[74-87-3]  · CH3Cl  · Chloromethane  · (MW 94.95)

(methylating agent attacking C-, O-, N-, P-, S-, Se-, and Te-based nucleophiles; organometallic derivatives provide source of Med- in reactions with >C=O, M-X, halogen, etc., and also as a base towards C-H; radical substitution of Me by C&bdot;, halogen, etc.)

Alternate Name: methyl chloride.

Physical Data: mp -97.7 °C; bp -24.22 °C; d 0.991 g cm-3 (-25 °C).

Solubility: miscible with most organic solvents, sparingly with aqueous media.

Form Supplied in: colorless gas.

Purification: gas passed through conc. H2SO4 then water, and dried with P2O5 and fractionally distilled.

Handling, Storage, and Precautions: usually available in cylinders. Potent alkylating agent; high toxicity. Use in a fume hood.

Methylating Agent.2

Nucleophilic displacement occurs readily at carbon (eq 1), often via anions as in the methylation of lithio-rhenocene (LiReCp2)3a and the more classical methylation of acetoacetic, malonic, and cyanoacetic esters,3 or in the alkylation of cyclopentadiene, or the a-attack of aliphatic ketones.4 The Friedel-Crafts reaction with benzene may be modified to provide any or all of the possible polymethylbenzenes, as in the preparation of 1,2,4,5-tetramethylbenzene.5 A range of Lewis acid catalysts have been applied6a,6b and the use of boron triflate exemplifies the introduction of more novel catalysts.6c,6d Methyl cyanate may be obtained from metal cyanates (MeCl, xylene-N,N-dialkylamide mixtures)7 and dimethyl carbonate similarly from K2CO3 (phase-transfer catalysts; dipolar aprotic solvent).8

The carbonylation of MeCl leading to Acetyl Chloride is achieved in the presence of superacids or metal catalysts (eq 2).9 Correspondingly, metal sulfites are advocated10 as routes to Methanesulfonic Acid (eq 3). N-Methylation, either to give more fully alkylated amines or to give quaternary ammonium salts, has been widely reported (eq 4).

In cases where the substrate is very susceptible to electrophilic attack, both methylation and formylation are observed when such reactions are carried out in DMF. The analogous reaction with phosphorus (R3P, (RO)3P) provides phosphonium salts, the deprotonation of which leads to synthetically useful phosphonium ylides (eq 5).

Reductive methylation is observed when Cl or another displaced group is removed by single-electron transfer to give Cl- and, effectively, Me&bdot;. An example is the formation of Me2SO2 by the electrochemical reduction of MeCl in dipolar aprotic solvents containing SO2.11 Nucleophilic oxygen (e.g. OH-, OR-, RCO2-) and sulfur (e.g. S2-, HS-, RS-, SCN-, S2O32-, RSO2-, thiourea) are similarly methylated, while Te and Se show analogous chemistry. Halide ion exchange reactions (including N3-) are valuable routes between the various methyl halides and also allow the synthesis of labelled RCl (e.g. Me36Cl).

Asymmetric methylation is achieved using chiral phase-transfer catalysts (e.g. N-benzylcinchoninium salts), as in the attack at C-2 of 2-phenyl-5-methoxy-6,7-dichloroindanone.12


Methylmagnesium chloride (MeCl, Mg, Et2O under dry, O2-free conditions) provides a nucleophile capable of reacting with (i) metal halides in a transmetalation reaction, (ii) proton sources, including alcohols, phenols, amines, imines, and amides, (iii) electrophilic carbon, as in aldehydes, ketones, carboxylic acid derivatives, nitriles, and epoxides, and (iv) elements such as O2, S8, I2, interhalogens such as CNCl, and species such as CO2 and SO2. While Grignard reactions give alcohols with many carboxylic acid derivatives, the reaction with RCOCl (eq 6) may be used to form methyl ketones in good yield (63-92%) by the presence of Tris(acetylacetonato)iron(III) (THF, rt).13 Such a process replaces the older techniques which used FeCl3, or the formation of organozinc or -cadmium intermediates.

Substitution in the Alkyl Group.

Hydrogen abstraction provides a carbon-based radical which leads to substituted derivatives. Thus further chlorination of MeCl leads to CH2Cl2, CHCl3, and CCl4 (eq 7); fluorination of MeCl proceeds similarly.14 Hydrogen isotope exchange may also be achieved in this way.

Related Reagents.

Bromomethane; Iodomethane.

1. Holbrook, M. T. In Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed.; Wiley: New York, 1993; Vol. 5, p 1028.
2. (a) de la Mare, P. B. D.; Swedlund, B. E. In The Chemistry of the Carbon-Halogen Bond; Patai, S., Ed.; Wiley: New York, 1973; Part 1, p 409. (b) Katritzky, A. R.; Brycki, B. CSR 1990, 19, 83. (c) Feast, W. J. In Rodd's Chemistry of Carbon Compounds, Supplements to the 2nd Edition; Ansell, M. F., Ed.; Elsevier: Amsterdam, 1975; Vol. 1, Parts A-B, p 31. (d) Bolton, R. In Rodd's Chemistry of Carbon Compounds, Second Supplements to the 2nd Edition; Sainsbury, M., Ed.; Elsevier: Amsterdam, 1991; Vol. 1, Parts A-B, p 214.
3. (a) Heinekey, D. M.; Gould, G. L. OM 1991, 10, 2977. (b) Carruthers, W. Some Modern Methods of Organic Synthesis, 3rd ed.; Cambridge University Press: Cambridge, 1986. (c) House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: New York, 1972. (d) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. OR 1984, 31, 1.
4. Caine, D. In Carbon-Carbon Bond Formation; Augustine, R. L., Ed.; Dekker: New York, 1979; Vol. 1, p 85.
5. Smith, L. I. OSC 1950, 2, 248.
6. (a) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973. (b) Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation Chemistry; Dekker: New York, 1984. (c) Olah, G. A.; Olah, J. A.; Ohyama, T. JACS 1984, 106, 5284. (d) Olah, G. A.; Farooq, O.; Farnia, S. M. F.; Olah, J. A. JACS 1988, 110, 2560.
7. Khydyrov, D. N.; Gadzhiev, F. R.; Nizker, L. L.; Promonenkov, V. K.; Kutov, V. M. USSR Patent 1 641 815, 1991 (CA 1991, 115, 280 068w).
8. Cella, J. A.; Bacon, S. W. JOC 1984, 49, 1122.
9. (a) Erpenbach, H.; Gehrmann, K.; Lork, W.; Prinz, P. Ger. Patent 3 106 900, 1981 (CA 1982, 96, 19 680a). (b) Eur. Patent Appl. 48 335, 1982 (CA 1982, 97, 109 563q).
10. Wuest, W.; Eskuchen, R.; Lohr, C. Eur. Patent Appl. 405 287, 1991 (CA 1991, 114, 145 831d).
11. Wille, H. J.; Kastening, B.; Knittel, D. J. Electroanal. Chem. Interfacial Electrochem. 1986, 214, 221 (CA 1987, 106, 74 888z).
12. Dolling, U. H.; Davis, P.; Grabowski, E. J. JACS 1984, 106, 446.
13. Fiandanese, V.; Marchese, G.; Martina, V.; Ronzini, L. TL 1984, 25, 4805.
14. Adcock, J. L.; Kunda, S. A.; Taylor, D. R.; Nappa, M. J.; Sievert, A. C. Ind. Eng. Chem. Res. 1989, 28, 1547 (CA 1989, 111, 156 362r).

Roger Bolton

University of Surrey, Guildford, UK

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