Dimethylcarbamoyl chloride

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Dimethylcarbamoyl chloride
Dimethylcarbamoylchlorid Strukturformel.svg
Names
Preferred IUPAC name
Dimethylcarbamoyl chloride
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.001.099 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C3H6ClNO/c1-5(2)3(4)6/h1-2H3
    Key: YIIMEMSDCNDGTB-UHFFFAOYSA-N
  • CN(C)C(=O)Cl
Properties
C3H6ClNO
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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.

Contents

Production and occurrence

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

Synthesis of dimethylcarbamoyl chloride with dimethylamine DMCC mit Dimethylamin.svg
Synthesis of dimethylcarbamoyl chloride with dimethylamine

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]

Synthesis of dimethylcarbamoyl chloride with trimethylamine DMCC mit Trimethylamin.svg
Synthesis of dimethylcarbamoyl chloride with trimethylamine

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]

Synthesis of dimethylcarbamoyl chloride from chloramine DMCC aus Chloramin.svg
Synthesis of dimethylcarbamoyl chloride from chloramine

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]

Synthesis of dimethylcarbamoyl chloride with dimethylformamide DMCC mit Dimethylformamid.svg
Synthesis of dimethylcarbamoyl chloride with dimethylformamide

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]

Reactions of dimethylcarbamoyl chloride with nucleophiles DMCC-Reaktion mit Nukleophilen.svg
Reactions of dimethylcarbamoyl chloride with nucleophiles

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]

Synthesis of dienyl carbamates with dimethylcarbamoyl chloride Synthese von Dienylcarbamaten mit DMCC.svg
Synthesis of dienyl carbamates with dimethylcarbamoyl chloride

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]

Synthesis of tris(dimethylamino)methane with dimethylcarbamoyl chloride Synthese von Tris(dimethylamino)methan.svg
Synthesis of tris(dimethylamino)methane with dimethylcarbamoyl chloride

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.

Synthesis of dimetilane with dimethylcarbamoyl chloride Synthese von Dimetilan.svg
Synthesis of dimetilane with dimethylcarbamoyl chloride

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]

Synthesis of neostigmine with dimethylcarbamoyl chloride Synthese von Neostigmin.svg
Synthesis of neostigmine with dimethylcarbamoyl chloride

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

Synthesis of pyridostigmine with dimethylcarbamoyl chloride Synthese von Pyridostigmin.svg
Synthesis of pyridostigmine with dimethylcarbamoyl chloride

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

Synthesis of camazepam with dimethylcarbamoyl chloride Synthese von Camazepam.svg
Synthesis of camazepam with dimethylcarbamoyl chloride

See also

Related Research Articles

<span class="mw-page-title-main">Protecting group</span> Group of atoms introduced into a compound to prevent subsequent reactions

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<span class="mw-page-title-main">Fischer–Speier esterification</span>

Fischer esterification or Fischer–Speier esterification is a special type of esterification by refluxing a carboxylic acid and an alcohol in the presence of an acid catalyst. The reaction was first described by Emil Fischer and Arthur Speier in 1895. Most carboxylic acids are suitable for the reaction, but the alcohol should generally be primary or secondary. Tertiary alcohols are prone to elimination. Contrary to common misconception found in organic chemistry textbooks, phenols can also be esterified to give good to near quantitative yield of products. Commonly used catalysts for a Fischer esterification include sulfuric acid, p-toluenesulfonic acid, and Lewis acids such as scandium(III) triflate. For more valuable or sensitive substrates other, milder procedures such as Steglich esterification are used. The reaction is often carried out without a solvent or in a non-polar solvent to facilitate the Dean-Stark method. Typical reaction times vary from 1–10 hours at temperatures of 60-110 °C.

In organic chemistry, an acyl chloride is an organic compound with the functional group −C(=O)Cl. Their formula is usually written R−COCl, where R is a side chain. They are reactive derivatives of carboxylic acids. A specific example of an acyl chloride is acetyl chloride, CH3COCl. Acyl chlorides are the most important subset of acyl halides.

<span class="mw-page-title-main">Acyl halide</span> Oxoacid compound with an –OH group replaced by a halogen

In organic chemistry, an acyl halide is a chemical compound derived from an oxoacid by replacing a hydroxyl group with a halide group.

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

Triphosgene (bis(trichloromethyl) carbonate (BTC) is a chemical compound with the formula OC(OCCl3)2. It is used as a solid substitute for phosgene, which is a gas and diphosgene, which is a liquid. Triphosgene is stable up to 200 °C. Triphosgene is used in a variety of halogenation reactions.

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

Oxalyl chloride is an organic chemical compound with the formula Cl−C(=O)−C(=O)−Cl. This colorless, sharp-smelling liquid, the diacyl chloride of oxalic acid, is a useful reagent in organic synthesis.

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

Phosphorus pentachloride is the chemical compound with the formula PCl5. It is one of the most important phosphorus chlorides/oxychlorides, others being PCl3 and POCl3. PCl5 finds use as a chlorinating reagent. It is a colourless, water-sensitive solid, although commercial samples can be yellowish and contaminated with hydrogen chloride.

<i>N</i>-Bromosuccinimide Molecule

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<span class="mw-page-title-main">Claisen rearrangement</span> Chemical reaction

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<span class="mw-page-title-main">Curtius rearrangement</span> Chemical reaction

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

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<i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-Tetramethylformamidinium chloride Chemical compound

N,N,N′,N′-Tetramethylformamidinium chloride is the simplest representative of quaternary formamidinium cations of the general formula [R2N−CH=NR2]+ with a chloride as a counterion in which all hydrogen atoms of the protonated formamidine [HC(=NH2)NH2]+ are replaced by methyl groups.

<span class="mw-page-title-main">Tris(dimethylamino)methane</span> Chemical compound

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tert-Butoxybis(dimethylamino)methane is an organic compound with the formula (CH3)3COCH(N(CH3)2)2. The compound is classified as an aminal ester, i.e. the tert-butyl alcohol derivative of the aminal bis(dimethylamino)methane. It is a colorless liquid with a amine odor.

References

  1. ↑ Pohanish, R. P. (2011). Sittig's Handbook of Toxic and Hazardous Chemicals and Carcinogens (6th ed.). Amsterdam: Elsevier. pp. 1045–1047. ISBN   978-1-4377-7869-4.
  2. ↑ Michler, W.; Escherich, C. (1879). "Ueber mehrfach substituirte Harnstoffe" [On multiply-substituted ureas]. Berichte der Deutschen Chemischen Gesellschaft (in German). 12 (1): 1162–1164. doi:10.1002/cber.187901201303.
  3. ↑ Slocombe, R. J.; Hardy, E. A.; Saunders, J. H.; Jenkins, R. L. (1950). "Phosgene derivatives. The preparation of isocyanates, carbamyl chlorides and cyanuric acid". Journal of the American Chemical Society. 72 (5): 1888–1891. doi:10.1002/ja01161a009 (inactive 31 January 2024).{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  4. ↑ Karimipour, G.; Kowkabi, S.; Naghiha, A. (2015). "New aminoporphyrins bearing urea derivative substituents: synthesis, characterization, antibacterial and antifungal activity". Brazilian Archives of Biology and Technology. 58 (3): 431–442. doi: 10.1590/S1516-8913201500024 .
  5. ↑ Babad, H.; Zeiler, A. G. (1973). "Chemistry of phosgene". Chemical Reviews. 73 (1): 75–91. doi:10.1021/cr60281a005.
  6. ↑ Saegusa, T.; Tsuda, T.; Isegawa, Y. (1971). "Carbamoyl chloride formation from chloramine and carbon monoxide". The Journal of Organic Chemistry. 36 (6): 858–860. doi:10.1021/jo00805a033.
  7. ↑ Stare, M.; Laniewski, K.; Westermark, A.; Sjögren, M.; Tian, W. (2009). "Investigation on the formation and hydrolysis of N,N-dimethylcarbamoyl chloride (DMCC) in Vilsmeier reactions using GC/MS as the analytical detection method". Organic Process Research & Development. 13 (5): 857–862. doi:10.1021/op900018f.
  8. ↑ Levin, D. (1997). "Potential toxicological concerns associated with carboxylic acid chlorination and other reactions". Organic Process Research & Development. 1 (2): 182. doi:10.1021/op970206t.
  9. ↑ Queen, A. (1967). "Kinetics of the hydrolysis of acyl chlorides in pure water". Canadian Journal of Chemistry. 45 (14): 1619–1629. doi: 10.1139/v67-264 .
  10. 1 2 Kreutzberger, C. B.; Olofson, R. A. (2001). "Dimethylcarbamoyl chloride". e-EROS Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.rd319. ISBN   0-471-93623-5.
  11. ↑ Jäger, P.; Rentzea, C. N.; Kieczka, H. (2014). "Carbamates and carbamoyl chloride". Ullmann's Fine Chemicals. Weinheim: Wiley-VCH. pp. 57–58. ISBN   978-3-527-33477-3.
  12. ↑ "Dimethylcarbamoyl Chloride, CAS No. 79-44-7" (PDF). Report on Carcinogens (13th ed.). National Toxicology Program, Department of Health and Human Services. Retrieved 2016-09-25.
  13. ↑ De Cusati, P. F.; Olofson, R. A. (1990). "A simple synthesis of 1-(1,3-butadienyl)carbonates and carbamates". Tetrahedron Letters. 31 (10): 1405–1408. doi:10.1016/S0040-4039(00)88817-6.
  14. ↑ Lawson, J. K. Jr.; Croom, J. A. T. (1963). "Dimethylamides from alkali carboxylates and dimethylcarbamoyl chloride". The Journal of Organic Chemistry. 28 (1): 232–235. doi:10.1021/jo1036a513 (inactive 31 January 2024).{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  15. ↑ US 3597478,Weakly, M. L.,"Preparation of tetramethylurea",issued 1971-08-03, assigned to Nipak Inc.
  16. ↑ Arnold, Z. (1959). "The preparation of tetramethylformamidinium salts and their vinylogues". Collection of Czechoslovak Chemical Communications. 24 (3): 760–765. doi:10.1135/cccc19590760.
  17. ↑ Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. (1961). "Über Säureamidacetale, Harnstoffacetale und Lactamacetale" [On acid amide acetals, urea acetals and lactam acetals]. Justus Liebigs Annalen der Chemie (in German). 641 (1): 1–39. doi:10.1002/jlac.19616410102.
  18. ↑ Bredereck, H.; Effenberger, F.; Brendle, Th. (1966). "Synthese und Reaktionen von Trisdimethylaminomethan" [Synthesis and reactions of tris(dimethylamino)methane](PDF). Angewandte Chemie (in German). 78 (2): 147–148. Bibcode:1966AngCh..78..147B. doi:10.1002/ange.19660780212.
  19. ↑ US 3452043,Grauer, T.&Urwyler, H.,"Production of 1-N,N-dimethylcarbamoyl-5-methyl-3-N,N-dimethylcarbamoyloxypyrazole",issued 1969-06-24, assigned to J. R. Geigy AG
  20. ↑ Aeschlimann, J. A.; Reinert, M. (1931). "Pharmacological action of some analogues of physostigmine". Journal of Pharmacology and Experimental Therapeutics. 43 (3): 413–444.
  21. ↑ US 1905990,Aeschlimann, J. A.,"Disubstituted carbamic acid esters of phenols containing a basic constituent",issued 1933-04-25, assigned to Hoffmann-La Roche Inc.
  22. ↑ US 2572579,Urban, R.,"Disubstituted carbamic acid esters of 3-hydroxy-1-alkyl-pyridinium salts",issued 1951-10-23, assigned to 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)",issued 1976-09-16, assigned to Siphar SA
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