Applicability of a fiber-supported catalyst on a Buchwald-Hartwig amination reaction

Article abstract of DOI:10.1021/op7000996

The applicability of four different heterogeneous palladium catalysts has been evaluated for the Buchwald-Hartwig animation reaction between p-bromotoluene and piperazine in the presence of the base NaO-t-Bu. The catalyst that provided the highest selectivity toward the desired animation reaction was found to be a polymer-supported palladium dichloride/triphenylphosphine catalyst. Experimental investigations of the catalyst in a reactor setup showed that the undesired reduction reaction of the aryl halide was dominant when the catalyst was reused and washed in solvent prior to reaction and when additional reactants were added to an already reacted reaction mixture. A significant washout of triphenylphosphine and palladium from the catalyst was also identified during the course of reaction and separation.

Full text of DOI:10.1021/op7000996

Organic Process Research & Development 2007, 11, 956–965
Applicability of a Fiber-Supported Catalyst on a Buchwald–Hartwig Amination
Reaction
Henrik Christensen, Søren Kiil,* and Kim Dam-Johansen
Department of Chemical Engineering, Technical UniVersity of Denmark, Building 229, DK-2800 Kgs. Lyngby, Denmark
Ole Nielsen
H. Lundbeck A/S, Process DeVelopment, OttiliaVej 9, DK-2500 Valby, Denmark
Abstract:
Table 1. Comparison of heterogeneous and homogeneous
6
catalysts
The applicability of four different heterogeneous palladium
catalysts has been evaluated for the Buchwald–Hartwig amination
reaction between p-bromotoluene and piperazine in the presence
of the base NaO-t-Bu. The catalyst that provided the highest
selectivity toward the desired amination reaction was found to be
a polymer-supported palladium dichloride/triphenylphosphine
catalyst. Experimental investigations of the catalyst in a reactor
setup showed that the undesired reduction reaction of the aryl
halide was dominant when the catalyst was reused and washed in
solvent prior to reaction and when additional reactants were added
to an already reacted reaction mixture. A significant washout of
triphenylphosphine and palladium from the catalyst was also
identified during the course of reaction and separation.
homogeneous
catalysis
heterogeneous
catalysis
property
activity (relative to
metal content)
selectivity
reaction
conditions
service life
high
variable
high
mild
variable
harsh
variable
low
long
high
of catalysts
sensitivity towards
catalyst poisons
diffusion problems
none
may be
important
not necessary
not possible
catalyst recycling
variability of steric
and electronic
expensive
possible
properties of catalysts
1. Introduction
Palladium catalysts are widely employed in organic chemical
synthesis, and their application covers a large number of
different kinds of reactions. These are, for example,
separation of the catalyst from the reaction mixture. Apart from
ensuring a product that is not contaminated by heavy metals,
the separation may also facilitate reuse of the catalyst. This
approach is interesting from an industrial point of view, because
this gives an opportunity for lowering of the production costs.
Therefore it has been of interest to investigate the possibilities
for anchoring the homogeneous catalyst on an insoluble polymer
support and thereby combining the advantages of both the
homogeneous and heterogeneous catalytic system. Normally
the immobilization is done by anchoring the catalytically active
ligands to a polymer support and subsequently adding the
palladium source. Previously these polymer-supported homo-
geneous catalysts have been applied successfully in different
reactions that traditionally take place in the presence of a
homogeneous catalyst. Among others these have been the R,R-
1
2
3
coupling reactions such as Heck, Suzuki-Miyaura, Stille,
4
and Buchwald–Hartwig reactions and more traditional
5
reduction and hydrogenation reactions. Homogeneous and
heterogeneous catalysts are known; the homogeneous catalyst
is kept in solution by organic ligands, and the heterogeneous
catalyst is often supported on different kinds of supporting
materials such as activated coal, silica, or barium sulfate
oxides, which ensure a large surface area of the reactive
5
metal. This means that the nature of the two catalytic
systems is different; some of the advantages and drawbacks
are listed in Table 1.
Table 1 shows that the properties of the catalyst are strongly
dependent on whether it is homogeneously or heterogeneously
distributed within the reaction mixture. One of the major
advantages of the heterogeneous catalyst is the convenient
7
8
diarylation reaction, Suzuki coupling reaction, hydroformy-
9
10,11
lation reaction, and amination reaction
More general
*
To whom correspondence should be addressed. Tel: (+45)45252827. Fax:
(
+45)45882258. E-mail: sk@kt.dtu.dk.
introductions to the area of polymer-supported and recyclable
(
(
(
(
(
1) Heck, R. Org. React. 1982, 27, 345–390.
2) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
3) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524.
4) Hartwig, J. Angew. Chem., Int. Ed. 1998, 37, 2046–2067.
5) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry; John
Wiley & Sons Inc: New York, 2001.
(7) Churruca, F.; SanMartin, R.; Tellitu, I.; Domínguez, E. Tetrahedron
Lett. 2003, 44, 5925–5929.
(8) Colacot, T. J.; Gore, E. S.; Kuber, A. Organometallics 2002, 21, 3001–
3304.
(
6) Cornils, B.; Herrmann, W. Applied homogeneous Catalysis with
Organometallic Compounds; VCH Verlagsgesellschaft: Germany,
(9) Zeelie, T.; Root, A.; Krause, A. Appl. Catal., A 2005, 285, 96–109.
(10) Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 3820–3827.
(11) Guinó, M.; Hii, K. K. M. Tetrahedron Lett. 2005, 46, 7363–7366.
1
996.
9
56
•
Vol. 11, No. 6, 2007 / Organic Process Research & Development
10.1021/op7000996 CCC: $37.00  2007 American Chemical Society
Published on Web 10/23/2007

Scheme 1. Model reaction for formation of N-arylated
amines
catalysts can be found in reviews.12,13 However, in terms of
reuse and separation of the polymer-supported homogeneous
catalyst, the results are less prospective. Leaching of metal from
the supporting polymer and deactivation of the catalyst upon
8,11
separation have been reported as unsolved problems. The
existence of leaching of both active ligands and palladium has
the consequence that the polymer-supported catalyst in practice
is ending up as a homogeneous catalyst without the advantages
of easy separation and reuse. It is essential to solve these
problems prior to further implementation of these catalysts.
Therefore it is the intention of this article to elaborate on the
applicability of a polymer-supported homogeneous catalyst and
increase the knowledge of the leaching and deactivation
processes. The evaluation of the results may be used to design
future production methods to convert homogeneous catalysts
into solid-supported catalysts. The investigations will be based
on a Buchwald–Hartwig amination reaction, giving both a
mono- and a disubstituted piperazine. The analysis will also
consider the formation of side products, which are formed
outside the catalytic cycle for the amination reaction. Further-
more, the results will be supported by a physical characterization
of the catalyst using a scanning electron microscope.
Figure 1. Reaction mechanism for the formation of N-aryl
17
amine and the reduction of the aryl halide.
aryl halide. In the search for alternative production methods of
monosubstituted piperazine, we have chosen to base the study
on piperazine, thus allowing information on both the mono-
and bisubstitution to be obtained. This investigation is based
on the reaction between p-bromotoluene (1) and piperazine (2).
The reaction proceeds in the presence of a palladium FibreCat
system (referred to as the catalyst). Sodium tert-butoxide (NaO-
t-Bu) is employed as the base, and 1,4-dioxane is used as
solvent, because it has been concluded in a previous article that
this solvent suppressed the formation of undesired side prod-
17
ucts. The overall reaction with the observed products, 1-(4-
methylphenyl)piperazine (3), 1,4-bis(4-methylphenyl)piperazine
(4), toluene (5), and 1,1′-dimethyl-4,4′-biphenyl (6), is shown
in Scheme 1.
2.2. The Reaction Mechanism. Discussions and evalua-
tions of the performance of the FibreCat on the Buchwald–
Hartwig amination reaction will be based on the knowledge
of the chemical reaction mechanism for the reaction, which
is shown in Figure 1. This reaction mechanism has previously
2
. Characterization of the Reaction System
2.1. The Reaction. The Buchwald–Hartwig amination reac-
tion has technical challenges that make it relevant as a model
reaction: the reaction can be conducted in the presence of a
homogeneous palladium catalyst, and it is a reaction that gains
more interest in industrial applications. A reason for this is
that the product from the reaction, the N-aryl amines, are
important building blocks in drugs. This is emphasized by the
fact that more than 25 antidepressants and more than 15
antipsychotics that contain N-arylated amine blocks were
commercially available in 2001. Mono- and diarylated pip-
erazines are examples of important compounds in pharmaceuti-
cal production. However, the existence of two vacant nitrogen
atoms is a major challenge, because most often it is only desired
to obtain the monosubstituted piperazine. Typically, the
monosubstituted piperazine is obtained by introducing protection
groups or by using an excess of piperazine compared to the
1
7
been presented and discussed by the authors. This is the
generally accepted reaction mechanism for the homoge-
14
18–20
neously catalyzed reaction,
and in this work it is assumed
that the same mechanism applies in the polymer-supported
catalyzed reaction. According to the catalytic cycle in Figure
1
, the Buchwald–Hartwig amination reaction proceeds
15
through six different intermediate reaction steps. This reac-
tions mechanism also applies in the formation of 1,4-bis(4-
methylphenyl)piperazine.
During the course of reaction, toluene from the catalyzed
reduction of p-bromotoluene and 1,1′-dimethyl-4,4′-biphenyl
from the homocoupling of p-bromotoluene are also formed.
These products are unwanted side products. The literature
proposes a mechanism for the reduction of the aryl halide, which
1
6
(
(
12) Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron 2001, 57, 4637–
662.
13) McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. ReV. 2002, 102,
4
(17) Christensen, H.; Kiil, S.; Dam-Johansen, K.; Nielsen, O.; Sommer,
M. B. Org. Process Res. DeV. 2006, 10, 762–769.
(18) Negishi, E. Handbook of Organopalladium Chemistry for Organic
Synthesis; John Wiley & Sons Inc: New York, 2002.
(19) Singh, U.; Strieter, E.; Blackmond, D.; Buchwald, S. J. Am. Chem.
Soc. 2002, 124, 14104–14114.
3
275–3300.
(
(
14) Schlummer, B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 1599–1626.
15) Prins, L. D. Psychotropics 2000/2001; Herman & Fischer A/S:
Denmark, 2002.
16) Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, A.; Goodman, A.
Tetrahedron Lett. 2002, 43, 3359–3363.
(
(20) Urgaonkar, S.; Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003, 68, 8416–
8423.
Vol. 11, No. 6, 2007 / Organic Process Research & Development
•
957

Table 2. Application and chemical composition of the
2
8
catalysts
primary type
of reaction
wt %
Pd
name
composition
Pd(OAc) on
TTP fibers
FibreCat 1001 bromo and iodo
coupling reactions
FibreCat 1007 chloro coupling
reactions
FibreCat 1026 bromo and iodo
coupling reactions
FibreCat 1032 not dedicated to
2
5.05
1.77
4.14
PdCl
TTP fibers
Pd(OAc) /TTP on 4.26
2
on
2
any specific reactants TTP fibers
involves a ꢀ-hydride elimination reaction from the amine,21,22
this reaction is also shown in Figure 1. The reaction mechanism
for the formation of 1,1′-dimethyl-4,4′-biphenyl (i.e., the ho-
mocoupling of p-bromotoluene) is more unclear. In the litera-
ture, coupling of aryl iodide in the presence of a palladium
Figure 2. Structure of a heterogeneous catalyst.7
Table 3. Experimental protocol
experiments
1
2
3
4
5
6
screening of catalysts
23–25
catalyst has been described.
Furthermore, homocoupling of
course of reaction
arylboronic esters and possible reaction mechanism have been
reuse of catalyst
26,27
discussed in other connections.
Whether these results can
wash of catalyst in solvent prior to reaction
reuse of entire reaction mixture
reactivation of catalyst
be applied in this article is unknown, but they may be used as
an inspiration.
2.3. Review of Prospective Catalysts. The Buchwald–
Hartwig amination reaction is normally carried out in the
presence of a homogeneous catalyst, which is constituted by
palladium coordinated to a phosphine ligand. These character-
istics (palladium and phosphine ligand) were formulated as
requirements in the survey for the polymer-supported catalytic
systems that are to be evaluated in this article. Johnson Matthey
has developed four different immobilized catalysts that meet
these requirements. The catalyst are listed in Table 2 together
with the type of reaction they may facilitate, their chemical
Table 4. Results for the screening of catalysts after 3 h of
reaction at 90 °C
X
1
ꢁ
3,4
ꢁ
5
Y
3
Y
4
Y
5
Y
6
catalyst
FibreCat 1001 0.98 0.11 0.69 0.10 0.01 0.68 0.19
FibreCat 1007 0.47 0.16 0.76 0.07 0.36 0.04
(eq 1) (eq 2) (eq 3) (eq 4) (eq 5) (eq 6) (eq 7)
0
FibreCat 1026 0.99 0.81 0.18 0.58 0.23 0.18 0.01
FibreCat 1032 0.96 0.59 0.40 0.48 0.09 0.38 0.01
28
composition, and the loading of palladium on a weight basis.
It has not been possible to identify the exact physical
3
. Results and Discussion
7,28
structure of the four catalysts. However, in the literature
it
3.1. Experimental Protocol. To obtain knowledge of the
has been reported that the catalyst consists of a polymer
backbone to which the catalytically active components are
advantages and limitations of a fiber (or polymer)-supported
catalyst, the experimental protocol in Table 3 has been
formulated. This protocol will contribute knowledge to the area
of heterogeneously catalyzed Buchwald–Hartwig amination
reactions. The protocol will reveal the most suitable catalyst
for the reaction in Scheme 1, and further investigations of this
catalyst will form the basis for preliminary discussions of the
prospectives of reusing the catalyst.
7
linked; see Figure 2, where R represents the places where the
active components are bonded.
According to the chemical composition of R the catalyst is
able to facilitate the type of reactions presented in Table 2.
However, a more elaborate discussion about the chemical
composition of R will be given later. Table 2 indicates that
FibreCat 1001 and 1026 are successfully employed in the model
reaction presented in Scheme 1. However, experimental inves-
tigations of the four different catalysts will form a more
elaborate basis for the choice of the most efficient catalyst.
The evaluation of the course of the reaction is based on a
number of calculations, which can be found in the chemical
29
reaction engineering literature. First it is of interest to
determine if the catalytic system is able to convert 1 into
products. This is evaluated by eq 1, which gives a number for
the fraction of starting material that has been converted. Next
it is investigated how the catalytic system is able to perform
the desired reaction and suppress unwanted side reactions.
Therefore, the fractional yield for the amination reaction has
been calculated according to eq 2. Both 3 and 4 are included
in eq 2, because it is desired to evaluate the ability of the catalyst
to support the amination reaction. In practice this means that it
is desired to obtain a value of 1 for ꢁ3,4; in this case all formed
(
(
(
(
(
(
21) Wagaw, S.; Rennels, R.; Buchwald, S. J. Am. Chem. Soc. 1997, 119,
8
451–8458.
22) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805–818.
23) Qiang, L.; Juan, N.; Yang, F.; Zheng, R.; Gang, Z.; Tang, J. Chin.
J. Chem. 2004, 22, 419–421.
24) Luo, F.-T.; Jeevanandam, A.; Basu, M. K. Tetrahedron Lett. 1998,
3
9, 7939–7942.
25) Alonso, D. A.; Nájera, C.; Pacheco, M. C. J. Org. Chem. 2002, 67,
588–5594.
26) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett.
5
2
003, 44, 1541–1544.
(
(
27) Yamamoto, Y. Synlett 2007, 18, 1913–1916.
28) Matthey, J. The Catalyst Technical Handbook; Johnson Matthey:
United Kingdom, 2005.
(29) Levenspiel, O. Chemical Reaction Engineering; John Wiley & Sons
Inc: New York, 1999.
9
58
•
Vol. 11, No. 6, 2007 / Organic Process Research & Development

products are the mono- and bisubstituted piperanzine (3 and
). The fractional yield of toluene (5) is found by eq 3; 5 is the
primary side product for the reaction, and therefore it is desired
that ꢁ equals 0. It is also of interest to investigate how much
4
5
of each product that has been formed. This is done by applying
eqs 4–7. These equations give the fraction of the maximum
theoretical yield of each of the products that have been
produced. The subscript t in the formulas represents the time
of reaction when the numbers have been evaluated.
[
1]t
X1, t ) 1 -
(1)
(2)
(3)
(4)
(5)
(6)
(7)
[
1]t)0
[
3] + 2[4]t
t
ꢁ3,4, t
)
Figure 3. Structure of unused catalyst.
[
3] + 2[4] + [5] + 2[6]
t t t t
[
5]t
ꢁ5, t
)
[
3] + 2[4] + [5] + 2[6]
t
t
t
t
[
3]t
Y3, t
)
)
)
)
[
[
[
[
1]t)0
2
[4]t
Y4, t
Y5, t
Y6, t
1]t)0
[
5]t
1]t)0
Figure 4. Structure of used catalyst, which was separated by
filtration at room temperature.
2
[6]t
1]t)0
supports the desired amination reaction; compare Figure 1.
FibreCat 1026 gives a significantly higher ꢁ3,4 of 0.81. This
catalyst also gives the lowest fractional yield of the undesired
The reactions presented in the coming part have been
performed using the following initial conditions: 1.0 equiv 1,
.0 equiv 2, 1.5 equiv NaO-t-Bu, and 0.030 molar equiv
2
side product 5 (ꢁ ) 0.18), and only traces of 6 is observed.
5
FibreCat. The solvent applied throughout the article is 1,4-
dioxane. The reaction was carried out in a microwave cavity at
These observations conclude that the catalyst that has the desired
properties is FibreCat 1026.
9
0 °C. Data collected for the reactions have been obtained by
3.3. Characterization of FibreCat 1026. To obtain more
information on a macroscopic scale, scanning electron micro-
scope (SEM) pictures were taken of the fresh catalyst, and a
representative picture can be seen in Figure 3. This picture
shows that the catalyst consists of rods of a length of
approximately 200 µm (seen from another not shown SEM
picture) and with a diameter of approximately 10–17 µm.
SEM pictures were also taken of the catalyst that has
been employed in a reaction in 1,4-dioxane for 3 h at 90
°C, Figure 4.
From the picture it can be seen that the catalyst differs from
the one shown in Figure 3. After the reaction the catalyst is
covered with a layer of NaBr (confirmed by EDX), which is a
side product from the reaction in Scheme 1. Two mechanisms
for the precipitation of NaBr on the catalyst may exist: either
NaBr precipitates on the catalyst when the reaction mixture is
cooled to room temperature, or NaBr precipitates on the catalyst
during the course of reaction. In an attempt to reveal which of
the two mechanisms is valid, the catalyst was also separated at
temperatures close to the reaction temperature, Figure 5.
HPLC. This has allowed the following compounds to be
quantified: 1, 3, 4, 5, and 6.
3.2. Screening of Different Catalytic Systems. The per-
formance of the four different catalysts is initially evaluated
on the model reaction in Scheme 1. It is desired to identify the
catalyst that facilitates the amination reaction to the highest
extent and suppresses the formation of 5 and 6 the most. The
results are displayed in Table 4, and the reaction conditions
can be found in the Experimental Section. The first conclusion
is that all of the catalysts facilitate conversion of p-bromotolu-
ene, 1. Except FibreCat 1007, all of the catalysts offer nearly
full conversion of 1 within the first 3 h of the reaction. The
reason for the incomplete conversion may be due to the relative
low palladium loading compared to that of the three other
catalysts; see Table 2. The relatively low palladium loading of
1007 required that more of the supported catalyst be used, and
it was harder to ensure efficient mixing in the thicker slurry.
The next parameter to evaluate is the fractional yield of 3
and 4, ꢁ3,4. This number expresses how well the catalyst
Vol. 11, No. 6, 2007 / Organic Process Research & Development
•
959

Figure 6. Course of reaction at 90 °C.
Figure 5. Structure of used catalyst, which was separated by
filtration at 90 °C.
Comparing Figures 4 and 5, no obvious differences in the
precipitation of NaBr are observed. This may indicate that NaBr
precipitates during the course of reaction. Finally, the pictures
of the used catalyst reveal that the polymer swells during the
course of reaction, and the diameter has increased to ap-
proximately 25–45 µm.
The BET surface area of fresh catalyst has also been
determined, and an average of two measurements gave a surface
2
area of 0.57 ( 0.015 m /g. This value is compared to a
theoretical calculation of the BET surface area based on eq 8.
The dimensions of the rods are obtained from Figure 3. Thus,
the dimensions are measured as diameter (average obtained from
Figure 3), d , 14 µm; length, L, 200 µm; and the density, F, is
r
assumed to be 1.0 g/mL.
Figure 7. Performance of a catalyst that is reused two times
(
3 h at 90 °C).
2
r
πd L + 2πd
surface area of rod
BET )
r
4
8
5
On the contrary the fractional yield of ꢁ is increasing from
)
)
+
mass of rod
π
2
p
drF LF
0.05 to approximately 0.13 in the same period. This change in
the fractional yield may either be due to different rates of
formation for 3, 4, and 5 or be due to a change in the reaction
mechanism during the course of reaction.
d LF
4
(
8)
By inserting the values into eq 8, the theoretical surface area
is estimated to be 0.33 m /g. This is close to the measured value
of the surface area, and it can be concluded that the support
material is nonporous. The slightly higher measured value of
the area can be subscribed to irregularities in the surface of the
support material.
3.5. Reaction with Reuse of the Catalyst. One of the
possible advantages of applying heterogeneous catalysis is that
it may be possible to reuse the catalyst. To investigate the
prospective of this approach the following experiment is carried
out. A catalyst that has been used once in a reaction is separated
from the reaction mixture by filtration and subsequently re-
employed in the same reaction. This separation of the catalyst
followed by subsequent reaction is repeated twice. The results
are presented in Figure 7.
The results in Figure 7 clearly illustrate that the activity of
the catalyst decreases significantly; going from nearly full
conversion in reaction 1 to about 50% conversion in reactions
2 and 3. More interesting a change in the fractional yield of 3
and 4, ꢁ3,4, is observed. This decreases from 0.81 to 0.22 over
the three reaction runs, and the fractional yield of the undesired
side product 5 increases from 0.18 to 0.76. These observations
indicate that the catalyst after the workup supports the reduction
reaction rather than the desired amination reaction. It is not
known what causes this deactivation process during the reaction
2
3.4. Course of Reaction. Besides obtaining understanding
of how the catalyst performed during different kinds of
treatments, it is also desired to elucidate how the reaction
evolves over time. Therefore the concentrations of 1 and the
products were investigated over time. These results are presented
in Figure 6.
Figure 6 shows that more than 90% of 1 has been converted
within the first 10 min of reaction and that nearly all (99%)
has been converted after 60 min. Reaction profiles from 60 to
1
80 min showed that no futher changes in the degree of
conversions of all measurable compounds are observed.
In the lower part of Figure 6 it can be seen that the fractional
yield ꢁ3,4 decreases from 0.95 to 0.86 during 1 h of reaction.
9
60
•
Vol. 11, No. 6, 2007 / Organic Process Research & Development

Table 5. Performance of the FibreCat with and without
wash prior to reaction (3 h at 90 °C)a
X
1
ꢁ
3,4
ꢁ
5
Y
3
Y
4
Y
5
Y
6
reaction (eq 1) (eq 2) (eq 3) (eq 4) (eq 5) (eq 6) (eq 7)
untreated 0.99 0.81 0.18 0.58 0.23 0.18 0.01
catalyst
washed
catalyst
dioxane
from the
wash
0.76 0.19 0.73 0.14 0.01 0.56 0.06
0.64 0.95 0.05 0.46 0.15 0.03
0
a
In a flask 0.073 (0.029 equiv) g of FibreCat 1026 was mixed with 2.0 mL of
,4-dioxane. The flask was left for 30 min at room temperature with agitation and
1
nitrogen atmosphere. The FibreCat was separated by filtration and introduced to a
process vial.
runs, but it may be due to washout of some of the active
components from the FibreCat during the filtration of the
catalyst, deposition of NaBr on the catalyst, or some unknown
deactivation reaction of the catalyst. To clarify if either of the
two possibilities exists, two different experiments were carried
out and are reported in the following.
Figure 8. Results for successive reactions in the same process
vial (3 h at 90 °C).
3.7. Reaction with Reuse of the entire Reaction Mixture.
At this point of the work it had been concluded that the
catalytically active components are released from the catalyst
during reaction and wash, respectively. This means that the
catalyst becomes homogeneous and then subsequently is lost
when the catalyst is separated. This observation motivates an
experiment where the entire reaction mixture is used in
successive reactions. The results are given in Figure 8.
From Figure 8 it is clearly seen that the activity of the catalyst
does not decrease to the same extent as in the experiments where
the catalyst has been separated from the reaction mixture prior
to the reuse; compare Figure 7. The activity of the catalyst is
still decreasing during the different reactions runs. It is seen
that from reaction 1 to reaction 2 the product distribution
changes significantly and ꢁ3,4 decreases from 0.80 to 0.08; on
3.6. Wash of the Catalyst prior to Reaction. To clarify if
the changes in the activity of the catalyst is caused by wash
out of active components during the separation of the catalyst,
an experiment where the catalyst is washed prior to reaction is
carried out. The results are given in Table 5. The first result
reported in the table corresponds to the result obtained in Section
3.2; this result is used as a reference in the discussion of the
following two results.
The results obtained with the washed catalyst reveal that the
catalyst still is able to convert 1 to products. However, compared
to the performance of the untreated catalyst the reaction rate
has decreased: only 76% of the initial amount of 1 has been
converted, in contrast to 99% being converted with the untreated
catalyst. A more serious challange observed is the low fractional
yield of 3 and 4, ꢁ3,4, this has decreased from 0.81 to 0.19. At
the same time the fractional yield of 5 has increased significantly
from 0.18 to 0.73. These numbers clearly illustrate that the
properties of the catalyst applied has changed during the
washing process, and by that indicating that active compounds
are washed out of the catalyst.
A HPLC analysis of the solvent applied in the wash of the
catalyst showed a peak in the chromatogram. It may be possible
that the active ligand is released during the wash, thus indicating
that the peak originates from triphenylphosphine. Analyzing a
reference of pure triphenylphosphine gave a retention time that
is equal to the peak observed. After having proved that
triphenylphosphine in all probability is released from the catalyst
it is decided to perform a reaction where 1, 2, and NaO-t-Bu
are added to the 1,4-dioxane applied in the washing process.
The results from this experiment are also presented in Table 5.
The results show that the dioxane from the washing process
has properties similar to the untreated catalyst. Only 64% of
the initial amount of 1 has been converted, but it has been
efficiently transformed to 3 and 4 (ꢁ3,4 ) 0.95), and only traces
the contrary φ
primarily facilitates the reduction reaction.
.8. Reactivation of the Catalyst. Previously in section 3.6
5
increases from 0.19 to 0.83. Thus, the catalyst
3
it was concluded that both Pd and triphenylphosphine are
released from the polymer support during both reaction and
simple wash of the catalyst. Therefore, it is of interest to
investigate if the washout of the active compounds from the
support is reversible, by that meaning that the catalyst can be
reactivated. To obtain a deeper understanding of this release
mechanism the experiments reported in Table 6 were carried
out.
Reaction 1 represents a reaction carried out with fresh
catalyst. Reaction 2 is the results obtained when the catalyst
from reaction 1 is reused. As reported earlier the activity of the
catalyst decreases and the selectivity toward 5 increases when
the catalyst is reused. The catalyst employed in reaction 2 is
separated, and in an attempt of reactivating the catalyst it is
mixed with PdCl and TPP. Subsequently, the treated catalyst
2
is employed in reaction 3. From Table 6 it is seen that the
activity of the catalyst is not regained upon the treatment. On
the contrary it is seen that the fractional yield of 5, ꢁ , increases
5
further. The lack of success for the reactivation may be due to
of 5 are detected (ꢁ
5
) 0.05). The dioxane from the wash is
the fact that both PdCl and TPP are added in the same
2
able to facilitate the reaction; this indicates that both palladium
2
operation. PdCl may have a higher affinity toward the TPP in
and triphenylphosphine are released from the FibreCat.
the solution than toward the TPP anchored to the polymer
Vol. 11, No. 6, 2007 / Organic Process Research & Development
•
961

Table 6. Reactivation experiment (3 h at 90 °C)
reaction
X
1
(eq 1)
ꢁ3,4 (eq 2)
ꢁ
5
(eq 3)
Y
3
(eq 4)
Y
4
(eq 5)
Y
5
(eq 6)
Y
6
(eq 7)
1
2
3
4
0.97
0.72
0.48
0.31
0.86
0.33
0.04
0.06
0.10
0.60
0.75
0.69
0.52
0.16
0.02
0.02
0.31
0.07
0
0.09
0.44
0.36
0.22
0.04
0.05
0.10
0.08
2
(addition of PdCl /TPP)
(Addition of PdCl
2
)
0
change in the reaction behavior due to the use of microwaves
31,32
are ongoing in the literature.
In previous articles it has been
concluded that no specific microwave effects are observed.
Differences in the reaction behavior compared to conventional
heating (i.e., oil bath or electrical heating) is caused by the fact
that the microwave irradiated system is pressurized. This allows
the reaction temperature to be elevated above the boiling point
at atmospheric pressure (which is applied in an oil bath), which
causes higher reaction rates and increases the solubility of the
31,32
reactants.
Since all experiments in this article were carried
Figure 9. Dissociation reaction of the palladium complex.
support, thus inhibiting the reactivation process. Therefore, an
experiment where only PdCl is added to the used catalyst is
2
conducted (reaction 4). However, from the results it can be
concluded that this treatment only leads to a further decrease
of the activity.
Taking the reaction mechanism in Figure 1 into consider-
ation, it appears to be challenging to develop a heterogeneous
catalyst for this reaction system, which is not leaching pal-
ladium. The precondition for the catalyst to be active is the
ability for the palladium to dissociate a pair of phosphine
ligands; compare Figure 9. Furthermore, it is not known if all
TPP is covalently bonded to the polymer support. On the basis
of the results reported in this article it does not seem plausible,
because it is unlikely that the bond between TPP and the support
is broken by a simple wash in 1,4-dioxane at room temperature.
out below the boiling point of 1,4-dioxane, we have concluded
that we have no effect of applying the microwaves. Issues in
connection to the scale-up of microwave-assisted reactions are
another area of interest from an industrial point of view. Two
different approaches have been discussed in the literature: scaled
glass vessels up to 100 mL, which are automatically loaded
33
with reaction mixture and subsequently automatically emptied,
30
and microwave cavities equipped with a flow cell. Some of
the limiting factors in connection to scaling up of the glass
vessels are the limited penetration depth of the microwaves;
thus it is difficult to ensure efficient heat transfer in the scaled
systems. Regarding the microwave cavity equipped with a flow
cell, other parameters such as particles and high viscosity may
cause problems. This means that a proper solution varies from
reaction to reaction.
4
. Improvements of the Catalyst
On the basis of the experimental results, suggestions for the
6
. Conclusion
A study of the prospectives of employing a heterogeneous
design of future catalysts can be provided. The results clearly
show that the major challenge to solve is the leaching of
palladium and the catalytically active ligands. As previously
mentioned the leaching seems to be difficult to suppress, because
palladium is not covalently bonded to the polymer support;
compare Figure 9. A way of improving the ability of the
polymer support to withhold the palladium may be to increase
the number of polymer-supported TPP per surface unit. Another
approach has been to encapsulate both the metal and the active
catalyst in a Buchwald–Hartwig amination reaction has been
reported. The catalyst was able to facilitate the desired amination
reaction; however, it was also found that the side products
toluene and 1,1′-dimethyl-4,4′-biphenyl were produced during
the course of reaction. This product distribution is also observed
when a homogeneous catalyst is employed. With the aim of
reusing the catalyst in subsequent reactions, it was found that
the separation of the catalyst from the reaction mixture led to
a change in the activity of the catalyst. The recovered catalyst
facilitated a slower conversion of p-bromotoluene, and the
primary product had changed from the amination products to
the side product toluene. Further investigations revealed that
the changes in the behavior of the catalyst were due to a washout
of both palladium and triphenylphosphine from the support
material. Attempts to reactivate the catalyst with the addition
of additional palladium dichloride and triphenylphosphine
indicated that the release mechanism may not be reversible.
This addition had the consequence that the fractional yield of
30
ligand in a polymer. In this method it is the intention that the
reactants diffuse into capsules where the reaction takes place
and that the products subsequently diffuses out into the reaction
mixture. Whether this is a better design for the Buchwald–
Hartwig amination reaction is not known. However, the
encapsulated homogeneous catalyst has successfully been
applied in a flow reactor employed in a Suzuki coupling
3
0
reaction.
5. Applicability of Microwaves in Chemical Reactions
All reported experiments in the article are conducted using
microwaves as heating source. Discussions about a possible
(
31) Maes, B.; Loones, K.; Hostyn, S.; Diels, G.; Rombouts, G. Tetrahedron
004, 60, 11559–11564.
2
(
32) Kuhnert, N. Ang. Chem., Int. Ed. 2002, 41, 1863–1866.
(
30) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K.
(33) Loones, K. T. J.; Maes, B. U. W.; Rombouts, G.; Hostyna, S.; Dielsb,
Chem.–Eur. J. 2006, 12, 4407–4416.
G. Tetrahedron 2005, 61, 10338–10348.
9
62
•
Vol. 11, No. 6, 2007 / Organic Process Research & Development

Table 7. Course of reaction
component
time of reaction (min)
1
2
NaO-t-Bu
FibreCat 1026
1,4-dioxane
5
1
2
3
6
0.172 g; 1.0 equiv
0.167 g; 1.0 equiv
0.166 g; 1.0 equiv
0.168 g; 1.0 equiv
0.168 g; 1.0 equiv
0.168 g; 2.0 equiv
0.168 g; 2.0 equiv
0.169 g; 2.0 equiv
0.168 g; 2.0 equiv
0.168 g; 2.0 equiv
0.140 g; 1.5 equiv
0.144 g; 1.5 equiv
0.140 g; 1.5 equiv
0.140 g; 1.5 equiv
0.140 g; 1.5 equiv
0.074 g; 0.029 equiv Pd
0.076 g; 0.030 equiv Pd
0.075 g; 0.029 equiv Pd
0.074 g; 0.029 equiv Pd
0.075 g; 0.029 equiv Pd
2.0 mL
2.0 mL
2.0 mL
2.0 mL
2.0 mL
0
0
0
0
Table 8. Screening experiments of FibreCats
component
reactor
FibreCat
1
2
NaO-t-Bu
FibreCat
1,4-dioxane
A
B
C
D
1001; 5.05 wt % Pd 0.165 g; 1.0 equiv 0.167 g; 2.0 equiv 0.143 g; 1.5 equiv 0.0613 g; 0.031 equiv Pd 2.0 mL
1007; 1.77 wt % Pd 0.165 g; 1.0 equiv 0.167 g; 2.0 equiv 0.144 g; 1.6 equiv 0.175 g; 3.0 equiv Pd
1026; 4.14 wt % Pd 0.164 g; 1.0 equiv 0.166 g; 2.0 equiv 0.143 g; 1.6 equiv 0.076 g; 0.031 equiv Pd
1032; 4.26 wt % Pd 0.168 g; 1.0 equiv 0.171 g; 2.0 equiv 0.147 g; 1.6 equiv 0.073 g; 0.030 equiv Pd
2.0 mL
2.0 mL
2.0 mL
Table 9. Reuse of catalyst
component
FibreCat 1026
0.076 g; 0.031 equiv Pd
reaction
1
2
NaO-t-Bu
1,4-dioxane
1
2
3
0.164 g; 1.0 equiv
0.168 g; 1.0 equiv
0.165 g; 1.0 equiv
0.166 g; 2.0 equiv
0.166 g; 2.0 equiv
0.169 g; 2.0 equiv
0.143 g; 1.6 equiv
0.140 g; 1.5 equiv
0.142 g; 1.5 equiv
2.0 mL
2.0 mL
2.0 mL
toluene increased further as the production of 1,1′-dimethyl-
,4′-biphenyl did. These observations lead to the conclusion
that, prior to further reuse application of the heterogeneous
catalyst, it is necessary to identify parameters that can slow
down the release rate of the active components from the polymer
support.
The reaction was carried out using standard condition. After
reaction the reaction mixture was analyzed by HPLC. The
catalyst from reaction 1 was collected by filtration, and no
further workup of the catalyst was carried out. The catalyst was
transfered to a new process vial and compounds according to
reaction 2 in Table 9 were introduced. The reaction and analysis
were carried out similar to reaction 1. This procedure was also
applied in reaction 3.
4
7
. Experimental Section
7.1. Materials. p-Bromotoluene was purchased from Merck;
7.2.4. Wash of the Catalyst Prior to Reaction. In a flask
piperazine, toluene, 1,1′-dimethyl-4,4′-biphenyl, and 1,4-dioxane
were purchased from Aldrich. All chemicals and solvents were
used without any prior treatment. Johnson Matthey Catalyst
delivered the four different immobilized catalysts, which have
been designed to facilitate cross-coupling reactions. Palladium
dichloride and reference compound for the analysis calibration
of 1-(4-methylphenyl)piperazine was from Fluka. A reference
compound for 1,4-bis(4-methylphenyl)piperazine was produced
0
.073 (0.029 equiv) g of FibreCat 1026 was mixed with 2.0
mL of 1,4-dioxane. The flask was left for 30 min at room
temperature with agitation and nitrogen atmosphere. The
FibreCat was separated by filtration and introduced to a process
vial, which contained 0.168 g (1.0 equiv) of 1, 0.168 g (2.0
equiv) of 2, 0.142 g (1.5 equiv) of NaO-t-Bu, and 2.0 mL of
1,4-dioxane. Subsequently, it reacted under standard condition
and was finally analyzed by HPLC. The dioxane used in the
initial treatment of the catalyst was introduced to a process vial
together with 0.164 g (1.0 equiv) of 1, 0.165 g (2.0 equiv) of
16
according to a literature procedure.
.2. Preparation of the Reaction Mixtures. In the follow-
7
ing sections each of the experiments carried out is described.
Where nothing else is specified, the reaction was carried out in
a microwave cavity under nitrogen atmosphere and agitation
2
, and 0.140 g (1.5 equiv) of NaO-t-Bu. This vial reacted under
the same conditions as above.
.2.5. Reuse of the Entire Reaction Mixture. Compounds
7
(600 rpm) for 3 h at 90 °C.
according to reaction 1 in Table 10 were placed in a process
vial. The reaction was carried out using standard condition. After
reaction the reaction mixture was analyzed by HPLC. After the
analysis new reactants according to reaction 2 in Table 10 were
added to the process vial, and it was allowed to react for another
7
.2.1. Course of Reaction. Process vials containing the
amounts given in Table 7 were prepared. They reacted under
standard conditions for 5, 10, 20, 30, and 60 min. Subsequently,
the reaction mixtures were analyzed using HPLC.
7.2.2. Screening of the FibreCats. Four process vials were
3
h under same conditions as above.
prepared according to Table 8. The reaction was carried out
using standard conditions. After reaction the reaction mixture
in the process vials was analyzed by HPLC.
7.2.6. ReactiVation of the Catalyst. In a flask 0.073 (0.029
equiv) g of FibreCat 1026 was mixed with 2.0 mL of
1,4-dioxane. The flask was left for 30 min at room temperature
with agitation and nitrogen atmosphere. The FibreCat was
7.2.3. Reaction with Reuse of the Catalyst. In a process vial
the compounds listed in reaction 1 in Table 9 were introduced.
Vol. 11, No. 6, 2007 / Organic Process Research & Development
•
963

Table 10. Reuse of catalyst
component
reaction
1
2
NaO-t-Bu
FibreCat 1026
1,4-dioxane
2.0 mL
1
2
0.166 g; 1.0 equiv
0.166 g; 1.0 equiv
0.164 g; 2.0 equiv
0.164 g; 2.0 equiv
0.140 g; 1.5 equiv
0.143 g; 1.5 equiv
0.072 g; 0.029 equiv Pd
separated by filtration and introduced to a process vial, which
contained 0.168 g (1.0 equiv) of 1, 0.168 g (2.0 equiv) of 2,
Table 11. Relative standard deviation for the detectable
compounds
0.142 g (1.5 equiv) of NaO-t-Bu, and 2.0 mL of 1,4-dioxane.
component
Subsequently, it reacted under standard condition and was
finally analyzed by HPLC. The dioxane used in the initial
treatment of the catalyst was introduced to a process vial
together with 0.164 g (1.0 equiv) of 1, 0.165 g (2.0 equiv) of
1
3
4
5
6
relative
55.1
4.4
10.4
14.1
41.1
standard
deviation (%)
average
2, and 0.140 g (1.5 equiv) of NaO-t-Bu. This vial reacted under
0.004 0.2038
0.0454
0.0577
0.002
the same conditions as above.
The catalyst from reaction 3 in section 7.2.3 was separated
from the reaction mixture by filtration. The catalyst was mixed
concentration
(
mol/L)
with 0.007 g PdCl
basis of Pd in the FibreCat) and 0.007 g triphenylphosphine
corresponds to half the initial amount on a molar basis of Pd
in the FibreCat) in 2.0 mL of 1,4-dioxane. The mixture was
left for 1 h at room temperature (N atmosphere and agitation).
After 1 h the catalyst was collected by filtration and transfered
to a process vial together with 0.170 g (1.0 equiv) of 1, 0.167
g (2.0 equiv) of 2, 0.140 g (1.5 equiv) of NaO-t-Bu, and 2.0
mL of 1,4-dioxane. The reaction was carried out using standard
conditions. Finally, the reaction mixture was analyzed by HPLC.
2
(corresponds to the initial amount on a molar
From Table 11 it is observed that the standard deviation
(
differs for the five components. The high standard deviations
for 1 and 6 are due to the low concentration present in the
sample (respectively, 0.004 and 0.002 mol/L). In reality the
relative standard deviation is expected to be in the same area
as for 3.
7.4. Methods. The reaction mixtures were heated in a 300
W Emrys Optimizer microwave cavity from Personal Chem-
istry. Emrys Process Vials 2–5 mL were used as reactors. An
infrared detector monitored the temperature of the reaction
mixture. In all reactions the temperature of the reaction mixture
in the microwave cavity did not exceed the boiling point of the
solvents at atmospheric pressure.
2
7.3. Reproducibility of the Experimental Results. The
quantification of compounds 1, 3, 4, 5, and 6 was obtained by
using HPLC. On the basis of the measured intensities and
Lambert–Beers law (eq 9) the concentrations were calculated.
The experimental results were obtained by HPLC using UV
detection at 215 nm. The general procedure for the analysis of
the reaction mixtures was as follows. Approximately 0.5 mL
of the reaction mixture was transfered to a vial, which was
centrifuged for 5 min at 2000 RPM. This treatment ensured an
efficient separation of the reaction mixture and the FibreCat.
Subsequently, 20 µL of the reaction mixture was transferred
from the vial to a sample vial, which contained 1.00 mL of
methanol. The HPLC was operated under isocratic conditions,
A
ε · l
C )
(9)
From eq 9 it follows that the uncertainties in the calculation
of the concentrations, C, are introduced in the determination of
the expansion coefficient, ꢀ · l, and the absorbance, A, of the
reaction mixture. In order to make a conclusion of the
reproducibility of the experiments, the standard deviation of a
composite measurement needs to be found. The standard
deviation of a composite measurement is calculated on the basis
of the standard deviation of the direct measured values for ꢀ ·
and the mobile phase consisted of methanol and HCOONH
4
/
NH buffer (0.20 M, pH ) 9.0, 7:3). The method of analysis
3
34
applied allowed the following components to be detected and
quantified: 1, 3, 4, 5, and 6. The quantification of the five
components was done by applying the Lambert–Beers law. The
extinction coefficient was calculated for each of the five
components based on a standard row of four. The components
were dissolved in 1,4-dioxane.
l and A. The expansion coefficients were determinedon the
2
basis of a linear regression. A R -value higher than 0.995 was
obtained for all components. Because of the satisfying correla-
tion it was concluded that uncertainties only were introduced
35
to the system from the HPLC analysis. The standard deviation
for each of the following components were found using the
following method. Four independent process vials were pre-
pared. Each of the vials reacted for 3 h at 90 °C. For each of
the vials two samples were prepared, which subsequently were
analyzed twice on the HPLC. The standard deviation for the
concentration determination was then calculated, and the relative
standard deviations are shown in table 11.
The formation of 3 and 4 was confirmed by H and 13C
NMR, LC-MS, and HPLC; 5 was confirmed by HPLC; and 6
was confirmed by HPLC and GC-MS. The spectra obtained
were compared to the spectra for the reference compounds.
Conditions for HPLC: MERCK-HITACHI L-5025 column
thermostat, L-4250 UV–vis detector, D-6000 interface, L-6200A
intelligent pump, As-2000A autosampler, Colombus column
100 × 4.60 mm, 5µ, C8, 110A. Conditions for NMR: Bruker
Avance 500 MHz 2-channel spectrometer. Conditions for LC-
MS: API150ex single quadrupole mass spectrometer. Conditions
1
(
34) Crossland, H. HVordan man bruger statistik på kemiske bestemmelser;
AiO Tryk as: Odense (Denmark), 1989.
35) Montgomery, D. C. Design and Analysis of Experiments; John Wiley
(
&
Sons, Inc.: New York, 1997.
9
64
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Vol. 11, No. 6, 2007 / Organic Process Research & Development

for GC-MS: Varian Star 3400 CX, Varian Saturn 2000 equipped
with a column from Zebron, ZB-5, 15 m, 0.25 mm, 0.25 µm.
University of Denmark, together with among others H.
Lundbeck A/S. The experimental work was carried out
in the laboratories at H. Lundbeck A/S.
Acknowledgment
This work was financed by the Graduate School In
Received for review May 10, 2007.
OP7000996
Chemical Engineering: MP
2
T, which is founded by the
Department of Chemical Engineering at the Technical
Vol. 11, No. 6, 2007 / Organic Process Research & Development
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965