Dimethyl sulfate

Dimethyl sulfate (DMS) is a chemical compound with formula (CH₃O)₂SO₂. As the diester of methanol and sulfuric acid, its formula is often written as ( CH₃)₂ SO₄ 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 (although smelling it would represent significant exposure). Like all strong alkylating agents, Me₂SO₄ is extremely toxic. Its use as a laboratory reagent has been superseded to some extent by methyl triflate, CF₃SO₃CH₃, the methyl ester of trifluoromethanesulfonic acid.

History

Dimethyl sulfate was discovered in the early 19th century in an impure form. J. P. Claesson later extensively studied its preparation.

It was investigated as a candidate for possible use 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.

Production

Dimethyl sulfate can be synthesized in the laboratory by many different methods, the simplest being the esterification of sulfuric acid with methanol:
::2 CH₃OH + H₂SO₄ → (CH₃)₂SO₄ + 2 H₂O
Another possible synthesis involves distillation of methyl hydrogen sulfate:
::2 CH₃HSO₄ → H₂SO₄ + (CH₃)₂SO₄
Methyl nitrite and methyl chlorosulfonate also result in dimethyl sulfate:
::CH₃ONO + (CH₃)OSO₂Cl → (CH₃)₂SO₄ + NOCl

Me₂SO₄ has been produced commercially since the 1920s. A common process is the continuous reaction of dimethyl ether with sulfur trioxide.
::(CH₃)₂O + SO₃ → (CH₃)₂SO₄

Uses

Dimethyl sulfate is best known as a reagent for the methylation of phenols, amines, and thiols. One methyl group is transferred more quickly than the second. Methyl transfer is assumed to occur via an S_N2 reaction. Compared to other methylating agents, dimethyl sulfate is preferred by the industry because of its low cost and high reactivity.

Methylation at oxygen

Most commonly Me₂SO₄ is employed to methylate phenols. Some simple alcohols are also suitably methylated, as illustrated by the conversion of ''tert''-butanol to t-butyl methyl ether:
::2 (CH₃)₃COH + (CH₃O)₂SO₂ → 2 (CH₃)₃COCH₃ + H₂SO₄
Alkoxide salts are rapidly methylated:
::RO⁻ Na⁺ + (CH₃O)₂SO₂ → ROCH₃ + Na(CH₃)SO₄

The methylation of sugars is called Haworth methylation.

Methylation at amine nitrogen

Me₂SO₄ is used to prepare both quaternary ammonium salts or tertiary amines:
::C₆H₅CH=NC₄H₉ + (CH₃O)₂SO₂ → C₆H₅CH=N⁺(CH₃)C₄H₉ + CH₃OSO₃⁻
Quaternized fatty ammonium compounds are used as a surfactant or fabric softeners. Methylation to create a tertiary amine is illustrated as:
::CH₃(C₆H₄)NH₂ + (CH₃O)₂SO₂ (in NaHCO₃ aq.) → CH₃(C₆H₄)N(CH₃)₂ + Na(CH₃)SO₄

Methylation at sulfur

Similar to the methylation of alcohols, mercaptide salts are easily methylated by Me₂SO₄:
::RS⁻Na⁺ + (CH₃O)₂SO₂ → RSCH₃ + Na(CH₃)SO₄
An example is:
::p-CH₃C₆H₄SO₂Na + (CH₃O)₂SO₂ → p-CH₃C₆H₄SO₂CH₃ + Na(CH₃)SO₄
This method has been used to prepare thioesters:
::RC(O)SH + (CH₃O)₂SO₂ → RC(O)S(CH₃) + HOSO₃CH₃

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 sequencing, and the RNA is inferred to be single-stranded at bases with above-background mutation rates.

Dimethyl sulfate can effect 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 (e.g., 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.

Alternatives

Although dimethyl sulfate is highly effective and affordable, its toxicity has encouraged the use of other methylating reagents. Methyl iodide is a reagent used for O-methylation, like dimethyl sulfate, but is less hazardous and more expensive. Dimethyl carbonate, which is less reactive, has far lower toxicity compared to both dimethyl sulfate and methyl iodide. High pressure can be used to accelerate methylation by dimethyl carbonate. In general, the toxicity of methylating agents is correlated with their efficiency as methyl transfer reagents.

Safety

Dimethyl sulfate is carcinogenic and mutagenic, highly poisonous, 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 / 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 hours. 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.

References

External links

WebBook page for C2H6SO4

{{DEFAULTSORT:Dimethyl Sulfate
Methyl esters
Methylating agents
IARC Group 2A carcinogens
Sulfate esters