Dimethyl sulfate

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Dimethyl sulfate
Dimethyl sulfate.svg
Dimethyl-sulfate-from-xtal-3D-balls.png
Names
Preferred IUPAC name
Dimethyl sulfate
Other names
Dimethyl sulphate; Sulfuric acid dimethyl ester; Me2SO4; DMSO4; Dimethyl ester of sulfuric acid; Methyl sulfate, di-
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.963 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C2H6O4S/c1-5-7(3,4)6-2/h1-2H3 Yes check.svgY
    Key: VAYGXNSJCAHWJZ-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C2H6O4S/c1-5-7(3,4)6-2/h1-2H3
    Key: VAYGXNSJCAHWJZ-UHFFFAOYAK
  • COS(=O)(=O)OC
Properties
C2H6O4S
Molar mass 126.13 g/mol
AppearanceColorless, oily liquid
Odor faint, onion-like [1]
Density 1.33 g/ml, liquid
Melting point −32 °C (−26 °F; 241 K)
Boiling point 188 °C (370 °F; 461 K) (decomposes)
Reacts
Solubility Methanol, dichloromethane, acetone
Vapor pressure 0.1 mmHg (20 °C) [1]
−62.2×10−6 cm3/mol
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Extremely toxic, contact hazard, inhalation hazard, corrosive, environmental hazard, carcinogenic, mutagenic
GHS labelling:
GHS-pictogram-silhouette.svg GHS-pictogram-acid.svg GHS-pictogram-skull.svg
Danger
H301, H314, H317, H330, H335, H341, H350
NFPA 704 (fire diamond)
NFPA 704.svgHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
4
2
1
Flash point 83 °C; 182 °F; 356 K [1]
Lethal dose or concentration (LD, LC):
8.6 ppm (rat, 4 hr)
75 ppm (guinea pig, 20 min)
53 ppm (mouse)
32 ppm (guinea pig, 1 hr) [2]
97 ppm (human, 10 min) [2]
NIOSH (US health exposure limits):
PEL (Permissible)
TWA 1 ppm (5 mg/m3) [skin] [1]
REL (Recommended)
Ca TWA 0.1 ppm (0.5 mg/m3) [skin] [1]
IDLH (Immediate danger)
Ca [7 ppm] [1]
Related compounds
Related compounds
 Diethyl sulfate, methyl triflate, dimethyl carbonate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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. Like all strong alkylating agents, Me2SO4 is toxic. [3] Its use as a laboratory reagent has been superseded to some extent by methyl triflate, CF3SO3CH3, the methyl ester of trifluoromethanesulfonic acid.

Contents

History

Impure dimethyl sulfate was prepared in the early 19th century. [4] J. P. Claesson later extensively studied its preparation. [5] [6]

It was investigated for possible use in chemical warfare in World War I [7] [8] in 75% to 25% mixture with methyl chlorosulfonate (CH3ClO3S) called "C-stoff" in Germany, or with chlorosulfonic acid called "Rationite" in France. [9]

The esterification of sulfuric acid with methanol was described in 1835: [10]

2 CH3OH + H2SO4 → (CH3)2SO4 + 2 H2O

Production

Dimethyl sulfate is produced commercially by the continuous reaction of dimethyl ether with sulfur trioxide: [3]

CH3OCH3 + SO3 → (CH3)2SO4

Dimethyl sulfate can be synthesized in the laboratory by several methods. [11] The reaction of methyl nitrite and methyl chlorosulfonate also results in dimethyl sulfate: [6]

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

Reactions and uses

Dimethyl sulfate is 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 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

Commonly dimethyl sulfate is employed to methylate phenols. [12] [13]

C6H5ONa + (CH3O)2SO2 → C6H5OCH3 + Na(CH3O)SO3Na

In some cases, simple alcohols are also methylated, as illustrated by the conversion of tert-butanol to t-butyl methyl ether:

(CH3)3COH + (CH3O)2SO2 →(CH3)3COH + Na(CH3O)SO3H

The methylation of sugars is called Haworth methylation. [14] The methylation of ketones is called the Lavergne reaction.

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 softener. Methylation to create a tertiary amine is illustrated as: [13]

CH3(C6H4)NH2 + (CH3O)2SO2 (in NaHCO3 aq) → CH3(C6H4)N(CH3)2 + Na(CH3)SO4

Methylation at sulfur

Thiolate salts are easily methylated by Me2SO4 to give methyl thioethers: [13]

RSNa + (CH3O)2SO2 →CH3SR + Na(CH3O)SO3Na

In a related example: [15]

p-CH3C6H4SO2Na + (CH3O)2SO2 → p-CH3C6H4SO2CH3 + Na(CH3)SO4

This method has been used to prepare thioesters from thiocarboxylic acids:

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, [16] 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. [17] Dimethyl sulfate also methylates adenine in single-stranded portions of DNA (for example, 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 it is less hazardous and more expensive. [15] Dimethyl carbonate, which is far less reactive, has far lower toxicity compared to both dimethyl sulfate and methyl iodide. [18] 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 [19] and mutagenic, highly poisonous, corrosive, and environmentally hazardous. [20] 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 per 4 hours (rat). [21] The vapor pressure of 65 Pa [22] 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. [20] Symptoms may be delayed 6–24 h. 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.

One hypothesis regarding the apparently mysterious 1994 "toxic lady" incident is that the person at the centre of the incident had built up dimethyl sulfone crystals in her blood, which were converted by an unknown mechanism to dimethyl sulfate vapour that poisoned attending medical staff. [23] [24]

Related Research Articles

<span class="mw-page-title-main">Ether</span> Organic compounds made of alkyl/aryl groups bound to oxygen (R–O–R)

In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom bonded to two organyl groups. They have the general formula R−O−R′, where R and R′ represent the organyl groups. Ethers can again be classified into two varieties: if the organyl groups are the same on both sides of the oxygen atom, then it is a simple or symmetrical ether, whereas if they are different, the ethers are called mixed or unsymmetrical ethers. A typical example of the first group is the solvent and anaesthetic diethyl ether, commonly referred to simply as "ether". Ethers are common in organic chemistry and even more prevalent in biochemistry, as they are common linkages in carbohydrates and lignin.

<span class="mw-page-title-main">Ester</span> Compound derived from an acid

In chemistry, an ester is a functional group derived from an acid in which the hydrogen atom (H) of at least one acidic hydroxyl group of that acid is replaced by an organyl group. Analogues derived from oxygen replaced by other chalcogens belong to the ester category as well. According to some authors, organyl derivatives of acidic hydrogen of other acids are esters as well, but not according to the IUPAC.

In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula CH3. In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many organic compounds. It is a very stable group in most molecules. While the methyl group is usually part of a larger molecule, bonded to the rest of the molecule by a single covalent bond, it can be found on its own in any of three forms: methanide anion, methylium cation or methyl radical. The anion has eight valence electrons, the radical seven and the cation six. All three forms are highly reactive and rarely observed.

Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and biology.

<span class="mw-page-title-main">Dimethylaniline</span> Chemical compound

N,N-Dimethylaniline (DMA) is an organic chemical compound, a substituted derivative of aniline. It is a tertiary amine, featuring a dimethylamino group attached to a phenyl group. This oily liquid is colourless when pure, but commercial samples are often yellow. It is an important precursor to dyes such as crystal violet.

<span class="mw-page-title-main">Alkylation</span> Transfer of an alkyl group from one molecule to another

Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene. Alkylating agents are reagents for effecting alkylation. Alkyl groups can also be removed in a process known as dealkylation. Alkylating agents are often classified according to their nucleophilic or electrophilic character. In oil refining contexts, alkylation refers to a particular alkylation of isobutane with olefins. For upgrading of petroleum, alkylation produces a premium blending stock for gasoline. In medicine, alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells. Alkylation is accomplished with the class of drugs called alkylating antineoplastic agents.

<span class="mw-page-title-main">Dimethyl sulfoxide</span> Organosulfur chemical compound used as a solvent

Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula (CH3)2SO. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water. It has a relatively high boiling point. DMSO is metabolised to compounds that leave a garlic-like taste in the mouth after DMSO is absorbed by skin.

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 to other organic compounds and an aerosol propellant that is currently being demonstrated for use in a variety of fuel applications.

<span class="mw-page-title-main">Anisole</span> Organic compound (CH₃OC₆H₅) also named methoxybenzene

Anisole, or methoxybenzene, is an organic compound with the formula CH3OC6H5. It is a colorless liquid with a smell reminiscent of anise seed, and in fact many of its derivatives are found in natural and artificial fragrances. The compound is mainly made synthetically and is a precursor to other synthetic compounds. Structurally, it is an ether with a methyl and phenyl group attached. Anisole is a standard reagent of both practical and pedagogical value.

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 hydrogen atom by an atom of iodine. It is naturally emitted by rice plantations in small amounts. It is also produced in vast quantities estimated to be greater than 214,000 tons annually by algae and kelp in the world's temperate oceans, and in lesser amounts on land by terrestrial fungi and bacteria. It is used in organic synthesis as a source of methyl groups.

<span class="mw-page-title-main">Diethyl sulfate</span> Chemical compound

Diethyl sulfate (DES) is an organosulfur compound with the formula (C2H5)2SO4. It occurs as a colorless, oily liquid with a faint peppermint odor. It is toxic, combustible, and likely carcinogenic chemical compound. Diethyl sulfate is used as an ethylating agent.

<span class="mw-page-title-main">Trimethylsilyldiazomethane</span> Chemical compound

Trimethylsilyldiazomethane is the organosilicon compound with the formula (CH3)3SiCHN2. It is classified as a diazo compound. Trimethylsilyldiazomethane, which is a commercially available, reagent used in organic chemistry as a methylating agent of carboxylic acids. Its behavior is akin to the reagent diazomethane, but the trimethylsilyl (TMS) analog is nonexplosive.

<span class="mw-page-title-main">Methyl bisulfate</span> Chemical compound

Methyl bisulfate is a chemical compound with the molecular formula (CH3)HSO4. This compound is the mono-methyl ester of sulfuric acid. Its structure is CH3−O−S(=O)2−OH. The significance of methyl bisulfate is that it is an intermediate in the hydrolysis of the important reagent dimethyl sulfate, (CH3)2SO4:

<span class="mw-page-title-main">Dimethyl carbonate</span> Chemical compound

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 as a co-solvent in lithium-ion batteries. Notably, dimethyl carbonate is a weak methylating agent, and is not considered as a carcinogen. Instead, dimethyl carbonate is often considered to be a green reagent, and it is exempt from the restrictions placed on most volatile organic compounds (VOCs) in the United States.

<span class="mw-page-title-main">Methyl trifluoromethanesulfonate</span> Chemical compound

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. The compound is closely related to methyl fluorosulfonate (FSO2OCH3). Although there has yet to be a reported human fatality, several cases were reported for methyl fluorosulfonate (LC50 (rat, 1 h) = 5 ppm), and methyl triflate is expected to have similar toxicity based on available evidence.

<span class="mw-page-title-main">Methyl fluorosulfonate</span> Chemical compound

Methyl fluorosulfonate, also known as magic methyl, is the organic compound with the formula FSO2OCH3. It is a colorless liquid that is used as a strong methylating agent in organic synthesis. Because of its extreme toxicity, it has largely been replaced by the related reagent methyl trifluoromethanesulfonate.

Acetone cyanohydrin (ACH) is an organic compound used in the production of methyl methacrylate, the monomer of the transparent plastic polymethyl methacrylate (PMMA), also known as acrylic. It liberates hydrogen cyanide easily, so it is used as a source of such. For this reason, this cyanohydrin is also highly toxic.

Isopropyl alcohol is a colorless, flammable organic compound with a pungent alcoholic odor.

<span class="mw-page-title-main">Trimethyloxonium tetrafluoroborate</span> Chemical compound

Trimethyloxonium tetrafluoroborate is the organic compound with the formula [(CH3)3O]+[BF4]−. This salt is a strong methylating agent, being a synthetic equivalent of CH+3. It is a white solid that rapidly decomposes upon exposure to atmospheric moisture, although it is robust enough to be weighed quickly without inert atmosphere protection. Triethyloxonium tetrafluoroborate is a closely related compound.

Copper(I) sulfate, also known as cuprous sulfate, is an inorganic compound with the chemical formula Cu2SO4. It is a white solid, in contrast to copper(II) sulfate, which is blue in hydrous form. Compared to the commonly available reagent, copper(II) sulfate, copper(I) sulfate is unstable and not readily available.

References

  1. 1 2 3 4 5 6 NIOSH Pocket Guide to Chemical Hazards. "#0229". National Institute for Occupational Safety and Health (NIOSH).
  2. 1 2 "Dimethyl sulfate". Immediately Dangerous to Life or Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH).
  3. 1 2 Weisenberger, Karl; Mayer, Dieter; Sandler, Stanley R. (2000). "Dialkyl Sulfates and Alkylsulfuric Acids". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a08_493. ISBN   978-3-527-30385-4.
  4. ↑ Dumas, J.; Péligot, E. (1835). "Mémoire sur l'esprit de bois et sur les divers composés ethérés qui en proviennent" [Memoir on spirit of wood [i.e., methanol] and on various ethereal compounds that come from it]. Annales de Chimie et de Physique. 2nd series (in French). 58: 5–74.
  5. ↑ Claesson, Peter (1879). "Ueber die neutralen und sauren Sulfate des Methyl- und Aethylalkohols" [On the neutral and acid sulfates of methyl and ethyl alcohol]. Journal für praktische Chemie. 2nd series (in German). 19: 231–265. doi:10.1002/prac.18790190123.
  6. 1 2 Suter, C. M. (1944). The Organic Chemistry of Sulfur: Tetracovalent Sulfur substans. John Wiley & Sons. pp. 49–53. LCCN   44001248.
  7. ↑ "Dimethyl Sulfate 77-78-1". EPA.
  8. ↑ "Poison Facts: Low Chemicals: Dimethyl Sulfate". The University of Kansas Hospital.
  9. ↑ Sartori, Mario (1939). The War Gases. D. Van Nostrand. pp. 262, 266.
  10. ↑ Dumas, J.; Péligot, E. (1835). "Mémoire sur l'esprit de bois et sur les divers composés ethérés qui en proviennent" [Memoir on spirit of wood [i.e., methanol] and on various ethereal compounds that come from it]. Annales de Chimie et de Physique. 2nd series (in French). 58: 5–74.
  11. ↑ Shirley, D. A. (1966). Organic Chemistry. Holt, Rinehart and Winston. p. 253. LCCN   64010030.
  12. ↑ G. S. Hiers, F. D. Hager (1929). "Anisole". Organic Syntheses. 9: 12. doi:10.15227/orgsyn.009.0012.
  13. 1 2 3 "Dupont product information". Archived from the original on 2008-11-19. Retrieved 2006-05-08.
  14. ↑ W. N. Haworth (1915). "III. A New Method of Preparing Alkylated Sugars". Journal of the Chemical Society, Transactions . 107: 8–16. doi:10.1039/CT9150700008.
  15. 1 2 Fieser, L. F.; Fieser, M. (1967). Reagents for Organic Synthesis . John Wiley & Sons. p.  295. ISBN   9780471258759.
  16. ↑ Zubradt, Meghan; Gupta, Paromita; Persad, Sitara; Lambowitz, Alan; Weissman, Jonathan; Rouskin, Silvi (2017). "DMS-MaPseq for genome-wide or targeted RNA structure probing in vivo". Nature Methods. 14 (1): 75–82. doi:10.1038/nmeth.4057. PMC   5508988 . PMID   27819661.
  17. ↑ Streitwieser, A.; Heathcock, C. H.; Kosower, E. M. (1992). Introduction to Organic Chemistry (4th ed.). Macmillan. p.  1169. ISBN   978-0024181701.
  18. ↑ Shieh, W. C.; Dell, S.; Repic, O. (2001). "1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and Microwave-Accelerated Green Chemistry in Methylation of Phenols, Indoles, and Benzimidazoles with Dimethyl Carbonate". Organic Letters . 3 (26): 4279–4281. doi:10.1021/ol016949n. PMID   11784197.
  19. ↑ "Dimethyl Sulfate CAS No. 77-78-1" (PDF). 12th Report on Carcinogens (RoC). US Department of Health and Human Services. 2011.
  20. 1 2 Rippey, J. C. R.; Stallwood, M. I. (2005). "Nine Cases of Accidental Exposure to Dimethyl Sulphate — A Potential Chemical Weapon". Emergency Medicine Journal. 22 (12): 878–879. doi:10.1136/emj.2004.015800. PMC   1726642 . PMID   16299199.
  21. ↑ "Material Safety Data Sheet - Dimethyl sulfate MSDS". ScienceLab. Archived from the original on 2012-04-06. Retrieved 2011-10-02.
  22. ↑ ICSC
  23. ↑ "What's the story on the "toxic lady"?". The Straight Dope. 1996-03-22. Retrieved 2024-01-15.
  24. ↑ Grant, P. M.; Haas, J. S.; Whipple, R. E.; Andresen, B. D. (1997-06-23). "A possible chemical explanation for the events associated with the death of Gloria Ramirez at Riverside General Hospital". Forensic Science International. 87 (3): 219–237. doi:10.1016/s0379-0738(97)00076-5. ISSN   0379-0738. PMID   9248041.
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