Development of a continuous-flow system for catalysis with palladium(0) particles

Article abstract of DOI:10.1002/ejoc.200400194

Heterogeneous catalysis for organic synthesis under continuous-flow conditions becomes possible by a new reactor-based approach. Continuous-flow reactors with a monolithic glass/polymer composite interior are loaded with palladium particles by ion exchange followed by reduction. When incorporated into a continuous-flow setup (PASSflow) this reactor allows the transfer-hydrogenation of alkenes, alkynes, nitro-substituted aromatic compounds and benzyl ethers in the flow-through mode. In addition, the activity of the catalysts is well suited to achieve Suzuki, Sonogashira and Heck cross-coupling reactions in the absence of phosphanes or any other ligands, resulting in a greatly simplified purification. As an extension to this concept a bifunctional support was prepared inside the reactor consisting of Pd particles and an ion-exchange group (hydroxide form). In the Suzuki-Miyaura reaction the reactor serves as a base for immobilisation and activation of the boronic acid as boronate and as a catalyst for promoting the C-C coupling reaction under continuous-flow conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400194

FULL PAPER
Development of a Continuous-Flow System for Catalysis with Palladium(0)
Particles
Wladimir Solodenko,[a] Hongliang Wen,[a] Stefanie Leue,[b] Friedrich Stuhlmann,[b]
Georgia Sourkouni-Argirusi,[a] Gerhard Jas,[b] Hagen Schönfeld,[c] Ulrich Kunz,[c] and
Andreas Kirschning*[a]
Keywords: Continuous-flow processes / Heterogeneous catalysis / Hydrogenation / Palladium / Supported catalysts
Heterogeneous catalysis for organic synthesis under continu-
ous-flow conditions becomes possible by a new reactor-
based approach. Continuous-flow reactors with a monolithic
glass/polymer composite interior are loaded with palladium
particles by ion exchange followed by reduction. When in-
other ligands, resulting in a greatly simplified purification.
As an extension to this concept a bifunctional support was
prepared inside the reactor consisting of Pd particles and an
ion-exchange group (hydroxide form). In the Suzuki−
Miyaura reaction the reactor serves as a base for immobilis-
corporated into a continuous-flow setup (PASSflow) this re- ation and activation of the boronic acid as boronate and as a
actor allows the transfer-hydrogenation of alkenes, alkynes,
nitro-substituted aromatic compounds and benzyl ethers in
the flow-through mode. In addition, the activity of the cata-
lysts is well suited to achieve Suzuki, Sonogashira and Heck
cross-coupling reactions in the absence of phosphanes or any
catalyst for promoting the C−C coupling reaction under con-
tinuous-flow conditions.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
chiometrically employed immobilised reagents, the degree
of loading is often of minor interest. Finally, the oppor-
tunity to employ this technique in conjunction with con-
tinuous-flow processes is a particularly important feature as
this setup creates an ideal, almost workup-free technique
for automated solution-phase synthesis.[3] Recently, we re-
ported on the polymer-assisted solution-phase synthesis in
the follow-through mode (PASSflow) technique[4] which re-
lies on a reactor system containing a monolithic block
based on a chemically functionalized and highly porous
polymer/glass composite material. The monolithic com-
posite was designed in such a way that the polymer particles
inside the pore volume can swell and shrink (but to a lesser
extent than conventional resins), whereas the outer dimen-
sions of the rod stay stable. This composite material was
embedded in a solvent-resistant tube, followed by encap-
sulation within a pressure-resistant, fibre-reinforced epoxy
resin casing with two standard HPLC fittings.[5] Thus, the
technical problems such as bypassing or the high pressure-
drop observed in sole polymer packings are avoided. A
vinylbenzyl chloride based polymer was transformed into a
quaternary ammonium ion which can be used for the load-
ing of various anions that can react as immobilised stoi-
chiometric agents in continuous-flow processes.[4] In the
current study we disclose continuous-flow applications of
catalysts by using the ionic exchange functionality for
specifically positioning a palladium-based catalyst inside
the reactor. The resulting catalytic system allows us to per-
Solid supports functionalized with reactive species that
are employed in solution-phase transformations have re-
ceived a great deal of interest lately.[1] The intrinsic advan-
tage of this hybrid solid/solution-phase technique lies in the
simple purification and the possibility to use immobilised
reagents in excess to drive reactions in solution to com-
pletion. Among functionalized supports, immobilised cata-
lysts will play a major role in future applications because
the realm of newly developed homogeneous transition-me-
tal catalysts, including those with chiral ligand systems for
asymmetric transformations, can be used under hetero-
geneous conditions.[2] Indeed, the supported catalyst can
easily be separated from a reaction mixture by filtration and
washing and be reused after regeneration. In some cases it
has been shown that immobilised catalysts show chemical
differences to their soluble counterparts, such as prolonged
activity or altered selectivity. In addition, compared to stoi-
[a]
Zentrum für Organische Chemie, Universität Hannover,
Schneiderberg 1B, 30167 Hannover, Germany
Fax: (internat.) ϩ 49-511-762-3011
E-mail: andreas.kirschning@oci.uni-hannover.de
[b]
Chelona GmbH,
Hermannswerder Haus 15, 14473 Potsdam,Germany
[c]
Institut für Chemische Verfahrenstechnik, Technische
Universität Clausthal,
Leibnizstr. 17, 38678 Clausthal-Zellerfeld, Germany
Fax: (internat.) ϩ 49-5323-72-2182
E-mail: kunz@icvt.tu-clausthal.de
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form transfer hydrogenations as well as CϪC cross-coup- According to Vaultier and co-workers[8] anionic exchange
ling reactions in a continuous-flow environment without the resins (hydroxide form) are ideally suited to activate boronic
need for additional ligands.[6]
acids as tetrahedral arylboronate anions, which indeed is
the case when pumping boronic acid (2Ϫ4 mmol) through
a PASSflow reactor (hydroxide form; about 1 mmol ca-
pacity). The arylboronic acid or vinylboronic acid is loaded
onto the reactor (about 0.7 mmol effective loading). After
washing, the remaining aryl halide (0.15Ϫ0.3 mmol) and
the catalyst [tetrakis(triphenylphosphane)palladium(0),
2Ϫ5 mol %] dissolved in tetrahydrofuran are circulated at
60 °C (oven temperature) through the reactor to finally
yield the cross-coupling products 2Ϫ10 in good yields
(Table 1; method A).
Results and Discussion
In initial studies we first tested a simple application of
the SuzukiϪMiyaura cross-coupling reaction under con-
tinuous-flow conditions. The SuzukiϪMiyaura cross-coup-
ling reaction is typically initiated by base-promoted acti-
vation of boronic acid under heterogeneous conditions,
commonly with inorganic salts. This procedure can result
Ϫ
in the formation of the tetrahedral ArB(OH)3 anion,
which is more reactive in electrophilic reactions than the
As expected, aryl iodides showed greater reactivity than
neutral boronic acid itself.[7] However, in order to promote aryl bromides. Aryl bromides with electron-withdrawing
SuzukiϪMiyaura cross-coupling reactions in our continu- substituents (Table 1; Entries 1, 3, 9 and 10) turned out to
ous-flow device containing irregular microchannels we had be more reactive than those with electron-donating groups
to choose homogeneous conditions that prevent blocking. (Table 1; Entry 6), as oxidative addition of Pd0 has been
Table 1. SuzukiϪMiyaura cross-coupling reaction under continuous-flow conditions (method A)[a]
[a]
b]
After washing of the reactor with 2  HCl, 1  NaOH, and water (pH ϭ 7) it was reused more than 20 times.
All reaction
temperatures in this report refer to oven temperatures. As the reaction mixture is pumped as a convective flow through the reactor it
[c]
never reaches the oven temperature. We determined that the reaction mixture leaves the reactor at about 40Ϫ45 °C. Isolated yields
after flash column chromatography.
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demonstrated to be the rate-determining step for aryl bro- up is envisaged. In the context of ligand-free catalysis tran-
mides.[7] The vinylboronic acid (Table 1; Entry 12) showed sition-metal nanoparticles[10] have attracted a great deal of
only moderate reactivity in comparison to arylboronic ac- attention in the last decade.[11] Nanoparticles are defined as
ids. In some cases, formation of minor amounts of aryl- having a diameter of 1Ϫ50 nm. In this size range metals
boronic acid derived symmetrical biaryl compounds was show size-dependent properties: the smaller the cluster of
observed.[9] This side reaction has no influence on the prod- atoms the higher the percentage of atoms on the surface,
uct yields because the boronic acids were typically em- rendering particles with diverse catalytic properties.[6] In-
ployed in excess. In this context it is noteworthy that the deed, transition-metal nanoparticles are highly active het-
excess of boronic acid as well as the boron-based by-prod- erogeneous catalysts partly as a result of their high surface/
ucts are not released into solution but stay immobilised in volume ratio. Colloidal nanoclusters based on Pd/Cu which
the reactor by ion exchange.
are stabilised by tetraoctylammonium bromide show en-
Interestingly, the SuzukiϪMiyaura cross-coupling reac- hanced activity due to synergistic effects.[12] In this context,
tion in the PASSflow mode can also be carried out without Zecca and co-workers have investigated the activity en-
preliminary immobilisation of the boronic acids on the hancement in relation to various acidic cation-exchange re-
anion-exchange resin. In a modified procedure (method B), sins of different properties bearing immobilised pal-
a solution of the arylboronic acid (1.5 equiv.), aryl halide ladium(0).[13] Additionally, palladium(0) particles can be
(1.0 equiv.), and palladium catalyst (2 mol %) in THF was generated after reduction of tetrachloropalladate anions de-
passed through the reactor 11 (hydroxide form), which led posited on anion-exchange resins. Taking advantage of
to immediate trapping of the boronic acid (as 1) while both ionic stabilisation, as demonstrated by Reetz et al.,[14,15] we
the aryl halide and the catalyst were circulated through the anticipated long life-cycles of our reactors and easy regener-
system until the reaction was complete (Scheme 1).
ation of the palladium(0) catalyst.
We continued the project by uniformly immobilising pal-
ladium on the surface of the polymeric composite material
inside the PASSflow reactor. This was achieved by treat-
ment of the anion-exchange resin 12 (chloride form) with
an aqueous solution of sodium tetrachloropalladate
(Na2PdCl4; Scheme 2).
Each palladate anion was then exchanged onto the qua-
ternary trimethylammonium groups 13 and its reduction
with hydrazine or a borohydride solution led to pal-
ladium(0) particles 14. These are stable inside the reactor
and hence easily storable. At this stage, we can only specu-
late about the size of the metal particles generated by this
method. From the high reactivity of the palladium(0) spec-
ies reported here, we assume that nanoparticles of so far
unknown size are the active species.[6]
Scheme 1. SuzukiϪMiyaura cross-coupling reaction without pre-
liminary immobilisation of the boronic acids (method B); isolated
yields after flash column chromatography; for the regeneration pro-
cedure see Table 1
Scanning electron microscopy with a microprobe [elec-
tron probe microanalysis (EPMA), energy dispersive X-ray
microanalysis (EDX)] revealed that two kinds of palladium
Yields for biaryl compounds 3 and 6, reaction times and particles are present. Larger palladium clusters are found
conditions are comparable with those found with pre-im- on the surface of the polymer (bright white spots in Fig-
mobilisation of the boronic acid (see Table 1). However, ures 1 and 2), whereas much smaller particles are often lo-
simplification of the continuous-flow process is substantial cated inside the polymeric beads (size close to the detection
in terms of handling, time and amount of boronic acid limit of the equipment). From the mass balance calculated
needed.
after the loading step it can be concluded that most of the
Nevertheless, the use of a soluble Pd0 catalyst is still a palladium is located inside the polymer particles as nano-
major drawback of this process, particularly when scaling- particles. It seems that the reduction with NaBH4 leads to
Scheme 2. Immobilisation of palladium(0) particles onto the monolithic phase inside the microreactor
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Figure 1. Palladium particles on/inside polymer phase of the micro-
reactors after reduction with NaBH4 (the light areas reveal the lo-
cations of the palladium particles but not the polymeric spheres)
Figure 2. Palladium particles on/inside polymer phase of the micro-
reactors after reduction with hydrazine
Table 2. Transfer hydrogenation of alkenes and alkynes in the continuous-flow mode using palladium(0) particles (yields refer to
purified products)[a]
[a]
After washing of the reactor with ethanol, water, 1  NaOH, water, 1  HCl and finally water, it was reused in further experiments.
Isolated yields after flash column chromatography.
[b]
smaller numbers of larger sized particles on the polymer ladium(0) species 14 under transfer-hydrogenation and con-
surface. However, in the catalytic reduction of nitrobenzene tinuous-flow conditions. During the last few years the de-
to aniline no rate differences were found.
velopment of versatile heterogeneous catalysts has received
Since catalytic hydrogenation is a key step in various in- much attention in light of their selectivity, their removal
dustrial processes,[16] we first tested the supported pal- from the reaction mixture and their reuse for further reac-
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Continuous-Flow System for Catalysis with Palladium(0) Particles
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tions, thereby reducing process costs. Thus, triethylammon- of 0.24 mmol of palladium was determined by elemental
ium formate was used as a hydrogen source in the reduction analysis. The PASSflow reactor could conveniently by re-
of α-ionone (Table 2; Entries 1 and 2) which selectively generated after the palladium particles had lost their ac-
yielded a single reduction product within 70 h in 99% yield tivity by reloading of the anion-exchange resin with chlo-
and high purity (Ͼ 95%). The reaction time can be de- ride ions and their exchange with palladate anions, followed
creased to 3 h by using lithium formate as the hydrogen by reduction (see Scheme 2).
source. Other alkenes (Table 2; Entries 3 and 5) react simi-
Reduction of nitro-substituted aromatic compounds
larly, even when 1,4-cyclohexadiene or hydrazine are used (Table 3; Entries 1Ϫ3) to primary amines is achieved with-
as transfer reagents. Trisubstituted double bonds, such as out the common formation of by-products like hydroxylam-
those present in menthenol (Table 2; Entry 6), are hydro- ines,[18] as was carefully checked by GC-MS analysis. Hy-
genated after prolonged reaction times under these con- drogenolysis of p-benzyloxyacetophenone (Table 3; Entry 4)
ditions. Other functional groups include triple bonds in afforded the free hydroxy group at 55 °C after only 1.5 h
alkynes (Table 2; Entries 7 and 8), which are reduced to and without the need for molecular hydrogen. Again,
the corresponding alkanes; in these cases, the less-reactive workup was highly simplified as only removal of the solvent
cyclohexene can also serve as a hydrogen source.[17] With in vacuo was necessary to isolate the pure product. A
this transfer reagent, which at the same time serves as sol- methyl glycoside which contains two benzyl ether protecting
vent, workup is highly simplified by direct concentration of groups (Table 3; Entry 5) could also be deblocked under
the reaction mixture in vacuo, leading to almost pure com- transfer-hydrogenation conditions.[19]
pounds.
In the next stage of the project we studied the use of
Depending on the extent of palladium leaching, the reac- the Pd0 particles dispersed inside the composite material for
tor could be reused up to 20 times after simple washing. CϪC-coupling reactions. The Heck reaction is a versatile
From ICP-MS analysis, we found that leaching is influ- tool for palladium-catalysed vinylation of aryl halides.[21]
enced by the polarity of the solvents used: more leaching Using the palladium(0) particles, iodoacetophenone
was observed when reactions were performed in polar sol- smoothly underwent coupling with n-butyl acrylate
vents or in strongly acidic media. Higher temperatures also (Scheme 3).[22] The coupling product 25 was obtained in
seem to result in greater leaching. In contrast, in transfer 78% yield [only (E) isomer] and free of homocoupled by-
hydrogenations using cyclohexene as solvent, leaching did products after aqueous workup. At this point we evaluated
not exceed 6 ppm. The amount of immobilised catalyst in- the activity of the palladium particles in the Heck reaction
side the reactor could not be determined directly, although of 4-iodoanisole and isobutyl acrylate. Using 0.5 mol % of
as a conclusion from experiments with identical glass/poly- Pd0 loaded on the glass/polymer composite material (chlo-
mer composite materials shaped as Raschig rings a loading ride form), DMF as solvent and triethylamine as base, com-
Table 3. Transfer hydrogenation of nitro-substituted aromatic compounds and benzyl ethers (yields refer to purified products)[20]
[a]
[b]
For the regeneration procedure see Table 2. Isolated yields after flash column chromatography.
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tion of alkyne 26 with only negligible traces (Ͻ 9%) of
homo-coupling product, as judged by GC-MS analysis
(Scheme 3).[25]
Finally, we studied the SuzukiϪMiyaura reaction, which
has become one of the most versatile and important reac-
tions for the construction of CϪC bonds.[26] Again, the
Pd0-doped reactor proved to be well suited for the coupling
of 4-iodoacetophenone (Table 4; Entries 2 and 4) and other
aryl halides (Table 4; Entries 1, 3 and 5) with arylboronic
acids to yield the corresponding biaryl compounds 2, 3 and
28 within 3 h without formation of homocoupling by-prod-
ucts. After collecting the reaction solution, aqueous workup
is necessary in order to remove the base and residual bo-
ronate. However, soluble palladium(0) catalysts like
Pd(PPh3)4 often require complex chromatographic purifi-
cation due to the phosphane ligands present in the reaction
mixture (vide supra).
Therefore, we have combined the concept of immobilis-
ation of boronic acid as boronate (see Scheme 1) with the
catalytic activity of specifically located Pd nanoparticles
(see Scheme 2) by exchanging the chloride anions in resin
14 by hydroxide anions (Table 5). The resulting bifunc-
tionalised monolith 29, which is located inside the reactor,
shows good activity in the SuzukiϪMiyaura reaction. The
crude products contained traces of starting materials (En-
tries 1 and 2) or small amounts of homocoupled dimers
(Entry 6).
Scheme 3. Ligand-free palladium-catalysed Heck and Sonogashira
reactions in the PASSflow reactor (yields refer to purified products;
TBAA ϭ tetrabutylammonium acetate; NMP ϭ N-methylpyrrolid-
inone)
plete transformation was achieved at 110 °C within 30 min
affording isobutyl ester 27 (see Exp. Sect.). The material
was reused directly several times for the same transform-
ation after washing of the material with DMF after each
run. After 3 h, the amount of transformation was deter-
mined as: 92% (2nd run), 90% (3rd run), 90% (4th run),
88% (5th run), 84% (6th run) and 71% (7th run), irrespec-
tive of whether the material was reloaded with chloride ions
in between each run.
The Sonogashira reaction offers a convenient access to
substituted alkynes.[23] The reactions are usually conducted
in polar solvents like NMP or DMF employing a palladium
catalyst and copper iodide as co-catalyst. This co-catalyst is
insoluble under these conditions and may block the irregu-
lar microchannels within the reactor. Therefore, we chose
[24]
´
to adapt Najera’s homogeneous copper-free conditions,
Conclusions
which are based on a palladacarbacycle as catalyst, tetrabu-
tylammonium acetate (TBAA) as base and NMP as sol-
In summary, we have developed a new palladium(0)-
vent. Using the palladium(0) particles, the Sonogashira re- loaded microreactor that can be used in continuous-flow
action of phenylacetylene and 4-iodoacetophenone led to mode, providing a range of advantages. Since the catalyst is
complete consumption of the starting material and forma- present in high concentration while the substrates passes
Table 4. Ligand-free palladium-catalysed SuzukiϪMiyaura reactions in the PASSflow reactor
[a]
[b]
[c]
KOH, H2O, DMF, 100 °C.
Isolated yields after flash column chromatography (yield of transformation in parentheses). For the
regeneration procedure see Table 2.
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Table 5. SuzukiϪMiyaura cross-coupling reaction under continuous-flow conditions (method A)[a,b]
[a]
[b]
Isolated yields after flash column chromatography.
water.
The reactor was regenerated by washing with ethanol, water, 1  NaOH and
through the microreactor, the reactions can rapidly be for- Experimental Section
ced to completion. The catalyst facilitates its separation
from the reaction mixture, is reusable more than 20 times General: NMR spectra were recorded with a Bruker DPX-400 spec-
trometer at 400 MHz (1H NMR) and at 100 MHz (13C NMR)
after simple washing, and it is easy to store. We have dem-
using CDCl3 and [D6]DMSO both as solvents and internal stand-
onstrated its application in transfer-hydrogenation reactions
1
ards (δ ϭ 7.26 ppm and 2.50 ppm, respectively, for H NMR and
using various transfer reagents, thereby circumventing the
need for molecular hydrogen. The palladium(0)-doped mic-
roreactor also revealed high performance in three types of
CϪC cross-coupling reactions. This is one of very few ex-
amples which allows recovery and reuse of the catalytically
active dispersed palladium without substantial loss of ac-
tivity. It is important to note that this continuous-flow ap-
δ ϭ 77.16 ppm and 39.52 ppm, respectively, for 13C NMR). Mass
spectra (EI) were obtained at 70 eV with a type VG autospec appar-
atus (Micromass). GC analyses were conducted using an HPGC
series 6890 Series Hewlett Packard equipped with an SE-54 capillar
column (25 m, MachereyϪNagel) and an FID detector 19231 D/
E. IR spectra were recorded with a Bruker FT-IR Vector 22 appar-
atus. Melting points were determined in open glass capillaries with
proach offers great potential for industrial applications, es- a Gallenkamp apparatus and are uncorrected. Analytical thin-layer
chromatography was performed using precoated silica gel 60 F254
plates (Merck, Darmstadt), and the spots were visualised with UV
light at 254 nm. Merck silica gel 60 (230Ϫ400 mesh) was used for
flash column chromatography. Tetrahydrofuran was distilled from
sodium/benzophenone ketyl. Commercially available reagents and
dry solvents (toluene, dimethylformamide) were used as received.
The reported compounds 4-acetyl-1,1Ј-biphenyl (2),[28] 4-acetyl-4Ј-
methyl-1,1Ј-biphenyl (3),[29] 4-methoxy-1,1Ј-biphenyl (4),[29] 4-
methoxy-3Ј-(trifluoromethyl)-1,1Ј-biphenyl (5),[29] 4-methoxy-4Ј-
methyl-1,1Ј-biphenyl (6),[30] 3-nitro-1,1Ј-biphenyl (7),[31] 3-nitro-3Ј-
(trifluoromethyl)-1,1Ј-biphenyl (8),[29] 4-acetamido-4Ј-methyl-1,1Ј-
pecially with respect to rapid scaleup from laboratory scale
to the process plant without the need for substantial op-
timisation. Indeed, the transfer hydrogenation could be
scaled-up to 2 mol [reduction of nitrobenzene using the
transfer reagent cyclohexene; Pd0 (5 mmol)] without alter-
ing the conditions found for the millimol-scale hydrogen-
ation. For this purpose, a continuous-flow apparatus typical
in process engineering was constructed at the Institut für
Chemische Verfahrenstechnik (Technische Universität
Clausthal).[27]
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biphenyl (9),[29] (E)-1-(4-methoxyphenyl)-2-phenylethene (10),[32] (30 mL; 3 mL/min flow rate), an aqueous solution of NaBH4 (0.2
4Ј-methyl-3-nitro-1,1Ј-biphenyl (28),[33] 4-acetyl-4Ј-methoxy-1,1Ј- , 50 mL) was pumped through the reactor (1 mL/min), followed
biphenyl (30),[34] p-(2-thienyl)anisole (31),[35] p-(2-thienyl)aceto-
by water (30 mL; 3 mL/min flow rate), HCl (1 , 10 mL; 3 mL/
phenone (32)[36] (see Scheme 1 and Tables 1, 4, and 5), 4-(2,6,6- min flow rate), water (30 mL; 3 mL/min) and finally EtOH (20 mL)
trimethylcyclohex-2-enyl)-butan-2-one (15),[37] ethyl 3-phenylpropi-
onate (16),[38] 2-acetoxybicyclo[2.2.1]heptane (17),[39] p-menthan-4-
which regenerated the chloride form on the resin. A total loading
of 0.24 mmol of palladium was determined. This standardised reac-
ol (18),[40] 1-ethylcyclohexanol (19),[41] 4-(4-aminobenzyl)pyridine tor was used in all the following transformations.
(22),[42] N-(4-aminophenyl)acetamide (21),[43] methyl 2-deoxy-α--
General Procedure for the Transfer Hydrogenation of Alkenes Using
Microreactor 14
rhamnopyranoside (24),[44] commercially available aniline and p-
hydroxyacetophenone (see Tables 2 and 3), n-butyl trans-4-acetyl-
cinnamate (25),[45] 1-(4-acetylphenyl)-2-phenylethyne (26)[46] (see
Scheme 3) isobutyl 4-methoxycinnamate (27)[47] have been de-
scribed previously and were identified by comparison of their
physical and spectroscopic data (1H and 13C NMR, IR, MS) with
those in the cited references; their purities were confirmed by GC
analyses. All reactions were carried out in a continuous-flow appar-
atus from Chelona GmbH, Potsdam. All reaction temperatures in
this report refer to oven temperatures. As the reaction mixture is
pumped as a convective flow through the reactor it never reaches
the oven temperature. When the reaction mixture leaves the column
it is about 10 to 15 °C below the oven temperature.
1. 1,4-Cyclohexadiene as Transfer Agent: Just before starting the
reaction, the column 14 (prepared as described above) was rinsed
with THF (15 mL). A solution of the starting material (1 mmol)
and 1,4-cyclohexadiene (190 µL, 160 mg, 2 mmol) in THF (7 mL)
was circulated (2 mL/min) through the microreactor at 60 °C for
48 h. The microreactor was washed with THF (20 mL) and the
combined organic solutions were concentrated under vacuum to
yield the pure products. For regenerating the reactor into the chlo-
ride form, it was washed with ethanol (20 mL), water (20 mL), aq.
NaOH (15 mL), water (20 mL), HCl (1 , 25 mL) and finally
water (40 mL).
General Procedure for the Suzuki؊Miyaura Cross-Coupling Reac-
tion using Pre-Immobilised Boronic Acid (Method A; Table 1): The
PASSflow reactor (anion exchange; chloride form) was washed suc-
cessively with NaOH (1 , 60 mL), water (until the eluate reached
pH ϭ 7), methanol (15 mL), and anhydrous THF (15 mL). Then,
a solution of 4-methylbenzeneboronic acid (544 mg, 4 mmol) in an-
hydrous THF (20 mL) was pumped through the reactor followed
by anhydrous THF (30 mL). After this procedure, a degassed solu-
tion of 4-bromoacetophenone (25.8 mg, 0.129 mmol) and tetrakis-
(triphenylphosphane)palladium(0) (7.0 mg, 6 µmol) in anhydrous
THF (3 mL) was allowed to circulate through the reactor (2.5 mL/
min) at 60 °C (external thermostat) under nitrogen. After com-
pletion of the reaction (4.5 h, GC monitoring), the reactor system
was rinsed with anhydrous THF (10 mL) and methanol (10 mL).
The combined organic extracts were concentrated in vacuo to yield
a white solid. Flash chromatography on silica gel (cyclohexane/
ethyl acetate, 95:5) afforded pure 4-acetyl-4Ј-methyl-1,1Ј-biphenyl
(3; 23 mg, 0.109 mmol; 85%) as a white solid; m.p. 118Ϫ119 °C
(ref.[29] 118Ϫ120 °C).
2. Lithium Formate as Transfer Agent: The starting material
(1 mmol) in ethanol (10 mL) was added to lithium formate
monohydrate (210 mg, 3 mmol), dissolved in water (3 mL). The re-
sulting solution was circulated through the column 14 (chloride
form, previously rinsed with ethanol) at 120 °C for 3 h. For product
isolation, the column was washed with ethanol (10 mL) and the
combined solutions were concentrated almost to dryness. The
product was dissolved in hexane, sodium sulfate was added to re-
move residual water, and the solution was filtered. Evaporation of
the solvents yielded the pure products.
3. Cyclohexene as Transfer Agent: Just before the reaction was in-
itiated, the reactor column 14 (chloride form, previously rinsed
with ethanol) was rinsed with cyclohexene (10 mL). A solution of
the starting material (1 mmol) in cyclohexene (10 mL) was circu-
lated (3 mL/min) at 70 °C for 24 h. For product isolation, the mic-
roreactor was washed with EtOH (20 mL) and the combined or-
ganic solutions were concentrated under vacuum to yield the prod-
ucts.
General Procedure for the Suzuki؊Miyaura Cross-Coupling Reac-
tion without Preliminary Immobilisation of the Boronic Acid in the
Reactor (Method B; Scheme 1): The PASSflow reactor (hydroxide
form) was washed successively with methanol (15 mL) and anhy-
drous THF (30 mL). Then, a degassed solution of 4-methylben-
zeneboronic acid (26.3 mg, 0.193 mmol), 4-iodoanisole (30.2 mg,
4. Triethylammonium Formate as Transfer Agent: The starting ma-
terial (1 mmol) was dissolved in formic acid (5 mL) and ethanol
(5 mL). Triethylamine (10 mL) was slowly added, and the mixture
was circulated through the reactor column 14 (chloride form, pre-
viously rinsed with ethanol) at 100 °C. The reactor column was
rinsed with ethanol (20 mL). The combined organic solutions were
subjected to aqueous workup and evaporation of the solvent
yielded the pure product.
0.129 mmol),
and
tetrakis(triphenylphosphane)palladium(0)
(2.9 mg, 2.5 µmol) in anhydrous THF (3 mL) was pumped through
the reactor (2.5 mL/min) in a cycle mode under nitrogen, the reac-
tor being heated at 60 °C. After complete conversion of the aryl
iodide (1 h, GC monitoring), the reactor was rinsed with anhydrous
THF (10 mL) and methanol (10 mL). The combined organic mix-
tures were concentrated in vacuo to yield a white solid. Flash chro-
matography on silica gel (cyclohexane/ethyl acetate, 98.5:1.5) af-
forded pure 4-methoxy-4Ј-methyl-1,1Ј-biphenyl (6; 22 mg,
0.111 mmol; 86%) as a white solid; m.p. 107Ϫ108 °C (ref.[30] 108
°C).
5. Hydrazine as Transfer Agent: The starting material (1 mmol) was
dissolved in methanol (10 mL). Hydrazine (3 mmol) was added,
and the solution was passed through the reactor column 14 (chlo-
ride form, previously rinsed with methanol) at 40 °C (oven temp.).
Evaporation of the solvent gave the pure products.
General Procedure for the Heck Reaction in the PASSflow Mode
Using Microreactor 14: The microreactor (chloride form) was
washed with THF (20 mL) and NMP (10 mL). A solution of 4-
iodoacetophenone (246 mg, 1 mmol), n-butyl acrylate (192 mg,
Preparation of the Palladium-Loaded Microreactor 14: Sodium
tetrachloropalladate (348 mg, 1 mmol) in water (100 mL) was 1.5 mmol) and NEt3 (0.2 mL, 1.4 mmol) in NMP (10 mL) was
pumped (0.5 mL/min flow rate) through the reactor (chloride form, pumped through the microreactor 14 at 130 °C (oven temperature).
maximum capacity 0.4 mmol). This step was repeated once again After completion of the reaction (2.5 h), the microreactor was
with the recycled solution. After rinsing the column with water rinsed with NMP (10 mL) and dichloromethane (10 mL). The com-
3608
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3601Ϫ3610

Continuous-Flow System for Catalysis with Palladium(0) Particles
FULL PAPER
Solodenko, T. Frenzel, A. Kirschning, in Polymeric Materials
bined organic mixtures were diluted with hexane, washed with
water, dried with Na2SO4 and concentrated in vacuo to yield the
pure product 25 (192 mg, 0.78 mmol; 78%). For regeneration, the
microreactor was washed with ethanol (20 mL). In case of deacti-
vation of the catalyst, the microreactor can be washed with ethanol
(20 mL), water (20 mL), NaOH aq. (15 mL), water (20 mL), HCl
(1 , 20 mL) and finally water (20 mL). The reactor is then ready
to be reloaded with palladate as described above.
in Organic Synthesis and Catalysis (Ed.: M. R. Buchmeiser),
[2b]
Wiley-VCH, Weinheim, 2003, pp. 201Ϫ240.
Recoverable
Catalysts and Reagents (Guest Ed.: J. A. Gladysz), Chem. Rev.
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Int. Ed. 1999, 38, 2476Ϫ2514.
E. Lindner, T. Schneller, F.
General Procedure for the Sonogashira Reaction in the PASSflow
Mode Using Microreactor 14: The microreactor 14 (chloride form)
was washed with methanol (20 mL) and NMP (20 mL). A solution
of 4-iodoacetophenone (492 mg, 2 mmol), tetrabutylammonium
acetate (1.2 g, 4 mmol) and phenylacetylene (308 mg, 3 mmol) in
NMP (14 mL) was circulated through the microreactor 14 (3 mL/
min) at 110 °C (oven temperature). After completion of the reac-
tion, the microreactor was rinsed with NMP (10 mL) and dichloro-
methane (10 mL). The combined organic mixtures were diluted
with hexane, washed with water, dried with Na2SO4 and concen-
trated in vacuo to yield the pure product 26 (356 mg, 1.62 mmol;
81%). Regeneration was conducted as described above.
Auer, H. A. Mayer, Angew. Chem. 1999, 111, 2288Ϫ2309; An-
gew. Chem. Int. Ed. 1999, 38, 2154Ϫ2174.
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Unfortunately, we were unable to obtain a transition electron
microscopy (TEM) view of the composite material due to the
glass — it was impossible to obtain appropriately cut samples.
Comparing the reactivity pattern of our particles with known
Pd nanoparticles it can be assumed that the size should be
smaller than 10 nm. For a short but comprehensive survey on
the use of metal nanoparticles in carbonϪcarbon bond-
forming reactions and leading references regarding formation
and size of nanoparticles see: M. M. Moreno-Man˜as, R.
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General Procedure for the Suzuki؊Miyaura Reaction in the
PASSflow Mode Using Microreactor 14: 4-Iodoacetophenone
(246 mg, 1 mmol), phenylboronic acid (151 mg, 1.2 mmol) and
aqueous potassium hydroxide (0.5 , 1 mL) were dissolved in DMF
(10 mL). The resulting homogeneous solution was circulated
through the reactor column 14 (3 mL/min) at 100 °C (oven temp.)
for 3 h. Aqueous workup and column chromatography afforded the
pure product 2 (151 mg, 0.77 mmol; 77%).
[5]
[6]
General Procedure for the Suzuki؊Miyaura Reaction Using Bifunc-
tionalised Solid Phase 29: The microreactor loaded with palladium
particles (14; chloride form) was transformed into the hydroxide
form as described above (SuzukiϪMiyaura reaction; Table 1,
method A). The microreactor 29 obtained was washed with DMF
(20 mL). Then, a solution of organoboronic acid (0.24 mmol) and
aryl iodide (0.2 mmol) in a mixture of DMF and water (10:1; 11
mL) was circulated through the microreactor at 120 °C (oven tem-
perature). The microreactor was washed with DMF (20 mL), the
combined organic phases were diluted with water (40 mL) and ex-
tracted with cyclohexane (3 ϫ 20 mL). The combined organic
phases were washed with an aqueous solution of saturated NaCl,
dried (Na2SO4) and concentrated in vacuo. The microreactor was
regenerated by the washing procedure ethanol (20 mL), water
(20 mL), aqueous NaOH (1 , 50 mL) and water (30 mL).
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3610
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www.eurjoc.org
Eur. J. Org. Chem. 2004, 3601Ϫ3610