CHLOROMETHANE

1

Chloromethane

1

CH

3

Cl

[74-87-3]

CH

3

Cl

(MW 94.95)

InChI = 1/CH3Cl/c1-2/h1H3
InChIKey = NEHMKBQYUWJMIP-UHFFFAOYAW

(methylating agent attacking C-, O-, N-, P-, S-, Se-, and Te-based
nucleophiles; organometallic derivatives provide source of Me

δ−

in reactions with >C=O, M–X, halogen, etc., and also as a base

towards C–H; radical substitution of Me by C

•

, 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. H

2

SO

4

then water, and

dried with P

2

O

5

and fractionally distilled.

Handling, Storage, and Precautions:

usually available in cylin-

ders. Potent alkylating agent; high toxicity. Use in a fume hood.

Methylating Agent.

2

Nucleophilic displacement occurs read-

ily at carbon (eq 1), often via anions as in the methylation of
lithio-rhenocene (LiReCp

2

)

3a

and the more classical methylation

of acetoacetic, malonic, and cyanoacetic esters,

3

or in the alkyla-

tion of cyclopentadiene, or the α-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 applied

6a,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 K

2

CO

3

(phase-transfer catalysts; dipolar aprotic solvent).

8

MeCl

+

X

–

MeX

+

Cl

–

(1)

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 advocated

10

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).

MeCOCl

MeCl

+

CO

(2)

MeCl

+

SO

3

2–

MeSO

3

–

+

Cl

–

(3)

(4)

RNMe

3

+

RNH

2

RNHMe

RNMe

2

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 (R

3

P, (RO)

3

P) provides phosphonium salts, the

deprotonation of which leads to synthetically useful phosphonium
ylides (eq 5).

(5)

(RCH

2

)

3

P

+

MeCl

[(RCH

2

)

3

PMe]

+

Cl

–

[(RCH

2

)

2

PMe]

+

[CHR]

–

Reductive methylation is observed when Cl or another dis-

placed group is removed by single-electron transfer to give
Cl

−

and, effectively, Me

•

. An example is the formation of

Me

2

SO

2

by the electrochemical reduction of MeCl in dipolar

aprotic solvents containing SO

2

.

11

Nucleophilic oxygen (e.g.

OH

−

, OR

−

, RCO

2

−

) and sulfur (e.g. S

2−

, HS

−

, RS

−

, SCN

−

,

S

2

O

3

2−

, RSO

2

−

, thiourea) are similarly methylated, while Te

and Se show analogous chemistry. Halide ion exchange reactions
(including N

3

−

) are valuable routes between the various methyl

halides and also allow the synthesis of labelled RCl (e.g. Me

36

Cl).

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

Organometallics.

Methylmagnesium chloride (MeCl, Mg,

Et

2

O under dry, O

2

-free conditions) provides a nucleophile capa-

ble 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) ele-
ments such as O

2

, S

8

, I

2

, interhalogens such as CNCl, and species

such as CO

2

and SO

2

. 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 FeCl

3

, or the

formation of organozinc or -cadmium intermediates.

(6)

MeCl

+

Mg

MeCOR

+

MgCl

2

MeMgCl

RCOCl

Substitution in the Alkyl Group. Hydrogen abstraction pro-

vides a carbon-based radical which leads to substituted derivatives.
Thus further chlorination of MeCl leads to CH

2

Cl

2

, CHCl

3

, and

CCl

4

(eq 7); fluorination of MeCl proceeds similarly.

14

Hydrogen

isotope exchange may also be achieved in this way.

(7)

MeCl

+

X

2

H

2

CXCl

+

HX

X = Cl, F

CHX

2

Cl

CX

3

Cl

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., Chem. Soc. Rev. 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., Organometallics 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., Org. React. 1984, 31, 1.

Avoid Skin Contact with All Reagents

2

CHLOROMETHANE

4.

Caine, D. In Carbon–Carbon Bond Formation; Augustine, R. L., Ed.;
Dekker: New York, 1979; Vol. 1, p 85.

5.

Smith, L. I., Org. Synth., Coll. Vol. 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., J.
Am. Chem. Soc. 1984

, 106, 5284. (d) Olah, G. A.; Farooq, O.; Farnia,

S. M. F.; Olah, J. A., J. Am. Chem. Soc. 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 (Chem. Abstr. 1991, 115,
280 068w).

8.

Cella, J. A.; Bacon, S. W., J. Org. Chem. 1984, 49, 1122.

9.

(a) Erpenbach, H.; Gehrmann, K.; Lork, W.; Prinz, P. Ger. Patent 3 106
900, 1981 (Chem. Abstr. 1982, 96, 19 680a). (b) Eur. Patent Appl. 48
335, 1982 (Chem. Abstr. 1982, 97, 109 563q).

10.

Wuest, W.; Eskuchen, R.; Lohr, C. Eur. Patent Appl. 405 287, 1991
(Chem. Abstr. 1991, 114, 145 831d).

11.

Wille, H. J.; Kastening, B.; Knittel, D., J. Electroanal. Chem. Interfacial
Electrochem. 1986

, 214, 221 (Chem. Abstr. 1987, 106, 74 888z).

12.

Dolling, U. H.; Davis, P.; Grabowski, E. J., J. Am. Chem. Soc. 1984,
106

, 446.

13.

Fiandanese, V.; Marchese, G.; Martina, V.; Ronzini, L., Tetrahedron
Lett. 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 (Chem. Abstr. 1989, 111, 156 362r).

Roger Bolton

University of Surrey, Guildford, UK

A list of General Abbreviations appears on the front Endpapers