Copper(0) in the Ullmann heterocycle-aryl ether synthesis of 4-phenoxypyridine using multimode microwave heating

Article abstract of DOI:10.1016/j.tetlet.2009.10.126

The action of nanoparticulate copper catalysts with a mean particle size of 10 nm in the Ullmann ether synthesis is reported using multimode microwave heating and employing stable chloropyridine salts and unactivated phenol, with stabilized copper nanopar

Full text of DOI:10.1016/j.tetlet.2009.10.126

Tetrahedron Letters 51 (2010) 248–251
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper(0) in the Ullmann heterocycle-aryl ether synthesis
of 4-phenoxypyridine using multimode microwave heating
Faysal Benaskar a, , Volker Engels , Narendra Patil , Evgeny V. Rebrov , Jan Meuldijk , Volker Hessel ,
b,
a
a
a
a
c
b
a,
b,
*
*
Lumbertus A. Hulshof , David A. Jefferson , Jaap. C. Schouten , Andrew E. H. Wheatley
Laboratory of Chemical Reactor Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Applied Organic Chemistry, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The action of nanoparticulate copper catalysts with a mean particle size of 10 nm in the Ullmann ether
synthesis is reported using multimode microwave heating and employing stable chloropyridine salts
and unactivated phenol, with stabilized copper nanoparticles outperforming other copper catalysts in
terms of stability and reusability.
Received 28 September 2009
Revised 19 October 2009
Accepted 28 October 2009
Available online 30 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ullmann synthesis
Copper nanoparticles
Microreactors
Microwave heating
Catalysis
The Ullmann ether synthesis has been a topic of intense interest
since it was first reported by Ullmann and Goldberg in 1905, with
While it has been used as a catalyst in organic synthesis at the
molecular level for many decades, nanoparticulate copper has only
recently been deployed. This represents part of a recent research
trend towards the use of nanoparticles in process intensification.
1
many Ullmann reaction products acting as precursors for fine
chemicals and pharmaceuticals.2 Many refinements have been
made, leading to a better understanding of the beneficial ligand ef-
In this context, exploitable methods now exist for the fabrication
3
4
3a
fects to be had by tailoring homogeneous copper and palladium
2
of the copper-based nanomaterials Cu(0), CuO and Cu O. These
catalysts. Moreover, solvent effects in the synthesis have been
intensively investigated by Cherng.5 Recently, the industrial
solvents DMF and DMA have attracted particular attention, being
have been tested in fine chemical syntheses, including C–H (N–
H) activation reactions in the quantitative preparation of propar-
gylamines, bis-(4-hydroxy-2-oxothiazolyl)methanes in ionic liq-
uids and the selective aza-Michael reaction of N-alkyl- and N-
arylpiperazines in the presence of aromatic amino or aliphatic hy-
6
successfully used in conjunction with microwave heating. These
solvents possess strong polar moments and so rapidly heat up when
microwaves are applied suggesting green chemical benefits
through enhanced yields and decreased energy consumption by
selective heating. Hence, for example, the single mode micro-
wave-assisted synthesis of phenoxypyridines using chlorohetero-
cycles has resulted in higher yields than those that could be
3
b
droxy groups. Proof-of-concept has been achieved for the use of
nanoparticulate Cu, with nano-Cu O-catalyzed Ullmann-type ami-
2
9
nation using aryl chlorides and very long reaction times, and
nano-Cu-catalyzed etherification using expensive aryl iodides10
described. Although this use of nanocatalysts offers new opportu-
nities in terms of economic and sustainable processes where
homogeneously catalyzed reactions suffer from major drawbacks
such as an inability to easily recover the catalyst, product contam-
ination and space-time yield limitations, the sensitivity of nanop-
articulate copper towards oxidation has previously limited
applications.
7
achieved with conventional heating, albeit on a small scale. These
heating effects can be amplified, allowing less harsh bulk tempera-
tures, when microwave-absorbing materials are used in conjunc-
tion with the catalyst, through hotspot formation at the solid
8
surface.
We report here what is, to the best of our knowledge, the first
use of nanoparticulate Cu in a microwave-assisted Ullmann ether
synthesis. We varied both the metal oxidation state and particle
size in combination with multimode microwave irradiation. The
use of microwave methods was shown to result in a near 20-fold
*
Corresponding authors. Tel.: +31 40 247 3088; fax: +31 40 244 6653 (J.C.S),
tel.: +44 1223 763122; fax: +44 1223 336362 (A.E.H.W.).
E-mail addresses: J.C.Schouten@tue.nl (J.C. Schouten), aehw2@cam.ac.uk
(
A.E.H. Wheatley).
These authors contributed equivalently.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.126

F. Benaskar et al. / Tetrahedron Letters 51 (2010) 248–251
249
increase in heating rate relative to that achievable using an oil bath
Fig. 1) and we compared catalyst effectiveness using both micro-
microwave set-up. The data are given in Table 1 (and more details
are supplied in the Supplementary data).
(
wave and oil bath heating in the synthesis of 4-phenoxypyridine
from chloropyridine salts and unactivated phenol (Scheme 1).
Rapid microwave heating can be attributed to the uniform vol-
umetric heating effect, which cannot be attained by surface heat-
ing using an oil bath. As a consequence, microwave heating
offers much higher efficiencies with respect to energy consump-
tion. From the heating profiles it was found that the initial energy
consumption for microwave heating was 14.1 kJ in 60 s, while for
an oil-bath this was 1.4 MJ in 20 min for the same reaction volume.
The use of copper nanocatalysts has been made possible by the
development of catalytically stable, zero-valent copper nanoparti-
cles that exhibit long-term oxidation stability. The results indicate
a reproducible route to the large-scale application of Ullmann-type
chemistry with previously unachievable yields and excellent
selectivity. Only after reaction times of more than 5 h could mass
spectrometry detect 1-(pyridin-4-yl)pyridin-4(1H)-one as a side-
product upon neutralization of the product solution. The results
also suggest large-scale reusability of the catalyst in a multimode
To prepare 4-phenoxypyridine, chloropyridine (6 mmol), phenol
(9 mmol), Cs CO (18 mmol) and DMA (15 ml) were stirred with
2 3
the corresponding amounts of catalyst (Table 1) in a baffled glass
reactor in an oil bath or in the microwave apparatus. Yields were
1
determined by H NMR spectroscopy and the bulk temperatures
during the reaction measured with a fibre optic probe and an infra-
1
1,12
red sensor (Fig. 1).
Metallic Cu and Cu(I) and Cu(II) chlorides
were obtained commercially, while Cu wire was fabricated
mechanically. Poly(N-vinylpyrrolidone) (PVP)-capped Cu nanopar-
ticles were made by treating a PVP/ethylene glycol mixture con-
taining Cu(OAc)
2
and sodium hypophosphite coreductant.
Purification of the crude suspension with acetone yielded particles
with a mean diameter of 9.6 ± 1.0 nm. These were characterized
using high-resolution transmission electron microscopy (HRTEM),
energy dispersive X-ray spectroscopy (EDS) and powder X-ray dif-
1
3
fractometry (PXRD, Fig. 2).
Entries 1–3 (Table 1) reveal that, for metallic Cu, decreasing the
particle size (by a factor of 25) enhances the yield of 4-phenoxy-
pyridine, underlining surface area/turnover relationships for heter-
ogeneous copper catalysts in solid-liquid-type reactions. However,
although the experiments were performed under an argon atmo-
sphere, the observation that the solid catalyst changed colour from
brown to green suggested copper oxidation in the case of
non-nanodimensional catalysts. Further, a trial to recover copper
by filtration and washing resulted in <30% recovery. In contrast,
nanoparticles sterically protected by PVP as a coordinative capping
agent proved very stable to oxidation (entries 4 and 5), giving excel-
lent yields of 4-phenoxypyridine after 240 min, with 72% catalyst
recovery. Importantly, the PVP coating on the surface provides
long-term stability not only against nanoparticle agglomeration,
but also against oxidation, and it is noteworthy that, after 30 days,
EDS and HRTEM confirmed no change in either particle size or oxi-
dation state. It has been previously noted that the use of N,O-chelat-
ing ligands, such as amides, exhibit a ‘promotional effect’ on Cu(I)
1
4
Figure 1. Heating profiles and set-up of microwave and oil bath experiments.
catalysts by inhibiting oxidation to Cu(II), with such effects also
Cu-source (0.1 eq.)
Cs CO (2 aeq.)
Cl
HO
O
2
3
+
N
DMA, Ar
Microwave 60-90 W
Oil-bath 120-140 ºC
N
HCl
1 eq.)
(
(1.5 eq.)
Scheme 1. The Ullmann ether synthesis of 4-phenoxypyridine.
Table 1
Cu-catalyzed formation of 4-phenoxypyridine
Entry
Cu-sourcea
Particle size (lm)
T (°C)
Heating methodb
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
Metallic Cu
Metallic Cu
Metallic Cu
Nano-Cuc
Nano-Cuc
Cu(I)Cl
75
45
3
120
120
120
140
140
120
120
120
120
140
140
140
140
MW
MW
MW
MW
MW
MW
MW
O.B.
O.B.
MW
MW
O.B.
O.B.
90
90
90
120
240
40
40
90
90
90
90
90
90
Trace
3
20
63
80
5
4
11
Trace
Trace
Trace
55
À3
9.6 Â 10
À3
9.6 Â 10
—
—
—
—
Cu(II)Cl
Cu(I)Cl
Cu(II)Cl
2
2
1
1
1
1
Cu-wire
Cu-wire
Cu-wire
Cu-wire
50
20
50
20
90
a
b
c
1
0 mol %.
Microwave (MW) or oil bath (O.B.).
Protected by poly(N-vinylpyrrolidone).

2
50
F. Benaskar et al. / Tetrahedron Letters 51 (2010) 248–251
tion, though it seems probable that the wires act as antennae
a
b
in the microwave field, carrying high electric loads. When dis-
charges occur, plasma temperatures destroy the wire surface giv-
ing carbide-coated copper due to solvent combustion. This
process is similar to the concept of electric discharge machining
(
EDM) by which method metals can be etched using electric
1
8
discharges.
In summary, nanoscopic Cu catalysts have been used to achieve
excellent selectivity in the microwave-assisted Ullmann ether syn-
thesis of 4-phenoxypyridine. This has been enabled using oxida-
tion-resistant nanoparticle catalysts stabilized by a protective
anti-agglomerant coating of PVP to deliver good-to-excellent yields
in 4 h. Studies are now focusing on the influence of PVP and other
capping agents on reaction rate and on the systematic variation of
nanoparticle size. Concurrently, we are supporting Cu nanoparti-
cles on glass beads packed into fused silica capillaries as micro-
wave-assisted continuous flow capillary microreactors in which
the beads provide the extra surface area required for efficient mic-
roreactor activity, and may also accelerate the reaction through
hotspot formation. Lastly, microwires have proved excellent cata-
lysts in oil bath-heated systems, and the methods for the synthesis
of protected nanowires for microwave applications are being
developed.
5
nm
10 nm
c
1000
d
Cu(111)
Ti Kα1
1
1
500
000
500
Cu(200)
5
00
0
C Kα1
O Kα1
Ti Kβ1
PVP
Cu(220)
Cu Kα2
Cu Kβ1
0
0
5
10
15
20 30 40 50 60 70 80
energy (keV)
2θ / º
Figure 2. Cu nanoparticles. (a, b) Representative HRTEM images, (c) EDS data (4 nm
beam width; C, O and Ti lines from carrier grid material), (d) PXRD data (see also
Supplementary data).
Acknowledgements
The authors would like to acknowledge the European Commis-
sion (NOE EXCELL NMP3-CT-2005-515703), the Royal Society
International Joint Project 2008/R4), DSM Research, Friesland-
Campina, IMM, LioniX, Milestone s.r.l. (Italy) and the Technology
Foundation STW (MEMFiCS GSPT-07974) for financial support.
Also, scientific support from Dr. Jef A. J. M. Vekemans as a co-super-
visor is gratefully acknowledged.
reported in studies on the stabilization of nanoparticulate Cu(0)
against cuprite formation.15 Thus, we believe that complex forma-
(
tion between heterogeneous, nanoscale Cu(0) and the keto-func-
tions in PVP stabilizes our nanocatalysts with respect to
oxidation. This is underlined by the observations of Gedanken,
who in the case of unprotected 50–70 nm particles noted rapid oxi-
1
6
dation to Cu(I) in the Ullmann coupling reaction of iodobenzene.
Furthermore, the synthesis of Cu O-coated Cu nanoparticles for Ull-
2
Supplementary data
mann-type chloroheterocyclic aromatic substitutions revealed
excellent catalytic performance of the uncapped particles, with
Supplementary data (synthetic and analytical procedures,
HRTEM, EDS, PXRD data, nanoparticle size distribution analysis)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.10.126.
the protecting oxide layer apparently preventing further oxida-
9
tion. Of course, the same protecting property of both Cu
2
O and
PVP has the drawback that it limits the accessibility of the catalyst
surface for the reagents, incurring a diffusion limited reaction rate.
2
Nevertheless, whereas for Cu O-coated catalysts, reaction times of
1
8 h were necessary for Ullmann-type substitutions, our PVP-
References and notes
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2
1
1. Cu wire was fabricated mechanically by specialized equipment providing an
accuracy of 3%. Uniform size distribution according to the suppliers’
specifications was subsequently confirmed by optical microscopy.
S C
colloidal gold. The electron optical parameters were C = 0.6 mm, C = 1.2 mm,
electron energy spread = 1.5 eV and beam divergence semi-angle = 1 mrad. The
mean particle size was calculated to be 9.6 ± 1.0 nm by counting the diameters
of 100 particles in the lower magnification images. Data processing/calculation
of standard deviation used Origin Pro. 8.0. Elemental composition was
elucidated by energy dispersive X-ray emission spectroscopy (EDS, nominal
beam width = 4 nm) using a PGT prism Si/Li detector and an Avalon 2000
analytical system. PXRD data were collected on a Roentgen PW3040/60 XPert
PRO powder X-ray diffractometer with a high resolution PW3373/00 Cu LFF
1
2. Synthesis and characterization of 4-phenoxypyridine:
chloropyridine (6 mmol), phenol (9 mmol), Cs CO (18 mmol) and DMA
15 ml) in a baffled glass reactor was treated with an appropriate amount of
catalyst and the resulting slurry was heated in either a circulating oil bath
Lauda Ecoline staredition 012, type E312, 2.3 kW) or a microwave (Milestones
Multimode Microwave, type ETHOS 2450 MHz, 2.5 kW) (120–140 °C for 40–
40 min). Bulk temperatures during the reaction were measured using a fibre
A
mixture of
2
3
(
(
2
optic probe and an infrared sensor. The yield of 4-phenoxypyridine was
(unmonochromated) tube at k = 1.5404 Å (Cu Ka). The powder sample was
1
determined by measuring the H NMR spectra of reaction aliquots against
prepared by solvent evaporation from the colloidal suspensions deposited on
the 0.5 mm deep ground area of a glass flatplate sample holder using a
microscope slide so that the powder sample was smooth, flat and flush with
the sample holder surface. The sample holder was inserted onto the sample
stage (PW3071/60 Bracket) such that the sample material was just free of the
reference plane of the sample stage.
1
unreacted material. The H NMR data were compared with those in the
literature and additional qualitative GC–MS measurements (Shimadzu QP
5
000, zebron column ZB35).
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mmol) and 0.8 g of poly(N-vinylpyrrolidone) (PVP, M(average) = 24000) were
1
1
added to anhydrous ethylene glycol (120 ml) in a two-necked round-bottomed
flask. The resulting mixture was heated to 80 °C and stirred for 2 h.
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of sodium hypophosphite monohydrate (0.213 g, 2 mmol) in
H
2
O
(5 ml,
millipore) was added promptly. After adjusting the pH value to 9–11 by
adding 5 ml of 1 M NaOH (aq, millipore), the reaction mixture was stirred for
1
h at 140 °C to yield a brownish-red colloidal suspension. Aliquots of
nanoparticle product were purified for analysis by extracting 50 ml
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