Williamson ether synthesis, phenyl

The anions of phenols (phenoxide ions) may be used in the Williamson ether synthesis, especially with very reactive alkylating reagents such as dimethyl sulfate. Using phenol, dimethyl sulfate, and other necessary reagents, show how you would synthesize methyl phenyl ether. 

Synthesis of Phenyl Ethers A phenol (aromatic alcohol) can be used as the alkoxide fragment, but not the halide fragment, for the Williamson ether synthesis. Phenols are more acidic than aliphatic alcohols (Section 10-6), and sodium hydroxide is sufficiently basic to form the phenoxide ion. As with other alkoxides, the electrophile should have an unhindered primary alkyl group and a good leaving group. 

Show how you could synthesize allyl phenyl ether from phenol and allyl bromide. STRATEGY AND ANSWER Use a Williamson ether synthesis (Section 21.6A). 

The Williamson ether synthesis cannot be used to prepare tert-butyl phenyl ether. 

In Summary The oxygen in phenols and alkoxybenzenes can be protonated even though it is less basic than the oxygen in the alkanols and aUcoxyalkanes. Protonated phenols and their derivatives do not ionize to phenyl cations, but the ethers can be cleaved to phenols and haloalkanes by HX. Alkoxybenzenes are made by Williamson ether synthesis, aryl alkanoates by acylation. 

Butylation of phenylacetonitrile with aqueous NaOH, as shown in Scheme 25, proceeds faster by use of high DF (>0.5) anion exchange resins.The strongly alkaline conditions degrade the quaternary ammonium ions of the catalyst. Catalyst (64) (1% DVB) is active for alkylation of phenylacetonitrile and benzyl phenyl ketone, and for Williamson ether synthesis, and it is much more stable in base than AERs. AERs in OH form are catalysts for dichlorocyclopropane syntheses from alkenes, chloroform and solid sodium hydroxide, and for dehydration of amides to nitriles. AERs in the appropriate hydroxide, acetate, or cyanide form are catalysts for aldol condensations, Michael reactions, Knoevenagel condensations, cyanoethylations and cyanohydrin syntheses. " ... 

How would you prepare ethyl phenyl ether Use whichever method you think is more appropriate, the Williamson synthesis or the alkoxymercuration reaction. 

Examples of the preparation of alkyl benzyl ethers by the Williamson synthesis are included in Section 5.6.2, p. 583. An example of an alkyl phenyl ether is provided by the synthesis of phenacetin (Expt 6.109) where p-aminophenol is first converted into its Af-acetyl derivative by reaction with slightly more than one equivalent of acetic anhydride. Treatment of the product with ethanolic sodium ethoxide solution followed by ethyl iodide then yields the ethyl ether of AT-acetyl-p-phenetidine (phenacetin). This compound is biologically active and has been widely employed for example as an antipyretic and analgesic however, owing to undesirable side reactions, its use is now restricted. 

Williamson synthesis of phenyl alkyl and dialkyl ethers. Phenols react with alkyl halides in 20% aqueous NaOH containing 1 equiv. of this surfactant at 80° to form phenolic ethers in 85-97% yield. There is no reaction in the absence of CTAB. This procedure is not useful for preparation of dialkyl ethers from alcohols and alkyl halides. Instead, the alkyl chloride, alcohol, a trace of water, and CTAB are heated in THF at 70° with NaOH (2 equiv.). 

Problem 18.3 How would you prepare the following compounds using a Williamson synthesis (a) Methyl propyl ether (b) Anisole (methyl phenyl ether)... 

Draw the target ether, identify the two groups attached to oxygen, and recall the limitations of the two methods for preparing ethers. The Williamson synthesis uses an Sn2 reaction and requires that one of the two groups attached to oxygen be either secondary or (preferably) primary. The alkoxymercura-tion reaction requires that one of the two groups come from an alkene pis-cursor. Ethyl phenyl ether could be made by either method. 

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