Dimethyl sulfate (DMS) is a
chemical compound
A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...
with
formula
In science, a formula is a concise way of expressing information symbolically, as in a mathematical formula or a ''chemical formula''. The informal use of the term ''formula'' in science refers to the general construct of a relationship betwe ...
(CH
3O)
2SO
2. As the
diester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are ...
of
methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
and
sulfuric acid
Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular fo ...
, its formula is often written as (
CH3)
2 SO4 or Me
2SO
4, where CH
3 or Me is
methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
. Me
2SO
4 is mainly used as a methylating agent in
organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
.
Me
2SO
4 is a colourless oily
liquid
A liquid is a nearly incompressible fluid that conforms to the shape of its container but retains a (nearly) constant volume independent of pressure. As such, it is one of the four fundamental states of matter (the others being solid, gas, ...
with a slight onion-like odour (although smelling it would represent significant exposure). Like all strong
alkylating agent
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
s, Me
2SO
4 is extremely
toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a sub ...
. Its use as a laboratory reagent has been superseded to some extent by
methyl triflate, CF
3SO
3CH
3, the methyl ester of
trifluoromethanesulfonic acid
Triflic acid, the short name for trifluoromethanesulfonic acid, TFMS, TFSA, HOTf or TfOH, is a sulfonic acid with the chemical formula CF3SO3H. It is one of the strongest known acids. Triflic acid is mainly used in research as a catalyst for es ...
.
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
World War I (28 July 1914 11 November 1918), often abbreviated as WWI, was List of wars and anthropogenic disasters by death toll, one of the deadliest global conflicts in history. Belligerents included much of Europe, the Russian Empire, ...
in 75% to 25% mixture with methyl chlorosulfonate (CH
3ClO
3S) called "C-stoff" in Germany, or with
chlorosulfonic acid
Chlorosulfuric acid (IUPAC name: sulfurochloridic acid) is the inorganic compound with the formula HSO3Cl. It is also known as chlorosulfonic acid, being the sulfonic acid of chlorine. It is a distillable, colorless liquid which is hygroscopic and ...
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
Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular fo ...
with
methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
:
::2 CH
3OH + H
2SO
4 → (CH
3)
2SO
4 + 2 H
2O
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
Dimethyl ether (DME; also known as methoxymethane) is the organic compound with the formula CH3OCH3,
(sometimes ambiguously simplified to C2H6O as it is an isomer of ethanol). The simplest ether, it is a colorless gas that is a useful precursor ...
with sulfur trioxide
Sulfur trioxide (alternative spelling sulphur trioxide, also known as ''nisso sulfan'') is the chemical compound with the formula SO3. It has been described as "unquestionably the most important economically" sulfur oxide. It is prepared on an ind ...
.
::(CH3)2O + SO3 → (CH3)2SO4
Uses
Dimethyl sulfate is best known as a reagent for the methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
of phenol
Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it r ...
s, amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
s, and thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
s. 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
Most commonly Me2SO4 is employed to methylate phenols. Some simple alcohols
In chemistry, an alcohol is a type of organic compound that carries at least one hydroxyl () functional group bound to a saturated carbon atom. The term ''alcohol'' originally referred to the primary alcohol ethanol (ethyl alcohol), which is ...
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 sugar
Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or do ...
s 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
Protein secondary structure is the three dimensional form of ''local segments'' of proteins. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well. Secondary struct ...
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
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genom ...
frequently adds an incorrect DNA base when it encounters a methylated RNA base. These mutations can be detected via sequencing
In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which suc ...
, 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
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...
rings present in guanine. Dimethyl sulfate also methylates adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
in single-stranded portions of DNA (e.g., those with proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
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
Iodomethane, also called methyl iodide, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one ...
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 carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...
ic[ and mutagenic, highly ]poison
Poison is a chemical substance that has a detrimental effect to life. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broa ...
ous, corrosive, and environmentally hazardous
An environmental hazard is a substance, state or event which has the potential to threaten the surrounding natural environment or adversely affect people's health, including pollution and natural disasters such as storms and earthquakes. It can ...
. 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 Pa[ICSC] 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