Fluorescent Probes for Detection of Organophosphorus Nerve Agents and Simulants

Bin Li; Yanyan Fu; Jiangong Cheng

doi:10.7536/PC200829

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (9) : 1461-1472 DOI: 10.7536/PC200829

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Fluorescent Probes for Detection of Organophosphorus Nerve Agents and Simulants

Bin Li ¹^,²
, Yanyan Fu ¹^,³^,^*
, Jiangong Cheng ¹^,³^,^*

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Abstract

Organophosphorus nerve agents are a kind of chemical weapon with great killing power, which paralyze the central nervous system of human body by destroying the neurotransmitter acetylcholinesterase. A very small dose can cause death. Therefore, it is of great significance for the rapid and simple detection of organophosphorus nerve agents. Fluorescence chemical sensing has the advantages of high sensitivity, good selectivity, and short response time. In recent years, the detection of organophosphorus nerve agents and their simulants using fluorescent sensing methods has attracted increasing attention. In this paper, the principle of fluorescence sensing is briefly introduced, and various new fluorescent materials and methods developed by researchers at home and abroad in recent years for the detection of organophosphorus nerve agents and simulants are reviewed. The prospect of the application of fluorescence sensing methods in the detection of organophosphorus nerve agents is also discussed.

Contents

1 Introduction

2 Fluorescence detection of organophosphorus nerve agents and simulants

2.1 Nitrogen-based nucleophiles

2.2 Oxygen-based nucleophiles

2.3 Nitrogen-oxygen bifunctional nucleophiles

3 Conclusion and outlook

Graphical abstract

Keywords

organophosphorus nerve agents / detection / fluorescent probe / sensing materials

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Bin Li, Yanyan Fu, Jiangong Cheng. Fluorescent Probes for Detection of Organophosphorus Nerve Agents and Simulants. Progress in Chemistry, 2021, 33(9): 1461-1472 DOI:10.7536/PC200829

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1 Introduction

Organophosphorus nerve agent is a kind of highly toxic volatile colorless oily liquid, which can poison people through respiratory tract, skin and other ways, and a very small dose can cause death^[1,2]. Organophosphorus nerve agents are divided into G and V series, of which G series includes tabun (GA), sarin (GB), soman (GD), cyclosarin (GF) and so on, and V series includes VX and so on^[3]. The V-series nerve agents are more toxic than the G-series. The reason why organophosphorus nerve agents are toxic to human body is that they can inhibit the activity of acetylcholinesterase, a bioactive substance in human body, thus destroying the transmission of nerve impulses by acetylcholine, thus causing irreversible damage to human nervous system^[4]. Organophosphorus nerve agents have been used in warfare many times since they were made. In 1995, the cult used sarin gas to carry out terrorist attacks in the Tokyo subway in Japan, causing thousands of deaths and injuries^[5]. Sarin gas has also been used many times in the Syrian civil war^[6]. In view of the great harm of organophosphorus nerve agents to human beings, it is necessary to analyze and detect them quickly and simply.

At present, the main methods for the detection of organophosphorus nerve agents are gas chromatography-mass spectrometry (GC-MS), enzyme-based biosensors and surface-enhanced Raman scattering (SERS), but these technologies have some shortcomings, such as slow detection speed, complex detection process or heavy detection equipment, which can not meet the needs of real-time detection in the field^[7,8]^[9⇓⇓~12]^[13]. Fluorescent sensors have been widely used in the detection of organophosphorus nerve agents due to their high sensitivity, good selectivity, short response time and convenient detection^[14]. It is worth mentioning that because of the strong toxicity of organophosphorus nerve agents, diethyl chlorophosphate (DCP) and other mimics with similar structural properties are widely used in current experiments. Organophosphorus nerve agents and their common mimics are shown in Figure 1^[15].

In this review, we first briefly introduce the basic principle of fluorescence sensing technology, and then classify it according to the response group, including nucleophiles based on N functional group, nucleophiles based on O functional group and nucleophiles Based on N and O functional groups.In this paper, the research progress in the application of fluorescence sensing technology in the detection of organophosphorus nerve agents and their mimics in recent years is introduced in detail.Finally, the current research is summarized, and the future application of fluorescence sensing technology in the detection of organophosphorus nerve agents and their mimics is prospected.

2 Fluorescence Detection of Organophosphorus Nerve Agents and Their Mimics

Organophosphorus nerve agent is a kind of strong electrophilic reagent, so the sensing materials for detecting organophosphorus nerve agent generally contain nucleophilic groups. The nucleophilic group attacks the phosphorus atom, resulting in the replacement of chlorine or fluorine atoms in the nerve agent and the attachment of the nerve agent to the sensing compound, resulting in a change in fluorescence emission. Another strategy for designing organophosphorus nerve agent sensing materials is to give the sensing compound a functionality that is coordinated with the P = O functional group to give a significant change. At present, the common mechanisms of fluorescence sensing are: (1) photoinduced electron transfer^[16,17]; (2) fluorescence resonance energy transfer (FRET)^[18,19]; (3) intramolecular charge transfer (ICT)^[16]; (4) excimer association^[20].

2.1 Nucleophiles based on N-functional group

The nucleophiles based on N-functional groups mainly include amines, pyridines, quinolines and quinoxalines, etc. The detection of organophosphorus nerve agents by these nucleophiles is generally based on the following two mechanisms: the protonation process that enhances intramolecular charge transfer (ICT) and the phosphorylation process that inhibits photoinduced electron transfer (PET). Both of these mechanisms cause significant changes in the fluorescence of the probe molecules.

Fluorescein, as an excellent fluorescent matrix, is often used to construct new fluorescent probes. In 2006, Bencic-Nagale et al. Adsorbed fluorescein amine (FLA) 1 on poly (2-vinylpyridine) (PVP) coated carboxylic acid functionalized polymer to prepare sensing beads. When the beads contacted DCP, FLA was converted to phosphoramide, resulting in rapid and intense fluorescence enhancement^[21]. The PVP layer was used to provide a high density of proton accepting pyridine nitrogen sites and to neutralize the HCl generated during the reaction, allowing the beads to remain fluorescent after exposure to DCP vapor (fig. 3). When the microbeads were exposed to other nerve agent mimics or other volatile organic vapors, no significant fluorescence changes occurred, showing good selectivity. In 2015, Singh et al. Reported a self-propelled micromotor-based fluorescence detection method for nerve agents, in which fluorescein 2 was coated on Si/Pt-Janus micromotors, and the movement of multiple micromotors resulted in greatly enhanced mass transport of the sample.Compared with the static micromotor assembly, the reaction rate between the contaminated solution and the micromotors is increased, and the motion of the FLA coated micromotors accelerates their real-time fluorescence quenching after contact with nerve agents, enabling real-time field detection of sarin and soman mimics^[22].

In 2014, D'Díaz de Grenu et al. Synthesized a series of fluorescent probes 3 based on N functional groups, which showed different fluorescence changes in different solvent combinations of nerve agents and their mimics, and could achieve trace detection of organophosphorus nerve agents and their mimics in water and organic solvents^[23]. Sarkar et al. Synthesized the norbornenyltriazolyl functionalized 8-hydroxyquinoline (NCHQ) fluorescent probe 4 and its polymer PNCHQ. The probe 4 reacted with nerve agents and turned on after intramolecular rearrangement, showing very strong green fluorescence^[24]. The polymer PNCHQ-coated paper strip responded instantaneously after exposure to DCP with a detection limit of 25 ppb, allowing real-time detection in the field.

In 2015, Yadav et al synthesized two 3-cinnamoylcoumarin fluorescent probes 5, which showed large fluorescence quenching when exposed to DCP. This study has certain reference value for the design of coumarin biological imaging probes and nerve agent gas sensors^[25].

In 2016, our research group reported a charge transfer colorimetric fluorescence probe 6 (Figure 4). The probe molecule has both electron donating and electron withdrawing groups. After contacting with the detected substance DCP, the electron donating and electron withdrawing effect in the molecule is affected, and the fluorescence emission band is red-shifted from 410 nm to 522 nm, with a quenching rate of 98% within 25 s. HAc and DMMP do not interfere with the detection process^[26]. The detection limit of DCP was significantly reduced to 2. 6 ppb, which was lower than the concentration directly harmful to human health.

Churchill et al. Synthesized a colorimetric fluorescence probe 7 in 2017. The pyridine group reacted with DCP, resulting in a significant change in the fluorescence emitted by the chromophore. The detection limit of DCP was 3. 36 μmol/L. The synthesis process of the probe was simple, and the fluorescence response was visible to the naked eye, which was expected to be used for on-site real-time detection^[27].

Rhodamine is also an excellent fluorescent parent. So et al. Prepared a colorimetric fluorescent probe 8 with rhodamine as the fluorescent parent in 2016. When it was mixed with DCP in the 3%Et₃N-DMF, the amide spiro ring of probe 8 was opened.Resulting in a significant increase in fluorescence and absorbance and a color change of the solution (fig. 5). The probe 8 has a linear response to DCP in the range of 2.0×10^-5~15×10^-5mol/L with a detection limit as low as 1.42×10^-7mol/L, allowing selective detection of DCP over a wide pH range of 7 to 11^[28]. Under alkaline conditions, the probe 8 has good photostability, high sensitivity and selectivity to DCP (liquid phase and gas phase). The study also tested a portable test kit made with probe 8 to verify its practical application in real-time detection.

Zhou et al. reported an o-phenylenediamine-pyronin bonded dye, which was made into a fluorescent and colorimetric probe 9 for the selective detection of phosgene and DCP at the same time. Due to the different reactivity of the probe with phosgene and DCP, its color and emission response were also significantly different^[29]. The probe 9 is fixed on a polymer film to construct a portable kit which can be used for on-site real-time monitoring of DCP and phosgene and has the characteristics of simplicity and safety. Huang et al. Developed a novel fluorescence probe 10 based on an aggregation-induced emission (AIE) fluorophore. The pyridine group of the probe 10 reacted with DCP vapor, resulting in a red shift of the emission spectrum from 546 nm to 624 nm, and the fluorescence changed from yellow to orange. The detection limit was as low as 1.82 ppb, which could be observed by naked eyes under a portable ultraviolet lamp^[30]. By directly depositing the AIE probe on the filter paper, a portable solid test strip can be conveniently prepared, which has good light stability and is favorable for long-term application. This strategy provides a useful inspiration for the design of convenient and economical solid-state colorimetric fluorescence sensors.

In 2018, Khan et al. Reported two iminocoumarin-benzothiazole probes 11A and 11b, which have significant fluorescence switch response and good recognition performance.When DCP is added to the probe, the fluorescence can be quenched, the response time is very fast and the sensitivity is good, and the accompanying color change can be observed by naked eyes, while other organic phosphates do not give any obvious reaction^[31]. The detection limits of the two probes were 0. 065 μmol/L and 0. 21 μmol/L, respectively. Cai et al. Prepared N-substituted 6-aminoquinoline fluorescent probe 12 as a chemical sensor for nerve agent mimic DCP. The fluorescent probe 12 with nucleophilic pyridine-N atom as the active center detected DCP by catalytic hydrolysis method, showing a significant ratio fluorescence response to DCP, with a detection limit of 8 nmol/L^[32].

In this paper, we have designed and synthesized a small molecule fluorescent probe 13 B. 13 B uses terpyridine as the sensing unit, which has the advantages of simple structure, easy modification and good solubility^[33]. In DCP saturated vapor, the fluorescence was almost completely quenched within 3 s, and the response speed was fast, which met the basic requirements of fluorescence detection. In addition, a hyperbranched polymer fluorescent probe 13 a was synthesized with pyrene as the core, fluorene as the linking unit and terpyridine as the recognition group.The fluorescent probe 13 a showed excellent photostability, and its fluorescence was almost completely quenched within 3 s when exposed to DCP vapor, and it had good selectivity. The actual detection results showed that the fluorescence quenching rate of probe 13 a was 3. 6% for 65 ppt DCP, which was much better than other detection methods. Aich et al., 2017, prepared a ratiometric triphenylamine-benzimidazole (TPIM) fluorescent probe14 for organophosphorus nerve agent vapors^[34]. When DCP was added, a fluorescent color change from cyan to dark yellow was observed, which was visible to the naked eye under both ambient and ultraviolet light. The detection limit of probe 14 for DCP in solution is as low as 10^-8mol/L. A portable DCP detection kit has also been developed using the probe 14, which can detect DCP vapor with high sensitivity.

In 2018, our group also reported two small molecule fluorescent probes 15A and 15b, which can detect DCP vapor in real time and in situ by introducing amine groups into the Schiff base skeleton. The sensing is based on the fluorescence "on" mode, which can avoid the interference caused by photobleaching agents or fluorescence quenchers in the fluorescence "turn-off" mode, and the detection limit is as low as 0.14 ppb^[35].

Sun et al. reported a rapid, ultrasensitive method for the detection of DCP using 1-carbazolyl nanofibers 16 (fig. 6), in which the formation of a pyridine phosphorylation product in the nanofibers caused an amplified ratiometric fluorescence response when exposed to trace amounts of DCP,Fluorescence quenching is amplified by quenching the exciton within the diffusion length of the nanofiber, while opening the fluorescence response is amplified by trapping the exciton within the diffusion length, resulting in intramolecular charge transfer (ICT) emission at longer wavelengths^[36]. Based on the ratiometric fluorescence response, a fast (3 s), ultrasensitive (4 ppb) and highly selective DCP detection was achieved.

Dey et al. synthesized a chromogenic fluorescent probe 17 based on a bis-indolyl oxide scaffold, which was used to detect DCNP in water at pH 8. The indole group assisted the hydrolysis of the phosphorus heteroatom bond through hydrogen bonding, and then the released cyanide ions reacted with the electron-deficient C = C bond of the compound in a Michael addition reaction, which was characterized by a clear change in color from red to colorless^[37]. In addition, a dye-assembled inorganic nanocomposite designed with the probe can achieve more sensitive fluorescence "turn-on" detection of DCNP in water.

In 2019, Li et al. Reported two visualized fluorescent probes 18a and 18b for rapid, highly sensitive DCP detection^[38]. When exposed to saturated DCP vapor, the 18 B strip showed a rapid fluorescence response in less than 1 s, accompanied by a color change from green to red, with an estimated detection limit of 0.15 ppb. In addition, the test strip has high selectivity and good reversibility, and shows a good application prospect in the real-time detection of organophosphorus nerve agents. Zeng et al. reported a fluorescent chemosensor 19 for the differential detection of phosgene and DCP.The probe 19 consists of an anthracenecarboxyimide fluorophore and an o-phenylenediamine (OPD) reaction site^[39]. When OPD was phosphorylated, the probe showed an obvious fluorescence turn-on reaction to DCP at 588 nm. The sensor has the advantages of immediate response and low detection limit (88 nmol/L). In addition, the test membrane loaded with probe 19 was prepared for real-time, portable and efficient detection of trace gaseous phosgene and DCP vapor with different optical responses.

Sahoo et al. Designed and synthesized a carbazole-pyrrole conjugated fluorescent probe 20, which has the unique characteristics of simultaneous detection of DCNP and Cd²⁺^[40]. The detection limits of probe 20 for DCNP and Cd²⁺ were 7. 75 nmol/L at pH 7. 0.

The structures of the above probes are shown in fig. 2.

2.2 Nucleophiles based on O functional group

The nucleophiles based on O functional group mainly include phenol and oxime. Phosphorylation of a phenolic compound usually does not result in a significant change in the fluorescence of the sensing material, but if the phosphorylation is capable of altering the molecular rotation of the chromophore, the fluorescence may be altered. Various fluorescent materials based on oxime nucleophiles have been developed for the detection of solutions, typically exhibiting a fluorescent turn-on response.

In 2011, Sancen Sancenón et al. Reported a colorimetric fluorescent probe based on a triarylmethanol derivative21 that contains two reaction sites: a hydroxyl group that provides a suitable reaction site for nerve agents and a TBDMS moiety that can react with fluorine, a specific by-product of the phosphorylation of hydroxyl groups by DFP^[41]. This study shows the unique reactivity of specific by-products obtained by general phosphorylation reactions induced by nerve agents, which is expected to be used for selective detection of certain nerve agent gases or their mimics.

In 2012, Lee et al. designed a molecular fluorescent probe22 using oxime-modified polydiacetyl (PDA) liposomes, which can be used for rapid, selective, sensitive and convenient colorimetric detection of organophosphorus nerve agents^[42]. The rapid reaction between the oxime group and the nerve agent caused both intraliposomal repulsion and interliposomal hydrophobic aggregation, resulting in a conformational change in the PDA backbone that produced a rapid and sensitive colorimetric change (fig. 8). The detection limit of optimized liposome fluorescent probe for DFP was as low as 160 ppb. They have further developed a portable solid-state PDA sensing system using cellulose acetate filter paper, which is expected to be used for real-time monitoring in the field.

In 2013, Wang Wei et al. First developed a colorimetric fluorescence probe 23 based on fluorescence resonance energy transfer (FRET), which is a carboxylate salt that can promote the formation of highly active nucleophilic phenol anions, in which rhodamine analogues act as acceptors in fluorescence resonance energy transfer.Coumarin analogues are used as donors, and the fluorescence spectrum of the fluorescent molecular donor overlaps with the excitation spectrum of the fluorescent molecular acceptor, so that the excitation of a fluorescent molecular donor can induce a fluorescent molecular acceptor to emit fluorescence, and meanwhile, the fluorescence intensity of the donor itself is attenuated^[19]. The sensing mechanism of the probe for DCP is that the carboxylate undergoes lactonization to form a closed five-membered spironolactone ring, after which DCP phosphorylates the phenolate, the FRET effect is inhibited, and only the coumarin fluorophore signal appears, thus realizing the colorimetric detection of DCP (Figure 9). The detection limit of the probe for DCP was as low as 0. 17 ppm, and the color change of the probe could be observed by naked eyes under ultraviolet irradiation.

In 2014, Churchill et al. proposed a reversible fluorescence sensor using fluorescein as a nerve agent mimetic, 24 in which superoxide can regenerate fluorescein^[43]. Compared with other fluorescence sensors, this method is cheap, practical and reliable. They have since also reported a fluorescent probe for a photoinduced electron transfer (PET) -based sensing mechanism25 (Fig. 10)^[44]. Photo-induced electron transfer is the most widely used mechanism in fluorescence sensors at present. Fluorescent molecules do not emit or emit very weak fluorescence before reacting with the detected substance. Once the recognition group combines with the detected substance, the photo-induced electron transfer is inhibited or even blocked, and the luminescent group will emit very strong fluorescence. Probe 25 has both an oxime group and a phenolic hydroxyl group, and has different reactivity with DCP, DEMP, and DECP. In the presence of DECP, the PET process in the probe molecule was blocked and the fluorescence intensity of the molecule increased, while in the presence of DCP and DEMP, the PET process in the probe molecule still existed and the fluorescence was weak.

Rusu et al. Reported a new chemical detection method by combining the sensitivity of fluorescent units with the response of "smart" polymers to environmental changes to design and synthesize a fluorescent polymer probe26, which is sensitive to DCP as low as 12 ppb and can distinguish interfering molecules well^[45]. Sancenon et al. reported a new colorimetric probe based on BODIPY27, which contains three reaction sites: (1) a nucleophilic phenolic hydroxyl group capable of phosphorylation with a nerve agent^[46]; (2) a carbonyl group as a cyanide reaction site; (3) a triisopropylsilyl (TIPS) protecting group that can react with a fluoride. The detection limits of DCNP and DFP were 0. 36 and 0. 40 ppm, respectively, indicating that the method has high sensitivity. A simple test strip for colorimetric detection of DCNP and DFP in the gas phase has been developed by incorporating the probe 27 into a silica gel plate or a polyethylene oxide membrane. Goud et al. Reported a new fluorescein hydroxamic aldehyde fluorescent probe 28. When the probe reacted with DCNP, a nucleophilic substitution reaction occurred first, and then a specific product was obtained by the reaction of cyanohydrin with DCNP, showing a specific spectral behavior. This specific product occurred only in the presence of DCNP and therefore had excellent selectivity^[47].

Sancenon et al. synthesized a new selective chromogenic recognition probe 29 for the detection of DFP. The phosphorylation of the probe and the hydrolysis of the silyl ether moiety caused by fluorine caused an obvious color change. Since fluoride is the product of the reaction of DFP with hydroxyl, the probe has good selectivity^[48]. Belger et al. synthesized two highly sensitive fluorescent probes 30 for the detection of nerve agent mimics, which showed a colorimetric reaction when exposed to nerve agent mimics gas, and when they were combined with a copolymer prepared on the basis of ring-opening metathesis polymerization (ROMP), the theoretical detection limit was as low as 1 ppm^[49]. The use of hydrogel-promoting units as side chains results in polymers that can respond immediately and can be regenerated with ammonium hydroxide vapor.

In 2016, Qi Yanyu et al. Designed and synthesized a new photochemically stable p-phenylethynylbenzene (BPEB) derivative fluorescent probe 31 with 8-hydroxyquinoline (8-HQ) as the capture group and cholesterol (Chol) as the auxiliary structure. The fluorescence spectrum of the compound consists of the fluorescence emission of 8-HQ and BPEB. The fluorescence emission is extremely sensitive to the presence of DCP, and the calculated detection limit can be below 1×10^-9mol/L^[50]. In this study, a fluorescent probe 32 for the detection of trace sarin mimics was assembled, and a new method to activate the aggregation reactivity of ICT-type fluorescent probe was proposed.The multiple hydrogen bonds formed by the oxime group together with the phenol anion can activate the aggregation state reactivity of the oxime group, and the porous membrane structure is constructed by improving the frontier orbital energy level, so that the probe is more suitable for efficient gas phase reaction^[51]. The probe can distinguish different organic phosphates, the fluorescence changes significantly, and the detection limit of DCP is 1. 2 ppb.

In 2018, Lu et al. designed and synthesized a fluorescent probe 33 with fast response, which contains an electron donor-acceptor system, in which the main part is a fluorescent group, the hydroxyl group is the reaction site of nerve agent mimics, and the electron-deficient cyano group is introduced to reduce the background fluorescence of the fluorescent probe^[52]. Probe 33 has a fast fluorescence turn-on response to DCP within 540 s, and the color change from colorless to green can be easily observed by the naked eye under UV irradiation.The lowest detection limit is 20. 7 ppb at room temperature. Manna et al. synthesized a fluorescein-hydroxybenzothiazole conjugate fluorescent probe 34, which can be used to detect and identify DCP and DCNP with fluorescence and naked eyes. The detection limit of DCP is 1.6 mmol/L, and the sensing mechanism is that the Zn²⁺ triggers the process of decoupled excited state intramolecular proton transfer (ESIPT)^[53].

Cai et al. reported three 6-substituted aminoquinoline oxime probes 35 with different substituents. The oxime hydroxyl group, as an active site, is rapidly phosphorylated by DCP through nucleophilic substitution reaction and generates HCl, which leads to protonation of quinoline nitrogen and enhancement of intramolecular charge transfer (Fig. 11)^[54]. When the ¹R and ²R were n-Bu and Boc, respectively, the probe showed the most significant fluorescence change, and the lowest detection limit of DCP in solution was 21 nmol/L. In addition, a simple test strip was prepared, which can realize the visual detection of DCP vapor and the identification of DCP vapor and acid gases in the air.

Churchill et al. Synthesized and characterized a 1,8-naphthalimide based fluorescent probe 36 in 2017. The probe has two reactive groups: an oxime group and a phenol group, allowing dual emission with different kinetic reactions. The probe 36 showed a selective fluorescence turn-on response of DECP in an aqueous medium over a wide pH range. The enhanced fluorescence response was observed within about 30 s^[55]. The gas phase and liquid phase DCP can be detected by using the silica gel plate analysis technology through a double emission channel.

In 2018, Liu et al. developed a fluorescence-fractionated nanofiber bundle fluorescence probe37 for rapid and sensitive detection of DCP vapor^[56]. Light excitation can weaken the strength of hydrogen bonds between fibers, thus increasing the distance between fibers and reducing the fluorescence intensity. When exposed to a trace amount of DCP vapor, the strong interaction between DCP and the hydroxyl groups on the nanofibers can effectively cause the nanofibers to re-emit light and enhance the fluorescence as a detection signal.The rapid signal response (about 3 s) and highly sensitive (15 ppb) fluorescence detection of DCP are achieved. Ali et al. Synthesized and characterized three highly selective and highly sensitive fluorescent probes 38. The phenolic hydroxyl of the probes, as the reactive site, can be rapidly phosphorylated after nucleophilic substitution by DCP, and intramolecular cyclization occurs within 45 s, producing a fluorescent response to DCP^[57]. When R is nitro, the probe shows strong green fluorescence under UV light after interacting with DCP, which has the advantages of fast response, high selectivity, high sensitivity and low detection limit (0. 10 μmol/L). The probe was also used to develop a low-cost portable cellulose paper strip for real-time visual detection of DCP vapors. In addition, the probe has been widely used to detect DCP in living cells.

By modifying the structure of salicylaldehyde Schiff base with high fluorescence, our group prepared a fluorescent probe 39 with strong green emission in solution, which can be used as a chemical sensor for DCP^[58]. The sensing mechanism is that the phenol anion reacts with DCP, which enhances the electron-withdrawing ability of the acceptor and quenches the fluorescence. The detection limit of the probe is as low as 1.94 nmol/L.

In 2019, Qin et al. Reported a new oxime-modified flavonoid fluorescent probe 40 for the detection of DCP. In the presence of DCP, obvious fluorescence enhancement and emission color change could be observed by naked eyes in solution, the response time was less than 90 s, and the detection limit was 0. 78 mmol/L^[59]. In addition, the sensor strip was successfully constructed with polyethylene glycol as the matrix, and the sensitive and selective detection of DCP vapor was realized. Jung et al. report a selective fluorescence open probe 41 that can be used for that detection of DCNP^[60]. This study proposes a novel sensing approach: fluorescence is switched on by reaction-based suppressed excited-state intramolecular proton transfer (ESIPT) fluorescence quenching in intramolecular hydrogen bonds containing electron-donor- and acceptor-type fluorophores. Probe 41 has the advantages of high selectivity, high sensitivity (8. 16 ppm) and fast response time (less than 3 min).

The structure of the probes involved in this section is shown in fig. 7.

2.3 Nucleophiles based on N, O bifunctional group

Alcohols are more nucleophilic than phenols, but phosphorylation does not change the π-conjugation of the chromophore, resulting in a change in fluorescence. However, the alkyl alcohol can be incorporated into the fluorescent probe together with pyridine and amine, and the cyclization reaction after phosphorylation will produce a new structure, the photoluminescence of which is different from that of the original sensing compound, so that the fluorescent sensing material can be designed.

The switching action of the five-membered ring in the rhodamine parent structure is often used to design fluorescent probes. In 2011, Han Shoufa et al. Reported a nerve agent fluorescent probe 42 based on rhodamine B deoxylactam. After the hydroxyl group was phosphorylated, the nitrogen on the deoxylactam made a nucleophilic attack on the phosphate, and the deoxylactam opened to form a new five-membered heterocyclic ring (Figure 12). In DMF solution containing 3% triethylamine, with the addition of DCP, the color of the solution changed from colorless to red^[61].

Wu et al. reported a similar fluorescent probe43, but the difference was that the fluorescent parent of the probe was rhodamine lactam. After the hydroxyl group was phosphorylated, the oxygen on the ketone nucleophilically attacked the phosphate ester, and then the phosphate ester left, and the lactam opened and produced oxazoline^[62]. Later, Han et al. Reported a similar fluorescent probe 44, which was different from 42 in that after the hydroxyl group was phosphorylated, the nitrogen on the deoxylactam attacked the phosphate nucleophilically, the phosphate left, and the lactam opened and formed a piperidine ring^[63]. Goswami et al. Also designed and synthesized a rhodamine-based fluorescent probe 45 for DCP detection^[64]. In 2009, Heo et al. Designed and synthesized a rhodamine colorimetric fluorescence probe 46, which has the characteristics of fast response, obvious color change and high sensitivity, and the presence of other metal ions and acids has no effect on the detection of DCP, so it is suitable for real-time detection^[65]. Li et al. Designed and synthesized a new thioureido-rhodamine fluorescent probe 47 for color development and fluorescence detection of nerve agents. In the presence of DCP, the phosphorylation of thiosemicarbazide leads to the opening of the spiro-ring to form a seven-membered heterocyclic ring, which is accompanied by a significant color change from colorless to pink^[66]. The detection limit of the probe is 2×10^-6mol/L, and the probe can be used for rapid and simple detection of GD in liquid and gas phases.

In 2014, Gotor et al. synthesized a new fluorescent probe 48 based on dipyrrole fluoroborate, which uses hydroxyl as the reaction site and dipyrrole fluoroborate core as the chromophore and fluorophore, and can detect DCNP and DFP in solution in the range of 1-20 ppm^[67]. In addition, it is adsorbed on a solid silica matrix with a detection limit as low as 0.2 ppm. Lei et al. Developed a fluorescent probe 49 for sarin detection, which was designed based on a novel covalent assembly principle and has the characteristics of compact structure, easy synthesis, zero background, highly sensitive colorimetric and fluorescence turn-on signals^[68].

In 2015, Mahapatra et al. First reported a colorimetric fluorescent probe 50 based on a naphthothiazole-benzothiazole conjugate for DCP detection, whose detection mechanism is a tandem phosphorylation reaction through irreversible ring opening and ring formation processes.Probe 50 clearly showed the change of intensity ratio of the two well-separated emission peaks of the conjugate induced by DCP, the red-shifted emission amount was 135 nm, the red-shifted emission intensity ratio was 0. 5%, and the color changed from green to red^[69]. The probe 50 tape shows a transient response when it contacts the DCP and can be used for field testing. Furthermore, the probe is suitable for ratiometric imaging of changes in DCP levels in living cells. Jiang Yunbao et al. reported a DCP fluorescent probe 51 using a heptamethine cyanine dye with near-infrared emission as a fluorescent parent, in which the carboxyl group of the probe reacts with a nerve agent to form an acylated product.A five-membered heterocyclic ring was formed by the subsequent molecular lactam reaction, resulting in the decrease of the electron-donating ability of the bridgehead amino group of the heptamethine cyanine dye and a red shift of the absorption wavelength.The detection limit of the probe 51 was 0. 136 nmol/L^[70].

In 2016, Balamurugan et al. Introduced a unique visible light-responsive chromophore and nucleophilic hydroxyl group into the polymer backbone. The direct phosphorylation of hydroxyl group and the subsequent intramolecular cyclization formed a six-membered cyclic morpholine cation, which enabled the probe to achieve rapid and selective colorimetric detection of DC NP in solution and gas phase^[71].

In 2017, Rurack et al. reported a BODIPY-modified fluorescent probe 53, which was immobilized on a silica matrix to avoid aggregation in water, and showed that the probe could detect nerve agents in water samples below pmol/L within seconds (Fig. 14)^[72].

Churchill et al. Synthesized a fluorescent probe 54 containing coumarin-4-dimethylimino aryl scaffolds. The hydroxyl group on the probe reacted with DCP to form an O — P bond, followed by an intramolecular cyclization reaction. The cyclization reaction strongly inhibited the photoinduced electron transfer process, resulting in the enhancement of fluorescence intensity^[73]. Mahapatra et al. synthesized and characterized a novel proportional fluorescent probe 55 based on hydroxynaphthalene hemicyanine hybrid, which can react rapidly and sensitively to DCP within 60 s through phosphorylation and intramolecular cyclization reactions, with a detection limit as low as 18. 86 nmol/L^[74]. In addition, the probe is suitable for ratiometric imaging of changes in DCP levels in living cells.

In 2018, Lloyd et al. Synthesized a fluorescent probe 56 for organophosphorus nerve agent detection, which reacted with organophosphorus nerve agent mimics and cyclized to form a dihydroquinoline ring, resulting in enhanced fluorescence response to UVA excitation^[75]. In addition, the added silicon dioxide eliminates the false positive reaction to the mineral acid and improves the accuracy of the detection.

In 2019, Mahapatra et al. reported a colorimetric and ratiometric fluorescence probe57 in which PET inhibition from the oxime hydroxyl group to the triphenylamine moiety and cyclization of benzisoxazole resulted in a color change from cyan to green upon exposure to DCP vapor (fig. 15)^[76]. The probe 57 can detect DCP in gas and liquid phase, and the detection limits calculated from the absorption and fluorescence data are 0. 14 μmol/L and 0. 23 μmol/L, respectively. In addition, the probe can also be used for the detection of trace DCP (10-50 ppm) in soil, and can be used for colorimetric fluorescence cell imaging.

Puglisi et al. synthesized two kinds of naphthalimide derivative fluorescent probes 58a and 58b with different numbers of ethanolamine arms. Both 58a and 58b recognize DMMP by forming a hydrogen bonding network and a multi-directional supramolecular pathway, and the sensor with two ethanolamine groups has better sensitivity and selectivity^[77].

The structures of the probes involved in this section are shown in fig. 13.

3 Conclusion and prospect

Because organophosphorus nerve agents have great lethality to human beings and are often used to create terrorist attacks or military strikes, the detection of organophosphorus nerve agents has attracted more and more attention. Fluorescence sensing technology has been widely used in the detection of organophosphorus nerve agents because of its obvious advantages such as high sensitivity, fast response and simple and portable detection equipment.There are still some difficulties and challenges, such as: (1) the fluorescent sensing materials developed at present still lack high selectivity in complex and special practical environments, and are easily interfered by some acids or analogues, which affects the accuracy of detection; (2) Most of the reported fluorescent sensors have a single detection substance and can detect a variety of trace nerve agents and mimics at the same time, and there are still few reports on multi-functional fluorescent probes that give different signal responses; (3) Although there are a large number of fluorescent sensing materials, the corresponding circuit and optical path design is needed to make them into devices with excellent practical application. It is believed that with the efforts of researchers step by step, new fluorescent sensing materials and methods will continue to emerge, and these difficulties and challenges will be gradually solved.

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