A simple, fast, and easy assay for transition metal-catalyzed coupling reactions using a paper-based colorimetric iodide sensor

Article abstract of DOI:10.1039/c2cc31679j

A paper-based colorimetric iodide sensor (PBCIS) that consists of filter paper treated with starch and an oxidant is developed. It has been employed as a protocol to obtain the extent of conversion of aryl iodides in C-C, C-N, C-O and C-S bond formations, including polymer-supported Heck reactions, by transition metal catalysts such as palladium, nickel and copper.

Full text of DOI:10.1039/c2cc31679j

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A simple, fast, and easy assay for transition metal-catalyzed
coupling reactions using a paper-based colorimetric iodide
sensor.
A paper-based colorimetric iodide sensor (PBCIS) that consists
of a filter paper treated with starch and an oxidant is developed.
It has been employed as a protocol to obtain the extent of
conversion of aryl iodides in C-C, C-N, C-O, and C-S bond
formations, including polymer-supported Heck reactions,
by transition metal catalysts such as palladium, nickel, and copper.
This sensor is very simple, easy, quick, reliable, and tolerant toward
the functional groups of all reagents.
See Min Su Han and Sunwoo Lee et al.,
Chem. Commun., 2012, 48, 8751.
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COMMUNICATION
A simple, fast, and easy assay for transition metal-catalyzed coupling
reactions using a paper-based colorimetric iodide sensorw
a
b
Sudeok Kim,z Eunhye Jung,z Mi Jin Kim,a Ayoung Pyo,b Thiruvengadam Palani,b
Min Sik Eom,a Min Su Han*a and Sunwoo Lee*b
Received 6th March 2012, Accepted 2nd April 2012
DOI: 10.1039/c2cc31679j
A paper-based colorimetric iodide sensor (PBCIS) that consists
of filter paper treated with starch and an oxidant is developed.
It has been employed as a protocol to obtain the extent of
conversion of aryl iodides in C–C, C–N, C–O and C–S bond
formations, including polymer-supported Heck reactions, by
transition metal catalysts such as palladium, nickel and copper.
the coupling reaction of substrates (such as thiol derivatives)
that have a high binding affinity to gold nanoparticles; (2) the
synthesis of gold nanoparticles and the preparation processes
of their stock solution are required; and (3) a specific instrument
such as a microplate reader is required to determine the extent
of conversion precisely. Therefore, it was necessary to develop
an easily accessible, simple method that does not require
expensive or specific instruments.
A number of new methodologies have been reported, and
among them, much attention has been paid to catalytic
reaction systems, especially transition metal-catalyzed coupling
reactions.1 The necessary analysis of the effect of the source of
the metal; the ligand, base, and solvent; and time and temperature
is time-consuming. To address this problem, a variety of high-
throughput screening (HTS) methods have been developed for use
in transition metal-catalyzed reactions.2 Because of the favorable
analysis time of the reaction, fluorescence spectroscopy3a is a more
powerful analytical tool than traditional methods such as nuclear
magnetic resonance spectroscopy (NMR),3b infrared spectroscopy
(IR),3c mass spectrometry (MS),3d gas chromatography (GC),3e
and high-performance liquid chromatography (HPLC).3f
However, fluorescence spectroscopy has been limited to the
coupling reactions of substrates with fluorophores.4 Although
the colorimetric assay is one of the most convenient methods
for monitoring reactions,5 it is limited to specific reactions and
does not show the progress of the reaction through color
changes that could be quantified. To find a new reaction
method using HTS, multi-component systems of random
libraries using robotics, LC/MS, GC/MS and DNA-templated
synthesis have been reported.6 However, they all required
expensive instruments or specific materials.
Compared to solution-based colorimetric sensors, paper-based
colorimetric sensors such as litmus paper are simple, rapid,
inexpensive, and user-friendly. They are used for diagnostics,
monitoring food and water, environmental analysis, and assaying
biocatalysts.8 Although many solution-based colorimetric sensors
have been used for catalysts in HTS, few HTS techniques have
used paper-based colorimetric sensors.9
We designed paper bearing starch and an oxidant as a
colorimetric iodide sensor. This sensor was prepared by soaking
pure filter paper in a solution of starch and oxidant, and then
drying it. The oxidant in the sensor oxidizes the iodide ions to
iodine and the iodine reacts with starch to form a blue-violet
complex. The paper can be scanned in a flatbed scanner and,
using Adobe Photoshop, the image converted to show the
iodide concentration.10 The sensor also can be used as a general
monitoring method for cross-coupling reactions using an Ar–I
substrate because it detects the iodide ions released (Fig. 1).
We developed a colorimetric paper type-sensor for iodide by
examining various combinations of starch quantity, oxidant
Recently we developed a colorimetric HTS method that uses
gold nanoparticles in the palladium-catalyzed coupling reaction
of aryl iodides.7 This method provides a non-substrate-specific
way to calculate the extent of the reaction. Although the gold
nanoparticle colorimetric assay is an easy and fast screening
method, it has some drawbacks: (1) it could not be applied to
a Department of Chemistry, Chung-Ang University,
Seoul, 156-756, Republic of Korea. E-mail: mshan@cau.ac.kr
b Department of Chemistry, Chonnam National University, Gwangju,
500-757, Republic of Korea. E-mail: sunwoo@chonnam.ac.kr
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc31679j
z These authors contributed equally to this work.
Fig. 1 Schematic representation of the experimental setup.
Chem. Commun., 2012, 48, 8751–8753 8751
c
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Table 1 Correlation of the extent of conversion obtained by GC and
PBCIS in the decarboxylative coupling reactionsa
Grayscale Conv.b
Conv.c
Yield
Entry Copper
intensity (PBCIS) (%) (GC) (%) (%) Dev.d
1
2
3
4
5
6
7
8
Cu powder 245.19
0 (ꢀ1)e
0
6
0
5
0
ꢀ6
ꢀ5
+1
+7
+2
ꢀ6
ꢀ5
CuBr2
Cu2Se
CuCl
244.38
236.94
211.07
183.43
0
7
12
31
51
71
86
100
10
30
51
71
85
98
32
Cu2O
58
73
80
95
CuSO4ꢁ5H2O 167.18
CuI
Cu(acac)2
160.15
143.88
a
Reaction conditions: 4-iodotoluene (0.30 mmol), phenylpropiolic
acid (0.45 mmol), Cu source (0.03 mmol), 1,10-phenanthroline
(0.03 mmol), Cs2CO3 (0.60 mmol), and dimethylformamide (DMF)
Fig. 2 The preparation of PBCIS and method of determining the
concentration of iodide. (a) Schematic illustration of the procedure
used for preparing PBCIS and detection of Iꢀ using PBCIS. (b) Linear
calibration curve for Iꢀ. (c) Response of PBCIS to various anions.
b
were stirred at 140 1C for 24 h. The extent of conversion of
4-iodotoluene was determined by the equation [conversion (PBCIS)
% = (grayscale intensity ꢀ 244.43)/(ꢀ1.055)] which was obtained
c
from the linear plot of standard samples. The extent of conversion of
4-iodotoluene and yield of product were determined by gas chromato-
agents, and paper types to find the optimal conditions. First,
various stable oxidizing reagents were tried.10 Among the
oxidants, ferric nitrate was selected as the optimal oxidant
component because the starch paper bearing the oxidant
displayed the largest color changes and reproducibility. The
other optimal conditions such as the amount of starch and
kind of paper were also determined by trial and error.11 The
paper-based colorimetric iodide sensor (PBCIS) consists of filter
d
graphy with an internal standard material. Deviation = conversion
e
(PBCIS) % ꢀ conversion (GC) %. The minus values were obtained
from the equation, which means no conversion.
paper (Whatmans 3) soaked in a solution of starch (10 g Lꢀ1
)
and oxidant agent (Fe(NO3)3 10 mmol Lꢀ1) and then dried
(Fig. 2a). This sensor exhibited a high correlation between color
change and iodide concentration and a high selectivity for
iodide over potential additive anions in coupling reactions
(Fig. 2b and c). We converted the color changes into grayscale
values and then the value of the grayscale intensity was
quantified using Adobe Photoshop. The sensor provided similar
results during subsequent reactions in minimum 16 days.12
Therefore, the sensor satisfies the requirements for probe-based
HTS, viz. a high signal to noise ratio and good reproducibility.
We employed the colorimetric assay to monitor the extent of
conversion in the coupling reactions of aryl iodides. The
copper-catalyzed decarboxylative coupling reaction of phenyl
propiolic acid and iodotoluene was chosen as a model reaction.13
Screening of copper sources was conducted in a model reaction
(Table 1). The reaction mixture was diluted with H2O (10 mM)
and treated with 0.2 N HCl (aq) to provide a sample solution with
a concentration of 5 mM. Drops of this solution were put onto the
prepared paper-based colorimetric iodide sensor (PBCIS). All of
the reaction mixtures mentioned in the entries in Table 1 displayed
different colors in the PBCIS (Fig. 3a). The spots on the scanned
PBCIS (Fig. 3b) were converted into grayscale values (Fig. 3c)
using Adobe Photoshop. A conversion equation [conversion
(PBCIS) % = (grayscale intensity ꢀ 244.43)/(ꢀ1.055)] was
obtained from the standard sample and used to calculate the
extent of conversion of 4-iodotoluene. Spots showed good correla-
tion with the extent of conversion of 4-iodotoluene measurements
obtained through gas chromatography with an internal standard.
To examine the general application of the PBCIS method, a
variety of transition metal-catalyzed coupling reactions including
the reaction of substrates bonded to polymers were examined.14
Fig. 3 PBCIS results of the decarboxylative coupling reactions.
(a) Picture of the PBCIS results of the reactions given in Table 1.
(b) Scanned image of PBCIS. (c) Grayscale image of PBCIS. The
numbers in the images refer to entry numbers in Table 1.
Copper, nickel, and palladium were used as catalysts in the
coupling reactions of aryl iodides, and then C–S, C–O, C–N,
and C–C bond formations were evaluated (Fig. 4a).
After finishing the evaluation of the coupling reactions, all
of the samples were diluted with 0.1 N HCl solution so that the
final concentrations of iodide ions in these samples were 5 mM
with the assumption that the reactions afforded 100% conversion.
2 mL aliquots of the samples were dropped onto the PBCIS
(Fig. 4b). The resulting PBCIS was scanned and the colors of the
samples were converted into grayscale values based on the equation
[conversion (PBCIS) % = (grayscale intensity ꢀ 245.88)/
(ꢀ1.0967)] obtained from 6 standard samples (Fig. 4c). All showed
positive correlation to the extent of conversion values obtained
from gas chromatography with an internal standard.
Notable features include: (1) it takes a total of 20 minutes,
including the scanning step, to get the extent of conversion of
96 samples. (2) The color change in proportion to the concen-
tration of iodide was not affected by catalysts, ligands, bases,
or solvents. The extent of conversion of 84 out of 90 samples
(the 6 standard samples excluded) obtained from the PBCIS is
within 10 standard deviations of those obtained from the GC
methods. (3) This method is suitable for screening, under a variety
c
8752 Chem. Commun., 2012, 48, 8751–8753
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iodides in transition metal-catalyzed cross-coupling reactions,
including for substrates supported on a polymer. This method
has several advantages and features: (1) it is easily accessible in
any general laboratory. Only paper, oxidants, and a desktop
scanner are required. (2) It is an economical and environmentally
friendly method. (3) It is very simple, easy, quick, and reliable.
This work was supported by a National Research Foundation of
Korea Grant funded by the Korean Government (2010-0002350 &
2009-0072357), 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).
Notes and references
1 A. de Meijere and F. Diederich, Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, 2004.
2 J. P. Stambuli and J. F. Hartwig, Curr. Opin. Chem. Biol., 2003,
7, 420.
3 (a) G. D. Cremer, B. F. Sels, D. E. De Vos, J. Hofkens and
M. B. Roeffaers, Chem. Soc. Rev., 2010, 39, 4703; (b) Z. J. A.
Komon, G. M. Diamond, M. K. Leclerc, V. Murphy, M. Okazaki
and G. C. Bazan, J. Am. Chem. Soc., 2002, 124, 15280;
(c) S. J. Taylor and J. P. Morken, Science, 1998, 280, 267;
¨
(d) C. Markert, P. Rosel and A. Pfaltz, J. Am. Chem. Soc., 2008,
130, 3234; (e) X.-B. Jiang, P. W. N. M. van Leeuwen and
J. N. H. Reek, Chem. Commun., 2007, 2287; (f) C. Cai, J. Y. L.
Chung, J. C. McWilliams, Y. Sun, C. S. Shultz and M. Palucki,
Org. Process Res. Dev., 2007, 11, 328.
4 (a) P. Vicennati, N. Bensel, A. Wagner, C. Creminon and F. Taran,
´
Angew. Chem., Int. Ed., 2005, 44, 6863; (b) R. V. Rozhkov,
V. J. Davisson and D. E. Bergstrom, Adv. Synth. Catal., 2008,
350, 71; (c) J. P. Stambuli, S. R. Stauffer, K. H. Shaughnessy and
J. F. Hartwig, J. Am. Chem. Soc., 2001, 123, 2677; (d) V. Sashuk,
D. Schoeps and H. Plenio, Chem. Commun., 2009, 770.
5 (a) J. Pawlas, Y. Nakao, M. Kawatsura and J. F. Hartwig, J. Am.
Chem. Soc., 2002, 124, 3669; (b) O. Lober, M. Kawatsura and
J. F. Hartwig, J. Am. Chem. Soc., 2001, 123, 4366; (c) O. Lavastre
and J. P. Morken, Angew. Chem., Int. Ed., 1999, 38, 3163.
6 (a) P. J. Fagan, E. Hauptman, R. Shapiro and A. Casalnuovo,
J. Am. Chem. Soc., 2000, 122, 5043; (b) A. B. Beeler, S. Su,
C. A. Singleton Jr and J. A. Porco, J. Am. Chem. Soc., 2007,
129, 1413; (c) M. W. Kanan, M. M. Rozenman, K. Sakurai,
T. M. Snyder and D. R. Liu, Nature, 2004, 431, 545;
(d) D. W. Robbins and J. F. Hartwig, Science, 2011, 333, 1423.
7 E. Jung, S. Kim, Y. Kim, S. H. Seo, S. S. Lee, M. S. Han and
S. Lee, Angew. Chem., Int. Ed., 2011, 50, 4386.
8 (a) M. M. Ali, S. D. Aguirre, Y. Xu, C. D. M. Carlos, R. Pelton
and Y. Li, Chem. Commun., 2009, 6640; (b) M. Ornatska,
E. Sharpe, D. Andreescu and S. Andreescu, Anal. Chem., 2011,
83, 4273; (c) Z. Gu, M. Zhao, Y. Sheng, L. A. Bentolila and
Y. Tang, Anal. Chem., 2011, 83, 2324; (d) C.-M. Cheng,
A. W. Martinez, J. Gong, C. R. Mace, S. T. Phillips,
E. Carrilho, K. A. Mirica and G. M. Whitesides, Angew. Chem.,
Int. Ed., 2010, 49, 4771.
9 (a) E. Reddington, A. Sapienza, B. Gurau, R. Viswanathan,
S. Sarangapani, E. S. Smotkin and T. E. Mallouk, Science, 1998,
280, 1735; (b) O. M. Busch, C. Hoffmann, T. R. F. Johann,
H.-W. Schmidt, W. Strehlau and F. Schuteh, J. Am. Chem. Soc.,
2002, 124, 13527; (c) M. Zanger and J. R. McKee, J. Chem. Educ.,
1988, 65, 1106.
10 (a) N. A. Rakow and K. S. Suslick, Nature, 2000, 406, 710;
(b) K. S. Suslick, N. A. Rakow and A. Shen, Tetrahedron, 2004,
60, 11133.
11 See ESIw S3–S6.
12 See ESIw S7.
13 D. Zhao, C. Gao, X. Su, Y. He, J. You and Y. Xue, Chem.
Fig. 4 HTS of transition metal-catalyzed coupling reactions using
PBCIS. (a) Reaction type of transition metal-catalyzed coupling
reactions. (b) Picture of PBCIS of 96 samples. (c) Correlation of the
extent of conversion between GC and PBCIS.
of reaction conditions, coupling reactions of aryl iodides and
any substrates bearing a sulfur group, such as thiols and
thioacetates. (4) This is the first report of an HTS protocol
for polymer-supported coupling reactions which gives the
extent of conversion in less time and in fewer steps than
traditional methods.
In conclusion, the PBCIS is prepared by soaking filter paper
in a solution of starch and ferric nitrate and then drying it. The
PBCIS afforded reliable values of the conversion of aryl
Commun., 2010, 46, 9049.
14 see ESIw S9–S16.
c
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Chem. Commun., 2012, 48, 8751–8753 8753