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 betwee ...
(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 a ...
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 formu ...
, 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 many ...
. 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, a ...
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 effecting al ...
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 subst ...
. Its use as a laboratory reagent has been superseded to some extent by
methyl triflate
Methyl trifluoromethanesulfonate, also commonly called methyl triflate and abbreviated MeOTf, is the organic compound with the formula CF3SO2OCH3. It is a colourless liquid which finds use in organic chemistry as a powerful methylating agent. T ...
, 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 este ...
.
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 one of the deadliest global conflicts in history. Belligerents included much of Europe, the Russian Empire, the United States, and the Ottoman Empire, with fightin ...
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 formu ...
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 a ...
:
::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
Methyl nitrite is an organic compound with the chemical formula . It is a gas, and is the simplest alkyl nitrite.
Structure
At room temperature, methyl nitrite exists as a mixture of ''cis'' and ''trans'' conformers. The ''cis'' conformer is ...
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 t ...
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 req ...
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 substituen ...
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 double ...
s is called Haworth methylation.
Methylation at amine nitrogen
Me2SO4 is used to prepare both quaternary ammonium
In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cations ...
salts or tertiary 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 such a ...
s:
::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 conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
of RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
. 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 genomes, ...
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 succ ...
, 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 Diazole refers ...
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 derivati ...
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
In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template.
Using the enzyme helicase, RNAP locally opens the ...
progressively melting and re-annealing the DNA). Upon re-annealing, these methyl groups interfere with adenine-guanine base-pairing. Nuclease S1
Nuclease S1 () is an endonuclease enzyme that splits single-stranded DNA (ssDNA) and RNA into oligo- or mononucleotides. This enzyme catalyses the following chemical reaction
: Endonucleolytic cleavage to 5'-phosphomononucleotide and 5'-phosph ...
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 h ...
is a reagent used for O-methylation, like dimethyl sulfate, but is less hazardous and more expensive.[ ]Dimethyl carbonate
Dimethyl carbonate (DMC) is an organic compound with the formula OC(OCH3)2. It is a colourless, flammable liquid. It is classified as a carbonate ester. This compound has found use as a methylating agent and more recently as a solvent that is e ...
, 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 substan ...
ic[ and ]mutagen
In genetics, a mutagen is a physical or chemical agent that permanently changes nucleic acid, genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can ca ...
ic, 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
A corrosive substance is one that will damage or destroy other substances with which it comes into contact by means of a chemical reaction.
Etymology
The word ''corrosive'' is derived from the Latin verb ''corrodere'', which means ''to gnaw'', ...
, 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
In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...
(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