Direct C-H Arylation of Heteroarenes with Copper Impregnated on Magnetite as a Reusable Catalyst: Evidence for CuO Nanoparticle Catalysis in Solution

Article abstract of DOI:10.1021/acscatal.6b01288

A reusable copper-based catalyst system was employed for the direct arylation of electron-rich heteroarenes. Under mild and operationally simple reaction conditions good yields and selectivities were obtained using diaryliodonium salts as coupling partners. A combination of experimental methods including kinetic studies, filtration tests, and a series of analytical tools (TXRF, ICP-MS, SEM, XPS, TEM, EFTEM) provide evidence for catalytically active soluble nanoparticles formed from an amorphous heterogeneous precursor. Mechanistic studies hint at a redox-neutral process which promotes counterion dissociation from the diaryliodonium salt by a copper(II) oxide species.

Full text of DOI:10.1021/acscatal.6b01288

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Article
Direct C–H Arylation of Heteroarenes with Copper Impreg-nated on Magnetite
as a Reusable Catalyst: Evidence for CuO Nanoparticle Catalysis in Solution
Suhelen Vásquez-Céspedes, Kathryn Megan Chepiga, Nadja Möller, Andreas H. Schaefer, and Frank Glorius
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01288 • Publication Date (Web): 28 Jul 2016
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ACS Catalysis
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Direct C–H Arylation of Heteroarenes with Copper Impregnat-
ed on Magnetite as a Reusable Catalyst: Evidence for CuO
Nanoparticle Catalysis in Solution
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Suhelen Vásquez-Céspedes,† Kathryn M. Chepiga,† Nadja Möller,† Andreas H. Schäfer‡ and
Frank Glorius*†
†Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstrasse 40, 48149 Münster
(Germany)
‡Nano Analytics GmbH, Heisenberg Strasse 11, 48149 Münster (Germany)
ABSTRACT: A reusable copper-based catalyst system was employed for the direct arylation of electron-rich heteroarenes.
Under mild and operationally simple reaction conditions good yields and selectivities were obtained using diaryliodoni-
um salts as coupling partners. A combination of experimental methods including kinetic studies, filtration tests, and a
series of analytical tools (TXRF, ICP-MS, SEM, XPS, TEM, EFTEM) provide evidence for catalytically active soluble nano-
particles formed from an amorphous heterogeneous precursor. Mechanistic studies hint at a redox-neutral process which
promotes counterion dissociation from the diaryliodonium salt by a copper(II)oxide species.
KEYWORDS: reusable copper catalyst, direct C
ing-redeposition.
–
H arylation, electron-rich heteroarenes, nanoparticle catalysis, leach-
eroarenes has emerged in the field of photocatalysis.
However, these reactions require a large excess of starting
INTRODUCTION
The regioselective construction of aryl–aryl bonds is of
fundamental importance in organic synthesis and com-
pounds containing polyaryl moieties are ubiquitious in
natural products and pharmaceuticals.1 To accomplish
biaryl or heteroaryl–aryl bond formation, cross-coupling
methods have been developed and broadly employed over
the past century.2 Among them, the Ullmann,3 Stille,4
Suzuki5 and Kumada-Corriu6 couplings are some of the
most important and highly utilized methods. However,
the need for pre-functionalized starting materials com-
promises the efficiency of these processes as their synthe-
sis can be a significant challenge.7 Transition-metal-
catalyzed C–H activation is a powerful and efficient tool
for the modification of organic molecules8 and the direct
arylation (DA) of (hetero)arenes remains one of the most
useful methodologies in organic synthesis.9 Most catalytic
DA processes are conducted with late transition metals
such as rhodium, ruthenium, iridium and, most common-
ly, with palladium.9 The use of more abundant first-row
transition metals in DA catalysis is still limited.10 Direct
arylation with simple, abundant copper salts represents
an economically viable alternative to precious metal ca-
talysis and yet remains a challenge in industry and aca-
demia. From the pioneering work of Daugulis,11 Gaunt,12
You13 and more recently, Greaney,14 the use of homogene-
ous copper salts as precatalysts became relevant. The
need for coordinating ligands and/or bases, high catalyst
loadings and temperatures, however, hinder the practical
use of these methodologies (Scheme 1). A potential alter-
native which enables mild and direct arylation of het-
materials compromising their utility from an economic
standpoint.15
Scheme 1. Copper-catalyzed direct arylation of elec-
tron-rich heteroarenes
Along the same lines, transition-metal-free alternatives
are gaining relevance. These reactions, however, generally
involve the in situ formation of free radicals and thus
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display a limited functional group tolerance as well as
regioselectivity issues.16
and benzofuran. We observed mostly decomposition of
1
2
3
4
5
6
7
8
starting material after a low conversion (10-20 %) was
obtained. We speculated that the acid generated in situ
from the counterion of the iodonium salt promoted start-
ing material decomposition and thus tested different
supports that could neutralize the reaction media and
allow for the arylation reaction to take place. Moreover, a
support could also improve reusability. Due to the ease of
preparation, separation and high optical basicity,23 we
Heterogeneous catalysis has several potential advantages
over homogeneous catalysis. The reactions are usually
unaffected by air or moisture and the catalyst can be easi-
ly removed from the reaction mixture which enables its
reuse.17 Our group has recently contributed to the area of
heterogeneous C–H functionalization. Employing simple
Pd/C and Pd/Al2O3 catalyst systems, we developed the
direct C–H thiolation and arylation of electron-rich het-
erocycles and polyaromatics.18 However, the reaction
yields were highly variable depending on the commercial
catalyst source and these supported palladium-based
catalysts could not be easily recycled. Considering these
limitations in addition to the need for the development of
synthetic methodologies using recyclable, sustainable and
abundant metal catalysts, we decided to explore hetero-
geneous copper sources as potential alternatives.
Heterogeneous copper catalysts are recognized for their
applications in oxidation, click chemistry and Ullmann
and Goldberg coupling reactions.19 Their use in C–H func-
tionalization, however, is much less developed and com-
prehensive studies on the active catalytic species of cop-
per-based systems has only recently started to be ex-
plored.20 For example, Corma and co-workers reported on
the elucidation of clusters as active catalytic species in
“homogeneous” copper-catalyzed cross-coupling reac-
tions.21 However, to the best of our knowledge, similar
studies targeting elucidation of active catalytic species on
solid or supported copper-catalysts, in the area of direct
C–H functionalization, have yet to be described.
Herein, we report a reusable magnetic copper-based cata-
lyst for the regioselective direct arylation of a variety of
electron-rich heteroarenes with diaryliodonium salts
(Scheme 1).22 These reactions proceed in good yields un-
der mild, operationally simple conditions. Moreover, a
combination of experimental methods including kinetic
studies, mass spectrometry, filtration tests, transmission
electron microscopy (TEM), total X-ray fluorescence
(TXRF), X-ray photoelectron spectroscopy (XPS), energy-
filtered transmission electron microscopy (EFTEM) pro-
vide a better understanding of the active catalytic species
in the reaction. Additionally, mechanistic data preclude a
radical pathway and suggest a copper(II)oxide-promoted
electrophilic aromatic substitution.
decided to explore
a
superparamagnetic support.
9
CuO/Fe3O4, easily prepared from a basified mixture of
CuCl2 and Fe3O4,24 gave 3a in 17% yield (Table 1, entry 4).
Changing the solvent to 1,2-dichloroethane (DCE) (Table
1, entry 5) and then to dichloromethane (Table 1, entry 6),
as well as changing the counterion of the iodonium salt
from triflate to tetrafluoroborate gave the desired product
in 70% yield (Table 1, entry 7). The optimized conditions
were found by modifying the stoichiometry of the reac-
tion and adding 2 equivalents of the heteroarene to avoid
the formation of the bisarylated byproduct. 2-n-Butyl-5-
phenylthiophene (3a) was isolated in 78% yield with a
selectivity of 90:10 (C5/C4) (Table 1, entry 8).
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Table 1. Optimization of reaction conditionsa
Entry
Catalyst
(y mol%)
X
Solvent
Temp. Yieldb
(°C)
1
Cu/C (10)
Cu/C (10)
CuO (5)c
OTf
OTf
OTf
OTf
Toluene
Toluene
Toluene
Toluene
80
60
60
60
20%
39%
44%
17%
2
3
4
CuO/Fe3O4
(5.6)
5
6
CuO/Fe3O4
(5.6)
OTf
OTf
BF4
BF4
DCE
70
70
70
70
55%
62%
70%
CuO/Fe3O4
(5.6)
CH2Cl2
CH2Cl2
CH2Cl2
7
CuO/Fe3O4
(5.6)
8d
CuO/Fe3O4
(5.6)
84%
(78%)e
0%
9d
10d
11d
Fe3O4
BF4
BF4
BF4
BF4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
70
70
70
70
-
0%
44%
33%
Cu/C (10)
12d
CuO/Al2O3
(10)
RESULTS AND DISCUSSION
13d
14d
15d
16d
17d
CuCl2 (10)
BF4
BF4
BF4
BF4
BF4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
70
70
70
70
70
51%
56%
7%
We commenced our exploration of heterogeneous copper
catalysts using Cu/C (Sigma-Aldrich) in the reaction of 2-
n-butylthiophene (1a) with diphenyliodonium salts, 2.
The desired C5-arylated product, 3a, was obtained in 20%
yield using toluene as the solvent (Table 1, entry 1). Re-
ducing the reaction temperature from 80 to 60 °C im-
proved the product yield (Table 1, entry 2) and using a
nanoparticle-based catalyst such as CuO (nanopowder, 50
nm, Sigma-Aldrich, Table 1, entry 3) resulted in an in-
crease in the formation of 3a.
Cu(OTf)2 (10)
CuBr (10)
CuI (10)
0%
Cu2O
71%
aReaction conditions: 2-n-butylthiophene (1.0 equiv.),
diphenyliodonium salt (1.0 equiv., 0.10 mmol), solvent
(0.50 mL) for 22 h. bGC-FID yield. cNanopowder (50 nm) .
e
d2.0 equiv. of 1a. Isolated yield.
Unfortunately, CuO nanopowder failed to catalyze the
reaction of other substituted thiophene moieties along
with different electron-rich heterocycles such as furan
Running this reaction in the absence of copper either
with or without the magnetite support failed to afford the
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page S29 for further details). 2-n-Butylfuran underwent
desired product (Table 1, entries 9-10). Also, the magnet-
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7
8
ite proved superior to other supports (Table 1, entries 11-
12). This CuO/Fe3O4 catalyst system outperformed a series
of commonly employed homogeneous Cu(II) and Cu(I)
salts (Table 1, entries 13-17 and Table S1, page S9) and
furthermore, showed better tolerance when diverse elec-
tron-rich heteroarenes such as indole, furan and benzofu-
ran were employed (vide infra). Additionally, other cata-
lysts with magnetic support failed to catalyze this reaction
(Table S2, page S9).
C5-arylation with perfect selectivity albeit in low yield
(3h).
Similarly, a disubstituted furan afforded the desired ary-
lated product with high regioselectivity (3i). Where lower
yields were obtained, we observed either starting material
decomposition (acid-sensitive substrates such as furans
3h, 3i) or an influence of electronic effects when electron
withdrawing groups were directly attached to the het-
eroarene (3g), probably indicating an electrophilic type of
mechanism. The versatility of the magnetic catalyst was
not limited to thiophenes and furans. We were pleased to
find that unprotected indoles as well as N-methylindoles
reacted highly selectively and in acceptable to good yields
under our optimized conditions (3k-3o).
The C3-arylation of the indole in a thiophene-indole moi-
ety (3j) highlights the regioselectivity of our catalytic
system. Moreover, functional groups were tolerated such
as 5-iodo- and 5-benzyloxyindole, which would allow for
further derivatization of these compounds (3m, 3o). Un-
substituted benzofurans were selectively arylated at the
C2-position (3r) and, remarkably, the arylation took place
at C3-position when C2-substituted benzofurans were
employed (3q). To our surprise, when benzo[b]thiophene
was tested under our conditions, no product was ob-
served (3s).
The importance of the support was once again highlight-
ed when we observed that unsupported CuO nanopowder
performed poorly in the arylations of 2-n-butylfuran and
benzofuran (3h, 3r). Furthermore, CuO/Fe3O4 proved
superior to commonly employed homogeneous copper
sources, especially in the reaction with oxygen-containing
heterocycles such as benzofuran and furan derivatives.
The copper salts failed to achieve high yields (0 to 20%) in
the reaction primarily due to acid-promoted starting
material decomposition, as was observed in kinetic meas-
urements comparing CuO/Fe3O4 to 3 different copper-
based catalysts (See SI pages S30-S31 for further detail).
The utility of the catalytic system was tested on a 5 mmol
scale reaction and we were pleased to obtain 3a in 75%.
Next, we explored the scope of the diaryliodonium salt
(Scheme 3). Electronically diverse iodonium salts were
found to be efficient coupling partners, although a clear
preference for electon-poor iodonium salts was observed
in reactions with 1a (4a, 4d). Diaryliodonium salts con-
taining meta or para-substitution on the arene were well-
tolerated as were arenes with electron withdrawing
groups such as –Br, –F, –NO2 and –CO2Et (4a, 4h, 4j, 4d,
4e, 4k, 4l) which would allow for further functionaliza-
tion of the products. Notably, this simple catalytic system
enabled the reaction of electronically diverse, unsymmet-
rical iodonium salts containing a cheap, non-transferable
arene (2,4,6-triisopropylphenyl, TRIP) (4d, 4k). A modi-
fied robustness screen was applied for further exploration
of functional group tolerance of the reaction (see SI, pag-
es S32-S33).25
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Scheme 2. Substrate scope of different heterocyclesa
Isolated yields are given. aGeneral procedure: heteroarene
(2.0 equiv.), diphenyliodonium salt (1.0 equiv., 0.30 mmol),
b
CuO/Fe3O4 (5.6 mol%), in CH2Cl2 at 70 °C, 22 h. 5.0 mmol.
d
cIsolated as a mixture of isomers. 2.5 equiv. of heteroarene.
e50 °C in CH2Cl2.
With the optimized conditions in hand, we focused on
the exploration of the reaction scope. First, different het-
eroarenes were investigated (Scheme 2). Electron donat-
ing (3a, 3b) and withdrawing (3e, 3g) substituted thio-
phenes were found to be suitable substrates for the reac-
tion. The C5-regioselectivity was maintained for 2-
substitued thiophenes. Notably, a disubstituted thio-
phene could be employed in the reaction (3c). We ob-
served that the 3-substitued thiophenes proved to be
more challenging substrates under the reaction condi-
tions and usually lower yields were obtained (3f) (see SI,
3
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hours and a sigmoidal reaction profile (Figure 1). These
results are indicative of the in situ formation of a new
R1
CuO/Fe3O4
(5.6 mol%)
1
2
3
4
5
6
7
8
A
Ar2IBF4
R
B Ar2IOTf
C ArI(TRIP)BF4
2
1
+
active catalytic species derived from the heterogeneous
catalyst.18c The presence of an induction period was also
detected when other common copper sources such as
CuO nanopowder, CuCl2, or Cu(OTf)2 were employed.
One of most common methods to differentiate between
heterogeneous surface catalysis and solution-phase catal-
ysis is the hot filtration test.26 We decided to apply this
technique to our reaction at various stages of the reaction.
Filtration of the crude reaction through Celite at 15%
conversion showed a 5% increase after allowing the fil-
trate to stir at 70 °C for the remainder of the standard
reaction time. Intrigued by this result, the reaction was
filtered at 45% conversion. After the standard 22 hours of
reaction time, GC-FID analysis of the filtrate showed that
the yield had increased to 84%, clearly indicating the
formation of a soluble active species. In further kinetic
analysis of the separated filtrate, we observed no induc-
tion period for the formation of product 3a, strongly indi-
cating the presence of the active catalytic species in solu-
tion (Figure 1). Moreover, the separated solid catalyst still
presented an induction period but produced 3a in the
same yield as the filtrate after the standard reaction time.
These results support the formation of a soluble active
species from the heterogeneous precursor. A leaching-
redeposition mechanism would be in accordance with the
recycling results observed for the catalyst.27 If such a phe-
nomenon was operational, a variation of the metal con-
tent in solution should be observed throughout the reac-
tion and the copper content on the solid catalyst should
remain fairly constant at the end of the reaction time.
CH2Cl2
X
4
50 to 70 °C, 22 h
X = S, O, NH, NMe
Me
Bu
Bu
S
S
Bu
R
S
b
4a
R = Br; : 79%, 90:10 ,
R = Me; 4b: 64%, 90:10b, B
R = OMe; 4c: 56%, 90:10b, B
R = NO2; 4d: 87%, 90:10b, C
R = F; 4e: 73%, 94:6b, B
B
b
4f
A
: 59%, 75:25 ,
Br
4g: 80%, 90:10b, A
9
R
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Me
O
R
O
N
H
c
4j
B
: 52% ,
R = Br; 4h: 57%, 98:2c, B
R = Me; 4i: 50%, 98:2c, B
R = CO2Et; 4k: 57%, >99:1d, C
d
4l
B
R = F; : 41%, >99:1 ,
Scheme 3. Substrate scope of the iodonium salta
Isolated yields are given. For 2-n-butylthiophenes selectivi-
ties refer to C5/C4, C2/C3 for benzofurans and C3/C2 for
indole. General procedure: heteroarene (2.0 equiv.), diphe-
nyliodonium salt (1.0 equiv., 0.30 mmol), CuO/Fe3O4 (5.6
a
b
mol%), in CH2Cl2 at 70 °C, 22 h. Isolated as a mixture of
isomers. c2.5 equiv. of heteroarene. d50 °C in CH2Cl2.
We were pleased to find that the catalyst could be easily
recovered using a magnet and reused. The reusability
experiments showed no loss in reactivity over five con-
secutive cycles, however, after the 5th cycle, a loss of reac-
tivity was observed (Scheme 4).
CuO/Fe3O4
+
Ph2IBF4
CH2Cl2, 70 °C
22 h
S
S
Bu
Bu
2a
3a
1a
(2 equiv.)
Cycle
Yield
1
2
3
4
5
6
78 %
76 %
77 %
77 %
78 %
68 %
Scheme 4. Reusability study of the copper-based
catalyst systema
a
Isolated yields are given. General procedure: See Scheme 2
and SI. The catalyst was washed with CH2Cl2 (4 times) and
dried at 75 °C for 45 min after every cycle.
Figure 1. Kinetic results for the reaction of 2-n-
butylthiophene (1a) and diphenyliodonium tetrafluoroborate
(2a) catalyzed by CuO/Fe3O4. The line represents the mo-
ment when the reaction mixture was filtered.
STUDIES
TOWARDS
ELUCIDATING
THE
ACTIVE CATALYTIC SPECIES
Next, we were interested in understanding whether the
catalysis was taking place on the surface of the magneti-
cally recoverable heterogeneous catalyst or if the active
catalytic species was in solution. Therefore, we started our
investigation into the details of the reaction through a
series of kinetic measurements, high-resolution mass
spectrometry, heterogeneity tests, poisoning experiments
and catalyst analyses with XPS, SEM, TXRF, ICP-MS,
TEM, EFTEM and diffraction pattern.
In order to verify this “boomerang” phenomena, a series
of TXRF measurements were conducted to determine the
abundance of metal in solution (Table 2). In line with a
leaching-redeposition mechanism, TXRF results con-
firmed the presence of metal (predominantly copper) in
solution. Additionally, an increase in the metal concentra-
tion after the induction period and a decrease towards the
end of the reaction time was observed. ICP-MS analysis of
the catalyst showed a loss of 13% in mass of copper after
The kinetics of the standard reaction providing 2-n-butyl-
5-phenyl-thiophene (3a) showed an induction period of 2
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the 6th catalytic cycle. These results could help explain the
B
A
1
2
3
4
5
6
7
8
drop in reactivity observed when the catalyst was used for
a 6th reaction cycle and are in accordance with the find-
ings of the hot filtration test. Furthermore, after the 6th
catalytic cycle SEM and XPS analysis revealed an exten-
sive coverage of the catalyst surface by a fluorinated com-
pound, likely deposited tetrafluoroborate on the surface
of the CuO/Fe3O4 (see SI, pages S35-S39). This effect
could either slowly prevent the redeposition of CuO onto
the support or block the release of the metal oxide from
the surface and thus prevent the formation of the active
catalytic species.28 The coverage of the surface changed
the morphology of the magnetic catalyst as observed in
Figure 2.
9
Figure 3. TEM-images of the nanoparticles, which are em-
bedded into an amorphous layer. A and B show the aggre-
gates after 40% conversion. The size of the aggregates varied
from small (10-100 nm, A) to large (100-400 nm, B).
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EFTEM-images confirmed the presence of an amorphous
layer surrounding the particles. The electron beam from
the EFTEM destroyed the outer layer completely, reveal-
ing the underlying nanoparticles. The difference between
the exposed nanoparticles (Figure 4B) and those embed-
ded in an amorphous layer (Figure 4A) can be seen by
laying the TEM and EFTEM-images side-by-side. Also,
EFTEM measurements showed a homogeneous distribu-
tion of the nanoparticles throughout the analyzed sample
(see SI, pages S41-S47).
Table 2. Abundance of metal in solution at different
reaction times according to TXRF measurements
Reaction
time
Cu
Cu in
solutiona
Fe (mg/L) Conversion
by GC-FID
(mg/L)
2 h
7 h
2.34
323.42
88.14
0.50
< 1 %
45 %
12 %
1.58
2.27
0.57
0.24
0%
40%
75%
84%
11 h
22 h
< 1 %
A
B
aWith respect of starting percentage of copper (5.6 mol%).
B
A
0.5 µm
0.5 µm
Figure 2. SEM images of fresh catalyst (A) and the reused
catalyst after 6th catalyitic cycle (B) showing change in
morphology.
C
Intrigued by these results, we decided to further investi-
gate the nature of the active soluble catalytic species and
thus TEM, EFTEM and diffraction pattern measurements
were conducted for a sample with a 40% conversion.
TEM-images showed a series of aggregates ranging from
small (10-100 nm) to significantly larger (100-400 nm)
(Figure 3.). We wondered whether these aggregates could
contain embedded nanoparticles in an amorphous layer
of organic material and hence, EFTEM studies were con-
ducted.
Figure 4. TEM-images of the nanoparticles, which are em-
bedded into an amorphous layer before (A) and after the
EFTEM measurements (B and C). During the measurements
the electron beam destroys the outer layer, which reveals the
underlying nanoparticles. The particles give a high contrast
both in bright field (B) and dark field (C) TEM-images.
Additionally, the corresponding diffraction pattern sup-
ports these findings (Figure 5).29 Prior to EFTEM, no sig-
nals could be detected. After destroying the outer layer
that covers the nanoparticles, however, a crystalline struc-
ture was observed and hkl planes for CuO and Fe3O4 were
found. The copper within the nanoparticles was identified
as only copper(II)oxide (Figure 5). These results strongly
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indicate that CuO nanoparticles are present in the active by the cationic diaryliodonium species. Once the starting
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catalytic species.
material (diaryliodonium) is consumed, the particles
could deaggregate and redeposit on the support.
The original description of the magnetic catalyst by Yus
and co-workers24 mentions a homogeneous distribution
of copper on the magnetite and the absence of nanoparti-
cles by TEM imaging. Hence, our findings suggest that
the observed particles could be formed in situ during the
reaction. To the best of our knowledge, this phenomenon
has not yet been described for copper-based amorphous
heterogeneous precursors in direct C–H functionalization
reactions.32,33
According to literature reports,30 changes in nanoparticle
structure could be induced by irradiation with high ener-
gy electron beams from transmission electron microscopy
techniques however, during our measurements we did
not observe any changes in the morphology or structure
of the nanoparticles.
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REACTION MECHANISM
To gain more insight into the reaction mechanism we
considered 3 main pathways:
a) A single electron transfer (SET) from Cu(II) to
promote the homolytic reduction of the diarylio-
donium salt with a concomitant formation of a
phenyl radical.34
b) A Cu(I)/Cu(III) cycle initiating with a Cu(I) spe-
cies from the Cu(II) precursor through either re-
duction by the nucleophile or disproportionation
of Cu(II).12
c) A Cu(II) induced dissociation of the counterion
of the diaryliodonium salt generating a highly
electrophilic aromatic species followed by attack
from the heteroarene.12c
Figure 5. Diffraction pattern of the nanoparticles. A diffrac-
tion pattern could only be detected after the organic layer
was destroyed. The most prominent hkl planes are marked
for CuO.
Recently, a study from Ananikov and coworkers31 showed
the formation of soluble copper-thiolate as the active
catalytic species in the cross-coupling reaction of thiols
and arylhalides using CuO nanoparticles as precatalyst.
Inspired by their ability to observe their catalytically ac-
tive leached copper species by mass spectrometry, we
wondered if similar analysis could provide us with the
same insight. A series of ESI-MS, MALDI-TOF and HPLC-
MS measurements showed no evidence of ionizable cop-
per and/or copper oxide species in solution.
However, from a stoichiometric experiment, we were able
to detect that a positively charged dimeric diaryliodonium
species appeared after heating the catalyst with the dia-
ryliodonium salt. This suggests an activation process that
is not observed when the iodonium salt is heated in the
absence of the catalyst. Moreover, formation of nanopar-
ticles was observed by TEM when a stoichiometric
amount of the diaryliodonium salt was heated with the
catalyst, strongly suggesting the need for an interaction
between these components in order to achieve nanoparti-
cle formation.
Although the exact scenario for the formation of nanopar-
ticles is difficult to describe, the combination of data
collected from the several characterization and kinetic
measurements allows us to propose a CuO nanoparticle
formation mechanism. The formation of the particles is
initiated by ripening of CuO from the surface by interac-
tion with the diphenyliodonium salt and consequent
agglomeration. The likely-formed negatively-charged
nanoparticles would promote removal of the counterion
from the I(III) salts and consequently favor stabilization
Copper-catalyzed Meerwein C–H arylation reactions are
known to involve the generation of an aryl radical species
from suitable precursors such as diazonium salts.35 In a
similar fashion, we considered that an SET from Cu(II) to
the diaryliodonium salt could induce the formation of an
aryl radical. In order to determine if this pathway was
operative, we prepared radical clock substrate 3-
cyclopropylthiophene (1j) to use as a probe for the well-
established radical clock reaction (Scheme 5).36 Under our
standard reaction conditions we observed a mixture of
both the C2- and C5-monoarylated regioisomeric prod-
ucts (3j and 3j’ in a 2:1 ratio respectively) as well as the
C2,5-bisarylated product. These three arylated products
were obtained in 52% combined yield. The mixture was
isolated by preparative HPLC and fully characterized as
the corresponding arylated cyclopropylthiophenes (3j, 3j’
and 3j’’), strongly suggesting that the arylation reaction is
not operating via a radical mechanism. Moreover, addi-
tion of radical inhibitors such as dibutylhydroxytoluene
(BHT) and 1,1-diphenylethylene did not affect the reaction
yield.
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Scheme 5. Radical clock test experiments.a
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aFor reaction conditions see Scheme 2 and SI.
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Previous work by Gaunt and coworkers has suggested the
possibility of a Cu(I)/Cu(III) catalytic cycle from the re-
duction or disproportionation of Cu(II).12 This proposal
on the meta-arylation of acetanilides has been supported
by density functional theory (DFT) calculations from the
groups of Li and Wu.37 Futhermore, Stahl and Ribas have
achieved the isolation and characterization of Cu(III)
complexes.38 In the proposed Cu(I)/Cu(III) catalytic cycle,
the diaryliodonium salt oxidatively adds to a Cu(I) species
forming a putative highly electrophilic Cu(III)–aryl spe-
cies. Reaction of this electrophilic species with the het-
eroarene would be facilitated by its intrinsic nucleophilic-
ity. Reductive elimination would regenerate Cu(I) and
release the product from the catalytic cycle. Alternatively,
Gaunt and co-workers proposed a counterion dissociation
facilitated by the metal to account for the selectivity that
they observed in uncatalyzed reactions with diphenylio-
donium salts.12c Hence, we conducted a series of experi-
ments to gain a better understanding of the reaction
mechanism. A competition experiment between an elec-
tron-rich and an electron-poor thiophene (1a’ and 1a’’) led
to the preferential formation of 3b, indicating a prefer-
ence for electron-rich heteroaryl-substrates (Scheme 6A).
Moreover, a competition experiment between two elec-
tronically different iodonium salts (2b and 2c) favored
formation of 4b, suggesting a preferred reactivity with
more electrophilic coupling partners (Scheme 6B). A
competition KIE of 0.8 was observed for the standard
reaction suggesting that C–H activation is not involved in
the rate determining step.39 Moreover, we observed the
selective transfer of the least sterically hindered arene
when employing unsymmetrical diaryliodonium salts.
Together, these results suggest that an electrophilic aro-
matic substitution mechanism promoted by transition
metal catalysis is taking place under our reaction condi-
tions.
Scheme 6. Competition experiments between elec-
tronically distinct thiophenes (A) and electronically
distinct iodonium salts (B)a
aFor reaction conditions see SI. For experiment A, yields
given are isolated. For experiment B, yields were deter-
mined by GC-FID.
We also observed a change in the reaction rate when we
preheated the catalyst for 4 hours in the presence of di-
phenyliodonium tetrafluoroborate (2a). After adding 2-n-
butylthiophene (1a), the induction period of the reaction
was reduced to 30 min. TXRF measurements of the pre-
heated solution showed a higher amount of dissolved
copper compared to preheated solutions of only the cata-
lyst or a mixture of CuO/Fe3O4 and 2-n-butylthiophene
(1a) (see SI, page S40). This result suggests an interaction
between the catalyst and the iodonium salt being a criti-
cal step of the catalytic cycle. Although, we have no con-
clusive evidence of this interaction either resulting in an
oxidative addition of the iodonium salt to the copper
catalyst or a catalyst-promoted dissociation of the coun-
terion, the results of EFTEM analysis showed the presence
of only Cu(II) oxide species in solution. Several mass
spectrometry techniques showed no evidence of copper-
aryl or any copper-based ionizable species in solution.
Considering the combination of these results, it is likely
that a redox-neutral process featuring a metal-promoted
counterion dissociation is taking place in our reaction.
CONCLUSIONS
A reusable copper impregnated on magnetite system was
used to catalyze the direct arylation of electron-rich het-
eroarenes. Under mild and operationally simple reaction
conditions, acceptable to good yields and high regioselec-
tivities were obtained using diaryliodonium salts as cou-
pling partners. A radical clock experiment, KIE measure-
ment and competition tests preclude a radical mechanism
and suggest either a metal-promoted counterion dissocia-
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tion from the iodonium salt or a Cu(I)/Cu(III) cycle as
Page 8 of 10
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111,
1
plausible reaction mechanisms.
1780. (d) L. McMurray, F. O’Hara, M. J. Gaunt, Chem.
Soc. Rev. 2011, 40, 1885. (e) Zhao, D.; You, J.; Hu, C.
Chem.–Eur. J. 2011, 17, 5466. (f) K. M. Engle, T.-S. Mei,
M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2011, 45, 788. (g)
Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc.
Rev. 2011, 40, 5068. (h) T. Brückl, R. D. Baxter, Y. Ishi-
hara, P. S. Baran, Acc. Chem. Res. 2012, 45, 826. (i) Ya-
maguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem.,
Int. Ed. 2012, 51, 8960. (j) Neufeldt, S. R.; Sanford, M. S.
Acc. Chem. Res. 2012, 45, 936. (k) Arockiam, P. B.;
Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
(l) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glo-
rius, F. Angew. Chem., Int. Ed. 2012, 51, 10236. (m)
Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Al-
drichimica Acta 2012, 45, 31. (n) Kuhl, N.; Schröder, N.;
Glorius, F. Adv. Synth. Catal. 2014, 356, 1443. (o) L.
Ackermann, Acc. Chem. Res. 2014, 47, 281. (p) Ye, B.;
Cramer, N. Acc. Chem. Res. 2015, 48, 1308. (q) G. Song,
X. Li, Acc. Chem. Res. 2015, 48, 1007.(r) Gensch, T.;
Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem.
Soc. Rev. 2016, 45, 2900.
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Importantly, a series of experimental methods including
kinetic studies, filtration tests and various analytical
techniques indicate the formation of a soluble active cata-
lytic species. Further characterization provided evidence
for the likely generation of nanoparticles from the amor-
phous heterogeneous precursor. This finding represents a
starting point on the comprehension of active catalytic
species on C–H functionalization reactions using copper-
based catalytic systems, and could be considered a begin-
ning on questioning whether other copper-based trans-
formations (regardless of being “homogeneous” or “heter-
ogeneous”) might be catalyzed by in situ generated nano-
particles.40
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ASSOCIATED CONTENT
Supporting Information. Experimental details, characteri-
zation data, and copies of NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174. (b) Ackermann, L.; Vicente, R.; Kapdi, A.
R. Angew. Chem., Int. Ed. 2009, 48, 9792.
AUTHOR INFORMATION
(10) (a) Mousseau, J. J.; Charette, A. B. Acc. Chem. Res. 2013,
46, 412. (b) Kulkarni, A.; Daugulis, O. Synthesis. 2009,
4087.
Corresponding Author
*glorius@uni-muenster.de
(11) (a) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 15185. (b) Daugulis, O.; Do, H.-
Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
(12) (a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am.
Chem. Soc. 2008, 130, 8172. (b) Phipps, R. J.; Gaunt, M.
J. Science 2009, 323, 1593. (c) Ciana, C.-L.; Phipps, R. J.;
Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2011, 50, 458.
ACKNOWLEDGMENT
Generous financial support by the Deutsche Forschungsge-
meinschaft (Leibniz award, SFB 858) and the Alexander von
Humboldt Foundation (K. M. C.) is gratefully acknowledged.
We thank Karin Gottschalk for experimental support, Dr.
Lisa Candish, Tobias Gensch, and Andreas Lerchen for help-
ful discussions, Michael Holtskamp and Prof. Dr. Uwe Karst
for TXRF and ICP-MS determination, Dr. Martin Peterlech-
ner for support on TEM and EFTEM measurements and Dr.
Matthias Letzel for mass spectrometry measurements (all
WWU Münster).
(13) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.;
You, J. Angew. Chem. Int. Ed. 2009, 48, 3296.
(14) Modha, S. G.; Greaney, M. F. J. Am. Chem. Soc. 2015,
137, 1416.
(15) Recent examples of C–H arylation by photoredox ca-
talysis: (a) Hari, D. P.; Schroll, P.; König, B. J. Am.
Chem. Soc. 2012, 134, 2958. (b) Liu, Y. X.; Xue, D.;
Wang, J. D.; Zhao, C. J.; Zou, Q. Z.; Wang, C.; Xiao, J.
Synlett 2013, 24, 507. (c) Zoller, J.; Fabry, D. C.;
Rueping, M. ACS Catal. 2015, 5, 3900.
REFERENCES
(1) (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Le-
maire, M. Chem. Rev. 2002, 102, 1359.
(16) For recent reviews: (a) Bonin, H.; Sauthier, M.; Felpin,
F.-X. Adv. Synth. Catal. 2014, 356, 645. (b) Rossi, R.;
Lessi, M.; Manzini, C.; Marianetti, G.; Bellina, F. Adv.
Synth. Catal. 2015, 357, 3777.
(2) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot,
T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062.
(3) Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan,
P. C. Chem. Soc. Rev. 2014, 43, 3525.
(17) For recent reviews on heterogeneous C–H functionali-
zation: (a) Djakovitch, L.; Felpin, F.-X. ChemCatChem
2014, 6, 2175. (b) Reay, A. J.; Fairlamb, I. J. S. Chem.
Commun. 2015, 51, 16289. (c) Cano, R.; Schmidt, A. F.;
McGlacken, G. P. Chem. Sci. 2015, 6, 5338. (c) Vaccaro,
L.; Santoro, S.; Ackermann, L.; Kozhushkov, S. Green
Chem. 2016, 18, 3471.
(4) Cordovilla, C.; Bartolomé, C.; Martínez-Ilarduya, J. M.;
Espinet, P. ACS Catal. 2015, 5, 3040.
(5) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270.
(6) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359.
(7) Podgorsek, A.; Zupan, M.; Iskra, J. Angew. Chem., Int.
Ed. 2009, 48, 8424.
(18) (a) Tang, D.-T. D.; Collins, K. D.; Glorius, F. J. Am.
Chem. Soc. 2013, 135, 7450. (b) Tang, D.-T. D.; Collins,
K. D.; Ernst, J. B.; Glorius, F. Angew. Chem. Int. Ed.
(8) Selected reviews and accounts: (a) Colby, D. A.; Berg-
man, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (b)
Satoh, T.; Miura, M. Chem.–Eur. J. 2010, 16, 11212 (c)
8
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2014, 53, 1809. (c) Collins, K. D.; Honeker, R.; Vásquez-
(28) However, we observed less recycling ability and a low-
er copper content on the catalyst when the crude mix-
ture from the reaction was left in contact with the
catalyst for extended periods of time. Dissolution of
CuO, probably by the HBF4 formed in situ, might be
accountable for this observation.
1
2
3
4
5
6
7
8
Céspedes, S.; Tang, D.-T. D.; Glorius, F. Chem. Sci.
2015, 6, 1816. (d) Vásquez-Céspedes, S.; Ferry, A.; Can-
dish, L.; Glorius, F. Angew. Chem. Int. Ed. 2015, 54,
5772.
(19) For recent examples: (a) Wang, L.; Zhang, J.; Sun, J.;
Zhu, L.; Zhang, H.; Liu, F.; Zheng, D.; Meng, X.; Shi, X.;
Xiao, F.-S. ChemCatChem 2013, 5, 1606. (b) Al-Hmoud,
L.; Jones, C. W. J. Catal. 2013, 301, 116. (c) Al-Hmoud,
L.; Bali, S.; Mahamulkar, S.; Culligan, J.; Jones, C. W. J.
Mol. Catal. A Chem. 2014, 395, 514.
(29) For copper: (a) Tunell, G.; Posnjak, E.; Ksanda, C. J.
Zeitschrift fuer Kristallographie, Kristallgeometrie,
Kristallphysik, Kristallchemie (-144,1977), 1935, 90, 120.
For iron: (b) Natl. Bur. Stand. (U.S.) Monogr., 1967, 25,
5, 31.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(20) For examples of heterogeneous/ nanoparticle Cu-
catalyzed C–H functionalizations: (a) Lee, E. Y.; Park, J.
ChemCatChem 2011, 3, 1127. (b) Zhang, W.; Zeng, Q.;
Zhang, X.; Tian, Y.; Yue, Y.; Guo, Y.; Wang, Z. J. Org.
Chem. 2011, 76, 4741. (c) Honraedt, A.; Le Callonnec, F.;
Le Grognec, E.; Fernandez, V.; Felpin, F.-X. J. Org.
Chem. 2013, 78, 4604. (d) Priyadarshini, S.; Amal
Joseph, P. J.; Lakshmi Kantam, M. Tetrahedron 2014,
70, 6068. (e) Le, H. T. N.; Nguyen, T. T.; Vu, P. H. L.;
Truong, T.; Phan, N. T. S. J. Mol. Catal. A Chem. 2014,
391, 74.
(30) a) Latham, A. H.; Wilson, M.; Schiffer, P.; Williams, M.
E. J. Am. Chem. Soc., 2006, 128, 12632. b) Latham, A.
H.; Williams, M. E. Langmuir, 2008, 24, 14195.
(31) Panova, Y. S.; Kashin, A. S.; Vorobev, M. G.; Degtyare-
va, E. S.; Ananikov, V. P. ACS Catal. 2016, 6, 3637.
(32) Recently, a study showed the in situ formation of cop-
per nanoparticles from a homogeneous solid precursor
during reduction with H2: van den Berg, R.; Elkjaer, C.
F.; Gommes, C. J.; Chorkendorff, I.; Sehested, J.; de
Jongh, P. E.; de Jong, K. P.; Helveg, S. J. Am. Chem. Soc.
2016, 138, 3433.
(21) Oliver-Meseguer, J.; Oliver-Messeguer, J.; Liu, L.; Gar-
cía-García, S.; Canós-Giménez, C.; Domínguez, I.; Ga-
vara, R.; Doménech-Carbó, A.; Concepción, P.; Leyva-
Pérez, A.; Corma, A. J. Am. Chem. Soc. 2015, 137, 3894.
(22) Reviews on the use of diaryliodonium salts as coupling
partners: (a) Zhdankin, V. V; Stang, P. J. Chem. Rev.
2008, 108, 5299. (b) Merritt, E. A.; Olofsson, B. Angew.
Chem. Int. Ed. 2009, 48, 9052.
(33) (a) Gawande, M. B.; Goswami, A.; Felpin, F.-X.; Asefa,
T.; Huang, X.; Silva, R.; Zou, X.; Zboril, R.; Varma, R. S.
Chem. Rev. 2016, 116, 3722. (b) Pla, D.; Gómez, M. ACS
Catal. 2016, 6, 3537.
(34) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3464.
(35) Meerwein, H.; Buchner, E.; van Emsterk, K. J. Prakt.
Chem. 1939, 152, 237.
(23) Mills, K.C. ISIJ International 1993, 33, 148.
(36) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
(37) Chen, B.; Hou, X.-L.; Li, Y.-X.; Wu, Y.-D. J. Am. Chem.
Soc. 2011, 133, 7668.
(24) Cano, R.; Ramón, D. J.; Yus, M. J. Org. Chem. 2011, 76,
5547.
(25) For more details on the robustness screen, please see
SI and: a) Collins, K. D.; Glorius, F. Nature Chem. 2013,
5, 597; b) Collins, K. D.; Glorius, F. Tetrahedron 2013,
69, 7817; c) Collins, K. D.; Rühling, A.; Glorius, F. Na-
ture Protocols 2014, 9, 1348; d) Collins, K. D.; Glorius,
F. Acc. Chem. Res. 2015, 48, 619; e) Gensch, T.; Glorius,
F. Science 2016, 352, 294.
(38) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ri-
bas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068.
(39) Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.
2012, 51, 3066.
(40) Corma, A. Angew. Chem. Int. Ed. 2016. DOI:
10.1002/anie.201601231.
(26) (a) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A Chem.
2003, 198, 317. (b) Crabtree, R. H. Chem. Rev. 2012, 112,
1536. (b) Pagliaro, M.; Pandarus, V.; Ciriminna, R.; Bé-
land, F.; Demma Carà, P. ChemCatChem 2012, 4, 432.
(27) For studies on this phenomena with Pd based systems:
(a) Zhao, F.; Shirai, M.; Ikushima, Y.; Arai, M. J. Mol.
Catal. A Chem. 2002, 180, 211. (b) Genelot, M.; Dufaud,
V.; Djakovitch, L. Adv. Synth. Catal. 2013, 355, 2604.
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