Metal-Organic Framework Modified Glass Substrate for Analysis of

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Metal-Organic Framework Modified Glass Substrate for Analysis of Highly Volatile Chemical Warfare Agents by Paper Spray Mass Spectrometry Elizabeth S Dhummakupt, Daniel Carmany, Phillip M Mach, Trenton M Tovar, Ann M. Ploskonka, Paul S Demond, Jared B. DeCoste, and Trevor Glaros ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b19232 • Publication Date (Web): 07 Feb 2018 Downloaded from http://pubs.acs.org on February 8, 2018

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ACS Applied Materials & Interfaces

Metal-Organic Framework Modified Glass Substrate for Analysis of Highly Volatile Chemical Warfare Agents by Paper Spray Mass Spectrometry Elizabeth S. Dhummakupt†, Daniel O. Carmany‡, Phillip M. Mach‡, Trenton M. Tovar†, Ann M. Ploskonkaǁ, Paul S. Demond‡, Jared B. DeCoste† and Trevor Glaros†,* †

Research and Technology Directorate, US Army Edgewood Chemical Biological Center (ECBC), Aberdeen Proving Ground, MD 21010, USA ‡ Excet, Inc. 6225 Brandon Ave, Suite 360, Springfield, VA 22150, USA ǁ Leidos, Inc. PO Box 68, Edgewood Chemical Biological Center (ECBC), Aberdeen Proving Ground, MD 21010, USA

KEYWORDS: mass spectrometry, metal-organic frameworks, volatile chemistry, paper spray, chemical warfare agents

ABSTRACT Paper spray mass spectrometry (PS-MS) has been shown to successfully analyze chemical warfare agent (CWA) simulants. However, due to the volatility differences between the simulants and real G-series (i.e. sarin, soman) CWAs, analysis from an untreated paper substrate proved difficult. In order to extend the analytical lifetime of these G-agents, metalorganic frameworks (MOFs) were successfully integrated onto the paper spray substratesto increase adsorption and desorption. In this study, several MOFs and nanoparticles were tested to extend the analytical lifetime of sarin, soman, and cyclosarin on paper spray substrates. It was found that the addition of either UiO-66 or HKUST-1 to the paper substrate increased the analytical lifetime of the G-agents from less than five minutes detectability to at least 50 minutes.

INTRODUCTION Recent world events, such as the Ghouta1 and Khan Shaykhun2 chemical attacks in Syria, have emphasized the need for more rapid and sensitive detection of chemical warfare agents (CWAs). Current fielded/onsite detection methods for nerve agents (i.e. sarin, soman, tabun) include three color detector (TCD) paper, the residual vapor detection (RVD) kit, the water poison detection kit (WPDK), and sorbent tubes for gas chromatography mass spectrometry (GC-MS) analysis.3 However, each of these methods have disadvantages including low specificity, inability to detect all warfare agents, false positives, and long chromatographic analysis times.4, 5

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Paper spray (PS) is a substrate based ambient ionization technique for mass analysis.6 This method requires little to no sample preparation, with the analyte directly sampled from the substrate while being rapidly (≈1 min) analyzed by MS. Previously, paper spray has been used to analyze bacteria7, herbicides8, drugs of abuse9, 10, and explosives11, in addition to CWA simulants in biological matrices12 and aerosol samples.13 However, due to the volatility of Gagents14, 15, particularly sarin (GB), analysis from a sorbent-less capture method is difficult. Since the initial concept of paper spray ionization, a variety of modified papers have been created and tested for a wide range of applications. Narayanan et al. developed carbon nanotube (CNT) coated paper that allowed successful paper spray ionization with low (>3 V) voltages.16 This CNT coated paper was then used to directly analyze in-gel proteins.17 More recently, Damon et al. has increased the hydrophobicity of the paper substrate through treatment with silanes.18 This treatment was recently used in our laboratory to monitor enzyme activity. A recent publication by Wang et al. has demonstrated that zirconium (Zr)-based metalorganic frameworks (MOFs) can be integrated onto paper spray substrates for increased adsorption and desorption.19 Results from this study showed UiO-66 (Zr-based MOF) treated paper demonstrated increased absorbance of drugs in complex matrices, like blood. MOFs are modular materials consisting of inorganic metal nodes, known as secondary building units (SBUs), connected together by multidentate organic linkers in a predictable crystalline manner.20,21 Many of these structures have void spaces leading to large internal surface areas and pore volumes. MOFs have applications in gas storage22, 23 and 24,21,25,26,27,28,29 30, 31, 32 separations , catalysis , sensing33,34, and toxic gas removal.35,36 The amount of analyte adsorbed at a given set of conditions is dictated by the density of sites for the analyte to interact with and the energy of the intermolecular forces between the analyte and the active site. Farha and co-workers have shown that the Zr-based MOFs, including the UiO (University of Oslo) series, NU-1000, and PCN-222 are able to catalytically hydrolyze nerve agent simulant methyl paraoxon, as well as soman (GD) in solution.37,38,39 Due to the volatility of the G-agents, MOFs with pore sizes similar to that of the G-agents and with a proven track record of insolution G-series agent absorption37, 38, 40,41 were selected for these experiments. Utilizing MOFs to potentially aid in the retention of select G-agents, in this study we modified the typical paper substrate with a variety of MOFs, including UiO-66, UiO-67, and HKUST-1 (Hong Kong University of Science and Technology), as shown in Figure 1, as well as titania (TiO2) and zirconium hydroxide (Zr(OH)4). The paper spray material is impregnated with the desired adsorbent in preparation for exposure to small quantities of G-series agent. Subsequent analysis of the adsorbent-CWA interaction via paper spray MS explored the proclivity of the MOF to retain the CWA for an extended period of time. Ultimately, this technique extends the amount of time an operator has before analysis, preserving sample for forensic analysis of CWA exposure. This methodology has impacts on both direct analysis of environmental samples in contaminated areas and being utilized in an atmospheric capture device13 for other volatile chemistries of interest. Ultimately, several surface additives were shown to extend the analytical lifetime of GB, GD, and GF on paper spray substrates for chromatography-less rapid analysis of chemical warfare agents. Experimental Chemicals and Materials


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Optima-grade high-performance liquid chromatography (HPLC) solutions of methanol, isopropanol (IPA), and water were purchased from Thermo Fisher Scientific (Waltham, MA, USA). Borosilicate glass fiber A/E filters in 25 mm diameter were purchased from Pall Corporation (Port Washington, NY, USA). Paper spray cartridges containing ET31 chromatography paper (Whatman plc, Maidstone, U.K.) were purchased from Prosolia (Indianapolis, IN, USA). MacroSpin columns with TARGA C18 silica particles were purchased from The Nest Group, Inc (Southborough, MA, USA). HKUST-1 and methyl-paraoxon (MPO) were purchased from Sigma-Aldrich (St. Louis, MO, USA), Titania (TiO2) anatase nanoparticles were purchased from Nanostructured & Amorphous Materials Inc. (Houston, TX, USA) and zirconium hydroxide (Zr(OH)4) was purchased from MEL Chemicals (Middlesex, NJ, USA). UiO66 and UiO-67 were synthesized by methods detailed previously in the literature.42,43 Sample Preparation Chemical nerve agents at greater than 95% purity were diluted from a ≈1 mg mL-1 in IPA stock to 10 µg mL-1 working solution. The working solution contained 10 µg mL-1 of all of the following: GB, GD, GF, and MPO in IPA. CAUTION: Experiments using GB, GD, and GF should be run by trained personnel using appropriate safety procedures only! Substrate Preparation The die-cut glass fiber filters were treated with MOFs based upon previously described method44. Briefly, a 100 mg of each MOF material was weighed out along with 100 mg of cornstarch as an adhesive agent, and the mixture was dispersed in 5 mL of water. The slurry was vortexed before each aliquot was taken. A 100 µL aliquot was spotted onto a previously cut glass fiber filter and allowed to dry for at least 12 hours at ambient temperature. Once dry, treated glass cartridges were stored in a box at ambient temperature. The same treatment was done for TiO2 and Zr(OH)4. Borosilicate glass fiber tickets and paper tickets were treated with cornstarch only for control purposes. Paper Spray Ionization & Mass Spectrometer Data Acquisition A home-built paper spray ionization housing that was fitted to a Thermo Fisher Nanospray Flex Ionization source was used in this study, along with the PS cartridges available from Prosolia, Inc. For the time course, a 10 µL aliquot of mixed CWA and internal standard was pipetted onto the PS substrate. The spray solvent was 95/5 methanol/water with 0.01% formic acid. A total of 80 µL of spray solvent was aliquoted onto the PS substrate – approximately 10 µL at the front of the substrate and 70 µL at the rear. MS analysis for the paper spray samples was performed using a Thermo Fisher Scientific Orbitrap Elite mass spectrometer. The temperature of the MS capillary inlet was set to 325°C, and the tube lens voltage was set at 60 V. The MS method run time was 1.3 minute, broken down into 3 time segments with varying spray voltages: 0–1.0 min, +5 kV; 1.0-1.15 min, 0 kV; and 1.15-1.30 min, -4.5 kV. Tandem mass spectra were recorded using collision-induced dissociation (CID). The sodiated [M+Na]+ precursor ions and sodiated [M+Na]+ primary fragment ions observed for the G-series chemical warfare agents were as follows: GB (m/z 163.03 120.98) at CE 28 V, GD (m/z 205.08 120.98) at CE 28 V, and GF (m/z 203.06 120.98) at CE 31. The internal standard, MPO, was monitored at m/z 270.28. Powder X-ray Diffraction



Powder X-ray diffraction (XRD) measurements were taken of each material using a Rigaku Mini Flex 600 equipped with a DteX detector (Tokyo, Japan). Samples were scanned at 40 kV and 15 mA using Cu kα radiation (λ = 1.54 Å) at a scan rate of 5° min-1 over a 2θ range of 5 to 50°. Zero background discs were used to minimize background scatter. N2 Isotherms Nitrogen adsorption isotherms were measured for each activated adsorbent sample using a Micromeritics ASAP 2420 analyzer (Norcross, GA, USA) at 77 K. Prior to analysis, each sample was activated overnight at 150 °C under vacuum. Brunauer-Emmett-Teller (BET) modeling was performed to obtain the specific surface area (m2 g-1). The BET model was applied over the pressure range as described by Walton et al. to obtain physically meaningful parameters.45 The total pore volume was determined at a P/P0 = 0.99. Results and Discussion The high volatility of G-series chemical agents (Figure 2), especially GB, makes delayed analysis difficult, especially for extremely dilute samples, as desorption occurs rapidly.46 For this study, methyl paraoxon was chosen as the internal standard since it has a low vapor pressure (3.5x10-6 mm Hg47) but still shares many chemical similarities with the G-series nerve agents.48 GB, GD, and GF were first analyzed by paper spray ionization using commercially available paper spray cartridges containing Whatman ET1 chromatography paper. As shown in Figure 3, the product ion at m/z 120.98 for GB and GD were not detectable, even at the five minute time point. This five minute time point is the earliest time point that can be generated when spotting the agent under safety controls, walking to the instrument, placing the cartridge in front of the inlet and running the sample. GB and GD are volatile enough that analysis at this earliest time point does not produce a positive result; however, the control peak can be seen at these time points. GF’s vapor pressure is low enough that its product ion is still visible after 25 min. Work recently performed in our group demonstrated that a glass-based substrate showed improved performance for the capture and analysis of aerosolized G-series simulants.13 Unmodified fiber glass based substrates served as the initial starting point and as the material of choice for further additives, including the MOFs. As demonstrated in Figure 4, the analytical lifetime for GB and GD was increased to ten min, then the signal rapidly decreased until it was undetectable at 15 min. Unlike the paper substrate, GF was no longer detectable from the glass substrate beyond 15 min. Although, the analytical lifetime of GF was shortened, there was significant improvement over the paper for both GB and GD. In line with our previous work, efforts to passivate the glass surface were performed, but the analytical lifetime of the agents was not improved. The cornstarch-treated control tickets showed no signal difference from the untreated paper and glass substrates. Given the benefits of the glass substrate, a series of adsorbents were selected and used to modify the glass substrate to extend the analytical longevity of the G-agents. Each of these materials was characterized via PXRD to confirm their crystal structure (Figure 5) and nitrogen adsorption at 77 K to determine their BET surface area and pore volume (Figure 5 and Table 1). Each of the MOFs (HKUST-1, UiO-66, and UiO-67) was confirmed to have a crystal structure, before and after the addition of the cornstarch, and surface area that agreed well with the literature.49,50 The higher than theoretical surface area of UiO-66 and -67 indicates the presence of missing linker defects, which are common in the UiO series.51 TiO2 shows the


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known mixture the characteristic anatase (2Θ = 25.6°) crystal structure expected; however, this material has a much smaller surface area than the MOFs due to the nonporous nature of nanoparticles. Conversely, Zr(OH)4 exhibits an amorphous structure with a higher surface area than TiO2 indicative of its porous nature. Interestingly, Zr(OH)4 exhibits mesoporous behavior in the N2 isotherm, which can be seen in its total pore volume that is comparable to the MOFs. Table 1. BET surface areas and pore volumes calculated from the nitrogen isotherm for each of

Material HKUST-1 UiO-66 UiO-67 TiO2 Zr(OH)4 the materials studied.

BET Surface Area (m2 g-1) 1770 1380 1880 170 420

Pore Volume (cc g-1) 0.72 0.58 0.77 0.32 0.74

The results of the analysis of the different G-agents on the adsorbent modified glass substrates is shown in Figure 6. The independent variable is the amount of time the analyte intermixed on the modified substrate at ambient temperature before mass analysis, and the yaxis is the percent retention of the analyte. The percent retention is calculated using the ratio of the area under the curve of the G-series agent to the area under the curve of the internal standard, then normalizing this ratio to the ratio calculated at five minutes. As previously stated, analysis at the five minute mark is the earliest time point that is safely possible to obtain. As expected, each G-series agent in Figure 6 results in a decay of retention over time, indicating that the analytes slowly desorb off each of the materials. The addition of C18, TiO2, Zr(OH)4, and UiO-67 did not increase the amount of time these volatile G-agents remained onsubstrate, indicating that these materials may not have strong adsorptive interactions with the analytes either due to having pore sizes that were too large to readily retain the analyte or too small to absorb the analyte in the first place. It is also possible that the adsorption binding energies of these analytes with the material of interest was either too weak, so there were minimal attractive forces to retain the analyte, or they were too strong and could not be desorbed with the spray voltages used. The addition of the MOFs HKUST-1 and UiO-66 to the glass substrate was found to extend the analytical lifetime of each of the agents. For GB, approximately 10% of the signal is still detectable at 50 min post-application on the HKUST-1 glass substrate, while the UiO-66 glass substrate showed a faster decay to 20% of the signal at 20 min. Both of these results were a stark improvement over the only 10 min of detectable signal for GB on untreated glass. For GD, approximately 16% of the signal is detectable at 30 min post-spotting on a UiO-66 glass substrate, and 20% of the signal is still detectable at 60 min post-spotting (the last data point taken) on an HKUST-1 glass substrate. These results were also an improvement over the only 15 min of detectable signal for GD on untreated glass. Lastly for GF, approximately 35% of the signal is still detectable at 30 min post-spotting on a UiO-66 glass substrate, and 15% of the signal is still detectable at 60 min post-spotting (the last data point taken) on an HKUST-1 glass substrate. Again, these results were an improvement over the 15 min of detectable signal for GF.



Comparison of the three MOFs utilized allows for the assessment of two different SBUs, a Cu pillar paddle wheel as found in HKUST-1 and a 12-connected Zr6O6 in the UiO-66 and -67. Additionally, the relative pore diameters and window sizes can be evaluated when analyzing the UiO-66 and UiO-67 MOFs. This comparison is of particular interest as UiO-66 extended the retention time of the G-agents, while UiO-67 had minimal effects. In comparing UiO-66 to UiO67, it is important to note that the topology is the same with just the extension of the organic linker. This expands the triangular window from 10 to 13 Å in its largest dimension from one SBU to the opposite organic linker, and from 6 to 8 Å for organic linkers that are opposite from one another. While the differences in window size may seem minimal, it is important to note that they are very close to the sizes of GB (~7 Å), GD (~9 Å), and GF (~9 Å). It would be reasonable to conclude that diffusion through the pores of the MOFs would be slower in UiO-66 than UiO-67 due to these discrepancies. Interestingly, HKUST-1 has two kinds of pores. In order to access the larger cage, a window surrounded by four secondary building units and four organic linkers must be passed through. In this window, organic linkers opposite from one another are approximately 11 Å while the SBUs opposite one another are approximately 9 Å apart. However, the smaller cage is accessible through a triangular window comprised of three SBUs and three organic linkers. This triangular window is approximately 9 Å in its largest dimension from one SBU to the opposite organic linker, and 5 Å between organic linkers that are opposite from one another. This dichotomy of these two different cage structures could also be cause to limit the rate of diffusion through the MOF structure.

Interaction of the analyte with the SBU must also be considered. It has been shown by Plonka et al. that organophosphates chemisorb to the SBU of UiO and other zirconium MOFs.52 This type of interaction would potentially extend the analytic lifetime of the sample. While the most obvious explanation for the decay of signal over time on the MOFs would certainly be desorption of the analyte, it is important to note that zirconium based MOFs have been shown to hydrolyze the P-F bond of soman.38,40, 53 This would presumably be applicable to GB and GF as well. While these products were not included in the experimental parameters, they have much lower vapor pressures than the CWAs and would not be as readily volatilized for subsequent detection. Furthermore, they may be strongly adsorbed to the MOF SBU either via a phosphate linkage, or hydrogen bonding of the hydroxyl group.52 On the other hand, HKUST-1 has been shown to adsorb G-agents; however, the rate of hydrolysis is very slow as to not adversely affect the signal over time.41 HKUST-1 proved to have the best overall performance for the retention of the G-agents for PS-MS. This MOF is considered to be an ‘ultra-high porosity’ material54,20, and these porous frameworks have shown significant retention of gaseous mixtures.55,56,57 Additionally, stronger interactions with these frameworks occur with more polar analytes58, like the G-series chemical agents tested in this work. However, the main advantage over UiO-66 for detection is that the substrate is relatively inert toward the analytes of interest. UiO-66 also performed well as an on-substrate modifier and retained the volatile agents for up to 30 min. However, as UiO-66 has the ability to react the P-F bond of the G-agents, detection can get more complicated as the parent material of interest is not present.37 Conclusions


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Treating glass substrates with metal-organic frameworks, specifically HKUST-1 and UiO66, extends the analytical lifetime of volatile G-series chemical warfare agents from less than 15 min to 60 min and beyond. The high volatility of these chemicals, particularly GB, does not allow for successful analysis on traditional paper spray substrates (i.e. paper). The addition of the HKUST-1 MOF extends the analytical detectability of GB four-fold. This method is a presumptive test for G-agents, therefore quantitation is not necessary. The microporous nature of these MOFs maximizes analyte interactions with the internal MOF surfaces slowing down desorption of the G-agents examined here. While the ability to catalytically hydrolyze these CWAs with MOFs may be of interest, this work was focused on retention of volatile parent chemical species. However, quantitation of G-agents from direct substrate analysis should be explored, and further research needs to be done to trap or complex these volatile chemistries on substrates that allow for more robust paper spray based analysis. Corresponding Authors *T.G.: [email protected] Funding Sources Funding for this project was provided by the Defense Threat Reduction Agency–Joint Science and Technology Office for Chemical and Biological Defense to T.G. Acknowledgements The authors thank Samuel Pierce and Benjamin Hollingsworth for their support in completing this research during their summer internship program through the Army Education Outreach Program-College Qualified Leaders (AEOP-CQL). This research was performed while two of the authors (E.S.D. and T.M.T.) held NRC Research Fellowship Awards at The Edgewood Chemical Biological Center. Conclusions and opinions presented here are those of the authors and are not the official policy of the U.S. Army, ECBC or the U.S. Government. Information in this report is cleared for public release and distribution is unlimited.


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Figure 1. Crystal structures of UiO-66, UiO-67, and HKUST-1; H (white), C (grey), O (red), Zr (blue), and Cu (brown).


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Figure 2. Structures of sarin (GB), soman (GD), and cyclosarin (GF).



Figure 3. Tandem mass spectral analysis of (A) GB, (B) GD, and (C) GF time course on untreated paper. Any visible signals in panels A and B are background noise.


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Figure 4. Tandem mass spectral analysis of (A) GB, (B) GD, and (C) GF time course on untreated glass.



Figure 5. (A) Powder X-ray diffraction patterns and (B) nitrogen isotherms measured at 77K for HKUST-1, UiO-66, UiO-67, TiO2, and Zr(OH)4.


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Figure 6. Retention curves over time of GB (left), GD (center), and GF (right). Each data point is an average of four individual samples.



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