Experiment 4: Williamson Ether Synthesis of Propyl-p-tolyl Ether

Organic anions such as alkoxides (RO-) and amides (RNH-) are very strong Lewis bases, and therefore are expected to be strong nucleophiles for SN2 reactions. The Williamson ether synthesis involves the reaction of an alkoxide or phenoxide anion with an alkyl halide to produce an ether. This reaction can occur inadvertently as a side reaction when alkoxides are used as bases in elimination reactions:

+ NaOCH2CH3
Br OCH2CH3

2-bromobutane

However, it is also utilized in synthetic chemistry, particularly in the preparation of aryl ethers. This synthetic method is particularly powerful because the starting phenoxide anions are much weaker bases than the alkoxides, so competing elimination reactions are minimized:
O OR

+ R-X

To further minimize competing elimination reactions, it is preferable that the reaction be conducted in a nonprotic solvent. The alkyl halide starting material typically has better solubility in nonprotic, low polarity solvents as well. The drawback is that the phenoxide anion is highly polar, particularly when paired with a cation such as sodium or potassium. This limits its availability to react with the alkyl halide, resulting in long reaction times. This problem can be addressed through the use of a cationic phase transfer catalyst. These substances are typically trialkylammonium salts that can react with the anion to form a lipophilic (nonpolar solvent loving) salt:
O Na+ O R4N+

+ R4N+ Cl-

+ NaCl

This complex then can move into the nonprotic, low polarity phase containing the halide to react to form the aryl ether. A second advantage in using the phase transfer catalyst is that while the phenoxide is in a polar protic phase, the anion is surrounded by a strong solvent shell, which greatly reduces its reactivity. Once the anion has been moved into a nonprotic, low polarity phase, solvent interactions are much weaker; as a result, the anion becomes a much more reactive nucleophile.

In this experiment, you will form the anion of p-cresol (4-methylphenol) in situ by reacting the compound with aqueous sodium hydroxide. The phase transfer catalyst tetrabutylammonium bromide (TBAB) is used to carry the phenoxide into the organic phase of the reaction mixture to react with iodopropane. In one sense the reaction is being conducted under neat conditions, meaning that there is no additional solvent. At the start of the reaction, the organic phase consists of the alkyl halide; as the reaction progresses, the composition of the organic phase becomes enriched with the aryl ether product. During the reaction it will be important to maintain good agitation to facilitate exchange between the aqueous and organic phases.
OH
+ O Na

+ NaOH
H3C
+ O Na

-H2O

H3C OCH2CH2CH3

+ CH3CH2CH2I
H3C

Bu4N Br

+ NaI
H3C

Phenols and cresols are prone to oxidation, so the starting material in the synthesis is likely to be contaminated with highly polar by-products. As the aryl ether product of the synthesis is relatively nonpolar, it is possible to purify the product by chromatography. Reagents: p-cresol, iodopropane, tetrabutylammonium bromide, 25% sodium hydroxide, dichloromethane, anhydrous sodium sulfate, silica, sand Equipment: 5.0 ml reaction vial, large spin vane, water condenser, magnetic stirrer, sand bath, heating mantle, 100 ml beaker, 10 ml Erlenmeyer flask, scintillation vial.

Procedure:

Questions: 1. Draw the mechanism of this reaction. Show the movement of electrons. 2. 3. How does the tetrabutylammonium bromide catalyze this reaction? Why is vigorous stirring required in step 3?