Dimethylcarbamoyl chloride explained

Dimethylcarbamoyl chloride (DMCC) is a reagent for transferring a dimethylcarbamoyl group to alcoholic or phenolic hydroxyl groups forming dimethyl carbamates, usually having pharmacological or pesticidal activities. Because of its high toxicity and its carcinogenic properties shown in animal experiments and presumably also in humans,[1] dimethylcarbamoyl chloride can only be used under stringent safety precautions.

Production and occurrence

The production of dimethylcarbamoyl chloride from phosgene and dimethylamine was reported as early as 1879 (reported as "Dimethylharnstoffchlorid" – dimethylurea chloride).[2]

DMCC can be produced in high yields (90%) at 275 °C by reacting phosgene with gaseous dimethylamine in a flow reactor.[3] To suppress the formation of ureas, excess phosgene is used (in a 3:1 ratio).

The reaction can also be carried out at the laboratory scale with diphosgene or triphosgene and an aqueous dimethylamine solution in the two-phase system of benzene–xylene and water in a stirred reactor with sodium hydroxide as an acid scavenger. However, considerably lower yields (56%) are achieved due to the hydrolysis sensitivity of DMCC.[4]

Dimethylcarbamoyl chloride is also formed (together with methyl chloride) when reacting phosgene with trimethylamine.[5]

A more recent process is based on chlorodimethylamine, which is converted practically quantitatively to dimethylcarbamoyl chloride on a palladium catalyst under pressure with carbon monoxide at room temperature.[6]

DMCC can also be formed in small amounts (up to 20 ppm) from dimethylformamide (DMF) in the Vilsmeier–Haack reaction[7] or when DMF is used as a catalyst in the reaction of carboxylic acids with thionyl chloride to the corresponding acyl chloride.[8]

The tendency towards DMCC formation depends on the chlorination reagent (thionyl chloride > oxalyl chloride > phosphorus oxychloride) and is higher in the presence of a base. However, dicarbamoyl chloride hydrolyses very quickly to dimethylamine, hydrochloric acid and carbon dioxide (with a half-life of about 6 minutes at 0 °C) so that less than 3 ppm of dicarbamoyl chloride is found in the Vilsmeier product after aqueous workup.[9]

Properties

Dimethylcarbamoyl chloride is a clear, colorless, corrosive and flammable liquid with a pungent odor and a tear-penetrating effect, which decomposes rapidly in water.[10] Because of its unpleasant, toxic, mutagenic and carcinogenic properties,[11] [12] it has to be used under extreme precautions.

DMCC behaves like an acyl chloride whose chlorine atom can be exchanged for other nucleophiles. Therefore, it reacts with alcohols, phenols and oximes to the corresponding N,N-dimethylcarbamates, with thiols to thiolourethanes, with amines and hydroxylamines to substituted ureas, and with imidazoles and triazoles to carbamoylazoles.[10]

DMCC is less reactive and less selective to substrates with multiple nucleophilic centers than conventional acyl chlorides.

Unsaturated conjugated aldehydes such as crotonaldehyde (trans-but-2-enal) react with DMCC forming dienyl carbamates, which can be used as dienes in Diels–Alder reactions.[13]

Alkali metal carboxylates react with DMCC forming the corresponding dimethylamides. DMCC reacts with anhydrous sodium carbonate[14] or with excess dimethylamine to form tetramethylurea.[15]

The reaction of DMCC with DMF forms tetramethylformamidinium chloride,[16] which is a major intermediate in the preparation of tris(dimethylamino)methane, a reagent for the introduction of enamine functions in conjunction with activated methylene groups[17] and the preparation of amidines.[18]

DMCC is a starting material for the insecticide class of the dimethyl carbamates which act as inhibitors of acetylcholinesterase, including dimetilane,[19] and the related compounds isolane, pirimicarb and triazamate.

The quaternary ammonium compounds neostigmine[20] finds pharmaceutical applications as acetylcholinesterase inhibitors. It is obtained from 3-(dimethylamino)phenol and DMCC and subsequent quaternization with methyl bromide or dimethyl sulfate[21]

and pyridostigmine, which is obtainable from 3-hydroxypyridine and DMCC and subsequent reaction with methyl bromide.[22]

DMCC is also used in the synthesis of the benzodiazepine camazepam.[23]

See also

Notes and References

  1. Book: Pohanish, R. P. . Sittig's Handbook of Toxic and Hazardous Chemicals and Carcinogens . 6th . Elsevier . Amsterdam . 1045–1047 . 978-1-4377-7869-4 . 2011.
  2. W. . Michler . C. . Escherich . Berichte der Deutschen Chemischen Gesellschaft . Ueber mehrfach substituirte Harnstoffe . On multiply-substituted ureas . 12 . 1 . 1162–1164 . 1879 . German . 10.1002/cber.187901201303.
  3. R. J. . Slocombe . E. A. . Hardy . J. H. . Saunders . R. L. . Jenkins . Journal of the American Chemical Society . Phosgene derivatives. The preparation of isocyanates, carbamyl chlorides and cyanuric acid . 72 . 5 . 1888–1891 . 1950 . 10.1002/ja01161a009. 31 January 2024 .
  4. G. . Karimipour . S. . Kowkabi . A. . Naghiha . Brazilian Archives of Biology and Technology . New aminoporphyrins bearing urea derivative substituents: synthesis, characterization, antibacterial and antifungal activity . 58 . 3 . 2015 . 431–442 . 10.1590/S1516-8913201500024 . free .
  5. H. . Babad . A. G. . Zeiler . Chemical Reviews . Chemistry of phosgene . 73 . 1 . 75–91 . 1973 . 10.1021/cr60281a005.
  6. T. . Saegusa . T. . Tsuda . Y. . Isegawa . The Journal of Organic Chemistry . Carbamoyl chloride formation from chloramine and carbon monoxide . 36 . 6 . 858–860 . 1971 . 10.1021/jo00805a033.
  7. M. . Stare . K. . Laniewski . A. . Westermark . M. . Sjögren . W. . Tian . Organic Process Research & Development . Investigation on the formation and hydrolysis of N,N-dimethylcarbamoyl chloride (DMCC) in Vilsmeier reactions using GC/MS as the analytical detection method . 13 . 5 . 857–862 . 2009 . 10.1021/op900018f.
  8. D. . Levin . Organic Process Research & Development . Potential toxicological concerns associated with carboxylic acid chlorination and other reactions . 1 . 2 . 182 . 1997 . 10.1021/op970206t.
  9. A. . Queen . Canadian Journal of Chemistry . Kinetics of the hydrolysis of acyl chlorides in pure water . 45 . 14 . 1619–1629 . 1967 . 10.1139/v67-264. free .
  10. Encyclopedia: C. B. . Kreutzberger . R. A. . Olofson. e-EROS Encyclopedia of Reagents for Organic Synthesis. Dimethylcarbamoyl chloride . 2001 . 10.1002/047084289X.rd319. 0-471-93623-5 .
  11. Encyclopedia: P. . Jäger . C. N. . Rentzea . H. . Kieczka . Carbamates and carbamoyl chloride . Ullmann's Fine Chemicals . Wiley-VCH . Weinheim . 57–58 . 978-3-527-33477-3 . 2014.
  12. Web site: Dimethylcarbamoyl Chloride, CAS No. 79-44-7 . Report on Carcinogens . 13th . National Toxicology Program, Department of Health and Human Services . 2016-09-25.
  13. P. F. . De Cusati . R. A. . Olofson . Tetrahedron Letters . A simple synthesis of 1-(1,3-butadienyl)carbonates and carbamates . 31 . 10 . 1405–1408 . 1990 . 10.1016/S0040-4039(00)88817-6.
  14. J. K. Jr. . Lawson . J. A. T. . Croom . The Journal of Organic Chemistry . Dimethylamides from alkali carboxylates and dimethylcarbamoyl chloride . 28 . 1 . 232–235 . 1963 . 10.1021/jo1036a513. 31 January 2024 .
  15. US . 3597478 . Preparation of tetramethylurea . 1971-08-03 . 1967-09-14 . Weakly, M. L. . Nipak Inc..
  16. Z. . Arnold . Collection of Czechoslovak Chemical Communications . The preparation of tetramethylformamidinium salts and their vinylogues . 24 . 760–765 . 1959 . 3 . 10.1135/cccc19590760.
  17. H. . Meerwein . W. . Florian . N. . Schön . G. . Stopp. Justus Liebigs Annalen der Chemie . Über Säureamidacetale, Harnstoffacetale und Lactamacetale . On acid amide acetals, urea acetals and lactam acetals . 641 . 1 . 1–39 . 1961 . German . 10.1002/jlac.19616410102.
  18. H. . Bredereck . F. . Effenberger . Th. . Brendle . Angewandte Chemie . Synthese und Reaktionen von Trisdimethylaminomethan . Synthesis and reactions of tris(dimethylamino)methane . 78 . 2 . 147–148 . 1966 . German . 10.1002/ange.19660780212. 1966AngCh..78..147B .
  19. US . 3452043 . Production of 1-N,N-dimethylcarbamoyl-5-methyl-3-N,N-dimethylcarbamoyloxypyrazole . 1969-06-24 . 1967-03-08 . Grauer, T. . Urwyler, H. . J. R. Geigy AG.
  20. J. A. . Aeschlimann . M. . Reinert . Journal of Pharmacology and Experimental Therapeutics . Pharmacological action of some analogues of physostigmine . 43 . 3 . 413–444 . 1931.
  21. US . 1905990 . Disubstituted carbamic acid esters of phenols containing a basic constituent . 1933-04-25 . 1931-04-08 . Aeschlimann, J. A. . Hoffmann-La Roche Inc..
  22. US . 2572579 . Disubstituted carbamic acid esters of 3-hydroxy-1-alkyl-pyridinium salts . 1951-10-23 . 1948-05-18 . Urban, R. . Hoffmann-La Roche Inc..
  23. DE . 2558015 . Verfahren zur Herstellung des 3-N,N-Dimethylcarbamoyl-oxy-1-methyl-5-phenyl-7-chlor-1,3-dihydro-2H-1,4-benzodiazepin-2-on (Process for the preparation of 3-N,N-dimethylcarbamoyloxy-1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one) . 1976-09-16 . 1975-12-22 . Siphar SA.

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