Mixed Ethers The Mechanism

Freedman and Dubois [ 1 ] have found that a variety of ethers can be prepared by the reaction of either primary or secondary alcohols with inexpensive primary alkyl chlorides in the presence of excess concentrated aqueous sodium hydroxide solution and tetrabutylammonium hydrogen sulfate as catalyst. The formation of -butyl n-hexyl ether is shown in equation 5.1. Typically, the 8 2 displacement reaction was not successful with secondary alkyl halides even under phase transfer conditions. 

Nevertheless, this procedure is significantly easier than the traditional Williamson ether synthesis which requires prior generation of the alkoxide salt, usually by reaction of the alcohol with a strong base such as sodium hydride, sodamide, or sodium metal. 

In the two phase Williamson ether synthesis, the base used is concentrated aqueous sodium hydroxide. Ordinarily, 50% aqueous sodium hydroxide is used, but even more concentrated solutions seem to be more effective. The alcohol in solution is deprotonated by hydroxide either in the aqueous phase or at the interface and then solubilized in the organic phase by ion pairing with the quaternary ammonium ion. 

The success of the reaction depends on the preferential extraction of tetrabutylammonium alkoxide rather than the corresponding hydroxide salt. The preference of the quaternary ammonium ion for alkoxide over hydroxide can be attributed to two factors. First, the soft (larger, more polarizable) quat prefers to pair with the soft (larger, more polarizable) alkoxide rather than the hard hydroxide ion. Second, hydroxide is more effectively solvated by the aqueous medium than is the alkoxide and prefers to remain in that phase. Under phase transfer conditions, secondary alcohols react more slowly than do primary alcohols, probably due to the lower acidity of secondary alcohols or to steric factors. 

After deprotonation of alcohol (Eq. 5.2) and ion pairing with the quaternary ion (Eq. 5.3), reaction occurs between it and the alkyl halide (Eq. 5.5). For each mole of ether formed, a mole of quaternary ammonium halide is also formed. Exchange of the nucleofuge for a molecule of nucleophile followed by phase transfer completes the catalytic cycle which is shown in equations 5.2—5.6. 

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