Sensitivity-Tunable Colorimetric Detection of Chloropicrin Vapor on

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Sensitivity-tunable Colorimetric Detection of Chloropicrin Vapor on Nylon-6 Nanofibrous Membrane Based on a Detoxification Reaction with Biological Thiols Peixin Tang, Ho Ting Leung, Maria Trinidad Gomez, and Gang Sun ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.8b00135 • Publication Date (Web): 28 Mar 2018 Downloaded from http://pubs.acs.org on March 28, 2018

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Sensitivity-tunable Colorimetric Detection of Chloropicrin Vapor on

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Nylon-6 Nanofibrous Membrane Based on a Detoxification Reaction with

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Biological Thiols Peixin Tang†, Ho Ting Leung‡, Maria Trinidad Gomez‡, Gang Sun†,*

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†

Division of Textiles and Clothing, University of California, Davis, CA 95616, USA

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‡

Department of Chemistry, University of California, Davis, CA 95616, USA

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Abstract

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Detoxification reaction of chloropicrin in the human body with biological thiols was selected

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for detection of chloropicrin in the air. The consumption of free sulfhydryl group in

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biological thiols by chloropicrin is colorimetrically detectable with the addition of the

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Ellman’s reagent. In this study, glutathione, N-acetyl-l-cysteine, l-homocysteine, cysteamine,

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and thioglycolic acid were tested as sensing agents for chloropicrin vapor detection in ppb

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concentration range. The reactivity of the selected biological thiols was investigated based on

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both their redox properties and the nucleophilic strength of the sulfhydryl groups. Nylon-6

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nanofibrous membrane and an organic solvent were used as a sensor matrix and a vapor

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sorbent, respectively, to provide solid supports with ultrahigh surface area and enhanced

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adsorption to chloropicrin vapor. The tunable sensitivity and detection range by using

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different biological thiols were achieved on the sensors due to the different reactivity of thiols

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towards chloropicrin.

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Keywords: Detoxification reaction, fumigants, biological thiols, colorimetric sensor,

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reactivity, Nylon-6 nanofibrous membrane

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* Corresponding author: Tel.: +1 530 752 0840; [email protected] (G. Sun).

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Fumigants are a group of toxic volatile chemicals that are widely used in agricultural

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production for controlling growth of soil-borne pests.1,2 The production of strawberries,

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potatoes, grapes and other crops is heavily dependent on the application of fumigants as

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pre-planting pesticides in California, USA.1 Although fumigants are highly efficient in pests

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control, the extreme toxicity of the fumigants poses a health threat to farm workers and local 1

ACS Paragon Plus Environment

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residents.2 Chloropicrin is one of the fumigants that is commonly used as a replacement of

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methyl bromide1, and is also mixed with other odorless fumigants as a warning agent. It was

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famous as a warfare agent during World War I because of its neurotoxicity.3 The

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over-exposure of chloropicrin could cause human serious health consequences including

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respiratory irritation, nerve system damage, and cancer.2,3 Therefore, the US Occupational

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Safety and Health Administration (OSHA) strictly regulates the permissible exposure limit

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(PEL) of eight-hour exposure of chloropicrin as 100 ppb.4 Moreover, the California

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Department of Pesticide Regulation (DPR) requires the respirator-use concentration threshold

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of chloropicrin as 150 ppb.5 Violations of the regulations could lead to strict punishments.6

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On the other side, easy and accurate detection of fumigants in the environment is extremely

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important to dramatically improve protections of people from unwanted-exposure to the

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fumigants.7

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Traditionally, gas chromatography is used for the detection of fumigants including

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chloropicrin in the environment.8,9 Other techniques like quartz crystal micro/nano

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balances,10,11 laser-based photoacoustic spectroscopy,12 surface enhanced Raman scattering13

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and electronic sensors/biosensors14,15,16 have been applied and designed for the detection of

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different fumigants and pesticides. Although these sophisticated instruments provide precise

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and accurate detection results with very low detection limits, the processes are time- and

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labor-consuming and hard to be used by farm workers and residents on sites. Therefore,

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development of sensors with the features of easy-to-use, portable and ultrasensitive is

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indispensable. In the past decades, colorimetric sensors have attracted attentions from

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researchers for the detections of toxic compounds like heavy metals,17,18,19 volatile organic

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compounds,20,21 and pesticides

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show a color change, which is visible to naked eyes after the exposure to target compounds.

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Very high concentration of chloropicrin vapor (920‒1570 mg/m3) can be detected through a

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colorimetric method based on quantification of nitrite ions, resulted from decomposition of

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chloropicrin 25. Commercial chloropicrin detector tubes (SensidyneTM, FL, USA) are suitable

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for the detection of chloropicrin in the concentration range of 0.05‒16 ppm. However, the

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operation of the tubes relies on a gas pump for gas sampling 26. Another colorimetric sensor

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in the environment. The desired sensor system will

2


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system for chloropicrin has been developed based on leucomethylene blue, which can be

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oxidized by chloropicrin to show a blue color.23 However, the sensitivity of the sensor was

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only able to reach to 1 ppm.

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Biological thiols like glutathione (GSH) and N-acetyl-l-cysteine (NAC) can react with

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chloropicrin, and the reaction is fast and quantative.3 The detoxification and metabolism of

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chloropicrin in living systems are reported as a dechlorination reaction by reacting with

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GSH.4,27 Thus, biological thiols could be potential efficient and unique reagents for

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chloropicrin detection.

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According to the reaction of biological thiols and chloropicrin, we designed a novel

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sensitivity-tunable colorimetric sensor for detection of chloropicrin vapor. The thiol reactivity,

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more specifically the nucleophilic property, was studied and analyzed based on experimental

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and computational results, which provided a guide to predict their detection sensitivity. The

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optimal sensing agent was expected to present an “unambiguous” detection sensitivity to

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naked-eyes with a detection limit which is lower than the PEL of chloropicrin. The reaction

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rate between the thiols and chloropicrin in the liquid phase was monitored with UV-vis

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spectrophotometer. Nylon-6 nanofibrous membrane was employed as a solid support matrix,

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and N,N-dimethylformamide was selected as a sorbent for chloropicrin. The color changes on

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tested sensors were measured based on RGB color system with a mobile application in a

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smartphone.28,29

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Materials and methods

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Chemicals

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Reduced glutathione (GSH), N-acetyl-l-cysteine (NAC), cysteamine (CA), monobasic

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sodium phosphate monohydrate (MSP), sodium hydroxide, and N, N-dimethylformamide

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(DMF) were purchased from Fischer Scientific Co. (New Jersey, USA). L-homocysteine

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(HCYS) and thioglycolic acid (TGA) were purchased from Biosynth International Inc. (Itasca,

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IL, USA) and TCI America (Portland, OR, USA), respectively. Chloropicrin (1000 µg/mL in

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methanol) was bought from SPEX CertiPrepTM (New Jersey, USA). Ellman’s reagent

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(5,5'-dithiobis-(2-nitrobenzoic acid) or DTNB) was purchased from Thermo Fisher Scientific

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Co. (Waltham, MA, USA). Ethylenediaminetetraacetic acid disodium salt dihydrate (EDTA) 3


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and formic acid were bought from Sigma-Aldrich (St. Louis, MO, USA). Nylon-6 polymer

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pellet was purchased from ACROS Organics (New Jersey, USA). All the chemicals were used

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as received.

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Fabrication and SEM imaging of nylon-6 nanofibrous membrane

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Nylon-6 nanofibrous membrane was fabricated based on a method available in a literature.30

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Specifically, nylon-6 polymer pellets were dissolved in formic acid (15 wt%) and stirred

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vigorously for 24 hours at room temperature. The polymer solution was then transferred into

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four syringes capped with metallic needles. The solution was fed with a controllable rate of

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0.15 mL/h with assistance of a syringe pump (Kent Scientific). A high voltage of 30 kV was

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applied to four needle tips that are connected in series to generate a continuous jetting stream.

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The resulting nylon-6 nanofibrous membranes were loaded on a grounded metallic roller

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covered with waxed paper with a tip-to-collector distance of 15 cm. The nanofibrous

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membrane was directly peeled out from the waxed paper and used as a sensor matrix.

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The morphology and fiber sizes of the fabricated nylon-6 nanofibrous membrane were

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monitored with a scanning electron microscope (SEM) (FEI/Philips XL30 FEG-SEM,

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Oregon, USA). The membrane was attached to a carbon tape and coated with gold before

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SEM imaging.

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Vapor sensor setup

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Nylon-6 nanofibrous membrane was cut into a circular shape (radius=3.0 mm). Different

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thiols were dissolved in monobasic sodium phosphate (MSP) aqueous buffer (0.1 M MSP, 1

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mM EDTA). The pH of the buffer was adjusted with 10 M NaOH. Each sensor was wet with

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10 µL DMF and 7.5 µL thiol solution (1.0 mM) before putting into a 2.6 L gas chamber. Then,

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a specific volume of chloropicrin solution was directly injected into the gas chamber with a

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Hamilton gas-tight syringe (Reno, NV, USA). The amounts of injected chloropicrin solution

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were calculated based on the intended molar concentration (ppm) of chloropicrin to air in the

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gas chamber, and the results are shown Table S1. The chamber was well sealed, and the

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sensor was exposed to different concentrations of chloropicrin for 15 min. After that, the

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Ellman’s reagent (5,5'-dithiobis-(2-nitrobenzoic acid) or DTNB) (4 mg/mL in MSP buffer,

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pH=8.0) was dropped onto the sensor to visually detect the residual sulfhydryl groups in the 4


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thiols by showing different intensities of a yellow color. Chloropicrin is a highly volatile

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toxic compound, so all the sensing procedures were run in a fume hood. The yellow color and

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corresponding color changes shown up on the paper sensors are visible to naked eyes. The

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deeper the color on the tested sensor stands for the lower concentration of chloropicrin vapor.

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The color on tested sensors was monitored with a commercially available smartphone

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application called ColorAssist (FTLapps, Inc.) to standardize the color reading process. The

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color on the sensors was detected and reproduced into three color channels, which are red,

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green, and blue (RGB) for intensity evaluation and chloropicrin quantification by the

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program. RGB values ranging from 0 to 255 were measured with ColorAssist through a

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camera on an iPhone 7 Plus (Apple Inc.). A homemade scanning box with dimensions of

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37×32×20 cm was used to control the light condition during the color measurements. Two

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LEDs were fixed in the box to provide a constant intensity of white light. All the sensors were

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scanned twice to get an average number of R, G, and B values. The detection sensitivity was

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calculated through Eq. 1. The sensor setups are shown in Scheme 1.

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Sensitivity on sensor matrix

100%

(Eq. 1)

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Where B0 and Bi are RGB values in the blue color channel (B value) that scanned by a

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smartphone with ColorAssist. The RGB values are integral numbers ranging from 0 to 255.

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Scheme 1. Paper-based sensor setup and detection procedures.

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UV-vis spectroscopy

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The sulfhydryl groups in biological thiols can break the disulfide bond in the Ellman’s

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reagent (DTNB) and release a yellow ion (TNB2‒) in aqueous solution for the colorimetric

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detection of the reaction. The color in the liquid system was measured on an Evolution 600 5


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UV-vis spectrophotometer (Thermo Scientific, New Jersey, USA) to obtain UV-vis

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absorption spectra in a wavelength range of 400 nm‒500 nm. A calibration curve of different

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concentrations of thiols is shown in supporting information in Figure S1. The residual

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concentrations of the thiols were quantified with the assistance of DTNB through a

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calibration method on the UV-vis spectrophotometer at λmax=412 nm.31,32 The reaction

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sensitivity in the liquid phase was calculated according to Eq. 2.

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Sensitivity in liquid phase

" " "

100%

(Eq. 2)

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Where C0 and Ci are the concentrations of biological thiols in the liquid system without and

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with the injection of chloropicrin after incubation, respectively.

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Computational method

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Electrostatic potentials of biological thiols and electron charges on atoms were calculated

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based on the structure optimization that performed using Gaussian 09 program based on

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density functional theory (DFT) with B3LYP/6-31G (d, p) basis set. The calculations were

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performed in water system.

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Measurement of reduction potentials

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Reduction potentials of biological thiols under different pH conditions were measured with a

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dual channel pH & potential meter (Accumet XL600, NJ, USA) according to a standard

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measurement available in literature

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diluted with an MSP buffer from stock solutions of specific thiols (5.0 mM). The final

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concentration of each thiol solution was finally determined with a UV-vis spectrophotometer

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following the method discussed below. The Ag/AgCl (saturated KCl) potential electrode was

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standardized with a 200 mV±5 mV redox buffer (Aqua Solution Inc., TX, USA). The

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standard reduction potentials of each thiol solution were read at different pH values at 25 °C,

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and then the real reduction potentials of the thiols were calculated based on Eq. 3 33.

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. Two different concentrations of thiol solutions were

E0 thiol = E0 standard + E0 Ag/AgCl

(Eq. 3)

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Measurements and calculations of ‒SH/‒S- concentrations

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The thiol solutions for liquid phase reaction with chloropicrin were prepared by adding 250

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µL of 0.25 mM thiol solutions into 2.5 mL MSP buffer with specific pH. The molar ratio

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between the thiol and chloropicrin was controlled as 2:1 with 5 µL injection of chloropicrin 6


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(1000 µg/mL).

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The thiolate group intensity in GSH solution under different pH values were measured

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with UV-vis spectrophotometer since the thiolate group in GSH shows an absorbance at λmax

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= 235 nm 34. The tested solutions were prepared by adding 250 µL of 1.0 mM GSH into 2.5

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mL MSP buffers which pH varies from 7.0 to 9.5.

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The relative concentration of sulfhydryl group (‒SH) and thiolate group (‒S‒) were calculated through the Handerson-Hasselbach equation that shown in Eq (4) 35,36 [() ]

pH pKa + log [+(]

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(Eq. 4)

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Results and discussions

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Detoxification reaction of chloropicrin with biological thiols

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For the development of a sensor system which is highly sensitive to very diluted but toxic

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concentration of chloropicrin (ppb range), selection of a detection reaction needs to meet

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three criteria: 1) the detection reaction of chloropicrin should be ultra-sensitive and unique; 2)

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the reaction can trigger a color change with or without additional color probes; and 3) the

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sensing agents are non-toxic during the detection. The toxicity of chloropicrin drives a fast

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oxidation reaction of reduced biological thiols in mammalian bodies.3 The redox reaction

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results in an inactivation of free sulfhydryl groups (‒SH) in thiols, which can be

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colorimetrically detected with the Ellman’s reagent. Consequently, all three requirements can

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be achieved by using the detoxification reaction of chloropicrin with the biological thiols as a

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detection reaction since the biological thiols are derived from the living systems.

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The reactions of chloropicrin with glutathione (GSH), N-acetyl-l-cysteine (NAC),

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l-homocysteine (HCYS), cysteamine (CA) and thioglycolic acid (TGA) were performed at a

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physiological pH (pH=7.4). The inactivation amount of ‒SH groups in the biological thiols

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and the chemical structures of the thiols are presented in Figure 1 (b) and 1 (c), respectively.

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Clearly, the acute toxicity of chloropicrin makes the reaction with the thiols extremely fast

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with over 50% of the thiols inactivated within 10 min, except for TGA (Figure 1b). Different

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biological thiols in an original concentration of 0.25 mM show varied reactivity towards

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chloropicrin. The consumption (inactivation) of ‒SH groups in CA system reached to 72%,

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while that of ‒SH group in TGA was only 31% (Figure 1b). The reaction rate between the 7


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thiols and chloropicrin will highly affect the response time and the detection sensitivity of the

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sensor. Therefore, the factors that potentially alter the reactivity of the thiols towards

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chloropicrin will be discussed in detail.

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The reported reaction mechanism of chloropicrin with biological thiols is a redox

200

reaction,4,27 so the reduction potential (RP) of the thiols may affect their reactivity towards

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chloropicrin. As shown in Figure 1 (a), the reaction results in an oxidation of thiols (RSH) to

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disulfides (RSSR) and a dehalogenation of chloropicrin to dichloronitromethane, which can

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be expressed as a combination of two half-cell reactions (Scheme 2). From the equation

204

shown in Scheme 2, the smaller the RP of the anode reaction, the more spontaneous the redox

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reaction since it leads to a more negative number of the Gibbs free energy change of the

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whole reaction. The measured RPs of 0.25 mM thiols under physiological pH (pH=7.4) at 25

207

0

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is expected to increase with the decreasing of RPs as NAC < GSH < TGA < HCYS < CA.

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Unfortunately, the tested results are not fully consistent with the order of the measured RPs

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(Figure 1b). For instance, the inactivation of ‒SH groups in TGA is much lower than that of

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GSH, however, its RP at pH=7.4 is 223 mV lower than that of GSH. Such a fact makes us

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believe that there might be other factors more critical in controlling the reaction rate between

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thiols and chloropicrin.

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C are shown in Figure 1 (b). CA has the lowest RP of ‒40 mV, and the reactivity of the thiols

Cathode: Chloropicrin + 2e + H 0 → Dichloronitromethane + Cl Anode: RSSR + 2e + 2H 0 → RSH + RSH

: 3"456789

: 3(=789

Overall: Chloropicrin + 2RSH → Dichloronitromethane + RSSR + HCl

: 3"9??

: : : 3"9?? 3"456789 − 3(=789 : ∆B −CD3"9??

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Scheme 2. Half-cell equations of redox reaction between chloropicrin and biological thiols. : : : Where 3"456789 , 3(=789 and 3"9?? are the standard reduction potential of the reactions in cathode, anode and the whole cell, respectively. ∆B is the Gibbs free energy change of the reaction; n refers to the number of electron that transferred in the reaction; F stands for Faraday constant.

8


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Figure 1. (a) Reaction mechanism of biological thiols with chloropicrin. (b) Reaction results of biological thiols (250 µL of 0.25 mM thiols in 2.5 mL MSP buffer) with 5 µL chloropicrin (1000 µg/mL). The molar ratio is controlled as thiol:chloropicrin = 2:1) at the physiological pH (pH=7.4) with 10 min incubation time. (c) Chemical structures of biological thiols.

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The existence of three chlorines and one nitro group on chloropicrin structure makes the

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central carbon in chloropicrin electron deficient and electrophilic, which becomes a good

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reaction site for nucleophiles. The ‒SH group is one of the active “soft” nucleophiles that

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exists in the biological systems.37 As presented in Figure 1 (a), the reaction mechanism

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between the thiols and chloropicrin can be proposed as a two-step reaction. Firstly, ‒SH

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group in the thiols attacks the carbon in chloropicrin as a nucleophile to form an intermediate

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which can be called as a thiol-chloropicrin (TCP) conjugate, then the second ‒SH group

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attacks the S atom on the conjugate, which is also electron deficient, to complete the whole

235

reaction. The reaction of thiols with chloropicrin can be treated as a two-step nucleophilic

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substitution reaction. It seems that the nucleophilicity of the ‒SH is the crucial factor for the

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determination of the whole reaction rate. A series of tests were performed in the liquid phase

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to evaluate the reactivity of thiols and to optimize the conditions for chloropicrin detection.

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The generations of the disulfide bonds from the thiols reacting with chloropicrin were

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demonstrated through

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disulfides with the incubation of chloropicrin, shown in supporting information in Figure S2.

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The effect of thiol dissociation

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Since the first step of the detection reaction is a nucleophilic attack process, the

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nucleophilicity of the ‒SH group is important for evaluating the reaction rate of the first step

13

C NMR. All the thiols can be completely or partially converted to

9


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to consequently analyze the reactivity of the thiols towards chloropicrin. As we all know that

246

the negatively charged group is a better nucleophile than its neutral form, i.e. the thiolate

247

group (‒S‒) is a stronger nucleophile to attack the electrophilic chloropicrin than the neutral ‒

248

SH group in thiols.34 The effect of thiolate concentration on the reaction rate between thiols

249

and chloropicrin was first analyzed by varying the reaction pH. The results are shown in

250

Figure 2 (a). Obviously, the dissociation of ‒SH group to ‒S‒ group by increasing the pH

251

highly improved the consumption of the thiols (Figure 2a). The inactivation of ‒SH groups in

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the thiol systems is dramatically improved by around 30% with a pH increment from 7.0 to

253

8.5. At slightly basic condition (pH=8.5), over 50% of the thiols can be inactivated by

254

chloropicrin within 5 min (Figure 2a).

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GSH was selected as a model compound to monitor the variation of thiolate

256

concentration according to pH change, and the results are shown in Figure 2 (b). With

257

increasing the pH of GSH solution from 7.0 to 9.5, the absorbance intensity at λmax=235 nm

258

increased from 0.012 to 0.227 (Figure 1b). Therefore, it is concluded that the reaction rate

259

between the thiols and chloropicrin increased with increasing the pH since more thiolate

260

groups, a better nucleophile, were generated. The dissociation degree of ‒SH in thiols is

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related to their pKa values of the ‒SH groups. The literature reported pKa values of the

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selected thiols are listed in Table 1. The ‒SH group in CA is reported to have the lowest pKa

263

values (pKa=8.35) compared with other thiols, and the ‒SH group in TGA barely dissociates

264

when the pH increased from 7.0 to 8.5 since its pKa is as high as 9.93 (Table 1). Meanwhile,

265

the changes of ‒SH and ‒S‒ concentrations in percentage according to pH can be calculated

266

through Eq. 4, and the results are plotted in Figure 3. When the pH of the reaction is 7.5,

267

12.38% of ‒SH dissociates into ‒S‒ in CA, which is 5.3, 15.7, 3.0, and 206.3 times higher

268

than that of GSH (2.34%), NAC (0.79%), HCYS (4.09%), and TGA (0.06%), respectively.

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Under this condition, the consumption of ‒SH groups in GSH, NAC, HCYS, CA, and TGA

270

by chloropicrin reaches to 50.81%, 47.24%, 59.15%, 60.24%, and 18.95%, respectively

271

(Figure 2a). With further increase in the pH, the concentrations of thiolate group in different

272

thiols keep increasing with the acceleration of thiol consumptions (Figure 3a). Based on the

273

listed pKa values and the calculated ionic concentrations, the reactivity of the thiols at a 10


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constant pH (in a pH range of 7.0–9.0) should follow the order of CA > HCYS > GSH >

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NAC > TGA, which agrees with the tested results (Figure 1b and Figure 2a). Consequently,

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we proposed that the dissociation degree of ‒SH group dominates the reaction rate between

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the thiols and chloropicrin since the nucleophilicity of the thiolate is higher than that of

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sulfhydryl group. The nucleophilic strength difference between ‒SH and ‒S‒ groups needs

279

further evidence and analysis to support our hypothesis.

280 281 282 283 284 285 286

Figure 2. (a) Reaction results between thiols and chloropicrin according to different pH values (reaction time: 5 min). (b) Absorbance intensity of thiolate group in GSH under different pH values. The inserted graph shows the UV-vis spectrum of GSH solution with different pH values. (c) Reaction results between thiols and chloropicrin under specific pH conditions. The incubation time was 5 min. The solution preparation procedures are shown in Materials and Methods section.

287 288 289

Figure 3. Ionic concentration of (a) thiolate group (‒S‒) and (b) sulfhydryl group (‒SH) under varied pH conditions.

290

Table 1. pKa values of sulfhydryl groups in biological thiols. 11


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Thiol-containing biomolecules Glutathione (GSH) N-acetyl-l-cysteine (NAC) l-Homocysteine (HCYS) Cysteamine (CA) Thioglycolic acid (TGA)

Page 12 of 25

pKa 9.12 9.60 8.87 8.35 9.93

Reference 38 39 40 40 39

291

The effect of electron density on functional atoms

292

The nucleophilic attack of the thiol on chloropicrin occurs in both steps of the reactions

293

(Figure 1a). Both –SH and thiolate groups are nucleophiles, their differences in nucleophilic

294

strength were further analyzed with computational calculations. The electron density of the

295

sulfur atom in different ‒SH/‒S‒ groups are calculated with Gaussian 09, and the results are

296

shown in Figure 4. The color variations from blue to red illustrate the enhancement of

297

electron density. The deeper the red color (smaller the values) on ‒SH/‒S‒ groups represents

298

the more electrons around the atom and the higher the possibility for electron donation in

299

nucleophilic attack process.41 There is no doubt that the electron density of a sulfur atom

300

dramatically increased when the ‒SH group dissociates to a thiolate group (‒S‒). The

301

negative charge on sulfur generally increased by 0.7 units when the neutral -SH group is

302

dissociated into the ‒S‒ group (Figure 4). The electron cloud around the sulfur in different

303

thiols shows an obvious color change from yellow to deep red. These results visually reveal

304

the increment of the nucleophilic strength of the thiols when the neutral compounds

305

dissociated into negatively charged thiolates, representing increased reactivity towards

306

chloropicrin if the ‒S‒groups become dominated in the reaction system (Figure 2a).

307

According to Eq. 4 and the pKa values of the thiols (Table 2), 10.0% of the thiolate

308

group can be generated in GSH, NAC, HYCS, CA, and TGA system under the pH of 8.17,

309

8.65, 7.92, 7.40, and 9.75, respectively, but the consumption rates of the thiols are still

310

different (Figure 2c). The chemical structures of the thiols could affect the electron density of

311

the sulfur atoms. As we can see from Figure 4 (c), the amino group in CA, which is an

312

electron-donation group, pushes electrons to the direction of ‒SH group, resulting in a denser

313

electron density on either ‒SH or ‒S‒ groups. However, the presence of a carboxylic group,

314

an electron-withdrawing group in TGA structure, reduces the electron density on sulfur atom

315

(Figure 4e). The electron density on ‒SH and ‒S‒ in CA is 0.076 and 0.088 units higher than 12


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that of TGA, which explains their reactivity difference, even though the concentration ratio of

317

‒SH/‒S‒ groups in these two systems are comparable. The inactivation of CA reached to

318

70.08%, nevertheless, the inactivated TGA was only 56.57% (Figure 2c). Moreover, the

319

electron density of ‒SH/‒S‒ groups in GSH, NAC, and HCYS are similar (Figure 4), which

320

resulted in a comparable inactivation of thiols (around 60.0%) when the thiolate

321

concentration was controlled at 10.0% (Figure 2c).

322

The electron density on S atoms in the thiol-chloropicrin (TCP) conjugates is another

323

factor affecting the reaction rate, especially for the rate of the first step nucleophilic

324

substitution process. The optimized TCP structures are shown in Table 2. The electronic

325

charges of S and C atoms in the TCP structures, indicated by the black arrow in the Table 2,

326

were calculated based on geometry optimizations of the TCPs. The calculated electron

327

densities on S and C atoms are listed in Table 2 as well. The sulfur atoms in the TCP

328

structures are more electron deficient and electrophilic, becoming a reaction site for the thiols.

329

Clearly, the S atoms show positive charges, whereas the C atoms in the chloropicrin fragment

330

are electron sufficient (Table 2). Theoretically, the reaction rate can be accelerated when the S

331

atom in the TCP structure is more electrophilic. Nevertheless, the results shown in Figure 2 (c)

332

demonstrate that the electron densities of S atoms are not crucial to the reaction rate. The

333

reactivity of the thiols towards chloropicrin were not significantly affected by the differences

334

of the electron density on the S atoms in TCP structures.

335

Overall, the reactivity of the thiols is controlled not only by the dissociation degree of ‒

336

SH groups, but also by the electron density on ‒SH/‒S‒ groups, which is determined by the

337

chemical structures of the thiols. The electrophilic site of the TCP affects the formation of

338

RS-SR, and this step reaction is not rate determining.

13


ACS Sensors 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 25

339 340 341 342

Figure 4. Electron density of ‒SH/‒S‒ groups of different biological thiols. Table 2. Optimized chemical structures and electronic charges of C and S atoms of TCP conjugates GSH-S-CP NAC-S-CP HCYS-S-CP CA-S-CP TGA-S-CP

C S

-0.277 0.261

-0.277 0.278

-0.271 0.236

-0.251 0.223

-0.259 0.272

343

The effect of reduction potential

344

The overall reaction between chloropicrin and the biothiols is a redox reaction, so the

345

reduction potential (RP) values of the selected thiols were measured under varied pH

346

conditions and thiol concentrations. The results are shown in Figure 5. Obviously, the RP

347

values of the selected thiols present a decreasing trend with increasing pH, which is

348

consistent with the Nernst equation shown in Eq. 5. To compare the RPs of the selected thiols,

349

all the thiol solutions were kept in a same concentration so the second term in Eq. 5 is a

350

constant, which can simplify the analysis using the Nernst equation. Thus, the RP values of

351

these thiols would only be affected by pH, in a relationship of a negative slope. The measured

352

RP values of the thiols with two concentrations of 1.00 mM and 0.25 mM are shown in

353

Figure 5 (a) and 5 (b), respectively, which present an order of CA < HCYS < TGA < GSH ≈

354

NAC under a pH range of 6.5–10.5, and the order keeps the same in both thiol concentrations

355

(Figure 5). More specifically, CA possesses the highest reactivity to be oxidized by

356

chloropicrin since its lowest RP, which further decreased from ‒59 mV to ‒185 mV when the

357

pH increases from neutral to pH=10.5 at concentration of 1.00 mM (Figure 5a). Because the 14


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358

RPs of GSH and NAC are almost the same, the reactivity difference of these two thiols

359

should be similar due to the little difference on the nucleophilic strength of ‒SH/‒S‒ groups

360

discussed in the previous section.

36 3: −

361

:.:FGH =

J"KL JMKN

log IJ(KO JKP Q −

:.:FGH6 =

RS

Eq. (5)

362

Where Eh is the reduction potential, E0 is the standard reduction potential, n is the number of

363

electrons involved in the reaction, {A}, {B}, {C}, {D} are the concentrations of reactants and

364

products, a, b, c, and d are the stoichiometric coefficients of the reaction; h is a constant for

365

each compound.42

366

Interestingly, the measured RPs of GSH never reach to the potentials of CA over the

367

whole pH range, although the reaction result of GSH with chloropicrin at pH=8.50 is

368

comparable to that of CA with chloropicrin at pH=7.50. The consumed ‒SH groups of GSH

369

and CA were 64.07% and 60.24%, respectively (Figure 2a) when the concentration of the

370

thiols was controlled at 0.25 mM in all systems. Moreover, this phenomenon can also be

371

noticed when the concentration ratios of ‒SH/‒S‒ are comparable in NAC and HCYS systems.

372

The consumption of ‒SH/‒S‒ groups in NAC at pH=8.66 and in HCYS at pH=7.92 are 64.03%

373

and 64.39%, respectively, whereas, the RPs of NAC (268 mV) and HCYS (46 mV) differ by

374

222 mV at specific pH conditions (Figure 2c and Figure 5b). Therefore, the RP of the thiols

375

plays a less important role in determining the reaction rate between the thiols and

376

chloropicrin.

377

Thus, the nucleophilic strength of the thiol has been proven as a crucial factor for

378

accelerating the reaction rate of the thiols with chloropicrin, which provides a guidance of

379

selection of optimal thiol-containing compounds as potential sensing agents or synthesis of

380

novel sensing agents. Based on the overall analysis of the thiols, a proposed order of

381

reactivity is as following: CA > HCYS > GSH > NAC > TGA.

15


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382 383 384 385

Figure 5. Reduction potentials of biological thiols in two different concentrations (a) 1.00 mM, and (b) 0.25 mM at 25 °C. The solution preparations are shown in Materials and Methods section.

386

Detection of chloropicrin vapor

387

Since different thiols possess versatile reactivity towards chloropicrin, they can be used as

388

different sensing agents to colorimetrically detect chloropicrin vapor with tunable

389

sensitivities and detection limits. In other words, the sensor system can be designed by

390

selecting thiols for the detection of chloropicrin in different concentration ranges. Therefore,

391

a relationship between chloropicrin concentrations versus color intensity was explored in

392

different thiol systems. The sensor setup is shown in Scheme 1, and the color intensity was

393

evaluated with the RGB color system. The RGB values of tested sensors that scanned from

394

ColorAssist are present in Figure S3. Based on our previous studies and other successful

395

sensor designs,31,43,44 the application of specifically selected organic solvents and nanofibrous

396

membranes highly improves the detection sensitivity of toxic vapor by providing the

397

ultra-high surface area and enhanced chloropicrin vapor adsorption on the surfaces. More

398

interestingly, the “paper-based” design of the sensor, which was achieved by using a

399

nanofibrous membrane, could make the sensor portable and lab-instrument free. A nylon-6

400

nanofibrous membrane (N6NM) with a fiber diameter around 200 nm made by

401

electrospinning was chosen as a sensor matrix. The SEM images of the material are shown in

402

Figure 6 (a) and 6 (b). DMF was selected as an extra sorbent based on Hansen solubility 16


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403

parameter theory, due to its higher affinity to chloropicrin than that of water.30,45 The

404

application of DMF provides an enhanced attractive force to concentrate chloropicrin vapor

405

from the air to the sensor system, thereby accelerating the reaction rate and lowering the

406

detection limit. The Hansen solubility parameters of chloropicrin, water and DMF are listed

407

in Table S2. The color images and detection sensitivities of the tested sensors are shown in

408

Figure 6.

409

The chloropicrin detection results of the nanofibrous membrane sensors containing

410

different thiol systems were performed with concentration and pH of the thiol solutions

411

controlled as 1.0 mM and 8.0, and an exposure time of 15 min, and are shown in Figure 6 (c).

412

CA is not stable during the detection duration even exposing to ambient air, so CA cannot be

413

used for chloropicrin detection on the matrix. HCYS revealed the lowest detection limit of 55

414

ppb with a naked-eye distinguishable sensitivity of 35.32% (Figure 6c and 6d). The detection

415

limit in GSH, NAC and TGA systems were 110 ppb (sensitivity=36.64%), 550 ppb

416

(sensitivity = 36.94%), and 1.10 ppm (sensitivity = 33.73%), respectively, with a sensitivity

417

higher than 30%, which is defined as an “unambiguous” detection sensitivity to naked eyes.

418

The detection limits of different thiols are fully consistent with the reactivity order that

419

concluded in above discussion (HCYS > GSH > NAC > TGA). The color strip that shows

420

color intensity decrement in percentage can be found in supporting information in Figure S4.

421

Based on the versatile reactivity of the thiols with chloropicrin, the detection range of

422

chloropicrin concentration can be tuned from 2.7 ppm to 55 ppb, 3.8 ppm to 110 ppb, 2.7

423

ppm to 33 ppb, and 3.8 ppm to 275 ppb by using GSH, NAC, HCYS, and TGA as different

424

sensing agents, respectively (Figure 6c).

425

More importantly, the sensor system can be adjusted to detect threshold concentration of 5

426

chloropicrin (150 ppb)

427

HCYS and GSH. The fast response time of a sensor is essential to improve the personal

428

protection to fumigant applicators. The results of the shortest exposure time for 150 ppb

429

chloropicrin in both GSH and HCYS systems are shown in Figure 6 (e). Obviously, the

430

detection sensitivity of HCYS is much higher than that of GSH, with detection sensitivity

431

reaching to 44.24% with 5 min exposure. In GSH system, 20 min exposure achieved the

with the shortest response time by using more active thiols like

17


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432

“unambiguous” sensitivity of 43.64% for naked-eye detection.

433

The concentration of the thiols in the sensor system can also be controlled in order to

434

adjust the detection limit and sensitivity. HCYS was used as a model compound to study the

435

effect of the thiol concentration on the detection results and limit, and the color images are

436

shown in Figure 6 (g). When decreasing the thiol concentration from 1.00 mM to 0.25 mM,

437

the color intensity on the control group decreased, which can cause the loss of sensitivity to

438

some degree. For instance, the color intensity of 0.25 mM of HCYS on the sensor was barely

439

noticeable by naked eyes, and the detection sensitivity reached to 35.80% (Figure 6h).

440

However, when the HCYS concentration is 0.50 mM, trace amounts of chloropicrin in the air

441

lead to a color change from yellow to white, which is clearly visible to naked eyes compared

442

with the pale-yellow color of the control. Consequently, 55 ppb and 33 ppb of chloropicrin

443

can be visually detected in 1.00 mM and 0.50 mM HCYS systems with a detection sensitivity

444

of 33.88% and 31.00%, respectively (Figure 6h).

445 446 447 448 449 450 451

Figure 6 (a) and (b) SEM images of the nylon-6 nanofibrous membrane. (c) Color images of tested sensors with different thiols (1.00 mM) at pH=8.0. (d) The detection sensitivity of tested sensors in (c). (e) Color images of tested sensors according to varied exposure times. The chloropicrin concentration is 150 ppb. (f) The detection sensitivity of tested sensors in (e). (g) Color images of tested sensors with different concentrations of HCYS (pH=8.0, exposure time=10 min). (h) The detection sensitivity of tested sensors in (g). 18


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452

Conclusion

453

An ultra-sensitive paper-based colorimetric sensor for chloropicrin vapor has been prepared

454

based on the detoxification reaction of chloropicrin with biological thiols. The reactivity of

455

GSH, NAC, HCYS, CA, and TGA towards chloropicrin was discussed based on the reaction

456

mechanism. The reaction was found to be a two-step nucleophilic substitution process. The

457

nucleophilic strength of the thiols dominates their reactivity and detection sensitivity of

458

chloropicrin. The tunable detection limit and sensitivity were achieved in different thiol

459

systems. It was the first time that chloropicrin vapor can be detected on a paper-based

460

colorimetric sensor with a detection limit of 33 ppb and 55 ppb reading through a mobile

461

application and naked eyes, respectively. Moreover, 33 ppb of chloropicrin can also be

462

detected with naked eyes in 0.50 mM HCYS system with 10 min operation time. The shortest

463

time for 150 ppb chloropicrin detections were 20 min and 5 min in GSH and HCYS systems,

464

respectively.

465

Acknowledgement

466

This research is financially supported by California Department of Pesticide Regulations.

467 468

Supporting Information Available: The following file is available free of charge.

469

Supporting materials. Detailed information about fumigant vapor preparation, the calibration

470

curve of thiol/thiolate concentration, and reaction mechanism demonstration. Additional

471

information on the color scanning by using ColorAssist.

472

Reference

473

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