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Hydrazine Exposé: The Next-Generation Fluorescent Probe Yuna Jung, In Gyoung Ju, Young Ho Choe, Youngseo Kim, Sungnam Park, Young-min Hyun, Myung Sook Oh, and Dokyoung Kim ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.8b01429 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 18, 2019

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Hydrazine Exposé: The Next-Generation Fluorescent Probe Yuna Jung,†,# In Gyoung Ju,‡,# Young Ho Choe,§ Youngseo Kim, Sungnam Park, Young-Min Hyun,*,§ Myung Sook Oh,*,‡, and Dokyoung Kim,*,†,||,, †Department

of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea

‡Department

of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea §Department

of Anatomy and Brain Korea 21 PLUS Project for Medical Science, Yonsei University, College of Medicine, Seoul 03722, Republic of Korea Department

of Chemistry, Korea University, Seoul 02841, Republic of Korea

Department

of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea ||Department

Korea

of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of

Center for Converging Humanities, Kyung Hee University, Seoul 02447, Republic of Korea Biomedical

Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea

ABSTRACT: Hydrazine (N2H4) is one of the most important pnictogen hydride chemicals, and is utilized within a wide spectrum of industries. As a result of its extensive use, hydrazine’s monitoring methods have constantly come under fire due to its potential health risk and the subsequent environmental pollution. Fluorometric molecular sensing systems generally report with a major emphasis on the merit of fluorescence analysis. What we are proposing within this report is a next-generation fluorescent probe that allows hydrazine to become fully traceable, within multifarious environments that show fast and intuitional fluorescence transformation. A new sensing moiety, ortho-methoxy-methyl-ether (oOMOM) incorporated electron donor (D)–acceptor (A) type naphthaldehyde provides high selectivity and sensitivity amidst its superiority within practical applications for sensing hydrazine. The new probe overcomes most of the drawbacks of currently used fluorescent probes, and due to its successful demonstrations, such as real-time spray-based sensing, soil analysis, and two-photon tissue imaging, its potential for practical application is beyond reproach. KEYWORDS: fluorescent probe, hydrazine, hydrazone-formation, chemical sensor, two-photon tissue imaging The development of fluorescence-based molecular probes for hydrazine (N2H4) have only recently come to light. Hydrazine is a simple colorless pnictogen hydride, which has been widely used within a spectrum of industries such as aerospace (rocket fuels), engineering (precursor to polymerization catalysts and gas precursors in air-bags), agrochemistry, and pharmaceutics.1-2 However, its high biological toxicity and perilous instability requires strict regulations regarding its usage; classified as hazard group B2, a potential carcinogen, by the U.S. Environmental Protection Agency (EPA).3 In particular, the long-term exposure to hydrazine can cause a series of health risks to human main organs (liver, lungs, and kidney) and the central nervous system (CNS) mainly from biological metal ion (copper, iron)-catalyzed which can damage DNA.2, 4-5 Recognizing the importance of hydrazine detection and monitoring methods, purely for the sake of public health, we have seen many analytical techniques introduced over

the past decade, including mass-based spectrometric analysis, electrochemical approach, electrophoresis, and colorimetric-/fluorometric-analysis.6-15 Among them, the fluorescent techniques are now becoming popular due to their ease of operation, cost effectiveness, high sensitivity and selectivity, fast-response, and high adaptability to biological and environmental samples.16-17 Many scientists within the field of molecular recognition wanted to quickly develop a new chemical sensing moiety adapting on fluorophores, which give high selectivity and sensitivity to hydrazine.18 Current sensing moieties can be categorized into two, based on the reaction mechanism: (i) cleavage-based probes: acetate, vinyl-malononitrile, 4-bromo-butyryl, nitrobenzenesulfonyl, nitro-benzoic-ester, phthalimide, and many derivatives. (ii) addition-based probes: -diketone, ketone, aldehyde, levulinate, trifluoroacetyl acetonate, ortho-hydroxy aromatic aldehyde, and many derivatives (Figure 1).

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Although the current probes show superior sensing ability for hydrazine, the practical applications are limited and unknown mostly due to (i) a restricted sensing ability within the specific environment; applicable only to pure organic solvent or aqueous-organic co-solvent, under the specific pH, surfactant additive, (ii) limited applications due to the defined sensing condition; vial assay, paper strips and cell image, (iii) need for accomplished personnel and specialist instruments that can monitor the signal changes, and (iv) the existence of only an on-off system; therefore making it difficult to trace the signals of both the probe and the sensing products (see summary of known probes in Table S1, Supporting Information). There has been a desperate need for the development of a new hydrazine sensing system, which exceeds the limitations of the current system and that is practically applicable. In this study, we discovered a next-generation fluorescent probe that allows the tracing of hydrazine within any given environment, such as aqueous media, neat, and biological composition. The application was demonstrated in the pure water, user-friendly real-time paper strip assay, spray-based hydrazine tracing, soil analysis, and two-photon deep tissue imaging in mouse organs. All the analysis and application results represent that newly developed probe can overcome the drawbacks of known hydrazine sensing systems which described above. This study sets the foundation for future studies of a new sensing platform that detects amine species and their by-products as an exciting new class of sensing tools.

RESULTS AND DISCUSSION Probe design and synthesis. The naphthalene-based electron donor (D)–bridge–acceptor (A) type dipolar fluorophore has been widely used as a superior fluorescent material. Acedan, 6-acetyl-2-(dimethylamino) naphthalene, is a representative dye in this class, and its derivatives have been applied for the sensing of biologically important species.19 Recently, we focused on the development of naphthalene-based D-A type platforms by introducing functionalities on the orthoposition of naphthaldehyde and its ring-formation in order to make pi-extended coumarine derivatives.20-21 Within this research process, we found that there was an unusual fast and selective hydrazone-formation of naphthaldehyde toward dipnictogen-tetrahydrides, such as hydrazine in the presence of ortho-methoxy-methylether (o-OMOM) moiety (Figure 1). After discovering this unique reaction property, we introduced a dimethylamine on the 2-position, an aldehyde on 6-position, and oOMOM moiety on the 7-position within the final structure of naphthalene core to materialize it as a D-A type fluorescent probe (named HyP-1, Figure 1). According to our current know-how, the reason why oOMOM assists the selective and fast hydrazone-formation of aldehyde toward hydrazine is because it is deemed to be the catalytic activation of aldehyde via hydrazine coordination and the facile electrophilic addition of hydrazine supported by o-OMOM moiety.

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The HyP-1 was prepared from the naphthalene-2,7-diol, for the three steps reaction by following the (i) Bucherer reaction within a sealed-tube containing dimethylamine, (ii) Protection of naphthol using chloro-methyl methyl ether, and (iii) directed lithiation with tert-butyllithium and subsequent formylation with DMF (N,N-dimethylformamide). This synthetic method was developed by our group in 2012 for the first time.22 Other controlling compounds were prepared by following the known method (Figure S1, Supporting Information). Photophysical property analysis. Bearing the aforementioned rationales in mind and conforming their initial sensing results for hydrazine, we prepared two more derivatives, DMHNA (orthohydroxynaphthaldehyde) and DMANA (no methoxy methyl ether moiety), and compared their photophysical property changes with the presence of hydrazine (Figure 2a). The absorption and fluorescence spectra of these compounds were monitored within deionized water (DI H2O) containing no organic co-solvent. The maximum absorption and emission wavelength of HyP-1, DMHNA, and DMANA was recorded at the abs 350-450 nm and emi 500-600 nm range respectively (Figure 2b, 2c). The HyP-1 showed slightly longer wavelength of absorption (abs.max= 391 nm) and emission (emi.max= 556 nm) than DMANA (abs.max= 369 nm, emi.max= 535 nm) as green fluorescent dye under the 365 nm UV light. As we know, the excited state intramolecular proton transfer (ESIPT) induced fluorescence quenching effect was observed in DMHNA.23-24 Upon treatment with hydrazine, HyP-1 emitted strong blue fluorescence at 496 nm with a blueshifting absorption peak (391 nm to 336 nm) as a hydrazone-compound was produced (HyP-1+N2H4, Figure 1), whereas DMHNA and DMANA showed almost no change (Figure 2d, 2e, Figure S2). The formation of hydrazone-product was monitored through NMR analysis (Figure S3), and the mono-imine formation with hydrazine (hydrazone) was verified by high-resolution mass spectrometry (HR-mass, m/z= 273.1480, calc. = 273.1477, Supporting Information). Within the timecourse study, a significant fluorescence enhancement of HyP-1 upon addition of hydrazine was observed within 10 min and seemed to show further saturation within 1 hour (Figure 2g, Figure S4, S5). A good linear relationship between the fluorescence intensity of HyP-1 and hydrazine concentration was observed both in the highconcentration range (0–1 mM, Figure 2h, Figure S6) and the low-concentration range (1 nM–0.5 M, Figure 2h inset, Figure S6). Based on a S/N (signal-to-noise) criteria ratio of more than three, in order to limit detection of hydrazine with the HyP-1, which was estimated to be around 0.035 ppb, which is below the concentration level set by U.S. EPA (10 ppb).3 From the photophysical property comparison data of HyP-1 and its derivatives (DMHNA, DMANA), we confirmed that o-OMOM moiety could boost the formation of hydrazone between naphthaldehyde and hydrazine, and its effect is very dramatic.


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The selectivity of the HyP-1 toward various other metal ions and biomolecules was evaluated (Figure 3a, figure S7, S8). Only dipnictogen-tetrahydride, hydrazine, induced fluorescence change of HyP-1, and most of the other species gave no change despite the possibility of metalcoordinated hydrolysis/reduction of aldehyde,25-26 bisulfide/thiol addition to aldehyde,27-28 and imineformation with amine containing amino acid,29-30 even at high concentration (30 eq). The optimal pH range for the fluorescence sensing of hydrazine with HyP-1 was found to be pH 6–9 including physiological pH (Figure 3b, Figure S9, S10). In the acidic pHs, small absorption spectra change of HyP-1+N2H4 was observed during a long incubation time (2 h) (Figure S9), and this result represent the high stability of Schiff type product, HyP1+N2H4, from the hydrolysis. These results represent that HyP-1 can be applicable for selective hydrazine sensing within complex media, such as environmental samples as well as biological samples. The high photo-stability of HyP-1 and its reaction product with hydrazine (HyP1+N2H4) was observed under the UV light irradiation (365 nm, ~3 W at focal plane) for up to 1 h; negligible fluorescence changes of HyP-1, approximately 20% decrement for HyP-1+N2H4 (Figure S11). In the timeresolved fluorescence (TRF) study, HyP-1 and HyP1+N2H4 showed nano-second lifetimes of fluorescence, 1.4 ns and 3.5 ns, respectively, which are typical lifetime ranges for organic fluorophores (Figure S12).31 High fluorescence quantum yield (Q.Y., ) of HyP-1 (=0.56) and HyP-1+N2H4 (=0.40) was derived by using the coumarin 153 and DPA (9,10-diphenylanthracene) as a reference dye (Figure S13). The high quantum yield enables HyP-1 to be applied for the prominent sensing of hydrazine. Quantum chemical calculation. The most stable molecular conformation, HOMO/LUMO level, and electronic absorption spectra of HyP-1 and HyP-1+N2H4 were calculated using the density functional theory (DFT) (Figure 4).32 An oxygen atom in the aldehyde moiety of HyP-1 and primary-amine group of HyP-1+N2H4 is situated far from the o-OMOM because of the steric factor (Figure 4a). The gaps between HOMO and LUMO level of HyP-1 and HyP-1+N2H4 were 3.55 eV (349 nm) and 3.77 eV (328 nm), respectively, indicating the blueshift of absorption after the hydrazone-formation (Figure 4b). The electron density is mainly localized within the donor part (-N(Me)2) in the HOMO and moves to the acceptor part (-CHO, CHNNH2) in the LUMO, which is a representative feature of D-A type fluorophore, that could undergo intramoleculer charge transfer (ICT) upon electronic excitation.33 Such results are well reflected in the calculated absorption spectra as well (Figure 4c), and are consistent with the experimental result (Figure 2b, 2d). Paper strip application. Given that HyP-1 is highly selective, sensitive, fast-responsive, and intuitional fluorescence change, we demonstrated the applicability of HyP-1 to practical applications. For the first application, we designed the HyP-1 modified cellulose paper that

shows stable green fluorescence under the UV light (commercial hand-hold 365 nm UV lamp) and gives fluorescence change to blue upon exposure of hydrazine (Figure 5a, 5b). A droplet of HyP-1 solution was placed to a cellulose filter paper and dried at room temperature (repeated five times). The HyP-1 treated paper (strip) shows a bright green fluorescence with steady intensity in an ambient atmosphere and temperature. Just as the Litmus paper, the prepared strips were utilized to probe the hydrazine in two different condition: (1) Strip exposure to aqueous solution of hydrazine (in DI H2O). As shown in Figure 5b and 5c, a dramatic fluorescence change of strip appeared from green to blue within 1 min, and after being exposed to hydrazine the changes were more dramatic within high concentration. (2) Strip exposure to vaporized hydrazine. The test demonstrated with hydrazine or other vaporized organic compounds such as dimethyl-amine (HN(CH)2), hydrogen chloride (HCl), formaldehyde (H2CO), including H2O (Figure 5d, 5e, Supporting Movie S1). Upon exposure of vaporized organic compounds, distinctive fluorescence changes were observed only for the hydrazine and mixture of hydrazine/formaldehyde, indicating sufficient reactivity of o-OMOM aldehyde in HyP-1 toward hydrazine despite the interruption of an reactive formaldehyde. The fluorescence quenching of strip for hydrogen chloride seems to be caused by protonation of amine within the donor part. Spray application. We evaluated the sensing capabilities of hydrazine with a simple spraying approach using HyP-1 solution (Figure 6a). For the demonstration, a drop (~ 4 L) of hydrazine solution DI H2O was placed in the cell culture dish (Figure 6b, A-C: 50 mM, D-F: 100 mM), and the HyP-1 stock solution in DMSO was sprayed. Within a minute, the strong blue fluorescence was observed in the drop of hydrazine under the UV light (365 nm), and the signal was significant compared to the background noise (Figure 6c). The simple operation and intuitional signal response under the hand-held UV lamp provide the users with a more convenient approach for sensing hydrazine within on-site analysis. Soil analysis. Next, we applied HyP-1 for the environmental analytical purpose; the detection of hydrazine within soil. For the demonstration, hydrazine was pretreated to various soils (sand soil, clay soil and field soil), and it was observed that each soil showed their original physical property with no change. (Figure 6d, Figure S14). Therefore, it is difficult to distinguish hydrazine exposure within soils purely using our eyes. We poured hydrazine-pretreated (10 mM, 50 mM) soils (~ 1 g) to the solution of HyP-1 (100 M in DI H2O) and monitored the fluorescence changes for 30 min at room temperature (25 °c). Interestingly, within 5 min, a clear blue fluorescence emission was observed in all soils (Figure 6f, Figure S14-S16), and the signal response was more dramatic within the sand soil (Figure 6g). Moreover, the fluorescence signal could be viewed over an extended period of time, more than 5 days (Figure S14). This is the world’s first successful demonstration of a hydrazine


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probe for environmental analysis, and particularly within soils. Bio-imaging application. In order to further explore the potential of HyP-1 for bio-imaging applications, we applied HyP-1 to tissues (organs from a mouse including: brain, liver, lung, skin and kidney) and monitored their fluorescence response upon the treatment of hydrazine (Figure 7a). For the deep tissue imaging, two-photon microscopy (TPM) was applied that shows the following benefits: (1) enabling tissue imaging at increased depths by use of excitation at near infrared wavelength (700-1000 nm, called biological optical window), (2) localized excitation of a low volume (~1 fL) that could serve highresolution imaging, and (3) less photo-damage and photobleaching to tissues than the typical one-photon fluorescence microscopy.34-35 Sizeable two-photon action cross-section (TPACS, GM; Goeppert-Mayer unit) values were experimentally derived for the HyP-1 (~44 GM) and HyP-1+N2H4 (~31GM) at 810 nm. The tissue samples were immersed in the hydrazine solution for 1 h at normal body temperature (37 °C) and washed thoroughly with phosphate buffered saline (PBS) prior to incubating it with the HyP-1 solution. After incubation for 30 min, the tissue samples were washed with PBS buffer and the fluorescence signal changes were monitored using TPM. Prior to conducting the image recording, we searched for the optimization of two-photon excitation wavelength and laser power at a focal plane that gives the best imaging result, with minimized interference of tissue autofluorescence for both HyP-1 (green fluorescence, abs.max= 391 nm) and HyP-1+N2H4 (blue fluorescence, abs.max= 336 nm). The 810 nm excitation and approximately 50 mW laser power yielded the best results. As shown in Figure 7a, a strong fluorescence signal was observed within the green-channel (500–550 nm) for HyP-1-only treated tissue samples under TPM imaging with negligible signal in the red-channel (575–610 nm) and blue-channel (420–480 nm). The hydrazinepretreated tissue sample with HyP-1, a significantly increased fluorescence signal was observed within the blue-channel across all tissue samples, and the signal seemed to be co-localized within HyP-1 signal particularly in the green-channel. The depth dependence of the TPM signal was conducted from the superficial layer to the internal layer (~50 m) with a 10 m imaging depth interval (Figure 7b). Strong green and blue fluorescence signals were observed even within the internal layer, representing the high permeability of hydrazine as well as HyP-1 in tissue. From the bright imaging ability of HyP-1 towards the hydrazine within the tissue samples under TPM, it is expected that HyP-1 could be applicable for the hydrazine-related biological study as well as bio-medicine.

CONCLUSION In conclusion, we developed a next-generation fluorescent probe, HyP-1, that allows the tracing of hydrazine with high selectivity and sensitivity, and universal applicability. For the first time, we found that unusual fast hydrazone-formation of naphthaldehyde

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toward hydrazine in the presence of ortho-methoxymethyl-ether (o-OMOM) moiety, and invented a new sensing probe which shows different fluorescence emission upon exposure to the hydrazine. We systematically analyzed the photophysical properties compared with its derivatives, and demonstrated the ability of HyP-1 for the practical applications such as realtime spray-based sensing, soil analysis, and bio-imaging in tissue samples. The hydrazine sensing ability of HyP-1 in any environment such as pure water, neat, and biological composition encourages further applications in a variety of fields.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details and supporting figures (PDF); UV/Vis absorption spectra, fluorescence spectra, NMR analysis, and photos for soil analysis. Hydrazine sensing application with paper strip (AVI).

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (D.K) *E-mail: [email protected] (M.S.O) *E-mail: [email protected] (Y-M.H)

ORCID *Dokyoung Kim: 0000-0002-7756-3560 *Myung Sook Oh: 0000-0001-8189-4066 *Young-Min Hyun: 0000-0002-0567-2039

Author Contributions #Y.J.

and I.G.J. contributed equally.

Notes

The authors declare the following competing financial interest(s): The authors are listed as inventors on a pending patent application related to technology described in this work.

ACKNOWLEDGMENT This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) of Korea funded by the Ministry of Science & ICT (NRF-2018-M3A9H3021707). This research was also supported by Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (NRF-2018-R1A6A1A03025124, NRF-2018-R1D1A1B07043383) and by the Medical Research Center Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (NRF2017R1A5A2014768). Y-M. H. thanks to the financial support from the NRF grant funded by the Korea government (MSIP) (2016R1A2B4008199).

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(33) Singha, S.; Kim, D.; Roy, B.; Sambasivan, S.; Moon, H.; Rao, A. S.; Kim, J. Y.; Joo, T.; Park, J. W.; Rhee, Y. M.; Wang, T.; Kim, K. H.; Shin, Y. H.; Jung, J.; Ahn, K. H., A structural remedy toward bright dipolar fluorophores in aqueous media. Chem. Sci. 2015, 6 (7), 4335-4342.

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(34) Zipfel, W. R.; Williams, R. M.; Webb, W. W., Nonlinear magic: multiphoton microscopy in the biosciences. Nat. Biotech. 2003, 21, 1369. (35) Yao, S.; Belfield, K. D., Two-Photon Fluorescent Probes for Bioimaging. Eur. J. Org. Chem. 2012, 2012 (17), 3199-3217.


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FIGURES

Figure 1. Current sensing systems and a new fluorescent probe for hydrazine shown within this study. (a, b) Current sensing approaches for hydrazine and the representative sensing moiety (X, Y). Moiety Z is the reaction product of moiety Y. The main drawbacks of the current sensing systems are described in detail. (c) This work: ortho-OMOM benzaldehyde moiety as a new sensing moiety and the structure of newly developed fluorescent probe (HyP-1) for hydrazine. Schematic illustration of the sensing mode, merits, and practical applicability are described.


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Figure 2. Hydrazine sensing properties of HyP-1 and their derivatives. (a) The chemical structure of HyP-1, DMHNA, and DMANA. (b–e) Absorption and fluorescence spectra of probes (10 M) upon addition of hydrazine (1 mM) in DI H2O, measured after 60 min at 25 C. The emission spectra was measured under excitation at the maximum absorption wavelength. (f) Fluorescence spectra of HyP-1(10 M) upon addition of hydrazine (1 mM) in DI H2O, measured after 60 min at 25 C. Inset: photos of HyP-1 before and after treatment of hydrazine under the UV light (365 nm). (g) Fluorescence spectra changes of HyP-1 (10 M) upon addition of hydrazine (1 mM) in DI H2O at 25 C. The emission spectra was measured under excitation at the maximum absorption wavelength in each condition. Spectrum was recorded at 0–60 min (10 min interval) after mixing together. (h) Fluorescence spectra of HyP-1 (10 M) upon addition of hydrazine (0-1 mM) in DI H2O, measured after 60 min at 25 C. Inset: a plot of fluorescence intensity changes of HyP-1 (0.5 M) with the low concentration of hydrazine (0.001-0.1 M). The emission spectra was measured under excitation at the maximum absorption wavelength within each concentration.


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Figure 3. Sensing screening of HyP-1. (a) fluorescence changes (peak height at 498 nm) of HyP-1 (10 M) upon addition of metal ions/anions (30 eq) or biomolecules (30 eq) in DI H2O, measured after 60 min at 25 C. Metal ions/anions; (A) HyP-1, (B) HyP-1 + N2H4, (C) CaCl2, (D) K2CO3, (E) ZnCl2, (F) NaSH, (G) KCl, (H) NaOH, (I) NaOAc, (J) NaN3, (K) NaI, (L) NaHSO3, (M) NaH2PO4, (N) NaF, (O) NaCN, (P) NaCl (anion), (Q) NaCl, (R) MgSO4, (S) MgCl2. Biomolecules; (T) Glu (Glutamine), (U) GSH(Glutathione), (V) Asp (Aspartic acid), (X) Cys (Cysteine), (Y) Lys (Lysine), (Z) Hcy (Homocysteine). The emission spectra was recorded under excitation at 391 nm. (b) Fluorescence changes (peak height at 495 nm) of HyP1 (10 M) upon addition of hydrazine (1 mM) in various pHs (pH 4, 5, 6, 7, 7.4, 8, 9), measured after 60 min at 25 C. The emission spectra was recorded under excitation at the maximum absorption wavelength within each pHs.


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Figure 4. Quantum chemical calculation of HyP-1 and its reaction product. (a) The most stable conformational structure of HyP-1 and its reaction product (HyP-1+N2H4) within water. (b) The HOMO/LUMO and their energy difference (E, unit: eV) of HyP-1 and product (HyP-1+N2H4) obtained by DFT calculations (APFD/6-31+G(d,p)). (c) Calculated electronic absorption spectra of HyP-1 and product (HyP-1+N2H4) in water.


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Figure 5. Paper strip application of HyP-1. (a) The schematic illustration of the paper strip test. Expose: vapor and soak. (b) Photos of paper (control), HyP-1-treated paper strip (100 M HyP-1moistened), and N2H4-exposed paper strip (1 sec soaking to 10 mM N2H4solution). (c) Photos of HyP-1-treated paper strip under the natural light (upper) and UV light (bottom)with N2H4 expose (concentration from (i) to (vi): 0 M, 10 M, 100 M, 1 mM, 10 mM, and 100 mM). (d) Photos of HyP-1 treated paper strip after exposure to an excess quantity of various vapors, including H2O, N2H4, HN(CH)2, HCl, H2CO, and the mixture of H2CO and N2H4 for 3 min, respectively. The photos were taken under the UV light (365 nm). (e) Fluorescence intensity plot of paper strips as shown in panel (d). The relative intensity was calculated using ImageJ software. The intensity indicates the signal within blue wavelength region. See experimental details within the Supporting Information.


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Figure 6. Spray application of HyP-1. (a) The illustration of spray test. (b) The picture of hydrazine placed on the culture dish in bright field (left) and UV irradiation (365 nm) after HyP-1 (100 M stock solution in DMSO) sprayed (10 times, approximately 1 L). The photo was taken after 10 min at 25 C. The N2H4 concentration at point A–C and D–F is 50 mM and 100 mM, in DI H2O, respectively. (c) Relative fluorescence intensity at points A–F shown within panel (b). The relative intensity was calculated using ImageJ software (NIH, USA). The intensity indicates the signal in blue wavelength region. (d) Photos for N2H4 moistened soils under natural light. (e) Schematic illustration of the soil test. N2H4 moistened soils transferred to a vial of DI H2O (3 mL) containing HyP-1 (100 M). (f) Photos of HyP-1 (upper, 100 M) in DI H2O and upon addition of N2H4 moistened soils (1 g, N2H4 content: 50 mM) (bottom). The photo was taken after 10 min at 25 C. (g) Fluorescence intensity plot of solutions as shown in panel (f) and lower N2H4 content (10 mM) after the soil settles. The relative intensity was calculated using ImageJ software. The intensity indicates the signal within blue wavelength region. See experimental details in Supporting Information.


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Figure 7. TPM tissue imaging with HyP-1. (a) TPM images of different mouse organ tissues, treated with N2H4 (5 mM) for 30 min and incubated with HyP-1 (50M) for 60 min at 37 C. The images were recorded at a middle depth layer (~30 m) of tissue piece (thickness ~ 50 m). TPM images obtained by collecting the fluorescence from an emission channel of 420– 480 nm (for blue), 500–550 nm (for green), and 575–610 nm (for red), under excitation at 810 nm with laser power of approximately 50 mW at the focal plane. (b) TPM images of mouse brain, kidney, Liver, Lung, and skin tissue at the indicated depths (0–50 m). Each image represents the merged image of fluorescence in blue, green, and red channel at the indicated depth. See experimental details in Supporting Information.


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