Omethylating

O-methylating is the process of introducing a methyl group onto an oxygen atom in a molecule, forming a methyl ether (R–O–CH3). In organic synthesis it is used to convert hydroxyl groups into methoxy groups, either as a protective step or to alter the molecule’s properties. The term also covers enzymatic methylation by biological enzymes.

Chemical methods employ methylating agents such as dimethyl sulfate, methyl iodide, and methyl triflate. Reactions typically proceed via deprotonation to generate an alkoxide or phenoxide, followed by SN2 attack on the methyl donor. Dimethyl sulfate and methyl triflate are highly reactive; methyl iodide is milder. Solvents like DMF, DMSO, or acetone and bases such as potassium carbonate or sodium hydride are common. Phenolic O-methylation is often favored, but overmethylation or O/C methylation side reactions can occur.

Applications include preparation of aryl methyl ethers (anisoles), protection of alcohols in multi-step syntheses, and modification of natural products to adjust polarity and metabolic stability. In medicinal chemistry, O-methyl ethers can influence pharmacokinetic properties and receptor binding.

Biological O-methylation is carried out by O-methyltransferases, which transfer a methyl group from S-adenosyl-L-methionine to oxygen atoms on substrates such as phenols, catechols, and flavonoids. These enzymes are central to plant secondary metabolism and neurotransmitter regulation, and they are often highly regio- and substrate-specific.

Safety and sustainability: many chemical methylating agents are toxic or carcinogenic. Handling requires proper controls, and greener alternatives are pursued in research.