to oscillate 360ꢁ in a clock-
wise–counterclockwise fashion while being agitated in a hor-
izontal motion, the agitation being set to 50% of maximum.
After allowing the reaction mixtures to cool to room temper-
ature, the crude products were characterized by comparison
of NMR data with that in the literature.
4. For recent reviews see: (a) Bellina, F.; Carpita, A.; Rossi, R.
ꢀ
Synthesis 2004, 2419; (b) Hassan, J.; Sevignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359; (c)
Kotha, S.; Lahiri, S.; Kashinath, D. Tetrahedron 2002, 58,
9633.
5. For a review, see: Leadbeater, N. E. Chem. Commun. 2005,
2881.
6. Leadbeater, N. E.; Williams, V. A.; Barnard, T. M.; Collins,
M. J. Org. Process Res. Dev. 2006, 10, 833.
7. Arvela, R. K.; Leadbeater, N. E.; Collins, M. J. Tetrahedron
2005, 61, 9349.
8. For other reports of microwave-promoted Suzuki couplings in
water, see: (a) Blettner, C. G.; Konig, W. A.; Stenzel, W.;
Schotten, T. J. Org. Chem. 1999, 64, 3885; (b) Han, J. W.;
Castro, J. C.; Burgess, K. Tetrahedron Lett. 2003, 44, 9359;
(c) Appukkuttan, P.; Orts, A.; Chandran, R. P.; Goeman,
J. L.; Van der Eycken, J.; Dehaen, W.; Van der Eycken, E.
Eur. J. Org. Chem. 2004, 3277; (d) Gong, Y.; He, W. Org.
Lett. 2002, 4, 3803; (e) Namboodiri, V. V.; Varma, R. S.
Green Chem. 2001, 3, 146; (f) Zhang, W.; Chen, C. H.-T.;
Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473; (g)
4.10. Reaction of anilines with methyl acrylate using the
multimode function and with the addition of TBAOAc
The reaction vessels were loaded and heated in an identical
manner to the case of the analogous experiments above
but with the addition of tetrabutylammonium acetate
(0.25 mmol, 76.0 mg) to each vessel. Additionally, the
vessels were irradiated using the ‘multimode irradiation’
function with the maximum power needed to reach 200 ꢁC
in 6 min rather than10 min. The hold time was the same
(20 min).
€
Solodenko, W.; Schon, U.; Messinger, J.; Glinschert, A.;
Kirschning, A. Synlett 2004, 1699.
9. Banerjee, A.; Lee, K.; Falvey, D. E. Tetrahedron 1999, 55,
12699.
10. For other reports on microwave-promoted ether formation, see:
(a) Yadav, G. D.; Desai, N. M. Catal. Commun. 2006, 7, 325;
(b) Park, K. K.; Jeong, J. S. Tetrahedron 2005, 61, 545; (c)
Lloung, M.; Loupy, A.; Marque, S.; Petit, A. Heterocycles
2004, 63, 297; (d) Raner, K. D.; Strauss, C. R.; Trainor,
R. W.; Thorn, J. S. J. Org. Chem. 1995, 60, 2456.
11. Kremsner, J. M.; Stadler, A.; Kappe, C. O. J. Comb. Chem.
2007, 9, 285.
Acknowledgements
Milestone is thanked for the provision of a MultiSynth
microwave apparatus. Funding from the University of
Connecticut is acknowledged.
€
€
12. Nuchter, M.; Ondruschka, B.; Tied, A.; Lautenschlager, W.;
Borowski, K. J. American Genomic/Proteomic Technology
2001, 34.
References and notes
1. A number of books on microwave-promoted synthesis have
been published recently: (a) Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2006; (b)
Kappe, C. O.; Stadler, A. Microwaves in Organic and
13. For a review, see: Leadbeater, N. E.; Torenius, H. M.; Tye, H.
Comb. Chem. High Throughput Screen. 2004, 7, 511.
14. Amore, K. M.; Leadbeater, N. E.; Miller, T. A.; Schmink, J. R.
Tetrahedron Lett. 2006, 47, 8583.