Cu-based nanoalloys in the base-free ullmann heterocyle-aryl ether synthesis

Article abstract of DOI:10.1021/op9003423

We report the first liquid-liquid Ullmann etherification process mediated not only by oxidatively stable Cu but also by CuZn and CuSn nanoparticle catalysts in conjunction with microwave heating that also avoids the use of solid and expensive bases. Condi

Full text of DOI:10.1021/op9003423

Organic Process Research & Development 2010, 14, 644–649
Cu-Based Nanoalloys in the Base-Free Ullmann Heterocyle-Aryl Ether Synthesis
Volker Engels,†,§ Faysal Benaskar,‡,§ Narendra Patil,‡ Evgeny V. Rebrov,‡ Volker Hessel,‡ Lumbertus A. Hulshof,⊥
David A. Jefferson,† Jef A. J. M. Vekemans,⊥ Saurabh Karwal,‡ Jaap C. Schouten,*,‡ and Andrew E. H. Wheatley*,†
Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K., Laboratory of Chemical
Reactor Engineering, EindhoVen UniVersity of Technology, P.O. Box 513, 5600 MB, EindhoVen, The Netherlands, and Applied
Organic Chemistry, EindhoVen UniVersity of Technology, P.O. Box 513, 5600 MB, EindhoVen, The Netherlands
Abstract:
influencing catalyst performance has been achieved. Solvents
typically employed in these reactions possess strong polar
moments. As a result of the work of Strauss,16 the industrially
important solvent DMA has attracted particular attention by
virtue of its ability to enhance yields through improved catalyst
solubility and decreased energy consumption through selective
heating effects when deployed in tandem with microwave
heating.17-19 Hence, the single-mode microwave-assisted syn-
thesis of phenoxypyridines using chloroheterocycles in conjunc-
tion with activated phenols has resulted in higher product yields
than were achievable with conventional heating. However, in
common with other applications of single-mode microwave-
assisted reactions, this setup suffered from the drawback that
reactions could only be conducted on a small scale.20 More
recently, efforts have been made to circumvent these limitations
of scale in batch-type reactions and also to avoid difficulties
associated with the reliable monitoring of reaction temperatures
under single-mode microwave irradiation, by deploying mul-
timode microwave apparatus in the synthesis of 4-phenoxypy-
ridine.21
We report the first liquid-liquid Ullmann etherification process
mediated not only by oxidatively stable Cu but also by CuZn and
CuSn nanoparticle catalysts in conjunction with microwave heat-
ing that also avoids the use of solid and expensive bases. Conditions
have led to improved turnovers and excellent yields in heteroaro-
matic Ullmann-type coupling reactions. Further enhancement is
achieved upon the addition of 18-crown-6 as a kinetic promoter.
Introduction
Despite being introduced more than 100 years ago,1-3
Ullmann-type aryl ether syntheses remain an essential tool for
industrial-scale fine chemical synthesis4-6 and have recently
been the subject of review.7,8 Commensurate with their impor-
tance, research efforts have been directed towards tailoring
homogeneous catalysts of copper9-11 and palladium,12-15 and
in this context a better understanding of the ligand effects
* To whom correspondence should be addressed: Telephone: +44 (0)1223
763122. Fax: +44 (0)1223 336362. E-mail: aehw2@cam.ac.uk.
† University of Cambridge.
Whilst the deployment of copper-based molecular catalysts
in organic synthesis is not new, the employment of nanopar-
‡ Laboratory of Chemical Reactor Engineering, Eindhoven University of
Technology.
⊥ Applied Organic Chemistry, Eindhoven University of Technology.
§ These authors contributed equivalently to the work.
(12) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.;
Buchwald, S. L. Novel electron-rich bulky phosphine ligands facilitate
the palladium-catalyzed preparation of diaryl ethers. J. Am. Chem.
Soc. 1999, 121 (18), 4369–4378.
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V.; Hulshof, L. A.; Jefferson, D. A.; Schouten, J. C.; Wheatley,
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10.1021/op9003423  2010 American Chemical Society
Published on Web 03/11/2010

ticulate copper represents a much more recent research trend.
Exploitable methods exist for the fabrication of Cu(0),22-25 CuO
and Cu2O nanomaterials,26,27 and applications have been
reported in “click” chemistry (in both stirred batch reactor and
supported modes)28 and Suzuki29 and Sonogashira30 coupling
reactions. Other applications exist in fine chemical synthesis,
for example, in the fields of arene-sulfur bond formation in
the synthesis of thiophenols (by Cu(0)), and aryl dithiocarbam-
ates, and also in the asymmetric hydrosilylation of ketones (by
CuO).10,31 Further tests have demonstrated the potential of Cu
nanoparticles in the reduction of carbonyl compounds and
imines, where they achieved yields comparable to those noted
using more toxic nickel catalysts.32 Increases in Fermi potential
resulting from particle sizes being in the nanoregime have been
invoked to explain the promotion of reactions proceeding, for
instance, via radical pathways (e.g., coupling aryl halides and
thiophenols).31
effects between the metals,37,38 with the presumed formation
of reactive CuZn proceeding by highly dynamic behavior of
the corresponding alloy phases.39 In spite of the potential
of these systems, bottom-up approaches for the synthesis of
CuZn(O) nanocatalysts remain little explored,40 with a wet-
chemical process for colloidal CuZn nanoparticles having been
reported in 2003.39 This development notwithstanding, the
thermodynamic instability of organozinc reagents has presented
obstacles to the precise control of stoichiometry in CuZn
systems.37,38 In a similar vein, few reports exist detailing
preparations, via chemical reduction, of CuSn nanoparticles.41-43
While Calò et al. have demonstrated the efficiency of bronze
alloys as catalysts in the Heck reaction of aryl iodides and
activated aryl bromides,44 Saito and Koizumi reported the use
of CuSn in the Ullmann-type synthesis of aromatic nitro
compounds.45 In this latter case, yields of up to 91% were
achieved in 3 h. However, as with CuZn, CuSn alloy phases
have previously exhibited instability, and this has been seen as
being responsible for the leaching of Cu during catalytic tests.44
Cu nanocatalysts have previously been deployed in
etherification, although this required the use of both
expensive and chemically unstable aryl iodide substrates.46
More recently, practical limitations associated with the
oxidative instability of Cu nanoparticles47 have been
overcome by utilizing the stabilizing properties of anti-
agglomerants used during the reduction-by-solvent of
Cu(OAc)2 to Cu(0). The resulting nano-Cu exhibited long-
term oxidative stability and was employed in the micro-
wave-assisted Ullmann-type ether synthesis of 4-phenox-
ypyridine from stable chloropyridine salts and unactivated
phenol.21 For this type of Ullmann reaction, oxidatively
stable nano-Cu was shown to be more efficient than
homogeneous Cu(I) and Cu(II) catalysts, giving superior
yields in significantly less time than was previously
The potential for synergic effects between metals has led to
investigation of the activity of bimetallic nanoparticles in
catalysis.33-36 Hence, ZnO-supported copper has already es-
tablished itself as a catalyst system in such industrial methanol
syntheses as the Haldor-Topsøe process, and considerable
effort has been directed towards the elucidation of cooperative
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in click chemistry: an alternative catalytic system for the cycloaddition
of terminal alkynes and azides. Tetrahedron Lett. 2009, 50 (20), 2358–
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Regioselective synthesis of [1,2,3]-triazoles catalyzed by Cu(I) gener-
ated in situ from Cu(0) nanosize activated powder and amine
hydrochloride salts. Tetrahedron Lett. 2005, 46 (16), 2911–2914.
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required for comparable systems.48 We now report the
extension of these initial studies to the bimetallic nano-
copper systems CuZn and CuSn, demonstrating the
potential of bimetallic nanocatalysts for further and sig-
nificant increases in turnover frequency. Moreover, with
the aim of fabricating a continuously operating reactor, it
is necessary to avoid the in situ use or generation of solid
substrates or byproducts that could otherwise limit process
intensification due to process operation failure (e.g., by
clogging pipework). Continuous processing is a convenient
method for up-scaling, albeit thus far mainly applied in
bulk chemical synthesis and far less in fine chemical
production. Nevertheless upon up-scaling, continuously
operated systems are economically favorable if byproduct
formation and reaction times are minimized through
chemistry optimization. We have, therefore, sought to
enhance the mass transfer properties of the system by
obviating the use of a cesium carbonate base for phenol
activation49,50 and by kinetically promoting etherification.
We now report liquid-liquid-type Ullmann etherification
using copper-based bimetallic nanoparticle catalysts.
coated Ni grids and were examined using a JEOL JEM-
3011 high-resolution transmission electron microscope at
nominal magnifications in the range 300,000-800,000.
The exact magnification was previously characterized
using images of lattice fringes in large (>10 nm) colloidal
gold particles. Electron optical parameters CS ) 0.6 mm,
CC ) 1.2 mm, electron energy spread ) 1.5 eV, beam
divergence semiangle ) 1 mrad were used. Mean particle
sizes were calculated by counting the diameters of 100
randomly chosen particles in lower magnification images.
Data processing and calculation of standard deviation used
Origin Pro. 8.0. Elemental composition was elucidated by
energy dispersive X-ray emission spectroscopy (nominal
beam width ) 4 nm) using a Princeton Gamma-Tech
prism Si/Li detector and an Avalon 2000 analytical system.
Synthesis and Characterization of 4-Phenoxypyridine. A
baffled glass reactor was loaded with DMA (15 mL) and
4-chloropyridine (6 mmol, equating to 0.4 mol dm-3), pheno-
l(ate) (9 mmol, equating to 0.6 mol dm-3), and 18-crown-6
(∼0.01 equiv with respect to phenolate) as appropriate, were
added. The mixture was stirred at 45 °C until complete
dissolution occurred. The solution was treated with an appropri-
ate amount of catalyst (1.5 mol % with respect to 4-chloropy-
ridine). The resulting slurry was heated in a microwave device
(Milestones Multimode Microwave, type ETHOS 2450 MHz,
2.5 kW) (130-140 °C for 120 min.). Bulk temperatures during
the reaction were measured using a fibre-optic probe and an
infrared sensor. All reactions were carried out under argon. The
yield of 4-phenoxypyridine was determined by measuring the
1H NMR spectra of reaction aliquots against unreacted material.
Experimental Section
Nanoparticle Synthesis and Characterization. Monome-
tallic Cu(0) nanoparticles were prepared by a literature
route.21 For bimetallic colloids, copper(II) sulfate pen-
tahydrate (0.250 g, 1 mmol) and 0.8 g of poly(N-
vinylpyrrolidone) (PVP, M(average) ) 24000) were added
to 120 mL of anhydrous ethylene glycol in a two-necked
round-bottom flask. The resulting mixture was heated to
80 °C and stirred for 2 h. The resulting blue solution was
cooled to 0 °C. Solutions of zinc(II) chloride (0.136 g, 1
mmol) or tin(II) chloride (0.261 g, 1 mmol) in 2 mL of
water (LC-MS grade, resistivity 18.2 MΩ · cm at 25 °C;
purified by a Millipore purification system with a com-
bined Jetpore ion-exchange resin, activated carbon and
UV irradiation at 185 and 254 nm), and a solution of
sodium hypophosphite monohydrate (0.213 g, 2 mmol)
in 5 mL of water (LC-MS grade) were added promptly.
After adjusting the pH value to 9-11 by adding 5 mL of
1 M NaOH (aq, LC-MS grade), the reaction was stirred
for 1 h at 120 °C to yield a yellowish-red colloidal
suspension. Aliquots were purified by extracting 50 mL
suspensions using excess acetone (∼250 mL). After
sedimentation of the particles overnight, ∼90% of the
supernatant was decanted and the remaining suspension
centrifuged for 5 min. Upon removal of the acetone layer,
the colloidal precipitate was resuspended in 50 mL of
DMA. Samples for electron microscopy were prepared by
droplet coating of DMA suspensions on carbon holey film-
1
The H NMR spectroscopic data were compared with the
literature, as were additional qualitative GC-MS measurements
(Shimadzu QP 5000, zebron column ZB35).
Results and Discussion
The preparation of oxidatively stable poly(N-vinylpyr-
rolidone) (PVP)-capped Cu nanoparticles from Cu(OAc)2
has been noted recently,21 and the adaptability of the
reported method is shown by the simplicity with which
heterometallic CuM colloids can be targeted. Accordingly,
a mixture of copper(II) sulfate pentahydrate and PVP in
ethylene glycol was treated with either zinc(II) chloride
or tin(II) chloride and thereafter with sodium hypophos-
phite monohydrate at 0 °C and the pH adjusted to 9-11.
A colloidal suspension resulted after 1 h at 120 °C (Figure
1). Using nanostructured Cu(0) and CuM (M ) Zn, Sn)
in the absence or presence of a crown ether (vide infra)
the etherification temperature can be lowered from 140
to 130 °C (Scheme 1) whilst recording yields of up to
90% after 2 h. At temperatures below 115 °C yields
decreased considerably, leading to 130 °C being taken as
the optimum operational temperature for these nanoalloys.
Data are given in Table 1.
(48) Son, S. U.; Park, I. K.; Park, J.; Hyeon, T. Synthesis of Cu2O coated
Cu nanoparticles and their successful applications to Ullmann-type
amination coupling reactions of aryl chlorides. Chem. Commun. 2004,
778–779.
Entries 1 and 2 reveal that, in spite of the higher
reaction temperature, the use of nano-Cu in conjunction
with phenol/Cs2CO3 gives an inferior turnover in com-
parison to that obtained when potassium phenolate is used
instead. Taken together with the need to avoid the
(49) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.; Taillefer, M.
A general and mild Ullmann-type synthesis of diaryl ethers. Org. Lett.
2004, 6, 913–916.
(50) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. A general copper-
catalyzed synthesis of diaryl ethers. J. Am. Chem. Soc. 1997, 119 (43),
10539–10540.
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Figure 1. CuZn and CuSn nanoparticles (left and right columns, respectively). Representative HRTEM images (a, b; ×800k,
respectively), EDS data (c, d; 4 nm beam, C, O, and Ni lines from carrier grid), particle size distributions (e, f; mean sizes 9.30 (
0.94 nm and 8.15 ( 0.88 nm, respectively).
Scheme 1. Ullmann ether synthesis of 4-phenoxypyridine with and without addition of 18-crown-6a
a Conditions: microwave heating, 130 °C, batch stirred at 1500 rpm.
generation of solid deposits (controlling solubility, mass
transfer, and ion-exchange mechanisms), this observation
led us to focus on base-free conditions. Since the role of
Cs2CO3 is to deprotonate the phenol, affording a naked
ion as a nucleophilic substituent in the subsequent SNAr
reaction, it follows that omission of the base requires the
deployment of an activated phenol. In this context, the
use of potassium phenolate led to an improvement in yield
from 63% (reached after 2 h, entry 1) to 75% (entry 2,
Figure 2a) at reduced temperature. Under the same
conditions, heterobimetallic nanocatalysts showed higher
conversions. Hence, 4-phenoxypyridine was formed in
82% yield using nano-CuSn and in 87% yield using nano-
CuZn (entries 4 and 6). Noting that equilibrium was
reached after 2 h (Figure 2a), we hypothesized that K+
deactivated the catalyst over time. This could occur
through complexation by the capping agent altering the
conformation of the polymer and rendering the catalyst
Vol. 14, No. 3, 2010 / Organic Process Research & Development
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647

Table 1. Cu(M)-catalyzed formation of 4-phenoxypyridine
entry
Cu-sourcea
particle size (nm)
additive
T (°C)
time (min)
yield (%)c
TOF (s-1
)
1b
2d
3d
4d
5d
6d
7d
Nano-Cu
9.6
9.6
9.6
8.2
8.2
9.3
9.3
Cs2CO3
-
140
130
130
130
130
130
130
120
120
120
120
120
120
120
63
75
85
82
87
87
90
0.02
0.04
0.05
0.11
0.12
0.10
0.06
Nano-Cu
Nano-Cu
18-crown-6
-
Nano-CuSn
Nano-CuSn
Nano-CuZn
Nano-CuZn
18-crown-6
-
18-crown-6
a 0.015 equiv with respect to 4-chloropyridine. b See ref 21. c By 1H NMR spectroscopy. d Potassium phenolate used as nucleophile.
This is consistent with our preliminary observations for both
bimetallic systems, which in contrast to monometallic copper,
rapidly lost their activity. It seems likely that in either case the
alloying metal undergoes sacrificial oxidation, with segregation
leading to the formation of a zinc/tin oxide shell, as has been
noted elsewhere for nanobrass.52 Detailed further studies that
seek to compare pre- and postreaction catalyst surface structures
by X-ray photoelectron spectroscopy (XPS) are currently
underway.
In conclusion, we have extended recent advances in
the field of microwave-assisted etherification with nano-
scopic Cu(0)21 to encompass the copper-based nanoalloys
CuSn and CuZn. This has allowed reductions in both
reaction time and temperature with respect to the use of
slurry-type Ullmann-type etherification reactions employ-
ing either commercial Cu(0) or stable Cu nanoparticles.21
Similarly, excellent selectivity was maintained while
improving on previously reported yields for the multimode
microwave-assisted synthesis of 4-phenoxypyridine. Tar-
geting the fabrication of continuous-flow operation as a
means of overcoming limits of scale traditionally associ-
ated with microwave-assisted transformations, we have
successfully eliminated Cs2CO3 without depleting ef-
ficiency. This step, whilst it introduces the need for using
metal phenolate reagents, avoids the use of an additive
that otherwise represents an additional cost and source of
processing difficulties. Notably, we have demonstrated
kinetic enhancement of the reaction through the application
of 18-crown-6 as an alkali metal scavenger. In addition,
only 1.5 mol % of nanostructured copper catalyst was
needed to obtain yields of up to 90%, whereas previous
experiments required the use of as much as 10 mol % of
commercial copper or copper-wires. We next aim to marry
this research with previous reports of the fabrication of
nanocatalyst-supporting fused silica capillary microreac-
tors53 and so develop the reusability of nano-CuM systems
in continuous-flow microreactors. To achieve this, we are
supporting CuM colloids on glass beads packed into fused
silica capillaries, with the beads providing both the extra
surface area required for efficient operation and promising
further amplification of the benefits of microwave heating
Figure 2. Conversion vs time in the absence (a) and presence
(b) of 18-crown-6.
surface inaccessible to substrate. Alternatively, it is
possible that KCl formed during the reaction could not
be retained in the solvent phase. To exclude these effects,
crown ether was added as a solubilizing agent for both
potassium phenolate and KCl. When nano-Cu was tested
in the presence of 18-crown-6 (0.01-0.014 equiv relative
to phenolate) as a kinetic promoter, the yield of 4-phe-
noxypyridine improved from 75% to 85% (entry 3 and
Figure 2b). Similar enhancements were noted for the use
of nano-CuSn (yield increased to 87%, entry 5) and nano-
CuZn (yield increased to 90%, entry 7). We attribute the
performance maximum noted for CuZn to a combination
of particle ligand-shell effects and intermetallic effects
stemming from interaction of the alloying metals. Hence,
the coordinative strength of the capping agent (which is
dependent on ligand characteristics and particle surface
structure) is known to influence substrate access through
variations in polymer density (e.g., for Pd colloids51).
However, whilst intermetallic effects may be important,
it should be noted that the alloy phase fluxionality
discussed in the Introduction is known to result in
segregation of the metals during the reaction, ultimately
causing catalyst deactivation.44
(52) Cokoja, M.; Parala, H.; Schro¨ter, M. K.; Birkner, A.; van den Berg,
M. W. E.; Klementiev, K. V.; Grunert, W.; Fischer, R. A. Nano-brass
colloids: synthesis by co-hydrogenolysis of [CpCu(PMe3)] with
[ZnCp*2] and investigation of the oxidation behaviour of R/ꢀ-CuZn
nanoparticles. J. Mater. Chem. 2006, 16 (25), 2420–2428.
(53) Rebrov, E. V.; Berenguer-Murcia, A.; Skelton, H. E.; Johnson, B. F. G.;
Wheatley, A. E. H.; Schouten, J. C. Capillary microreactors wall-
coated with mesoporous titania thin film catalyst supports. Lab Chip
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(51) Li, Y.; El-Sayed, M. A. The effect of stabilizers on the catalytic activity
and stability of Pd colloidal nanoparticles in the Suzuki reactions in
aqueous solution. J. Phys. Chem. B 2001, 105 (37), 8938–8943.
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through hotspot formation at the catalyst-decorated
surface.54-57 These studies are ongoing and will be
reported in due course.
(International Joint Project 2008/R4), DSM Research,
FrieslandCampina, IMM, LioniX, Milestone srl (Italy) and
the Technology Foundation STW (MEMFiCS GSPT-
07974) for financial support. Also, we acknowledge Jan
Meuldijk for scientific support.
Acknowledgment
We acknowledge the European Commission (NOE
EXCELL NMP3-CT-2005-515703), the Royal Society
(54) Buchelnikov, V. D.; Louzguine-Luzgin, D. V.; Xie, G.; Li, S.;
Yoshikawa, N.; Sato, M.; Anzulevich, A. P.; Bychkov, I. V.; Inoue,
A. Heating of metallic powders by microwaves: Experiment and
theory. J. Appl. Phys. 2008, 104, 113505.
Supporting Information Available
Details of catalytic tests, spectroscopic data, nano-CuM
synthesis, and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
(55) He, P.; Haswell, S. J.; Fletcher, P. D. I. Microwave heating of
heterogeneously catalysed Suzuki reactions in a micro reactor. Lab
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(56) Larhed, M.; Lindeberg, G.; Hallberg, A. Rapid microwave-assisted
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Received for review December 30, 2009.
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