Hg(II)-mediated intramolecular cyclization reaction in aqueous media and its application as Hg(II) selective indicator

Article abstract of DOI:10.1021/ol4000873

The Hg(II)-specific intramolecular cyclization reaction of ethynyl phenols was carried out for the first time in semiaqueous media at ambient temperature. The reaction unit (ethynyl phenol) was coupled with a malononitrile derivative (signal unit), which afforded the chromogenic Hg(II) indicator 7. The reaction of the chromogenic Hg(II) indicator 7 was further optimized in DMSO/water (3:7, v/v) (10 mM PBS buffer, pH = 7.0). Compound 7 displays a color change from blue to pale yellow in the presence of Hg(II).

Full text of DOI:10.1021/ol4000873

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1072–1075
Hg(II)-Mediated Intramolecular Cyclization
Reaction in Aqueous Media and Its
Application as Hg(II) Selective Indicator
Ananta Kumar Atta,† Seul-Bi Kim,† Jungseok Heo,‡ and Dong-Gyu Cho*,†
Department of Chemistry, Inha University, 253 Yonghyundong, Namgu, Incheon
402-751, Republic of Korea, and Department of Chemistry, Chungnam National
University, 99 Daehak-ro, Yuseong-go, Daejeon, 305-764, Republic of Korea
dgcho@inha.ac.kr
Received January 11, 2013
ABSTRACT
The Hg(II)-specific intramolecular cyclization reaction of ethynyl phenols was carried out for the first time in semiaqueous media at ambient
temperature. The reaction unit (ethynyl phenol) was coupled with a malononitrile derivative (signal unit), which afforded the chromogenic Hg(II)
indicator 7. The reaction of the chromogenic Hg(II) indicator 7 was further optimized in DMSO/water (3:7, v/v) (10 mM PBS buffer, pH = 7.0).
Compound 7 displays a color change from blue to pale yellow in the presence of Hg(II).
Many metal ions are necessary to sustain life, and they
are precisely controlled in ecology and biology. Never-
theless, one heavy metal ion, Hg(II), is extremely toxic and
possesses no benign effect. The toxicity of the Hg(II) cation
isrelatedtothefactthatbiological ligands suchasproteins,
DNA, and enzymes can coordinate with mercury cations.
Consequently, toxic levels of Hg(II) cause significant
damage to the brain, kidney, stomach, and central ner-
vous system.1 Therefore, detection of toxic Hg(II) ions in
environmental and biological samples is of primary inter-
est. Many different chemical sensors have been developed
as prototype tools for detecting toxic Hg(II). Since Czar-
nik’s seminal work,2 analyte-specific reaction indicators3
have attracted considerable attention and become an im-
portant research area in supramolecular chemistry. This
approach relies on an irreversible chemical reaction rather
than on reversible interactions.4 Consequently, all the
characteristics, including sensitivity and selectivity, depend
on a Hg(II)-specific reaction instead of a shape-recognition
process (lock and key concept). Thus far, most of the
reported Hg(II) selective reaction-based detection strate-
gies can be classified as Hg(II)-specific hydration reactions
of alkynes or alkenes5 or reactions related to the thiophilic
nature of Hg(II), which constitute the majority of Hg(II)
selective reaction-based indicators. This thiophilic nature
of Hg(II) is interrelated to many different Hg(II) selective
reactions, including intramolecular cyclic guanylation of
† Inha University.
‡ Chungnam National University.
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r
10.1021/ol4000873
Published on Web 02/20/2013
2013 American Chemical Society

thiourea derivatives,6 ring-opening of spirocyclic systems,7
desulfurizationÀlactonization reactions,8desulfurization
of thiocarbonyl compounds,2,9 deprotection of dithiol-
protected aldehydes,10 and hydrolysis reactions of thioethyl
carbamate.11 Some of the above Hg(II) indicators have their
own novel Hg(II)-specific reaction, which displayed dif-
ferent advantages. For example, a rarely known hydrolysis
reaction of thioethyl carbamate was first used as a Hg(II)-
specific reaction, which enabled us to synthesis the coumarin-
based Hg(II) indicator in a single step from commercially
available starting materials.11 Since then, our interests
have been further extended to finding Hg(II)-specific
reactions that have never been used for detecting Hg(II)
analytes. This approach necessarily includes a new reac-
tion methodology and a better understanding of existing
mechanisms. Here, we report the first (to the best of our
knowledge) Hg(II)-mediated synthesis of benzofuranyl-
mercury derivatives from ethynyl phenol substrates in a
semiaqueous solution. Hg(II)-specific intramolecular cy-
clization between phenol and acetylene occurs to form a
benzofuranylmercury chloride, which was characterized
by X-ray crystallograpy. This methodology was further
applied to develop a Hg(II) selective indicator.
Surprisingly, the reaction with an alkyl group on ethynyl
nitrophenol 5 proceeded faster than 3, affording 5a in 95%
yield after only 2 min (entry 5).
Table 1. Various Phenolic Substrates in the Hg(II)-Mediated
Cyclization Reactiona
Intramolecular alkoxymercuration reactions were first
reported in 1984,12 and the utility of similar reactions has
been proven many times in the literature.13 Unfortunately,
the alkoxymercuration reaction is known to proceed best
in acetic acid, which is not suitable for Hg(II) selective
reaction-based detection strategies due to the harsh acidic
conditions and longer reaction times. Here, we hypothe-
sized that a more reactive phenolic OH may be able to
accelerate the reaction. Various ethynyl phenol substrates
were tested for the cyclization reaction, as shown in Table 1;
simple phenol did not induce the formation of the desired
product or of any other products (entry 1). To activate the
phenolic OH more, electronic effects were examined. A
nitro group on phenolic substrate 3 afforded cyclized
product 3a with 93% yield in 10 min, while methoxylated
substrate 2 did not result in any desired product even after
an extended time. To obtain a simple Hg(II) indicator, less
substituted phenolic substrates 4 are highly desired. How-
ever, substrate 4 was unreactive under the same conditions.
a All reactions were run on a 17 mM scale (phenolic substrate). HgCl2
(2 equiv, in water) was added to a solution of the substrate in DMSO at
25 °C. The final solvent ratio (water/DMSO = 1/4, v/v) was carefully
adjusted (cf. the Supporting Information). b Isolated yields.
Most of the unknown compounds were characterized by
1H and 13C NMR spectroscopy and high-resolution mass
spectrometry. However, not all of the 13C NMR spectra of
the products in Table 1 were clear, and we found that 13
C
NMR spectra of benzofuranylmercury chloride com-
pounds were not reported in the literature.11 The unavail-
ability of the 13C NMR spectra should be related to the
fact that two Hg isotopes (199Hg and 201Hg) possess spin
quantum numbers that interact with the 13C isotope. To
confirm the product of the cyclization reaction (or the
expected mechanism), a single crystal of 5a was grown
from a mixture of ethyl acetate and n-hexane by slow
evaporation of the solvent. The X-ray structure of 5a
clearly proves that the Hg(II)-specific reaction affords
the benzofuranylmercury chloride derivative (Figure 1).
An interesting feature of the cyclization reaction of
phenolic substrates to benzofuranylmercury derivatives is
that the cyclization products change the conjugation path-
way of the phenolicsubstrates (Table 1, see entries 3 and 5).
We thus imagined that this reaction could be used to
produce a specific Hg(II)-mediated color change, provided
a suitably colored phenol derivative could be obtained. To
test this hypothesis, π-extended 7 was designed and pre-
pared from 4-formyl-2-iodophenyl acetate, as shown in
Scheme 1. Compound 6 was obtained in 92% yield by
Sonogashira coupling between 4-formyl-2-iodophenyl acetate
(7) (a) Wang, H.-H.; Xue, L.; Yu, C.-L.; Qian, Y.-Y.; Jiang, H. Dyes
Pigm. 2011, 91, 350–355. (b) Lin, W.; Cao, X.; Ding, Y.; Yuan, L.; Long,
L. Chem. Commun. 2010, 3529–3531. (c) Shi, W.; Ma, H. Chem.
Commun. 2008, 1856–1858. (d) Yang, Y.-K.; Ko, S.-K.; Shin, I.; Tae,
J. Nat. Protoc. 2007, 2, 1740–1745. (e) Yang, Y.-K.; Yook, K.-J.; Tae, J.
J. Am. Chem. Soc. 2005, 127, 16760–16761.
(8) Jiang, W.; Wang, W. Chem. Commun. 2009, 3913–3915.
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Chang, S.-K. Tetrahedron Lett. 2010, 51, 167–169. (b) Choi, M. G.; Kim,
Y. H.; Namgoong, J. E.; Chang, S.-K. Chem. Commun. 2009, 3560–
3562. (c) Song, K. C.; Kim, J. S.; Park, S. M.; Chung, K.-C.; Ahn, S.;
Chang, S.-K. Org. Lett. 2006, 8, 3413–3416.
(10) Kim, J. H.; Kim, H. J.; Kim, S. H.; Lee, J. H.; Do, J. H.; Kim,
J. S. Tetrahedron Lett. 2009, 50, 5958–5961.
(11) Kim, S.-B.; Cho, D.-G. Eur. J. Org. Chem. 2012, 2012, 2495–
2498.
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Org. Lett., Vol. 15, No. 5, 2013
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and phenyl acetylene. Compound 6 was then condensed
with a malononitrile derivative. Deacetylation occurred
simultaneously to afford 7 in 44% yield.
by increasing the PBS buffer content from 30% to 70% in
DMSO (Supporting Information, Figure S1). Under the
optimal conditions, the reaction of 7 (11 μM) was fast
enough to reach completion in 20 min in the presence of
2 equiv of Hg(II). In the absence of Hg(II), the absorption
maximum of compound 7 was observed at 608 nm, as
illustrated in Figure 2. After addition of 2 equiv of HgCl2,
further spectral changes were not observed after 20 min.
Figure 1. Single-crystal X-ray diffraction structure of 5a. Ther-
mal ellipsoids are scaled to the 50% probability level. Disorder
of alkyl group was found in the X-ray structure of 5a.
Scheme 1. Synthesis of Hg(II)-specific Indicator
Figure 2. UVÀvis spectra of indicator 7 (11 μM) in DMSO/
water (3:7, v/v) (10 mM PBS buffer, pH = 7.0), recorded before
and 20 min after the addition of HgCl2 (2 equiv, 6.60 Â 10À3 M
in water) at 25 °C.
To test the selectivity of compound 7, 2 equiv of each
cation (Cu(I), Cu(II), Au(III), Co(II), Hg(II), Fe(III),
Zn(II), Ag(I), Pb(II), Na(I), Pt(II), Fe(II), Ni(II), Al(III),
Mg(II), K(I), Cd(II), and Ca(II)) were added to solutions
of 7 (11 μM) in DMSO/water (3:7, v/v) (10 mM PBS
buffer, pH = 7.0), and the absorbance spectra were re-
corded20min later. Asshown in Figure 3a, the absorbance
band at 608 nm completely disappeared in the presence of
Hg(II). In this case, a dramatic color change was also
observed, from blue to pale yellow (Figure 3b). Although a
slight color change was observed for Au(III) due to the
alkynophilicity of gold ions,14 no color change was seen
upon the addition of other metals. In the presence of gold
ions, the solution shows a different color as well (Figure 3b).
Competition experiments were also carried out by add-
ing 2 equiv of Hg(II) to the buffered solutions in the
presence of 2 equiv of other metal ions, as shown in
Figure 3c. The presence of other metal ions did not
interfere with the detection of Hg(II) ions, which indicates
that the system of compound 7 and Hg(II) was barely
affected by these coexistent ions (Figure 3c).
Scheme 2. Proposed Mechanisms of Hg(II)-Mediated
Intramolecular Cyclization
The cyclization reaction of 7 was monitored by UVÀvis
spectroscopy. We found that the progress of the Hg(II)-
specific reaction of 7 is inversely proportional to the
absorbance of 7 at 608 nm (Figure 2). This characteristic
absorbance change of 7 enabled us to monitor the progress
of the reaction with a UVÀvis spectrophotometer. It should
be noted that the reaction was complete in 3 h, and 7a was
isolated in 80% yield under the conditions listed in Table 1.
The isolated product was confirmed by 1H NMR spectros-
copy and high-resolution mass spectrometry. From these
results, it can be concluded that compound 7 underwent
Hg(II)-mediated intramolecular cyclization in aqueous buf-
fered media (Scheme 2). The reaction was further optimized
The sensitivity of 7 to Hg(II) was evaluated upon the
addition of various amounts of Hg(II) to solutions of 7.
The reactions were carried out for 20 min to ensure
completion of the reaction, and the absorbance at 608 nm
was recorded (Figure 4a). To obtain the detection limit,
four independent UVÀvis titrations were carried out at
(14) For Au(III) indicators using alkynes, see: Seo, H.; Jun, M. E.;
Egorova, O. A.; Lee, K.-H.; Kim, K.-T.; Ahn, K. H. Org. Lett. 2012, 14,
5062–5065 and references cited therein.
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Org. Lett., Vol. 15, No. 5, 2013

Figure 4. (a) UVÀvis spectra were recorded 10 min after adding
various quantities of Hg(II) (0À2 equiv of Hg(II)) to compound
7(11μM) in DMSO/water (3:7, v/v) (10 mM PBS buffer, pH = 7.0).
(b) Observed color change seen 10 min after adding various
quantities of Hg(II) (0À4 equiv of Hg(II)) to compound 7(33μM)
in the above conditions.
In conclusion, we disclosed a Hg(II)-specific intramolec-
ularcyclizationreactionofethynylphenolsinsemiaqueous
media at ambient temperature. The reaction was further
optimized and utilized as a Hg(II)-specific reaction for the
application of 7 as a Hg(II) indicator. Compound 7 dis-
plays a color change from blue to pale yellow in the presence
of Hg(II). More importantly, this stepwise approach that
discovered a new analyte-specific reaction, which affords an
analyte-specific indicator, could result in new research
avenues in supramolecular analytical chemistry.
Figure 3. (a) Absorbance responses of 7 (11 μM) with various
metal ions (2 equiv) in DMSO/water (3:7, v/v) (10 mM PBS
buffer, pH = 7.0). All measurements were conducted 20 min
after the addition of various ions. (b) Observed color change of 7
(11 μM) seen without or with various metals (2 equiv) in DMSO/
water (3:7, v/v) (10 mM PBS buffer, pH = 7.0). From left to
right: Hg(II), no metal, Cd(II), Cu(III), Au(III), Ni(II), Ag(I).
(c) Metal-ion selectivity of 7 (11 μM). The black bars represent
the absorbance of 7 at 608 nm in the presence of other cations
(2 equiv). The gray bars represent the absorbance that occurs
upon the subsequent addition of 2 equiv of Hg(II) to the above
solution.
Acknowledgment. This research was supported by the
Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the
Ministry of Education, Science and Technology (Grant
No. 2010-0004206). We acknowledge Dr. Kun Cho from
the mass spectrometry laboratory of Korea Basic Science
Institute for MS analysis.
Hg(II) concentrations from 0 to 5.5 μM, which afforded
average values with the standard deviation (σ = 0.0028)
and the linear slope (absorbance vs Hg(II) concentration,
m = 64198 MÀ1, and R2 = 0.9995) shown in Figure S2
(Supporting Information). The corresponding detection
limit was determined to be 0.13 μM based on the expres-
sion 3σ/m.15 As mentioned above, Hg(II) triggered a
color change of 7; the colorimetric detection limit can
be less than 8.3 μM, as shown in Figure 4b.
Supporting Information Available. Experimental pro-
cedures, structural proofs, and spectral data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Hasebe, K.; Osteryoung, J. Anal. Chem. 1975, 47, 2412–2418.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
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