Methylation

What is Methylation?

Methylation refers to the addition of a methyl group (CH3 group) to a compound or the substitution of one of its functional groups with a methyl group. It can be considered as a specific type of alkylation in which only a CH3 group is transferred. An illustration detailing the methylation of cytosine (one of the four major bases found in DNA and RNA) is provided below.

Methylation

It can be noted that the opposite process (i.e. the removal of a methyl group from a compound) is known as demethylation.

Electrophilic Methylation

In electrophilic methylations, the source of the methyl group is an electrophile. Examples of electrophilic methylating agents include iodomethane, dimethyl carbonate, dimethyl sulphate, and diazomethane. In these reactions, the methylation proceeds via an SN2 reaction.

Examples of electrophilic methylation include:

  • The methylation of a carboxylate ion at its oxygen to afford a methyl ester.
  • The formation of an ether from the methylation of an alkoxide ion.
  • The methylation of the enolate of a ketone to yield a new ketone.
  • The Purdie methylation reaction in which the oxygen belonging to some carbohydrate is methylated with the help of silver oxide and iodomethane.

Electrophilic Methylation

Nucleophilic Methylation

When a nucleophilic methylating agent is used for the transfer of a CH3 group, the process is referred to as nucleophilic methylation. Examples of nucleophilic methylating agents include:

  • Grignard reagents in which the R group is a methyl group (such as CH3-Mg-Br)
  • Methyllithium (CH3Li)
  • Tetramethyltin ((CH3)4Sn)
  • Trimethyl aluminium (Al2(CH3)6)
  • Dimethyl zinc (Zn(CH3)2)

When aldehydes and ketones are subjected to methylation with the help of a nucleophilic methylating agent, the CH3 group is usually added to the carbonyl carbon (as illustrated below).

Nucleophilic Methylation

The Eschweiler-Clarke Reaction

In this named reaction, a primary/secondary amine undergoes methylation upon its treatment with formaldehyde and an excess of formic acid. The general format of this reaction is illustrated below.

Eschweiler-Clarke Reaction

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