Chloroalkyl ether

Chloroalkyl ethers are a class of organic compounds with the general structure R-O-(CH2)n-Cl, characterized as an ether connected to a chloromethyl group via an alkane chain.

Chemical structure of chloromethyl methyl ether (MOM-Cl)

Chloromethyl methyl ether (CMME) is an ether with the formula CH3OCH2Cl. It is used as an alkylating agent and industrial solvent to manufacture dodecylbenzyl chloride, water repellents, ion-exchange resins, polymers, and as a chloromethylation reagent. In organic synthesis the compound is used for the introduction of the methoxymethyl (MOM) protecting group.

Closely related compounds of industrial importance are bis(chloromethyl) ether (BCME) (closely related to chemical weapon sulfur mustard)[1] and benzyl chloromethyl ether (BOMCl).

Chloromethyl etherRMolar massCAS numberBoiling point °C
Benzyl chloromethyl etherBenzyl156.613587-60-8102 °C @ 14 mmHg (1.9 kPa)
Chloromethyl methyl etherMethyl80.51107-30-255-57
Bis(chloromethyl) ether114.96542-88-1106
tert-Butyl chloromethyl etherButyl124.5
Methoxyethyl chloromethyl ether124.573970-21-650-52 °C @ 13 mmHg (1.7 kPa)
Dichloromethyl methyl ether114.964885-02-382 - 85.5 °C
Representative chloroalkyl ethers[2]

Alcohol protection

2-Methoxyethoxymethyl (MEM) group is commonly used in organic synthesis as a protecting group for alcohols. Typically, the alcohol is deprotonated with a strong base such as sodium hydride followed by etherification by addition of 2-methoxyethoxymethyl chloride.[3] The MEM group can also be installed at ambient temperature with 2-methoxyethoxymethyl chloride and a mild base such as N,N-diisopropylethylamine (DIPEA) in dichloromethane.[4]

In the case of methoxymethyl (MOM), these ethers can be produced similarly, using strong or weak bases.[5][6]

Deprotection

The 2-methoxyethoxymethyl and the MOM protecting groups can be cleaved with a range of Lewis and Bronsted acids.[7]

Safety

Chloroalkyl ethers are strong alkylating agents with attendant dangers. These compounds are human carcinogen.[8]

References
  1. Bis(Chloromethyl) ether Safety Data Sheet, Division of Occupational Health and Safety, US National Institutes of Health
  2. "Sigma-Aldrich: Analytical, Biology, Chemistry & Materials Science products and services".
  3. Corey, E. J.; Gras, Jean-Louis; Ulrich, Peter (1976-03-01). "A new general method for protection of the hydroxyl function". Tetrahedron Letters. 17 (11): 809–812. doi:10.1016/S0040-4039(00)92890-9.
  4. Lee, Hong Myung; Nieto-Oberhuber, Cristina; Shair, Matthew D. (2008-12-17). "Enantioselective Synthesis of (+)-Cortistatin A, a Potent and Selective Inhibitor of Endothelial Cell Proliferation". Journal of the American Chemical Society. 130 (50): 16864–16866. doi:10.1021/ja8071918. ISSN 0002-7863. PMID 19053422.
  5. Wuts, Peter G. M.; Greene, Theodora W. (2006). Greene's Protective Groups in Organic Synthesis, Fourth Edition - Wuts - Wiley Online Library. doi:10.1002/0470053488. ISBN 9780470053485.
  6. Enders, Dieter; Geibel, Gunter; Osborne, Simon (2000-04-17). "Diastereo- and Enantioselective Total Synthesis of Stigmatellin A". Chemistry – A European Journal. 6 (8): 1302–1309. doi:10.1002/(SICI)1521-3765(20000417)6:8<1302::AID-CHEM1302>3.0.CO;2-J.
  7. Amano, Seiji; Takemura, Noriaki; Ohtsuka, Masami; Ogawa, Seiichiro; Chida, Noritaka (1999-03-26). "Total synthesis of paniculide A from d-glucose". Tetrahedron. 55 (13): 3855–3870. doi:10.1016/S0040-4020(99)00096-4.
  8. Bis(chloromethyl) Ether and Technical-Grade Chloromethyl Methyl Ether CAS Nos. 542-88-1 and 107-30-2, Report on carcinogens, Eleventh edition
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