Suggest ways in which the yield of the product could be improved on a laboratory
ID: 1032838 • Letter: S
Question
Suggest ways in which the yield of the product could be improved on a laboratory scale by manipulating the solvent used for the reaction. Would these modifications be practical for a large scale industrial process using the Williamson method to make guaifenesin? Consider cost and waste disposal in your answer. (What reaction conditions could be changed to improve yields? Could your suggested changes be incorporated into an industrial scale synthesis?
OH o- CI OH OH NaOH EtoH guaiacol (t)-guaifenesin Scheme 5-2. Williamson synthesis of guaifenesin.Explanation / Answer
TThe Williamson ether synthesis employs generation of an alkoxide from the alcohol to generate the nucleophile that attacks the alkyl halide to form the ether desired. Since the reaction goes through a SN2 mechanism with the base also giving the possibility of an E2 reaction, first the alkoxide is chosen such that the alkyl halide is primary or secondary thus facilitating its feasibility for the former thus improving the yield.
Moreover the choice of base should be such that it does not interact with a solvent producing a better basic alkoxide from the alcohol solvent itself thus giving a competitve reaction between the solvent alkoxide and the alkoxide we desire to produce. To avoid this, the solvent used ideally should be the conjugate base of the alkoxide used. Here since it is not possible, a strong base like NaH or Na metal can be used, in water. This will generate the desired phenoxide ion and the other product NaOH also being a strong base does not produce interfering nucleophiles. Thus a desirable combination will be Na or NaH in water rather than NaOH in EtOH. Cutting costs however, using NaOH in water will also do the trick. This solvent and base combination will also ensure that the alkoxide desired does not attain an equilibrium state and decompose to give back the phenol.
Therefore the only change required to boost the reaction's efficiency is to use Na metal or NaH or NaOH in water with the compound guanicol being added slowly in batches to avoid rapid reaction such that the suspension formed dissipates steadily over time showing the formation of the alkoxide following which the alkyl halide can be added again in batches to ensure high yield of the desired ether.
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