Williamson Ether Synthesis

• General Characteristics

-The synthesis of unsymmetrical ethers by S_N2 displacement of alkyl halides by alkoxides is called the Williamson ether synthesis. The reaction works best when the R group is primary.

-In certain cases such as trityl protection, the reaction proceeds by S_N1 pathway.

–E2 elimination is the main competing reaction, which predominates for tertiary alkyl halides.

-S_N2-promoting aprotic polar solvents such as acetonitrile and DMF are generally used.

-The leaving group is not limited to halides. Alkyl sulfonates are equally usable.

• General References

・Williamson, W. Liebigs Ann. Chem. 1851, 77, 37.
・Williamson, W. J. Chem. Soc. 1852, 106, 229.
・Dermer, O. C. Chem. Rev. 1934, 14, 385. DOI: 10.1021/cr60049a002

• Reaction Mechanism

• Examples

 

 

 

In S_NAr type reactions, note that the reactivity decreases in the order of F > Cl > Br > I.

• Experimental Procedure

• Experimental Tips

• References

[1] J. R. Prous, ed. Drugs Fut. 1992, 17, 1093.
[2] J. R. Prous, ed. Drugs Fut. 2002, 27, 339.
[3] J. R. Prous, ed. Drugs Fut. 1990, 15, 1080.

• Related Books

SN2 reaction, synthesis of ethers