Recent progress in the development of fluorescent probes for hydrazine

R E V I EW m so Henan Key Laboratory of Biomolecular n im aration of textile dyes, pharmaceuticals, pesticides and so on. Despite its widespread industrial applications, hydrazine is highly toxic and exposure to this chemical can cause many symptoms and severe damage to the liver, kidneys, and central nervous system. As a consequence, many efforts have been devoted to the development of , is an inorganic compound [1] Ascribed to its other unique properties, including nucleophility, [8] ical techniques, including titrimetry, voltammetry, Abbreviations used: AIE, aggregation‐induced emission; DMSO, dimethyl Received: 29 January 2018 Revised: 8 April 2018 Accepted: 26 April 2018 DOI: 10.1002/bio.3505ph te10 ppb. Thus, it is highly desirable to develop selective and sensitive assays for the detection of trace hydrazine. Several traditional analyt- [9] [10–12] sulfoxide; LOD, limit of detection; N2H4, hydrazine; NIR, near‐infrared; PBS, osphate‐buffered saline; TICT, twisted‐intramolecular charge transfer; TPE, traphenylethylene.with the chemical formula N2H4. Hydrazine can also be written as H2NNH2, called diamidogen, therefore it has basic (alkali) chemical properties (Kb = 1.3 × 10 −6) like ammonia. At ambient conditions, hydrazine is a colourless fuming liquid with a faint ammonia‐like odour. Since the by‐products are typically nitrogen gas and water, hydrazine often acts as a convenient reductant such as antioxidant, oxygen scavenger and corrosion inhibitor. Additionally, hydrazine is also used as a propellant in space vehicles or used as a component reductibility and double nucleophilic character, hydrazine also can be utilized as an important reactant for many chemical products, including textile dyes, pharmaceuticals and pesticides.[2–5] Despite its wide- spread industrial applications, hydrazine is highly toxic. Exposure to hydrazine may cause symptoms of irritation of the eyes, nose, and throat, dizziness, headache, nausea, pulmonary edema, seizures, coma in humans, as well as damage to the liver, kidneys and the central ner- vous system.[6,7] The US Environmental Protection Agency (EPA) iden- tified hydrazine as a potential carcinogen with a threshold limit ofRecognition and Sensing, College of Chemistry and Chemical Engineering, Shangqiu Normal University, Shangqiu, Henan Province, P. R. China Correspondence Yuanqiang Hao, Henan Key Laboratory of Biomolecular Recognition and Sensing, College of Chemistry and Chemical Engineering, Shangqiu Normal University, Shangqiu, Henan Province, 476000, P. R. China. Email: hao0736@163.com You‐Nian Liu, College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan Province, 410083, P. R. China. Email: liuyounian@csu.edu.cn Funding information National Natural Science Foundation of China, Grant/Award Numbers: 21476266, 21475084, 21505091, U1404215 and B061201; Innovation Scientists and Techni- cians Troop Construction Projects of Henan Province, Grant/Award Number: 41 1 | INTRODUCTION Hydrazine, coined by Emil Fischer in 1875Luminescence. 2018;1–21.fluorescent probes for the selective sensing and/or imaging of N2H4. Although great efforts have been devoted in this area, the large number of important recent studies have not yet been systematically discussed in a review format so far. In this review, we have summarized the recently reported fluorescent N2H4 probes, which are clas- sified into several categories on the basis of the recognition moieties. Moreover, the sensing mechanism and probes designing strategy are also comprehensively discussed on aspects of the unique chemical characteristics of N2H4 and the structures and spectral properties of fluorophores. KEYWORDS fluorescent probes, hydrazine, review in rocket fuel due to its high heat of combustion and since large vol- umes of hot gas are generated during its decomposition.Recent progress in the develop hydrazine Khac Hong Nguyen1 | Yuanqiang Hao2 | Wan Minghui Yang1 | You‐Nian Liu1 1College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan Province, P. R. China 2 Abstract Hydrazine (N2H4) is awileyonlinelibrary.com/journal/bient of fluorescent probes for ng Chen1 | Yintang Zhang2 | Maotian Xu2 | portant and commonly used chemical reagent for the prep-Copyright © 2018 John Wiley & Sons, Ltd.o 1 chromatography,[13,14] and chemiluminescence[15] have been widely used for hydrazine detection. However, most of these approaches have major disadvantages associated with the need for sophisticated instrumentation and time‐consuming manipulations, and the inability to be miniaturized for in situ and in vivo studies. Alternatively, analytical techniques based on fluorescence sensor systems are very popular because fluorescence measurements are usually easy to perform, inexpensive, very sensitive (parts per billion/ trillion) with detection limits as low as sub‐parts‐per million, and able to be employed for in situ and in vivo monitoring.[16–22] Hydrazine can act as a good nucleophile for a variety of transformations in syn- thetic chemistry, such as hydrazone formation, Wolff–Kishner reduc- tion, heterocyclic chemistry, deprotection of phthalimides and so on. Recently, these characters of hydrazine have provide a starting point for the development of a large number of efficient fluorescent hydra- zine probes (Figure 1). Although great efforts have been devoted in this area, a large number of important recent studies have not yet been systematically discussed in a review format to the best of our knowledge. Herein, we make such an effort to summarize the rapid progress in the development of fluorescent hydrazine probes and highlight a variety of inventive strategies to achieve good reactivity and selectivity. The topics of this review are classified into several cat- egories based on the different sensing mechanisms and recognizing moieties of these probes for hydrazine, including probes based on ace- tyl, 4‐bromobutyryl, vinyl malononitrile, phthalimide, β‐diketone, levulinate and other moieties. 2 | PROBES BASED ON ACETYL MOIETY Phenol acetate can be readily hydrazinolyzed by hydrazine to generate its phenolic analogue (Figure 2). Based on this reaction, several probes containing phenol acetate moieties have been developed for sensing of hydrazine. Chang and co‐workers developed two phenylacetate‐ based fluorescent probes (1 and 2) for hydrazine detection by incorpo- rating acetate group onto dichlorofluorescein and resorufin fluorophore scaffolds, respectively (Figure 3).[23] In a mixture of dimethyl sulfoxide (DMSO) and Tris buffer solution (pH 8.0, 10 mM, 1:1, v/v), probe 1 is colourless and non‐fluorescent. Treating the probe solution with 100 equivalents of hydrazine creates a strong absorption band at 512 nm with a corresponding colour change from colourless to greenish yellow and a prominent green emission at 534 nm, which mechanisms 2 NGUYEN ET AL.FIGURE 2 Proposed sensing mechanism of probe for hydrazine (N2H4) based onFIGURE 1 Fluorescent hydrazine (N2H4) probes based on different reactionhydrazinolysis of phenol acetate are the characteristic spectral features of free dichlorofluorescein. Hydrazinolysis of probe 2 also causes evident chromogenic and fluo- rescent turn‐on type signals. Both 1 and 2 exhibit excellent selectiv- ities for hydrazine with limits of detection (LODs) of 9.0 × 10−8 M and 8.2 × 10−8 M, respectively, which is sensitive enough for industrial chemical detection. Peng and co‐workers reported a NIR (near‐infared region) ratiometric fluorescent probe (3) for hydrazine based on a heptamethine cyanine dye derivative (Figure 4).[24] In the presence of hydrazine in a mixture of acetate buffer (pH 4.5, 10 mM) and DMSO (1:9, v/v), 3 undergoes a hydrazinolysis process to release enol form, which further transforms it into its corresponding ketone increase with the concentration of hydrazine in the range 10–80 μM. And the LOD of 3 for hydrazine was determined to be 2.5 × 10−8 M. Moreover, the probe was successfully utilized for imaging hydrazine in living MCF‐7 cell line and visualizing hydrazine in mice (Figure 4B). Pang and co‐workers designed a ESIPT (excited state intramo- lecular proton transfer) probe 4 by masking the phenol group of flavonoid with the ethyl ester (Figure 5).[25] Hydrazine can selec- tively remove the ester protection group, leading to the recovery of flavonoid ESIPT. Addition of 20 equivalents of hydrazine to the probe solution causes a large fluorescence enhancement, giving intense green fluorescence, which increases by about eight‐fold. Under optimized conditions, the fluorescence intensity of the probe solution was nearly proportional to the hydrazine concentration range from 0 to 50 μM with a calculated LOD of 1.0 × 10−5 M. The probe was also successfully used for monitoring hydrazine in live cells and zebrafish. Sun et al. developed a ratiometric fluorescent hydrazine probe 5 (Figure 6)[26] by incorporating an acetate moiety onto naphthalimide, a widely used scaffold for the construction of fluorescent probes.[27,28] Probe 5 displayed a fluorescence maximum at 432 nm. Upon addition FIGURE 3 Structures and reactions of probes 1 and 2 with hydrazine FIGURE 5 Structure and reaction of probe 4 with hydrazine NGUYEN ET AL. 3form, leading to large hypsochromic shifts in both absorption and emission maxima. Specifically, the colour of the solution changes from cyan (784 nm) to pink (520 nm), and the emission band shifts from 810 nm to 582 nm. The fluorescence intensity ratio at 582 and 810 nm (I582/I810) was found to linearlyFIGURE 4 (A) Structure and reaction of probe 3 with hydrazine. (B) In vi subsequent skin‐popping injection of hydrazine with the effect over differe 740 nm and an emission filter of 820 ± 20 nm, and the bottom ones were 600 ± 20 nm. (Reprinted from ref. 24)vo images of a mouse given a skin‐popping injection of probe 3 and a nt time intervals. The top images were taken with an excitation laser of taken with an excitation laser of 480 nm and an emission filter of Fluo nel 4 NGUYEN ET AL.of hydrazine, the emission intensity at 432 nm decreased gradually with the simultaneous appearance of a new red‐shifted emission band centred at 543 nm, affording the ratiometric detection. The emission intensity ratio (I543/I432) showed a good linearity against the hydrazine FIGURE 6 (A) Structure and reaction of probe 5 with hydrazine. (B) treated with 5 and hydrazine. (a, d) Bright‐field images, (b, e) blue chanconcentration in the range 0–10 μM, with a LOD of 2.1 × 10−8 M. Probe 5 has also been applied to image hydrazine in living cells (Figure 6B). Compound 6 was reported as a NIR and turn‐on fluorescent probe for hydrazine detection (Figure 7).[29] Reaction of the probe with hydrazine removes the acetate moiety, producing the highly fluorescent NIR hemicyanine fluorophore. In vitro experiments showed that a linear correlation existed between the fluorescence response and the concentration of the hydrazine in the range 0–50 μM, with a LOD of 1.9 × 10−7 M. Furthermore, the probe is capable of imaging hydrazine not only in living cells but also in living mice due to its efficient NIR emission, a critical feature for application in bioimaging.[30,31] Peng and co‐workers developed a two‐photon NIR fluorescent probe 7 for the detection of hydrazine (Figure 8).[32] The probe has an acetate moiety as the reaction site for hydrazine and a 2‐(2‐(4‐ hydroxystyryl)‐4H‐chromen‐4‐ylidene) malononitrile complex as the fluorescent reporter unit. The non‐fluorescent 7 reacts with hydrazine leading to the removal of an acetate group and the release of thehighly fluorescent moiety. The fluorescence increase at 680 nm is directly proportional to the hydrazine concentration from 0 to 40 μM with a LOD of 5.7 × 10−7 M. Obviously, the response time of 7 toward hydrazine is about 1 min, and the probe is also capable rescence images of 7860 cells, (a–c) cells incubated with 5; (d–f) cells , (c, f) green channel. (Reprinted from ref. 26)of visualizing hydrazine in MCF‐7 cells by two‐photon microscopy (TPM) imaging (Figure 8B). Yin and co‐workers recently reported a ratiometric fluorescent hydrazine probe 8 by incorporating an acetate moiety to a coumarin derivative (Figure 9).[33] Noticeably, this probe displayed a different rec- ognition mechanism for hydrazine, in which the carbanyl group of the probe reacts with hydrazine affording a Schiff‐base intermediate and further forming a stable heterocyclic structure. The probe exhibited a high sensitivity for hydrazine with a linear response range 0–10 μM. Cell imaging experiments also demonstrated the capacity of probe 8 for monitoring hydrazine in live samples. Incorporation of the acetate moiety onto a variety of other fluorophore scaffolds has afforded probes in a range of colour. Reports of hydrazine based on coumarin and its derivatives (9–11),[34–36] fluorescein (12),[37] 1,4‐dihydroxyanthraquinone (13),[38] 1,8‐naphthalimide (14),[39] benzthiazole (15),[40] the dicyanomethylenedihydrofuran scaffold (16)[41,42] and rhodamine derivative (17)[43] have been described. The structures of these fluo- rescent hydrazine probes are summarized in Figure 10. However, it FIGURE 7 Structure and reaction of probe 6 with hydrazine NGUYEN ET AL.should be pointed out that, the acetyl group located on the aromatic phenol is also a reaction site for BO3 − anion, and several fluorescent probes have been develop for BO3 − ions based on the acetyl recognition moiety,[44–47] indicating that BO3 − may interfere with the hydrazine detection by using this type of probe. 3 | PROBES BASED ON 4‐BROMOBUTYRYL MOIETY Hydrazine, also written as H2NNH2, can actually be regarded as a simple molecule consisted of two amino groups, which implies that it can perform two consecutive nucleophilic reactions. This double nucleophilic character is unique to hydrazine over other amines and FIGURE 8 (A) Structure and reaction of probe 7 with hydrazine. (B) Conf cells treated with hydrazine and subsequent treatment of the cells with 7; 650–750 nm; (g–i), TPM image of cells upon excitation at 820 nm, emissio FIGURE 9 Structure and reaction of probe 8 with hydrazine5anions. Thus, fluorescent probes with excellent selectivity for hydrazine would be afforded by taking advantage of this special reac- tivity. For exploiting the double nucleophilic ability of hydrazine, a 4‐bromo butyrate group has been employed as the reaction moiety for the design of hydrazine probes. This type of fluorescent probe is normally prepared via the incorporation of 4‐bromo butyrate onto a phenolic‐containing fluorophore. The sensing process involves two steps (Figure 11), hydrazine first nucleophilically substitutes bromine atom and then performs a nucleophilic attack on the ester carbonyl, followed by intramolecular cyclization to release the fluorophore. Goswami et al. firstly developed a fluorescent hydrazine probe (18) employing 4‐bromo butyrate as the reaction moiety (Figure 12).[48] The probe is designed in such a way that ESIPT of the HBT ocal microscope images of MCF‐7 cells. (a–c) cells treated with 7; (d–i) (d–f) OPM image of cells upon excitation at 560 nm, emission window n window 575–630 nm. (Reprinted from ref. 32) ac 6FIGURE 10 Structures of fluorescent hydrazine probes 9–17 with an(2‐(2'‐hydroxyphenyl)benzothiazole) moiety gets blocked by the substituted 4‐bromo butyrate group. The presence of hydrazine can result in the release of the HBT moiety as well as the recovery of the ESIPT of fluorophore through subsequent substitution, cyclization and elimination processes. Moreover, live‐cell imaging experiments establish the utility of this probe for tracking hydrazine in live cells. Incorporation of a 4‐bromo butyrate moiety onto a resorufin fluorophore afforded a turn‐on fluorescent probe (19) for N2H4 (Figure 13).[49] Reaction of the probe with hydrazine in a HEPES buffer (10 mM, pH 7.4, containing 10% acetonitrile (CH3CN)) leads to the release of fluorescent resorufin. The fluorescence increase is directly proportional to the hydrazine concentration in the range 10–200 μM with a LOD of about 2 × 10−6 M. The dramatic colour change of the probe solution from colourless to red upon the treatment with hydrazine demonstrated that 19 can serve as a ‘naked‐eye’ probe for hydrazine. Probe 19 also has been applied to image hydrazine in living cells (Figure 13B). FIGURE 11 Proposed sensing mechanism of 4‐bromobutyryl‐based prob FIGURE 12 Structure and reaction of probe 18 with hydrazineetate moiety NGUYEN ET AL.Recently, our group reported a ratiometric fluorescent hydrazine probe (20) based on the 1,8‐naphthalimide fluorophore (Figure 14). [50] The probe operates by hydrazine‐mediated removal of the 4‐bromo butyrate moiety via a substitution‐cyclization‐elimination process to liberate the 1,8‐naphthalimide moiety. Upon the treatment with hydrazine, the probe solution displayed a bathochromic shift in emission from 420 to 550 nm. The emission intensity ratio (I550/I420) is found to be proportional to the concentration of hydrazine in the range 1.0–30.0 μM with a LOD of 2.7 × 10−7 M. Moreover, the probe has been utilized for practical detection of gaseous hydrazine, as well as imaging hydrazine in live cells. By anchoring a 4‐bromo butyrate moiety onto a cyanine scaffold, Lu and co‐workers developed a NIR ratiometric fluorescent probe (21) (Figure 15) for hydrazine detection.[51] Addition of hydrazine to a solution of 21 in DMSO–H2O (1:4, v/v, phosphate‐buffered saline (PBS) 20 mM, pH 7.4) induced a significant hypsochromic shift of the emission maximum from 810 to 627 nm. The probe displayed high sensitivity (LOD = 1.2 × 10−8 M) and excellent selectivity over other interfering analytes. Furthermore, the probe is capable of imaging exogenous hydrazine not only in living cells but also in living mice (Figure 15B). Installation of a 4‐bromo butyrate moiety onto different fluorophores has afforded a series of fluorescent hydrazine probes in a variety of colours (Figure 16). Based‐on fluorescein, Goswami et al. reported a ‘turn on’ fluorescent probe (22).[52] By utilizing es for hydrazine NGUYEN ET AL.dicyanomethylenedihydrofuran scaffold, Li and co‐workers prepared a far‐red fluorescent hydrazine probe (23).[53] Zhu and co‐workers developed two flavonoid‐based fluorescent hydrazine sensors (24 and 25),[54,55] and both of them have been applied to the detection FIGURE 13 (A) Structure and reaction of probe 19 with hydrazine. (B) Co incubated with 19 (a–c); image of cells after treatment with 19 and subsequ images; (b and f) red channel; (c and g) merged images. (Reprinted from re FIGURE 14 Structure and reaction of probe 20 with hydrazine FIGURE 15 (A) Structure and reaction of probe 21 with hydrazine. (B) R with 21 and subsequently incubated with hydrazine. Images were taken af ref. 51)7of hydrazine in living cells. Chen et al. reported a highly sensitive fluo- rescent turn‐on probe (26) for hydrazine based on a coumarin fluorophore.[56] Using the similar strategy, a new ESIPT hydrazine probe (27) was also developed. It displayed good water solubility and nfocal fluorescence images of Chinese hamster ovary (CHO) cells: cells ent treatment of the cells with hydrazine for (e–g). (a and e) Bright‐field f. 49) epresentative fluorescence images of the mice that were pre‐treated ter incubation of hydrazine for 0, 3, 6, and 10 min. (Reprinted from and co‐workers (Figure 18).[60] Probe 29 displays a strong emission 4‐ 8with a maximum in the red region around 640 nm due to the intramo- lecular charge transfer (ICT) process from the 7‐N,N‐dieth