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Methylation

Because dimethyl sulfate is a strong methylating agent, it can be used to introduce a methyl group at the following reaction centers having unshared electron pairs:

  • Oxygen
  • Nitrogen
  • Carbon
  • Sulfur
  • Phosphorus
  • Some metals
  • Heteroatoms from Groups VA and VIA

Usually a base is required, either (1) to make the reaction site more reactive, e.g., convert phenol to sodium phenolate before conversion to anisole, or (2) to neutralize the monomethyl sulfuric acid or sulfuric acid that is produced, e.g., in the methylation of aliphatic alcohols.

Usually, only one of the methyl groups of DMS reacts. For research purposes, there is no need to try to use both methyl groups. However, for commercial applications in which the reaction site is highly reactive, e.g., the sodium salt of mercaptans, it would be desirable to use both groups if possible. The chances of utilizing the second methyl group are enhanced by employing higher reaction temperatures and by minimizing the competing reactions with water and the hydroxide ion. The competing reactions are reduced by using little or no water and by avoiding excess base. For example, base can be added as the reaction proceeds and only to the extent acid forms. Also, a reaction system of dimethyformamide/K2CO3 and comparable non-aqueous solvent/base combinations can be substituted for water in many cases.

Based on rate of reaction and compared with alkyl halides, dimethyl sulfate is a much preferred alkylating agent. Table 3 shows the relative alkylation rates with DMS and other agents in the reaction of the sodium salt of 2-methyl cyclohexanone6:


 

Methylation on Oxygen

Where salts can be readily prepared, DMS methylates rapidly. Examples are:
 


 

Alcohols can be methylated without first forming the alcoholate ion. An example is the synthesis of 2,2,3,3-tetrafluoropropyl methyl ether in 83% yield7:
 

 

Another example is the methylation of cotton.8 A U.S. patent covers the methylation of substituted hydroxybenzenes in the absence of a solvent.9
Reaction of carboxamides gives imino ether salts10:


 

Methylation on Sulfur

Mercaptan salts are methylated rapidly with DMS:
 

The thioethers are also reactive and can continue reaction to sulfonium salts:
 



The reaction has been patented as a means of separating organosulfur compounds and fuel hydrocarbons, such as isooctane.11
Another example of sulfur methylation is the preparation of thioacid esters:

Methylation of Nitrogen

Alkylation of amines is usually employed to make tertiary amines or quaternary ammonium salts. An example is the synthesis of N,N-dimethyl-p-toluidine:12

 

 

Syntheses of quaternary salts make amines more water soluble. For example, melamine resins that have been reacted with DMS are more soluble than untreated resins.13

It is not usually possible to stop a methylation of an amine at the monomethyl product, as it is more reactive with DMS than the starting material. Thus, blocking techniques are required when secondary amines are the desired product. The method is illustrated in the synthesis of butylmethylamine, where Ph-CHO is benzaldehyde:14

 

 

 

 

 


Sym-dimethylhydrazine can be synthesized from hydrazine by the method:15

Methylation on Carbon

Active carbons can be methylated, as illustrated with ethyl acetoacetate:16
 

 

 

 

 

Also, C-methylation occurs on metallated hydrocarbons. An example is the conversion of phenyl lithium to toluene:17
 

 

Another route is the use of Grignard derivatives:17
  
Aromatic hydrocarbons can be methylated by DMS in the presence of AlCl3 in typical Friedel Crafts reaction.

Methylation of Inorganic Compounds

Many inorganic centers can be methylated, as in the following example:18

REFERENCES
6 G. Vavon and J. Conia, Compt. rend., 223, 157 (1946).
7 R.D. Bagnall, W. Bell, and K. Pearson, J. of Fluorine Chemistry, 11, 93 (1978).
8 F.S.H. Head and G.E. Hadfield, J. Polym. Sci. 7A, 2517 (1969).
9 U.S. Pat. 4,065,504 (Dec. 27, 1977), D.M. Findlay (to Domtar Ltd.).
10 H. Bredereck, et al., Chem. Ber., 97, 1834 and 3076 (1964).
11 U.S. Pat. 3,661,771 (May 9, 1972), R.H. Havens (to Gulf Research and Development Co.).
12 S. Hunig, Chem. Ber., 85, 1056 (1956).
13 U.S. Pat. 3,645,841 (Feb. 29, 1972), J. Cabestany (to Nobel Hoechst Chimie).
14 Organic Syntheses, 44, 72 (1964).
15 Ibid, Coll. Vol. II, 208 (1943).
16 Ann. 309, 187 (1899).
17 K.A. Anderson and S.W. Fenton, J. Org. Chem., 29, 3270 (1964).
18 Chem. Ber., 94, 3251 (1961).