A colorimetric high-throughput screening method for palladium-catalyzed coupling reactions of aryl iodides using a gold nanoparticle-based iodide-selective probe

Article abstract of DOI:10.1002/anie.201100378

Catching the couplings: A general and simple screening method for palladium-catalyzed coupling reactions of aryl iodides utilizes gold nanoparticles. This assay was successfully employed in several aminations, α-arylation of ketones, and decarboxylative couplings. 96 samples were screened in a few minutes. Copyright

Full text of DOI:10.1002/anie.201100378

Communications
DOI: 10.1002/anie.201100378
Colorimetric Assays
A Colorimetric High-Throughput Screening Method for Palladium-
Catalyzed Coupling Reactions of Aryl Iodides Using a Gold
Nanoparticle-Based Iodide-Selective Probe**
Eunhye Jung, Sudeok Kim, Yong Kim, Seong Hyeok Seo, Soo Suk Lee, Min Su Han,* and
Sunwoo Lee*
Palladium-catalyzed cross-coupling reactions are among the
most important methods in organic synthesis, the pharma-
ceutical industry, and materials science.[1] Recently, newly
developed catalytic systems have been reported for use in
coupling reactions, such as Suzuki, Stille, Heck, Sonogashira,
Hiyama, a arylation and Buchwald–Hartwig amination.[2]
Developing an efficient catalytic system requires costly and
time-consuming trial and error and consideration of numer-
ous variables, including catalyst, ligand, base, additive,
solvent, stoichiometry, and temperature. To address this
problem, we employed high-throughput screening (HTS)
assays, which were originally developed to accelerate the
discovery process in the pharmaceutical industry.[3] The major
advantage of HTS is its more rapid monitoring of chemical
transformations. Gas chromatography (GC),[4] high-perfor-
mance liquid chromatography (HPLC),[5] mass spectrometry
(MS),[6] infrared spectroscopy (IR),[7] colorimetry,[8] and
fluorescence spectroscopy[9] are currently employed as ana-
lytical methods. Recently, Hartwig, Taran, and Rozhkov
independently reported fluorescent screening methods for
coupling reactions to be viable. Therefore, the development
of more general and simple methods to apply to all types of
coupling reactions is desired.
Gold nanoparticles (AuNPs) have been widely used as
chromogenic components in colorimetric sensing systems
owing to their high extinction coefficients and distance-
dependent optical properties. As a result, many AuNP-based
colorimetric sensors have been developed to detect metal
ions, proteins, DNA, small molecules, and biocatalysts.[11]
However, to the best of our knowledge, colorimetric systems
using AuNPs have not been developed for high-throughput
screening of chemical reactions, such as palladium-catalyzed
cross-coupling reactions.
Recently, colorimetric sensing systems employing adeno-
sine triphosphate (ATP)-stabilized AuNPs (sAuNPs) have
been developed to detect biocatalysts, metal ions, and
anions.[12] Unlike citric acid capped AuNPs, the sAuNPs are
stable over a wide pH range, even in high salt concentrations,
but quickly aggregate when exposed to soft metal ligands,
such as thiol and iodide.[12,13] In palladium-catalyzed cross-
coupling reactions, aryl iodide is the most reactive substrate,
and its iodide ion is released after completion of the coupling.
With this information, we speculated that sAuNPs could be
used to detect released iodide by means of a colorimetric
sensing system. This method would allow a more general and
faster screening in palladium-catalyzed coupling reactions
(Scheme 1).
palladium-catalyzed C C bond formation.[10] However, these
À
methods have the disadvantage of allowing HTS of variable
parameters within the target reaction only, so that the target
materials have to be synthesized for the screening of the
[*] E. Jung,[+] Y. Kim, Prof. Dr. S. Lee
Department of Chemistry and Institute of Basic Science
Chonnam National University
Gwangju, 500-757 (Republic of Korea)
Fax: (+82)62-530-3389
E-mail: sunwoo@chonnam.ac.kr
S. Kim,[+] S. H. Seo, Prof. Dr. M. S. Han
Department of Chemistry, Chung-Ang University
Seoul 156-756 (Republic of Korea)
Fax: (+82)2-825-4736
E-mail: mshan@cau.ac.kr
Dr. S. S. Lee
Bio & Health Group, Emerging Center
Samsung Advanced Institute of Technology
Yongin-si, Gyeonggi-do, 446-712 (Republic of Korea)
Scheme 1. Sensing of iodide in palladium-catalyzed cross-coupling
reactions by using sAuNPs. ATP=adenosine triphosphate.
[+] These authors contributed equally to this work.
[**] This work was supported by a National Research Foundation of
Korea Grant funded by the Korean Government (2010-0002350 &
2009-0072357), POSCO, and the Priority Research Centers Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2009-
0093817).
First, we evaluated whether sAuNPs would selectively
detect iodide ions and if we could accurately assess the
concentration of iodide by measuring UV absorbance. A
stock solution of iodide ions was added to an assay solution
containing sAuNPs (3 nm) in a pH 7.0 buffer solution (10 mm
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100378.
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Angew. Chem. Int. Ed. 2011, 50, 4386 –4389

Table 1: The correlation of conversion extents by GC and UV in the Heck
sodium phosphate buffer (SPB) + 0.1m NaCl), so that the
final concentration was between 0 and 5 mm. The changes in
the absorbance of the assay mixtures were recorded at 520 nm
after adding the iodide ions. The observed absorbance
intensity at 520 nm decreased almost in proportion to the
decreasing iodide concentrations (See Figure S2 in the
Supporting Information). Furthermore, the sAuNPs showed
high selectivity for iodide over various other anions (Fig-
ure 1a), and the changes in absorbance caused by the addition
reactions.[a]
Entry Base
A[g]
Conv (UV) Conv (GC) Yield [%][g]
[%][h]
[%][i]
1
2
3
4
5
6
7
–
0.789413
0.758287
1
8
21
30
52
69
0
5
0
4
DBN[d]
NaOAc[e] 0.693869
21
37
50
70
100
18
37
56
65
98
Pyridine
0.653862
NaOAc[f] 0.548959
NaOAc
K2CO3
0.465500
0.317895 100
[a] Reaction conditions: 4-iodotoluene (0.3 mmol) and n-butyl acrylate
(0.36 mmol). [b] PEP-36=bis(2,6-di-tert-butyl-4-methylphenyl)pentaery-
thritol diphosphite. [c] DMF=dimethylformamide. [d] DBN=1,5-
diazabicyclo[4.3.0]non-5-ene. [e] Reaction time=1 h. [f] Reaction
time=7 h. [g] Absorbance intensity. [h] Determined by UV absorbance.
[i] Determined by GC with an internal standard material.
Figure 1. a) UV/Vis spectra obtained after the addition of various
anions (5 mm) to a buffer solution (pH 7.0, 10 mm SPB+0.1m NaCl)
containing sAuNPs (3 nm). b) UV/Vis spectra obtained by the addition
of IÀ (5 mm) to a buffer solution (pH 7.0, 10 mm SPB+0.1m NaCl)
containing sAuNPs (3 nm) and other anions (25 mm). c) The color of
the solution in the absence and presence of anions (5 mm, from left Àto
right): no anion, IÀ, FÀ, ClÀ, BrÀ, CH3COOÀ, ClO4À, NO3À, CNÀ, N3
,
À
SO42À, HSO3À, HSO4À, P2O74À, HPO42À, and HCO3
.
of iodide ions were almost unaffected by the presence of other
anions (Figure 1b). This means that the sAuNPs can selec-
tively detect iodide produced in a palladium-catalyzed cross-
coupling reaction despite the presence of various anions from
additive materials, such as NaOAc, K2CO3, CsF, and K3PO4.
Moreover, we found that sAuNPs afforded the blue solution
in the presence of iodide (Figure 1c). Therefore, the palla-
dium-catalyzed cross-coupling reaction can be evaluated
simply by detecting the concentration of iodide ions.
With the above data, we investigated the correlation of
absorbance with the conversion extent of aryl iodide in the
palladium-catalyzed coupling reaction. To do this, the Mizor-
oki–Heck coupling reaction of iodobenzene and n-butyl
acrylate was chosen as a model reaction and the reactions
were carried out with a variety of bases.[14] All of the samples
were taken from the reaction mixture and then diluted to
5 mm. After treatment with sAuNPs, the absorbance was
recorded at 10 min.[15] The absorbance was then used to
calculate the conversion extent by means of a linear plot
correlating absorbance to mole fraction of iodide.[16] As
shown in Table 1, the absorbance decreased as the conversion
extent increased. All conversion extents obtained from the
absorbance showed a high correlation with those from GC
with an internal standard material.
Figure 2. The color of the solutions corresponding to entries 1–7 of
Table 1 (from left to right).
The success of the Mizoroki–Heck reaction allowed us to
expand this assay for HTS of various palladium-catalyzed
cross-coupling reactions without the need to synthesize
specific target materials. We evaluated this assay in the
coupling reaction of aryl iodide with eight kinds of palladium-
catalyzed reactions: Heck,[14] Stille,[17] Sonogashira,[18]
Hiyama,[19] Suzuki,[20] a-arylation,[21] Buchwald–Hartwig ami-
nation,[22] and decarboxylative couplings.[23] The scope is
shown in Scheme 2.
After complete reaction, each sample was diluted to 5 mm
using H2O and transferred to a 96-well plate, and using a
multichannel pipette, a sAuNP solution was added.[25] The
resulting plate was left to stand for 2 min and then analyzed
on a microplate reader at 520 nm absorption. The correlation
equation obtained from the six standard samples was used to
convert the absorbance values to conversion extents (Sup-
porting Information, Figure S3, red line[26]). All reaction
results are shown in Figure 3 and Figure 4.
Several features were readily apparent from our results.
First, all of the conversion extents were obtained in a few
minutes using a microplate reader, and they compared
favorably with those from GC analysis for 90 representative
samples from the crude reaction mixtures. The response time
We also found that the color of the solution changed from
red to blue as the conversion extent increased, as shown in
Figure 2. This allowed us to apply this method in the
colorimetric assay of the cross-coupling reactions.
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Communications
Scheme 2. Scope of the palladium-catalyzed cross-coupling reactions
of aryl iodides for high-throughput screening.[24]
Figure 4. Colorimetric assay for palladium-catalyzed coupling reac-
tions. a) The expected colors drawn from the conversion extents of the
GC analysis. b) The detected colors. 1–3 Heck, 4 Stille, 5 Sonogashira,
6 Hiyama, 7,8 decarboxylative coupling, 9,10 Suzuki, 11 a arylation of
ketones, 12 Buchwald–Hartwig amination.
Figure 3. The correlation between GC and UV spectroscopy for the
extent of conversion. Values for the standard (absorbance, red
diamonds) are shown.
for the change in absorbance and color decreased from 10 min
to 2 min owing to the small scale of the assay.
assay could be readily applied to screening palladium sources
and ligands (columns 7, 8, and 11). Most coupling reactions
require a base or an activator, so we screened a variety of
bases, including organic, inorganic, strong, and weak bases.
Most bases showed a high correlation between the assay data
and GC data even though competitive anions were present in
the reaction mixtures. However, correlations were not found
when either Ag2CO3 or tetrabutylammonium iodide (TBAI)
was employed as a base or an additive (row C, columns 1 and
5,: see orange dotted boxes in Figures 3 and 4a). In the case of
Ag2CO3 (C1), the absorbance data showed lower conversion
than the GC conversion because the silver cation reacts with
the iodide ion rather than the carbonate ion to form a
precipitate. In the case of TBAI (C5),[27] the iodide ion reacted
with sAuNPs to decrease the absorbance. All of the organic
solvents tested showed high correlation regardless of the
solubility of the iodide ion in the various solvents. Reliable
data were obtained when this assay was conducted two
further times.[28]
As shown in Figure 3, most of conversion extents in this
assay showed high correlation with those from GC, with
errors in the range of Æ 10%. Furthermore, the color change
gives information about the range of conversion extents
(Figure 4). We compared the detected colors of this assay with
the expected colors obtained from the conversion extents of
the GC analysis (given as five colors corresponding to five
conversion ranges).
A variety of aryl iodides and nucleophiles were screened,
and all showed reliable conversion extents, regardless of
whether they had an electron-donating or electron-withdraw-
ing group. Notably, this assay does not suffer interference
from stoichimetric amounts of metals present in nucleophiles,
such as tin (Stille), silane (Hiyama), and boron (Suzuki), even
though they could produce complexes with iodide ions in the
reaction mixture (Figure 4, columns 4, 6, 9, and 10). More-
over, this assay showed reliable conversion extents in the
presence of 5 mol% CuI (Sonogashira, column 5). It is well
known that finding a suitable palladium source and ligand is
the most important factor in cross-coupling reactions. This
In conclusion, we have developed a gold nanoparticle
based assay for sensing iodide ions and demonstrated the
usefulness of this method as a general and simple way for
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Angew. Chem. Int. Ed. 2011, 50, 4386 –4389

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One of the most important features of this assay is that it does
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screen each target coupling reaction. Furthermore, this assay
showed a high tolerance of the functional groups of substrates,
metals in nucleophiles, bases, solvents, and even anions of
salts. We obtained information on conversion extents from
the absorbance and the change in color under very dilute
conditions. Moreover, this assay allows the conversion extents
of 96 samples to be recorded in a few minutes and at
concentrations of less than 5 mm. Although the assay pre-
sented herein is restricted to obtaining the extent of
conversion, we believe that its efficiency and versatility will
be of great help in finding optimal conditions for any
substituted reactions of organic iodides.
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Received: January 16, 2011
Published online: April 11, 2011
Keywords: cross-coupling · gold · high-throughput screening ·
.
palladium · sensors
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[28] Data from two additional experimental runs are shown in the
Supporting Information, Tables S15 and S16.
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