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Recent Advances in the Development of ChromophoreBased Chemosensors for Nerve Agents and Phosgene Liyan Chen, Di Wu, and Juyoung Yoon ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.7b00816 • Publication Date (Web): 12 Dec 2017 Downloaded from http://pubs.acs.org on December 12, 2017

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Recent Advances in the Development of Chromophore-Based Chemosensors for Nerve Agents and Phosgene Liyan Chen,† Di Wu,† Juyoung Yoon*,† †

Department of Chemistry and Nano Science, Ewha Womans University, Seoul, 120-750, Korea

ABSTRACT: The extreme toxicity and ready accessibility of nerve agents and phosgene has caused an increase in the demand to develop effective systems for the detection of these substances. Among the traditional platforms utilized for

this purpose, chemosensors including surface acoustic wave (SAW) sensors, enzymes, carbon nanotubes, nanoparticles and chromophore based sensors have attractive increasing attentions. In this review, we describe in a comprehensive manner recent progress that has been made on the development of chromophore-based chemosensors for detecting nerve agents (mimic) and phosgene. This review is comprised of two sections focusing on studies of the development of chemosensors for nerve agents (mimic) and phosgene. In each of the sections, the discuss follows a format which concentrate on different reaction site/mechanisms involved in the sensing processes. Finally, chemosensors uncovered in these efforts are compared with those based on other sensing methods and challenges facing the design of more effective chemosensors for the detection of nerve agents (mimic) and phosgene are discussed. KEYWORDS: chromophore-based chemosensors, chemical warfare agents (CWAs), nerve agents (mimic), organophosphate, phosgene, phosphorylation reaction, colorimetric, ratiometric

The production of chemical warfare agents (CWAs), substances which have intended uses as weapons in battlefields, reached the peak during World War I (WWI).1-6 CWAs can be classified into several types including nerve, pulmonary (such as phosgene), asphyxiant/blood and blister or mustard agents. Nerve agents, which have been identified as being one of the most dangerous CWAs,7 are typically members of the organophosphate family (OPs) that form covalent adducts with esterase enzymes.8-9 Specifically, nerve agents covalently inhibit acetylcholinesterase (AChE) which is a critical central nervous system enzyme responsible for the breakdown of the neurotransmitter acetylcholine, leading to the rapid and severe effects on humans and animals.10-11 Phosgene (COCl2), known also as carbon oxychloride, carbonyl chloride, chloroformyl chloride and carbonic acid dichloride is another harmful CWA.12 Exposure to phosgene induces eye, nose, throat and respiratory tract irritation, contributing to pulmonary edema, respiratory failure and even death.13-19 Owing to their extreme toxicities, nerve agents and phosgene have become serious threats to global security and public health. Consequently, intensive efforts have been given to the development of selective and sensitive systems for the detection of these substances, such as those involving surface acoustic wave (SAW) sensors, enzyme, carbon nanotubes, nanoparticles and chromophore based sensors et al.20-27 It is not possible to

summarize all these methods in this review. Thus, emphasis is given to descriptions of chromophore-based chemosensors for the detection of nerve agents (mimic) and phosgene. Chromophore-based chemosensors function on the basis of absorption and (or) fluorescence intensity changes that accompany chemical reactions with the target analytes.28-41 By taking advantages of the chromophore-based chemosensor concept, low cost, realtime visual detection instruments with capabilities of high levels of selectivity and sensitivity have been created. Molecular Structures and Brief History of Nerve Agent Nerve agents are members of the organophosphorus (OP) family of compounds, which were first synthesized in 1854 and developed into CWAs during the past eight decades. Tabun (GA) (Scheme 1) was the first substance of this type to be used as a nerve agent in the military in the early 1930s. It was synthesized as part of a search for more effective OP pesticides by Schrader. In the next few years other members of this family including Soman (GD), Sarin (GB) and Cyclosarin (GF) were synthesized and recognized to be effective as nerve agents. Further efforts carried out in the early 1950s led to the development of new kinds of nerve agents, including the V-agents, such as VM, VG, VE ,VX, whose toxicities are approximately ten-folds more than that of Sarin (Scheme 1).

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Nerve Gas Mimic

Nerve Agents G-agents

O

O

O

P O CN

P O F

P O F

Tabun/GA

Sarin / GB

N

O P O S

O P O O S

O P O F

O P EtO OEt OEt

Soman/GD Cyclosarin (GF) O P O S

O P O S

V-agents N

VG

N

VM

N

VX

N

RO

O P OR X

R = CH2CH3, X = Cl Diethyl Chlorophosphate (DCP) R = CH2CH3, X = CN Diehtyl Cyanophosphate (DECP) Triethyl Phosphate R = CH(CH3) 2, X = F Diisopropyl Fluorphosphate (DFP) O P Cl Cl O

VE

EDCP

O P O O

Ph

DPEP

O P O O

S

DMTMP

O P O O

DOPP

O O

S P O

Cl

DCTP

Scheme 1. The general structures of nerve agents (mimic). Structurally, nerve agents are esters of phosphoric (RO(O=P(X)OR') and phosphonic (R(O=P(X)OR') acids, with X being F, CN and SR”, which readily react by nucleophilic phosphoryl substitution process serving as the labile leaving groups39,40 Except for Tabun (GA), whose structure is [(EtO)O=P(-CN)(NMe2)], members of this family referred to as G-agents possess a [O=P-CH3] group. In contrast, V-agents contain a pendant amino group and an additional sp3-hybridized group. In contrast to G-agents, which are generally volatile, members of the V-series degrade much slowly and are less volatile. As a result of these properties, V-agents are more persistent and poisonous. The common characteristic of nerve agents is that they are highly reactive with the active site, serine hydroxyl group of the enzyme acetyl cholinesterase (AChE). The irreversible or only slowly irreversible reactions that pursue results in formation of covalently inhibited, phosphorylated or phosphonylated enzymes that do not process acetylcholine (Ach) causing its accumulation in synaptic junctions, which will block muscle relaxation. In order to avoid the direct use of extremely toxic nerve agents in laboratory research, less persistent nerve gas mimics (structures shown in Scheme 1) such as diethylchlorophosphate (DCP) and diethylcyanophosphate (DECP) are typically employed as model compounds. Nerve Agents Chemosensors Based on HydroxylActivation The complex platinum 1,2-enedithiolate 1 containing an appended alcohol moiety (Scheme 2) was developed as the first fluorescent chemosensor for detection of nerve agents by Pilato and co-workers.42 Upon exposure to nerve agents in the presence of triazole, the alcohol moiety in 1 is converted to the corresponding phosphate ester, which upon intramolecular displacement reaction with the pyridine moiety leads to the generation of the highly fluorescent platinum-enedithiolate containing pyridinium salt 2 with emission bands focused at 605 nm and 710 nm. Unfortunately, the fluorescence of 2 is readily

quenched by molecular oxygen, which limits its use to only a nitrogen atmosphere. Based on a similar intramolecular cyclization concept, Swager and co-workers designed a series of fluorescent chemosensors 3a-3c for nerve agents (Scheme 2).43 The thienylpyridyl based sensor 3a undergoes rapid phosphorylation reaction with DCP and DFP to generate the corresponding phosphorylated species. However, the sequent cyclization does not occur. The phenyl ring containing sensor 3b displays a remarkable emission enhancement upon the addition of DCP or DFP owing to the formation of the highly fluorescent cyclization product 4b. Notably, several chemosensors suffer from interference by acidic substances, especially those that contain amine groups. Although protonation of the pyridine nitrogen in sensor 3b occurs in the presence of HCl, only minimal fluorescent enhancement takes place because the geometrical changes in the excited state of aromatic rings in 3b facilitate nonradiative processes. In order to improve the rate of the reaction, sensor 3c with a rigid naphthalene subunit was synthesized. The results show that 3c displays a rapid reaction rate, a lower detection limit, and it can be used for ratiometric detection of DCP and DFP. Ratiometric sensors are generally more advantageous because they provide a built-in correction that lessens experimental artifacts including the heterogeneous distribution of the sensor, photobleaching and instrumental variability. In 2006, a series of turn-on sensors 5a-5d based on pyrene were designed and synthesized by Rebek and co-workers (Scheme 2).44 All of these chemosensors show weak fluorescence owing to the existence of photoinduced electron transfer (PET) quenching. Reaction of 5a with the nerve agent DCP promotes a sequential phosphorylation-cyclization process, which results in blocking of PET quenching of the pyrene fluorophore by the amine donor and a large, 22-fold fluorescence enhancement. In contrast, sensors containing a larger number of methylene units (e.g., 5b, 5c, 5d) between the amine and the fluorophore display less efficient fluorescence quenching and, as a result, lower fluorescence intensity enhancements in the presence of nerve agents.

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(Scheme 3b). To extend this method, Costero and coworkers successively developed other DAPE-based sensors 12 and 13, in which the reaction centers are linked to BODIPY dyes through phenyl and alkynyl moieties, respectively.48,49 These sensors have great potential for practical applications. For example, 12 functions well on solid supports while 13 operated in solid-gas detection on silica matrices. Recently, the coumarin-based sensor 14 (Scheme 3b) containing a dimethylaminophenyl moiety was designed and synthesized by Churchill and coworkers.50 Observations made in the study show that 14 possesses a high selectivity towards DCP over DECP and DEMP with a large Stokes shift.

Scheme 2. Structures of 1, 3, 5 and their sensing mechanisms towards nerve agent mimic. The approaches described above, all of which take advantage of the high reactivity of nerve gas agents with alcohols, possess the distinct advantages of being highly sensitive and selective. These efforts have paved a way for the design of novel chemosensors for the detection of nerve agents. For example, using a similar strategy, Costero and Martínez-Máñez designed sensors that contain 2-(2-(N,N-dimethylamino)phenyl)ethanol (DAPE) and 2-(2-(N,N-dimethylamino)phenoxy)ethanol as functional moieties and incorporate azo and stilbene dye scaffolds (sensor 7 in Scheme 3a).45,46 The hydroxyl moiety in these substances acts as a nucleophile in phosphoryl transfer reactions with phosphonate nerve agents to form intermediates 8, which subsequently undergo intramolecular N-alkylation to yield the quaternary ammonium salts 9. These sensors display a high selectivity towards DCP over other relevant nerve agents and exhibit the signaling abilities associated with color modulations in both the vapour and mixed aqueous solution states. Linking the 2-(2-(N,Ndimethylamino)phenyl)ethanol reacting group to a boron dipyrromethene (BODIPY) fluorophore, enabled Costero and Harriman to create the new fluoro-colorimetric sensor 10 (Scheme 3b), which undergoes a colorimetric change from purple to pink and a remarkable emission enhancement in the presence of DECP or DFP.47 In this effort, another kind of BODIPY-based sensor 11, containing 2-2-{2-[methyl(phenyl)amino]ethoxy}ethanol as the reactive group, was designed.47 11a and 11b show the similar colorimetric response (blue to pink) to DECP

Scheme 3a). Colorimetric sensing mechanisms of 7; b) Structures of molecules utilizing BODIPY and coumarin as the fluorophores. Stimulated by the advantageous features of the rhodamine scaffold, including a high fluorescence quantum yield and a controllable equilibrium between a nonfluorescent spirolactam and a strongly fluorescent ring-opened form, Han and co-workers developed the rhodamine-deoxylactam based nerve agent sensors 15 (Scheme 4a).51 The hydroxamate group in 15 reacts with DCP to generate the corresponding spirolactam in 15’ which sequentially undergoes Lossen rearrangement and hydrolysis to generate aniline derivative 19. This sensor sensitively detects DCP (detection limit 25 ppm) through a characteristic color change and sharp fluorescent enhancement. Two new fluorescent sensors 16 and 17 were developed as improvements of 15 by the same group (Scheme 4b, 4c). Addition of DCP to a solution of 16 leads to initial phosphorylation of the hydroxyl group. Nucleophilic attack of deoxylactam amine in the formed intermediate 16’ generates the highly fluorescent species 20.52 In the case of sensor 17, the phosphate ester formed by reaction with the nerve agent undergoes intramolecular nucleophilic substitution to produce the ring opened piperidine derivative 21.53 Wu and Dong also synthesized 18, a structural analog of 16 that contains a spirolactam ring (Scheme 4d).54 Interestingly, this sensor

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utilizes a quite different sensing mechanism in which 18 detects DCP through a process involving spirolactam ring opening followed by cyclization of the generated amide to form the oxazoline product 22. The above results suggest that slight structural modifications of the rhodamine deoxylactam derivatives leads to the operation of extremely different sensing mechanisms. N

O

N

a)

N

O

N

N

O

N

DCP N OH

N O OEt P O OEt

O

15 N

NH 2

15'

O

N

b)

N

19

O

N

DCP N

N

N

OH

O

N

OEt

16 N

16'

O

N

N

c)

N

O O P OEt

O P OEt O

20

O

N

N

O

N

DCP N

N

O O P OEt OEt

OH

17 N

N

17'

O

N

d)

N

21

O

N

DCP N

N

O

N

O N

OH

O

N

O P OEt OEt

O

O

18

18'

22

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The above sensors, which utilize phosphorylationintramolecular cyclization reaction sequences, have good sensitivities and selectivities for nerve agents. However, a key limitation exists in common cases because of the phosphorylation reaction is generally slow causing long response times. In order to improve this general approach to nerve agent detection, more reactive nucleophiles moieties have been incorporated in the sensor platform. Oximate, a well-known ‘supernucleophile’ formed from an oxime by deprotonation, has been incorporated into sensor 25 by Morey and Anslyn to detect nerve agents(Scheme 6).58 Reaction between the phosphorus (V) center of the nerve agent mimic and the hydroxyl group of 25 takes place rapidly in conjunction with an absorption shift from 461 nm to 410 nm. Using a closely related strategy, Huggins and Wallace developed the N,Ncarbonyl-bridged dipyrrinone based sensor 26 (Scheme 6),59 which upon derprotonation of the oxime group reacts with OPs or pesticides to generate minimal “turn on” fluorescence and an obvious color change. However, in order to avoid the formation of hydrolysis products in reactions of bases with nerve agents under the strongly basic conditions required for oximate ion formation, expensive bases such as the phosphazene P4-tBu or Verkade’s base are needed for operation of these sensors.

Scheme 4. Structures and sensing mechanisms of four rhodamine-based sensors 15, 16, 17 and 18.

H

NOH N

In contrast to emission loaded in the visible region, fluorescences in the near-infrared (NIR) region suffer from lower spectral interference resulted from the nonspecific absorption or competitive fluorescence of environmental or biological substances.55,56 Zheng and coworkers developed a NIR fluorescent chemosensor 23 for DCP in which cyanine is employed as the fluorophore and a carboxylic acid group as the reaction site (Scheme 5).57 Upon addition of DCP, phosphorylation of the carboxylate takes place to form an acylphosphate which undergoes intramolecular amidation. This chemistry promotes a color change from blue to light green and a significant fluorescence increase in the NIR region at 807 nm.

NO2

N OH

O

O

NH 2

25

H

N

26

Scheme 6. Structures of sensors 25 and 26 for detection of nerve agents in the presence of base. A new, non-base requiring sensor 27, containing a pyrene1-carbaldehyde O-tert-butyldimethylsilyl oxime moiety, was developed by Lee and co-workers (Figure 1).60 Addition of oxime group in 27 to the phosphonyl moieties in the nerve agents GB or GD, forms unstable intermediates 27’, which undergo spontaneous Beckmann fragmentation to afford the corresponding nitrile 28 in conjunction with a fluorescence change from an initial deep blue to a strong green color.

EtO O P O OEt O

O N

OH

NH

O

N

3

N N

N I

O P O CH

O

N

O P O N CH3

N I

23'

NH N

F

O N

I

27

27'

28

24 23

Figure 1. Sensing mechanism of 27 for the detection of nerve agents and photographs of the fluorescent change in the presence and absence of nerve agents.

Scheme 5. Proposed sensing mechanism of 23 for DCP.

More recently, the effective ratiometric sensor 29 based on 6-substituted aminoquinoline platform was developed for nerve agent detection by Song and co-workers.61 As displayed in Figure 2a, the mechanism for operation of the sensor involves phosphorylation-protonation by DCP,

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which promotes a ratiometric fluorescent change from blue to yellow. Furthermore, it was shown that test strips, containing immobilized 29, can be used to visually detect DCP vapor in a dose-dependent manner, as is illustrated in Figure 2b.

Figure 2. a) Sensing mechanisms of 29 towards DCP ; b) Fluorescent photographs of 29 immobilized test strips upon exposure to various concentrations (0−130 ppm) of DCP vapor.

PET quenching of the BODIPY fluorophore, leading to strong fluorescence. Although 36 shows great selectivity and sensitivity for DECP, its ability to operate at neutral and its sensitivity to pH were not investigated. For optimal versatility, functioning of CWA chemosensors should be largely pH-independent. Thus a detection system, which provides a stable response to samples over a wide pH range, is needed. In order to meet this need, Churchill and co-workers prepared the naphthalimidebased salicylaldoxime containing sensor 39 (Scheme 8b).66 Upon addition of DECP, two sequential nucleophilic substitution reactions occur to form product 41 which would emit strong fluorescence by inhibiting a PET quenching process. Notably, because it performs in aqueous media over a wide pH range, 41 provides a higher flexibility than the sensor systems whose use in aqueous solution is restricted by pH, or whose use is limited to organic solvent.

The oxime group also serves as the foundation of another strategy for nerve agent detection. For example, Rebek and co-workers developed sensor 31 (Scheme 7), which contains an o-hydroxyl substituted naphthaldehyde oxime group.62 Reaction of 31 with OP forms the oxime OP ester, which generates the benzisoxazole product 34 through cyclization promoted by the o-hydroxy group. This sensor displays a rapid reaction rate and a greatly increased sensitivity. The results of theoretical calculations confirmed that it is the quinoid form of the sensor 32 which is thermodynamically most stable.63 A related sensor, 35 (Scheme 7), was developed by Kim and coworkers based on the fluoreceinyl oxime platform. Nerve agents promote a cascade reaction of the oxime moiety in 35 to form the nitrile via the isoxazole resulting in enhanced fluorescence and thus, superior sensitivity.64 Scheme 8. a) Proposed mechanism of sensor 36 for the detection of DCP, DEMP, and DECP; b) Proposed sensing mechanism of sensor 39 with DECP.

Scheme 7. The hydroxyl oxime-based detection mechanism of 31 and the structure of the fluoresceinbased sensor 35. Churchill and co-workers developed another novel approach for nerve agent sensing which utilizes a salicylaldehyde oxime linked BODIPY fluorophore 36.65 As shown in Scheme 8a, the mechanism for sensing of DCP or DEMP involves triethylamine promoted conversion of 36 to the ester product 37. This transformartion results in a sharp decrease in the fluorescence intensity. In contrast, the nerve agent DECP promotes dehydration of the oxime in 36 to form an electron withdrawing nitrile group in 38, which prevents

Fluoride, which is recognized to be the smallest anion, has relevance to the detection of nerve gases because it is generated when G-agents react with nucleophilic reagents. In 1997, Swager and co-worker reported pioneering work on a fluorescent self-amplifying sensory polymer for fluoride ions, which provides a promising strategy for sensitive and selective monitor of nerve agents.67 In 2011, Costero and Martínez-Máñez described the triarylmethanol derivative containing colorimetric sensor 42 which contains two reactive sites including a nucleophilic hydroxyl group and a tert-butyldimethylsilylether (TBDMS) group (Scheme 9a).68 The OH group has the ability to react with the phosphorous center in nerve agents to yield the highly conjugated salt 43 in association with a color change from colorless to blue-green. While in the presence of DFP, the fluoride generated as a byproduct reacts with the silicon center in the TBDMS moiety to yield ketone 44,

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nBu N O

O

N

NH

OH N

F

O O

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P

O

O O

O

O P O

F F + F

-

O

O

Si O

NH

DFP

Si O

O

O O

O

O

NH

HN

F FF FF F

O

O nBu

O 48

F

N

NH O

n 49 Colorimetric Indicator

O

50

NH O

H2N

Nn Bu N

O

F

O

F F

O 3

2

1 NH2 3X

F

Si

O

nBu

1. F- generation: DFP + Benzaldoxime, acetonitrile 2. F- amplification: Self-propagating, isopropanol/water/pyridine= 7:2.5 :0.5 3. F- fluorometric sensing:Fluorescence probe x, acetonitrile

N O

51 Fluorometric indicator

NH2

NH2

F F

O

NH2

NH O

O

O F

F

F

F F

O

F

F

NH

O NH

F H2O

O OH OH

HO CO2

F F

OH

Scheme 10. The sensing mechanism for the detection of DFP through signal amplification. leading to the formation of respective complexes 46 and 47 and an accompanying loss of color. Finally, the thiol moiety in 47 can be removed by a thiophilic metal ion, releasing the original SQ with the reappearance of a blue color, while, no change is induced by the metal in the case of cyanide-containing complex 46.

Scheme 9. a) Sensing mechanism for sensor 42 in the presence of DCNP or DFP; b) Sensing mechanism for sensor 45 in the presence of Tabun and Vx. which displays a pink color. As a result of this elaborate design, sensor 42 selectively distinguishs Sarin/Soman from other nerve agents. Kumar and co-workers developed another privileged sensor 45 to discriminate Tabun and Vx based on fluoride anion production (Scheme 9b).69 Initially, fluoride anion reacts with Tabun and Vx to generate cyanide and thiolate anions, respectively. The generated anions subsequently attack the squaraine (SQ) based sensor 45,

Sensing systems which detect analytes through an amplifying signal response, are in great demand because of their high sensitivitities.67,70-76 Recently, Phillips and Anslyn developed a new protocol for quantitative sensing of DFP through colorimetric and fluorometric signal amplification.77 As shown in Scheme 10, initial reaction of benzaldoxime and DFP in the presence of base generates fluoride anion, which cleaves the Si-O bond in 48 and generates six equivalents of fluoride via 1,4- and 1,6quinone methide elimination. The generated fluoride ions trigger the self-propagating reaction until 48 is completely consumed. During the process, polymerization of intermediate 49 occurs which is responsible for generation of a yellow color. An alternate sensor 50, which contains three 4-amino-1,8naphthalimide fluorophores, was designed and synthesized. In this case, generated fluoride removes the tert-butyldimethylsilyl group leading to release of the 4amino-1,8-naphthalimide fluorophores 51. A ratiometric fluorescence response was achieved because of the regulation of the internal charge transfer (ICT) effect. In this approach, both colorimetric and fluorometric readouts with signal amplification occurs towards the nerve agent mimic DFP.

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N

O O P O O N

OH CF3

CF3

N N CF3

N CH 2 CH2 CH2

O +

CH2 H H2 HN C C N C C H O O O 52

N

F P4 -t-Bu

P O O

tBME

Resin

CF3 + F-

CH2 H H2 HN C C N C C H O O O n Bu N O

O

N N CH 2 CH2 CH2

1 eq. FH 2O

O

Resin 53

principle which was termed as the “covalent-assembly” approach (Scheme 12).80 The sensor, 56, in this system contains two aromatic rings, that couple upon reaction with Sarin to form an active chromophore. In other words, through cascade reaction with Sarin, the two rings in 56 covalently assemble as part of a push−pull color-enabling conjugative dye, contributing to both a turn-on colorimetric and fluorometric signal.

n Bu N O

Et2 N O

NH2 H N

O

n Bu

N

O O

O

O Si

R

R'

X

Et2 N

2

Nn Bu

O

HO

O

OH

54

56 Et2 N

O

NEt2

NEt2

O

R'

O

CO2 CO2 CO2

HO 1

H N

NEt2

O P

NH O

O

O

X

R O P O

Et2 N

O

NEt2

O

O

X

55

-

1. F generation : DFP + Resin oxime, MTBE 2. F - sensing: Probe x + BF + DBN, MTBE

H O

57 F

O (Bz,H)O

R R' P O

DBN (Bz,H)O > 1 eq. F-

O(H,Bz) O

BF

O

.

Scheme 11. The sensing mechanism for the detection of DFP through signal amplification. However, problems exist with this type of sensing system because long times are required for total signal amplification owing to the fact that fluoride is a poor leaving group and generation of the quinomethide intermediateis a high energy process. In addition, the sophisticated three-step procedure requires the use of different media for the fluoride generation, amplification (colorimetric readout) and fluorometric sensing steps (Scheme 10 inset). Thus, Anslyn and co-workers developed a new approach in which more rapid ratiometric signal amplification was achieved using an integrated two-stage process.78 Since oximate is susceptible to other strong electrophiles, the Wang resinoximate conjugate 52 was attached oximate to a resin (Scheme 11). The product 53 generated from DPF and 52 can be removed from the oximate by simple filtration. Thus, analyte detection utilizes a simple integrated twostage process using the same solvent for both steps (Scheme 11 inset). In addition, in order to accelerate the autoinductive process, benzoyl fluoride (BF)79 was used as a latent source of fluoride. Fluoride released from reaction of 52 and DFP cleaves the TBS group in 54 and generate three fluorophores and phenolate 55, which reacts with BF, causing the release of at least one and up to four fluorides in the presence of DBN (1,5diazabicyclo(4.3.0)non-5-ene). Finally, the released fluoride will retrigger self-immolation of 54 until it is completely consumed. In addition to the approaches described above, other systems that operate by O-activation have been reported. Indeed, Yang and co-workers described a novel design

Scheme 12. The sensing mechanism of sensor 56 designed via the “covalent-assembly” approach. Kim and Bouffard designed and synthesized the BODIPYbased sensor 58 in which an ortho substituted phenol was introduced to the meso position of BODIPY dye (Figure 3).81 Free rotation about the meso C−Ar bond in sensor 58 leads to a high nonradiative deactivation rate (knr) and low fluorescence quantum yield.82,83 Reaction with DCP results in phosphorylation of the phenol group in 58, which because of its greater bulk restricts bond rotation in the product 59, thereby increasing its fluorescence quantum yield relative to that of the sensor 58. Furthermore, 58 immobilized onto paper strips gives a rapid response to exposure to DCP vapour as is shown in Figure 3.

OH

O P Cl OEt OEt

O

N N B F F

N N B F F

58

59

O P O O

Figure 3. Structure of sensor 58 for DCP and the photographs of the emission change of 58- impregnated filter papers upon exposure to 132 ppm DCP vapor upon 0-300 seconds irradiation at 365 nm. In 2015, Mahapatra and co-workers developed the ratiometric fluorogenic and chromogenic sensor 60 containing a napthothiazolium-benzothiazole-based platform.84 The suggested mechanism of reaction between sensor 60 and DCP is shown in Scheme 13. Accordingly, DCP reacts with the oxyanion center of the ring-opened tautomer of 60 to form the triester adduct, which in a

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subsequent step undergoes cyclization to the eightmembered-ring product 61. Because the reaction is irreversible and the product 61 displays an enhanced emission, an instantaneous ratiometric fluorescence response is observed. Notably, 60 is the first chemosensor which can be used to detect DCP in the living RAW 264.7 cells. The successful detection of exogenous DCP in biological systems holds potential application for further research into the prevention and diagnosis of the human diseases caused by exposure to nerve agents.

Scheme 13. The sensing mechanism of 60 towards DCP. Wang and Zhou reported the first FRET-based ratiometric sensor for the detection of nerve agents (Figure 4). Sensor 62, a chimera of rhodamine and fluorescein, reacts rapidly with DCP to form product 63, in which FRET is disrupted resulting in a change of the green fluorescence emission derived from sensor 62 to the blue emission derived from product 63.85

Figure 4. Proposed mechanism of sensor 62 for DCP based on FRET mechanism and the photographs of the colorimetric and fluorogenic change with and without DCP. Nerve Agents Chemosensors Based on N-activation Pyridine-based chemosensors have been designed as part of an N-activation strategy in which attack of the pyridine ring nitrogen on phosphorus of the nerve agent leads to a product having altered fluorescence emission.86-88 Costero and Martínez-Máñez developed the novel sensor 64 (Scheme 14),89 which reacts with DECP, DCP or DFP thereby leading to a color change from pale orange to magenta because of an increase in the pull–push character of the chromophore. In the presence of DECP, the cyanide anion, generated in the pyridine phosphorylation step, catalyzes the migration of the phosphate group from the pyridine nitrogen to the aniline nitrogen, accompanied by a change of a emissive color to yellow. Sensor 64 was also shown to be effective in detecting the nerve agent Tabun.

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Scheme 14. Reaction mechanism of chemosensor 64 with DCP or DCNP and associated color changes in the fluorescence. The pyridine-based N-activation strategy has been extended to other fluorophores. For instance, He and Cheng prepared sensor 67 by linking the pyridyl unit to the electron donor triphenylamine (TPA) (Scheme 15).90 Reaction of 67 with DCP, causes a 112 nm shift in fluorescence emission maximum with a detection sensitivity of 2.6 ppb. Wu and Zeng synthesized sensor 68, in which the electron-donor diphenylamine and electronacceptor pyridine groups form an aggregation-induced emission (AIE) fluorophore tetraphenylethylene (TPE) matrix (Scheme 15).91 When deposited onto filter paper, sensor 68 emits strong fluorescence because of the AIE properties. When exposed to DCP vapors, fluorescence emission from the strip changes from yellow to orange. Fluorescence emission from the pyridyl-BODIPY-based sensor 69, developed by Churchill and co-workers (Scheme 15), is diminished and red-shifted upon reaction with the nerve agent Soman.92 A series of 6aminoquinolines, based on the core structure of 70 and possessing different N-substituents, were synthesized by Song and co-workers (Scheme 15).93 Reactions of these sensors with DCP leads to a red-shift in both absorption and fluorescence profiles owing to enhanced internal charge transfer (ICT). Within the series, ICT increases with increasing electron donation from the pyridine-N substituent. For example, 70c and 70d exhibit the largest red-shifts (110 nm) because of the strongest electron donating abilities of the NHn-Bu and NMe2 substituents, whereas 70a and 70b display smaller Stokes shifts of 87 nm and 90 nm, respectively. Within the series, sensor 70e immobilized on paper strips, displays the greatest sensitivity (8 nM) for the detection DCP vapour.

Scheme 15. The structures of pyridine-based sensors 67-70.

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Torroba and Wästerby developed an alternate design of sensors for the detection of nerve agents by incorporating of a free amine group as the N-terminal as in the sensor 71 shown in Scheme 16a.94 The reaction of the nerve agent Soman with the amine group in 71 produces a sharp fluorescence enhancement due to inhibition of PET process. Another unique detection system was created by Goswami and co-workers using rhodamine as the fluorophore as exemplified by sensor 73 (Scheme 16b).95 Upon reaction with the nerve agent DCP, the spirolactam ring of the rhodamine moiety in 73 opens, leading to a significant increasing of the fluorescence intensity and to a pink color. Sensor 73 can also be used to selectively detect DCP in the gas phase.

Scheme 16. a) The sensing mechanism of sensor 71 for Soman; b) The sensing mechanism of sensor 73 for DCP. Another N-activation strategy developed for nerve agent detection includes relay recognition. This is demonstrated by 75, which was recently reported by Goswami and coworkers (Scheme 17).96 The sensor contains a silyl protected 2-hydroxy-1-naphthaldehyde group, which undergoes desilylation to form the imino-coumarin containing intermediate 76 upon exposure to fluoride ion (see Scheme 17). Intermediate 76 forms a fluorescent imidophosphate adduct through reaction with the nerve agents DCP and DECP in conjunction with cyanide ioninduced cyclization leading to an enhancement of fluorescence and the appearance of a distinct pale-green color as shown in Scheme 17. On the other hand, the adduct formed by reaction with DCP, does not undergo cyclization and consequently it displays comparatively weaker fluorescence, a feature which can be exploited in distinguishing between DECP and DCP detection.

Scheme 17. The reactions of sensor 75 with nerve agents DCP and DECP and the changes in fluorescence emission associated with these reactions. More recently, Lee and co-workers synthesized the oazoaniline 80 for dual-responsive detection of DCP in the presence vs absence of Cu2+.97 As is illustrated in Scheme 18, reaction of sensor 80 with DCP in the absence of added Cu2+, results in the formation of adduct 79 and a change in color from yellow to red. On the other hand, pretreatment of sensor 80 with Cu2+ induces its cyclization to the benzotriazole 81. This results in the loss of absorption at 423 nm and a dramatic increase in fluorescence emission intensity at 455 nm. Subsequent addition of DCP to 81 is followed by formation of the amidophosphate adduct 82 and concomitant fluorescence quenching.

Scheme 18. The mechanism of dual-responsive sensor 80 for DCP and Cu2+. Metal ion based chemosensors for nerve agents In contrast to chemosensors that form covalent adducts through reaction with the nerve agents, metal-based chemosensors act via loss of intrinsic fluorescence that accompanies metal ion sequestration by the nerve agent. Lanthanide complexes in particular, are well suited for this purpose because of their long excited-state lifetimes, intense fluorescence and narrow excitation and emission bands.98-100 Specifically, in the presence of appropriate UVlight-absorbing ligands, intense luminescence can be exhibited by Eu3+ as the result of the so-called “antenna effect”.101 This process involves hv absorption by the ligands and subsequent ligand-to-metal energy transfer, leading to strong fluorescence emission from the metalion. Organophosphates compete with the chromophoric ligand for coordination to lanthanide, thereby reversing emission enhancement. Rowan and Weder prepared a series of 2,6-bis(1’-methylbenzimidazolyl)pyridine (Mebip) to serve as chromophoric ligands in combination with the lanthanide ions tested.102 As illustrated in Figure 5a and 5b, the intrinsic fluorescence emission by the Eu3+-Mebip complex 83 is eliminated upon the addition of triethylphosphate. The addition of triethyl phosphate to the lanthanide complex triggered a large blue shift and an enhancement in fluorescence intensity due to the competitive binding of phosphates versus lanthanide ion (Figure 5b). It is worth noting that this sensing system displayed an excellent specificity for triethyl phosphate

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over various common species including ketones, ethers, esters, alcohols, water, organic acids, and bulky aromatic phosphates. Terpyridines (terpy) functionalized in the 4-positions are molecules being widely used. Interestingly, terpy exhibits weak binding towards lanthanides because of the large atomic radii of the lanthanide and their small bite angles. Moreover, the addition of lanthanide ions to terpy leads to complexes that have excellent emission properties. Based on the inherent nature of terpy, Shunmugam’s group developed a norbornene derived terpyridine sensor 85 for the detection of G-type agents (Figure 5c).103 Diisopropylfluorophosphate (DIFP) was chosen as the model compound for G-type nerve agents due to its lower toxicity and similar reactivity. Upon exposure to DIFP, magenta emission of the lanthanide complex 85 disappeared due to the termination of antenna effect promoted by phosphorylation reaction at the terpy nitrogen atoms. Meanwhile, blue fluorescence was observed which is emitted by the norbornene derived terpy monomer. Furthermore, in contrast to rapid development for the detection of G-type nerve agents, the methods to selectively detect V-type nerve agents are still rare. Guided by this, Martínez-Máňez and co-workers developed two BODIPY-complexes 86a and 86b with the abilities to detect V-type nerve agent mimic over a G-type counterparts (Figure 5c).104 The BODIPY-based ligand is nearly non-fluorescent because of the strong ICT quenching action of BODIPY fluorophore from the aniline moiety. Upon binding with Eu3+ or Au3+, strong emission bands were observed caused by the inhibition of quenching process. Because of their stronger affinity, the V-type nerve agent mimic demeton-S coordinates to the metallic center of the complexes and promotes displacement of the BODIPY ligand, causing color modulation and fluorescence quenching. In contrast, Gtype nerve agents (mimic) only cause negligible responses. Simanoto and co-workers reported a new sensor containing the iron complex 87, prepared by mixing bipyridine ligand with iron chloride tetrahydrate (Scheme 19a).105 87 is initially highly colored as a result of the electronic transitions promoted by light absorption which are associated with metal–ligand charge transfer or d–d transitions. Upon the addition of diphenylchlorophosphate (DPCP), a simulant for nerve agents, the initial cis configuration forms because the rigid conjugated skeleton bearing nitrogen atoms in the trans geometry is energetically unfeasible. Furthermore, reaction between DPCP and nitrogen leads to the formation of the ammonium moiety, which is not able to coordinate with iron. Decomplexation of coordination complex then occurs and leads to a colorless solution. Metalloporphyrins are highly conjugated planar structures, which can exhibit long-lived singlet and triplet states. As shown in Scheme 19b, Larsen and co-workers synthesized the zinc(II) metalloporphyrins 88 for

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detection of diisopropyl methylphosphonate (DIMP), a nerve agent simulant.106 In the presence of DIMP, the phosphoryl oxygen in DIMP binds to the metal center of porphyrin zinc(II), accompanied by the alkoxyl group departed from the porphyrin macrocycle core. The binding types produces gauche and trans conformations according to the relative position of methyl group of DIMP and the porphyrin macrocycle and leads to the red shifts in both the emission and absorption spectra of the sensor.

Scheme 19. a) Structure and sensing protocol of metal complex 87; b) Structure of sensor 88 and two possible configurations during the sensing process. Nerve Agents Chemosensors Based on Polymers Owing to their higher detection sensitivity, polymeric chemosensors have been applied to the detection of nerve agents.107,108 Kim and co-workers developed a polydiacetylene (PDA)-based sensor, which utilizes an aldoxime moiety as the reactive group, for selective and rapid detection of nerve agents.109 The addition of DCP to an aqueous solution of this sensor induced a decrease in the intensity of the absorption peak at 650 nm and a remarkable enhancement at 550 nm. Moreover, this PDA based sensor, in gel and solid phases, can also be used to detect nerve agent stimulants with low detection limits. Nesterov and co-workers developed the conjugated polymer based polymeric sensor 89 containing a naphthalene oxime group as the reactive site (Scheme 20).110 Upon the addition of DCP to a solution of 89, both a small hypsochromic shift of the absorption band and an enhancement at the fluorescence intensity take place as a consequence of the creation of higher energy gap caused by binding of DCP to the polymer backbone. Shunmugam and co-workers developed sensor 90 that contains polynorbornene and 8-hydroxyquinoline groups (Scheme 20).111 Upon the addition of DCP to a solution of 90, absorption bands centered at 240 nm and 310 nm are shifted to 250 nm and 340 nm, respectively. The emission band also is red shifted from 398 nm to 488 nm. These spectroscopic changes are believed to result from an intramolecular rearrangement reaction. In addition, 91, a polymer form of 90, was prepared and coated onto filter paper. The sensor system rapidly detects DCP vapours at

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concentrations of DCP as low as 25 ppb.

Figure 5. a) Sensing mechanism developed by Rowan and Weder; b)Pictures of the sensor array which illustrates the selective detection of (EtO)3PO, (ArO)3PO (Ar = o-tolyl) and Et3N by metal ion complexes (25 μM) in CHCl3/ CH3CN (9:1, v/v); c) Structures of metal complexes 85 and 86 based on norbornene derived terpyridine and BODIPY ligands.

Scheme 20. Structures of sensors 89, 90, and 91. Li and co-workers developed the novel polymeric DCP sensor 92, which utilizes quinoxaline as electronaccepting moiety (Figure 6).112 Interestingly, emission from 92 is highly concentration dependent in both the solution and solid phases because of the linkage of quinoxaline moiety and the electron-donating fluorene groups (Figure 6). Furthermore, upon exposure 92 coated filter paper to DCP, the quinoxaline groups in the polymer react with the phosphorous center in DCP, causing a gradual quenching of emission.

Figure 6. Structure of sensor 92 and its fluorescence images in chloroform solutions and in the solids.

spectroscopic (absorption shifted from 480 nm to 784 nm) and colorimetric changes (color change from colorless to bright blue). Moreover, in order to create a film with high permeability, polymer 93b which contains hydrogelpromoting tetra(ethylene glycol) (TEG) monomethyl ether side chains was synthesized (Scheme 21). Polymer 93b undergoes a color change from faint yellow to bright blue upon the addition of DCP with the detection limit as low as 6 ppm. The practical value of sensor 93b was demonstrated by its use in a thin film, which displays dramatic colorimetric and spectroscopic responses upon exposure to DCP vapor.

Scheme 21. Structure of sensor 93 and the sensing mechanism towards DCP. Recently, Cheng and He developed the hyperbranched polymer based sensor 94, which contains terpyridine units conjugated to a hyperbranched fluorine-pyrene containing copolymer (Scheme 22).114 Exposure to DCP vapor causes the intensity of the emission band of 94 centered at 468 nm to rapidly decrease along with a redshift of the peak to 554 nm. The changes in the fluorescence spectrum result from energy/electron transfer arising from interaction of pyridyl nitrogen in sensor 94 and phosphoryl chlorides in DCP.

Another novel polymeric sensor 93a, comprised of methoxy-substituted dithienobenzotropone monomers, was reported by Swager and co-workers (Scheme 21).113 In the presence of DCP, 93a, undergoes phosphorylation and ionization to form the highly resonance-stabilized tropylium cation, in association with a drastic

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R

R k

i

C8H17 C8H17

C8H17 C8H17

C8H17

C8H17

C8H17

C8H17

R= N

R n

94

m

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R

N

N

Scheme 22. Structure of polymeric sensor 94. Lee and co-workers developed the new polymeric sensor 95, containing pyrene as the fluorophore, for CO2/pH tunable detection of DECP (Scheme 23).115 The free sensor 95 is non-fluorescent because of the operation of PET process involving the amine group. However, bubbling of CO2 gas to the solution of 95 induces a dramatic enhancement of fluorescence intensity because of the inhibition of PET process caused by CO2-triggered protonation of the amine group. Subsequent bubbling of N2 through the solution leads to deprotonation of the quaternary ammonium cation and simultaneous quenching of the fluorescence. This reversible process provides an efficient ON/OFF switch to sense DECP with tunable sensitivity. Specifically, addition of DECP to a N2pretreated solution of the sensor causes an enhancement of fluorescence intensity because PET is inhibited by the reaction between the hydroxyl group and DCNP. However, when the solution of sensor 95 is pretreated with CO2 gas, DECP does not induce an observable fluorescence enhancement because the tertiary amine group, the reactive site for DECP, is protonated.

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lanthanide complex Eu(DVMB)3(PMP)(NO3)2 (DVMB stands for divinylmethyl benzoate) and used it to prepare a MIP.117,118 Under the excitation at 465.8 nm, the solution of Eu(DVMB)3(PMP)(NO3)2 displays two emission bands at 610 nm and 613 nm, which are attributed to emission from Eu3+ and a complex formed by binding PMP to Eu3+, respectively. Moreover, common pesticides and some chemical analogues of nerve agents were used to elucidate the selectivity of this sensor. The appearance of several emission bands in the range of 612 to 620 nm indicates the high level selectively of this sensor due to the noninterference to the peak induced by PMP (610 nm). Jenkins and co-workers developed another MIP to detect nerve agents selectively. The MIP is comprised of Eu(NO3)2 as the Eu3+ source, divinyl benzene (DVB) as the crosslinking agent and vinyl benzoate as the ligating molecule.119 Notably, washing the prepared MIP with 1 N HNO3 removes the nerve agent in order to prepare the MIPs for VX, Sarin and Soman, respectively. The prepared polymers are then coated onto optical fibers, which are then used for the detection of the corresponding nerve agent. In the presence of increasing concentrations of the nerve agents, an enhancement at the emission between 610 and 630 occurs, indicating that binding between nerve agents and Eu3+ center takes place. A new MIP prepared by a reversible addition fragmentation chain transfer (RAFT) reaction was developed by Houten and coworkers (Scheme 24).120 Initially, 97 and its complex with PMP, 98, were synthesized. The polymer 99 was then prepared utilizing the complex 98 and an ethylene glycol dimethylacrylate/methyl methacrylate (EGDMA/MMA) matrix. Soxhlet extraction with isopropanol leads to the release of PMP, generating the polymeric sensory system with a free binding site. This polymeric sensor selectively senses PMP over other relevant analytes such as dimethyl methyl phosphonate and dimethyl hydrogen phosphate.

Scheme 24. Synthetic pathway of the MIP for PMP. Scheme 23. CO2/pH tunable fluorometric sensing mechanism towards DECP. Because of their ability to mimic the function of biological receptors and their relatively high stability, molecularly imprinted polymer (MIP) has been used in the design of detectors for nerve agents.116 Generally, MIPs for sensing nerve agent incorporate a luminescent lanthanide, which serves as a signal transducer into the polymer. The coordination of Eu3+ and nerve agents triggers the occurrence of spectroscopic changes. In

1999, Murray

and

co-workers

synthesized

the

Brief History and Molecular Structure of Phosgene Phosgene (carbonyl chloride), with the structure formula of O=CCl2, is an extreme toxic gas which had been used in WWI as a chemical weapon. Phosgene can cause serious damage to the lungs and respiratory track of human beings, inducing pulmonary emphysema, noncardiogenic pulmonary edema, and even death. In addition, phosgene is a widely used intermediate in several industrial processes especially in the production of insecticides, plastics, pharmaceuticals, pesticides and isocyanate-based polymers. For this reason, in sharp contrast to nerve agents whose use has been forbidden by laws, phosgene is

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always more readily accessible. Consequently, phosgene has become a serious threat to the environment and public health. Therefore, a strong demand exists for sensitive and selective methods for phosgene detection. Several chemosensors that have been devised for phosgene detection are described in this chapter. Advances in Phosgene Chemosensors Rudkevich and co-workers developed a fluorescence resonance energy transfer (FRET) based approach for the detection of the phosgene (Scheme 25).121 In the new sensor, coumarin derivatives 100 and 101 function as FRET donor and acceptor fluorophores respectively. In the presence of phosgene, 100 and 101 undergo crosslinking to form the hybrid urea 102, a process that leads to an increase in FRET promoted emission at 464 nm and a decrease at 424 nm when excited at 343 nm. It is worth being mentioned that this system is the first example in which detection of phosgene utilizes a ratiometric change. However, the sensitivity of the system is low because it is difficult to prevent competitive formation of the acceptoracceptor and donor-donor complex in the reaction of phosgene with 100 and 101. To improve sensitivity, Hwang and co-workers utilized combinations of six weakly or non-fluorescent molecules to detect phosgene and found that the detection limit for phosgene detection can be as low as 1-18 nM.122

Scheme 26. The rhodamine-deoxylactam sensor to detect phosgene.

based

Utilizing a similar concept, Tian and co-workers developed a new type of fluorescent sensor for phosgene based on 8-substituted BODIPY fluorophore and utilizing ethylenediamine as the recognition moiety (Scheme 27).124 Upon the addition of phosgene, 105 undergoes phosgenemediated nucleophilic substitution and intramolecular cyclization, to form the imidazolone product 106 in association with the formation of vivid green fluorescence. More importantly, this is the first demonstration of a phosgene sensor with a capability of detecting subnanomolar-concentration levels phosgene with the detect limit as low as 0.12 nM.

Scheme 27. Sensing mechanism of sensor 105 for the detection of phosgene.

Scheme 25. A fluorescence resonance energy transfer (FRET) based method for phosgene detection. In 2012, Han and his co-workers described the rhodamine-deoxylactam based phosgene chemosensor 103 (Scheme 26).123 The spiro-(deoxy)lactam sensor 103 is colorless and non-fluorescent. However, addition of triphosgene triggers opening of the spiro-(deoxy)lactam and in conjunction with the production of a highly fluorescent and deep colored rhodamine fluorophore 104. This success of this assay is associated with the speed of the color response process, low-background interference and high sensitivity. More importantly, this chemosensor is able to detect gaseous phosgene utilizing portable manners through the use of paper strips and silica gel, which enables “naked eyes” detection and the on-the-spot detection with routine instruments.

The above detection strategy takes advantage of reactions occurring between phosgene and hydroxyl or amine groups in the sensor. Although these processes are useful for this purpose, they can be only difficultly employed to distinguish between phosgene, nerve agents which display similar nucleophilic substitution reaction behaviors. A novel sensor designed to efficiently distinguish phosgene from nerve agents was developed by Yoon and co-workers.125 As shown in Scheme 28, the pyronin based sensor 107 containing o-phenylenediamine (OPD) undergoes reaction with phosgene to form benzimidazolone 108. During this transformation, the electron-donating amine group was transformed to the electron-withdrawing urea group, which blocks it from participating in PET fluorescent quenching. Thus, a strong red emission band and naked-eye-observable color change arises when 107 is treated with phosgene. In contrast, when DCP was added to the sensor solution, phosphoramide 109 is formed from the reaction occurred at the more reactive primary NH2 group. The partial blocking of PET quenching effect causes a green fluorescence band to arise. This substance is the first fluorescent and colorimetric sensor to distinguish nerve agents and phosgene and it can be fabricated as a practical sensor for the detection of phosgene and nerve agents using a polymer membrane.

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red shift emission and the fluorescence change from blue to green with the detection limit as low as 1.87 ppm.

Scheme 28. The approach of sensor 107 discriminating between phosgene and DCP.

for

In order to further explore the utilization of this strategy, three other OPD-based phosgene chemosensors 110-112 were prepared by Yoon’s lab utilizing 4-chloro-7nitrobenzo[c]-[1,2,5]oxadiazole (NBD), rhodamine (RB) and naphthalimide (NAP), respectively (scheme 29).126 In the presence of phosgene, the NBD-based sensor 110 undergoes an obvious fluorescence increasing and the distinct colorimetric change from dark orange to pale yellow, while RB-based sensor 111 undergoes a color change from colorless to pink along with a sharp enhancement in fluorescence intensity at 575 nm (excitation at 530 nm). Also, sensors 110 and 111embedded polymeric fibers show the distinct color and fluorescent changes upon exposure to phosgene. NAPbased sensor 112 is an extremely reactive phosgene sensor possessing a detect limit as low as 2.8 ppb. In a similar approach, Song and co-workers developed two selective phosgene sensors 113 and 114 utilizing coumarin and BODIPY units as fluorophores and OPD as the reactive site (Scheme 29).127,128 These two sensors react with phosgene with high selectivity and sensitivity over other toxic analytes including nerve agent mimics and various chlorides. Notably, 113 and 114 can be used to distinguish phosgene from triphosgene based on different reaction rates. Recently, a new fluorescent sensor 115 designed using a combination of benzothiadiazole (BTD) and OPD moiety was developed by Wang and co-workers (Scheme 29).129 The two free NH2 groups in the OPD moiety participate in rapid acylation reaction with oxalyl chloride as well as phosgene, forming a piperazine-2,3dione or 2-imidazolidinone ring, respectively. As a promising addition to the limited ratiometric strategy for phosgene detection, Song and co-workers incorporated diamine group into 4,5-diamino-1,8-naphthalimide core to develop the new ratiometric sensing system 116 (Scheme 29).130 In his system, each phosgene molecule reacts with the primary amine centers in 116 to form a carbamylate that leads to a change in ICT character, resulting in the fluorescent color changing from green to blue. Moreover, 116 immobilized test papers are able to detect phosgene at a low concentration and to distinguish phosgene over other relevant analytes including nerve agent mimic, various acyl chlorides and triphosgene. Notably, during the preparation of this review, Wu and co-workers reported another ratiometric sensor 117 based on aggregation-induced emission (AIE) fluorophore.131 Upon the addition of phosgene, sensor 117 displays the

Scheme 29. The phosgene sensors 110-117 containing o-phenylenediamine (OPD) as the reactive site based on various fluorophores. The main limitation of these OPD based sensors appears to reside in the fact that the reaction for sensing phosgene is easily interfered with by other species such as nitric oxide or formaldehyde. To overcome this limitation, Yoon and co-workers developed another sensor 118 based on an excited state intramolecular proton transfer (ESIPT) process (Scheme 30).132 The dual reactive sites for twofolds carbamylation reactions were generated in situ taken advantage of the fact that 2-(2aminophenyl)benzothiazole underwent ESIPT process and formed the keto tautomer which will react with phosgene to generate the product 119. This sensor can detect phosgene in solutions and in gas phase beyond other relevant analytes including nitric oxide or formaldehyde. Moreover, the sensitive ratiometric and colorimetric changes occurring make 118 a practical tool for phosgene sensing.

Scheme 30. The sensing mechanism of the ESIPT based sensor 118 to phosgene. Conclusion Both nerve agents and phosgene are CWAs with high toxicity. Their ready uses in terrorist attacks or in war would lead to a serious threat to national security and public safety. In consequence, varies of detection methods including surface acoustic wave (SAW) devices, gas chromatograph (GC)/high performance liquid chromatography (HPLC), electrochemistry, enzymatic

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assay, and interferometry have been developed to sense these substances. Although they can be used to detect nerve agents or phosgene under appropriate conditions, these classical approaches have various limitations. For example, although the SAW strategy can be used to detect analytes with low detection limits, specific sensing materials are needed especially for the nerve agents (mimic) due to their native hydrogen-bond basic property;20 Although GC/HPLC can quantitatively detect nerve agents/phosgene with high selectivity and accuracy, the instrument is non-portable. Moreover, the sophisticated operation procedures lead to longer time and more difficult methods for real-time analysis that are not amenable to detection of hazardous substances in human body.133 Other traditional methods such as electrochemistry, enzymatic assays, mass spectrometry, nuclear magnetic resonance spectroscopy (NMR) and interferometry also suffer at least one of the following limitations including limited selectivity, lack of specificity, low responses and low sensitivity, expensive fee and operational complexity.134-140 In contrast, the use of chemosensors is an efficient strategy for designing systems that detect nerve agents and phosgene with various advantages, such as naked-eyes-available detection, high sensitivity and even the applications in living systems under some specific conditions. However, despite of advances made in the design of chemosensors for nerve agents and phosgene, several challenges and problems still exist. For instance, the exact reasons leading to good selectivity of the sensor towards one specific nerve agent (mimic) over another have not been clarified in some cases. As mentioned in the Scheme 3b, similar reactive group exhibit the same reactivity towards different kinds of nerve agents. Also, extremely different mechanisms are followed even when the same reaction groups are incorporated to different fluorophores (see Schemes 4 and 8). It seems that incorporated fluorophores can tune the reactivity of the reactive group to a certain degree. These observations are worthy of further inspection using DFT calculation in order to gain a better method for selecting proper fluorophores. Moreover, few chemosensors have applied to detect these toxic analytes in the living systems. Although these analytes do not exist in vivo, the applications of chemosensors to in vivo detection will provide a potential method to investigate the mechanism for the pathogenic processes followed by nerve agents and phosgene in living systems. Thus, more biological applications should be the target of future studies of nerve agent and phosgene chemosensors.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Author Contributions The manuscript was written through contributions of all

authors.

Notes The author declares no competing financial interest

ACKNOWLEDGMENT This work was financially supported by the the grants from the National Creative Research Initiative programs of the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (No. 2012R1A3A2048814).

ABBREVIATIONS CWA, Chemical warfare agents; WWI, world War I; OP, organophosphate; SAW, surface acoustic wave spectroscopy; PET, photoinduced electron transfer; BODIPY, borondipyrromethene; NIR, near-infrared; ICT, internal charge transfer; TPA, triphenylamine; AIE, aggregationinduced emission; TPE, tetraphenylethylene; FRET, fluorescence resonance energy transfer; ESIPT, excited state intramolecular proton transfer; GC, gas chromatograph; HPLC, high performance liquid chromatography; NMR, nuclear magnetic resonance spectroscopy.

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