Dimethyl sulfate

Dimethyl sulfate
Names
Other names
Sulfuric acid dimethyl ester; Me2SO4; DMSO4; Dimethyl ester of sulfuric acid, Methyl sulfate
Identifiers
77-78-1 YesY
ChEBI CHEBI:59050 YesY
ChEMBL ChEMBL162150 YesY
ChemSpider 6252 YesY
Jmol interactive 3D Image
KEGG C19177 YesY
PubChem 6497
Properties
C2H6O4S
Molar mass 126.13 g/mol
Appearance Colorless, 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]
Hazards
Main hazards Extremely toxic, contact hazard, inhalation hazard, corrosive, environmental hazard, carcinogenic, mutagenic
R-phrases R45, R25, R26, R34,
R43, R68
S-phrases S53, S45, S30, S60, S61
NFPA 704
Flammability code 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 fuel Health code 4: Very short exposure could cause death or major residual injury. E.g., VX gas Reactivity code 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g., calcium Special hazards (white): no codeNFPA 704 four-colored diamond
2
4
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]
US health exposure limits (NIOSH):
TWA 1 ppm (5 mg/m3) [skin][1]
Ca TWA 0.1 ppm (0.5 mg/m3) [skin][1]
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).
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Infobox references

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 Its use as a laboratory reagent has been superseded to some extent by methyl triflate, CF3SO3CH3, the methyl ester of trifluoromethanesulfonic acid.

History

Dimethyl sulfate was first discovered in the early 19th century in an impure form. P Claesson later extensively studied its preparation.[3] It was used in chemical warfare in WW I.[4][5]

Production

Dimethyl sulfate can be synthesized in the laboratory by many different syntheses,[6] the simplest being the esterification of sulfuric acid with methanol:

2 CH3OH + H2SO4 → (CH3)2SO4 + 2 H2O

Another possible synthesis involves distillation of methyl hydrogen sulfate:[3]

2 CH3HSO4 → H2SO4 + (CH3)2SO4

Methyl nitrite and methyl chlorosulfonate also result in dimethyl sulfate:[3]

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

Me2SO4 has been produced commercially since the 1920s. A common process is the continuous reaction of dimethyl ether with sulfur trioxide.[7]

(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 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-butanol to t-butyl methyl ether:

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

Alkoxide salts are rapidly methylated:[8]

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

The methylation of sugars is called Haworth methylation [9]

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:[8]

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:[8]

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

An example is:[10]

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 affect the base-specific cleavage of guanine in DNA by rupturing the imidazole rings present in guanine.[11] 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.

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.[10] Dimethyl carbonate, which is less reactive, has far lower toxicity compared to both dimethyl sulfate and methyl iodide and can be used instead of dimethyl sulfate for N-methylation.[12] 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[7] and mutagenic, highly poisonous, corrosive, environmentally hazardous and volatile (presenting an inhalation hazard). It is considered a potential chemical weapon.[13] Dimethyl sulfate 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).[14] The vapor pressure of 65 Pa[15] 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.[13] 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 product, monomethyl sulfate, is environmentally hazardous. In water, the compound is ultimately hydrolysed to sulfuric acid and methanol.

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 and Health. National Institute for Occupational Safety and Health (NIOSH).
  3. 1 2 3 Suter, C. M. (1944). The Organic Chemistry of Sulfur: Tetracovalent Sulfur Compounds. John Wiley & Sons. pp. 49–53. LCCN 44001248.
  4. ↑ "Dimethyl Sulfate 77-78-1". EPA.
  5. ↑ "Poison Facts: Low Chemicals: Dimethyl Sulfate". The University of Kansas Hospital.
  6. ↑ Shirley, D. A. (1966). Organic Chemistry. Holt, Rinehart and Winston. p. 253. LCCN 64010030.
  7. 1 2 "Dimethyl Sulfate CAS No. 77-78-1" (PDF). 12th Report on Carcinogens (RoC). US Department of Health and Human Services. 2011.
  8. 1 2 3 Dupont product information
  9. ↑ 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.
  10. 1 2 Fieser, L. F.; Fieser, M. (1967). Reagents for Organic Synthesis. John Wiley & Sons. p. 295. ISBN 9780471258759.
  11. ↑ Streitwieser, A.; Heathcock, C. H.; Kosower, E. M. (1992). Introduction to Organic Chemistry (4th ed.). Macmillan. p. 1169. ISBN 978-0024181701.
  12. ↑ 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.
  13. 1 2 Rippey, J. C. R.; Stallwood, M. I. (2005). "Nine Cases of Accidental Exposure to Dimethyl Sulphate — A Potential Chemical Weapon" (pdf). Emergency Medicine Journal 22 (12): 878–879. doi:10.1136/emj.2004.015800. PMC 1726642. PMID 16299199.
  14. ↑ "Material Safety Data Sheet - Dimethyl sulfate MSDS". ScienceLab.
  15. ↑ ICSC

External links

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