Methyl fluoroacetate (MFA) is an organic compound with the chemical formula FCH2CO2CH3. It is the extremely toxic methyl ester of fluoroacetic acid. It is a colorless, odorless liquid at room temperature. It is used as a laboratory chemical and as a rodenticide. Because of its extreme toxicity, MFA was studied for potential use as a chemical weapon. The general population is not likely to be exposed to methyl fluoroacetate. People who use MFA for work, however, can breathe in or have direct skin contact with the substance.
History MFA was first synthesized in 1896 by the Belgian chemist Frédéric Swarts by reacting methyl iodoacetate with silver fluoride. It can also be synthesized by reacting methyl chloroacetate with potassium fluoride Because of its toxicity, MFA was studied for potential use as a chemical weapon during World War II. It was considered a good water poison since it is colorless and odorless and therefore it can toxify the water supply and kill a big part of the population. By the end of the war, several countries began to make methyl fluoroacetate to debilitate or kill the enemy.
Synthesis The synthesis of methyl fluoroacetate consists of a two-step process:
Potassium fluoride (KF) and the catalyst are added into the solvent within the reactor; this is then stirred and heated up. The catalyst mentioned in this step is a phase-transfer catalyst and can be the chemicals dodecyl(trimethyl)ammonium chloride [(CH3(CH2)11)(CH3)3N]+Cl−, tetrabutylammonium chloride [(CH3(CH2)3)4N]+Cl−, tetrabutylammonium bromide [(CH3(CH2)3)4N]+Br−, or tetramethylammonium chloride [(CH3)4N]+Cl−. The mass ratio of the potassium fluoride and the catalyst in this step is 0.5~1 : 0.02~0.03. With the solvent mentioned in this step being a mixture of dimethylformamide (HCON(CH3)2) and acetamide (CH3CONH2) with a mass ratio of 1.4~1.6: 1. The mass ratio of the solvent and potassium fluoride is 1.1~2.0 : 0.5~1. When the reaction temperature of 100~160 °C is reached, methyl chloroacetate ClCH2CO2CH3 is continuously added in the reactor at a speed of 5~10 kg/min with the mass ratio of methyl chloroacetate and potassium fluoride being 1:0.5～1. The reaction between these chemicals produces a gas mixture, with the gases within this mixture then being split between two condensers according to their condensation temperature. Methyl chloroacetate is condensed within the condenser set at 100~105 °C, it is then returned to the reactor to continue participating in the chemical reaction. Methyl fluoroacetate in the other condenser then enters a two-stage nitration condensation at a temperature of 20~25 °C which then ensures that the methyl fluoroacetate is condensed into a liquid with it being the product of this reaction.
Structure and reactivity Methyl fluoroacetate is a methyl ester of fluoroacetic acid. MFA is a liquid, which is odorless or can have a faint, fruity smell. The boiling point of MFA is 104.5 °C and the melting point is −35.0 °C. It is soluble in water (117 g/L at 25 °C) and slightly soluble in petroleum ether. MFA is resistant to the displacement of fluorine by nucleophiles, so there is higher stability of the C−F bond compared to the other halogens (C−Cl, C−Br, C−I). The other haloacetates are more powerful alkylating agents that react with −SH group of proteins. This, however, does not happen for MFA and gives it a unique toxic action. Moreover, MFA is a derivative of fluoroacetate (FA) compound which is as toxic and has similar biotransformation to MFA.
Mechanism of action and metabolism Generally, fluoroacetates are toxic because they are converted to fluorocitrate by fluoroacetyl coenzyme A. Fluorocitrate can inhibit aconitate hydratase, which is needed for the conversion of citrate, by competitive inhibition. This interrupts the citric acid cycle (TCA cycle) and also causes citrate to accumulate in the tissues and eventually in the plasma. MFA is mainly biotransformed by glutathione transferase enzyme in a phase 2 biotransformation process. The GSH-dependent enzyme couples glutathione to MFA and thereby defluorinating MFA. As a result, a fluoride anion and S-carboxymethylglutathione are produced. The decoupling of fluoride is mediated by a fluoroacetate-specific defluorinase. The defluorinating activity is mainly present in the liver, but also kidneys, lungs, the heart, and the testicles show activity. In the brain, there are no signs of defluorination. Eventually, fluorocitrate (FC) is formed which is the main toxic compound. It binds the aconitase enzyme with a very high affinity and therefore intervenes in the TCA cycle. Citrate in normal circumstances is converted to succinate, but the process is inhibited. The cycle stops and oxidative phosphorylation is prevented since NADH, FADH2 and succinate are required from the TCA cycle. Respiration stops shortly. The poison acts very quickly and has no antidote. Mammals are intolerant to MFA. However, a few Australian species (e.g. brush-tailed possum) show a level of tolerance to fluoroacetate by metabolizing it using glutathione-S-transferase. Fluoride can be removed from fluoroacetate or fluorocitrate. It is involved in detoxifying the aryl and alkyl groups by converting them into glutathione conjugates. The C−F bond is cleaved because of a nucleophilic attack of carbon resulting in the formation of S-carboxymethyl glutathione. This can be afterward excreted in the form of S-carboxymethylcysteine. The elimination half-life of biotransformed MFA is about 2 days. When administered, the MFA mainly resides in blood plasma, but can also be traced in the liver, kidney, and muscle tissue.
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