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A BODIPY-Based Fluorescent Probe for Detection of Subnanomolar Phosgene with Rapid Response and High Selectivity Yuanlin Zhang, Aidong Peng, Xiaoke Jie, Yanlin Lv, Xuefei Wang, and Zhiyuan Tian ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b02013 • Publication Date (Web): 11 Apr 2017 Downloaded from http://pubs.acs.org on April 11, 2017

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ACS Applied Materials & Interfaces

A BODIPY-Based Fluorescent Probe for Detection of Subnanomolar Phosgene with Rapid Response and High Selectivity Yuanlin Zhang,† Aidong Peng, ‡ Xiaoke Jie,† Yanlin Lv,† Xuefei Wang† and Zhiyuan Tian*† †

School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences,

Beijing 100049, P. R. China, E-mail: [email protected]. ‡

College of Materials Science and Opto-Electronic Technology, University of Chinese Academy

of Sciences, Beijing 100049, P. R. China. KEYWORDS: Phosgene, Ethylenediamine Group, Intramolecular Cyclization, ICT, Detection Limit ABSTRACT: A new type of phosgene probe with limit of detection down to 0.12 nM, response time less than 1.5 seconds, and high selectivity over other similarly reactive toxic chemicals was developed using ethylenediamine as the recognition moiety and 8-substituted BODIPY unit as the fluorescence signalling component. The probe undergoes sequential phosgene-mediated nucleophilic substitution reaction and intramolecular cyclization reaction with high rate, yielding product with the intramolecular charge transfer (ICT) process from amine to the BODIPY core significantly inhibited. Owing to the emission feature of 8-substituted BODIPY that is highly sensitive to the substituent’s electronic nature, such inhibition on the ICT process strikingly

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generates strong fluorescence contrast, by factor of more than 23300, and therefore the superhigh sensitivity of the probe for phosgene. Owing to the high reactivity of ethylenediamine of the probe in nucleophilic substitution reaction, the probe displays very fast response rate to phosgene.

INTRODUCTION

Phosgene is a kind of colorless gas capable of causing life-threatening lungs and pulmonary complications. During World War I, phosgene was used as the highly lethal chemical warfare agent (CWA) and led to nearly 80% of the poison gas deaths.1,2 Phosgene displays an odor recognition threshold of 1.0 ppm,3 which is far higher than the safety margin, ∼0.6 ppb, that general population subject to a 24-hour-a-day exposure may be exposed.4 It is particularly noteworthy that patient after the inhalation of phosgene, except with extremely high doses, typically undergoes a symptom-free latent phase up to 48 h before the collection of phosgene in the lung provokes the life-threatening complications.5,6 Such toxicological feature and high odor recognition threshold make phosgene barely perceivable when it is inhaled. It is also noted that unlike other lethal nerve agents such as sarin, soman, and tabun that are extremely strictly controlled and regulated,7 phosgene is extensively used as a chemical intermediate in the industrial field.6,8 In light of its strong lethality and large-scale industrial use, phosgene virtually poses a serious threat to the public health and safety, either as a potential agent for chemical terrorist attack or the risk of unexpected release in industrial accidents. Thus, practical strategy for facile and rapid detection of phosgene with concentration below the safety margin is of great significance for protecting public health and safety from injury of phosgene. Fluorescence analysis possesses advantages in terms of sensitivity, spatiotemporal resolution, and simplicity for manipulation over other strategies.9-12 Several representative types


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of phosgene fluorescent probe have been developed in recent years with limit of detection spanning over the range of nanomolar to micromolar levels.13-16 Despite some innovations, the development of fluorescent probes with optimized performance in terms of sensitivity, response rate and selectivity still remains a challenge. Ultimately, stimuli-response fluorescence analysis demands larger fluorescence contrast to detect and monitor trace amount of analyte, higher rate of recgnition reaction to achieve rapid response, and higher recognition specificity to achieve excellent detection selectivity. The toxicity of phosgene mainly originates from its highly reactive electrophilicity in acylation reactions with nucleophilic moieties such as amino (–NH2), hydroxyl (-OH), and sulfhydryl (-SH) groups.17,18 Most systems developed to date for monitoring phosgene or organophosphorus (OP) nerve agents fulfilled their function based on such specific reactivity that generates contrast in outcoming signals such as fluorescence,13-16 absorbance,19 and conductivity.20 It has been demonstrated that phosgene and some OP nerve agents are capable of mediating double acidylation reactions that leads to hetero-dimerization13 or intramolecular cyclization of probes,14-16,21,22 which generates fluorescence contrast and therefore provides the basis for detection of phosgene or nerve agents. Thus, the response rate and sensitivity of phosgene probe based on such mechanism critically rely on the rate of phosgenemediated acidylation reactions and the fluorescence signal contrast between the probe and the reaction product, respectively. The challenge to construct phosgene fluorescent probe with improved performance therefore shifts focus to optimizing recognition moiety capable of expediting the phosgene-mediated acidylation reactions and fluorophores for providing augmented fluorescence contrast upon reactions with phosgene. With this in mind, in this work we developed a new type of BODIPY-based fluorescent probe for phosgene detecting with limit of detection down to ∼0.12 nM, response time less than 1.5 seconds and high selectivity over


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other similarly reactive toxic chemicals such as acryl chlorides and OP nerve agent mimics. To the best of our knowledge, this is the first demonstration of a fluorescent probe capable of detecting subnanomolar-concentration level phosgene with response time at time scale in seconds (Table 1 in ESI), which provides practical strategy for rapid detection of trace amount of phosgene in specific events.

Scheme 1 Chemical structures of the phosgene probe (8-EDAB), the reference compound (8EAB) for control study, analogues with aryl (thionyl) chloride moieties, diethyl chlorophosphate, acetic anhydride used as interfering substances, and schematic illustration of proposed mechanism responsible for detecting phosgene. To illustrate vision comparison, photographs of 8-EDAB/CH3CN solution in quartz cuvette before and after addition of triphosgene were acquired via 365-nm light illumination.


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RESULTS AND DISCUSSION Optical response of 8-EDAB to phosgene

Fig. 1 Evolution of UV-vis absorption (a) and emission spectra (b and c) of 8-EDAB/ CH3CN (10 µM) solution in the presence of Et3N (80 nM) upon gradual addition of triphosgene. Each spectrum was acquired 1 min. after the addition of triphosgene. Inset in (a) and (b): photographs of 8-EDAB/CH3CN solution before and after addition of triphosgene under room light (a) and UV light (b) illumination. (d) A plot of the fluorescence intensity (at 512 nm) as a function of triphosgene concentration-each data point was obtained based on the measurements of five parallel samples under identical condition. The red line is a linear fit to the experimental data (R2 = 0.998). It is known that phosgene is volatile and highly toxic while its precursor triphosgene is nonvolatile, less toxic and easier to manipulate.13,16,22-24 In addition, triphosgene decomposes into


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phosgene in the presence of strong nucleophiles such as tertiary amines.13,14,24 Taking this, triphosgene was used for generation of phosgene with the assistance of triethylamine (Et3N) and the optimum dosage of Et3N, ∼1.3% of the amount of triphosgene, was determined in this work. (Figure S2 in ESI). Fig. 1 displays the UV-vis absorption and fluorescence emission spectra of 8EDAB/CH3CN sample in the absence and presence of triphosgene with various concentrations. It can be seen that the 8-EDAB sample in the presence of Et3N was nearly colorless and displayed intense absorption band in the region of 350-425 nm with λmax ∼392 nm. Addition of small aliquots of triphosgene to the sample clearly induced appearance of a new band in the visible region with λmax ∼471 nm, which continued to increase at the expense of the band in the UV region upon further incremental addition of triphosgene. Upon 390-nm excitation, the 8EDAB/CH3CN sample emitted weak blue fluorescence in the region of 400-515 nm with λmax ∼445 nm and a quantum yield of 0.15. Upon incremental addition of triphosgene, a new emission band in the green region of 475-625 nm with λmax ∼512 nm emerged and became gradual predominance at the expense of the blue emission band. Upon addition of 0.60 equiv. of triphosgene, this green fluorescence intensity reached a plateau and generated a quantum yield of 0.65 accompanying with the disappearance of the blue band. Fig. 1c displays the evolution of fluorescence spectra acquired upon 465-nm excitation. This excitation wavelength is far away from the absorption region of 8-EDAB but very close to the absorption peak of the reaction product (∼471 nm), which is expected to generate larger contrast and higher sensitivity to triphosgene. Specifically, addition of 0.6 equiv. of triphosgene dramatically generated the fluorescence (at 512 nm) on/off conversion ratio with a factor of more than 23300. Fig. 1d displays a plot of the fluorescence intensity (at 512 nm) of the probe sample against the concentration of triphosgene ranging from 0 to 3.2 µM and the corresponding linear fit (R2 =


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0.998) to the experimental data. From such fit of the titration data, the detection limit of 8-EDAB for triphosgene is determined to be ∼0.04 nM, equivalent to ∼0.12 nM of phosgene. Such limit of detection is far lower than the counterpart results described to date in terms of detection of phosgene.13-16,19,20 For instance, the detection limit of ∼0.04 nM for triphosgene that 8-EDAB enabled is 500 times lower than the value in terms of triphosgene fluorescence detecting reported very recently.16 Additionally, such detection limit of 0.12 nM is about 40 times lower than the safety margin of phosgene that the general population may be exposed.4

Fig. 2 Fluorescence intensity at 512 nm evolution of the sample containing 8-EDAB (10 µM) and Et3N (80 nM) before and after the addition of triphosgene (0.60 equiv.) reveals the response rate of 8-EDAB to phosgene (λex = 465 nm). The response time of 8-EDAB to triphosgene was determined based on evaluation of five parallel samples under identical experimental condition. Response rate of 8-EDAB to phosgene. Another important parameter of an ideal probe for detecting toxic substance is its response rate. Fig. 2 displays the time-lapsed fluorescence intensity of 8-EDAB/CH3CN sample, in the presence of Et3N, before and after the addition of triphosgene. It can be clearly seen that upon


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addition of triphosgene, the emission intensity promptly increased and reached a plateau within 1.5 seconds, dramatically generating very strong fluorescence contrast. It is noted that takes time to fulfill the Et3N-triggered release of phosgene from triphosgene.24 Thus, 8-EDAB is expected to present a faster response rate for directly detecting phosgene than that in detecting triphosgene. Such rapid response of 8-EDAB to phosgene, together with the superhigh sensitivity that it displays, makes 8-EDAB a very encouraging candidate for monitoring phosgene in practical applications.

Fig. 3 Fluorescence responses of probe-adsorbed TLC plates upon exposure to gaseous phosgene with concentration of 0.5 ppm (~2.2 µg/L phosgene gas). Photographs of a TLC plate with one end dipped in 8-EDAB/CH3CN solution and then dried in the air (Sample 1) and those of a plate patterned with “ABCD” logo using 8-EDAB/ CH3CN solution and then dried in the air (Sample 2) were acquired before and after exposure to gaseous phosgene. Response feature of 8-EDAB to gaseous phosgene. In addition to the aforementioned ability of 8-EDAB probe for monitoring the solid phosgene precursor, triphosgene, in solution environment, the response feature of 8-EDAB to gaseous phosgene was also evaluated via investigating the fluorescence change of two representative kinds of 8-EDAB-loaded sample upon exposure to gaseous phosgene. Specifically,


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one end of a TLC plate was dipped in 8-EDAB/CH3CN solution and then dried in the air. Such plate was firstly imaged under illumination of room light and 365-nm UV light, respectively, and then put in a conical flask loaded with phosgene vapor with concentration of 0.5 ppm. One minute after the exposure of the plate to gaseous phosgene, photographs of the plate were acquired under illumination of room light and 365-nm UV light, respectively. Following the similar procedure, the counterpart photographs of the TLC plate with the probe-based pattern of “ABCD” were also acquired. It can be clearly seen from Fig. 3 that the 8-EDAB-loaded plates after exposure to phosgene gas displayed sharp contrast in fluorescence color as compared to the plates prior to exposure to phosgene. It deserves mentioning that the gas concentration of phosgene in abovementioned experiments was 0.5 ppm (~2.2 µg/L phosgene gas), which is more than 360-fold lower than the inferior limit of concentration described to date in terms of detection of gaseous phosgene14,25 and 50-fold sensitive than the “harmless” level that human response to acute phosgene exposure (~25 ppm/min).26 Additionally, the application of Haber’s Law (constant toxic effect = concentration x duration of exposure) indicates the exposure level of 0.5 ppm per minute is equivalent to 0.346 ppb per 24hr4, which is below the ceiling level that general population subject to a 24-hour-a-day exposure may be exposed (0.6 ppb). Thus, the sensitivity that 8-EDAB probe displayed herein validated its ability for monitoring trace amount of phosgene gas in specific events. Recognition selectivity of 8-EDAB to phosgene. To gauge the recognition specificity of 8-EDAB to phosgene, the fluorescence response of 8-EDAB/CH3CN sample to other similarly reactive toxic chemicals (interfering substances) such as acryl chlorides and OP nerve agent mimics were acquired. Among triphosgene and a series of interfering substances, triphosgene and sulfuryl chloride (SC) induced obvious red-shift of the


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absorption band while other interfering substances did not exert noticeable influence on the absorption spectra of the sample (Fig. 4a). The fluorescence excitation spectra of 8EDAB/CH3CN in the presence of phosgene and SC, respectively, were found highly consistent

Fig. 4. UV-vis absorption (a) and fluorescence emission (b) spectra of the 8-EDAB/CH3CN solution sample (10 µM), in the presence of triphosgene (0.60 equiv.) and reference reagents (20 equiv.). (c) Comparison of the fluorescence intensity (at 512nm) of the solution sample in the presence of triphosgene and reference reagents. λex = 465 nm. Each spectrum was recorded 1 min after the addition of triphosgene and reference reagents.


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with the counterpart absorption spectra illustrated in Fig. 4a (Figure S3 in ESI). These results indicated the formation of single reaction product from the phosgene-mediated reaction with phosgene and SC, respectively. As shown in Fig. 4b, fluorescence emission of the 8-EDAB probe upon addition of various interfering substances with identical concentration (20 equiv.) nearly kept unchanged or slightly affected as compared to the free 8-EDAB sample. Specifically, albeit displaying appreciable absorption at 465nm as compared to the cases of other interfering substances, the SC reaction product merely emitted faint fluorescence with PLQY of ~0.003 upon 465-nm excitation. In sharp contrast, the addition of triphosgene with much low concentration (0.6 equiv.) dramatically generated the fluorescence (at 512 nm) on/off conversion ratio with a factor of more than 23300, indicating a high selectivity of the 8-EDAB for detecting phosgene over other similarly reactive toxic reagents.

Fig. 5 Comparison between the UV-vis absorption (a) and fluorescence emission (b) spectra of 8-EDAB and the reference compound 8-EAB in the absence and presence of triphosgene. λex = 390 nm. Each spectrum was recorded 1 min after the addition of triphosgene. Response mechanism of 8-EDAB to phosgene. To gain a deeper insight into the underlying mechanism that 8-EDAB underwent, an 8amino BODIPY derivative with molecular structure closely similar to 8-EDAB but without the primary amine moiety was synthesized and its response features to triphosgene were investigated.


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Unlike 8-EDAB, the reference compound 8-EAB does not possess a primary aliphatic amine moiety that generally possesses higher nucleophilicity as compared to that of the secondary aliphatic amine. Thus, phosgene-mediated nucleophilic substitution reaction with the primary aliphatic amine, which is capable of generating highly active intermediate to trigger the subsequent intramolecular cyclization reaction, was not likely occur in the case of 8-EAB. As a result, reaction product with extended delocalization feature similar to that in the case of 8EDAB were not expected in the case of 8-EAB. As shown in Fig. 5a, the addition of triphosgene did not induce noticeable bathochromic shift in the absorption band of 8-EAB, which is in sharp contrast to the counterpart result in the case of 8-EDAB. Fig. 5b displays the comparison between the fluorescence response features of the 8-EAB and 8-EDAB samples to triphosgene. In contrast to the triphosgene-induced emergence of an intense green emission band at the expense of the blue emission band of 8-EDAB sample, the fluorescence emission spectrum of 8EAB sample upon addition of triphosgene nearly kept unchanged as compared to that of the solution sample in the absence of triphosgene. These results clearly suggest that unlike 8-EDAB, 8-EAB did not undergo reactions with phosgene to generate highly fluorescent product due to the absence of crucial recognition moiety.

H


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Fig. 6 Partial 1H NMR (600 MHz) spectral changes of 8-EDAB probe in CD3CN in the absence and presence of triphosgene at 25 ℃. The comparative analysis of the 1H NMR measurement results of 8-EDAB and the reaction product confirmed the molecular structure of the latter and presented a clue to the underlying mechanism that 8-EDAB underwent. As shown in Fig. 6, the free 8-EDAB probe in CD3CN solvent displays six nonequivalent pyrrole hydrogen signals (Ha-Hf) in the range of 6.4 -7.7 ppm and two proton signals at 3.75 (Hg) and 3.1 ppm (Hh), respectively, which can be assigned to the methylene hydrogen of ethylenediamine moiety. Upon phosgene-mediated formation of the cyclized compound, the proton signals of the methylene hydrogen were found downfield shifted to δ 4.34 and δ 3.58, respectively. Such marked downfield chemical shift is attributable to a deshielding effect that the carbonyl group in the 2-imidazolidinone unit exerted. Specifically, the strong electron-withdrawing ability of the carbonyl group facilitated the removal of electron density of the amine moieties and therefore led to the observed downfield chemical shift of the proximal methylene hydrogens. For the 8-amino BODIPY derivatives, it has been demonstrated that the N-lone electron pair can be delocalized over the π-system of the BODIPY core due to the strong electron-releasing nature of amine moiety. Specifically, such electron-delocalization gives rise to a rearrangement of the chromophoric π-system of the BODIPY core and therefore the resonance between a cyanine structure and a hemicyanine one.27-30 In terms of 1H NMR spectra, such resonant feature of 8-amino BODIPY derivatives typically generates nonequivalent proton signals as that observed in the case of free 8-EDAB molecule.29,30 Upon the formation of the reaction product with N-lone electron pair sequestrated in the 2-imidazolidinone unit, the abovementioned electron-delocalization that enables cyanine-hemicyanine resonance was inhibited. Consequently, such removal of resonance effect imparts the pyrrolic proton with


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equivalent signal features and three pyrrole H peaks in 1H NMR were eventually observed. Additionally, all the pyrrole hydrogen signals (Ha’-Hf’) in the reaction product displays obvious downfield chemical shift, which is also an evidence of the abovementioned deshielding effect that the carbonyl group in the 2-imidazolidinone unit exerted. The picosecond time-resolved fluorescence measurement provided further information regarding the phosgene-mediated formation of reaction product with photophysical feature significantly different from that of the 8-EDAB probe (Figure S4 in ESI). Specifically, the transient fluorescence decay curves of 8-EDAB probe acquired at 445 nm and 512 nm, respectively, presented identical average fluorescence lifetime of 110 ps. In sharp contrast, the decay curve of 8-EDAB in the presence of triphosgene acquired at 512 nm yielded a lifetime up to 5.74 ns while the curve acquired at 445 nm presented a lifetime of 3.91 ns. Such remarkably prolonged fluorescence lifetime of the reaction product provided further support for the proposed mechanism, namely the phosgene-mediated nucleophilic reaction attenuated the electrondonating ability of amine moiety and therefore inhibited the ICT process from the amine moiety to the BODIPY core and the radiationless deactivation channels of the excited components. Specifically, such inhibition effect on the nonradiative process enabled the relaxation of more excited-state species to ground state via photon emission and therefore contributed to the prolonged fluorescence lifetime.31,32 Owing to their salient photophysical and photochemical properties, BODIPY dyes have been widely used for construction of various fluorescent probes.33-36 Specifically, BODIPY dyes are characterized with the tunability of spectral characteristics upon small modification to their structures.37-40 It has been demonstrated that introducing electron-donating groups at the “sensitive” 8-position of BODIPY dyes leads to energy increase of the LUMO state because of


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their high electronic density at that position, which is responsible for the absorption spectrum shift towards higher energy with respect to that of the unsubstituted BODIPY dyes.41 For the reaction product, in contrast to that in free 8-EDAB, electron pair localizing at the amine moiety was sequestrated and its electron-donating ability was therefore attenuated. Such change virtually enabled the relaxation of the 8-position electron density of BODIPY and the stabilization of its LUMO orbital, which consequently brought about energy decrease of the LUMO state and the optical band gap.41 As a result, a large bathochromic shift of the absorption band of 8-EDAB upon reaction with phosgene, from ∼392 nm to ∼471 nm, was observed. Such large shift of the absorption band virtually spectrally separated the reaction product from the free 8-EDAB and therefore provides feasibility of generating high fluorescence contrast by optimizing excitation wavelength. In addition to the separation in absorption band, conversion from 8-EDAB to the reaction product generated a remarkable enhancement in the fluorescing ability. Specifically, the 8-position of BODIPY core is highly sensitive to the electronic nature of the substituent in terms of fluorescence emission maxima and quantum yield.29 For 8-EDAB, the strong electrondonating character of 8-position amine moiety is capable of entailing radiationless deactivation channels of the excited species via the ICT mechanism and therefore decreasing the fluorescing ability of BODIPY dyes.41 Upon formation of the reaction product carrying amine moiety with attenuated electron-releasing ability, the optical band gap decreased and the ICT processes were efficiently inhibited. Owing to the highly sensitive fluorescence features of 8-substituted BODIPY dye to the electronic nature of the substituent at 8-position, such change in the electronic state led to red-shifted fluorescence emission and significantly inhibited radiationless deactivation channels. As a result, more excited-state species underwent relaxation to ground state via a radiative manner, which contributed to the significantly improved fluorescing


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efficiency. Benefiting from the optimal excitation wavelength propitious to pump the reaction product while adverse to pump 8-EDAB and the significantly enhanced fluorescence yield, tremendous fluorescence signal contrast upon reaction with phosgene was eventually observed. Among a broad spectrum of nucleophiles involved in nucleophilic reactions, amines generally display the fastest reaction kinetics under identical condition due to their stronger nucleophilicity than their counterparts such as alcohol, phenol, and mercaptan.42 Additionally, for aliphatic amines and aromatic ones involved in nucleophilic substitution reactions, the more basic the amine (the higher pKa), the stronger its nucleophilicity and the more reactive it is as a nucleophile. Specifically, the pKa values for ethylenediamine and o-phenylenediamine are 9.92 and 4.63, respectively,43,44 indicating the former is capable of presenting higher rate of nucleophilic reaction with phosgene than the latter. Additionally, for ring-closure reactions via intramolecular nucleophilic substitution mechanism, it has been demonstrated that fivemembered nitrogen heterocycles are formed substantially faster than three-, four-, or sixmembered rings under identical conditions, which is likely a result of the balance of the entropy terms and the enthalpy ones.45,46 Thus, the relatively high reactivity of ethylenediamine in the nucleophilic substitution reactions and cyclization rate of ring-closure reactions jointly contributes to the faster response rate of 8-EDAB for phosgene detecting as compared to the previously reported results.16, 21 Conclusions In conclusion, we have developed a new kind of BODIPY-based phosgene probe with rapid response rate and sensitivity markedly outperforming the counterpart fluorescent probes reported to date. It is believed that the probe underwent phosgene-mediated nucleophilic substitution reaction and the subsequent intramolecular cyclization process, which yielded conversion from


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weak blue fluorescence to strong vivid green fluorescence and therefore tremendous fluorescence contrast for phosgene detection. This proposed mechanism was supported by UVVis absorption spectroscopy, steady-state and transient fluorescence spectroscopy, NMR and mass spectrum characterization results. It was demonstrated that the 8-amine BODIPY component with fluorescence highly sensitive to the electronic nature of 8-position substituent mainly contributed to the unprecedented sensitivity and the strong reactivity of ethylenediamine moiety in the phosgene-mediated nucleophilic substitution reaction was responsible for the rapid response rate of the probe. The unprecedented sensitivity, rapid response rate and the high recognition selectivity that the 8-EDAB probe displayed are unequivocally of vital importance for promptly detecting highly toxic phosgene characterized with toxicological property of “latent phase”, which votes such probe as a potential candidate for rapid and reliable detection of phosgene in practical applications. Acetonitrile was used as the medium in this work for the optimal detection sensitivity and response rate and our effort pursuing probe-loaded substrate with nontoxicity and merit of portability for facile detection of trace amount of phosgene gas is ongoing. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publication website. General information, synthesis of 8-EDAB probe and reference compound 8-EAB, general procedure for the spectral measurement, determination the fluorescence quantum yields and the limit of detection (LOD), optimization of solvent and the concentration of Et3N, 1

H NMR,

-

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C NMR, and MALDI-MS characterization results of 8-EDAB, 8-EAB, and the

reaction product obtained from the reaction of 8-EDAB with triphosgene.


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AUTHOR INFORMATION Corresponding Author *Email: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT Financial support from the National Natural Science Foundation of China (grant no. 21373218 and 21573234) the Instrument Developing Project of the Chinese Academy of Sciences (Grant YZ201455) are acknowledged. REFERENCES (1) Winternitz, M. C. Pathology of War Gas Poisoning. New Haven, CT: Yale University Press, 1920, 33-66. (2) Prentiss, A. M. Chemicals in War, 1st ed. New York: McGraw-Hill, 1937, 216-217. (3) Leonardos, G.; Kendall, D.; Barnard, N. Odor Threshold Determinations of 53 Odorant Chemicals. J. Air Pollut. Control Assoc. 1969, 19, 91-95. (4) Cucinell, S. A.; Arsenal, E. Review of the Toxicity of Long-Term Phosgene Exposure. Arch. Environ. Health 1974, 28, 272-275.


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