Dimethyl sulfate

Dimethyl sulfate is a chemical compound with formula (CH₃O)₂SO₂. As the dimethyl ester of sulfuric acid. Its formula is often written as (CH₃)₂SO₄ or even Me₂SO₄; where CH₃ or Me is methyl. Me₂SO₄ is mainly used as a methylating agent in organic synthesis.

Under standard conditions, 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 highly toxic. Its use as a laboratory reagent has been superseded to some extent by methyl triflate, CF₃SO₃CH₃, the methyl ester of trifluoromethanesulfonic acid.

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History

Dimethyl sulfate was first discovered in the early 1800s in an impure form. P. Claesson later extensively studied its preparation.^[1]

Production

Dimethyl sulfate can be synthesized in the laboratory by many different syntheses:^[2]

2 CH₃OH + H₂SO₄ → (CH₃)₂SO₄ + 2 H₂O

Another possible synthesis involves distillation of methyl hydrogen sulfate:^[1]

2 CH₃HSO₄ → H₂SO₄ + (CH₃)₂SO₄

Methyl nitrite and methyl chlorosulfonate also result in dimethyl sulfate^[1]:

CH₃ONO + (CH₃)OSO₂Cl → (CH₃)₂SO₄ + NOCl

In the United States, Me₂SO₄ has been produced commercially since the 1920s. A common process is the continuous reaction of dimethyl ether with sulfur trioxide.^[3]

(CH₃)₂O + SO₃ → (CH₃)₂SO₄

Uses

Dimethyl sulfate is best known as a reagent for the methylation of phenols, amines, and thiols. Typically, one methyl group is transferred more quickly than the second. Methyl transfer is typically assumed to occur via an S_N2 reaction. 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.^[4] Dimethyl carbonate has far lower toxicity compared to both dimethyl sulfate and methyl iodide and can be used to instead of dimethyl sulfate for N-methylation.^[5] In general the toxicity of methylating agents is correlates with their efficiency as methyl transfer reagents.

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-butyl alcohol to t-butyl methyl ether:

2 (CH₃)₃COH + (CH₃O)₂SO₂ → 2 (CH₃)₃COCH₃ + H₂SO₄

Alkoxide salts are rapidly methylated:^[6]

RO ^- Na ⁺ + (CH₃O)₂SO₂ → ROCH₃ + Na(CH₃)SO₄

Methylation at amine nitrogen

Me₂SO₄ is used to prepare both quaternary ammonium salts or tertiary amines:

C₆H₅CH=NC₄C₉ + (CH₃O)₂SO₂ → C₆H₅CH=N⁺(CH₃)C₄C₉ + CH₃OSO₃^-

Quaternized fatty ammonium compounds are used as a surfactant or fabric softeners. The methylation of a tertiary amine is illustrated as^[6]:

CH₃(C₆H₂)NH₂ + (CH₃O)₂SO₂ (in HNCO₂) → CH₃(C₆H₂)N(CH₃)₂ + Na(CH₃)SO₄

Methylation at sulfur

Similar to the methylation of alcohols, mercaptide salts are easily methylated by Me₂SO₄^[6]:

RS^-Na⁺ + (CH₃O)₂SO₂ → RSCH₃ + Na(CH₃)SO₄

An example is:^[4]

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

Other Uses

With DNA dimethyl sulfate can effect the base-specific cleavage of guanine by rupturing the imidazole rings present in guanine.^[7] This process can be used to determine base sequencing, cleavage on the DNA chain, and other applications.

Safety

Dimethyl sulfate is likely carcinogenic^[3] and mutagenic, poisonous, corrosive, environmentally hazardous and volatile (presenting an inhalation hazard). Some consider it a potential chemical weapon. Dimethyl sulfate is absorbed through the skin, mucous membranes, and gastrointestinal tract. Delayed toxicity allows potentially fatal exposures to occur prior to development of any warning symptoms.^[8] 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 in water, plain water cannot be assumed to hydrolyze dimethyl sulfate quickly enough for decontamination purposes. The hydrolysis products, monomethyl sulfate and methanol, are environmentally hazardous. In water, the compound is ultimately hydrolyzed to sulfuric acid and methanol, which is less toxic than dimethyl sulfate.

References