Paper-Based Colorimetric Sensor System for High-Throughput Screening of C?H Borylation

Article abstract of DOI:10.1002/chem.201701256

A paper-based colorimetric sensor system (PBCSS) was developed to detect the amount of bis(pinacolato)diboron (B₂Pin₂) and applied as a high-throughput screening protocol in Ir-catalyzed C?H borylation. First, 96 ligands were screened for the borylation of benzene, and then 12 of them were selected and tested for five substrates. These reaction mixtures were spotted in the PBCSS, showing a blue-violet color. The value of the gray scale of each reaction was obtained from these colored spots and converted to the extent of conversion of B₂Pin₂. The extents of conversion of B₂Pin₂ obtained from the PBCSS showed good correlation with those obtained from gas chromatography analysis. In addition, the modified conversion using blank data showed good correlation with the yield of products.

Full text of DOI:10.1002/chem.201701256

A Journal of
Accepted Article
Title: Paper-Based Colorimetric Sensor System for High-Throughput
Screening of C-H Borylation
Authors: Han-Sung Kim, Min Sik Eom, Min Su Han, and Sunwoo Lee
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201701256
Link to VoR: http://dx.doi.org/10.1002/chem.201701256
Supported by

Chemistry - A European Journal
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COMMUNICATION
Paper-Based Colorimetric Sensor System for High-Throughput
Screening of C-H Borylation
†
[a]
† [b]
[b]
[a]
Han-Sung Kim,
Min Sik Eom,
Min Su Han* and Sunwoo Lee*
Dedication ((optional))
Abstract: A paper-based colorimetric sensor system (PBCSS) was
2
developed to detect the amount of bis(pinacolato)diboron (B Pin )
expensive instruments and need at least several minutes to
analyze one sample. Although UV-visible and fluorescence
spectroscopy provide quick analysis results, and colorimetric
assays are simple and inexpensive, they are limited to specific
2
and applied as a high-throughput screening protocol in Ir-catalyzed
C-H borylation. First, 96 ligands were screened for the borylation of
benzene, and then 12 of them were selected and tested for five
substrates. These reaction mixtures were spotted in the PBCSS,
showing a blue-violet color. The value of the gray scale of each
reaction was obtained from these colored spots and converted to the
[12]
substrates and the latter does not give precise information. To
address these issues, we developed a simple and general HTS
assay for C-H borylation. To the best of our knowledge, an
efficient HTS assay for C-H borylation has not been reported.
Recently, we developed a colorimetric assay for the HTS of
the transition-metal-catalyzed coupling reaction of aryl or alkyl
2 2 2 2
extent of conversion of B Pin . The extents of conversion of B Pin
obtained from the PBCSS showed good correlation with those
obtained from gas chromatography analysis. In addition, the
modified conversion using blank data showed good correlation with
the yield of products.
[13]
iodides using gold nanoparticles or a paper-based colorimetric
[
14]
iodide sensor (PBCIS).
The PBCIS is a simple and easy
handling protocol for monitoring the transformation of aryl and
alkyl iodides. We also reported a general HTS protocol for the
[
15]
coupling reactions of aryl halides.
Although these protocols
Direct introduction of new functional groups or coupling
reactions through C-H activation are efficient, environmentally
friendly, and inexpensive in the synthetic chemistry field,
because they do not need a prefunctionalization step for the
have several advantages such as being simple, fast, and easily
accessible and not being limited by the structure of the
substrates, they might produce false-positive hits due to the
decomposition or unwanted coupling reactions of starting
materials. To address this drawback and to meet the
requirement of simple HTS protocol for C-H borylation, herein,
we report the development of a paper-based colorimetric sensor
system (PBCSS) for C-H borylation.
[1]
active species. Many C-H activation methodologies have been
developed in the last decades and used in the pharmaceutical
[
2]
and materials industry. Among them, C-H borylation is one of
the most useful reaction methods, because the products such as
aryl or alkyl borates are not only easily transformed to other
To develop a general HTS tool for C-H borylation, we focused
on a paper-type sensor that is readily accessible and simple.
The PBCSS is made by soaking a filter paper in a buffer solution
[
3]
functional groups, but also react with the coupling partners.
The most general method is the reaction of a substrate with
bis(pinacolato)diboron (B Pin ) or pinacolborane (HBpin) in the
presence of an Ir catalyst.
2
2
containing I
present in PBCSS is converted to I
reducing reagent such a carbon monoxide.
Pin in an Ir-catalyzed C-H borylation reaction mixture can
react with the I present in the PBCSS because B Pin is a
reducing agent, resulting in the formation of I forms a
2
O
5
and starch, followed by drying the paper. The
[
4]
The regioselectivity of C-H
I
2
O
5
2
when it reacts with a
borylation is controlled by the steric or electronic property of the
substrate. The efficiency of an Ir-catalyzed C-H borylation
depends on the Ir source, ligand, solvent, and temperature. To
determine the suitable parameters for a substrate, considering
large numbers of combination of parameters, it is important to
use an efficient high-throughput screening (HTS) assay that can
[16]
The residual
B
2
2
2
O
5
2
2
[17]
2
.
This I
2
complex with the starch present on the PBCSS, inducing a blue-
[18]
violet color as shown in Scheme 1.
[
5]
rapidly identify the outcome. Recently, Smith and co-workers
reported the optimization of Ir-catalyzed C-H borylation by HTS
[
6]
using an automated HPLC. Automated analysis instruments
[7]
[8]
[9]
[10]
[11]
such as NMR, HPLC, GC, MS, and GCMS have been
commonly used as HTS tools in metal-catalyzed transformations.
However, they have several drawbacks such as they are
[
a]
b]
H.-S. Kim, Prof. Dr. S. Lee
Department of Chemistry, Chonnam National University
Gwangju, 61186, Republic of Korea
E-mail: sunwoo@chonnam.ac.kr
[
M. S. Eom, Prof. Dr. M. S. Han
Department of Chemistry
Gwangju Institute of Science and Technology (GIST)
Gwangju, 61005, Republic of Korea
E-mail: happyhan@gist.ac.kr
Scheme 1. Preparation of PBCSS and method for determining the
concentration of B Pin .
2 2
†
These two authors contributed equally
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
2 2
To determine the optimal conditions of PBCSS for B Pin
quantification, the PBCSS was prepared using various
conditions of the PBCSS components. Various concentrations of
2 5
I O and pH levels were tested, and the concentration of starch
[
14]
was fixed at 10 g/L according to previous studies.
(see
Supporting Information) The optimal condition of a solution for
preparing the PBCSS involves a citrate buffer solution (pH 4,
2
B
B
50 mM) containing starch (10 g/L) and I
2
O
5
(5 mM). To quantify
, the PBCSS was spotted with various concentrations of
and scanned using a flat-bed scanner, and the scanned
2
Pin
Pin
2
2
2
image was converted to a grayscale. The grayscale intensities of
the spots were analyzed using a Photoshop program, and the
B
2
Pin
intensities. The grayscale intensities in the scanned image of the
PBCSS exhibited high correlation with the Pin
concentrations (Figures 1(a) and 1(b)). Moreover, the PBCSS
showed a high selectivity for B Pin over other potential borate
2
concentrations were calculated from the grayscale
a
B
2
2
2
2
species including HBpin generated in the Ir-catalyzed C-H
borylation reaction (Figures 1(c) and 1(d)).
Figure 1. (a) Grayscale image of the PBCSS for
2 2
B Pin titration. (b)
Calibration curve of the PBCSS for B Pin . (c) Grayscale image of the PBCSS
2
2
for borate species. (a : phenylboronic acid pinacol ester, b : phenylboronic acid,
c : boronic acid, d : HBpin). (d) Response of PBCSS to borate species.
With this PBCSS in hand, first 96 ligands used in Ir-catalyzed
C-H borylation were screened. The reaction of benzene (1) with
B
2
Pin
reaction.
Seven types of ligands – phenanthroline, monopyridine,
bipyridine, aliphatic amine, 1,3-diketone, heterocyclic
2 2
and [Ir(COD)(OMe)] was selected as the standard
compounds bearing nitrogen (imidazole, pyrazole), and
bisphosphine – were selected and applied to 96 ligands (L1~96)
in the standard reaction. After completing the reaction, the
reaction mixture was diluted to 25 mM. Then, 2 μL of the diluted
reaction mixture was dropped on the PBCSS. These 96 samples
showed different color from blue-violet to white in a few minutes
(
see Supporting Information).
The paper was scanned as shown in Figure 2(b), and the
image was converted to a grayscale. Based on these data and
the equation of the standard curve, the extent of conversion of
Figure 2. (a) Scheme of Ir-catalyzed C-H borylation. (b) Grayscale image of
the PBCSS for 96 reaction samples. (c) Grayscale image of the PBCSS for 96
blank reaction samples. (d) Correlation graph between the modified extents of
conversion from the PBCSS and yields obtained from GC analysis.
B
2
Pin
2
was obtained. However, the conversions did not always
Pin is
match with the yields of the products, because B
2
2
decomposed or converted to unwanted compounds. To address
this issue, blank reactions were run using the 96 ligands,
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Chemistry - A European Journal
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COMMUNICATION
[
Ir(COD)(OMe)]
reaction samples were spotted in the PBCSS, and the scanned
image is shown in Figure 2(c). Thus, the conversions of B Pin
2
, and B
2
Pin
2
without the substrate. All the
each ligand. [Modified conversion of B
Pin in the presence of substrate - conversion of B
absence of substrate].
2
Pin
2
= conversion of
B
2
2
2
Pin in the
2
2
2
in the absence of substrate, the blank data, were obtained from
the PBCSS. Considering of these blank data, the modified
extents of conversion of B Pin were recalculated.
2 2
Based on these data obtained from the PBCSS, the best
condition for each substrate was selected. As shown in Table 1,
the yields of the products are consistent with the extents of
As shown in Figure 2(d), the modified conversions correlate
with the yields of the product obtained from the GC analysis in
most of the cases. We found that the modified conversions did
not provide the wrong information which might be caused by the
false-positive hits. These data, provided information about the
activity of the ligands in the Ir-catalyzed C-H borylation.
Phenanthroline and bipyridine derivatives were good ligands,
other ligands were not suitable for this reaction. However, in
some cases, the yield of the product was higher than the
2 2
modified conversion of B Pin . In addition, the isolated yields are
consistent when the reaction were conducted using the best
condition.
[
a]
Table 1. Ir-catalyzed C-H borylation of five substrates
O
O
O
O
B
B
R1
O
O
R2
R3
R1
B
R2
R3
.
0 5 mol Ir COD OMe
)(
)]
2
%
[
(
O
,
B
O
12
O
1
S
mol% Ligand
o ven ,
O
conversion of B
ligands exhibited good activity for HBpin which was formed from
Pin in the reaction. In addition, the blank reaction data
provided information about the decomposition of B Pin
To further evaluate this PBCSS, five substrates such as 1,2-
dimethylbenzene (3), 1,3-dimethoxybenzene (4), 1,3-
2
Pin
2
. This false-negative hit, indicates that some
o
7
l
t
80
C
:
R1 R2
,
=
=
=
M
e
,
R
3
=
H
=
8
9
:
:
R
R
:
1,
R2
=
=
M
e
R
3
=
H
3
4
5
: R1
: R
,
,
=
3
OM
e
,
2
1,
3
e
,
2
=
,
=
R
R
R
H
R
OM
R
H
B
2
2
1
3
,
2
=
,
10 R1 R3 Cl
,
=
,
2
Cl
R
=
H
3
R
H
R
.
6 : R
1
B
r
,
R2
H
R
=
M
e
,
11
:
R
1
=
B
r
,
R2
=
H
3
=
,
M
e
2
2
B
r
R2
R3
=
R1 R2
,
1,
,
3
,
R4 Me
2,
3
=
R OH
=
L2
R
=
R1
R4 L3 =
,
R4
2
H O
R
H
H
R
dichlorobenzene (5), 1-bromo-3-methylbenzene (6), and
benzo[b]furan (7) were reacted with 12 ligands, which showed
good activity in the C-H borylation of benzene. These 60
reactions were conducted in THF. After the completion of the
reactions, all the samples were treated with similar methods and
the reaction mixtures were spotted on the PBCSS. As shown in
Figure 3, all the spots from substrates 5 and 6 showed very dark
color, indicating that THF is not a suitable solvent. Therefore,
heptane and methyl tert-butyl ether (MTBE) were selected for
substrates 5 and 6, respectively. These additional 24 reactions
were conducted, and the reaction mixtures were spotted on the
PBCSS. A total of 84 spots were scanned and transformed to
grayscale image.
N
N
L14 R1 R4
=
,
=
,
,
R2 R3
=
e
M
N
N
N
N
L9
L16
Yield
Yield
(%)
Substrate
Ligand
Solvent
M.PBCSS
Product
[b]
[c]
(
%)
85
74
85
92
88
3
4
5
6
7
L14
L16
L3
L2
L9
THF
THF
Heptane
MTBE
THF
100
99
100
100
100
8
9
10
11
12
77
71
80
84
83
[
a]
Reaction condition : substrate (15 mmol), B
2
2 2
Pin (3 mmol), [Ir(COD)(OMe)]
[c]
[b]
(
0.015 mmol), ligand (0.03 mmol). Determined by GC analysis. Isolated
yield.
In summary, a HTS protocol was developed for C-H borylation
using a PBCSS for the first time. This system was prepared by
soaking a filter paper in a buffer solution containing I and
starch. The PBCSS generated blue-violet color in the presence
of residual B Pin in an Ir-catalyzed reaction library. The color
change exhibited a high correlation with the B Pin concentration
2
O
5
2
2
2
2
and efficiency of Ir-catalyst. This PBCSS has several
advantages : 1) The preparation method is very simple and
inexpensive, 2) It is readily accessible because only a paper and
scanner are needed, 3) It provides fast and accurate extent of
2 2
conversion of B Pin by qualitative analysis using visual color
change and quantitative conversions using a grayscale image, 4)
The use of blank data removes the wrong information caused by
the false-positive hits.
Figure 3. Grayscale image of the PBCSS for 84 reaction samples.
2 2
Based on these values, the extent of conversion of B Pin in
each sample was calculated. Finally, the modified conversions
that removed the false-positive hits caused by the
2 2
decomposition of B Pin were obtained. These values were
obtained by excluding the conversions from the blank data of
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COMMUNICATION
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HTS : The reaction mixture (2 μL aliquot) was dropped onto the
prepared PBCSS. For reproducible results, the following
essential procedures were used. The first procedure is the
removal of the organic solvent in the PBCSS. Because of the
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presence of residual B Pin in the organic phase after the
completion of the reaction, the reaction mixture (0.2 mL) was
extracted with ethyl acetate (1.3 mL) and water (5 mL) in a 10-
mL vial. After the extraction, 3 M brine (1 mL) containing sodium
chloride (17.5 g) and water (100 mL) was added to break the
emulsion. Then, 1 M HCl (1 mL) diluted with water (5 mL) was
added. Then, the diluted solution was dropped on the PBCSS.
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water is added directly, the colored complex is eluted into the
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incubated for 30 min in a closed box filled with water vapor for
uniform water supply at room temperature. After the incubation,
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2 2
Keywords: B Pin • High-throughput screening • C-H activation
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Paper-based colorimetric sensor for
the detection of bis(pinacolato)diboron
Han-Sung Kim, Min Sik Eom, Min Su
Han*, Sunwoo Lee*
2 2
(B pin ) was developed and used as
the High-Throughput Screening (HTS)
protocol in the Ir-catalyzed C-H
borylation. It was proved to be an
efficient tool in the screening of the C-
H borylation.
Page No. – Page No.
Paper-Based Colorimetric Sensor
System for High-Throughput
Screening of C-H Borylation
Layout 2:
COMMUNICATION
Page No. – Page No.
.
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