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Dimethyl sulfate ( DMS) is a chemical compound with chemical formula (CH3O)2SO2. As the ester of methanol and sulfuric acid, its formula is often written as (Methyl)2Sulfate or Me2SO4, where CH3 or Me is methyl. Me2SO4 is mainly used as a methylating agent in organic synthesis. Me2SO4 is a colourless oily liquid with a slight onion-like odour. Like all strong , Me2SO4 is highly toxic. (2025). 9783527303854 ISBN 9783527303854 Its use as a laboratory reagent has been superseded to some extent by methyl triflate, CF3SO3CH3, the methyl ester of trifluoromethanesulfonic acid.
It was investigated for possible use in chemical warfare in World War I in 75% to 25% mixture with methyl chlorosulfonate (CH3ClO3S) called "C-stoff" in Germany, or with chlorosulfonic acid called "Rationite" in France.
The esterification of sulfuric acid with methanol was described in 1835:
Dimethyl sulfate can be synthesized in the laboratory by several methods. The reaction of methyl nitrite and methyl chlorosulfonate also results in dimethyl sulfate:
Despite its obvious appeal, the esterification of sulfuric acid with methanol produces only minuet quantities of dimethyl sulfate. The equilibrium constant does not favour its formation. Additionally, any dimethyl sulfate that is formed can react further and irreversibly with methanol to give methyl bisulfate and dimethyl ether:
In some cases, simple alcohols are also methylated, as illustrated by the conversion of Tert-Butanol to t-butyl methyl ether:
The methylation of is called Haworth methylation. The methylation of ketones is called the Lavergne reaction.
Dimethyl sulfate can affect the base-specific cleavage of DNA by attacking the imidazole rings present in guanine. Dimethyl sulfate also methylates adenine in single-stranded portions of DNA (for example, those with proteins like RNA polymerase progressively melting and re-annealing the DNA). Upon re-annealing, these methyl groups interfere with adenine-guanine base-pairing. Nuclease S1 can then be used to cut the DNA in single-stranded regions (anywhere with a methylated adenine). This is an important technique for analyzing protein-DNA interactions.
One hypothesis regarding the apparently mysterious 1994 "toxic lady" incident is that the person at the centre of the incident had built up dimethyl sulfone crystals in her blood, which were converted by an unknown mechanism to dimethyl sulfate vapour that poisoned attending medical staff.
Reactions and uses
Dimethyl sulfate is a reagent for the methylation of , , and . One methyl group is transferred more quickly than the second. Methyl transfer is assumed to occur via an SN2 reaction. Compared to other methylating agents, dimethyl sulfate is preferred by the industry because of its low cost and high reactivity.
Methylation at oxygen
Commonly dimethyl sulfate is employed to methylate .
Methylation at amine nitrogen
Me2SO4 is used to prepare both quaternary ammonium salts or :
Quaternized fatty ammonium compounds are used as a surfactant or fabric softener. Methylation to create a tertiary amine is illustrated as:
Methylation at sulfur
Thiolate salts are easily methylated by Me2SO4 to give methyl :
In a related example:
This method has been used to prepare from thiocarboxylic acids:
Reactions with nucleic acids
Dimethyl sulfate (DMS) is used to determine the secondary structure of RNA. At neutral pH, DMS methylates unpaired adenine and cytosine residues at their canonical Watson–Crick faces, but it cannot methylate base-paired nucleotides. Using the method known as DMS-MaPseq, RNA is incubated with DMS to methylate unpaired bases. Then the RNA is reverse-transcribed; the reverse transcriptase frequently adds an incorrect DNA base when it encounters a methylated RNA base. These mutations can be detected via DNA sequencing, and the RNA is inferred to be single-stranded at bases with above-background mutation rates.
Alternatives
Although dimethyl sulfate is highly effective and affordable, its very high toxicity has encouraged the use of other methylating reagents such as methyl iodide, which is less hazardous but more expensive, or dimethyl carbonate, which is far less reactive but has far lower toxicity than dimethyl sulfate or methyl iodide. In general, the toxicity of methylating agents is correlated with their efficiency as methyl transfer reagents.
Safety
Dimethyl sulfate is and , highly , corrosive, and environmentally hazardous. It is absorbed through the skin, mucous membranes, and gastrointestinal tract, and can cause a fatal delayed respiratory tract reaction. An ocular reaction is also common. There is no strong odor or immediate irritation to warn of lethal concentration in the air. The LD50 (acute, oral) is 205 mg/kg (rat) and 140 mg/kg (mouse), and LC50 (acute) is 45 ppm per 4 hours (rat). The vapor pressure of 65 PaICSC is sufficiently large to produce a lethal concentration in air by evaporation at 20 °C. Delayed toxicity allows potentially fatal exposures to occur prior to development of any warning symptoms. Symptoms may be delayed 6–24 h. Concentrated solutions of bases (ammonia, alkalis) can be used to hydrolyze minor spills and residues on contaminated equipment, but the reaction may become violent with larger amounts of dimethyl sulfate (see ICSC). Although the compound hydrolyses, treatment with water cannot be assumed to decontaminate it.
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