1 CHEMICAL WARFARE the Use of Chemical Agents in Warfare Goes Back to Ancient Times. Early Chemical Weapons Included Smoke

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CHEMICAL WARFARE

The use of chemical agents in warfare goes back to ancient times. Early chemical weapons included smoke and poisons; more recent weapons include chlorine gas, mustard gas, napalm and nerve agents. Chemical agents may be delivered by a variety of methods including bombs, spray tanks, rockets, missiles, land mines and artillery projectiles. Chemical warfare requires access to or the ability to make the materials, delivery systems that can be used in different battle situations, plans for safely handling the weapons, and self-protective measures. Because of the cumbersome and uncomfortable protective clothing that personnel must wear to defend against chemical weapons, the mere threat of chemical agents can greatly reduce military effectiveness.

In 1974, the United States signed the Geneva Protocol of 1925 that bans the use of poisonous substances in war; and in 1992 signed the Chemical Weapons Convention. The signatories of this treaty agree to stop producing chemical weapons and to destroy all of their existing stockpiles. To date, the U.S. has destroyed almost half of its chemical weapon stockpiles.

Classes of chemical weapons. There are three classes of chemical weapons:

1. Smoke. Smoke has taken on a new military significance in recent years, because it is an effective defense against laser and optically guided munitions. a. Vaporized oil. A simple way to make smoke is to inject oil onto a hot exhaust manifold and then let the oil recondense as small droplets. b. HC. HC is a mixture containing grained aluminum, zinc oxide and hexachloroethane. HC is used in grenades, candles and artillery shells.

c. White phosphorous. White phosphorous (WP), which burns when it comes in contact with air, produces P2O5. Artillery shells filled with WP are also used for their incendiary (fire- causing) effect.

2. Flame weapons. a. Oils. The most familiar incendiary, napalm, is merely gasoline or a similar fuel, to which a detergent-like thickener is added. Thickener is used to slow the burning, improve clinging properties, and cause the fuel to rebound off walls and go around corners. b. Metals. Thermite is the major metal incendiary. It is essentially a mixture of powdered iron oxide and granular aluminum. The casing of a thermite bomb is often made of magnesium, which is highly flammable, burning with a hot, white flame that can serve to ignite the thermite mixture.

3. Toxic agents. Toxic agents are classified into four groups depending on their action. Less toxic agents are also used for riot control (see section V).

I. Blister Agents Agents that cause blisters on skin and damage the respiratory tract, mucous membranes, and eyes. Name Physical Characteristics Persistency2 Commercial Uses of Chemicals or Precursor Chemicals3 Paper and rubber manufacturing, Sulfur Mustard Colorless to amber, oily liquid Persistent pharmaceuticals, insecticides, plastics, (HD) with odor of garlic detergents, cosmetics, lubricants Light amber liquid with odor of Lewisite Semi-persistent Ceramics, insecticides, pharmaceuticals geraniums Nitrogen Toiletries, insecticides, waxes, polishes, Amber, odorless liquid Persistent Mustard (HN-3)4 lubricants, cosmetics Paper and rubber manufacturing, Mustard- Liquid with garlic odor Semi-persistent pharmaceuticals, insecticides, plastics, Lewisite (HL) detergents, cosmetics, ceramics, lubricants Phosgene oxime Colorless liquid or crystalling Relatively non- (CX) solid with a disagreeable odor persistent II. Nerve Agents Lethal substances that disable enzymes responsible for the transmission of nerve impulses. Name (Symbol) Physical Characteristics Persistency2 Commercial Uses of Chemicals or Precursor Chemicals3 Brownish to colorless liquid Insecticides, gasoline additives, detergents, Tabun (GA) with odor ranging from none to Persistent missile fuel, plastics, dyes, and pigments fruity Colorless liquid with almost no Fire retardants, insecticides, disinfectants, paint Sarin (GB) Non-persistent odor solvents, ceramics, optical brighteners Colorless liquid with fruity to Fire retardants, paint solvents, ceramics, Soman (GD) Semi-persistent camphor like odor disinfectants, textile softeners Insecticides, pyrotechnics, textile softeners, VX Amber liquid with no odor Persistent pharmaceuticals Novichok Unknown Unknown Fertilizers, pesticides agents5

III. Choking Agents Substances that damage respiratory tract, causing extensive fluid build-up in the lungs. Name (Symbol) Physical Characteristics Persistency2 Commercial Uses of Chemicals or Precursor Chemicals3 Colorless to slightly yellow Disinfectants, plastics, pesticides, solvents, Chlorine Non-persistent with sharp, irritating odor chemical synthesis Colorless gas with odor of Phosgene (CG) Non-persistent Plastics, pesticides, dyes, and herbicides freshly mown hay, or corn Diphosgene Colorless liquid with odor of Non-persistent Plastics, pesticides, dyes, and herbicides (DP) corn or freshly mown hay Chloropicrin Oily, colorless liquid with Non-persistent Disinfectant, chemical synthesis (PS) pungent odor IV. Blood Agents Agents that interfere with the absorption of oxygen into the bloodstream. Name (Symbol) Physical Characteristics Persistency2 Commercial Uses of Chemicals or Precursor Chemicals3 Hydrogen Colorless gas with odor of bitter Pesticides, fumigating, electroplating, gold and Non-persistent Cyanide (AC) almonds silver extraction Cyanogen Colorless liquid with sharp, Non-persistent Dyes and pigments, nylon production Chloride (CK) pungent odor V. Riot Control (Incapacitating) Agents6 Substances that rapidly produce temporary disabling effects. Name (Symbol) Physical Characteristics Persistency2 Commercial Uses of Chemicals or Precursor Chemicals3 Tear Agent 2 Colorless, gray solid with sharp, Non-persistent Commercially available as mace (CN) irritating, floral odor Tear Agent O White crystalline substance Non-persistent (CS) with pepper-like odor Psychedelic White crystalline solid with no Non-persistent Pharmaceuticals, tranquilizers Agent 3 (BZ) odor

1. Sources: Central Intelligence Agency, The Chemical and Biological Warfare Threat (Washington, D.C.: Central Intelligence Agency, 1995); Office of Technology Assessment, Proliferation of Weapons of Mass Destruction: Assessing the Risks, OTA-ISC-559 (Washington, D.C.: Government Printing Office, 1993); Valerie Adams, Chemical Warfare, Chemical Disarmament (Indianapolis: Indiana University Press, 1990); Stockholm International Peace Research Institute, The Problem of Chemical and Biological Warfare Volume I The Rise of CB Weapons (New York: Humanities Press, 1971); Chemical Weapons Convention Verification: Handbook on Scheduled Chemicals (August 1993); Gordon Burck and Charles Floweree, International Handbook on Chemical Weapons Proliferation ( New York: Greenwood Press, 1991); U.S. Army Center for Health Promotion and Medicine, Detailed Chemical Fact Sheets, Office to the Deputy for Technical Services, last updated 23 July 1998; Iraqi Weapons of Mass Destruction Programs (Washington, D.C.: Central Intelligence Agency, 13 February 1998); Edward M. Spiers, Chemical Warfare (Urbana: University of Illinois Press, 1986); Robert E. Boyle, U.S. Chemical Warfare: A Historical Perspective, (Albuquerque, N.M.: Sandia National Laboratories, August 1998) 2. Persistency refers to the length of time that contact and inhalation effects of an agent remain operative (Burck & Floweree) 3. Precursors are chemicals changed by reaction to make a chemical warfare agent. 4. In total, three nitrogen mustard agents were developed. The first, HN-1, explored in the late 1920s and early 1930s, was originally designed as a pharmaceutical product. HN-2 followed as a military agent, but later transitioned into the pharmeutical realm. HN-3 was the last of the nitrogen mustards to be developed. These charts focus on HN-3 because its formidable blistering capabilities approach sulfur mustard (HD). 5. For more information regarding novichok agents, refer to Vil Mirzayanov's "Dismantling the Soviet/Russian Chemical Weapons Complex: An Insider's View," Chemical Weapons Disarmament in Russia: Problems and Prospects (Washington, D.C.: Henry L. Stimson Center, 1995). 6. Riot control agents listed are a partial representation of existing incapacitating agents. Other agents currently stockpiled around the world for law enforcement purposes can cause vomiting and irritation of the skin, among other symptoms.

Chemical agent detection and protection. Personnel at risk of exposure to chemical weapons are provided with personal chemical defense equipment that includes protective clothing (mask, battle dress overgarment, gloves and boots), decontamination kits, and detection devices. The exact nature of these items will vary according to the perceived threat.

The simplest detection devices are specially-treated paper and tape strips that are worn on the outer clothing (M8 paper and M9 tape). The M8 paper can be used to identify suspected liquid toxins as either a persistent or nonpersistent nerve agent or a blister agent. M9 paper can detect the presence of liquid agents but cannot distinguish between them. More sophisticated detectors, such as the Chemical Agent Monitor (CAM) and the M8A1 Chemical agent alarm can detect nerve and blister agents as vapors. These detectors use radioactive isotopes to generate alpha or beta-particles that will ionize airborne agents drawn into the unit by a pump. The ions are analyzed according to their mass and charge by a built-in microprocessor. CAM reports both the identity and the approximate concentration of volatile agents; M8A1 reports only on the presence of nerve agent vapors.

References: Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare; Zajtchuk, R., Ed.; Office of the Surgeon General: Bethesday MD, 1997, chapters 4-8, 11-12. http://www.chemistry.usna.edu/NavApps/PDF/Chemical%20Warfare_v2.pdf, http://www.newscientist.com/article.ns?id=mg18725095.600, http://en.wikipedia.org/wiki/Chemical_weapons, http://www.opcw.org/resp/html/detect.html http://www.fas.org/nuke/guide/usa/doctrine/army/mmcch/index.html Toxin info adapted from http://www.stimson.org/cbw/?sn=CB2001121892

CASE STUDY: Sarin

Sarin (NATO designation GB, IUPAC designation 2-(fluoro-methylphosphoryl)-oxypropane) disrupts the function of the enzyme acetylcholinesterase. This enzyme is necessary to “reset” cholinergic neurons and sarin prevents it from doing so by irreversibly occupying the binding pocket of the enzyme where acetylcholine would ordinarily bind. This leads to respiratory distress, convulsions, and death unless treatment is administered quickly.

Enzymatic Catalysis Enzymes are proteins that catalyze, or speed up, chemical reactions, without being consumed. Enzymes cannot alter the final state, or equilibrium, between reactants and products for the reaction; they can only increase the rate at which equilibrium is achieved. Enzymes are not used in stoichiometric quantities. Rather, a single enzyme molecule may act on tens of thousands of molecules, or substrates. During the enzyme-catalyzed reaction (shown in the figure below), the substrate is converted into a transition state. Transition states are not long-lived entities, but represent a fleeting moment in the reaction (depicted as peaks in the lower trace in the figure). The activation energy, Ea, is the difference in energy between the substrate and transition state. Transition states are strained variants of the substrate, in which bonds are in the process of being broken or formed. In addition, one or more reaction intermediates may form during the reaction. Unlike transition states, intermediates may be stable species (depicted as a valley in the lower trace in the figure). However, intermediates are ultimately converted to products. Enzymes, like all catalysts, accelerate chemical reactions by lowering their activation energy, Ea (recall the Arrhenius

equation, k = Ae− Εa /RΤ). Enzymes work by providing an alternative, lower-energy reaction pathway, or mechanism, and by stabilizing the transition state. Specifically, the active site of the enzyme provides a framework for orienting the substrate in the optimal geometry for reactivity. Binding energy released from the intermolecular forces involved in binding between enzyme and substrate helps to drive the reaction forward. Another key feature of enzymes is their specificity. Enzymes have evolved an exquisite specificity for their substrates. A molecule that is quite similar to the substrate may not be acted upon by the enzyme. Enzymes are also specific for temperature. While the rate of a non-enzymatic reaction is usually increased with increasing temperature (due to increased kinetic energy of the reactants), the effectiveness (and even the structural integrity) of enzymes is very sensitive to temperature. Enzymes are also sensitive to inhibitors, molecules that interfere with catalysis. Inhibitors lower the efficiency of an enzyme. Some inhibitors bind to the active site of an enzyme, thereby preventing the substrate from binding. Irreversible inhibitors bind covalently to the enzyme, while reversible inhibitors do not. Other inhibitors are transition-state analogs, which mimic the geometry of the transition state. Transition-state analogs may bind to the active site of the enzyme far more tightly than the substrate.

The mechanism of acetylcholinesterase: Acetylcholine is a neurotransmitter, a chemical messenger that propagates the nerve impulse across a synapse, the gap between neurons. Acetylcholine is the substrate for the enzyme acetylcholinesterase. This enzyme is essential for nerve transmission at neuromuscular junctions, the connections between nerves and muscles. Acetylcholinesterase removes excess acetylcholine from the synapse, allowing the neuron to reload and fire its next nerve impulse. If acetylcholine builds up at the junction, the muscles cannot relax, leading to sustained involuntary muscle contractions and, ultimately, death. The chemical reaction catalyzed by acetylcholinesterase is:

+ H2O Notice that this hydrolysis reaction is the reverse of the condensation O reaction you studied last semester in the context of polymers.

Acetylcholinesterase is potently and irreversibly inhibited by organophosphates, including sarin. Note the similar chemical structures for the acetylcholine and sarin:

H3C H H O H O + H3C N C C OCCH3 H3C C O P CH3

H3C H H CH3 F

acetylcholine sarin

Phosphorus substitutes for carbon in the methyl ester linkage of acetylcholine, however phosphorus atom has a tetrahedral geometry, like the geometry of the transition states for the acetylcholine reaction, rather than the planar geometry of the ester linkage itself. This chemical is a transition state analog. Because the enzyme has a higher affinity for the transition state than for the reactant acetylcholine, sarin preferentially binds to the enzyme. Once bound sarin forms a covalent bond between its phosphorus and the active site serine, preventing the enzyme from reacting with its natural substrate.

Figure 2. Sarin covalently bound in the active site binding pocket of acetylcholinesterase. (Millard et al. (1999) Biochemistry 38: 7032-7039.)

Recent use of sarin as a chemical weapon:

1987: Hussein uses sarin in ethnic warfare Iraq began producing sarin in 1984 and admitted to possessing 790 tons of it in 1995. Saddam Hussein used sarin on the Kurds in northern Iraq during a 1987-88 campaign known as the Anfal. The worst attack occurred in March 1988 in the Kurdish village of Halabja; a combination of chemical agents including sarin, mustard gas, and possibly VX killed as many as 5,000 people and left 65,000 others facing severe skin and respiratory diseases, abnormal rates of cancer and birth defects, and a devastated environment. Experts say Saddam Hussein also launched about 280 lesser chemical attacks against the Kurds. (http://cfrterrorism.org/weapons/sarin.html)

1995: Sarin used in Japanese domestic terrorism The sarin gas attack on the Tokyo subway was an act of domestic terrorism perpetrated by members of the religious group Aum Shinrikyo on March 20, 1995. In five coordinated attacks, the terrorists released sarin gas on several lines of the Tokyo Subway, killing twelve people and injuring some six thousand more. The attack was directed against trains passing through Kasumigaseki and Nagatacho, home to the Japanese government. (http://en.wikipedia.org/wiki/Sarin_gas_attack_on_the_Tokyo_subway)

6 Chemical Warfare Name ______

1. Sulfur mustard (a.k.a. mustard gas) has the structure Cl-CH2-CH2-S-CH2-CH2-Cl. a. Re-draw the structure in the space below and add any missing lone pairs to the structure.

b. What is the molecular geometry around the C and S atoms in the sulfur mustard molecule?

C atom ______S atom ______

c. What is the hybridization of the S atom in the molecule? ______

d. What is the bond angle about the S atom in the molecule? ______

e. Sulfur mustard is completely soluble in carbon tetrachloride but only slightly soluble in water (0.092 g/100 g water at 22 ˚C). What does this tell you about the polarity of sulfur mustard?

f. Calculate the mass percent of Cl in sulfur mustard?

2. Sulfur mustard exists as a liquid at room temperature but will evaporate to some extent. The density of sulfur mustard vapor is 5.4 times greater than air. Speculate as to why it was found that the maximum amount of casualties could be produced by mustard attacks that were carried out at night on soldiers in trenches during World War I.

3. The lethal dose of liquid sulfur mustard on the skin for 50% of an exposed population (i.e. the LD50), is about 100 mg/kg. If a person weighs 150 lbs, how many grams of liquid sulfur mustard would be needed to kill them? (1 kg = 2.2 lbs)

7 4. The density of liquid sulfur mustard is 1.27 g/mL at 20 ˚C. How many mL would comprise a lethal dose on the skin of a 150 lb person?

5. The water solubility for sulfur mustard is reported in question #1e above. If the density of water at 22 ˚C is 0.998 g/cm3, calculate the water solubility of sulfur mustard in units of molarity. (Assume the density of the solution is the same as that of water at 22 ˚C).

6. Describe how enzymes catalyze chemical reactions.

7. Draw the two products of the hydrolysis of acetylcholine (include lone pair electrons in your drawing). Circle and label the functional groups in each molecule.

8. Why are nerve agents such as sarin so effective at inhibiting acetylcholinesterase? (Consider the molecular structure/geometry of substrate versus inhibitor.)

8 9. Refer to the graph of initial rate vs. substrate concentration for a typical enzyme to answer the following questions.

Dependence of rate on substrate concentration 50

10 Initial rate (M/s)Initial rate

0 0 200 400 600 800 1000

[substrate] (M)

a. At low substrate concentration, what is the reaction order with respect to [substrate]?

b. What is the reaction order at high substrate concentration?

c. At high substrate concentration, the rate approaches a maximum value (Vmax). Estimate Vmax from the graph. Include the correct unit.

10. Fresh calcium hypochlorite solution is highly effective at decontaminating surfaces exposed to most chemical warfare agents. In particular, the destruction of the nerve agent VX by calcium hypochlorite at pH 10.5 is a first-order reaction with a half-life of 1.5 minutes at 20 °C. a. How long does it take for only 0.10% of the original amount of VX to remain on a surface after being treated with hypochlorite solution? (Assume the surface is non-porous.)

b. The destruction of VX by hypochlorite solution is an oxidation/reduction reaction. How would you expect the ambient temperature to affect the decontamination reaction? Explain in terms of the Arrhenius equation.

9 11. The Active Denial System (ADS) is a non-chemical based incapacitating weapon. In tests, the ADS fired a 95-gigahertz microwave beam, which is supposed to heat skin and to cause pain within 2 to 3 seconds of contact. Within 5 seconds of contact, the pain is expected to force people to move out of the beam before the skin can be burned.

a. What is the wavelength of the microwave radiation that this weapon produces in units of nm? (1 gigahertz = 1 x 109 Hz, c = 2.998 x 108 m/s, 1 m = 1 x 109 nm)

b. How much energy, in kJ, does one photon of the wavelength of the microwave beam in this weapon correspond to? (h = 6.626 x 10–34 J·s)

c. The average male body contains ~60% water by mass. How many kilojoules of heat would be required to boil an equivalent amount of water to that in the body of a 70 kg male? (specific heat of water = 4.184 J/g ˚C, average body temperature of a human is ~98.6 ˚F)

d. How many photons of the microwave radiation from the LDS does the energy that you calculated in part c. correspond to?

12. Below are the structures of CS gas (tear gas) and capsaicin (the main ingredient in pepper spray). How many sigma and/or how many pi bonds are in each of these molecules?

Cl H H C N C H H N

CS gas capsaicin _____ sigma bonds _____ pi bonds _____ pi bonds 10