Organic Chemodosimeter for Cyanide: A Nucleophilic Approach

Accepted Manuscript

Title: Organic Chemodosimeter for Cyanide: A NucleophilicApproach

Author: Palas Baran Pati

PII: S0925-4005(15)30222-7DOI: http://dx.doi.org/doi:10.1016/j.snb.2015.08.044Reference: SNB 18899

To appear in: Sensors and Actuators B

Received date: 12-6-2015Revised date: 7-8-2015Accepted date: 10-8-2015

Please cite this article as: P.B. Pati, Organic Chemodosimeter for Cyanide:A Nucleophilic Approach, Sensors and Actuators B: Chemical (2015),http://dx.doi.org/10.1016/j.snb.2015.08.044

This is a PDF file of an unedited manuscript that has been accepted for publication.As a service to our customers we are providing this early version of the manuscript.The manuscript will undergo copyediting, typesetting, and review of the resulting proofbefore it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers thatapply to the journal pertain.

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Organic Chemodosimeter for Cyanide: A Nucleophilic Approach

Palas Baran Pati*[a]

[a] Department of Chemistry, Ångström Laboratory, Uppsala University, Uppsala, Sweden

E-mail: [email protected]

Abstract: Out of the all anions cyanide is one of the most threaten for environmental and

social system and abundance of cyanide in environment generate not only from industrial

waste but also from the biological process of fungai and algae. It has very much toxic effect,

after a certain limit it may cause to death. The interest for qualitative and quantitative

detection of cyanide is growing on. Detection rely on the change in absorption and emission

properties of probe upon binding with cyanide is important because of its simple analysis

technique. Cyanide is a good nucleophile and this property can be very much useful to

develop organic probes to detect its presence. Here this review deals with the organic

chemodosimetric probes for cyanide, more specifically the detection mechanism is driven by

the nucleophilic attack of cyanide ion to the probe. Discussed organic probes are divided into

some classes according to their structural features and functional group present in the probe.

Keywords: Cyanide sensor • Chemodosimeter • Nucleophilic approach • Ratiometric sensor •

Colorimetric probe

1. Introduction

Anion chemistry is of continuous growing interest in the aspect of supramolecular chemistry

because of their tendency to form H-bonding.1,2,3

So design and introduction of molecular

probes for anion recognition is very much interesting topic of research now. Out of the several

anions cyanide is the most threaten for environment and human life. The worldwide

production of cyanide is very high due to their industrial use such as production of paper,

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textiles, plastics and nitrile as well as metalo-electroplating and the most the important one is

extraction of gold and silver. Cyanide is also released from biological processes of bacteria,

fungai and algae even from daily life of human and their activity such as cigarette smoking.4,5

Cyanide can form a stable complex with cytochrome c oxidase, which leads to inhibition of

the function of this enzyme, and supply of oxygen to the cell which resulted to cellular

asphyxiation. The consumption of excess cyanide resulted to disorder in nervous system,

respiratory problem and eventually death.6 By considering the adverse effect of cyanide the

World Health Organization fixed the maximum acceptable concentration level of cyanide in

drinking water is 0.2 ppm.7

There are many conventional detection methods for quantative determination cyanide

which are based on potentiometric, electrochemical and voltammetric techniques.8 These are

all costly and need sophisticated instrumentation. The interest on designing new molecular

probes which can selectively recognize cyanide by signaling through either absorption or

fluorescence or both is growing very fast. There are several factors which reduces the

practical application of the molecular probes; (a) Lack of water solubility (b) Interference of

other anions like OAc− and F

−. A popular strategy to design new sensor by introducing two

units one is signaling unit another is binding unit which are linked to each other by covalent

bond or some linker. Upon binding of cyanide to the binding site will cause a change in color

or fluorescence of the signaling subunit. Displacement approach to a coordination complex

also used very much specially Cu-complex and Zn-complex for determination of cyanide.9

The most important for the determination of cyanide is known as a chemodosimeter approach.

These type sensors have several advantages like fast and more specific detection. Drawback

of this approach is rely on irreversible chemical reactions, which take place upon an

interaction with cyanide that‟s why sensor can‟t be recovered and reused. Due to the

exceptional nucleophilicity of cyanide, nucleophilic addition on probes by cyanide is one of

the most important methods for probing it.

Recently some nice reviews on the aspect of designing chemosensors for cyanide and

report on recent literature have been published.9,10,11,12

Banks et al. presented a nice review on

the recent development on quantification of cyanide and hydrogen cyanide.13

This review

deals with the designing of the chemodosimetric probe for cyanide using organic dyes. More

specifically the detection mechanism relay on the nucleophilic attack of cyanide ion to the

probe. The review discloses a clear idea and advancement of probes based on pure organic

small molecules by nucleophilic attack approach by cyanide ion. Discussions in this review

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are divided by some part according to the structural class of probe that means the functional

group present in the probe.

2. Addition to the activated carbonyl group.

The carbonyl group in the salicylaldehyde moiety is activated by intra-molecular hydrogen

bonding with the phenolic –OH group. It is expected that the activated carbonyl group could

undergo nucleophilic addition with cyanide and subsequent proton transfer from phenol group

to alkoxy anion generated after addition of cyanide produce to cyanohydrins compound. The

sensing mechanism can be followed by change in color and also enhancement in fluorescence

due to restricted excited state proton transfer (ESIPT). Also the NMR titration can give the

better idea about mechanism by studying the shift of the aldehydic proton of salicylaldehyde

group which will not be the aldehydic anymore after addition of cyanide. Reported literature

contains a few probes which sense cyanide by following this mechanism. Kim et al. designed

and synthesized azo based salicylaldehide functionalised dye 1 (Fig. 1). The dye showed a

colour change from colourless to red upon the addition of cyanide ion. The higher sensitivity

(well below the WHO detection level) and affinity was due to the intramolecular hydrogen

bonding of phenol proton which stabilized the intermediate anion.14

Figure 1. Plausible sensing mechanism of cyanide

Then Kim and Hong et al. further introduced new coumarin-based fluorescent

chemodosimeter 2 (Fig. 2) which did not show any fluorescence initially but after the

nucleophilic attack toward the activated carbonyl functional group followed by proton transfer

of the phenol hydrogen to the developing alkoxide anion caused strong blue fluorescence.

This probe can detect cyanide in 260 ppb region in biological pH.15

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Figure 2. Plausible cyanide sensing mechanism of probe 2

Yoon and Park et al. introduced a microfluidic devices for selective cyanide detection using

fluorescein aldehyde-based 3 by applying the strategy of activated carbonyl group (Fig. 3).16

They tested the sensing study in CH3CN–H2O (9:1, v/v), by monitoring changes in emission

at 500 nm wavelength. The probe behave as clorometric and also fluoremetric sensor by

enhancing its emission intensity by 200 fold. The probe was also demonstrated for detection

of cyanide ion in living cells.

Figure 3. Plausible reaction pathway upon addition of cyanide

We introduced two new probes comprising triphenylamine and salicylaldehyde functionalities

4 and 5 (Fig. 4).17

Both the probes behave colorimetric (by changing color from colorless to

pale yellow) and “turn-on” fluorimetric chemodosimeter in THF-water (95:5) mix solvent

system. Theoretical investigation concluded that intramolecular charge transfer from

negatively charged quinone state to the triphenyl moieties may be the responsible for color

change upon addition of cyanide. These probes showed 350 fold enhancement of fluorescence

intensity upon addition of cyanide.

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Figure 4. Structures of triphenylamine and salicylaldehyde based probes

Malik et al. had designed and synthesized a new salicylaldehyde-appended fuorene-based

chemodosimeter 6 (Fig. 5).18

The probe recognized CN− by colorimetrically as well as

fluoremetrically. There was 9 fold enhancement of fluorescence intensity at 520 nm

wavelength upon addition of cyanide. The sensor showed high selectivity towards cyanide

with a very low detection limit (0.06 ppm). The turn-on fluorescence sensitivity upon addition

of cyanide was a result of obstruction ESIPT which was also supported by TD-DFT

calculation.

Figure 5. Proposed sensing mechanism

Mongkol et al. reported a series of new dyes, (7, 8 and 9) containing diphenylacetylene as

fluorogenic and salicylaldehyde functionalaties as cyanide receptor unit, which showed

colorimetric as well as fluorometric sensitivity towards cyanide (Fig. 6).19

These sensors can

detect cyanide as low as 1.6 µM concentration in water. They showed that paper strips of

these sensors can detect cyanide in nano molar concentration. Ravikanth et al. reported meso-

salicylaldehyde substituted BODIPY 10 as a chemodosimeter for the CN− ion.

20 This

molecule showed turn-off sensitivity towards cyanide by quenching the emission peak at 521

nm upon gradual increase in added cyanide concentration. Upon conversion from aldehyde to

cyanohydrin the electronic properties of 10 alter significantly which can be observed by

studying change in absorption, emissions and electrochemical processes.

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Figure 6. Structures of some more salicylaldehyde based probes

Goswami et al. reported a ratiometric probe for cyanide containing a 2-(2-

hydroxyphenyl)benzothiazole moiety 11 (Fig. 7).21

Initially it displayed green emission at 521

nm, upon gradual addition of CN− the intensity of emission at 521 nm decreased and a

simultaneous increase in the intensity of a newly appeared band at 436 nm was observed. That

probe can detect cyanide in μM range.

Figure 7. Plausible sensing mechanism of cyanide

3. Addition to the carbonyl group.

Organic dyes containing trifluoroactamide functionalities behave as selective probe of

cyanide due to stabilization of alkoxy ion, generated after addition of cyanide to the carbonyl

group, by intramolecular H-bonding with amide proton. On the other hand the nucleophilic

attack by cyanide to the ketone group can be facilitated by attaching strong electron

withdrawing group (-CF3) to the carbonyl group. Sessler et al. used the benzil–cyanide

reaction (Fig. 8) to designing colorimetric sensor for cyanide.22

They introduced two probes

with extended conjugation methanol–water (70:30) solvent system for detection of cyanide

selectively. By using these probes cyanide can be detected in ppb range by simple naked eye

analysis. Prior to this report, Sessler et al. also described a novel probe 12b (Fig. 9) that

undergoes benzyl rearrangement when treated with cyanide in ethyl acetate. There was a

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colour change from yellow to colorless and large fluorescence enhancement was observed

within 1 min in organic solvent.23

Figure 8. Plausible sensing mechanism of cyanide

Figure 9. Structure of benzyl compounds

Akkaya et al. introduced new probe 13 comprising the BODIPY and trifluroactamide

functionalities, which behaved as clorimetric and turn-off fluorimetric sensor for cyanide.24

Due to the electron withdrawing nature of trifluoromethyl group the carbonyl group was more

facile to the nucleophilic attack by cyanide and subsequent amide proton transfer to the

alkoxide formed is the reason for colour change (Fig. 10) and addition of trifluoroacetic acid

can restored the sensor intact. They also showed that highly emmisive polymeric film can be

generated by doping this probe in polymer matrix which can show turn-off sensitivity towards

cyanide.

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Figure 10. Plausible cyanide sensing mechanism of probe 13

Further Cheng et al. reported the two probes, 14a and 14b based on anthraquinone by simple

synthetic procedure. These probes detect cyanide by changing their color from colorless to

yellow with very low concentrations (0.51 μM) of cyanide in an aqueous environment.25

Cheng and coworkers devised an azo dye 15 (Fig. 11) that selectivity sense cyanide in

CH3CN–H2O (95:5, v/v) by changing its color from colorless to yellow.26

Figure 11. Some structures of acetamide based probes for cyanide

Ahn et al. introduced a ferrocene based heteroditopic receptor 16a and 16b containing both a

crown ether and a trifluoroacetylcarboxanilide group (Fig. 12). When this system was treated

with KCN it could simultaneously bind potassium ion in crown ether unit and cyanide was

added to the trifluoroacetyl group to produce an alkoxide adduct. The high association

constant of 16a with cyanide suggest the strong binding affinity which was two orders of

magnitude higher than that of 16b.27

The Ahn group also described a new probe 17 that

displays fluorescence quenching in the presence of cyanide in MeOH–water (9:1) solutions.28

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Figure 12. Structures of some probes

By applying the affinity of cyanide toward acyl carbonyl carbon Guo et al. reported a simple

N-nitrophenyl benzamide derivative 18 as cyanide selective probe (Fig. 13).29

It acts as the

„naked-eye‟ sensor of cyanide in DMSO–H2O (1:1, v/v). This sensor can detect cyanide at

concentrations as low as 23 ppb range. Sun et al. introduced dipyrrole carboxamide based two

probes, 19a and 19b (Fig. 13) as cyanide selective probe in the mix solvent CH3CN–H2O

(9:1, v/v).30

The reaction mechanism rely on nucleophilic attack on carbonyl group followed

by proton exchange finally cyanohydrins formation. Addition of cyanide resulted to a color

change from colorless to yellow and additionally compound 19a showed a color change in

emission from blue to green. Xie and Zhu et al. reported a series of dyes (20a–c) by altering

the R-group of carbonyl group of α-position of a dipyrrin unit (Fig. 14).31

These design

proved as an effective strategy for designing CN− sensors which can be utilized in both

organic solvent and aqueous medium, and the detection limit can be easily modulated by the

substituent attached to the carbonyl group. The detection method relay on the nucleophilic

attack on carbonyl group and followed by proton transfer from pyrrole nitrogen.

Figure 13. Structures and proposed sensing mechanism of cyanide for pyrrole based probes

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Figure 14. Plausible reaction pathway upon addition of cyanide

Bhuniya and Kim et al. developed a probe 21 for sensing KCN in aqueous environments

based on an intramolecular crossed-benzoin reaction. The probe 21 showed turn-on

fluorescence upon addition of cyanide due to the production of strong fluorescent resorufin

(Fig. 15). This probe can detect KCN as low as 4 nM. They also showed the use of this probe

in bio-imaging of KCN in cell and blood serum by amplifying the emission signal at 595

nm.32

Figure 15. Plausible reaction mechanism happen after the addition of cyanide to probe 21

Diketopyrrolopyrrole based probe 22 selective for cyanide was introduced by Jhang et al. and

the detection rely on the nucleophilic attack by cyanide to the both carbonyl group (Fig. 16).33

Compound 22 showed absorption at 442 nm and fluorescence emission at 512 nm. With the

addition of cyanide to the DCM solution of compound 22 resulted the disappearance of the

emission associated with a color change from green to red. The nucleophilic attack of cyanide

is also confirmed by NMR titration.

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Figure 16. Plausible way of cyanide adduct formation.

4. Michael addition

Cyanide is a good nucleophile so there is always a chance that cyanide can attack the Michael

type acceptor. There are few reports on selective and sensitive detection of cyanide by

applying Michael addition to the organic probe. Kim et al. described a α,β-unsaturated

carbonyl group containing probe for cyanide detection (Fig. 17).34

Compound 23 is

nonfluorescent whereas after addition of cyanide produces the fluorescent keto form (23-II)

via the enol intermediate (23-I). There was 1300-fold fluorescence intensity enhancement

upon addition of cyanide and additionally there was a change in color from yellow to

colorless. Probe 23 was found to have a detection limit for cyanide of 1.7 µM.

Figure 17. Plausible sensing mechanism of cyanide

Utilizing the doubly activated Michael acceptors Fang and Liu et al. introduced 3-

amidocoumarin based compound 24 to detect cyanide by colorimetrically and also

fluorometrically (Fig. 18).35

Michael addition was taking place at the 4-position of the

coumarins was confirmed by structure illucidation from X-ray diffraction.

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Figure 18. Plausible cyanide sensing mechanism of probe 24

Kim and Lee et al. reported enone-functionalized benzochromene compound 25 which

behave as a ratiometric fluorescence probe for cyanide anions in aqueous buffer (Fig. 19).36

The sensitivity rely on the Michael addition and a subsequent [1,3]-sigmatropic

rearrangement reaction. The probe can detect the presence of micromolar concentration of

cyanide.

Figure 19. Structures of triphenylamine and salicylaldehyde based probes

5. Additions to the dicyano-vinyl group.

The organic dye with extended conjugation with 1,1-dicyanovinyl group has also been

employed as a selectively reactive moiety in the design of CN− probes. The detection

mechanism based on the nucleophilic attack of cyanide to the 1,1-dicyano-vinyl group to

produce a stabilized anionic adduct (Fig. 20). The detection can be studied by colorimetrically

also fluoremetrically because the addition of cyanide disrupts the ICT in dye that generate

change in colour and also change in emission properties. Li and co-worker‟s probe 26 can

show the ratiometric colorimetric sensitivity toward CN− in CH3CN solutions.

37 Due to the

CN− addition to the dicyano-vinyl group molecular conjugation was hindered as a result

intramolecular charge transfer (ICT) efficiency was decreased. Due to the restricted ICT there

was a blue shift of the absorption peak from 515 to 435 nm upon addition of cyanide ion.

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Thus the probe can detect cyanide in naked eye by changing intense colour with a detection

limit of 1.1 μM.

Figure 20. Plausible sensing mechanism of cyanide

By applying the same technique Jang et al. devised a fluorescence turn-on sensor 27 (Fig. 21),

by comprising a dicyano-vinyl group and a BODIPY unit.38

This fluorophore worked in

aqueous medium. Initially the ligand showed very weak fluorescence however, upon addition

of CN−, a dramatic increase in the fluorescence intensity at 510 nm took place which might be

due to the disruption of ICT. Lee et al. reported a new calix[4]pyrrole-based probe which

behave as colorometric sensor for selective detection of cyanide.39

Complete bleaching of the

color of compound 28 (yellow) was observed when cyanide was added. 1:1 complex

formation from Jobs plot and NMR titration proved the nucleophilic attack of cyanide on di-

cyano vinyl group.

Figure 21. Structures of di-cyanovinyl based probes

Su and Li et al. reported the synthesis of two new biindenyl-based D–π–A derivatives 29 and

30, containing dicyanovinyl groups and tested as sensing for anions but both the probe

selective to cyanide only.40

Both the compound showed aggregation-induced emission (AIE).

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Both the compounds were successfully applied for prompt detection (100 seconds) of cyanide

in aqueous environment with the help of cetyltrimethylammonium bromide (CTAB).

Figure 22. AIE based Biindenyl probes

Yu and co-workers investigated solvatochromism and AIE properties of two new

tetraphenylethylene (TPE) derivatives 31 and 32 containing containing dicyanovinyl (Fig.

23).41

Those behaved as fluorescent sensors for the qualitative and quantitative detection of

low-level water content in THF or dioxane. Due to the AIE feature of TPE and nucleophilicity

of cyanide anion probe 31 selectively sense cyanide in water (containing 1% DMSO) under

the assistance of CTAB with low detection limit 0.2 μM. The CTAB provided a hydrophobic

environment to provoke the micelle formation which facile the nucleophilic attack of cyanide

in aqueous media.

Figure 23. TPE based probes for detection of cyanide in water

Chen et al. introduced probe 33 (Fig. 24) which showed a large blue shift (96 nm) in the

absorption spectra upon addition of cyanide to the probe. The resulted color change could

clearly be observe by the naked eye. They developed, the test strips based on this probe for

practical and efficient detection of cyanide.42

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Figure 24. Plausible cyanide sensing mechanism of probe 33

There a few probes 3443

3544

and 3645

were designed and synthesized comprising

triphenylamine and di-cyano vinyl moieties where triphenylamine play a role of

chromophoric unit (Fig. 25). The sensing mechanism was attributed to the interruption of π-

conjugation by a nucleophilic addition of cyanide to the dicyanovinyl group. Chow et al.

showed that probe 34 behave as colorimetric as well as turn-on fluorimetric probe for cyanide.

Whereas Zhao et al. successfully applied the probe 35 for cyanide detection in aqueous

environment with the help of CTAB. Hua et al. reported compound 36 showed high

sensitivity towards cyanide with a detection limit in the nano-molar range.

Figure 25. Structures of some triphenylamine based probes

He and Liu et al. introduced a dicyanovinyl-substituted benzofurazan compound (37) as an

efficient ratiometric probe for cyanide detection in aqueous acetonitrile mix solvent system.

Restricted ICT is the main reason for sensing mechanism that was studied by TD-DFT

calculation. Detection limit was 1.47 μM.46

Two new near-infrared chemodosimeters for

cyanide anion based on 5,10-dihexyl-5,10-dihydrophenazine were designed and synthesized

by Hua et al.47

Probe 38 exhibited turn-on sensitivity towards cyanide with green emission.

Probe 39 with an unreactive formyl group, instead of the two reactive dicyano-vinyl groups,

act as the electron-withdrawing component. Due to the blockage of the ICT of probe 39

showed both colorimetric and ratiometric near-infrared (NIR) fluorescent response to cyanide.

Both the probes can detect cyanide with high selectivity by naked eyes.

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Figure 26. Dicyano-vinyl substituted probes for cyanide detection

We introduced dicyanovinyl terthiophene compound 40 by following simple synthetic

pathway. Compound 40 act as a selective colorimetric as well as a ratiometric fluorescence

probe for cyanide anions in aqueous THF solution. It was investigated by theoretical study

that obstruction in an intramolecular charge transfer (ICT) by the nucleophilic addition of a

cyanide anion to the dicyanovinyl group induces colorimetric change upon addition of

cyanide from yellow to colorless. Compound 40 showed two emission bands at 462 nm and

589 nm but with the gradual increase in addition of cyanide the intensity of 462 and 589 nm

were increased and decreased, respectively with an isoemissive point at 534 nm. After adding

of excess of cyanide the peak at 589 nm totally dimished and led to blue emission. Reaction

kinetic study suggested that the response time is very fast.48

To support the reaction

mechanism we separated and characterized the all three adduct of compound 40 by NMR and

HRMS (Fig. 27).

Figure 27. Ter-thiophene based probes and cyanide adduct

6. Nucleophilic addition toward Indolium type moiety.

Attaching an indolium moiety with another chromophoric part is a nice technique for live cell

bio-imaging and sensing study. The electrophilicity of sp2-carbon atoms toward CN

− can be

enhanced due to the positively charged nitrogen atom in indolium unit. Due to the addition of

cyanide disruption of ICT in the probe resulted the color change and also change in emission.

Based on this property, several probes containing indolium moieties were developed for the

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sensing of CN−. By combining indole and coumarin moieties Lee and Kim et al. able to

develop new probe 41 (Fig. 28) which selectively sense cyanide by not only chromogenic but

also fluorogenic way.49

The response time is very short (< 1 sec) in acetonitrile-water (95:5)

solvent medium.

Figure 28. Plausible sensing mechanism of cyanide

Utilizing indolium unit and the AIE feature of the TPE group, Zhang et al. designed the

fluorescence probe 42 (Fig. 29) for selective detection of CN− in aqueous solution.

50 The

probe exhibits good selectivity and good sensitivity toward CN− in presence of other anions

and concentration as low as 91 nM of cyanide can be detected.

Figure 29. AIE and tetraphenylethylene based probe for cyanide detection

Liu et al. successfully developed BODIPY-indolium based probe 43 for ratiometric

fluorescent detection of cyanide ion (Fig. 30).51

Due to presence of tri(ethylene glycol)methyl

ether residue the probe was highly soluble in aqueous medium, which in turn for great

potential application in detection of cyanide ion in aqueous environment. This probe detect

cyanide ion by changing its emission colour from red to green.

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Figure 30. BODIPY based sensor moiety and sensing pathway

Guo and Yang et al. successfully developed a series of hybrid coumarin hemicyanine dyes

(44, 45 and 46) for CN− sensing (Fig. 31).

52 The sensing mechanism was followed by both

chromogenic and flurogenic way. Due to the nucleophilic addition reaction blocks the π-

conjugation between indolium and coumarin, which may be the main reason for colour

change and also generation of emission. The sensing pathway was followed by NMR titration

and mass spectrometry also.

Figure 31. Structures of coumarin-indolium hybridized probes

Goswami et al. introduced new probe 47, based on carbazole and indolium moieties, which

detect cyanide by both colorimetrically and fluorimetrically 53

The detection was very fast

(within 90 sec) with a low detection limit of 0.54 μM in aqueous-acetonitrile medium. The

test strip developed from TLC plate could be usefull for successfully detection of cyanide by

dip-stick method in naked eye. A new probe 48 containing three indolium units was

introduced by Yin and Huo et al.54

This probe showed turn-on sensitivity towards cyanide in

DMSO solvent system with blue-green emission. The nucleophilic addition of cyanide

resulted the disruption of the π-conjugation, which may be the reason behind sensing

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behaviour. The detection process was fast associated with high detection limit as low as 45

nM.

Figure 32. Sensor probe with multiple indolium unit

Yang and Li et al. introduced a new ratiometric fluorescent phenothiazine based probe 49 for

the detection of CN− (Fig. 33).

55 The probe had a short responding time, low detection limit

(6.67 × 10-8

M). The probe showed nice visible color change from purple to colorless and

green fluorescence upon addition of cyanide. It was shown that test strip developed using this

dye can detect cyanide very nicely. This probe can be used for bioimaging of intercellular

cyanide that was proved by visualizing cyanide in living GES, HeLa cell also in Zebra fish.

Figure 33. Plausible sensing mechanism of cyanide of phenothiazine based probe

Yang and co-workers designed and synthesized a new indolium based probe 50 which act as

turn-on fluorescence sensor for CN−.56

They showed this probe can detect cyanide in aqueous

medium with in very fast responding time. This probe showed change in color from red to

colorless with enhancement of fluorescence upon addition of cyanide. They had done TD-

DFT calculations to support the hypothesis: the blockage of ICT upon addition of cyanide.

Mahapatra et al designed and synthesized conjugated probe by combining thiophene-pyridyl

and indolium system 51 for sensory application.57

Upon the addition of cyanide this probe

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showed ratiometric fluorescence changes with a large emission shift of 115 nm. The detection

limit of 51 was reported about 1.5 µM. This probe was successfully used for bioimaging of

cyanide in the RAW cells.

Figure 34. Two new probes based on indolium unit for cyanide detection

Again Mahapatra et al. designed and synthesized a new benzthioimidazole-appended

spiropyran compound 52 (BISP) which undergo to the form of 52-I upon UV-light treatment

(Fig. 35). Then this open form showed a turn-on fluorescence response towards cyanide at

445 nm wavelength in aqueous HEPES buffer solution.58

The probe was highly sensitive to

cyanide with a detection limit of 1.7 μM. When the 52-II treated with Au3+

spiropyran

compound 52 was regenerated.

Figure 35. Plausible reaction way happen in the probe 52 upon addition of cyanide

Huo and Yin et al. reported the new probe 53 combining triphenyl and indolium moieties.59

This new probe showed turn-on fluorescence responses for CN− in water-ethanol (1:1)

medium. The detection limit was found to be 50 nM. They also used this probe for bio-

imaging of cyanide in HepG2 cell. Feng et al. recently develop a probe 54 containing a

phenanthroimidazole and indolium units.60

The detection of cyanide was rely on the

nucleophilic attack of cyanide on the indolium counterpart, resulting a change in color from

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yellow to colorless and also increase in fluorescence intensity at 432 nm. The detection limit

was found to be 26 nM in aqueous solution.

Figure 36. Indolium based probes

Sun and Duan et al. used the reactivity of indolium unit towards cyanide to design a

benzo[e]indolium containing ratiometric fluorescent probe 55 for cyanide (Fig. 37). Upon the

addition of CN− it showed a visible color change from yellow to colorless and red to blue

color change in emission also. The selectivity of 55 was demonstrated in water (pH = 5-9)

with a very low concentration (1.6× 10−8

M) of cyanide.61

Figure 37. Plausible cyanide sensing mechanism of probe 55

Goswami et al. have designed and synthesized a probe 56 containing triphenylamine and

benzothiazole that selectively sense cyanide by colorimetrically (Fig. 38). The recognition

relay on the nucleophilic attack of cyanide ion to indolium like counter part of the probe. This

probe showed a very fast response (<1 min) to cyanide. The TLC strip of this dye can detect

cyanide by changing its colour which can be detected by naked eye.62

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Figure 38. Plausible sensing mechanism of triphenylamine based probe

Bhatyacharya et al. introduced bis-indolyl based new probe 57 for detection of cyanide in

aqueous medium (Fig. 39).63

The response time for this probe was short and it detected

cyanide by both colorimetrically and fluorometrically. The detection limit calculated from

fluorescence titration was to be 0.38 ppm.

Figure 39. Proposed mechanism of formation of cyanide adduct

7. Additions to the imine group.

Schiff base is an important class of compound in ligand metal chemistry because of its simple

synthesis and purification method. Its application in metal ion sensing is well established.

There is a chance of nucleophilic attack on imine carbon by some strong nucleophile. Cyanide

is a strong nucleophile so it may be probed by Schiff base. Wei et al. had successfully applied

a Schiff base 58 as a highly selective chemosensor for CN−. The detection could be studied by

both clorometrically and fluoremetrically. The nucleophilic attack of cyanide toward the

imine groups was confirmed by 1H NMR titration and FTIR spectra (Fig. 40).

64 As there was

two imine groups the probe followed 1:2 binding stoichiometry, confirmed by Jobs plot. The

detection level was found to be 4.0 × 10-7

M.

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Figure 40. Proposed addition of cyanide to the imine carbon

Wu et al. introduced a pyrene based probe by very simple synthetic pathway. It act as

colorimetric (light yellow to green) and fluoremetric receptor for cyanide and also it showed

colorimetric response to fluoride (light yellow to red) in acetonitrile medium.65

The detection

limit of this probe was reported to be 0.28 and 0.41 ppm for F− and CN

− respectively. Kim et

al. developed an azo dye-based chemical probe (59) with an oxime functional group as the

reaction site of cyanides to detect cyanide in the aqueous environment. The nucleophilic

addition to the imine carbon followed by the proton transfer from phenolic OH to imine

displayed a dramatic color change of 59 (Fig. 41). The color of chemodosimeter 59 turned

from colorless to dark violet in the aqueous environment, which could be easily detectable by

the naked eye and use as deep-stick sensor.66

Figure 41. Proposed sensing mechanism through nucleophilic addition towards imine group

Guo et al. introduced hydrazone dyes 6067

, 6167

and 6268

as turn-on fluorescent and

colorimetric naked eye cyanide sensor. Addition to the immine group followed by the proton

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transfer (Fig. 42) was the main reason for turn on fluorescene which also supported by NMR

titration.

Figure 42. Hydrazone based dyes for cyanide detection and sensing mechanism

Again Guo et al. able to develop compound 63 containing the imine group as a nice

fluorescent probe for cyanide detection. The conversion from 4-(N,Ndimethylamino)

benzamide group to fluorescein was observed due to addition of cyanide to the probe which

was also highlighted from their characterstics emission band of fluorescein. The significant

changes in the color and fluorescence could be observable by the naked eye.69

Figure 43. Plausible sensing mechanism of cyanide of compound 63

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8. Addition to boron containing compound.

Due to the vacant p-orbital, boron centre has a tendency to bind strong electron donating

species. Cyanide has a tendency to attack electron deficient centre so there is a chance that

boron containing compound can probe cyanide. A series of Acceptor-Donor-Acceptor (A-D-

A) based probe containing naphthoquinoneimidazole and boronic acid was introduced by

Tomapatanaget group (Fig. 44). Those probes behaved as turn-on fluorescence sensor for

cyanide in water in the CTAB micellar system. These probes showed a blue emission by

increasing the intensity of 460 nm band.70

Figure 44. Plausible way of cyanide addition to boron containing compound

Gabbaї et al. introduced two new probes which showed turn-on fluorescence sensitivity

toward cyanide. Initially the probe 65 and 66 were very less fluorescent due to the

intramolecular photo-induced electron transfer from the fluorophore to the electron-deficient

phosphonium borane unit whereas after addition of cyanide to the boron center of the

phosphonium boranes the electron accepting abilities of the phosphonium borane unit

decreased as result to a revival of the fluorescence of the fluorophore happens (Fig. 45). The

detection limits of these probes were reported to be in the ppb range.71

Figure 45. Cyanide selective probe containing phosphonium borane

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Subphthalocyanine dyes are used as cynide sensing probe. Martίnez-Máňez et al. first

described the use of 67 as a probe for the „„naked eye‟‟ detection of cyanide by changing the

color from pink to pale yellow. By considering solvent dependence of the relative

nucleophilicities of fluoride and cyanide and tuning the solvent they able to rule out the

problem competitive addition effect of fluoride ion (Fig. 46).72

The detection limit of

compound 67 for cyanide was as low as 0.1 ppm at pH 9.6 [CH3CN–CHES (0.01 M)], and 10

ppm at pH 7 [CH3CN–HEPES (0.01 M)]. Later Palomares and Torres et al. introduced two

other selective colorimetric and fluorimetric molecular probes 68a and 68b for cyanide

detection (Fig. 46), which were also based on subphthalocyanine dye.73

Figure 46. Subphthalocyanine dyes applied for detection of cyanide

Do and Lee et al.74

recently described a strategy involving the coupling of borane as a donor

and BODIPY as an acceptor which resulted in the fabrication of a boron-based sensor 69 (Fig.

47). This receptor showed a 3-fold enhancement in fluorescence intensity in response to

cyanide ions as a consequence of an addition reaction (69-I) that blocks intramolecular

electron transfer.

Figure 47. Plausible pathway of formation of cyanide adduct

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Recently, Kawashima et al. reported new cationic triarylborane 70 (Fig. 48) which acts as an

optical sensor for cyanide in DMSO–HEPES buffer system (4:6, V/V).75

The change in

optical properties was observed due to the formation of 70-I which also supported from the

large association constant value between of cyanide and the probe.

Figure 48. Plausible sensing mechanism of cyanide with cationic boron containg compound

9. Some other reports.

Tae et al. reported recently chemodosimeter 71 based on the acridine moiety which showed

turn-off fluorescence sensitivity towards cyanide in DMSO–water (95:5, v/v) also associated

with a concomitant color change from orange to pale blue (Fig. 49).76

Addition of cyanide

followed the 1:1 stoichiometry that was shown from Jobs plot. The detection limit reported to

be 1.9 μM. As shown in Fig. 48, this strategy takes advantage of the nucleophilic addition of

cyanide at the 9-position of the N-methylacridinium yielded to the adduct 71-I, which rapidly

reacted with oxygen to produce acridinone 71-II.

Figure 49. Reaction pathway of acridine moiety with cyanide

Kaur and Singh et al. introduced triarylmethane–leuconitrile containing dye 72 as a cyanide

sensor by using nucleophilic addition of cyanide to triarylmethane unit. This dye detect

cyanide in water selectively by the by changing its color from blue–green to colorless which

further motivated to apply „„dip-in‟‟ sensing technology (Fig. 50).77

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Figure 50. Plausible cyanide adduct formation of probe 72

Afkhami et al. designed a colorimetric cyanide sensor by the immobilization of methyl violet

73 on an acetylcellulose membrane.78

When cyanide ion reacts with the methylviolet unit,

there is a decrease in the absorbance of the film at 598 nm (Fig. 51). The probe has a detection

limit of 62 ppm.

Figure 51. Plausible way for the addition of cyanide to the probe 73

Clevage of C-Si bond was successfully applied to develop the sensor for fluoride ion.

Machado et al. developed probe 74 and showed that it could selectively detect cyanide

colorimetrically in CTAB solution (pH = 8) by the cleavage of O-Si bond to produce an

anionic species 74-I whereas fluoride could also deprotect it but it needed longer time (Fig.

52). The detection and quantification limit of this probe were reported to be 1.48 × 10-5

and

4.93 × 10-5

mole/lit respectively. Also this probe was successfully applied to detect the

cyanide in human blood plasma.79

Figure 52. Plausible cyanide adduct formation of probe 74

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Mashraqui et al. designed a chemodosimeter 75 for cyanide based on pyridinium moiety. It

probed cyanide by both colorimetric fluoremetric way. The detection mechanism involved the

formation of C4-cyano adduct (75-I), which enhanced the ICT process (Fig. 53). The

formation of cyanide adduct was also supported by the 1:1 stoichiometry obtained from Job‟s

plot and NMR titration. The detection limit for this probe was found to be 1.6 μM.80

Figure 53. Plausible way for the addition of cyanide to the probe 75

10. Conclusion.

This present review covers recent reports on chemodosimetric probes for cyanide sensing.

Discussion mainly concentrated on the approaches that involve the nucleophilic addition

mainly to the organic dyes. As described above, the nucleophilicity of cyanide is the

depending factor and tool to design probes. The selectivity towards cyanide was tested by

signal production from electronic absorption spectral, emission spectral change and from

NMR also. The whole discussion is divided by some parts according to the structural

functionalities present in the probes. There were considerable efforts on the development of

cyanide sensing systems in recent years and my strong belief that demand of the new efficient

probes would be more interesting in forth coming years. For effective sensing in the term of

analytical aspect and further practical application of these sensors will need to have some or

all of the important properties like high stability, good solubility in aqueous media, low

detection limit and obviously good cell permeability for application live cell imaging.

Thorough out the whole discussion in the review it is obvious that the dicyano-vinyl group

and indolium functionalities are used a lot for development of new probes, still there is need

for introduction of new members in these classes with improved performance. Specially the

application of Schiff base in cyanide sensing has a lot of chance of improvement because it is

very easy to synthesize and characterize. I believe that this review could be very helpful to

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design the new organic efficient probes and further improvement in the search for selective

detection of cyanide with high sensitivity.

Acknowledgement Uppsala University is acknowledged for supplying research

infrastructure.

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Biographical Sketch: Dr. Palas Baran Pati earned his BSc degree from J. K. College, Purulia,

Westbengal, India. After getting MSc degree from the University of Burdwan in 2009 he

join Indian Institute of Science Education and Research Kolkata for PhD degree under the

supervision of Prof. Sanjio S. Zade. He earned PhD degree in 2014. After completing the

PhD he joined as a research associate at Department of Chemistry, National University of

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Singapore. Currently he is pursuing postdoctoral studies at Physical Chemistry Division,

Ångström Laboratory Uppsala University, Sweden.

Organic Chemodosimeter for Cyanide: A Nucleophilic Approach

Palas Baran Pati*[a]

[a] Department of Chemistry, Ångström Laboratory, Uppsala University, Uppsala, Sweden

E-mail: [email protected]

Synopsis: This review contains recent reports on the designing of the chemodosimetric probe

for cyanide using organic dyes. The detection mechanism relay on the nucleophilic attack of

cyanide ion to the probe. The compounds discussed in this review are subdivided into some

class according to their cyanide receptor unit present in the probe.