Chem unit 3

Williamson Ether Synthesis• The Williamson ether synthesis is an organic reaction used to convert
an alcohol and an alkyl halide to an ether using a base such as NaOH.
• The mechanism begins with the base abstracting the proton from the
alcohol to form an alkoxide intermediate.
• The alkoxide then attacks the alkyl halide in a nucleophilic
substitution reaction (SN2), which results in the formation of the final
ether product and a metal halide by-product.
WES reaction
Mechanism
• Guaifenesin is used as an expectorant in many common cold & cough
syrups, including Benylin, Robitussin & Novahistex.
• It loosens and thins bronchial secretions, which leads to more productive
cough. It is also available in tablet form both over-the-counter, and in a
higherdose prescription form.
• The compound is administered in racemic form, although it has been
suggested that the (S)-(+)-enantiomer is more potent.
• We will synthesize guaifenesin using a Williamson ether synthesis. In this
experiment, (±)-3-chloro-1,2-propane-diol will be allowed to react with the
guaicol via an SN2 reaction to provide guaifenesin.
• The product analyzed by IR spectroscopy.
Procedure
• 1. Add a magnetic stir bar to a 25ml round or pear shaped flask.
• 2. Add guaiacol (0.55ml,5mmoles) to the flask along with 3ml of 95%
ethanol. Make sure the guaiacol dissolves in the ethanol before
proceeding.
• 3. Add 1ml of 6M NaOH with stirring.
• 4. Attach a condenser.
• 5. Reflux for 10mins using a water bath. This will result in generation of a
phenoxide ion.
• 6. Using a 9” pipet , add 1ml of a 50% solution of (+/-)-3-chloro-1,2propane-diol(TOXIC,wear gloves,do not remove from the fumehood) in
ethanol dropwise through the top of the condenser, gradually over a
period of 5-10minutes.
• 7. A white precipitate should form.
• 8. Reflux for 1 hour.
• 9. Remove from heat and allow to cool.
• 10. Remove the ethanol using a rotary evaporator.
• 11. Add 3ml of water to dissolve the NaCl formed.
• 12. Pour mixture into a separatory funnel and extract twice with ethyl
acetate.(2x10ml). Wash out your 25ml round or pear bottomed flask
with acetone and leave to dry. You may need it again for step 15.
• 13. Dry the layers with anhydrous magnesium sulfate.
• 14. Filter. Rinse the filtrate into a pre weighed round or pear shaped round
bottom flask. The flask should not be more than half full before going on
the rotary evaporator. You may need to use a 50ml round bottom flask.
• 15. Remove the ethyl acetate using a rotary evaporator.
• 16. Cool the flask in ice water and add a magnetic stir bar.
• 17. Add hexanes (10ml) with rapid stirring.
• 18. If guaifenesin precipitates filter it off.
• 19. If it does not precipitate remove the solvent on a rotary evaporator.
• (Procedure adapted from Stabile, Ryan. G; P. Dicks; Andrew P., J. Chem. Ed
2003,80(3),313-315)