Altering Conformational States of Dynamic Ion Populations using Traveling Wave Structures for Lossless Ion Manipulations.

With its capacity to store and translate ions across considerable distances and times, traveling wave structures for lossless ion manipulations (TW-SLIM) provide the foundation to expand the scope of ion mobility spectrometry (IMS) experiments. While promising, the dynamic electric fields and consequential ion-neutral collisions used to realize extensive degrees of separation have a considerable impact on the empirical results and the fundamental interpretation of observed arrival time distributions. Using a custom-designed set of TW-SLIM boards (∼9 m) coupled with a time-of-flight mass spectrometer (SLIM-ToF), we detail the capacity to systematically alter the gas-phase distribution of select peptide conformers. In addition to discussing the role charge-transfer may play in TW-SLIM experiments that occur at extended time scales, the ability of the SLIM-ToF to perform tandem IMS was leveraged to confirm that both the compact and elongated conformers of bradykinin2+ undergo interconversion within the SLIM. Storage experiments in which ions are confined within SLIM using static potential wells suggest that factors aside from TW-induced ion motion contribute to interconversion. Further investigation into this matter suggests that the use of radio frequency (RF) fields to confine ions within SLIM may play a role in ion heating. Aside from interconversion, storage experiments also provide insight into charge transfer behavior over the course of extended periods. The results of the presented experiments suggest that considerations should be taken when analyzing labile species and inform strategies for the TW-SLIM design and method development.

Nonlinear Frequency Modulation for Fourier Transform Ion Mobility Mass Spectrometry Improves Experimental Efficiency.

Through optimization of terminal frequencies and effective sampling rates, we have developed nonlinear sawtooth-shaped frequency sweeps for efficient Fourier transform ion mobility mass spectrometry (FT-IM-MS) experiments. This is in contrast to conventional FT-IM-MS experiments where ion gates are modulated according to a linear frequency sweep. Linear frequency sweeps are effective but can be hindered by the amount of useful signal obtained using a single sweep over a large frequency range imposed by ion gating inefficiencies, particularly small ion packets, and gate depletion. These negative factors are direct consequences of the inherently low gate pulse widths of high-frequency ion gating events, placing an upper bound on FT-IM-MS performance. Here, we report alternative ion modulation strategies. Sawtooth frequency sweeps may be constructed for the purpose of either extending high-SNR transients or conducting efficient signal-averaging experiments for low-SNR transients. The data obtained using this approach show high-SNR signals for a set of low-mass tetraalkylammonium salts (<1000 m/z) where resolving powers in excess of 500 are achieved. Data for low-SNR obtained for multimeric protein complexes streptavidin (53 kDa) and GroEL (800 kDa) also reveal large increases in the signal-to-noise ratio for reconstructed arrival time distributions.

Ion-neutral clustering alters gas-phase hydrogen-deuterium exchange rates.

The rates and mechanisms of chemical reactions that occur at a phase boundary often differ considerably from chemical behavior in bulk solution, but remain difficult to quantify. Ion-neutral interactions are one such class of chemical reactions whose behavior during the nascent stages of solvation differs from bulk solution while occupying critical roles in aerosol formation, atmospheric chemistry, and gas-phase ion separations. Through a gas-phase ion separation technique utilizing a counter-current flow of deuterated vapor, we quantify the degree of hydrogen-deuterium exchange (HDX) and ion-neutral clustering on a series of model chemical systems (i.e. amino acids). By simultaneously quantifying the degree of vapor association and HDX, the effects of cluster formation on reaction kinetics are realized. These results imply that cluster formation cannot be ignored when modeling complex nucleation processes and biopolymer structural dynamics.

Evaluation of Hydrogen-Deuterium Exchange during Transient Vapor Binding of MeOD with Model Peptide Systems Angiotensin II and Bradykinin.

The advancement of hybrid mass spectrometric tools as an indirect probe of molecular structure and dynamics relies heavily upon a clear understanding between gas-phase ion reactivity and ion structural characteristics. This work provides new insights into gas-phase ion-neutral reactions of the model peptides (i.e., angiotensin II and bradykinin) on a per-residue basis by integrating hydrogen/deuterium exchange, ion mobility, tandem mass spectrometry, selective vapor binding, and molecular dynamics simulations. By comparing fragmentation patterns with simulated probabilities of vapor uptake, a clear link between gas-phase hydrogen/deuterium exchange and the probabilities of localized vapor association is established. The observed molecular dynamics trends related to the sites and duration of vapor binding track closely with experimental observation. Additionally, the influence of additional charges and structural characteristics on exchange kinetics and ion-neutral cluster formation is examined. These data provide a foundation for the analysis of solvation dynamics of larger, native-like conformations of proteins in the gas phase.

Condensable Vapor Sorption by Low Charge State Protein Ions.

Measurement of the gas-phase ion mobility of proteins provides a means to quantitatively assess the relative sizes of charged proteins. However, protein ion mobility measurements are typically singular values. Here, we apply tandem mobility analysis to low charge state protein ions (+1 and +2 ions) introduced into the gas phase by nanodroplet nebulization. We first determine protein ion mobilities in dry air and subsequently examine shifts in mobilities brought about by the clustering of vapor molecules. Tandem mobility analysis yields mobility-vapor concentration curves for each protein ion, expanding the information obtained from mobility analysis. This experimental procedure and analysis is extended to bovine serum albumin, transferrin, immunoglobulin G, and apoferritin with water, 1-butanol, and nonane. All protein ions appear to adsorb vapor molecules, with mobility "diameter" shifts of up to 6-7% at conditions just below vapor saturation. We parametrize results using κ-Köhler theory, where the term κ quantifies the extent of uptake beyond Köhler model expectations. For 1-butanol and nonane, κ decreases with increasing protein ion size, while it increases with increasing protein ion size for water. For the systems probed, the extent of mobility shift for the organic vapors is unaffected by the nebulized solution pH, while shifts with water are sensitive to pH.

Characterization of a Modulated X-ray Source for Ion Mobility Spectrometry.

As a highly deployed field instrument for the detection of narcotics, explosives, and chemical warfare agents, drift tube ion mobility spectrometry relies heavily upon the performance of the ionization source and mechanism of ion beam modulation. For this instrumental platform, ion chemistry plays a critical role in the performance of the instrument from a sensitivity and selectivity perspective; however, a range of instrumental components also occupy pivotal roles. Most notably, the mechanism of ion modulation or ion gating is a primary contributor to peak width in a drift tube ion mobility experiment. Unfortunately, physical ion gates rarely perform perfectly, and in addition to serving as physical impediments to ion transmission, their modulation also has undesirable field effects. Using a recently developed modulated, non-radioactive X-ray source, we detail the performance of an ion mobility spectrometry (IMS) system that is free of a gating structure and utilizes the pulsed nature of the modulated X-ray source (MXS) for both ion generation and initiation of the IMS experiment. After investigating the influence of pulse duration and spatial X-ray beam width on the analytical performance of the instrument, the possibility of using multiplexing with a shutterless system is explored. By increasing ion throughput, the observed multiplexing gain compared to a signal-averaged spectrum approaches the theoretical maximum and illustrates the capability of the MXS-IMS system to realize significant signal to noise improvements.

Separation and Collision Cross Section Measurements of Protein Complexes Afforded by a Modular Drift Tube Coupled to an Orbitrap Mass Spectrometer.

New developments in analytical technologies and biophysical methods have advanced the characterization of increasingly complex biomolecular assemblies using native mass spectrometry (MS). Ion mobility methods, in particular, have enabled a new dimension of structural information and analysis of proteins, allowing separation of conformations and providing size and shape insights based on collision cross sections (CCSs). Based on the concepts of absorption-mode Fourier transform (aFT) multiplexing ion mobility spectrometry (IMS), here, a modular drift tube design proves capable of separating native-like proteins up to 148 kDa with resolution up to 45. Coupled with high-resolution Orbitrap MS, binding of small ligands and cofactors can be resolved in the mass domain and correlated to changes in structural heterogeneity observed in the ion-neutral CCS distributions. We also demonstrate the ability to rapidly determine accurate CCSs for proteins with 1-min aFT-IMS-MS sweeps without the need for calibrants or correction factors.

Vaporized Cannabis Extracts Have Reinforcing Properties and Support Conditioned Drug-Seeking Behavior in Rats.

Recent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug used and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized Δ9-tetrahydrocannabinol-rich (CANTHC) or cannabidiol-rich (CANCBD) whole-plant cannabis extracts. Male Sprague-Dawley rats were trained to nose-poke for discrete puffs of CANTHC, CANCBD, or vehicle (VEH) in daily 1 h sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CANTHC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared with CANCBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CANTHC administration decreased hippocampal CB1 receptor binding. Removal of CANTHC reinforcement (but not CANCBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors.SIGNIFICANCE STATEMENT The evolving legal landscape concerning recreational cannabis use has increased urgency to better understand its effects on the brain and behavior. Animal models are advantageous in this respect; however, current approaches typically used forced injections of synthetic cannabinoids or isolated cannabis constituents that may not capture the complex effects of volitional cannabis consumption. We have developed a novel model of cannabis self-administration using response-contingent delivery of vaporized cannabis extracts containing high concentrations of Δ9 tetrahydrocannabinol (THC) or cannabidiol. Our data indicate that THC-rich cannabis vapor has reinforcing properties that support stable rates of responding and conditioned drug-seeking behavior. This approach will be valuable for interrogating effects of cannabis and delineating neural mechanisms that give rise to aberrant cannabis-seeking behavior.

Absorption Mode Fourier Transform Ion Mobility Mass Spectrometry Multiplexing Combined with Half-Window Apodization Windows Improves Resolution and Shortens Acquisition Times.

Fourier transform multiplexing enables the coupling of drift tube ion mobility to a wide array of mass spectrometers with improved ion utilization and duty cycles compared to dual-gate signal averaging methods. Traditionally, the data generated by this method is presented in the magnitude mode, but significant improvements in resolution and the signal-to-noise ratio (SNR) are expected if the data can be phase corrected and presented in the absorption mode. A method to simply and reliably determine and correct phase shifts in Fourier transform ion mobility mass spectrometry data using information readily available to any user is presented and evaluated for both small molecule and intact protein analyses with no modification to instrument hardware or experimental procedures. Additionally, the effects of apodization and zero padding are evaluated for both processing methods, and a strategy to use these techniques to reduce acquisition times is presented and evaluated. Resolution is improved by an average factor of 1.6, the SNR is improved by an average factor of 1.2, and acquisition times are reduced by up to 80% through the application of absorption mode processing combined with apodization and zero padding.

Masked Multiplexed Separations to Enhance Duty Cycle for Structures for Lossless Ion Manipulations.

The experimental paradigm of one ion packet release per spectrum severely hinders throughput in broadband ion mobility spectrometry (IMS) systems (e.g., drift tube and traveling wave systems). Ion trapping marginally mitigates this problem, but the duty cycle deficit is amplified when moving to high resolution, long pathlength systems. As a consequence, new multiplexing strategies that maximize throughput while preserving peak fidelity are essential for high-resolution IMS separations [e.g., structures for lossless ion manipulations (SLIMs) and multi-pass technologies]. Currently, broadly applicable deconvolution strategies for Hadamard-based ion multiplexing are limited to a narrow range of modulation sequences and do not fully maximize the ion signal generated during separation across an extended path length. Compared to prior Hadamard deconvolution errors that rely upon peak picking or discrete error classification, the masked deconvolution matrix technique exploits the knowledge that Hadamard transform artifacts are reflected about the central, primary signal [i.e., the true arrival time distribution (ATD)]. By randomly inducing mathematical artifacts, it is possible to identify spectral artifacts simply by their high degree of variability relative to the core ATD. It is important to note that the deweighting approach using the masked deconvolution matrix does not make any assumptions about the underlying transform and is applicable to any multiplexing strategy employing binary sequences. In addition to demonstrating a 100-fold increase in the total number of ions detected, the effective deconvolution of data from 5, 6, 7, and 8-bit pseudo-random sequences expands the utility and efficiency of the SLIM platform.

Non-contact detection of thiodiglycol vapors and associated degradation products using atmospheric flow tube mass spectrometry.

Thiodiglycol (TDG) is a synthetic precursor and an environmental degradation product of sulfur mustard (HD). Consequently, its presence can be indicative of illicit preparation or historical presence of chemical weapons, but its lower toxicity lends itself to use as an HD simulant for testing and method development. Detection of TDG vapor often proves elusive with existing techniques exhibiting undesirably high detection limits in the gas phase (>ppm). Moreover, traditional approaches to detecting TDG vapor rely upon non-specific approaches that do not provide the certainty afforded by mass spectrometry. Using atmospheric flow tube mass spectrometry (AFT-MS), which has previously demonstrated the capacity to detect parts-per-quadrillion levels of vapor, we evaluate the capacity of this approach for non-contact residue analysis based upon TDG vapor sampling and nitrate clustering chemistry. Furthermore, we discuss challenges with ambient vapor detection using the AFT-MS system and associated observations related to TDG degradation into 2,2'-sulfonyldiglycol from exposure to ambient conditions with vapor detection being possible even after 7-weeks of sample aging.

Assessing the Impact of Drift Gas Polarizability in Polyatomic Ion Mobility Experiments.

Due to the core assumptions of kinetic theory and the drive toward realizing reproducible gas-phase measurements, ion mobility experiments are commonly conducted in the presence of an inert, neat buffer gas, usually nitrogen or helium. Mixing drift gases in defined, static ratios can provide useful information not only for optimizing the separation of analytes but also for defining the interaction between the ion and neutral particle. In a foundational effort, we seek to validate the role of the drift gas polarizability on the observed mobility of the ions by systematically mixing drift gases to discretely access a range of bulk gas polarizabilities not given by pure drift gases. Compared to historical efforts to probe the role of polarizability on the ion-neutral collisional cross section where a linear relationship was assumed, the data collected in the present effort clearly illustrate a quadratic dependency of the ion-neutral particle collision cross section and polarizability (R2 > 0.999). When translating these data into the mobility dimension, we illustrate that the gas-phase mobility of polyatomic ions conforms to Blanc's law. These observations combined with considerations related to Langevin's polarization limit provide an experimental mechanism to estimate to what degree an ion-neutral interaction conforms to either the hard-sphere or induced-dipole model. To support these observations, additional comparisons are made with the respective reduced masses, polarizabilities, and mobilities of ions in mixtures where different degrees of hard-sphere interactions are present.

Recommendations for reporting ion mobility Mass Spectrometry measurements.

Here we present a guide to ion mobility mass spectrometry experiments, which covers both linear and nonlinear methods: what is measured, how the measurements are done, and how to report the results, including the uncertainties of mobility and collision cross section values. The guide aims to clarify some possibly confusing concepts, and the reporting recommendations should help researchers, authors and reviewers to contribute comprehensive reports, so that the ion mobility data can be reused more confidently. Starting from the concept of the definition of the measurand, we emphasize that (i) mobility values (K0 ) depend intrinsically on ion structure, the nature of the bath gas, temperature, and E/N; (ii) ion mobility does not measure molecular surfaces directly, but collision cross section (CCS) values are derived from mobility values using a physical model; (iii) methods relying on calibration are empirical (and thus may provide method-dependent results) only if the gas nature, temperature or E/N cannot match those of the primary method. Our analysis highlights the urgency of a community effort toward establishing primary standards and reference materials for ion mobility, and provides recommendations to do so. © 2019 The Authors. Mass Spectrometry Reviews Published by Wiley Periodicals, Inc.

Non-contact vapor detection of illicit drugs via atmospheric flow tube-mass spectrometry.

Real-time, non-contact detection of illicit drugs is a desirable goal for the interdiction of these controlled substances, but the relatively low vapor pressures of such species present a challenge for trace vapor detection technologies. The introduction of atmospheric flow tube-mass spectrometry (AFT-MS), which has previously been demonstrated to detect gas-phase analytes at low parts-per-quadrillion levels for explosives and organophosphorus compounds, also enables the potential for non-contact drug detection. With AFT-MS, direct vapor detection of cocaine and methamphetamine from ∼5 µg residues at room temperature is demonstrated herein. Furthermore, thermal desorption of low- to sub-picogram levels of cocaine, methamphetamine, fentanyl, and heroin is observed via AFT-MS using a carrier flow rate of several L min-1 of air. These low levels can permit non-contact sampling through collection of vapor, effectively preconcentrating the analyte before desorption and analysis. Quantitative evaluation of the thermal desorption approach has yielded limits of detection (LODs) on the order of 10 fg for cocaine and fentanyl, 100 fg for methamphetamine, and 1.6 pg for heroin. The LOD for heroin was lowered to 300 fg by using tributyl phosphate as a dopant to form a proton-bound heterodimer with heroin. When used with AFT-MS, the intentional formation of specific drug-dopant adducts has the potential to enhance detection limits and selectivity of additional drug species. Species that are prone to form adducts present a challenge to analysis, but that difficulty can be overcome by the intentional addition of a dopant. Molecules unlikely to form adducts will remain essentially unimpacted, but the adduct-forming species will interact with the dopant to compress the analyte signal into a single peak. This approach would be valuable in the application of non-contact screening for illicit substances via vapor collection followed by thermal desorption for analysis.

Optimized Reconstruction Techniques for Multiplexed Dual-Gate Ion Mobility Mass Spectrometry Experiments.

When coupling drift-tube gas-phase ion mobility separations with ion trapping mass analyzers an integrative, stepped approach to spectral reconstruction is a logical, yet highly inefficient means to determine gas-phase mobility coefficients. This experimental mode is largely predicated on the respective time scales of the two techniques each requiring tens of milliseconds to complete under routine conditions. Multiplexing techniques, such as Fourier and Hadamard based techniques, are a potential solution but still require extended experimental times that are not fully compatible with modern front-end separation schemes. Using a basis pursuit denoising (BPDN) approach to deconvolute Fourier transform ion mobility mass spectrometry (FT-IMMS) drift time spectra, we demonstrate significant time savings while maintaining a high degree of spectral resolution and signal-to-noise ratio. Under ideal conditions, the FT-IMMS operates with increased ion transmission (up to 25%); however, the linear chirp that spans into the kHz range often leads to significant levels of ion gate depletion, which limit both resolving power and ion transmission. The method proposed in this manuscript demonstrates the potential to reduce IMS acquisition time while simultaneously maximizing spectral resolution at longer effective gate pulse widths compared to the traditional set of multiplexing and signal averaging experiments.

Increased ion throughput using tristate ion-gate multiplexing.

For time dispersive ion mobility experiments detail control over the mechanism of ion beam modulation is necessary to establish optimum performance as this parameter greatly influences the temporal width of the ion beam arriving at the detector. When sampling continuous ion sources the temporal sampling or the incoming ion beam is often achieved by the electronic modulation of a grid or electric field. Not surprisingly, the rate at which a given ion population traverses this gating region is directly proportional to an ion's population and the applied electric field. This scenario establishes conditions where discrimination of the incoming ion beam may occur when the ion gate modulation rate is minimized. Recent developments in the mechanical construction of ion gates and their subsequent operation suggest that the mobility discrimination during ion gating may be minimized, however, it is remains unclear how this behavior will translate to ion beam multiplexing approaches. In this present work, we compare the performance levels of the tri-state ion shutter (3S-IS) to the two-state ion shutter (2S-IS) using a series of Fourier transform ion mobility mass spectrometry (FT-IMMS) experiments. The performance of the two different shutter operating principles were evaluated using ion multiplexing using tetraalkylammonium salts (TXA ions; T5-T8, T10, T12) bradykinin, and a set of reversed sequence isomeric pentapeptides using a variety of different ion gate frequency sweeps. Noticeable increases in ion throughput were observed for the 3S-IS with 95% and 45% increases in ion counts for the T5 and T12 ions respectively compared to the 2S-IS. Similarly, a 27% and 55% increase in ion counts was observed for the [M + 2H]2+ and [M + H]+ ions of bradykinin, respectively. In addition, a 10% increase in resolving power was also observed for the 3S-IS compared to the 2S-IS. Overall, utilization of the 3S-IS effectively minimizes both discrimination of slower ions and the impact of gate depletion effect common to traditional ion gating techniques.

Deducing Proton-Bound Heterodimer Association Energies from Shifts in Ion Mobility Arrival Time Distributions.

Through vapor modification of the counter-current drift gas in an atmospheric pressure drift tube ion mobility spectrometer (IMS), we demonstrate measurement of gas-phase association enthalpies and entropies for select proton-bound heterodimers formed from a phosphonic acid with 2-propanol. Previous efforts to determine gas-phase association thermodynamic properties have relied largely upon lower pressure systems and inference of the relative concentrations of m/ z isolated species. In contrast, the drift tube IMS based approach developed and applied in this study leverages the explicit gas-phase equilibrium that is established within an ion mobility drift cell. The inferred enthalpies and entropies of association are based solely upon monitoring a shift in the arrival time of an ion at different temperatures (and not on the signal intensity or on external instrument drift time calibration). We specifically report the gas-phase Gibbs free energy, enthalpy, and entropy changes for the association of 2-propanol with protonated methyl, ethyl, and propyl phosphonic acid ions (MPA, EPA, PPA) across the 100-175 °C temperature range. For all of these proton-bound heterodimers, the standard enthalpies and entropies of 2-propanol association were negative and positive, respectively. These data indicate that proton-bound heterodimer formation is both enthalpically and entropically favorable, though we find that the magnitude of the standard enthalpy change for vapor association is small (near 1 kcal/mol for all examined heterodimers). Though many prior results (largely obtained with high pressure mass-spectrometry) for other proton-bound organic heterodimer complexes show larger enthalpic favorability and an entropic barrier, our results qualitatively conform to the bulk Kelvin-Thomson-Raoult (KTR) model, which is commonly utilized in describing ion-induced nucleation of a vapor onto a soluble, nanometer scale ion. The KTR model suggests that heterodimer formation due to vapor binding to an ion should be slightly enthalpically favored (due to a larger Thomson effect than the Kelvin effect) and entropically favored because of ion solvation (Raoult's effect). The method presented in this study can be applied to any static-field ion mobility spectrometer and to a wide variety of heterodimers. Due to the ease of implementation and broad applicability, this approach may find consistent use in determining the thermodynamic properties of weakly bound gas-phase heterodimer complexes which are difficult to probe via alternative techniques. Moreover, this renewed implementation of the IMS experiment is directly compatible with soft ionization sources which will enable the characterization of vapor modifier-induced mobility shift experiments for larger molecular complexes.

Fourier Transform-Ion Mobility-Orbitrap Mass Spectrometer: A Next-Generation Instrument for Native Mass Spectrometry.

A new instrument configuration for native ion mobility-mass spectrometry (IM-MS) is described. Macromolecule ions are generated by using a static ESI source coupled to an RF ion funnel, and these ions are then mobility and mass analyzed using a periodic focusing drift tube IM analyzer and an Orbitrap mass spectrometer. The instrument design retains the capabilities for first-principles determination of rotationally averaged ion-neutral collision cross sections and high-resolution measurements in both mobility and mass analysis modes for intact protein complexes. Operation in the IM mode utilizes FT-IMS modes (originally described by Knorr ( Knorr , F. J. Anal. Chem . 1985 , 57 ( 2 ), 402 - 406 )), which provides a means to overcome the inherent duty cycle mismatch for drift tube (DT)-IM and Orbitrap mass analysis. The performance of the native ESI-FT-DT-IM-Orbitrap MS instrument was evaluated using the protein complexes Gln K (MW 44 kDa) and streptavidin (MW 53 kDa) bound to small molecules (ADP and biotin, respectively) and transthyretin (MW 56 kDa) bound to thyroxine and zinc.

Characterization of alkylphosphonic acid vapors using atmospheric flow tube-ion trap mass spectrometry.

RATIONALE: A key aspect of detecting hazardous compounds at ultra-trace levels for processing, compliance, and clean-up purposes involves developing methods that are not only sensitive, but also highly selective with minimal sampling effort. Atmospheric flow tube mass spectrometry (AFT-MS) using dielectric barrier discharge ionization has emerged as a technique that combines such features for vapor detection. AFT-MS is thus appealing for application to ambient screening for chemical warfare agents (CWAs) and their degradation products. Initial characterization of AFT-MS for CWA detection necessitates examining less harmful simulant species. A predominant hydrolysis product of most organophosphorus CWAs is methylphosphonic acid and most other hydrolysis products consist of some form of an alkylphosphonic acid. METHODS: An application of AFT-MS is presented wherein a homologous series of four alkylphosphonic acids (methyl-, ethyl-, propyl-, and t-butylphosphonic acid) were first qualitatively evaluated as anionic clusters with nitrate. These anionic adducts were subsequently quantified from non-equilibrium headspace vapor sampled over alkylphosphonic acid solutions in methanol. RESULTS: The series of phosphonic acids demonstrated consistent relative ion abundances thought to be related at least in part to the relative vapor pressures depending on their alkyl chains. For quantitation, the resulting linear ranges were found to be 2 to 50 ppmsoln for methylphosphonic acid, 5 to 50 ppmsoln for ethylphosphonic acid, and 2 to 25 ppmsoln for propylphosphonic acid and t-butylphosphonic acid; quality controls of 15 ppmsoln were used to assess the quantitation accuracy. CONCLUSIONS: Although measured over a limited dynamic range, the real-time analysis afforded by this method suggests the feasibility of using thermodynamically stable anionic adducts to monitor organophosphorus compounds via AFT-MS. In addition, this is proof-of-concept for the use of this ambient sensing technique to detect phosphonic acids. Furthermore, a discussion is included regarding gaps in clustering thermodynamics literature that would assist in uncovering physical or chemical explanations for observed trends.

Tuning Mobility Separation Factors of Chemical Warfare Agent Degradation Products via Selective Ion-Neutral Clustering.

Combining experimental data with computational modeling, we illustrate the capacity of selective gas-phase interactions using neutral gas vapors to yield an additional dimension of gas-phase ion mobility separation. Not only are the mobility shifts as a function of neutral gas vapor concentration reproducible, but also the selective alteration of mobility separation factors is closely linked to existing chemical functional groups. Such information may prove advantageous in elucidating chemical class and resolving interferences. Using a set of chemical warfare agent simulants with nominally the same reduced mobility values as a test case, we illustrate the ability of the drift-gas doping approach to achieve separation of these analytes. In nitrogen, protonated forms of dimethyl methyl phosphonate (DMMP) and methyl phosphonic acid (MPA) exhibit the reduced mobility values of 1.99 ± 0.01 cm2 V-1s-1 at 175 °C. However, when the counter current drift gas of the system is doped with 2-propanol at 20 µL/h, full baseline resolution of the two species is possible. By varying the concentration of the neutral modifier, the separation factor of the respective clusters can be adjusted. For the two species examined and at a 2-propanol flow rate of 160 µL/h, MPA demonstrated the greatest shift in mobility (1.58 cm2V-1s-1) compared the DMMP monomer (1.63 cm2V-1s-1). Meanwhile, the DMMP dimer experienced no change in mobility (1.45 cm2V-1s-1). The enhancement of separation factors appears to be brought about by the differential clustering of neutral modifiers onto different ions and can be explained by a model which considers the transient binding of a single 2-propanol molecule during mobility measurements. Furthermore, the application of the binding models not only provides a thermodynamic foundation for the results obtained but also creates a predictive tool toward a quantitative approach.