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Featuring work from the group of As featured in:

Professor Xiaojun Peng covering fluorescent
chemosensors for bio-staining, bio-imaging,
bio-labeling and environmental detection at the State
Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian, China.
Fluorescent chemodosimeters using “mild” chemical events

for the detection of small anions and cations in biological and
environmental media
Mild chemical events have sparked the development of

chemodosimeters for successfully detecting and studying a variety
of targets in the fields of chemistry, biology, and environmental See Peng, Fan et al.,
sciences, posing huge advantages and advancements especially in Chem. Soc. Rev., 2012, 41, 4511.
terms of selectivity and sensitivity.
www.rsc.org/chemsocrev
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Cite this: Chem. Soc. Rev., 2012, 41, 4511–4535
www.rsc.org/csr CRITICAL REVIEW

Fluorescent chemodosimeters using ‘‘mild’’ chemical events for
the detection of small anions and cations in biological and
environmental media
Jianjun Du, Mingming Hu, Jiangli Fan* and Xiaojun Peng*
Received 7th January 2012

DOI: 10.1039/c2cs00004k
Mild chemical processes of various analytes and detection methods involving revolutionary
strategies in the fields of analytical chemistry, biology and environmental sciences have been
extensively developed. This critical review focuses on representative examples of mild chemical
processes that can be used in fluorescent chemodosimeters for ion sensing (anions and cations).
A systematisation according to the type of reaction mechanism is established. Numerous examples
including extensions combined with catalytic and material sciences applicable in fluorescence
imaging and water treatment are also discussed (151 references).
1. Introduction mercury ions are toxic to organisms, and their early detection
is advantageous.4,5
Numerous small anions and cations, which play vital roles in In recent years, numerous analytical technologies have been
human life, exist within organisms and in the external environ- developed to detect such environmental, medical and cellular
ment. Consequently, the detection of such targets is of great analytes. For instance, techniques based on fluorescent probes
interest and importance to many chemists, biologists and can be both sensitive and selective. They are also rapid, easily
environmentalists. For instance, iron, sodium and zinc ions carried out in real time and space, as well as economical.
are functionally involved in key biological processes, such as Consequently, they have received special attention and notable
muscle contraction, transmission of nerve impulses and regula- progress has been made.6–9 Most fluorescent probes are
tion of cell activity.1–3 Anions also play fundamental and abiotic supramolecular systems that commonly bind analytes
functional roles in many biological processes, and thus, in by noncovalent interactions, such as hydrogen bonding, electro-
healthcare. Some small ions that induce biological dysfunctions static attractions and coordination phenomena.10,11 Many
are of paramount research importance. Cyanide, lead and effective fluorescent probes have been proposed for a wide
range of targets.8,12–18
State Key Laboratory of Fine Chemicals, Faculty of Chemical, Unlike traditional probes and chemosensors that can convert
Environmental and Biological Science and Technology, a chemical stimulus into some form of action, the recently
Dalian University of Technology, Dalian, China.
E-mail: fanjl@dlut.edu.cn, pengxj@dlut.edu.cn; discovered chemodosimeters have extensive applications as
Fax: +86-411-8498-6306; Tel: +86-411-8498-6327 reagents for measuring cumulative amounts of reactants based
Jianjun Du obtained his PhD Mingming Hu received her

from the Dalian University of Bachelor of Engineering degree
Technology (China) in 2010 from the Dalian Jiaotong
under the supervision of Prof. University (China) in 2007.
Xiaojun Peng. He is presently She is now a PhD candidate
working as a postdoctoral fellow under the supervision of Prof.
in the group of Prof. Chen Xiaojun Peng and Associate
Xiaodong in the School of Prof. Jiangli Fan in the Dalian
Materials Science and Engi- University of Technology
neering, Nanyang Technological (China). Her research interests
University, Singapore. His include fluorescent molecular
research is focused on fluoro- systems and their applications
genic and colorimetric probes in small molecule (ion)
based on organic and inorganic recognition.
Jianjun Du materials. Mingming Hu
This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 4511–4535 4511
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emits light at a certain wavelength, which is shifted after the

indicator reacts with an analyte.
However, unlike typical chemosensors, chemodosimeter
mechanisms can be divided into two main modes: (1) analytes
react with the chemodosimeters, and the products show changed
fluorescence signals; and (2) the analytes act as catalysts and the
chemodosimeters act as substrates of the catalysed reactions. If
the second mechanism can permit a greater turnover, the fluores-
cence signal is much more amplified with a lower detection limit.
Compared with coordination-based sensors, chemodosimeters
are very advantageous in terms of selectivity and sensitivity.
Various types of chemical reactions continuously occur within
the human body under ‘‘mild’’ conditions. Hence, chemo-
dosimeters based on ‘‘mild’’ reactions are appropriate, which

is clearly why this type of probe has been extensively developed
in recent years.19–21
Currently, the interconnection of multiple disciplines has

given rise to many new interesting research fields. via a variety
of combinations of analytical chemistry and materials science,
many fluorescent materials have been developed as powerful
carriers for fluorescent probes, and devices using these materials
have attracted increasing attention. Crego-Calama et al.22
have summarised the application of chemical approaches in
association with different polymers, sol–gels, mesoporous
materials, surfactant aggregates, quantum dots, and glass or
Scheme 1 Schematic illustration of fluorescent chemodosimeters. gold (Au) surfaces. The combination of chemodosimeters with
such materials/devices definitely produces even more fascinating
on reversible/irreversible chemical processes. Recent continuing and important probes that can be employed in real-world
demands for improving sensitivity and selectivity have brought environmental and biological applications.
about some fascinating chemodosimeters that have been designed State-of-the-art techniques for certain classes of analytes,
using chemical events. such as reactive oxygen and nitrogen species, heavy metal ions,
However, most important analyte-recognition systems some special anions, and thiols have been recently reviewed.23–29
and strategies of modern chemodosimeters are derived from Given that methods involving the ring opening/closing of
chemosensors. Consequently, parallel to the characteristics of rhodamine have been recently summarised elsewhere,30,31
chemosensors, the changes in optical signals generated by our classification of this class of dyes is not provided in a
chemodosimeters fall into two main types (Scheme 1). One separate chapter but in different sections based on the corre-
is the fluorescence OFF–ON (ON–OFF) system. The free sponding reactions, except the ring opening/closing reactions.
indicator is nonfluorescent (or fluorescent) and produces a In this review, we focus on chemical systems that can act as
fluorescent (or nonfluorescent) product after reacting with an chemodosimeters for anions and cations. The chemodosimeters
analyte. The other is the ratiometric system. The indicator are classified according to the reaction type.
Jiangli Fan received her PhD Xiaojun Peng received his PhD
from the Dalian University of from the Dalian University
Technology (China) in 2005. of Technology in 1990. After
In 2010, she attended the completing a postdoctoral
University of South Carolina research in Nankai University,
as a visiting scholar. She is he worked at the Dalian
currently an associate professor University of Technology in
at the State Key Laboratory 1992. In 2001 and 2002, he
of Fine Chemicals, Dalian attended the Stockholm
University of Technology. University and Northwestern
Her research is focused on University as a visiting scholar.
fluorescent dye-based probes He is currently the director of
and their biological applications. the State Key Laboratory of
Fine Chemicals of China at
Jiangli Fan Xiaojun Peng the Dalian University of
Technology, where he is also
a professor. His research interests cover fluorescent dyes for the
bio-imaging, biolabelling, and photochemistry of supramolecules.
4512 Chem. Soc. Rev., 2012, 41, 4511–4535 This journal is c The Royal Society of Chemistry 2012
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2. ‘‘De-reaction’’-based chemodosimeters
In this section, we describe special chemodosimeters based on
typical ‘‘de-reactions’’ including desulfurisation, deselenation
and deprotection, induced by Hg2+, MeHg+, Ag+, Cu2+,
Cu+, Pd2+, O2 , SO3 2 and S2. Some cyclization or
hydrolysis reactions following these de-reactions are also
discussed. These chemodosimeters largely depend on special Fig. 3 Basis of the reaction-based detection of Pd2+ by chemodosi-
characteristics towards the corresponding analytes, such as the meter 4.
thiophilic character of mercury.
homogeneously distributed pores (2–3 nm), a large specific
2.1 Ion-induced desulfurisation
surface area exceeding 1000 m2 g1, and nanoparticulate
Hg2+ is well known to be thiophilic and plays a critical role in character. Chemodosimeter 3 did not yield a response in the
desulfurisation reactions. Under special conditions, Pd2+ can presence of other metal ions (thiophilic transition metals and
also induce desulfurisation. alkali/alkaline earth metals) or various anions such as CO32,
The central cyclobutene ring of squaraine dyes is vulnerable Cl, PO43 and SO42. Reagent 3 acted not only as a probe
to nucleophilic attack because of its electron-deficient character. for detecting Hg2+, but also as an adsorbent for removing it
Such a reaction breaks the conjugation and changes the spectral from aqueous solutions.
properties of the dye. Martinez–Manez et al.32 designed highly Palladium and palladium-containing salts play important
selective and sensitive squaraine-based chemodosimeter systems roles in syntheses involved in drug development. They are
(1 and 2, Fig. 1) for the dual determination of Hg2+ by often used as catalysts in the Heck, Sonogashira and Suzuki–
chromogenic and fluorogenic changes in acetonitrile–CHES Miyaura reactions. Unfortunately, Pd-catalysed reactions
buffer (4 : 1, v/v, 10 mM, pH 9.6) based on the aforementioned often give products with potentially hazardous levels of Pd
mechanism. In their study, only the addition of Hg2+ resulted contamination even after purification. Thus, the detection and
in a dramatic colour change owing to the appearance of a new removal of palladium are of considerable concern. Anslyn
and intense absorption band at 642 nm belonging to the et al.34 developed the highly sensitive Pd2+ chemodosimeter 4,
squaraine dye. The reaction product showed a comparati- whose mode of action (Fig. 3) was based on the thiol-scavenging
vely large molar extinction coefficient and a moderate fluores- ability of Pd2+ in dimethyl sulfoxide (DMSO). Upon Pd2+
cence quantum yield. The detection limit for Hg2+ was less addition, the absorption band at 317 nm decreased but that at
than 2 parts per billion (ppb) as monitored by fluorescence 656 nm increased, turning ON the colour. This system could
spectroscopy. provide high sensitivity to palladium. The detection limit was
By combining the aforementioned chemodosimeter with 0.5 ppm with naked eye inspection in organic media, and as
the advantageous features of ordered 3D mesoporous silica, low as 100 ppb by instrumental detection.
Martinez–Manez et al.33 prepared a dual-function hybrid This system used a suitable dye of the ‘‘switched off’’ type,
material 3 (Fig. 2) for the detection and removal of Hg2+ produced by simple addition reaction with small organic
from aqueous environments. The mesoporous inorganic sup- molecules that acted as a ‘‘spectroscopic inhibitor’’. This leuco
port material UVM-7 (MCM41 type) in that work possessed form of the dye represented the actual chemodosimeter, being
colourless and non-fluorescent. In the second step, the target
analyte reacted with the inhibitor, restoring the chromophoric
system with the reappearance or ‘‘switching ON’’ of both
colour and fluorescence.
2.2 Ion-induced desulfurisation followed by oxidation

On one hand, the CQS double bond is weak. Thus, the
resonance structure of thiolate can easily form, which can
efficiently quench the fluorescence of the fluorophore via photo-
induced electron transfer (PET). On the other hand, given that
Fig. 1 Basis for the reaction-based detection of Hg2+ by chemodosi- Hg2+ exhibits thiophilicity, desulfurisation has been success-
meters 1 and 2. fully utilised for designing Hg2+-selective chemodosimeters
with sulfur-based functional groups, such as thioamide,
thiourea and thione.
An anthracene-based chemodosimeter, 5 (Fig. 4), was
reported by Czarnik et al.35 as early as 1992. This chemodosi-
meter enabled Hg2+ detection utilising a desulfurisation reac-
tion in 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid
(HEPES) buffer (pH 7.0) for the first time. The thioamide
group can quench the fluorescence of anthracene after desulfuri-
Fig. 2 Scheme for the reaction-based detection of Hg2+ by chemodosi- sation, but the amide group cannot. The addition of Hg2+
meter 3. induced an obvious enhancement in fluorescence, whereas other
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Fig. 4 Reaction route for the reaction-based detection of Hg2+ by

Fig. 7 Reaction route for the detection of Hg2+ by chemodosimeter 8.
chemodosimeter 5.
Fig. 5 Reaction route for the detection of Hg2+ by chemodosimeter 6.

Fig. 8 Reaction route for the detection of Hg2+ by chemodosimeters
metal ions caused no change in the emission intensity under 9 and 10.
the same conditions, except Ag+ with a stoichiometry of 2 : 1.

Chang et al.36 reported dosimeter 6 (Fig. 5) with selectivity 2% compared with Hg2+. The LOD was also maintained at a
for Hg2+ based on the irreversible conversion of thioamide sub-micromole level (8.9 107 M). The excitation wave-
into an amide similar to Czarnik’s work. The result is an length was improved to 487 nm.
OFF–ON fluorescent behaviour in acetonitrile–water solution Another important example of a thiourea-based chemo-
(7 : 3, v/v). Thioamide 6 showed a very weak fluorescence dosimeter (9) (Fig. 8) was presented by Resch-Genger et al.39
centred at around 475 nm because of intramolecular quenching as early as 2001. This chemodosimeter presented 46- and 34-fold
by the thioamide. The addition of Hg2+ induced an obvious fluorescence enhancements in the presence of Cu2+ and Hg2+
167-fold enhancement in fluorescence intensity with a quantum in acetonitrile due to typical Cu2+-induced redox and Hg2+-
yield of 0.38. Among the tested metal ions, only Cd2+ and Ag+ induced desulfurisation reactions, respectively. However, there
gave interferences of 10 and 13%, respectively. The entire were some interferences from Ag+, Ca2+ and Ni2+. Later
recognising process was completed within 1 min with a limit of another important chemodosimeter, 10 (Fig. 8), presented
detection (LOD) of 5.4 107 M. Here, the 8-hydrosyquinoline effective ratiometric fluorescence change towards Hg2+ due to
scaffold showed better optical properties than anthracene. the Hg2+-induced transformation of the thiourea-thiadiazole-
However, the excitation wavelength was rather short (345 nm), pyridine moiety into urea-thiadiazole-pyridine.40 Free 10 could
which is harmful to organisms. self-assemble into colloidal nanoparticles 200 nm in size and
Chang et al.37 later developed chemodosimeter 7, a typical exhibited a typical emission at 403 nm in a THF–water
thione analogue, for Hg2+ detection. A pronounced OFF–ON solution (1 : 2, v/v). In contrast, a significant increase with a
signalling towards Hg2+ was observed along with a transfor- remarkable red-shift (403 to 501 nm) was observed upon the
mation, as shown in Fig. 6. As a result of this transformation, addition of Hg2+. This system showed good selectivity towards
the weakly fluorescent flavothione 7 (F = 0.003 in 50% Hg2+ among other metal ions besides Ag+, and a linear relation-
aqueous methanol) was transformed into a strongly emitting ship between F501nm/403nm and the Hg2+ concentration. The
naphthoflavone (F = 0.107), whereas other metal ions did not LOD was 1.13 107 M.
give obvious responses. The Hg2+ signalling of 7 was complete Three Hg2+-induced irreversible desulfurisation reaction-
within about 30 min with an LOD of 1.6 106 M, although based chemodosimeters 11–13 (Fig. 9) were reported by Yen
the low water solubility remained problematic for practical et al.41 These chemodosimeters exhibited chromogenic and
application. fluorogenic behaviours to Hg2+ in DMSO–water media (9 : 1,
Chang et al.38 developed a thiocoumarin-based chemodosi- v/v). Among them, 11 had the best selectivity and sensitivity
meter 8 (Fig. 7) for Hg2+ detection in acetonitrile–water with an LOD of 0.5 mM without inference from other metal ions.
solution (1 : 1, v/v).38 The Hg2+-induced transformation of Upon the addition of Hg2+, a 63-fold increase in fluorescence
thiocoumarin to coumarin led to obvious blue-shifted absorp-
tion from 523 to 467 nm with a naked-eye-visible colour
change from pink to yellowish green. A 25.8-fold fluorescence
enhancement within 2 min was also observed. Interferences by
Ag+ and Cd2+ also appeared but were controlled to less than
Fig. 6 Basis of the reaction-based detection of Hg2+ by chemodosi- Fig. 9 Reaction route for the reaction-based detection of Hg2+ by
meter 7. chemodosimeters 11–16.
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intensity was observed both at 390 and 440 nm. Yen et al.42
later developed three similar probes 14–16 (Fig. 9) without an
azo dye moiety. Chemodosimeter 14 detected Hg2+ more
rapidly. However, there were some interferences from Cu2+
and Ag+.
Fig. 12 Sequence for the reaction-based detection of Hg2+/Ag+ by
chemodosimeter 19.
2.3 Ion-induced desulfurisation (deselenation) followed by
hydrolysis Chemodosimeter 18 was successfully applied in the fluores-
43 cence imaging of Hg2+ in living cells.
Ma et al. reported a rhodamine B thiolactone 17 as a highly
Similarly, exploiting the strong affinity of Se for mercury
selective and sensitive sensor for Hg2+ in phosphate-buffered
and silver (Ag), a fluorescent probe 19 based on rhodamine
saline (PBS; 20 mM, pH 7). Electrospray ionisation (ESI) mass
selenolacetone was presented by Ma et al.45 for imaging both
spectroscopy (MS) indicated that the reaction mechanism
Hg2+ and Ag+ in living cells. As shown in Fig. 12, the Se atom
proceeded via the route depicted in Fig. 10. The high thiophili-
first bound to Hg2+/Ag+. Subsequently, complex 19–Hg2+/Ag+
city of Hg2+ led to the formation of two types of complexes,
promoted the hydrolytic cleavage of the selenolacetone bond,
namely, A and B, which produced MS signals at m/z 559.1 and
which released fluorescent rhodamine B. This phenomenon
695.4, respectively. Complex A was relatively stable in the

was confirmed by ESI mass spectroscopic data. Chemodosimeter
solution, but complex B was further degraded to rhodamine B.
19 exhibited a rapid and rhodamine characteristic OFF–ON
Except for a slight interference from Ag+, 17 did not respond to
spectroscopic response to Hg2+ and Ag+ with LODs of
other metal ions. There was also good linearity in the fluores-
23 nM for Hg2+ and 52 nM for Ag+. The probe was
cence intensity within the concentration range of 0.5–5 mM for 9.
membrane permeable. Although it could sense Ag+ even in
The LOD was 20 nM.
the presence of Cl because Se had a higher affinity for Ag+
Selenium (Se) is metabolically significant for humans because
than Cl, the high concentration of Cl in cells slowed down
selenoprotein is antioxidative and antitoxic in biological systems.
the reaction between Ag+ and probe 19. Simultaneously,
Given the similar character of Se to sulfur, mercury also shows
Yoon et al.46 prepared the same molecular chemodosimeter 19.
selenophilicity. Exploiting this similarity, Tang et al.44 designed
However, they focused on the determination of both Hg2+
an organoselenium fluorescent probe 18 (Fig. 11) for Hg2+
and the more toxic methylmercury species in HEPES buffer
detection involving an irreversible deselenation mechanism.
(20 mM, pH 7.4, 1% acetonitrile). Emphasis was also placed
Chemodosimeter 18 exhibited no fluorescence in HEPES
on applications of monitoring inorganic and organic mercury
buffer solution (20 mM, pH 7.4). Only the addition of Hg2+
species in cells and zebrafish.
induced a large increase in fluorescence intensity (156-fold)
among various metal ions. The fluorescence intensity of 18 showed 2.4 Ion-induced desulfurisation (deiodination) followed
a linear response to Hg2+ from 7.0 108 to 3.4 106 M due to cyclisation
the strong affinity between Se and Hg2+. The LOD was 1.0 nM.
Based on the well-known mercury-promoted intramolecular
cyclic guanylation of thiourea, the first case of ratiometric
fluorescent chemodosimeter 20 (Fig. 13) for the selective
detection of Hg2+ was reported by Tian et al.47 In an
acetonitrile–water (4 : 1, v/v) solution, the addition of Hg2+
transformed the thiourea unit of the chemodosimeter into the
weaker electron-donating imidazoline moiety coupled with a
significant fluorometric and colorimetric change. The fluores-
cence emission changed from yellow–green (lem = 530 nm,
F = 0.35) to blue (lem = 475 nm, F = 0.48) with an
isoemissive point at 510 nm. The absorption spectra changed
from 435 to 350 nm with an isosbestic point at 391 nm.
Chemodosimeter 20 exhibited good selectivity and sensitivity
Fig. 10 Basis of the reaction-based detection of Hg2+ by chemo-

dosimeter 17.
Fig. 11 Reaction route for the reaction-based detection of Hg2+ by Fig. 13 Scheme for the reaction-based detection of Hg2+ by chemo-
chemodosimeter 18. dosimeters 20–22.
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at the micromolar level, but its poor solubility limited its

potential application. Thus, this constraint should be improved
by structural design.
The modification of 20 (Fig. 13) was then performed by
Tian et al.48 by introducing an N-allyl moiety instead of
N-butyl into naphthalimide. Chemodosimeter 21 exhibited much
better solubility than 20 both in acetonitrile and acetonitrile–
Fig. 15 Scheme for the reaction-based detection of Hg2+ and
water (1 : 9, v/v) solutions, which renders it favourable in
methylmercury by chemodosimeter 26.
biological system applications. The advantages of two-photon
excitation (TPE) compared with traditional single-photon 23–25 (Fig. 14) as Hg2+/MeHg+ chemodosimeters also based
excitation (SPE), such as avoiding the auto-fluorescence from on Hg2+-induced desulfurisation. In a methanol–water (8 : 2, v/v)
the native fluorophore in the cell, were also presented. The solution, after the recognition, the chemodosimeters exhibited
chemodosimeter in conjunction with TPE, with an excitation large red shifts resulting in a clear colour change from deep
in the near-infrared (NIR) region, can also extend the trans- blue to pea green. In the emission spectra, the addition of
mission depth in tissues and reduce the damage to living cells. Hg2+ led to radiometric fluorescence changes with a turn-off
The modified chemodosimeter 21 showed high sensitivity mode at 780 nm and a turn-on mode at 830 nm. The detection
down to the ppb level under either SPE at 405 nm or TPE limit for Hg2+ was evaluated at the nanomolar level by
at 800 nm. monitoring the fluorescence titration. A type of fast colori-
Au nanoparticles (NPs) provide high sensitivity for the metric and ratiometric NIR indicator for Hg2+ and MeHg+
detection of metal ions because they exhibit characteristic in aqueous solution was demonstrated. The NIR long wave-
surface plasmon resonance absorption properties, which length of excitation is not harmful to organisms.
strongly depend on the size, shape and interparticle distance. Tae et al.51,52 developed a highly selective and sensitive
Consequently, Tian et al.49 developed a selective Au NP-based rhodamine-based chemodosimeter 26 for Hg2+, which success-
nanosystem by the immobilisation of chemodosimeter 22 on fully functioned in the cells, tissues and organs of zebrafish, as
the surface of Au NPs to utilise the characteristic optical well as in an aqueous solution (Fig. 15). This system coupled
properties and good dispersity of Au NPs in water. The the well-known equilibrium of rhodamine derivatives between
sensing performance of the probe for the determination of spirolactam (fluorescence/absorption-OFF mode) and ring
Hg2+ was tested. In DMSO–water solution (1 : 1, v/v), 22 opening (fluorescence/absorption-ON mode). The stoichio-
displayed a main absorption band at 446 nm and an emission metric and irreversible Hg2+-induced reaction of thiosemi-
maxima at 542 nm. Upon the addition of Hg2+, the band at carbazides to 1,3,4-oxadiazoles resulted in a rapid colour change
446 nm decreased significantly, and a new absorption band from colourless to bright pink. The fluorescent response
was observed at 348 nm with an isosbestic point at 385 nm. (557 nm, F = 0.52) for Hg2+ over other metal ions was
Unlike compound 20 with a significant emission maxima shift, remarkably high, and the LOD of 2 ppb in aqueous solutions
the fluorescence of 22 was considerably quenched in the conformed to the standards of the US Environmental Protection
presence of Hg2+ with a hypsochromic shift of about 12 nm Agency (EPA). Chemodosimeter 26 was successfully applied in
from 542 to 530 nm. With the support of nanomaterials, the real-time monitoring of exogenous Hg2+ in C2C12 cells and
chemodosimeters can more efficiently detect essential metal in zebrafish, and in the imaging distribution of accumulated
ions in real environments. Hg2+ in different organs of zebrafish. This probe possessed the
In the natural environment, mercury exists in the form of most in demand properties of chemodosimeters including good
inorganic mercury species (e.g., elemental mercury and mercuric performance of various applications.
salts) and organomercury (e.g., MeHg+). Both elemental and Tae et al.53 observed that the aforementioned desulfurisation
ionic mercury can be converted into methylmercury by bacteria reaction can also be promoted by MeHg+. Upon the addition
in the environment, and subsequently, into methylmercury of MeHg+ to 10 mM solutions of rhodamine thiosemi-
species. This species can readily pass through biological carbazides 27 (Fig. 16) in water (1% DMSO) at 25 1C, probe
membranes and bioaccumulate in organisms via the food chain. 27 showed strong fluorescence intensity changes. Although the
Therefore, methylmercury is more toxic to fish, animals and desulfurisation reaction of MeHg+ was less efficient because
humans than inorganic mercury. Apart from a naphthaleneimide of its weaker thiophilicity than Hg2+, the detection limit of
series, Tian et al.50 devised a series of tricarbocyanine derivates probe 27 for MeHg+ was still observed at a nanomolar level
based on a fluorescence titration curve. Apart from living
cells, 27 can also be used to detect methylmercury in organisms
Fig. 14 Scheme for the reaction-based detection of Hg2+/MeHg+ by Fig. 16 Scheme for the reaction-based detection of Hg2+/MeHg+ by
chemodosimeters 23–25. chemodosimeter 27.
View Online
Fig. 17 Scheme for the reaction-based detection of Hg2+ by chemo-

dosimeter 28.
such as zebrafish, in which it demonstrated strong fluorescence

intensity especially in the eye lens and liver regions.
An ‘‘OFF–ON’’ fluorescent response associated with the
Hg2+-promoted cyclisation of a thiocarbazone derivative was
employed by Duan et al.54 in the design of a fluorescent probe.
Initially, 28 (Fig. 17) showed a very weak band at 530 nm with a

quantum yield of 0.001 in a methanol–water (1 : 1, v/v, pH 7.0)
solution. The addition of 1 equiv. Hg2+ induced increased
fluorescence intensity at 530 nm accompanied by the appear- Fig. 19 Scheme for the reaction-based detection of Hg2+ by chemo-
ance of a new peak at 635 nm with an increased quantum yield dosimeters 30–33.
of 0.022. This system exhibited high selectivity to Hg2+ except
for some fluorescence quenching by Cu2+ in competition of Hg2+ induced a 73-fold enhancement in fluorescence intensity
experiments. X-Ray crystal structure and elemental analyses with an LOD of 3.1 108 M. There was also fluorescence
were performed to confirm the occurrence of Hg2+-induced quenching induced by Ni2+, Cu2+ and Zn2+. Another coumarin-
desulfurisation and the cyclization that followed. based OFF–ON type chemodosimeter 33 was reported by
As shown in Fig. 18, Kim et al.55 first reported an example Peng et al.58 Upon the addition of Hg2+ into an acetonitrile–
of a two-photon Pt2+-containing rhodamine probe 29. In the Tris-HCl solution (3 : 7, v/v, 20 mM, pH 7.0), a 12.5-fold
presence of Hg2+, a significant 23-fold increase in fluorescence fluorescence enhancement and a red-shift of about 20 nm
intensity was observed in acetonitrile–HEPES buffer (1 : 4, v/v, (486/506 nm) were observed in the emission spectrum. However,
10 mM, pH 7.4). This system showed good selectivity and Co2+, Ni2+, Cu2+ and Zn2+ quenched the fluorescence due to
enabled the visualisation of Hg2+ accumulation as well as trace their intrinsic quenching nature.
Hg2+ in living HeLa cells by two-photon microscopy. Shiraishi et al.59 presented a benzosadiazole-thiourea conju-
Shiraishi et al.56 reported a highly selective fluorescent gate for Hg2+ detection based on the Hg2+-induced desulfuri-
probe composed of coumarin-thiourea for Hg2+ detection in sation of thiourea along with the formation of an imidazoline
acetonitrile–HEPES (1 : 1, v/v, 100 mM, pH 7.0). Without moiety. In the absence of Hg2+, free 34 (Fig. 20) showed
cations, the probe showed strong fluorescence at 450 nm with bright green fluorescence at 530 nm in acetonitrile–HEPES
a quantum yield of 0.45. Promoted by the Hg2+-induced buffer (9 : 1, v/v, 10 mM, pH 7.0), whereas the fluorescence was
desulfurisation of the thiourea moiety, 30 (Fig. 19) underwent quenched significantly with the addition of Hg2+. This ON–OFF
a significant decrease in the fluorescence intensity (F o 0.02) assay was rapid (o1 min) without other interference and enabled
due to a decrease in the intramolecular charge transfer (ICT).
Usually, an OFF–ON type sensor is preferred over the
ON–OFF type because fluorescence may be quenched not
only by targets but also by some uncertain factors in the
environment. Therefore, the simple OFF–ON type probes 31
and 32 were presented by Wu et al.57 also based on Hg2+-
induced desulfurisation followed by cyclization in acetonitrile–
Tris-HCl buffer (1 : 4, v/v, 10 mM, pH 7.4). Although 31
required heating at 60 1C (5 min) and both its excitation as
well as emission wavelengths were below 400 nm, the addition
Fig. 18 Scheme for the reaction-based detection of Hg2+ by chemo- Fig. 20 Scheme for the reaction-based detection of Hg2+ by chemo-
dosimeter 29. dosimeters 34–36.
View Online
a Hg2+ detection range above 0.6 mM. Kim et al.60 developed

a system using a rhodamine 6G derivative 35, which also
utilised the transformation of thiourea derivatives with amine
into guanidine derivatives with the promotion of Hg2+. The
use of a rhodamine chromophore resulted a better signal
response and gave rise to a sensitive OFF–ON behaviour.
The typical characteristics of rhodamine 6G were shown by
the chromomeric and fluorogenic changes. This sensor was
time dependent; it needed at least 10 min, 30 min, or more than
1 h in 10% 30% and 50% aqueous solutions, respectively.
Another new system 36 was also developed by Kim et al.,61 in
which Nile blue was used instead of rhodamine derivatives.
This change brought about a better solubility in 100% water
solution and an obviously improved sensitivity of as low as

1.0 ppb for Hg2+, even in blood plasma and albumin. The
reaction reached completion within 1 min. Based on chemo-
dosimeters 20–25, 30 and 34–36, the same reactive moiety can

be concluded to generate different properties such as solubility
and sensitivity when linked with different fluorophores.
Fluorescence resonance energy transfer (FRET) is defined
as the excited-state energy interaction between two fluoro- dosimeters 38 and 39.
phores in which the excited donor energy is transferred non-
radiatively to an acceptor unit. FRET-based ratiometric probes The developed probe 38 (Fig. 22) exhibited significant ratio-
can eliminate most ambiguities induced by instrumental efficiency, metric fluorescence enhancement and a remarkable yellow–
environmental conditions, and probe concentration by the magenta colour change towards Hg2+. Excellent selectivity in
built-in correction of the ratio between two different wave- an aqueous acetone solution was exhibited. The ratiometric
lengths. There are, however, few reports on FRET-based ion fluorescence response to Hg2+ also experienced no inter-
chemosensors. Fig. 21 shows a rhodamine–boron dipyrromethene ference from other metal ions. This ratiometric fluorescence
BODIPY (acceptor–donor) FRET system 37 for ratiometric and method showed a linear detection range of 0.0 106–10.0
intracellular Hg2+ detection. This probe was prepared by Xiao 106 M with an LOD of 5 108 M for Hg2+. Guo et al.64
et al.62 as inspired by the work of Tae et al. In an ethanol–water presented a 1,8-naphthalimide–rhodamine-based FRET system
(4 : 1, v/v) solution, the excitation of the BODIPY chromophore 39 with an energy transfer efficiency of 86.3% for the determi-
(lex = 488 nm) resulted in a 514 nm emission from BODIPY, nation of Hg2+. This system showed selectivity towards Hg2+
whereas no rhodamine emission was observed because of the among usual metal ions, but there was a slight interference from
closed spirolactam ring. Upon the addition of Hg2+, the Ag+. The probe exhibited an LOD of 3 108 M in
BODIPY emission at 514 nm decreased and a new emission methanol–Tris-HCl solution (2 : 1, v/v, 10 mM, pH 7.0). The
band of rhodamine with a maximum at 589 nm appeared, large shifts between the donor excitation and acceptor emission
which gradually increased in intensity. This finding was attri- ruled out the influence of excitation backscattering effects. The
buted to the energy transfer from the BODIPY to the ground- comparable intensities of two different wavelengths ensured the
state of the ring-opened rhodamine. This ratiometric method accuracy of the quantity compared with the intensity changes of
proved beneficial quantitative studies of Hg2+ both in ethanol– a single wavelength.
water solutions and living cells. Wang et al.65 reported a dithiorhodamine derivative based
Another typical FRET system with a well-suited FRET pair of chemodosimeter 40 (Fig. 23) for Hg2+ employing the strong
fluorescein–rhodamine was reported by Zheng et al.63 The system affinity of mercury for sulfur. Spectroscopic results revealed
exhibited a good spectral overlap within the range of 480–580 nm. real-time responses, high sensitivity, and selectivity for Hg2+
compared with other cations. These properties were mechanistically
ascribed to the transfer from rhodamine spirolactam to the
thiazoline-derived open-ring rhodamine via Hg2+-induced
desulfurisation.
Fig. 21 Scheme for the reaction-based detection of Hg2+ by chemo- Fig. 23 Scheme for the reaction-based detection of Hg2+ by chemo-
dosimeter 37. dosimeter 40.
View Online
2.5 Ion-induced deprotection

Protective groups are usually introduced into a molecule by
chemical modification for chemoselectivity in subsequent
reactions. The process of protection and deprotection can
sometimes be adopted in mild conditions. Therefore, these
processes can be used as an interesting strategy for designing
chemodosimeters.
Aldehydes can be protected by oximes, and the corre-
Fig. 24 Scheme for the reaction-based detection of Cu2+ by chemo- sponding deprotection can proceed rapidly using hypochlorite
dosimeter 41. at room temperature. Inspired by this transformation, Lin
et al.68 presented the first ratiometric example of a fluorescent
Hg2+ usually easily induces the irreversible desulfurisation probe 43 (Fig. 26) for ClO detection. In the absence of ClO,
of thioamide derivatives. However, Jung and Kim et al.66 43 exhibited maximum emission at 439 nm with an F509nm/439nm
reported a Cu2+-promoted desulfurisation and cyclization- of 0.28. Upon the addition of ClO, red-shift ratiometric
based chemodosimeter 41 (Fig. 24). In acetonitrile, free 41 had changes appeared and F509nm/439nm gradually increased to
an intense red colour with an absorption band at 500 nm and 2.74. Probe 43 showed a high selectivity towards ClO over
fluorescence emission at 590 nm. The addition of Cu2+ other species. The probe can also be used conveniently for
induced a blue shift to 450 nm in the absorption spectrum hypochlorite detection at the micromolar level by simple visual
and an emission shift from 590 to 555 nm with increased detection.
intensity. This system solved the problem of the inherent Hydrazone is one of the common protective groups for
fluorescence quenching nature of the paramagnetic species carbonyl compounds, and its deprotection process is easily
Cu2+ using fluoroionophores. In this work, silica-immobilised carried out under Cu2+-catalytic hydrolysis. Inspired by this
anthraquinone was prepared by a coupling reaction of the process, a new turn-on coumarin derivative for Cu2+ detec-
chemodosimeter receptor with mesoporous silica, which had a tion in acetonitrile–acetate buffer (1 : 1, v/v, 10 mM, pH 5.0)
weak fluorescence and red colour. Functionalised nanomaterials was presented by Han et al.69 Upon the addition of Cu2+,
such as mesoporous silica have homogeneous porosity and large coumarin dye regenerated from 44 (Fig. 27) induced an 18-fold
surface areas, making them promising inorganic supports for fluorescence enhancement at 502 nm, which was confirmed by
chemodosimeters. The introduction of Cu2+ induced an obvious coumarin 334 via UV-vis, fluorescence and 1H nuclear magnetic
increase in fluorescence intensity at 560 nm and a colour change resonance (NMR) spectra. Given that the catalytic cycle assisted
from pink to yellow, whereas other metal ions exhibited no by Cu2+ amplified the fluorescence signal, 44 exhibited an LOD
significant spectral changes. However, whether Hg2+ inter- of 8.7 108 M for Cu2+, which was below the EPA standard
fered with Cu2+ detection was not discussed because Hg2+ of 20 mM in drinking water. No significant increase in the
was not involved in the selectivity experiments. The process fluorescence intensity was observed upon the addition of any
would have produced more significant results if it was carried other metal ion.
out in aqueous media. 1,2-Ethanedithiol can be used for the protection of alde-
Ahn et al.67 devised a rhodamine B derivative 42 (Fig. 25) as hydes via reactions with aldehyde groups. The protected
a fluorogenic and chromogenic probe for the detection of Ag+ aldehyde group can be converted back upon addition of
and Ag NPs in various situations. They worked on the basis of Hg2+, which affected the ICT efficiency of the fluorophore.
Ag+-promoted ring opening and oxazoline formation by the Kim et al.70 proposed a water-soluble coumarin derivative 45
specific molecular interaction between Ag+ and iodide. The
addition of Ag+ to 42 afforded obvious fluorescence enhance-
ment centred at 580 nm (F = 0.71) within 10 min, and a
colour change from colourless to pink was observed. The
saturation titration plot indicated a 1 : 1 stoichiometry
between probe 42 and Ag+. The fluorescence response of
probe 42 towards Ag+ was linear within the range of Fig. 26 Scheme for the reaction-based detection of ClO by chemo-
0.1–5.0 mM Ag+ with an LOD of 14 ppb. The results clearly dosimeter 43.
demonstrated that the simple pioneering detection method can
be applied for the quantification of Ag NPs in consumer
products.
Fig. 25 Scheme for the reaction-based detection of Ag+ by chemo- Fig. 27 Scheme for the reaction-based detection of Cu2+ by chemo-
View Online
Fig. 30 Scheme for the reaction-based detection of O2 by chemo-

dosimeter 49.
Based on the nucleophilic mechanism of O2 in mediating the

deprotection of diphenylphosphinate fluorescein to fluorescein,
Tang et al.73 described a diphenylphosphinate fluorescein
probe 49 (Fig. 30). This probe is a new type of phosphinate-
based fluorescent chemodosimeter for O2 imaging in biological

environments. Probe 49 showed a weak fluorescence in PBS
(100 mM, pH 7.4) but a strong fluorescence at 530 nm upon
reaction with O2 . Owing to the simple nucleophile depro-
tection rather than a redox mechanism, 49 showed high

selectivity for O2 over other reactive oxygen species and
Fig. 28 Scheme for the reaction-based detection of Hg2+ by chemo- some biological compounds. Probe 32 was membrane perme-
dosimeters 45–47. able and can be used in fluorescence detection as well as O2
imaging in living cells.
(Fig. 28) capable of chemodosimetric Hg2+ detection in Yang et al.74 developed a highly sensitive chromo- and
methanol–water (3 : 7, v/v) media. The detection can be completed fluorogenic chemodosimeter 50 (Fig. 31) for sulfide detection
within 1 min under mild and environment-friendly conditions. in acetone–water (1 : 3, v/v) solution based on its nucleophili-
Free 45 had an absorption band at 393 nm and intense city. The introduction of 2,4-dinitrobenzenesulfonyl group
fluorescence emission at 400 nm. Only the addition of Hg2+ locked the fluorescence of probe 50. Upon the addition of
led to a colorimetric change with a red shift from 393 to 443 nm. sulfide, the 2,4-dinitrobenzenesulfonyl group of 50 was efficiently
The fluorescence obviously decreased due to the deprotection removed and fluorescein was released, leading to dramatically
transformation of thioacetal to aldehyde. Probe 45 exhibited a increased fluorescence and absorbance. The fluorescence
good selectivity to Hg2+ as well as an LOD of 2 ppm in aqueous increment at 512 nm was linear within the sulfide concen-
medium and human blood plasma. Li et al.71 reported probe 46 tration range of 50–1000 nM. The LOD was 4.3 nM. The
and its polymer derivative 47. The aldehyde emitted strong fluores- proposed chemodosimeter showed excellent selectivity towards
cence but the dithioacetal product 46 became non-fluorescent sulfide and was successfully applied in sulfide determination in
after reaction with ethanethiol. The introduction of Hg2+ synthetic wastewater samples.
recovered the fluorescence. This assay exhibited good selectivity Based on the selective and efficient cleavage of acetate
towards Hg2+ among normal metal ions except for Ag+. After groups by perborate ions, Chang et al.75 developed a convenient
introducing 46 to the backbone of conjugated polymers, the and selective fluorescein-based chemodosimeter 51 (Fig. 32) for
molecular wire effect of the polymer backbone amplified the perborate ions in acetonitrile–acetate buffer (9 : 1, v/v, 10 mM,
fluorescence signal. Upon the addition of Hg2+, the fluorescence pH 4.8). The absorption and fluorescence of fluorescein was
at 434 nm decreased with a red shift at around 500 nm. The
sensitivity was improved from 100 mM to 0.1 mM along with the
increase in the molecular weight of the conjugated polymers.
Mahapatra et al.72 presented a carbazole-based bis-dithiane
probe 48 (Fig. 29) for Cd2+ detection based on the protection/
deprotection of a special aldehyde group. Upon the addition
of Cd2+ in acetonitrile–HEPES solution (3 : 7, v/v, 50 mM,
pH 7.4), the maximum emission at 383 nm decreased gradually
Fig. 31 Scheme for the reaction-based detection of S2 by chemo-
and an intense new emission at 437 nm concomitantly occurred.
dosimeter 50.
Probe 48 showed good selectivity towards Cd2+ over other
interfering metal ions, especially Hg2+.
Fig. 29 Scheme for the reaction-based detection of Cd2+ by chemo- Fig. 32 Scheme for the reaction-based detection of perborate by
dosimeter 48. chemodosimeter 51.
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acetonitrile and acetonitrile–water (9 : 1, v/v) solutions. In

acetonitrile, probe 53 exhibited an absorption band at 337 nm
with a shoulder at 311 nm, and an extremely weak fluorescence
(F = 0.0003). The nearly blank background fluorescence
could increase the sensitivity. The addition of Hg2+ caused a
4316-fold fluorescence enhancement centred at 560 nm. The
selectivity for Cu2+ was attributed to the unique oxidation
capability of Cu2+, which promoted the cyclization reaction
of 53 into a strongly fluorescent compound. The fluorescence
Fig. 33 Scheme for the reaction-based detection of Cu+ by chemo-
enhancement was completed within 20 min and was propor-
dosimeter 52.
tional to the Cu2+ concentration range of 0–1.2 mg mL1.
Das et al.78 developed a weakly fluorescent thiosemicabazone
locked by the acetate group. After selective deblocking by 54 as a selective turn-on fluorescent chemodosimeter for Cu2+
perborate ions, a strong absorption band at 491 nm appeared in ethanol–water medium (1 : 1, v/v). The selectivity towards
with the characteristic colour of fluorescein, accompanied by an Cu2+ also resulted from the oxidative cyclization of the weak
intense fluorescence at 517 nm. Probe 51 exhibited pronounced fluorescent substrate into a highly fluorescent product. The
perborate selectivity over other commonly employed oxidants introduction of naphthaline instead of benzene increased the
with an LOD of 2.2 105 M. fluorescence intensity, and an acetone-based Schiff base exhibited
Cu+ and not Cu2+ is the dominant oxidation state in a greater water solubility than benzene derivatives.
cytosolic reducing environment. Cu+-selective probes, ideally Based on an oxidative cyclisation mechanism induced by
with a turn-on response in fluorescence intensity, are prefer- Cu2+, a variety of N-acylhydrazone compounds 55–58
able for cell imaging. Taki et al.76 developed a highly sensitive (Fig. 35) as chemodosimeters for Cu2+ were reported by Jiang
fluorescent probe 52 (Fig. 33) for the detection of intracellular et al.79 In the presence of Cu2+, these sensors can undergo
Cu+ in living systems. In HEPES buffer solution (50 mM, transformations from non-fluorescent N-acylhydrazones to
pH 7.2), the probe was non-fluorescent. However, upon the highly fluorescent rigid 1,3,4-oxadiazoles accompanied by
addition of Cu+, a 4 100-fold enhancement in fluorescence selective and dramatic fluorescence enhancements in aceto-
intensity at 513 nm was observed. Probe 52 displayed good nitrile and acetonitrile–water solutions. The mechanism was
selectivity among other metal ions except for Co2+. In the difficult to confirm by cyclic voltammograms. Nevertheless,
absence of GSH, which can rapidly reduce Cu2+ to Cu+, evidence for the sensing reaction was obtained from compari-
Cu2+ did not show a fluorescence response. This finding sons between the high-resolution MS, 1H NMR and 13C NMR
indicated that the formation of deprotected fluorescein by data of the oxidative cyclization products and synthetic
the cleavage of the benzyl ether linkage was the reason for 1,3,4-oxadiazeles. The chemodosimeters presented an LOD
the fluorescence enhancement. Imaging experiments in cells for Cu2+ at the nanomolar level in acetonitrile and at the sub-
verified the optical changes and proposed mechanism. micromolar level in aqueous environments. However, a longer
response time was required for aqueous media. With a design
3. Cyclisation-based chemodosimeters strategy similar to Cu2+-induced oxidation, Tong et al.72
designed a new probe 59 also based on Cu2+-induced oxidative
cyclization followed by hydrolysis derived from a rhodamine
typical cyclisation reactions. Ion-analyte-induced cyclisation can
fluorophore. Free 59 showed no obvious absorption but exhibited
obviously change the spatial pattern, conjugating morphology
green fluorescence from the Schiff base part at 515 nm. The
and electron distribution of a chemodosimeter, thereby affecting
introduction of Cu2+ led to the appearance of the rhodamine
its absorption and fluorescence properties.
characteristic colour and fluorescence.
Lin et al.77 utilised an irreversible Cu2+-promoting cyclization
The first OFF–ON fluorescent chemodosimeter 60 (Fig. 36) for
reaction of a Schiff base to develop a novel turn-on fluorescent
Au3+ detection in ethanol–HEPES (1 : 1, v/v, 10 mM, pH, 7.4)
chemodosimeter for Cu2+. 1-(2-Methoxybenzylidene)-4-phenyl-
semicarbazide 53 (Fig. 34) was used as the substrate in
Fig. 34 Scheme for the reaction-based detection of Cu2+ by chemo- Fig. 35 Scheme for the reaction-based detection of Cu2+ by chemo-
dosimeters 53 and 54. dosimeters 55–59.
View Online
Fig. 38 Scheme for reaction-based detection of F by chemodosi-

meter 64.
Gong et al.84 reported a novel chemodosimeter for F

detection based on F-induced intramolecular cyclization. In
the absence of F, 64 (Fig. 38) exhibited weak fluorescence at
Fig. 36 Scheme for the reaction-based detection of Au3+ by chemo- 469 nm in acetonitrile due to the PET process from the
dosimeters 60 and 61. aminophenyl moiety to the charged pyridinium ring. The
addition of F induced the intramolecular cyclization of 64 to
was reported by Yoon et al.80 The chemodosimeter displayed a form pyrido[1,2-a]benzimidazole, displaying intense fluorescence
highly selective fluorescence enhancement and colorimetric at 481 nm as proven by 1H NMR. Only F can induce this
OFF–ON fluorescence switch with an LOD of 2.72 106 M
change. Almost at the same time, Tae et al.81 reported another

intramolecular cyclization-based probe 61 also for Au3+ among Cl, Br, I, NO3, H2PO4 and AcO.
detection in PBS buffer (1% methanol, pH 7.4). The addition
of Au3+ induced an obvious enhancement both in the char- 4. Ion-induced hydrolysis reactions
acteristic fluorescence and absorption of rhodamine because of
the transformation of the glyamide moiety to oxazolecarbaldehyde. This section describes special chemodosimeters based on
The fluorescence responses of 60 increased linearly with the typical ion-induced hydrolysis reactions. Ester groups, Schiff
amount of Au3+ at the micromolar level with an LOD of bases and acylsemicarbazide groups are used as substrates for
63 ppb. The LOD of 61 can reach 50 nM, although the the efficient detection of Cu2+, Fe3+, Hg2+, Au3+ and OCl
cyclization process was not reversible. Both probes 60 and 61 based on hydrolysis reactions. Here, the analytes act as catalysts.
were successfully applied in the cell imaging of Au3+. Although However, in most examples, the hydrolysis does not go far
the detection process was similar to the Pd2+-induced cyclization beyond a single turnover (TN) because the corresponding
of propargylamide, the authors believed that the exact mecha- hydrolysis products are stronger binders of targets. Most
nism needs further scrutiny.82 importantly, if the analytes can be used as enzymes with high
Bhalla and Kumar et al.83 reported selective chemodosi- TN numbers, the detecting limits can be improved obviously by
meter 62 and 63 for F (Fig. 37), which induced an unprece- high orders of magnitudes by signal-amplified-like polymerase
dented irreversible cyclization. The mechanism for this chain reaction and enzyme-linked immunosorbent assay.
cyclization started from the cleavage of the Si–O bond with
increased amount of the negatively charged phenolate, followed 4.1 Ion-induced ester hydrolysis
by cyclization to triphenylene. Consequently, the conjugation Cu2+ has been known for almost 50 years to promote the
was extended (Fig. 37). In the absence of F, 62 exhibited a hydrolysis of a-amino acid esters at rates much greater than
characteristic absorption band at 295 nm and fluorescence those of other metal ions. However, in 1997, Czarnik et al.85
emission at 393 nm. Upon the addition of 0.0–4.2 equiv F, reported that a rhodamine derivative simulated the structure
new absorption peaks appeared at 342 and 663 nm, and the of a-amino acid esters for Cu2+ detection. Subsequently,
absorption peak at 295 nm completely disappeared. Upon various examples of a-amino acid esters, simulated a-amino
further addition of F, the peak at 663 nm decreased and three acid esters and normal esters had been developed for target
new peaks appeared at 287, 526 and 716 nm. The addition of F detection.
induced a red shift of emission at 425 nm with a 32% enhance- As aforementioned, a rhodamine derivative 65 (Fig. 39) that
ment in fluorescence emission. Compound 62 had a higher simulated the structure of an a-amino acid ester was presented
selectivity towards F over other anions with an LOD of
2 106 M for F. This LOD was sufficiently low for the
detection of the submillimolar concentration ranges of F
found in many chemical systems.
Fig. 37 Scheme for the reaction-based detection of F by chemo- Fig. 39 Scheme for the reaction-based detection of Cu2+ by chemo-
dosimeters 62 and 63. dosimeters 65 and 66.
View Online
Consequently, an active copper-responsive fluorescent probe

that can further detect Cu2+ with a large fluorescence enhance-
ment (350-fold) at 516 nm was released. There was a good
linear correlation between the fluorescence intensity and Cu2+
concentration over the range 2.5 107–1.0 105 M with an
LOD of 1.9 107. The photo-regulated sensing of Cu2+ with
spatial resolution was demonstrated in living cells, enabling
controlled sensing in a unique spatial fashion. This example
can also be applied as an ‘‘AND’’ logic gate in which photo-
emission and Cu2+ are the inputs.
Fig. 40 Scheme for the reaction-based detection of Cu2+ by chemo- Mokhir et al.88 demonstrated a possible application of
dosimeter 67.
optimised cyclic peptide nucleic acids (PNAs) 68 (Fig. 41),
which have a group of a-amino acid esters sensitive to Cu2+
as a chemodosimeter for Cu2+ detection by Czarnik et al.85 and can be used as a chemodosimeter for the sensitive and
Indicator 65 showed no absorption and fluorescence in selective detection of Cu2+. When Cu2+ induced hydrolysis of
HEPES buffer solution (10 mM, pH 7.0). Specifically, among the a-amino acid ester, cyclic PNAs transformed into nucleic
usual tested metal ions, only the addition of Cu2+ and Hg2+
acids. Linear PNA can then be detected as a result of its ability

can complete the hydrolysis reaction. Cu2+ required only to open molecular beacons, which led to increased fluores-
1 min in acetonitrile–HEPES buffer (4 : 1, v/v), whereas cence intensity. The hydrolysis of cyclic PNAs at pH 7 did not
Hg2+ required 50 h. Since then, 65 had become a milestone occur in the presence of other metal ions, such as Zn2+, Ni2+,
of chemodosimeter development. It opened a new gateway for Fe2+/3+, Co2+, Mn2+, Zr4+, Ce3+, Ln3+, Eu3+ and Pr3+.
rhodamine derivatives as chemodosimeters due to their unique The LOD of this effect was as low as 300 fM for Cu2+.
structures and excellent optical properties. Subsequently, a Tong et al.89 developed a highly selective and sensitive
rich variety of rhodamine derivatives for the detection of coumarin-based probe 69 (Fig. 42) for Cu2+ detection via
multiple kinds of targets were developed. Another example the Cu2+-induced hydrolysis of ester, as proven by ESI-MS
of 66 was reported later by Xie et al.86 using rhodamine 101. and 1H NMR. In Tris-HCl buffer (10 mM, pH 7.0), free 69
Probe 66 showed an ON–OFF change in fluorescence at 600 nm exhibited weak fluorescence at 454 nm, whereas strong fluores-
with good selectivity and micromolar-level sensitivity. cence was observed upon the addition of Cu2+ within 5 min.
By integrating the sensing platform of rhodamine hydrazide Probe 69 showed good selectivity over other metal ions within
for Cu2+ and the photocaging technology of fluorescein the linear range of 0.1–0.9 mM (R2 = 0.997). The LOD was 35 nM.
derivatives, Lin et al.87 described a new type of smart fluor- Compound 70 (Fig. 43), as a fluorescent chemodosimeter,
escent probe termed as a photo-controllable analyte-responsive effectively recognised Cu2+ via a selective hydrolysis of acetyl
fluorescent probe 67 (Fig. 40). The probe was essentially non- groups.90 Probe 70 showed a highly selective chelation-
fluorescent and inert to Cu2+-induced hydrolysis before light enhanced fluorescence) effect only with Cu2+ among the metal
exposure because it was locked by a nitrobenzyl group. Given ions examined. In the presence of Cu2+, the hydrolysis process
that light emission was the key for 67, it was unlocked by the from ester to hydroxyl groups was completed effectively within
removal of the photolabile nitrobenzyl group upon photoemission. 4 min. The association constant of 70 with Cu2+ was calcu-
lated as 55 000 M1 from a fluorescent titration experiment.
Fig. 41 Scheme for the reaction-based detection of Cu2+ by chemo- Fig. 43 Scheme for the reaction-based detection of Cu2+ by chemo-
Fig. 42 Scheme for the reaction-based detection of Cu2+ by chemodosimeter 69.
View Online
Fig. 46 Scheme for the reaction-based detection of Fe3+ by chemo-

dosimeters 74 and 75.
Fig. 44 Scheme for the reaction-based detection of Cu2+ by chemo- trace element that plays significant roles in chemical and
dosimeters 71 and 72. biological processes. However, most sensors undergo fluores-
cence quenching due to the paramagnetic nature of Fe3+.
Mokhir et al.91 described improved substrates for Cu2+- Bis(coumarinyl) Schiff bases 74 and 75 (Fig. 46) were designed
catalysed hydrolysis, namely, esters of 2-hydroxypyridines 71 by Lin et al.93,94 as fluorescence turn-on chemodosimeters for
(Fig. 44). These esters were defined as catalytic chemodosi- Fe3+ based on Fe3+-promoted hydrolysis. In the absence of
meters because they accumulated and amplified both the Fe3+, 74 showed only a weak emission at 402 nm with a low F
absorption and fluorescence signals in response to the analyte. of about 0.004 due to ICT process. However, upon the
The hydrolysis reaction did not proceed with other metal ions addition of Fe3+, the bis(coumarinyl) Schiff-base 74 hydro-
even with a 10-fold excess of Fe2+, Fe3+, Zn2+, Ni2+, Pb2+, lysed and released a product, highly fluorescent coumarin,
Co2+, Mn2+ and Hg2+, as well as a 100-fold excess of Mg2+ with a higher F of 0.27 in methanol–water solution (49 : 1, v/v).
and Ca2+. A maximum of 55 catalytic TNs were achieved for Chemodosimeter 74 exhibited negligible fluorescence varia-
acetic acid 2-hydroxypyridine ester. Although there were fewer tions in the presence of other metal ions, except obvious
TNs (12) achieved with 72, the lowest LOD reached 10 nM. quenching by Cu2+. Approximately 50 min was needed to
Compared with stoichiometric metal-promoted reactions, the reach the maximum fluorescence intensity. A very low signal
reactions in that study were more meaningful and useful for ratio for Fe3+ detection was observed due to the poor
the detection of catalytic targets. wavelength shift (10 nm). Chemodosimeter 75 was developed
by modifying the strong electron donor group diethylamino
4.2 Ion-induced Schiff-base hydrolysis moiety and the electron withdrawing group diaminomaleo-
Based on the mechanism of Hg2+-promoted hydrolysis, a new nitrile moiety based on 74. Probe 74 exhibited a significant red
fluorescent chemodosimeter 73 (Fig. 45) was reported by Peng shift because of effective ICT induced by the electron
et al.92 for the single-selective and ppb level-sensitive detection push–pull system. The emission spectrum of 75 displayed a
of Hg2+ in natural waters. An ethanol–water (1 : 1, v/v, pH 7.0) maximum emission of around 573 nm, which was red shifted
solution was used as the testing system to investigate the by about 171 nm compared with that of 74. When Fe3+ was
chemical response of 73 to Hg2+ at room temperature. A introduced, a coumarin derivative formed as a hydrolysis
time course study revealed that the recognising event can be product, accompanied by a fluorescence decrease at 573 nm
completed in 8 min. Probe 73 exhibited no evident fluorescence and the appearance of a strong peak at around 461 nm in
and absorption in the spirocyclic form. Only after the addition of methanol–water solution (99 : 1, v/v). This substantial shift of
Hg2+ the intensity of fluorescence emission significantly was up to 112 nm in the emission spectra enabled a near-complete
enhanced by 4370-fold at 579 nm, with a quantum yield of 0.75. separation of the emission peaks before and after treatment
An absorption band centred at 554 nm was clearly observed. The with Fe3+. However, about 35 min of maximum spectral
fluorescence response of 73 to Hg2+ had little interference from changes was needed after the addition of Fe3+.
sulfur compounds, such as cysteine and glutathione. Its cell Example 76 for Fe3+ detection (Fig. 47) was developed by
permeability and non-toxicity to cell cultures suggested its Kang and Kim et al.95 The process exploited the high affinity
potential use in Hg2+ imaging in living cells. of the ethylenediamine moiety towards Fe3+ and Schiff-base
Schiff bases are compounds with a functional group con- complex hydrolysis induced by Fe3+ due to its strong Lewis
taining a CQN bond, which is always involved in some acid activity over other metal ions. This hydrolysis reaction
enzymatic transformations. The hydrolysis of Schiff bases can turned on the absorption at 526 nm and green fluorescence
be promoted by acids, amines and metal ions. The detection of emission at 551 nm with an LOD of 0.1 mM in acetonitrile–
trace amounts of Fe3+ is critical because iron is an essential water solution (1 : 19, v/v). Probe 76 could also successful act as
an Fe3+ detector in living cells without any detrimental effect.
Fig. 45 Scheme for the reaction-based detection of Hg2+ by chemo- Fig. 47 Scheme for the reaction-based detection of Fe3+ by chemo-
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4.3 Ion-induced hydrazide hydrolysis

Hu et al.96 presented a novel hydrazide based chemodosimeter
77 for Cu2+ detection (Fig. 48). This assay relied on a Cu2+-
promoted hydrolysis reaction leading to pronounced chromo-
genic (557 nm) and fluorescent (570 nm) signalling OFF–ON Fig. 51 Scheme for the reaction-based detection of OCl by chemo-
behaviours to Cu2+ over common interfering metal ions in dosimeter 81.
acetonitrile–HEPES solution (1 : 1, v/v, 10 mM, pH 7.1). The
LOD of this system reached 10 nM with a good linear range of Probe 79 initially exhibited almost no fluorescence, but upon
10–60 nM for determination. Preliminary analytical appli- the addition of Au3+, a dramatic fluorescence increase appeared
cation proceeded well in wastewater samples. at 549 nm (233-fold). The LOD of 79 was related to the
Apart from detecting Hg2+ by desulfurisation and cycliza- proportion of organic solvent, which was determined to be
tion, Li et al.97 studied 78 (Fig. 49) as a Cu2+ chemodosimeter 290 nM in PBS buffer (pH 7.4, 0.3% DMF) and 75 nM in
based on Cu2+-promoted ring opening, redox and hydrolysis methanol–PBS buffer (1 : 1, v/v, pH 7.4). The favourable
reactions, which were attributed to the highly electron-rich features of 79 included rapid response (o1 min), cell
S atom in 78. When Cu2+ was gradually added to a colourless membrane permeability, high selectivity, as well as applica-
solution of 78, a new absorption band at 555 nm and a new tions in fluorescence imaging in living cells and detection of
emission band centred at 580 nm appeared. Probe 78 displayed residual Au content in Au-catalysed synthetic samples for the
high sensitivity with a LOD below 10 ppb for Cu2+, a rapid first time.
response time less than 1 min, and good selectivity for Cu2+ Ma et al.99 recently reported a chemodosimeter 81 (Fig. 51)
over other trace transition-metal ions and abundant cellular as a highly selective and sensitive fluorescent probe for hypo-
cations. Confocal and two-photon fluorescence microscopy chlorite anion (OCl). The proposed reaction mechanism
experiments established the in vivo utility of 78 for monitoring involved the OCl anion selectively oxidising the hydrazo
Cu2+. group to form the analogue of dibenzoyl diimide, which then
Based on the mechanism of the Au3+-promoted hydrolysis of hydrolyzed and released rhodamine B. Probe 81 showed no
acylsemicarbazides to carboxylic acids at room temperature, a obvious absorption and fluorescence, but both a pink colour
new rhodamine-based chemodosimeter, 79 (Fig. 50), was reported and intense fluorescence (lem = 578 nm) appeared upon the
by Lin et al.98 for Au3+ detection in PBS (pH 7.4, 0.3% DMF). addition of OCl. In Na2B4O7/NaOH buffer (30 mM, 30%
THF, pH 12), 58 displayed a high selectivity to OCl among
Ca2+, Cu2+, Fe3+, Fe2+, Hg2+, K+, Mg2+, Mn2+, Ni2+,
Pb2+, Zn2+, MnO4, H2O2, Cl, OCl, ClO3, SO42, NO3,
PO43 and SiO32. There was a good linear correlation
between the fluorescence increase and OCl concentration
over the range of 1–5 mM, with an LOD of 27 nm. The probe
was also stable at room temperature for as long as 1 week.
5. Hg2+-induced (oxy) mercuration

Fig. 48 Scheme for the reaction-based detection of Cu2+ by chemo- typical (oxy)mercuration reactions, a type of electrophilic
dosimeter 77. addition organic reaction.
Based on the selective direct mercuration to the 4 0 ,50 -position
of the xanthene moiety, Chang et al.100 reported chemodosi-
metric probes using the fluorescein and Nile red systems.
Fluorescein derivative 82 (Fig. 52) showed selective and
efficient signalling behaviour towards micromolar Hg2+ over
other common interfering metal ions in acetate buffer solution
(10% DMSO, pH 5.0). Dichlorofluorescein 82 exhibited char-
Fig. 49 Scheme for the reaction-based detection of Cu2+ by chemo- acteristic absorption bands at 475 and 505 nm, and a strong
dosimeter 78.
emission band at around 528 nm. Upon the addition of Hg2+,
the absorption bands at 475 and 505 nm gradually decreased
and red- shifted to 483 and 533 nm, accompanied with a
colour change from yellowish green to orange. However,
characteristic fluorescence was effectively quenched at the
same time. Other metal ions induced small changes only in
the intensities of absorbance and fluorescence. Although this
ON–OFF type probe was not the ideal choice for quantified
Fig. 50 Scheme for the reaction-based detection of Hg2+ by chemo- analysis, the chromogenic responses of this system facilitated
dosimeters 79 and 80. the detection of Hg2+ by the naked eye. For Nile red 83,
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strongly electron withdrawing than acetylene. Although the

fluorescence intensity of 85 at 488 nm showed an ON–OFF
response to Hg2+, it exhibited good selectivity among common
Fig. 52 Scheme for the reaction-based detection of Hg2+ by chemo- metal ions. Wang and Peng et al.104 developed a chemodosimeter
dosimeters 82–84. 86 based on 1,8-naphthalimide for the selective recognition of
Hg2+ and Au3+ by ratiometric fluorescent sensing. In HEPES
the intense fluorescence at 649 nm was also efficiently buffer (10 mM, pH 7.4, 0.05% DMSO) solution, the addition
quenched upon the addition of Hg2+ with a LOD of 28 mM of Hg2+ induced a clear ratiometric fluorescence change, i.e.,
(within 2 h).101 Chang et al.102 introduced the FRET strategy decreased at 543 nm but increased at 486 nm with an iso-emission
into this design using coumarin as the donor. In the absence of point at 509 nm. When the pH of the methanol–water (19 : 1, v/v,
Hg2+, 84 exhibited a strong emission at 525 nm and a weak pH 9.0) solution was changed, only Au3+ changed the fluores-
emission at 440 nm under excitation at 340 nm. This phenom- cence emission of 86 from 509 to 473 nm.
enon was due to the fact that the emission energy of coumarin Koide et al.105 reported a new type of Hg2+ chemodosimeter
was transported to fluorescein via the FRET process. The 87 (Fig. 54) based on a clever application of the oxymercuration
fluorescence intensity of coumarin at 440 nm increased signifi- reaction. In the presence of Hg2+, indicator 87 was found to be
cantly, whereas that of fluorescein decreased obviously in the converted into a product with green fluorescence. Interfering
presence of Hg2+ because the mercuration prevented the FRET metal ions induced little change (Li+, Na+, Mg2+, Ca2+,
process. Ba2+, Ni2+, Zn2+, Cu2+, Cr3+, Co2+, Mn2+, Pb2+, Cd2+,
Some chemodosimeters were developed for Hg2+ detection Fe3+ and Ag+). The application of the probe for Hg2+
based on the mechanism of the Kucherov reaction. In this detection extracted from salmon tissue or leached from a dental
reaction, alkynes reacted with water in the presence of a amalgam was also demonstrated. The probe was sufficiently
catalytic amount of Hg2+ to give an enol, which tautomerised sensitive at the ppb level for mercury in pure water or in pH 7
to a ketone. Kim et al.103 developed a novel fluorescent buffer solutions both at 90 1C. The probe was also compatible
chemodosimeter 85 (Fig. 53) based on a fluorescent coumarin- with strong oxidants such as cyanide.
derived alkyne. Upon the addition of Hg2+ in PBS buffer Similarly, based on the oxymercuration of vinyl ethers,
(pH 7.4), the absorbance of 85 at 425 nm decreased but that at Koide et al.106 developed another fluorescence chemodosi-
471 nm increased because the carbonyl group was more meter 88 for mercury detection in dental and environmental
samples. Although chloride ions can interfere with oxymer-
curation, the addition of AgNO3 solved this problem. Fine
electronic and structural tuning led to the development of a
more responsive probe that was less sensitive to chloride ion
interference. This second-generation probe was able to detect
1 ppb Hg2+ in water.
Ahn et al.107 presented a simple and efficient fluorescent
probe 89 (Fig. 55) for both organomercury and inorganic
mercury ions based on the mercury ion-promoted hydrolysis of
fluorescein-derived aryl vinyl ether. First, vinyl ether locked the
fluorescence of 89. Subsequently, with the addition of mercury ion,

dosimeters 85 and 86. Fig. 55 Scheme for the reaction-based detection of Hg2+/RHg+ by 89.
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oxymercuration generated a hemiacetal intermediate that

finally fragmented into fluorescein along with a turn-on
fluorescence change. HgCl2 reacted a little faster with 89 than
MeHgCl, which was inferred from the fluorescence recovery
time. Importantly and interestingly, the distribution of accu-
mulated methylmercury in grown zebrafish was realised and
studied by the fluorescence imaging of 89. Methylmercury was
found to be mainly centralised in the eye, heart, fin, gall
bladder and eggs, but not in the brain and liver. Fig. 57 Scheme for the reaction-based detection of Pd by chemo-
dosimeter 91.
6. Tsuji–Trost type reaction

red shift in absorption and a 73 nm red shift in fluorescence
This section describes special chemodosimeters based on the emission with a good linearity between the fluorescence
2+
typical Tsuji–Trost reaction. The Tsuji–Trost reaction was intensity ratio F553nm/480nm and the Pd concentration range
named after Jiro Tsuji, who first reported it in 1965, and of 0–7 mM. The LOD was 0.07 mM. The good selectivity
Barry Trost, who introduced phosphine ligands in 1973. This towards Pb2+ and the low toxicity to cultured cells enabled the
reaction is a palladium-catalyzed substitution reaction of a application of this probe in the fluorescence imaging of Pb2+
nucleophile with a substrate containing a leaving group in an in living cells.
allylic position.108,109
Koide et al.110 developed a fluorescein-based Pd probe
7. Rearrangement reactions
based on its capability to catalyze allylic oxidative insertion
to cleave the allylic C–O bond of an allylic ether into a This section describes special chemodosimeters based on
fluorescein derivative. The conversion of 90 (Fig. 56) to typical rearrangement reactions. These reactions are a broad
fluorescein dye was particularly efficient with Pd, whereas class of organic reactions that include the Beckmann, Claisen,
other p-philic metals such as Ag, Ni, Au, Rh, Co, Hg and Hofmann and Wolff rearrangements. Some rearrangements
Ru did not catalyze the deallylation reaction. In the quanti- under mild conditions can be used for the detection of
tative detection of Pd, this fluorescent method allowed the analytes.
detection of less than 50 ng of Pd and exhibited a good linear
relationship (R2 = 0.993) between the fluorescence intensity 7.1 Pd2+/4+ and Pt4+ catalyzed aromatic Claisen
and Pd concentrations of 0.95 to 95 ng. This fluorescent rearrangement reaction
chemodosimeter can be applied to Pd analyses in pharmaceu- As discussed earlier, Koide et al.113 demonstrated that the
tical products and Pd detection in rock samples. transformation of the non-fluorescent compound 92 (Fig. 58)
Similar to the Pd-catalyzed Tsuji–Trost reaction, Koide to the green fluorescent compound F was highly specific to Pd
et al.111 found that this indicator 90 could also undergo the and Pt, which could be used to detect these metals sensitively
Tsuji–Trost reaction when catalyzed by Pt. They realised the via the Tsuji–Trost reaction. The non-fluorescent 92 also
selective determination of palladium in the presence of platinum noticeably rearranged to the fluorescent compound G via the
by controlling the pH of the reaction media. This method can Claisen rearrangement. Although this rearrangement can be
be applied to palladium determination in soil samples. catalyzed by numerous metal species, extreme operating condi-
Zhang et al.112 introduced a 4-hydroxynaphthalimide-based tions such as high temperatures were needed. After screening
probe 91 (Fig. 57) for the ratiometric detection of palladium the different metals, only PdCl2 was found to promote this
species via the palladium-catalyzed depropargylation reaction. rearrangement at 50 1C after 4 h in DMSO–buffer (1 : 4, v/v,
In the absence of palladium species, free 91 showed characteri- pH 10), whereas the others needed high temperatures and
stic absorption at 364 nm and fluorescence emission at 480 nm organic solvents.
in PBS buffer (20 mM, pH 7.4). The introduction of the For PdCl2, the lower LOD was ca. 3.9 mM (390 ppb) in
palladium species (Pd4+, Pd2+ and Pd0) cleaved the propargyl DMSO–buffer (1 : 1, v/v, pH 10). Prolonged incubation resulted
ether, and the catalytic activity was Pd4+ 4 Pd2+ 4 Pd0. in proportionally increased sensitivity. The detection of Pd2+
For the most toxic Pd2+, the addition resulted in an 89 nm contamination in the presence of Pd0 also worked well at 50 1C
for 4 h in DMSO–buffer (1 : 4, v/v, pH 10), which are the
usual conditions for the synthesis of organic compounds.
Fig. 56 Scheme for the reaction-based detection of Pd by chemo- Fig. 58 The reaction scheme for the reaction-based detection of Pd
dosimeter 90. by chemodosimeter 92.
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Fig. 59 Scheme for the reaction-based detection of CN by chemo-

dosimeter 93.
On the other hand, based on its stronger p-electrophilicity

than Pt2+, Pt4+ also catalyzed the Claisen rearrangement and
used to monitor the progress of Pt4+ to Pt0 reduction. This
reduction was successfully detected in aqueous media with an
LOD of 0.54 nM (0.11 ppb) in the presence of Pt0 at 250 mM.
7.2 Benzil rearrangement reaction

Fig. 60 Scheme for the reaction-based detection of F by chemo-

Sessler et al.114 explored a benzil rearrangement reaction- dosimeters 94–96.
based cyanide indicator 93 (Fig. 59) at room temperature. In
the absence of anions, 93 exhibited the maximum absorption The good permeating ability and non-cytotoxicity to mammalian
at 412 nm, and after addition of CN, a large bathochromic cells ensured F imaging in living cells. However, the long assay
shift and obvious colour change (form yellow to colourless) time (4 h) should be further improved for practical applications.
was observed within 1 min. The cyanide-induced fluorescence Lee et al.118 presented a new coumarin-based probe 96 for F
enhancement lowered the LOD down to 20 mM in organic detection with some differences in the probe design. The emission
solution. Given that a well-defined covalent adduct was showed a red shift to 500 nm owing to the change in the electron
formed, this system also provided both remediation and push–pull effect in the molecule. A more reasonable assay time of
detection for cyanide. about 10 min was achieved in aqueous media, and the test paper
further simplified the detection.
Cho et al.119 developed a naphthalimide-based highly selective
8. F-triggered Si–O (B–O) bond cleavage
colourimetric and ratiometric fluorescent probe 97 (Fig. 61)
This section describes special chemodosimeters based on typical for fluoride ion. Upon fluoride-triggered Si–O bond cleavage,
fluoride-triggered Si(B, C)–O cleavage reactions. Fluoride is 97 showed dramatic spectral properties including colour changes
used to prevent dental caries and treat osteoporosis.115 However, (from colourless to green) and ratiometric fluorescence enhance-
a high intake of fluoride can cause fluorosis as a side effect. Thus, ments. The assays were also completed instantaneously in
the recognition and detection of F have received considerable acetonitrile, but required several hours in acetonitrile–HEPES
attention. buffer solution. Most importantly, both one- and two-photo
ratiometric changes can be obtained via two-photo microscopy
8.1 F triggered Si–O bond cleavage (TPM). Compared with traditional fluorescence microscopy,
As the smallest anion, F has unique chemical properties. TPM offered intrinsic three-dimensional (3D) resolution combined
Compared with other silyl halides, the Si–F linkage is one of with reduced phototoxicity, increased specimen penetration,
the strongest single bonds, which makes it significant in and negligible background fluorescence.
synthetic organic chemistry. Due to the high affinity of fluoride Akkaya et al.120 presented two BODIPY derivatives with
for silicon, silyl ether protecting groups can be easily removed silyl-protected phenolic functionalities for F detection both
by the fluoride ion. Therefore, many good chemodosimeters in in solution and in a poly(methylmethacrylate) matrix. The
aqueous media are developed based on this feature. positions of the Si–O bond were different; F-induced sensing
Hong et al.116 developed a novel chromogenic and fluorescent caused different spectrometric changes based on PET and ICT
chemodosimeter 94 (Fig. 60) based on the release of resorufin
upon the addition of F (tert-butylacrylate and Na+ salts) in
acetonitrile–water (1 : 1, v/v) solution. Upon the addition of F,
signal transduction occurred via the F-induced cleavage of the
Si–O bond. The result was increased fluorescence emission
intensity at 589 nm and a colour change from pale yellow to
pink. Other anions did not cause increased fluorescence emission
and a colour change. The same group then prepared a new
system by downsizing the probe size and introducing a
hydrophilic moiety (4-acetic acid) (95), which simplified the
synthesis and increased the solubility.117 The new system
showed a selective coumarin-characteristic OFF–ON change Fig. 61 Scheme for the reaction-based detection of F by chemo-
in emission at 461 nm in HEPES buffer (10 mM, pH 7.4). dosimeter 97.
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mechanisms for 98 and 99, respectively (Fig. 62). Probe 98 Fig. 65 Scheme for the reaction-based detection of F by chemo-
exhibited absorption at 498 nm and fluorescence emission at dosimeter 102.

506 nm. The gradual addition of F induced a little decrease
and blue shift in absorption, as well as obvious fluorescence In the absence of F, 101 showed light blue fluorescence in
quenching. Probe 99 exhibited absorption at 560 nm and tetrahydrofuran (THF) at 403 nm, but immediately exhibited
fluorescence emission at 577 nm. The gradual addition of F strong yellowish-green fluorescence at 520 nm after the addi-
induced ratiometric changes in absorption, in which the band tion of F. Probe 101 displayed a rapid response, excellent
at 560 nm decreased but a new band at 682 nm appeared and selectivity, and good sensitivity with an LOD of 1.0 mM. This
increased. There was also fluorescence quenching at 577 nm. detection process was investigated in a water–DMF mixture;
Ma et al.121 developed an ICT mechanism based chemo- however, the fluorescence enhancements decreased with increased
dosimeter 100 (Fig. 63) for the ratiometric detection of F in water content.
ethanol–HEPES (3 : 7, v/v, 20 mM, pH 7.4). Probe 100 Li et al.123 described a portable and sensitive probe for F
displayed an absorption band at 407 nm, but F addition detection based on the special affinity between fluoride and
triggered the cleavage of the Si–O bond and released a fluorescent silicon. In the absence of F, free 102 (Fig. 65) displayed an
dye. Consequently, there was a 110 nm red shift in the absorption emission band at 418 nm in an aqueous solution with the aid
spectrum. Similarly, the addition of F resulted in a ratiometric of cetyltrimethylammonium bromide. However, upon the
red shift in emission from 500 to 558 nm. The ratiometric change addition of F, this blue–violet emission decreased and a
of absorption made 100 a ‘‘naked eye’’ probe, and the ratiometric new band appeared and increased at 560 nm. This system
change in fluorescence enabled a quantitative determination of F showed good selectivity over normal anions and excellent
over the concentration range of 0.5–28 mM with an LOD of sensitivity with an LOD of 100 ppb. The development of the
0.08 mM. Ratiometric fluorescence imaging was achieved because test paper made F sensing easier and more convenient.
of its cell membrane-penetrating ability and low toxicity. 8.2 F triggered Si–C bond cleavage
Bai et al.122 reported a colourimetric and ratiometric chemo-
dosimeter 101 (Fig. 64) for F based on the combination of the Ravikanth et al.124 introduced trimethylsilylethynyl groups
desilylation reaction and excited-state proton transfer mechanism. into BODIPY dye at the 3,5-positions to act as a chromogenic
and fluorescent probe 103 for F detection (Fig. 66). The basis

dosimeter 100.
Fig. 64 Scheme for the reaction-based detection of F by chemo- Fig. 66 Scheme for the reaction-based detection of F by chemo-
dosimeter 101. dosimeters 103–105.
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There was also decreased fluorescence emission at 578 nm in

THF. This system showed good selectivity to F, whereas
other anions (such as Cl, Br and I) and cations (such as
Zn2+, Co2+, Ni2+ and Cu2+) hardly induced variations in
108 in both absorption and fluorescence.
Fig. 67 Scheme for the reaction-based detection of F by chemo- 9. CN-induced nucleophilic addition
dosimeters 106 and 107. This section describes special chemodosimeters based on
typical CN-induced nucleophilic addition reactions. Cyanide
was the F-induced transformation of the electron-rich trimethyl- ion is extremely toxic because it can inhibit the enzyme
silylethyne group to the electron-deficient ethyne group in cytochrome oxidase after absorption by the lungs, skin, and
CH2Cl2. Upon the addition of F, the cleavage of trimethylsilyl so on. The maximum allowable cyanide concentration in
groups by F led to ratiometric changes. These changes were
drinking water is 1.9 mM, as suggested by the World Health

reflected by the decreased intensity of absorption at 571 nm Organization (WHO). In organic chemistry, cyanide is a good
and appearance of a new peak at 551 nm, as well as the nucleophile in nucleophilic addition reactions. In a chemical
decreased fluorescence at 584 nm and appearance of a new
compound, a p bond is removed by the creation of two new

peak at 564 nm. Probe 103 showed a good selectivity towards covalent bonds upon the addition of a nucleophile. Therefore,
F among normal anions. Although this reaction can also the strong nucleophile cyanide ion is always used as a useful
occur in 104, there was no obvious spectral change because the mechanism of recognition.
phenyl group at the 4-position was not conjugated within
the whole conjugation system. Jiang et al.125 connected this 9.1 CN addition reaction of CQ
QO double bond
trihexylsilylacetylene moiety to the BODIPY dye at the 2,6- Sun et al.129 developed a unique colorimetric and ratiometric
positions. The expanded p-conjugation caused 105 to exhibit fluorescent chemodosimeter 109 (Fig. 69) with high selectivity
absorption at 555 nm and fluorescence emission at 571 nm. in acetonitrile–water (9 : 1, v/v). This probe relied on the
Similar ratiometric changes of blue shifts in both absorption cyanohydrin reaction to elicit a cyanide-triggered response
(555/538 nm) and fluorescence (571/554 nm) were observed via a highly electron-deficient amide moiety. Free 109 exhib-
within 5 min of the addition of F in acetone. Probe 105 had ited absorption at 290 and 379 nm, as well as emission at
an LOD that reached 67.4 nM and also a good selectivity. 427 nm with a quantum yield of 0.26. Upon the addition of
Bhosale et al.126 applied this mechanism on core-substituted CN, a cyanohydrin derivative was formed via the interaction
naphthalene diimide. Apart from the ratiometric change in between the receptor and cyanide by a highly electron-deficient
absorption, 106 (Fig. 67) also showed a different OFF–ON amide moiety. The reaction induced absorption decrease at
change in fluorescence emission. It emitted weak fluorescence 291 and 378 nm, but three new bands appeared at 299, 372 and
at 329 and 455 nm, which gradually increased with the 428 nm. Fluorescence emission showed a bathochromic shift
addition of F. Another example 107 was developed based from 425 nm to 554 nm. The result of the recognition reaction
on a pyrene derivative by Li et al.127 This probe showed high was proven by 1H NMR and ESI MS. Probe 109 exhibited
sensitivity, good selectivity, and a rapid response time (within good selectivity among other anions, including F, Cl, Br,
10 s) to F. There were blue-shift changes in both absorption I, OAc, PhCO2, NO3, ClO4, HP2O73, H2PO4, HSO4
and fluorescence emissions in THF. The test papers also and ClO4.
established the application of F determination in water. Akkaya et al.130 designed probe 110 for sensing cyanide ions
(Fig. 70), which exhibited colorimetric and fluorimetric optical
8.3 F triggered B–O bond cleavage
changes. Among different anions such as CN, F, Cl, Br,
Similar to the F-induced cleavage of Si–O, Tian et al.128 I, AcO, ClO4, H2PO4, HSO4 and NO3 only cyanide
presented 4-formylphenoxy(trinitrosubphthalocyaninato)boron ion produced large changes in both colour and fluorescence
108 (Fig. 68) as both a colorimetric and a fluorescent chemo- emission. The absorption band at 561 nm decreased but a new
dosimeter. This probe had the ability to recognise selectively band at 594 nm appeared with an isosbestic point at 571 nm.
and detect the concentration of F based on the cleavage of The fluorescence intensity at 571 nm decreased obviously. The
B–O. The addition of F resulted in increased absorption at sensing process was reversible upon the addition of trifluoroacetic
482 and 685 nm. However, an obvious decrease at 565 nm and acid. NMR spectroscopy proved the changes in UV/Vis
a change in colour visible to the naked eye were observed.
Fig. 68 Scheme for the reaction-based detection of F by chemo- Fig. 69 Scheme for the reaction-based detection of CN by chemo-
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in HEPES (pH 7.4), 112 showed a remarkably higher selecti-

vity for cyanide over the other anions because of the nucleo-
philicity of cyanide. Another example, 113, was reported by
Swamy et al.133 This probe used fluorescein as a signal moiety.
Apart from the turn-on change in fluorescence with a long
emission wavelength at 520 nm, 113 also displayed colori-
metric change upon the addition of CN in acetonitrile–
HEPES solution (9 : 1, v/v, 10 mM, pH 7.4), which can be
detected by the naked eye. Both 112 and 113 realised the
dosimeter 110. fluorescence imaging of cyanide in living cells.
9.2 CN addition reaction of CQ

QN double bond
Apart from salicylaldehyde, its derivatives such as Schiff bases
and hydrazone are also good substrates for nucleophilic

addition due to the active intramolecular hydrogen bonding
between the CQN and neighbouring phenolic hydroxyl
groups. Guo et al.134 developed a salicylaldehyde hydrazone-

based chemodosimeter 114 (Fig. 73) for CN detection due to
the nucleophilic attack of CN, in which the proton transfer of
the phenol hydrogen to the nitrogen anion rapidly occurred
Fig. 71 Scheme for the reaction-based detection of CN by 111.
and induced obvious spectroscopic change. Free 114 exhibited
an absorption band at 350 nm and a weak fluorescence at
absorption and fluorescence emission. Polymer matrices were
472 nm. Upon the addition CN in DMSO–water solution
obtained by doping the chemodosimeter compound in poly-
(1 : 1, v/v), a new absorption bond appeared at 390 nm and the
(methyl methacrylate), which was used for sensing cyanide
absorption band at 350 nm decreased. A 35-fold fluorescence
ions in the solid state.
enhancement with a blue shift was also observed. This system
Guo et al. displayed a chemdosimeter 111 (Fig. 71) for CN
showed good selectivity over normal anions and excellent
determination in methanol–water solution (4 : 1, v/v).131 This
sensitivity with an LOD of 5.6 108 M. Guo et al.135 further
probe was colourless and non-fluorescent due to its spirocyclic
employed this idea on a FRET system in which 115 was the
structure. However, the addition of CN opened the ring and
donor, fluorescein was the acceptor, and hydrazone was the
induced absorption at 495 nm (yellow) and fluorescence at
linker and receptor of CN. As expected, the FRET process
520 nm, respectively. Good selectivity and excellent sensitivity
occurred after the addition of CN along with a ratiometric
towards CN (2.66 108 M LOD) enabled its application in
change in emission. The emission at 350 nm decreased gradually
CN determination in drinking water.
but that at 550 nm increased. In DMF–water solution, the LOD
Kim et al. reported a selective fluorescent chemodosimeter
reached 4.4 107 M.
112 (Fig. 72) for cyanide ion detection with a coumarin group
Lee et al.136 prepared an indole-conjugated coumarin-based
as a fluorescent signal unit and a salicylaldehyde functionality
probe 116 (Fig. 74) for CN detection with dual changes in
as a recognition or reaction unit.132 The phenolic hydrogen
absorption and fluorescence emission due to the blocking of the
activated carbonyl for nucleophilic addition and quenched
ICT process. In the absence of CN, 116 showed two character-
the fluorescence via an intramolecular hydrogen bond. After
istic absorbance bands at 398 and 609 nm in acetonitrile–water
the nucleophilic attack by the cyanide ion, 112 underwent a
solution (19 : 1, v/v). However, in the presence of CN, the
fast proton transfer of phenol hydrogen to alkoxide. The
conjugation of the indole moiety and coumarin moiety was
transfer caused the fluorescence turn-on. In DMSO, both the
nucleophilicity and basicity of anions (F, H2PO4 and AcO)
may cause large changes in the UV-Vis spectra. In contrast,
Fig. 72 Scheme for the reaction-based detection of CN by chemo- Fig. 73 Scheme for the reaction-based detection of CN by chemo-
dosimeters 112 and 113. dosimeters 114 and 115.
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millimolar naked-eye detectable limit in HEPES buffer (pH 7.4).

Later, Peng et al.139 found that the ketone group was also a good
Fig. 74 Scheme for the reaction-based detection of CN by chemo- electron-withdrawing group and developed 119 as chemo-
dosimeters 116 and 117. dosimeter for CN determination. Although the fluorescence
was quenched with a slight blue shift from 364 to 365 nm by
destroyed and the ICT process was disrupted. Consequently, CN, an evident turn-on of absorption at 375 nm that can be
the absorption band at 398 nm red shifted to 409 nm and that observed by the naked eye was also obtained. Probe 119 displayed
at 609 nm disappeared. Interestingly, the fluorescence was also good selectivity and excellent sensitivity towards CN with an
enhanced with some red shift due to the blocking of the LOD of 13 ppb. Unlike other irreversible chemodosimeters, this
conjugation-based ICT process, as explained by density func- CN sensing behaviour was reversible with the help of Au3+. The
tional theory (DFT)/time-dependent DFT calculations. probe can also be used as an Au3+ probe.
Jung et al.137 introduced the FRET process using the Tae et al.140 developed a novel acridine orange-based chemo-
spiropyran-polythiophene conjugate, which was developed as dosimeter 120 (Fig. 76) to detect cyanide in DMSO–water
a probe 117 for CN. Polythiophene emitted at 556 nm. UV (19 : 1, v/v) system. The detection strategy was based on the
irradiation for 2 min induced a new absorption band at 585 nm nucleophilic addition of cyanide to the 9-position of the
and efficient fluorescence quenching in THF as a result of FRET. acridinium ion. This process broke the conjugation of the molecule,
There was a large overlap between the emission of polythiophene which induced a marked fluorescence decrease and colour
and absorbance of the opened merocyanine. This quenching was change from orange to pale blue. The selectivity of 120 for
reversible by irradiation with visible light. Among the normal CN in aqueous media was below 1.9 mM, the standard
anions, only the 117 solution with CN inhibited quenching due prescribed by the WHO for allowable cyanide concentration
to the formation of a CN-adduct. in drinking water. Mashraqui et al.141 developed 121 as a CN
probe based on the p-deficient pyridinium ring. After reacting
9.3 CN addition reaction of a CQ
QC double bond
with CN in DMSO–Tris-HCl buffer (7 : 3, v/v, pH 7.0), the
Based on a Michael addition reaction, a simple coumarin p-rich adduct of 1,4-dihydropyridine that enhanced the ICT
derivative 118 (Fig. 75) for cyanide detection in water was process was formed. The result was a red shift in absorbance
developed by Kim et al.138 The coumarin derivative was a from 330 to 406 nm and a fluorescence turn-on response
good Michael acceptor due to the electron-withdrawing ability (10-fold). This system showed good selectivity and sensitivity
of aldehyde. When cyanide ion was added to the b-position of towards CN with an LOD of 1.6 mM.
the aldehyde group in aromatic coumarin, the fluorescence of
118 was quenched and there was an absorption change from
10. Conclusions
446 to 282 nm. The probe showed a selective and sensitive
response to the cyanide anion over other various anions with a This review considered fluorescent chemodosimeters that
recognised biomedically and environmentally significant cations
(such as Hg2+, Pb2+, Cu+, Cu2+, Ag+, Fe3+, Au3+ and
MeHg+) and anions (such as CN, F, BO3, OCl, S2 and
O2 ) reported over the past two decades. The successful
development of systems that can monitor such analytes in real
time and space based on mild reactions was clearly demon-
strated. For a systematic elucidation, these chemodosimeters
were classified according to the reaction type, such as ‘‘de-type’’
(desulfurisation, deselenisation and deprotection), cyclization,
hydrolysis, (oxy)mercuration, Tsuji–Trost, rearrangement,
cleavage and nucleophilic addition reactions. Chemodosi-
meters are still in their infancy compared with classical
Fig. 75 Scheme for the reaction-based detection of CN by chemo- supramolecular systems. However, they have clear potential
dosimeters 118 and 119. uses in environmental, biomedical and industrial samples.
View Online
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This work was supported by the NSF of China (21136002, 36 K. C. Song, J. S. Kim, S. M. Park, K. C. Chung, S. Ahn and
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37 J. E. Namgoong, H. L. Jeon, Y. H. Kim, M. G. Choi and
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View Online / Journal Homepage / Table of Contents for this issue

Published on 25 April 2012 on http://pubs.rsc.org | doi:10.1039/C2CS00004K

Featuring work from the group of As featured in:

Fluorescent chemodosimeters using “mild” chemical events

Mild chemical events have sparked the development of

Cite this: Chem. Soc. Rev., 2012, 41, 4511–4535

www.rsc.org/csr CRITICAL REVIEW

Received 7th January 2012

Jianjun Du obtained his PhD Mingming Hu received her

emits light at a certain wavelength, which is shifted after the

dosimeters based on ‘‘mild’’ reactions are appropriate, which

Currently, the interconnection of multiple disciplines has

2.2 Ion-induced desulfurisation followed by oxidation

Fig. 4 Reaction route for the reaction-based detection of Hg2+ by

Fig. 5 Reaction route for the detection of Hg2+ by chemodosimeter 6.

the same conditions, except Ag+ with a stoichiometry of 2 : 1.

695.4, respectively. Complex A was relatively stable in the

Fig. 10 Basis of the reaction-based detection of Hg2+ by chemo-

at the micromolar level, but its poor solubility limited its

Fig. 17 Scheme for the reaction-based detection of Hg2+ by chemo-

such as zebraﬁsh, in which it demonstrated strong ﬂuorescence

Initially, 28 (Fig. 17) showed a very weak band at 530 nm with a

a Hg2+ detection range above 0.6 mM. Kim et al.60 developed

solution and an obviously improved sensitivity of as low as

dosimeters 20–25, 30 and 34–36, the same reactive moiety can

2.5 Ion-induced deprotection

Fig. 30 Scheme for the reaction-based detection of O2 by chemo-

Based on the nucleophilic mechanism of O2 in mediating the

based ﬂuorescent chemodosimeter for O2 imaging in biological

tection rather than a redox mechanism, 49 showed high

acetonitrile and acetonitrile–water (9 : 1, v/v) solutions. In

Fig. 38 Scheme for reaction-based detection of F by chemodosi-

Gong et al.84 reported a novel chemodosimeter for F

change. Almost at the same time, Tae et al.81 reported another

Consequently, an active copper-responsive ﬂuorescent probe

acids. Linear PNA can then be detected as a result of its ability

Fig. 42 Scheme for the reaction-based detection of Cu2+ by chemodosimeter 69.

Fig. 46 Scheme for the reaction-based detection of Fe3+ by chemo-

4.3 Ion-induced hydrazide hydrolysis

5. Hg2+-induced (oxy) mercuration

Fig. 54 Scheme for the reaction-based detection of Hg2+ by chemo-

strongly electron withdrawing than acetylene. Although the

Fig. 53 Scheme for the reaction-based detection of Hg2+ by chemo-

oxymercuration generated a hemiacetal intermediate that

6. Tsuji–Trost type reaction

Fig. 59 Scheme for the reaction-based detection of CN by chemo-

On the other hand, based on its stronger p-electrophilicity

LOD of 0.54 nM (0.11 ppb) in the presence of Pt0 at 250 mM.

7.2 Benzil rearrangement reaction

Fig. 60 Scheme for the reaction-based detection of F by chemo-

Fig. 62 Scheme for the reaction-based detection of F by chemo-

exhibited absorption at 498 nm and ﬂuorescence emission at dosimeter 102.

Fig. 63 Scheme for the reaction-based detection of F by chemo-

There was also decreased ﬂuorescence emission at 578 nm in

drinking water is 1.9 mM, as suggested by the World Health

compound, a p bond is removed by the creation of two new

in HEPES (pH 7.4), 112 showed a remarkably higher selecti-

9.2 CN addition reaction of CQ