 SP-(−)-VXenantiomer | |
 | |
 | |
| Names | |
|---|---|
| Preferred IUPAC name S-{2-[Di(propan-2-yl)amino]ethyl}O-ethyl methylphosphonothioate | |
| Other names [2-(Diisopropylamino)ethyl]-O-ethyl methylphosphonothioate Ethyl {[2-(diisopropylamino)ethyl]sulfanyl}(methyl)phosphinate EthylN-2-diisopropylaminoethyl methylphosphonothiolate | |
| Identifiers | |
3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| MeSH | VX |
| UNII | |
| |
| |
| Properties | |
| C11H26NO2PS | |
| Molar mass | 267.37 g·mol−1 |
| Appearance | amber liquid |
| Odor | odorless |
| Density | 1.0083 g cm−3 |
| Melting point | −51 °C (−60 °F; 222 K) |
| Boiling point | 300 °C (572 °F; 573 K) |
| logP | 2.047 |
| Vapor pressure | 0.09 Pa |
| Hazards | |
| NFPA 704 (fire diamond) | |
| Flash point | 159 °C (318 °F; 432 K)[3] |
| Lethal dose or concentration (LD, LC): | |
LD50 (median dose) | 7 μg/kg (intravenous, rat)[2] |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
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VX is an extremely toxicsyntheticchemical compound in theorganophosphorus class, specifically, athiophosphonate. In the class ofnerve agents, it was developed for military use inchemical warfare aftertranslation of earlier discoveries oforganophosphate toxicity inpesticide research. In its pure form, VX is an oily, relativelynon-volatile liquid that is amber-like in colour.[4] Because of its low volatility, VX persists in environments where it is dispersed.[5][6]
VX, short for "venomous agent X",[7] is one of the best known of the V nerve agents and originated from pesticide development work atImperial Chemical Industries (ICI). It was developed further atPorton Down in England during the early 1950s,[8] based on research first done byGerhard Schrader, a chemist working forIG Farben in Germany during the 1930s.[citation needed] It is now one of a broader V-series of agents which are classified asnerve agents. VX has been allegedly used in warfare and has been used in several assassinations. The brother of North Korean leaderKim Jong Un,Kim Jong Nam, had the substancethrown in his face inKuala Lumpur International Airport on February 13, 2017, by two women. He died while being rushed to hospital approximately 15 minutes later.
The substance is extremely deadly: VX fatalities occur with exposure to tens of milligram quantities via inhalation or absorption through skin. It is more potent thansarin, another nerve agent with a similarmechanism of action. On such exposure, these agents severely disrupt the body's signaling between thenervous andmuscular systems, leading to a prolongedneuromuscular blockade,flaccid paralysis of all the muscles in the body including thediaphragm, and death byasphyxiation.[9]
The danger of VX, in particular, lies in direct exposure to the chemical agent persisting where it was dispersed, and not through its evaporating and being distributed as a vapor; it is not considered a vapor hazard due to its relativenon-volatility. VX is considered anarea denial weapon due to these physical and biochemical characteristics.[10] As achemical weapon, it is categorized as aweapon of mass destruction by theUnited Nations and is banned by theChemical Weapons Convention of 1993,[11] where production and stockpiling of VX exceeding 100 grams (3.53 oz) per year is outlawed. The only exception is for "research, medical or pharmaceutical purposes outside a single small-scale facility in aggregate quantities not exceeding 10 kg (22 lb) per year per facility".[12]
VX is an odorless and tasteless[13][14] chiral organophosphorous chemical with a molecular weight of 267.37 g/mol.[15] Under standard conditions it is an amber-coloured liquid with a boiling point of 298 °C (568 °F), and a freezing point of −51 °C (−60 °F).[16] Its density is similar to that of water.[17] It has alog P value of 2.047, meaning it is relatively hydrophobic with about 100-fold more partitioning into octanol, over water.[18] Its lowvapor pressure of 0.09 pascals (1.3×10−5 psi) gives it a low volatility, resulting in a high persistence in the environment.[19]
When weaponized, it can be dispersed as a liquid, aerosol or as a mixture with aclay ortalc thickening agent.[19]
VX is anacetylcholinesterase inhibitor.[20]It blocks the function of theenzymeacetylcholinesterase (AChE). Normally, when amotor neuron is stimulated, it releases the neurotransmitteracetylcholine (ACh) into the space between the neuron and an adjacent muscle cell, the synaptic cleft. When acetylcholine binds to nicotinic receptors at the neuromuscular junction, it stimulates muscle contraction. To avoid a state of constant muscle contraction, the acetylcholine is then broken down (hydrolysed) into the inactive substancesacetic acid andcholine by AChE. VX blocks the action of AChE, resulting in an accumulation of acetylcholine in the space between the neuron and muscle cell. On a molecular level, this leads to the ongoing stimulation and eventual fatigue of all affectedmuscarinic andnicotinic ACh receptors. This results in initial violent contractions, followed by sustained supercontraction restricted to the fluid (sarcoplasm) of the subjunctionalendplate and prolonged, depolarizingneuromuscular blockade.[21] The prolonged blockade results in flaccid paralysis of all the muscles in the body, and it is such sustained paralysis of thediaphragm muscle that causes death byasphyxiation.[9]Accumulation of acetylcholine in the brain also causes neuronalexcitotoxicity, due to activation ofnicotinic receptors andglutamate release.[22]
The extreme toxicity of VX is partly due to the fact that the inhibitor was designed to be an excellent structural mimic for the transition state of the natural substrate (acetylcholine) of acetylcholinesterase. VX has a very high "on-rate" to react with the target enzyme and form a stable P-O-C bond (phosphorylation).[23] However, compared with other highly toxic nerve agents likesoman orsarin, VX undergoes relatively slow "aging". Aging is a time-dependent side reaction (loss of an alkoxyl group) that occurs on nerve agents after phosphorylation and renders the nerve agent-acetylcholinesterase complex highly resistant to regeneration by any known antidote. Slower aging by VX suggests it should be possible to develop more effective antidotes and treatments.[24]
The reaction products of acetylcholinesterase with VX before and after the "aging" reaction were solved in near atomic resolution byX-ray crystallography to aid in antidote development.[25][26] The X-ray structures revealed the specific parts of the VX molecule that interact with key residues and sub-sites of the target enzyme. The structural kinetic of phosphorylation followed by aging also showed an unexpected conformational change in the catalytic triad suggestive of an "induced fit" between the VX molecule and acetylcholinesterase.
VX ischiral at itsphosphorus atom. The individualenantiomers are identified asSP-(−)-VX, andRP-(+)-VX (where the "P" subscript highlights that the chirality is at phosphorus).[1]
VX is produced via thetransester process, which gives aracemic mixture of the two enantiomers. This entails a series of steps wherebyphosphorus trichloride ismethylated to producemethyl phosphonous dichloride. The resulting material is reacted withethanol to form adiester. This is thentransesterified withN,N-diisopropylaminoethanol to produceQL,a mixedphosphonite. Finally, this immediate precursor is reacted withsulfur to form VX.
VX can also be delivered inbinary chemical weapons which mix in-flight to form the agent prior to release. Binary VX is referred to as VX2,[27] and is created by mixing QL with sulfur as is done in theBigeye aerial chemical bomb. It may also be produced by mixing with sulfur compounds, as with the liquid dimethyl polysulfide mixture (known as NM) in the canceledXM736 8-inch projectile program.[citation needed]
Like otherorganophosphorus nerve agents, VX may be destroyed by reaction with strong nucleophiles. The reaction of VX with concentrated aqueoussodium hydroxide results in two competingsolvolysis reactions: cleavage of either the P–O or P–S esters. Although the P–S cleavage is the dominant pathway, the product of P–O bond cleavage is the toxic phosphonic thioesterEA-2192 and both reactions are slow.[28] In contrast, reaction with thehydroperoxide anion (hydroperoxidolysis) leads to exclusive cleavage of the P–S bond and a more rapid overall reaction.[28][29]
Early symptoms of skin contact include local sweating and muscular twitching at the area of exposure, followed by nausea or vomiting. Early symptoms of exposure to VX vapor includerhinorrhea (runny nose) and tightness in the chest with shortness of breath (bronchial constriction).Miosis (pinpointing of the pupils) may be an early sign of agent exposure but is not usually used as the only indicator of exposure.[30]
VX is extremely toxic. The potentially fatal dose is only slightly higher than the dose having any effect at all, and the effects of a fatal dose are so rapid that there is little time for treatment.[5] Themedian lethal dose (LD50), the exposure required to kill half of a tested population, as estimated for 70 kg human males via exposure to the skin is reported to be 5 to 10 mg.
When treating VX exposure, primary consideration is given to removal of the liquid agent from the skin, before removal of the individual to an uncontaminated area or atmosphere. After this, the victim is decontaminated by washing the contaminated areas with household bleach and flushing with clean water, followed by removal of contaminated clothing and further skin decontamination. When possible, decontamination is completed before the casualty is taken for further medical treatment.[31][32][33]
An individual known to have been exposed to a nerve agent, or who exhibits definite signs or symptoms of nerve-agent exposure is generally given the antidotesatropine andpralidoxime (2-PAM), and in the case of convulsions an injected sedative or antiepileptic such asdiazepam.[34] In several nations the nerve agent antidotes are issued for military personnel in the form of anautoinjector such as the United States militaryMark I NAAK.[30]
Atropine blocks a subset of acetylcholine receptors known asmuscarinic acetylcholine receptors (mAchRs), so that the buildup of acetylcholine produced by loss of the acetylcholinesterase function has a reduced effect on their target receptor.[citation needed] 2-PAM reactivates the acetylcholinesterase enzyme (AChE), thus reversing the effects of VX.[citation needed] VX and other organophosphates block AChE activity by binding to andcovalently inactivating the enzyme via transfer of thephosphonate moiety from VX to theactive site of AChE; this inactivates AChE and produces an inactive by-product from the remaining portion of the VX molecule.[citation needed] Pralidoxime (2-PAM) removes this phosphate group.[citation needed]
Controlled studies in humans have shown that minimally toxic doses cause 70–75% depression oferythrocytecholinesterase within several hours of exposure. The serum level ofethyl methylphosphonic acid (EMPA), a VX hydrolysis product, was measured to confirm exposure in one poisoning victim. There also exist procedures for determination of VX hydrolysis products in urine and of VX adducts to albumin in blood.[35]
The chemists Ranajit Ghosh and J. F. Newman discovered the V-series nerve agents at the British firmICI in 1952, patenting diethylS-2-diethylaminoethyl phosphonothioate (agent VG) in November 1952.[citation needed] Further commercial research on similar compounds ceased in 1955 when its lethality to humans was discovered. The U.S. started production of large amounts of VX in 1961 atNewport Chemical Depot.[citation needed]
The discovery occurred when the chemists were investigating a class oforganophosphate compounds (organophosphateesters of substituted aminoethanethiols).[36] LikeGerhard Schrader, an earlier investigator of organophosphates, Ghosh found that they were quite effectivepesticides. In 1954, ICI put one of them on the market under the trade nameAmiton. It was subsequently withdrawn, as it was too toxic for safe use. The toxicity did not go unnoticed, and samples of it were sent to the British government research facility atPorton Down inWiltshire for evaluation. After the evaluation was complete, several members of this class of compounds became a new group of nerve agents, the V agents. The best-known of these is probably VX, assigned the UKRainbow Code Purple Possum, with theRussian V-Agent (VR) coming a close second (Amiton is largely forgotten as VG). The name is a contraction of the words "venomous agent X".[37]
Beginning in 1959, the United States Army began volunteer testing of VX in humans. Dr. Van M. Sim underwent an intravenous infusion of VX to evaluate its effects and to establish a baseline for future experimentation. After approximately 3.5 hours following initial administration of the agent, Sim suddenly became pale and delirious. The experiment was immediately terminated to preserve his life. In their conclusion, the researchers estimated that 2.12 μg/kg of VX delivered intravenously over the course of several hours would be the maximum tolerable dosage and that any more would risk death in a human subject.[38]
In 1988, a United Nations inquiry established thatCuba was responsible for deploying VX against Angolan insurgents during theAngolan Civil War.[39][40] UN toxicologists obtained trace elements of VX from soil, water, and plant samples taken from areas where Cuban troops had recently carried out counter-insurgency operations.[39] Patients demonstrating symptoms of exposure to nerve agents first began appearing in Angolan hospitals around 1984.[41]
There was evidence of a combination of chemical agents having been used byIraq against the Kurds in theHalabja chemical attack in 1988 underSaddam Hussein, including VX.[42] Hussein later testified toUNSCOM that Iraq had researched VX but had failed to weaponize the agent due to production failure. After U.S. and allied forces invaded Iraq, no VX agent or production facilities were found. However, UNSCOM laboratories detected traces of VX on warhead remnants.[43]
In December 1994 and January 1995,Masami Tsuchiya ofAum Shinrikyo synthesized 100 to 200 grams (3.5 to 7.1 oz) of VX which was used to attack three people. Two people were injured, and one 28-year-old man died, who was the first victim of VX ever documented in the world at that time. The VX victim, whomShoko Asahara had suspected as a spy, was attacked at 7:00 am on December 12, 1994, on the street in Osaka byTomomitsu Niimi and another AUM member, who sprinkled the nerve agent on his neck. He chased them for about 90 metres (100 yd) before collapsing, dying ten days later without ever coming out of a deep coma. Doctors in the hospital suspected at the time he had been poisoned with an organophosphate pesticide, but the cause of death was pinned down only after cult members arrested for theTokyo subway sarin attack confessed to the killing. Metabolites of VX such as ethyl methylphosphonate, methylphosphonic acid and diisopropyl-2-(methylthio)ethylamine were later found in samples of the victim's blood seven months after his murder.[44] Unlike the cases forsarin gas (theMatsumoto incident andthe attack on the Tokyo subway), VX was not used for mass murder.
On February 13, 2017,Kim Jong-nam, half-brother of North Korean leaderKim Jong-un, died afteran assault atKuala Lumpur International Airport inMalaysia. According to the authorities he was murdered by poisoning with VX which was found on his face.[45][46] The authorities further reported that one of the women suspected of applying the nerve agent experienced some physical symptoms of VX-poisoning.[47] The director of a non-proliferation research program of theMiddlebury Institute of International Studies at Monterey stated that VX fumes would have killed the suspected attackers even if they had been wearing gloves, suggesting that the VX was applied astwo non-lethal components that would mix to form VX only on the victim's face.[48]
Some countries known to possess VX are the United States (prior to 2022),[49] Russia,[50] North Korea,[51] and Syria.[52] ASudanese pharmaceutical facility, theAl-Shifa pharmaceutical factory, was bombed by the U.S. in 1998 acting on information that it produced VX and that the origin of the agent was associated with both Iraq andAl Qaeda.[citation needed] The U.S. had obtained soil samples identified as containingO-ethyl hydrogen methylphosphonothioate (EMPTA), a chemical used in the production of VX which may also have commercial applications. Chemical weapons experts later suggested that the widely usedfonofos organophosphate insecticide could have been mistaken for EMPTA.[53] Cuba obtained VX during the 1980s and deployed it during itsmilitary intervention in Angola.[39]
In 1969, the U.S. government cancelled its chemical weapons programs, banned the production of VX in the United States, and began the destruction of its stockpiles of agents by a variety of methods. Early disposal included the U.S. Army'sCHASE (Cut Holes And Sink 'Em) program, in which old ships were filled with chemical weapons stockpiles and thenscuttled. CHASE 8 was conducted on June 15, 1967, in which the steamshipCpl. Eric G. Gibson was filled with 7,380 VX rockets and scuttled in 2,200 m (7,200 ft) of water off the coast ofAtlantic City, New Jersey.Incineration was used for VX stockpile destruction starting in 1990 withJohnston Atoll Chemical Agent Disposal System in the North Pacific with other incineration plants following atDeseret Chemical Depot,Pine Bluff Arsenal,Umatilla Chemical Depot andAnniston Army Depot with the last of the VX inventory at these facilities destroyed on December 24, 2008.[54] After 2008 the United States' only remaining stockpile of chemical weapons was located at theBlue Grass Army Depot inKentucky, which housed the last stockpiles ofsarin (GB),mustard gas (H) and VX. The Blue Grass stockpile consisted of 101,764 warheads and canisters containing a total of 523 tons of chemical agents loaded ontoM55 (rocket), M104155 mm caliberhowitzer andM426 8-inch shell artillery shells.[55] Efforts to destroy these agents began in 2019, with the goal of eliminating the United States entire stockpile of chemical weapons by September 30, 2023. TheCenters for Disease Control and Prevention announced in September of 2022 that the last of the United States' stockpile of VX gas had been destroyed, confirming that the last VX rocket was dismantled and destroyed on April 19, 2022.[49]
Worldwide, VX disposal has continued since 1997 under the mandate of theChemical Weapons Convention. When the convention entered force, the parties declared worldwide stockpiles of 19,586 tonnes (21,590 short tons) of VX. As of December 2015, 98% of the stockpiles had been destroyed.[56]
In fiscal year 2008, theU.S. Department of Defense released a study finding that the United States had dumped at least 112 tonnes (124 short tons) of VX into the Atlantic Ocean off the coasts of New York/New Jersey and Florida between 1969 and 1970. This material consisted of nearly 22,000M55 rockets, 19 bulk containers holding 640 kg (1,400 lb) each, and oneM23 chemical landmine.[57]
TheNewport Chemical Depot began VX stockpile elimination using chemical neutralization in 2005. VX was hydrolyzed to much less toxic byproducts by using concentrated caustic solution, and the resulting waste was then shipped off-site for further processing. Technical and political issues regarding this secondary byproduct resulted in delays, but the depot completed their VX stockpile destruction in August 2008.[58]
The remaining VX stockpile in the U.S. was treated by theBlue Grass Chemical Agent-Destruction Pilot Plant in Kentucky, part of theProgram Executive Office, Assembled Chemical Weapons Alternatives program. The program was established as an alternative to the incineration process successfully used by theArmy Chemical Materials Agency, which completed its stockpile destruction activities in March 2012. The Blue Grass Pilot Plant has been plagued by repeated cost over-runs and schedule slippages since its inception.[59]
In Russia, the U.S. provided support for these destruction activities with theNunn-Lugar Global Cooperation Initiative.[60] The Initiative has been able to convert a former chemical weapons depot atShchuchye, Kurgan Oblast into a facility to destroy those chemical weapons. The new facility, which opened in May 2009, has been working on eliminating the nearly 5,400 tonnes (5,950 short tons) of nerve agents held at the former storage complex. However, this facility only held about 14% ofRussian chemical weapons, which were stored at seven sites.[61]
The last of the United States remaining stockpile of chemical agents was destroyed on July 7, 2023 withPresident Biden issuing a press statement that the last of the United States' chemical weapons had been destroyed.[62] The United States was the last of the eight countries that signed the Chemical Weapons Convention to destroy its entire stockpile, this was due to adhering to higher safety protocols than other countries, the government wanted to ensure the protection of both the public and the workers above all, which actually put the United States in violation of the treaty as the last of the stockpile was destroyed after the deadline; the United States' stockpile was the last stockpile of chemical weapons in the world.[63] Although the destruction of the stockpiles does not make the world completely free of chemical weapons, there are nations that have used chemical weapons covertly in recent years likeSyria deployingchlorine gas during theSyrian civil war, Russia has used chemical agents for assassinations andNorth Korea's leaderKim Jong Un used a VX-based nerve agent to kill his half brotherKim Jong-nam.[63]
One of the best-known references to VX in popular culture is its use in the 1996 filmThe Rock,[64][65] which centers on a threatened VX attack onSan Francisco from the island ofAlcatraz. The film usesartistic license, notably with VX being ascribed corrosive powers it does not possess, permitting an early scene in which a VX victim is shown with his face melting, rather than dying through asphyxiation.
Other references to VX are found in the 2012 filmIt's a Disaster in which it is revealed that a nearbydirty bomb attack was a VX attack, prompting the four couples to contemplate a suicide pact, as well as the 2015 filmMission: Impossible – Rogue Nation, in which series protagonistEthan Hunt steals VX nerve gas fromChechen separatists on their way to Syria. Also season 5 of the TV series24, has a similar storyline.[66] The fifth episode of the 2020 anime seriesThe Millionaire Detective Balance: Unlimited features a tear gas bomb with canisters loaded with VX gas and placed inside a cabinet of asafe room within the embassy; the protagonist Daisuke Kambe and two other characters were trapped inside the room after relocating themselves due to security reasons, and figuring out how to escape before the bomb detonates.
The albumVIVIsectVI by theindustrial bandSkinny Puppy contains a song aboutchemical weapons called "VX Gas Attack".
In theBBC showSpooks, series 2 episode 5, a dirty bomb using VX is said to have gone off in a "training exercise". Artistic license is also used in this story, as VX is described as a gas, with "chlorine bonding" making it "almost indestructible." An incorrect formula is given, showing a diester rather than a thioester.
In the video gameEverybody's Gone to the Rapture, VX is alluded to as a nerve agent used by the government to contain a pattern which infects and kills humans and other animals.
In the bookNightshade, the twelfth book in theAlex Rider Series, VX plays a major role, as it is used by terrorists in an attempt to kill over half of the British government.
In the bookIce Cold, the eighth Rizzoli and Isles novel byTess Gerritsen, VX gas is featured and responsible for many deaths.
The second episode of the TV seriesSeal Team (season 1) focuses on a chemical weapons lab in an abandoned hospital, producing VX gas.
In theNetflix showDesignated Survivor, agent Hannah Wells is killed by VX in season 3, episode 7.
In theCBS showMacGyver, season 2 episode 9, a VX canister is the main plot point.
In the 2003 video gameTom Clancy's Rainbow Six 3: Raven Shield, the acquisition of VX by terrorists is a major plot point in both versions of the game.
In theCrackle showStartup, American soldiers discover a computer used by apparent terrorists inAleppo, Syria. "VX components" are displayed as an item for purchase on the computer, which is logged into Araknet, adark web created by the protagonists of the series.
Metal Gear includes references to VX nerve gas in its plotlines, often as a lethal chemical threat within its espionage and warfare scenarios.
{{cite book}}: CS1 maint: multiple names: authors list (link)Given favorable weather conditions, the use of persistent agents such as mustard and VX may pose a threat for many days. Such agents can deny or interfere with enemy occupation of terrain or use of equipment
{{cite web}}: CS1 maint: multiple names: authors list (link)Already in 1988, the United Nations Security Council has been informed of use of toxic weapons by Soviet-supported Cuba in Angola. Belgian toxicologists had certified that residue of chemical weapons—including sarin and VX gas—had been found in plants, water and soil where Cuban troops were alleged to have used chemicals against Savimbi's troops.
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