Sarin

Last updated

Sarin [1]
Sarin-2D-by-AHRLS-2011.png
Sarin-3D-balls-by-AHRLS-2012.png
Names
Pronunciation /ˈsɑːrɪn/
Preferred IUPAC name
Propan-2-yl methylphosphonofluoridate
Other names
(RS)-O-Isopropyl methylphosphonofluoridate; IMPF;
GB; [2]
2-(Fluoro-methylphosphoryl)oxypropane;
Phosphonofluoridic acid, P-methyl-, 1-methylethyl ester
EA-1208
TL-1618
T-144
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C4H10FO2P/c1-4(2)7-8(3,5)6/h4H,1-3H3 Yes check.svgY
    Key: DYAHQFWOVKZOOW-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C4H10FO2P/c1-4(2)7-8(3,5)6/h4H,1-3H3
  • InChI=1/C4H10FO2P/c1-4(2)7-8(3,5)6/h4H,1-3H3
    Key: DYAHQFWOVKZOOW-UHFFFAOYAY
  • FP(=O)(OC(C)C)C
Properties
C4H10FO2P
Molar mass 140.094 g·mol−1
AppearanceClear colourless liquid, brownish if impure
Odor Odourless in pure form. Impure sarin can smell like mustard or burned rubber.
Density 1.0887 g/cm3 (25 °C)
1.102 g/cm3 (20 °C)
Melting point −56 °C (−69 °F; 217 K)
Boiling point 158 °C (316 °F; 431 K)
Miscible
log P 0.30
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Extremely lethal cholinergic agent.
GHS labelling:
GHS-pictogram-skull.svg
NFPA 704 (fire diamond)
NFPA 704.svgHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
4
1
1
0.00003 mg/m3 (TWA), 0.0001 mg/m3 (STEL)
Lethal dose or concentration (LD, LC):
39 μg/kg (intravenous, rat) [3]
NIOSH (US health exposure limits):
IDLH (Immediate danger)
0.1 mg/m3
Safety data sheet (SDS) Lethal Nerve Agent Sarin (GB)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Sarin (NATO designation GB [short for G-series, "B"]) is an extremely toxic organophosphorus compound. [4] A colourless, odourless liquid, it is used as a chemical weapon due to its extreme potency as a nerve agent. Exposure can be lethal even at very low concentrations, where death can occur within one to ten minutes after direct inhalation of a lethal dose, [5] [6] due to suffocation from respiratory paralysis, unless antidotes are quickly administered. [4] People who absorb a non-lethal dose and do not receive immediate medical treatment may suffer permanent neurological damage.[ citation needed ]

Contents

Sarin is widely considered a weapon of mass destruction. Production and stockpiling of sarin was outlawed as of April 1997 by the Chemical Weapons Convention of 1993, and it is classified as a Schedule 1 substance.

Health effects

Sarin (red), acetylcholinesterase (yellow), acetylcholine (blue) Sarin Wirkungsweise.png
Sarin (red), acetylcholinesterase (yellow), acetylcholine (blue)

Like some other nerve agents that affect the neurotransmitter acetylcholine, sarin attacks the nervous system by interfering with the degradation of the neurotransmitter acetylcholine at neuromuscular junctions. Death usually occurs as a result of asphyxia due to the inability to control the muscles involved in breathing. [7]

Initial symptoms following exposure to sarin are a runny nose, tightness in the chest, and constriction of the pupils. Soon after, the person will have difficulty breathing and experience nausea and drooling. This progresses to losing control of bodily functions, which may cause the person to vomit, defecate, and urinate. This phase is followed by twitching and jerking. Ultimately, the person becomes comatose and suffocates in a series of convulsive spasms. Common mnemonics for the symptomatology of organophosphate poisoning, including sarin, are the "killer Bs" of bronchorrhea and bronchospasm because they are the leading cause of death, [8] and SLUDGE – salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis (vomiting). Death may follow in one to ten minutes after direct inhalation, but may also occur after a delay ranging from hours to several weeks, in cases where exposure is limited but no antidote is applied. [7]

Sarin has a high volatility (ease with which a liquid can turn into vapour) relative to similar nerve agents, making inhalation very easy, and may even absorb through the skin. A person's clothing can release sarin for about 30 minutes after it has come in contact with sarin gas, which can lead to exposure of other people. [9]

Management

Treatment measures have been described. [9] Treatment is typically with the antidotes atropine and pralidoxime. [4] Atropine, an antagonist to muscarinic acetylcholine receptors, is given to treat the physiological symptoms of poisoning. Since muscular response to acetylcholine is mediated through nicotinic acetylcholine receptors, atropine does not counteract the muscular symptoms. Pralidoxime can regenerate cholinesterases if administered within approximately five hours. Biperiden, a synthetic acetylcholine antagonist, has been suggested as an alternative to atropine due to its better blood–brain barrier penetration and higher efficacy. [10]

Mechanism of action

Sarin is a potent inhibitor of acetylcholinesterase, [11] an enzyme that degrades the neurotransmitter acetylcholine after it is released into the synaptic cleft. In vertebrates, acetylcholine is the neurotransmitter used at the neuromuscular junction, where signals are transmitted between neurons from the central nervous system to muscle fibres. Normally, acetylcholine is released from the neuron to stimulate the muscle, after which it is degraded by acetylcholinesterase, allowing the muscle to relax. A build-up of acetylcholine in the synaptic cleft, due to the inhibition of acetylcholinesterase, means the neurotransmitter continues to act on the muscle fibre, so that any nerve impulses are effectively continually transmitted.

Sarin acts on acetylcholinesterase by forming a covalent bond with the particular serine residue at the active site. Fluoride is the leaving group, and the resulting organo-phosphoester is robust and biologically inactive. [12] [13]

Its mechanism of action resembles that of some commonly used insecticides, such as malathion. In terms of biological activity, it resembles carbamate insecticides, such as Sevin, and the medicines pyridostigmine, neostigmine, and physostigmine.

Diagnostic tests

Controlled studies in healthy men have shown that a nontoxic 0.43 mg oral dose administered in several portions over a 3-day interval caused average maximum depressions of 22 and 30%, respectively, in plasma and erythrocyte acetylcholinesterase levels. A single acute 0.5 mg dose caused mild symptoms of intoxication and an average reduction of 38% in both measures of acetylcholinesterase activity. Sarin in blood is rapidly degraded either in vivo or in vitro. Its primary inactive metabolites have in vivo serum half-lives of approximately 24 hours. The serum level of unbound isopropyl methylphosphonic acid (IMPA), a sarin hydrolysis product, ranged from 2–135 μg/L in survivors of a terrorist attack during the first four hours post-exposure. Sarin or its metabolites may be determined in blood or urine by gas or liquid chromatography, while acetylcholinesterase activity is usually measured by enzymatic methods. [14]

A newer method called "fluoride regeneration" or "fluoride reactivation" detects the presence of nerve agents for a longer period after exposure than the methods described above. Fluoride reactivation is a technique that has been explored since at least the early 2000s. This technique obviates some of the deficiencies of older procedures. Sarin not only reacts with the water in the blood plasma through hydrolysis (forming so-called 'free metabolites'), but also reacts with various proteins to form 'protein adducts'. These protein adducts are not so easily removed from the body, and remain for a longer period of time than the free metabolites. One clear advantage of this process is that the period, post-exposure, for determination of sarin exposure is much longer, possibly five to eight weeks according to at least one study. [15] [16]

Toxicity

As a nerve gas, sarin in its purest form is estimated to be 26 times more deadly than cyanide. [17] The LD50 of subcutaneously injected sarin in mice is 172 μg/kg. [18]

Sarin is highly toxic, whether by contact with the skin or breathed in. The toxicity of sarin in humans is largely based on calculations from studies with animals. The lethal concentration of sarin in air is approximately 28–35 mg per cubic meter per minute for a two-minute exposure time by a healthy adult breathing normally (exchanging 15 liters of air per minute, lower 28 mg/m3 value is for general population). [19] This number represents the estimated lethal concentration for 50% of exposed victims, the LCt50 value. The LCt95 or LCt100 value is estimated to be 40–83 mg per cubic meter for exposure time of two minutes. [20] [21] Calculating effects for different exposure times and concentrations requires following specific toxic load models. In general, brief exposures to higher concentrations are more lethal than comparable long time exposures to low concentrations. [22] There are many ways to make relative comparisons between toxic substances. The list below compares sarin to some current and historic chemical warfare agents, with a direct comparison to the respiratory LCt50:

Production and structure

Sarin is a chiral molecule because it has four chemically distinct substituents attached to the tetrahedral phosphorus center. [25] The SPform (the (–) optical isomer) is the more active enantiomer due to its greater binding affinity to acetylcholinesterase. [26] [27] The P-F bond is easily broken by nucleophilic agents, such as water and hydroxide. At high pH, sarin decomposes rapidly to nontoxic phosphonic acid derivatives. [28]

It is almost always manufactured as a racemic mixture (a 1:1 mixture of its enantiomeric forms) as this involves a much simpler synthesis while providing an adequate weapon. [26] [27]

A number of production pathways can be used to create sarin. The final reaction typically involves attachment of the isopropoxy group to the phosphorus with an alcoholysis with isopropyl alcohol. Two variants of this process are common. One is the reaction of methylphosphonyl difluoride with isopropyl alcohol, which produces a racemic mixture of sarin enantiomers with hydrofluoric acid as a byproduct: [28]

Sarin synth with racemic stereochemistry.png

The second process, known as the "Di-Di" process, uses equal quantities of methylphosphonyl difluoride (Difluoro) and methylphosphonyl dichloride (Dichloro), rather than just the difluoride. This reaction also gives sarin, but hydrochloric acid as a byproduct instead. The Di-Di process was used by the United States for the production of its unitary sarin stockpile. [28]

The scheme below shows a generic example of the Di-Di process; in reality, the selection of reagents and reaction conditions dictate both product structure and yield. The choice of enantiomer of the mixed chloro fluoro intermediate displayed in the diagram is arbitrary, but the final substitution is selective for chloro over fluoro as the leaving group. Inert atmosphere and anhydrous conditions (Schlenk techniques) are used for synthesis of sarin and other organophosphates. [28]

An example of "di-di" process using arbitrary reagents. Sarin-di-di-process-by-AHRLS-2011.png
An example of "di-di" process using arbitrary reagents.

As both reactions leave considerable acid in the product, sarin produced in bulk by these methods has a short half life without further processing, and would be corrosive to containers and damaging to weapons systems. Various methods have been tried to resolve these problems. In addition to industrial refining techniques to purify the chemical itself, various additives have been tried to combat the effects of the acid, such as:

Another byproduct of these two chemical processes is diisopropyl methylphosphonate, formed when a second isopropyl alcohol reacts with the sarin itself and from disproportionation of sarin, when distilled incorrectly. The factor of its formation in esterification is that as the concentration of DF-DCl decreases, the concentration of sarin increases, the probability of DIMP formation is greater. DIMP is a natural impurity of sarin, that is almost impossible to be eliminated, mathematically, when the reaction is a 1 mol-1 mol "one-stream". [35]

This chemical degrades into isopropyl methylphosphonic acid. [36]

Degradation and shelf life

Rabbit used to check for leaks at former sarin production plant (Rocky Mountain Arsenal), 1970 Sarin test rabbit.jpg
Rabbit used to check for leaks at former sarin production plant (Rocky Mountain Arsenal), 1970

The most important chemical reactions of phosphoryl halides is the hydrolysis of the bond between phosphorus and the fluoride. This P-F bond is easily broken by nucleophilic agents, such as water and hydroxide. At high pH, sarin decomposes rapidly to nontoxic phosphonic acid derivatives. [37] [38] The initial breakdown of sarin is into isopropyl methylphosphonic acid (IMPA), a chemical that is not commonly found in nature except as a breakdown product of sarin (this is useful for detecting the recent deployment of sarin as a weapon). IMPA then degrades into methylphosphonic acid (MPA), which can also be produced by other organophosphates. [39]

Sarin with residual acid degrades after a period of several weeks to several months. The shelf life can be shortened by impurities in precursor materials. According to the CIA, some Iraqi sarin had a shelf life of only a few weeks, owing mostly to impure precursors. [40]

Along with nerve agents such as tabun and VX, sarin can have a short shelf life. Therefore, it is usually stored as two separate precursors that produce sarin when combined. [41] Sarin's shelf life can be extended by increasing the purity of the precursor and intermediates and incorporating stabilizers such as tributylamine. In some formulations, tributylamine is replaced by diisopropylcarbodiimide (DIC), allowing sarin to be stored in aluminium casings. In binary chemical weapons, the two precursors are stored separately in the same shell and mixed to form the agent immediately before or when the shell is in flight. This approach has the dual benefit of solving the stability issue and increasing the safety of sarin munitions.

History

Sarin was discovered in 1938 in Wuppertal-Elberfeld in Germany by scientists at IG Farben who were attempting to create stronger pesticides; it is the most toxic of the four G-Series nerve agents made by Germany. The compound, which followed the discovery of the nerve agent tabun, was named in honor of its discoverers: chemist Gerhard Schrader, chemist Otto Ambros, chemist Gerhard Ritter  [ de ], and from Heereswaffenamt Hans-Jürgen von der Linde. [42]

Use as a weapon

In mid-1939, the formula for the agent was passed to the chemical warfare section of the German Army Weapons Office, which ordered that it be brought into mass production for wartime use. Pilot plants were built, and a production facility was under construction (but was not finished) by the end of World War II. Estimates for total sarin production by Nazi Germany range from 500 kg to 10 tons. [43]

Though sarin, tabun, and soman were incorporated into artillery shells, Germany did not use nerve agents against Allied targets. Adolf Hitler refused to initiate the use of gases such as sarin as weapons. [44]

U.S. Honest John missile warhead cutaway, showing M134 Sarin bomblets (c. 1960) Demonstration cluster bomb.jpg
U.S. Honest John missile warhead cutaway, showing M134 Sarin bomblets (c. 1960)
Sarin gas used against animals in a weapons experiment

See also

Related Research Articles

Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that catalyzes the breakdown of acetylcholine, a neurotransmitter. Nerve agents are irreversible acetylcholinesterase inhibitors used as poison.

<span class="mw-page-title-main">Chemical warfare</span> Using poison gas or other toxins in war

Chemical warfare (CW) involves using the toxic properties of chemical substances as weapons. This type of warfare is distinct from nuclear warfare, biological warfare and radiological warfare, which together make up CBRN, the military acronym for chemical, biological, radiological, and nuclear, all of which are considered "weapons of mass destruction" (WMDs), a term that contrasts with conventional weapons.

<span class="mw-page-title-main">Tabun (nerve agent)</span> Chemical compound

Tabun or GA is an extremely toxic synthetic organophosphorus compound. It is a clear, colorless, and tasteless liquid with a faint fruity odor. It is classified as a nerve agent because it can fatally interfere with normal functioning of the mammalian nervous system. Its production is strictly controlled and stockpiling outlawed by the Chemical Weapons Convention of 1993. Tabun is the first of the G-series nerve agents along with GB (sarin), GD (soman) and GF (cyclosarin).

3-Quinuclidinyl benzilate (QNB) is an odorless and bitter-tasting military incapacitating agent. BZ is an antagonist of muscarinic acetylcholine receptors whose structure is the ester of benzilic acid with an alcohol derived from quinuclidine.

<span class="mw-page-title-main">Soman</span> Chemical compound (nerve agent)

Soman is an extremely toxic chemical substance. It is a nerve agent, interfering with normal functioning of the mammalian nervous system by inhibiting the enzyme cholinesterase. It is an inhibitor of both acetylcholinesterase and butyrylcholinesterase. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations according to UN Resolution 687. Its production is strictly controlled, and stockpiling is outlawed by the Chemical Weapons Convention of 1993 where it is classified as a Schedule 1 substance. Soman was the third of the so-called G-series nerve agents to be discovered along with GA (tabun), GB (sarin), and GF (cyclosarin).

<span class="mw-page-title-main">VX (nerve agent)</span> Chemical compound and chemical warfare nerve agent

VX is an extremely toxic synthetic chemical compound in the organophosphorus class, specifically, a thiophosphonate. In the class of nerve agents, it was developed for military use in chemical warfare after translation of earlier discoveries of organophosphate toxicity in pesticide research. In its pure form, VX is an oily, relatively non-volatile liquid that is amber-like in colour. Because of its low volatility, VX persists in environments where it is dispersed.

Binary chemical weapons or munitions are chemical weapons which contain the toxic agent in its active state as chemical precursors that are significantly less toxic than the agent. This improves the safety of storing, transporting, and disposing of the weapon. Commonly, firing the munition removes a barrier between two precursors. These react to form the intended agent which is then aerosolized and distributed by a bursting charge.

Cyclosarin or GF is an extremely toxic substance used as a chemical weapon. It is a member of the G-series family of nerve agents, a group of chemical weapons discovered and synthesized by a German team led by Gerhard Schrader. The major nerve gases are the G agents, sarin (GB), soman (GD), tabun (GA), and the V agents such as VX. The original agent, tabun, was discovered in Germany in 1936 in the process of work on organophosphorus insecticides. Next came sarin, soman and finally, cyclosarin, a product of commercial insecticide laboratories prior to World War II.

<span class="mw-page-title-main">Chemical weapon proliferation</span> Prevalence and spread of chemical weapons

Many nations continue to research and/or stockpile chemical weapon agents despite numerous efforts to reduce or eliminate them. Most states have joined the Chemical Weapons Convention (CWC), which required the destruction of all chemical weapons by 2012. Twelve nations have declared chemical weapons production facilities and six nations have declared stockpiles of chemical weapons. All of the declared production facilities have been destroyed or converted for civilian use after the treaty went into force.

<span class="mw-page-title-main">Diisopropyl fluorophosphate</span> Chemical compound

Diisopropyl fluorophosphate (DFP) or Isoflurophate is an oily, colorless liquid with the chemical formula C6H14FO3P. It is used in medicine and as an organophosphorus insecticide. It is stable, but undergoes hydrolysis when subjected to moisture.

Methylphosphonyl difluoride (DF), also known as EA-1251 or difluoro, is a chemical weapon precursor. Its chemical formula is CH3POF2. It is a Schedule 1 substance under the Chemical Weapons Convention. It is used for production of sarin and soman as a component of binary chemical weapons; an example is the M687 artillery shell, where it is used together with a mixture of isopropyl alcohol and isopropyl amine, producing sarin.

<span class="mw-page-title-main">VR (nerve agent)</span> Chemical compound

VR is a "V-series" unitary nerve agent closely related to the better-known VX nerve agent. It became a prototype for the series of Novichok agents. According to chemical weapons expert Jonathan Tucker, the first binary formulation developed under the Soviet Foliant program was used to make Substance 33, differing from VX only in the alkyl substituents on its nitrogen and oxygen atoms. "This weapon was given the code name Novichok."

<span class="mw-page-title-main">M55 (rocket)</span> American chemical weapon

The M55 rocket was a chemical weapon developed by the United States in the 1950s. The United States Army produced both Sarin and VX unitary warheads for the M55.

Chemical terrorism is the form of terrorism that uses the toxic effects of chemicals to kill, injure, or otherwise adversely affect the interests of its targets. It can broadly be considered a form of chemical warfare.

Throughout history, chemical weapons have been used as strategic weaponry to devastate the enemy in times of war. After the mass destruction created by WWI and WWII, chemical weapons have been considered to be inhumane by most nations, and governments and organizations have undertaken to locate and destroy existing chemical weapons. However, not all nations have been willing to cooperate with disclosing or demilitarizing their inventory of chemical weapons. Since the start of the worldwide efforts to destroy all existing chemical weapons, some nations and terrorist organizations have used and threatened the use of chemical weapons to leverage their position. Examples of the use of chemical weapons since World War II are Iraq’s Saddam Hussein on the Kurdish village Halabja in 1988 and their employment against civilian passengers of the Tokyo subway by Aum Shinrikyo in 1995. The efforts made by the United States and other chemical weapon destruction agencies intend to prevent such use, but this is a difficult and ongoing effort. Aside from the difficulties of cooperation and locating chemical weapons, the methods to destroy the weapons and to do this safely are also a challenge.

<span class="mw-page-title-main">Chemical weapon</span> Device that uses chemicals to kill or harm individuals

A chemical weapon (CW) is a specialized munition that uses chemicals formulated to inflict death or harm on humans. According to the Organisation for the Prohibition of Chemical Weapons (OPCW), this can be any chemical compound intended as a weapon "or its precursor that can cause death, injury, temporary incapacitation or sensory irritation through its chemical action. Munitions or other delivery devices designed to deliver chemical weapons, whether filled or unfilled, are also considered weapons themselves."

The Khan Shaykhun chemical attack took place on 4 April 2017 on the town of Khan Shaykhun in the Idlib Governorate of Syria. The town was reported to have been struck by an airstrike by government forces followed by massive civilian chemical poisoning. The release of a toxic gas, which included sarin, or a similar substance, killed at least 89 people and injured more than 541, according to the opposition Idlib Health Directorate. The attack was the deadliest use of chemical weapons in the Syrian civil war since the Ghouta chemical attack in 2013.

<span class="mw-page-title-main">EA-3990</span> Chemical compound

EA-3990 is a deadly carbamate nerve agent. It is lethal because it inhibits acetylcholinesterase. Inhibition causes an overly high accumulation of acetylcholine between the nerve and muscle cells. This paralyzes the muscles by preventing their relaxation. The paralyzed muscles include the muscles used for breathing.

<span class="mw-page-title-main">EA-4056</span> Chemical compound

EA-4056 is a deadly carbamate nerve agent. It is lethal because it inhibits acetylcholinesterase. Inhibition causes an overly high accumulation of acetylcholine between the nerve and muscle cells. This paralyzes the muscles by preventing their relaxation. The paralyzed muscles includes the muscles used for breathing.

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