Dimethyl sulfate
Encyclopedia
Dimethyl sulfate is a chemical compound
with formula
(CH3O)2SO2. As the diester
of methanol
and 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 Its use as a laboratory reagent has been superseded to some extent by methyl triflate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
.
with methanol
:
Another possible synthesis involves distillation of methyl hydrogen sulfate:
Methyl nitrite
and methyl chlorosulfonate also result in dimethyl sulfate:
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
.
of phenol
s, amine
s, and thiol
s. Typically, one methyl group is transferred more quickly than the second. Methyl transfer is typically 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.
to t-butyl methyl ether:
Alkoxide salts are rapidly methylated:
The methylation of sugar
s is called Haworth methylation
Quaternized fatty ammonium compounds are used as a surfactant or fabric softeners. The methylation of a tertiary amine is illustrated as:
An example is:
This method has been used to prepare thioesters:
in DNA by rupturing the imidazole
rings present in guanine. This process can be used to determine base sequencing, cleavage on the DNA chain, and other applications.
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.
, which is less reactive, has far lower toxicity compared to both dimethyl sulfate and methyl iodide and can be used to instead of dimethyl sulfate for N-methylation. 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.
ic and mutagen
ic, poison
ous, 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. There is no strong odor or immediate irritation to warn of lethal concentration in 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 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 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
.
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
with formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
(CH3O)2SO2. As the diester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
of methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
and sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
, its formula is often written as (CH3)2SO4
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
or even Me2SO4, where CH3 or Me is methyl. Me2SO4 is mainly used as a methylating agent in organic synthesis
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
.
Under standard conditions, Me2SO4 is a colourless oily liquid
Liquid
Liquid is one of the three classical states of matter . Like a gas, a liquid is able to flow and take the shape of a container. Some liquids resist compression, while others can be compressed. Unlike a gas, a liquid does not disperse to fill every space of a container, and maintains a fairly...
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
Methyl triflate
Methyl trifluoromethanesulfonate, is commonly called methyl triflate, and has the chemical formula CF3SO2-OCH3, and is used as a very powerful methylating reagent in chemistry....
, CF3SO3CH3, the methyl ester of trifluoromethanesulfonic acid
Trifluoromethanesulfonic acid
Trifluoromethanesulfonic acid, also known as triflic acid, TFMS, TFSA, HOTf or TfOH, is a sulfonic acid with the chemical formula CF3SO3H. It is one of the strongest acids. Triflic acid is mainly used in research as a catalyst for esterification.-Properties:Triflic acid is a hygroscopic, colorless...
.
History
Dimethyl sulfate was first discovered in the early 19th century in an impure form. P. Claesson later extensively studied its preparation. It may have been used in chemical warfare.Production
Dimethyl sulfate can be synthesized in the laboratory by many different syntheses, the simplest being the esterification of sulfuric acidSulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
with methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
:
-
- 2 CH3OH + H2SO4 → (CH3)2SO4 + 2 H2O
Another possible synthesis involves distillation of methyl hydrogen sulfate:
-
- 2 CH3HSO4 → H2SO4 + (CH3)2SO4
Methyl nitrite
Methyl nitrite
In organic chemistry, methyl nitrite is the simplest alkyl nitrite.-Structure:At room temperature, methyl nitrite exists as a mixture of cis and trans conformers...
and methyl chlorosulfonate also result in dimethyl sulfate:
-
- CH3ONO + (CH3)OSO2Cl → (CH3)2SO4 + NOClNitrosyl chlorideNitrosyl chloride is the chemical compound NOCl. It is a yellow gas that is most commonly encountered as a decomposition product of aqua regia, a mixture of hydrochloric acid and nitric acid...
- 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
Dimethyl ether
Dimethyl ether , also known as methoxymethane, is the organic compound with the formula . The simplest ether, it is a colourless gas that is a useful precursor to other organic compounds and an aerosol propellant. When combusted, DME produces minimal soot and CO, though HC and NOx formation is...
with sulfur trioxide
Sulfur trioxide
Sulfur trioxide is the chemical compound with the formula SO3. In the gaseous form, this species is a significant pollutant, being the primary agent in acid rain. It is prepared on massive scales as a precursor to sulfuric acid.-Structure and bonding:Gaseous SO3 is a trigonal planar molecule of...
.
-
- (CH3)2O + SO3 → (CH3)2SO4
Uses
Dimethyl sulfate is best known as a reagent for the methylationMethylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
of phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...
s, amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s, and thiol
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
s. Typically, one methyl group is transferred more quickly than the second. Methyl transfer is typically 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 are also suitably methylated, as illustrated by the conversion of tert-butanolTert-Butanol
tert-Butanol, or 2-methyl-2-propanol, is the simplest tertiary alcohol. It is one of the four isomers of butanol. tert-Butanol is a clear liquid with a camphor-like odor. It is very soluble in water and miscible with ethanol and diethyl ether...
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
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
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. The methylation of 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
Other uses
Dimethyl sulfate can effect the base-specific cleavage of guanineGuanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
in DNA by rupturing the imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
rings present in guanine. This process can be used to determine base sequencing, cleavage on the DNA chain, and other applications.
Dimethyl sulfate also methylates adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
in single-stranded portions of DNA (e.g., those with proteins like RNA polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
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 carbonateDimethyl carbonate
Dimethyl carbonate, often abbreviated DMC, a carbonate ester, is a flammable clear liquid boiling at 90 °C. This compound has found use as a methylating agent and more recently as a VOC exempt solvent in paints and adhesives . There is also interest in using this compound as a fuel oxygenate...
, which is less reactive, has far lower toxicity compared to both dimethyl sulfate and methyl iodide and can be used to instead of dimethyl sulfate for N-methylation. 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 likely carcinogenCarcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic and mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
ic, poison
Poison
In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....
ous, corrosive
Corrosive
A corrosive substance is one that will destroy or irreversibly damage another surface or substance with which it comes into contact. The main hazards to people include damage to the eyes, the skin, and the tissue under the skin; inhalation or ingestion of a corrosive substance can damage the...
, environmentally hazardous
Environmentally hazardous
Environmentally hazardous is a chemical hazard, where significant damage to the environment is caused by a chemical substance. It is defined in the Globally Harmonized System and in the European Union chemical regulations. The label is particularly applicable towards substances with aquatic toxicity...
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. There is no strong odor or immediate irritation to warn of lethal concentration in air. The LD50
LD50
In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...
(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 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 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
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
and methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
.