Ethers by the Williamson ether synthesis

Preparation of ethers by the Williamson ether synthesis is most successful with methyl and primary alkyl halides... 

PROBLEM 16.7 Only one combination of alkyl halide and alkoxide Is appropriate for the preparation of each of the following ethers by the Williamson ether synthesis. What is the correct combination in each case ... 

Show the combination of alcohol and haloalkane that can best be used to prepare each ether by the Williamson ether synthesis. 

The most generalJy useful method of preparing ethers is by the Williamson other synthesis, in which an alkoxidc ion reacts with a primary alkyl halide or tosylale in an Sfs[2 reaction. As we saw earlier in Section 17.2, the alkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, Nal l. 

The selection of reagents is governed by availability, cost, and, more importantly, the possible intrusion of side reactions. Thus in the above example, the action of the strongly basic ethoxide ion on t-butyl bromide would give rise to extensive alkene formation on the other hand little or no elimination would occur by the alternative reaction route. In general therefore, secondary or tertiary alkyl groups can only be incorporated into ethers by the Williamson synthesis by way of the corresponding alkoxide ions in reaction with a primary halide. 

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. 

Thioethers are easily synthesized by the Williamson ether synthesis, using a thiolate ion as the nucleophile. 

Perfluoroalloxy liquid crystals were prepared by the Williamson ether synthesis using perfluoro iodopropene. These materials can be mixed with nematic liquid crystal materials to provide liquid crystal compositions having low viscosity, low refractive index anisotropy, high dielectric anisotropy, and broad nematic phase ranges. 

CXE2C1, C1E3C1, and CXE4C1 were commercially supplied, while CxEsCx and CxEgCx were prepared by the Williamson ether synthesis. The infrared spectra of aqueous solutions of these compounds were measured for various concentrations at room temperature by using a horizontal ATR accessory with a ZnSe prism. Tibe lowest concentration studied was a mole fraction of approximately 0.005. The spectra were recorded on a JASCO FT/IR-7300 spectrometer. Each of the spectra was obtained by the coaddition of 200 scans at a resolution of 4... 

The alkyl allyl ethers used for the catalytic process were obtained from the corresponding sodium alkoxides and allylchloride by the Williamson ether synthesis. Hydrosilylation using triethoxysilane and Speier s catalyst turned out to be a straightforward reaction with yields of 65-85 %, depending on the allyl ethers applied. 

Sulfides, or thioethers, are sulfur analogues of ethers, and like ethers they can be either symmetrical (R2S) or unsymmetrical (RSR1, where R and R are different). Sulfides can be prepared from alkyl halides by a Williamson-type synthesis with sodium hydrogen sulfide, sodium thiolate or sodium sulfide from alkyl or aryl halides via the Grignard reagent (11) from alkenes by radical-catalysed addition of thiols or by reduction of sulfoxides (Scheme 9).2b... 

This ether is prepared by the Williamson ether synthesis from alcohols and phenols using a-bromomethylstyrene. It is cleaved by treating the ether in THF with f-BuLi at —78°C for 30 min (75-97% yield). The phenallyl ether can be cleaved in the presence of an allyl ether. Phenallyl amines and amides are cleaved similarly. Cleavage occurs by an addition of the alkyllithium to the olefin followed by elimination. 

Reactions.- Crown lactones are reduced to the corresponding crown ether on reaction with LiAlH at 0°C. The procedure may allow the synthesis of crown ethers which are inaccessible by the Williamson ether synthesis. The reduction of 2,6-pyrido-18-crown-6 N-oxide by (CH CHCHgCH BH appears to involve a single electron transfer as the rate-determining step, followed by transfer of a... 

PROBLEM 8.11 Write equations for the synthesis of the following ethers by the Williamson method ... 

Methylcellulose (MC) is produced, as in the case of CMC, by the Williamson synthesis, ie, by reaction of alkali cellulose with methyl chloride. World annual production is around 80,000 t/year (98). Other hydroxyalkyl derivatives or mixed ethers such as hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hy-droxybutylmethylcellulose, ethylmethylcellulose, and carboxymethylmethylcellu-lose have similar properties to MC. 

In Summary Ethers are prepared by the Williamson synthesis, an Sn2 reaction of an alkoxide with a haloaUcane. This reaction works best with primary halides or sulfonates that do not undergo ready elimination. Cychc ethers are formed by the intramolecular version of this method. The relative rates of ring closure in this case are highest for three- and five-membered rings. 

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