Oalkylation

O-alkylation is the introduction of an alkyl group onto an oxygen atom in a nucleophile, forming an ether. The most common context is the formation of alkyl ethers from alcohols or phenols via the Williamson ether synthesis: a metal alkoxide (RO−) is generated by deprotonation of an alcohol or phenol, then reacts with an alkylating agent such as an alkyl halide (R′X) or an alkyl sulfonate to furnish R−O−R′. Primary alkyl halides are preferred for SN2 displacement, though other leaving groups and conditions can be used.

Typical reaction conditions involve generating the alkoxide with a base (for example, sodium hydride, alkoxide bases, or carbonates) and using a polar aprotic solvent such as DMF, DMSO, or acetone to promote nucleophilic attack. The scope includes forming ethers from simple alcohols, as well as creating aryl ethers (e.g., anisoles) from phenols.

O-alkylation is also considered for ambident nucleophiles such as enolates, which can undergo competing O-alkylation and C-alkylation. In such cases, the choice of electrophile and reaction conditions influences selectivity: hard electrophiles and conditions favor O-alkylation, while soft electrophiles tend toward C-alkylation.

Applications of O-alkylation include protection of alcohols as alkyl ethers, synthesis of a wide range of ethers found in natural products and pharmaceuticals, and general methods for installing alkyl groups on oxygen-containing substrates. Limitations can include slower reaction with hindered substrates and side reactions when alternative alkylation pathways compete.