Chemical Warfare Nerve Agents Research Articles

Immediate dry decontamination using efficient absorbent materials is beneficial following skin exposure to low-volatile toxic chemicals.

In a chemical mass casualty incident requiring skin decontamination, dry removal using absorbent materials may be beneficial to enable immediate decontamination. The efficacy of absorbent materials has therefore been evaluated, alone or procedures including both dry and wet decontamination, following skin exposure to two low volatile toxic chemicals using an in vitro human skin penetration model. Additionally, removal using active carbon wipes was evaluated with or without the Dahlgren Decon solution. All dry decontamination procedures resulted in a significantly decreased skin penetration rate of the industrial chemical 2-butoxyethanol compared to the control without decontamination. Wet decontamination following dry absorption significantly improved the efficacy compared to dry removal alone. Dry decontamination post-exposure to the chemical warfare nerve agent VX showed no decontamination efficacy. However, dry and wet decontamination resulted in a decreased agent skin penetration rate during the last hour of the experiment. At -15°C, significantly reduced VX skin penetration rates were demonstrated for both dry decontamination alone and the dry and wet decontamination procedure. The Dahlgren Decon solution significantly reduced the amount of VX penetrating the skin, but the active carbon wipe alone did not impact the skin penetration rate. In conclusion, absorbent materials are beneficial for the removal of low-volatile chemicals from the skin, but the degree of efficacy varies between chemicals. Despite the variability, immediate dry decontamination using available absorbent materials prior to wet decontamination is recommended as a general procedure for skin decontamination. The procedure should also be prioritized in cold-weather conditions to prevent patient hypothermia.

Disentangling the formation, mechanism, and evolvement of the covalent methanesulfonyl fluoride acetylcholinesterase adduct: Insights into an aged-like inactive complex susceptible to reactivation by a combination of nucleophiles.

Chemical warfare nerve agents and pesticides, known as organophosphorus compounds inactivate cholinesterases (ChEs) by phosphorylating the serine hydroxyl group located at the active site of ChEs. Over the course of time, phosphorylation is followed by loss of an organophosphate-leaving group and the bond with ChEs becomes irreversible, a process known as aging. Differently, structurally related irreversible catalytic poisons bearing sulfur instead of phosphorus convert ChEs in its aged form only by covalently binding to the key catalytic serine. Kinetic and crystallographic studies of the interaction between Torpedo californica acetylcholinesterase (TcAChE) and a small organosulfonate, methanesulfonyl fluoride (MSF), indeed revealed irreversibly methylsulfonylated serine 200, to be isosteric with the bound aged sarin/soman analogues. The potent bulky reversible inhibitor 7-bis-tacrine (BTA) adopts, in the active site of the crystal structure of the MSF-enzyme adduct, a location and an orientation that closely resemble the one being found in the crystal structure of the BTA-enzyme complex. Remarkably, the presence of BTA accelerates the rate of methanesulfonylation by a factor of two. This unexpected result can be explained on the basis of two facts: i) the steric hindrance exerted by BTA to MSF in accessing the active site and ii) the acceleration of the MSF-enzyme adduct formation as a consequence of the lowering of the rotational and translational degrees of freedom in the proximity of the catalytic serine. It is well known that pralidoxime (2-Pyridine Aldoxime Methyl chloride, 2-PAM) alone or in the presence of the substrate acetylcholine cannot reactivate the active site serine of the TcAChE-MSF adduct. We show that the simultaneous presence of 2-PAM and the additional neutral oxime, 2-[(hydroxyimino)methyl]-l-methylimidazol (2-HAM), triggers the reactivation process of TcAChE within the hour timescale. Overall, our results pave the way toward the likely use of a cocktail of distinctive oximes as a promising recipe for an effective and fast reactivation of aged cholinesterases.

Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats.

Organophosphate (OP) compounds are highly toxic and include pesticides and chemical warfare nerve agents. OP exposure inhibits the acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-induced SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). In male Sprague-Dawley rats, we assessed hippocampal pathology and chronic SRS following SE induced by administration of OP agents paraoxon (2 mg/kg, s.c.), diisopropyl fluorophosphate (4 mg/kg, s.c.), or O-isopropyl methylphosphonofluoridate (GB; sarin) (2 mg/kg, s.c.), immediately followed by atropine and 2-PAM. At 1-hour post-OP-induced SE onset, midazolam was administered to control SE. Approximately 6 months after OP-induced SE, SRS were evaluated using video and electroencephalography monitoring. Histopathology was conducted using hematoxylin and eosin (H&E), while silver sulfide (Timm) staining was used to assess mossy fiber sprouting (MFS). Across all the OP agents, over 60% of rats that survived OP-induced SE developed chronic SRS. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus. This study demonstrates that OP-induced SE is associated with hippocampal neuronal loss, extensive MFS, and the development of SRS, all hallmarks of chronic epilepsy. SIGNIFICANCE STATEMENT: Models of organophosphate (OP)-induced SE offer a unique resource to identify molecular mechanisms contributing to neuropathology and the development of chronic OP morbidities. These models could allow the screening of targeted therapeutics for efficacious treatment strategies for OP toxicities.

Magnetic and Impedance Analysis of Fe2O3 Nanoparticles for Chemical Warfare Agent Sensing Applications

A dire need for real-time detection of toxic chemical compounds exists in both civilian and military spheres. In this paper, we demonstrate that inexpensive, commercially available Fe2O3 nanoparticles are capable of selective sensing of chemical warfare agents (CWAs) using frequency-dependent impedance spectroscopy, with additional potential as an orthogonal magnetic sensor. X-ray magnetic circular dichroism analysis shows that Fe2O3 nanoparticles possess moderately lowered moment upon exposure to 2-chloroethyl ethyl sulfide (2-CEES) and diisopropyl methylphosphonate (DIMP) and significantly lowered moment upon exposure to dimethyl methylphosphonate (DMMP) and dimethyl chlorophosphate (DMCP). Associated X-ray absorption spectra confirm a redox reaction in the Fe2O3 nanoparticles due to CWA structural analog exposure, with differentiable energy-dependent features that suggest selective sensing is possible, given the correct method. Impedance spectroscopy performed on samples dosed with DMMP, DMCP, and tabun (GA, chemical warfare nerve agent) showed strong, differentiable, frequency-dependent responses. The frequency profiles provide unique “shift fingerprints” with which high specificity can be determined, even amongst similar analytes. The results suggest that frequency-dependent impedance fingerprinting using commercially available Fe2O3 nanoparticles as a sensor material is a feasible route to selective detection.

Molecular modeling of Mannich phenols as reactivators of human acetylcholinesterase inhibited by A-series nerve agents

The A-series is the most recent generation of chemical warfare nerve agents (CWA) which act directly on the inhibition of the human acetylcholinesterase (HssAChE) enzyme. These compounds lack accurate experimental data on their physicochemical properties, and there is no evidence that traditional antidotes effectively reactivate HssAChE inhibited by them. In the search for potential antidotes, we employed virtual screening, molecular docking, and molecular dynamics (MD) simulations for the theoretical assessment of the performance of a library of Mannich phenols as potential reactivators of HssAChE inhibited by the Novichok agents A-230, A-232, and A-234, in comparison with the commercial oximes pralidoxime (2-PAM), asoxime (HI-6), trimedoxime (TMB-4), and obidoxime. Following the near-attack conformation (NAC) approach, our results suggest that the compounds assessed would face difficulties in triggering the proposed nucleophilic in-line displacement mechanism. Despite this, it was observed that certain Mannich phenols presented similar or superior results to those obtained by reference oximes against A-232 and A-234 model, suggesting that these compounds can adopt more favourable conformations. Additional binding energy calculations confirmed the stability of the model/ligands complexes and the reactivating potential observed in the molecular docking and MD studies. Our findings indicate that the Mannich phenols could be alternative antidotes and that their efficacy should be evaluated experimentally against the A-series CWA.

Targeted Metabolomics of Organophosphate Pesticides and Chemical Warfare Nerve Agent Simulants Using High- and Low-Dose Exposure in Human Liver Microsomes.

Our current understanding of organophosphorus agent (pesticides and chemical warfare nerve agents) metabolism in humans is limited to the general transformation by cytochrome P450 enzymes and, to some extent, by esterases and paraoxonases. The role of compound concentrations on the rate of clearance is not well established and is further explored in the current study. We discuss the metabolism of 56 diverse organophosphorus compounds (both pesticides and chemical warfare nerve agent simulants), many of which were explored at two variable dose regimens (high and low), determining their clearance rates (Clint) in human liver microsomes. For compounds that were soluble at high concentrations, 1D-NMR, 31P, and MRM LC-MS/MS were used to calculate the Clint and the identity of certain metabolites. The determined Clint rates ranged from 0.001 to 2245.52 µL/min/mg of protein in the lower dose regimen and from 0.002 to 98.57 µL/min/mg of protein in the high dose regimen. Though direct equivalency between the two regimens was absent, we observed (1) both mono- and bi-phasic metabolism of the OPs and simulants in the microsomes. Compounds such as aspon and formothion exhibited biphasic decay at both high and low doses, suggesting either the involvement of multiple enzymes with different KM or substrate/metabolite effects on the metabolism. (2) A second observation was that while some compounds, such as dibrom and merphos, demonstrated a biphasic decay curve at the lower concentrations, they exhibited only monophasic metabolism at the higher concentration, likely indicative of saturation of some metabolic enzymes. (3) Isomeric differences in metabolism (between Z- and E- isomers) were also observed. (4) Lastly, structural comparisons using examples of the oxon group over the original phosphorothioate OP are also discussed, along with the identification of some metabolites. This study provides initial data for the development of in silico metabolism models for OPs with broad applications.

A Hidden Gem: Highlighting the Indispensable Capabilities and History of the DoD Cholinesterase Monitoring Program and DoD Cholinesterase Reference Laboratory.

The DoD Cholinesterase Monitoring Program and Cholinesterase Reference Laboratory have safeguarded U.S. government employees in chemical defense for over five decades. Considering Russia's potential deployment of chemical warfare nerve agents in Ukraine, it is critical to maintain a robust cholinesterase testing program and its efficiency presently and in future.

MOF/polymer hybrids through in situ free radical polymerization in metal-organic frameworks.

We use the free radical polymerization initiator 4,4'-azobis(cyanovaleric acid) coordinated to the open metal sites of metal-organic frameworks (MOFs) to give rise to highly uniform MOF/polymer hybrids. We demonstrate this strategy on two robust zirconium MOFs (NU-1000 and MOF-808), which are the most effective catalysts for degradation of chemical warfare nerve agents. The resulting hybrid materials maintain their hydrolytic catalytic activity and have substantially improved adhesion to polypropylene and activated carbon textile fibers, yielding highly robust MOF/polymer/textile hybrid systems. These composites are suitable for the green production of active protective clothing and filters capable of detoxifying organophosphorus warfare agents.

Simple and efficient PET and AIEE mechanism-based fluorescent probes for sensing Tabun mimic DCNP

The highly sensitive, selective, easy-to-prepare, aqueous media based on two novel probes 2-(pyren-1-yl)imidazo[1,2-a]pyridine (IMP-Py) and (2-(pyren-1-yl)imidazo[1,2-a]pyridin-3-yl)methanol (IMP-Py-OH) are synthesized for the detection of toxic chemical warfare nerve agent mimic diethylcyanochlorophosphonate (DCNP). Both probes are found effective in the detection of DCNP but comparatively, IMP-Py shows better properties in terms of instantaneous response, specificity, selectivity and a low detection limit of 16.9 nM. A significant enhancement of fluorescence intensity of IMP-Py due to aggregation-induced emission enhancement (AIEE) and photoinduced electron transfer (PET) phenomenon was inhibited due to phosphorylation of the hydroxy group of IMP-Py-OH in presence of DCNP has been observed. Taking the advantages of good sensitivity and fast response, probe IMP-Py has been fabricated into a viable paper strips portable product, tested for its potential for the detection of DCNP in tap water as well as with its vapor and response is visible under a UV lamp of 365 nm wavelength.

Developing a Prenatal Acute Exposure and Medical Countermeasure Evaluation Model for Organophosphate Compounds in a Genetically Modified Mouse

Organophosphate (OPs) compounds make up the most common class of pesticides as well as chemical warfare nerve agents (CWNA), all of which covalently inhibit the active site of acetylcholinesterase (AChE), resulting in intoxication via a cholinergic crisis. While the biochemical mechanism of action resulting in acute intoxication of an exposed individual is well understood, less is known about the mechanism of OP intoxication via other exposure routes, particularly prenatal exposure. The clinical effects of non‐acute prenatal OP exposure have been previously studied primarily in cases involving diet and agricultural labor, while case studies documenting the effects on conception of acute exposure during chemical warfare attacks (Japan 1995, Syria 2013 and 2017) have also been published. Such exposure events were linked to a range of serious neurodevelopmental anomalies in children, but the underlying mechanism of action as well as the potential benefits of medical countermeasures have not been clearly elucidated. A robust human‐relevant animal model to test both is therefore essential for evaluating current and future OP countermeasures. The present study used a novel humanized mouse strain expressing human AChE and an inactivated native serum carboxylesterase to create a prenatal acute exposure and emergency medical countermeasure evaluation model. Pregnant mice were acutely exposed to an OP at a critical point in cholinergic development, generally equivalent to the first trimester in humans. Dams were challenged with either sarin or the pesticide paraoxon, followed by either a saline vehicle control or 2‐PAM and an atropine/midazolam cocktail, the currently fielded emergency treatment for OP intoxication. Mice were allowed to carry pups to term, and upon reaching maturity, cortex, cerebellum, bone marrow and gonads were collected from offspring in each exposure group. Phenotypical and histopathological evaluation of tissues and other factors in dams and offspring were evaluated. Gene expression analyses conducted for each tissue generated a detailed profile associated with each OP exposure/treatment group, providing robust criteria for model development. The resulting data demonstrated a significant beneficial impact of medical countermeasures for both sarin and paraoxon exposures, significantly reducing the amount and the scope of gene expression changes induced by OP exposure. This model provides insight into the developmental pathologies resulting from prenatal acute OP exposure as well as serves as an evaluation model for future treatments.

Cellulose Acetate-Cellulose Nanowhisker Nanocomposite Immobilized with a DCDHF-Hydrazone Chromophore toward a Smart Test Strip for Colorimetric Detection of Diethyl Chlorophosphate as a Nerve Agent Mimic.

Exposure to nerve agents, which are usually colorless and odorless gases, may cause organ failure, paralysis, or even quick death. Diethyl chlorophosphate (DCP) has been recognized as one of the most well-known chemical warfare nerve agent mimics. In the current study, we introduce a simple strategy for the development of a portable and reversible nanocomposite-based microporous strip for naked-eye detection of DCP within a few seconds. A dicyanomethylenedihydrofuran hydrazone (DCDHF-H) chromophore was synthesized by an easy azo-coupling reaction and encapsulated in situ during the preparation of cellulose acetate/cellulose nanowhisker/hydrazone (CA-CNW-H) nanocomposites. These CA-CNW-H nanocomposites displayed a bathochromic shift in the absorption intensity of about 142 nm from 438 to 580 nm with the increase of the DCP concentration. The present CA-CNW-H sensor strip displayed a detection limit for DCP ranging from 25 to 200 ppm. The color change of CA-CNW-H from yellow to purple due to exposure to DCP was detected by CIE Lab analysis. The morphology, fibrous crystallinity, thermal stability, and mechanical properties of the prepared CA-CNW-H sensor strips were investigated.

An Antidote Screening System for Organophosphorus Poisoning Using Zebrafish Larvae.

Organophosphorus (OP) cholinesterase inhibitors, which include insecticides and chemical warfare nerve agents, are very potent neurotoxicants. Given that the actual treatment has several limitations, the present study provides a general method, called the zebrafish-OP-antidote test (ZOAT), and basic scientific data, to identify new antidotes that are more effective than the reference pyridinium oximes after acute OP poisoning. The reactivation capacity of a chemical compound can be measured using in vivo and ex vivo acetylcholinesterase (AChE) assays. We demonstrated that it is possible to differentiate between chemical compound protective efficacies in the central and peripheral nervous system via the visual motor response and electric field pulse motor response tests, respectively. Moreover, the ability to cross the brain-blood barrier can be estimated in a physiological context by combining an AChE assay on the head and trunk-tail fractions and the cellular and tissue localization of AChE activity in the whole-mount animal. ZOAT is an innovative method suitable for the screening and rapid identification of chemicals and mixtures used as antidote for OP poisoning. The method will make it easier to identify more effective medical countermeasures for chemical threat agents, including combinatorial therapies.

Catalytic Performance of a Recombinant Organophosphate-Hydrolyzing Phosphotriesterase from Brevundimonas diminuta in the Presence of Surfactants

Phosphotriestease (PTE), also known as parathion hydrolase, has the ability to hydrolyze the triester linkage of organophosphate (OP) pesticides and chemical warfare nerve agents, making it highly suitable for environment remediation. Here, we studied the effects of various surfactants and commercial detergents on the esterase activity of a recombinant PTE (His6-tagged BdPTE) from Brevundimonas diminuta. Enzymatic assays indicated that His6-tagged BdPTE was severely inactivated by SDS even at lower concentrations and, conversely, the other three surfactants (Triton X-100, Tween 20, and Tween 80) had a stimulatory effect on the activity, especially at a pre-incubating temperature of 40 °C. The enzyme exhibited a good compatibility with several commercial detergents, such as Dr. Formula® and Sugar Bubble®. The evolution results of pyrene fluorescence spectroscopy showed that the enzyme molecules participated in the formation of SDS micelles but did not alter the property of SDS micelles above the critical micelle concentration (CMC). Structural analyses revealed a significant change in the enzyme’s secondary structure in the presence of SDS. Through the use of the intentionally fenthion-contaminated Chinese cabbage leaves as the model experiment, enzyme–Joy® washer solution could remove the pesticide from the contaminated sample more efficiently than detergent alone. Overall, our data promote a better understanding of the links between the esterase activity of His6-tagged BdPTE and surfactants, and they offer valuable information about its potential applications in liquid detergent formulations.

Novel Genetically Modified Mouse Model to Assess Soman-Induced Toxicity and Medical Countermeasure Efficacy: Human Acetylcholinesterase Knock-in Serum Carboxylesterase Knockout Mice.

The identification of improved medical countermeasures against exposure to chemical warfare nerve agents (CWNAs), a class of organophosphorus compounds, is dependent on the choice of animal model used in preclinical studies. CWNAs bind to acetylcholinesterase and prevent the catalysis of acetylcholine, causing a plethora of peripheral and central physiologic manifestations, including seizure. Rodents are widely used to elucidate the effects of CWNA-induced seizure, albeit with a caveat: they express carboxylesterase activity in plasma. Carboxylesterase, an enzyme involved in the detoxification of some organophosphorus compounds, plays a scavenging role and decreases CWNA availability, thus exerting a protective effect. Furthermore, species-specific amino acid differences in acetylcholinesterase confound studies that use oximes or other compounds to restore its function after inhibition by CWNA. The creation of a human acetylcholinesterase knock-in/serum carboxylesterase knockout (C57BL/6-Ces1ctm1.1LocAChEtm1.1Loc/J; a.k.a KIKO) mouse may facilitate better modeling of CWNA toxicity in a small rodent species. The current studies characterize the effects of exposure to soman, a highly toxic CWNA, and evaluate the efficacy of anti-seizure drugs in this newly developed KIKO mouse model. Data demonstrate that a combination of midazolam and ketamine reduces seizure duration and severity, eliminates the development of spontaneous recurrent seizures, and protects certain brain regions from neuronal damage in a genetically modified model with human relevance to organophosphorus compound toxicity. This new animal model and the results of this study and future studies using it will enhance medical countermeasures development for both defense and homeland security purposes.

Soman-induced toxicity, cholinesterase inhibition and neuropathology in adult male Göttingen minipigs.

Animal models are essential for evaluating the toxicity of chemical warfare nerve agents (CWNAs) to extrapolate to human risk and are necessary to evaluate the efficacy of medical countermeasures. The Göttingen minipig is increasingly used for toxicological studies because it has anatomical and physiological characteristics that are similar to those of humans. Our objective was to determine whether the minipig would be a useful large animal model to evaluate the toxic effects of soman (GD). We determined the intramuscular (IM) median lethal dose (LD50) of GD in adult male Göttingen minipigs using an up-and-down dosing method. In addition to lethality estimates, we characterized the observable signs of toxicity, blood and tissue cholinesterase (ChE) activity and brain pathology following GD exposure. The 24 h LD50 of GD was estimated to be 4.7 μg/kg, with 95 % confidence limits of 3.6 and 6.3 μg/kg. As anticipated, GD inhibited ChE activity in blood and several tissues. Neurohistopathological analysis showed neurodegeneration and neuroinflammation in survivors exposed to 4.7 μg/kg of GD, including in the primary visual cortex and various thalamic nuclei. These findings suggest that the minipig will be a useful large animal model for assessing drugs to mitigate neuropathological effects of exposure to CWNAs.

Cannabidiol reduces soman-induced lethality and seizure severity in female plasma carboxylesterase knockout mice treated with midazolam

Cannabidiol, approved for treatment of pediatric refractory epilepsy, has anti-seizure effects in various animal seizure models. Chemical warfare nerve agents, including soman, are organophosphorus chemicals that can induce seizure and death if untreated or if treatment is delayed. Our objective was to evaluate whether cannabidiol would ameliorate soman-induced toxicity using a mouse model that similar to humans lacks plasma carboxylesterase. In the present study, adult female plasma carboxylesterase knockout (Es1-/-) mice were pre-treated with cannabidiol (20−150 mg/kg) or vehicle 1 h prior to exposure to a seizure-inducing dose of soman and evaluated for survival and seizure activity. The muscarinic antagonist atropine sulfate and the oxime HI-6 were administered at 1 min after exposure, and the benzodiazepine midazolam was administered at 30 min after seizure onset. Cannabidiol (150 mg/kg) pre-treatment led to a robust increase in survival rate and attenuated body weight loss in soman-exposed mice treated with medical countermeasures, compared to mice pre-treated with vehicle. In addition, mice pretreated with cannabidiol (150 mg/kg) had a modest reduction in seizure severity after midazolam treatment compared to vehicle-pretreated. These findings of improved outcome with cannabidiol administration in a severe seizure model of soman exposure provide additional pre-clinical support for the benefits of cannabidiol against exposure to seizure-inducing chemical agents and suggest cannabidiol may augment the anti-seizure effects of midazolam.

Counteracting poisoning with chemical warfare nerve agents.

Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim’s survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning.

Photo-decontamination of chemical warfare dimethyl methylphosphonate, dimethyl phosphite, diethyl methylphosphonate, diethyl phosphite model molecules on Al and oxidized Al foils

Decontamination of organophosphorus chemical warfare nerve agents (CWNAs) is gaining importance for human security. Herein, we have employed a dry-photodecontamination method for CWNA model molecules of dimethyl methylphosphonate, dimethyl phosphite, diethyl methylphosphonate, and diethyl phosphite contaminated on aluminum (Al) and oxidized Al foils. For understanding their photo-degradation pathways, the photo-decomposition secondary chemical products generated as a result of UVC-decontamination were fully examined for the contaminated Al and oxidized Al target areas in a closed reactor system by gas chromatography and mass spectrometry. Solid residues were also fully examined by X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy. Density functional theory at the B3LYP/6–31 G level was used for geometric optimization, and the electronic energy state calculation was conducted on the level of TD-SCF/B3LYP/6–31 G. The new results further deepen the photo-decomposition mechanism of CWNAs, the development of dry UV light photo-decontamination methods, and the treatment of secondary by-products.

The decisive role of pericyclic reactions in the thermal decomposition of organophosphorus compounds

The understanding of the thermal decomposition chemistry of chemical warfare nerve agents is largely limited by the scarcity of kinetic data. Because of the high toxicity of these molecules, experimental determination of their chemical properties is very difficult. In the present work, a comprehensive detailed kinetic model for the decomposition of sarin and some simulants, i.e. di-isopropyl methyl phosphonate (DIMP), diethyl methylphosphonate (DEMP), and triethyl phosphate (TEP) were developed, containing possible molecular and radical pathways. The importance of unimolecular pericyclic decomposition led to evaluate precisely the rate constants of these reactions with high level theoretical calculations. The QCISD(T)/cc-PV∞QZ//B2PLYPD3/6–311+G(2d,d,p) level of theory was selected after a benchmark. The contribution of hindered rotors was included with the 1D-HR-U approach. Tunneling was taken into account for H-atom transfer. Transition state theory was used to calculate high-pressure limit rate constants and pressure dependent rate constants were calculated using Master Equation modeling. The model was validated against experimental pyrolysis and oxidation experimental data available in literature. Flux analyses showed that whatever the conditions are, the first step of decomposition of the studied phosphorus compounds are pericyclic eliminations leading to successive decompositions, whereas bond-breaking or H-atom abstraction remain negligible, even at high temperature.

Theoretical Study of VX Hydrolysis Mechanism Catalyzed by Phosphotriesterase Mutant H254R

AbstractPhosphotriesterase (PTE) is a bacterial enzyme that can catalyze the hydrolysis of V‐type chemical warfare nerve agents. Herein, the hydrolysis mechanism of VX analogs catalyzed by the H254R PTE mutant, in which the histidine 254 residue is replaced by an arginine, has been investigated using the hybrid density functional theory method B3LYP. The chemical model of the active site of H254R PTE mutant was constructed based on the high resolution X‐ray crystal structure. We have presented the energetics and the characterization of stationary points in the catalytic reaction. The calculations indicate that the catalytic process contain two SN2 displacement steps and the step of hydroxide regeneration is rate‐limiting with an overall barrier of 22.2 kcal/mol. The Arg254 plays an important role as a proton donor/acceptor for protonating leaving group and activating water molecule. Moreover, the H254R PTE mutant with binuclear cobalt center turns out to higher activity towards VX than the binuclear zinc H254R PTE.