Williamson ether synthesis, sodium hydride

The most generally useful method of preparing ethers is by the Williamson ether synthesis, in which analkoxido ion reacts with a primary alkyl halide or tosylate in an S 2 reaction. As we saw earlier in Section 17.2, thealkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH. 

Alcohol 6 is prepared by a copper-catalyzed reaction of (R)-benzylglycidyl ether with vinylmagnesium bromide. The first step here is a Williamson ether synthesis. The free alcohol 6 reacts with sodium hydride to a sodium alkoxide, which is treated with the sodium salt of bromoacetic acid. The acid is also converted into the sodium salt to avoid the formation of an ester as side product. After the reaction carboxylic acid 20 is released in 93 % yield by acidification with aqueous 10 % HC1 solution. 

Ethers For the synthesis of ether, the Williamson ether synthesis is considered as the best method. It involves the SN2 reaction between a metal alkoxide and a primary alkyl halide or tosylate. The alkoxide needed for the reaction is obtained by treating an alcohol with a strong base like sodium hydride. An alternative procedure is to treat the alcohol directly with the alkyl halide in the presence of silver oxide, thus avoiding the need to prepare the alkoxide beforehand. 

In the first step sodium hydride was used as a base in THF to introduce a benzyl protective group to the sn-3 position of the glycerol moiety by a Williamson ether synthesis using benzyl bromide. The benzylated solketal adduct was not isolated but introduced to deprotection of the isopropylidene... 

Methyl ethers are usually prepared by some variant of the Williamson ether synthesis in which an alcohol reacts with either iodomethane, dimethyl sulfate, or methyl triflate (HAZARD) in the presence of a suitable base. A word of caution dimethyl sulfate and methyl triflate, tike all powerful alkylating agents, are potentially carcinogenic and therefore should only be handled in a well-ventilated fume hood. For the 0-methylation of phenols (pKa 10) a comparatively weak base such as potassium carbonate in conjunction with dimethyl sulfate is sufficient,193 whereas simple aliphatic alcohols require stronger bases such as sodium hydride [Scheme 4.111]22 or lithium hexamethyldisilazide [Scheme 4.112].203 The latter transformation is notable for the fact that 0-methyiation was accomplished without competing elimination. 

The alkoxide ion (RO ) for the Williamson ether synthesis is prepared by using sodium metal or sodium hydride (NaH) to remove a proton from an alcohol. 

Phenols can be converted to ethers through the Williamson synthesis (Section 11.1 IB). Because phenols are more acidic than alcohols, they can be converted to sodium phen-oxides through the use of sodium hydroxide (rather than sodium hydride or metallic sodium, the reagents used to convert alcohols to alkoxide ions). 

Sodium hydride Is a good base, and deprotonates the alcohol alkylation with Mel, via a nucleophilic substitution mechanism, gives the final ether product (Williamson ether synthesis). 

Abstract. Crown ethers derived from tartaric acid present a number of interesting features as receptor frameworks and offer a possibility of enhanced metal cation binding due to favorable electrostatic interactions. The synthesis of polycarboxylate crown ethers from tartaric acid is achieved by simple Williamson ether synthesis using thallous ethoxide or sodium hydride as base. Stability constants for the complexation of alkali metal and alkaline earth cations were determined by potentiometric titration. Complexation is dominated by electrostatic interactions but cooperative coordination of the cation by both the crown ether and a carboxylate group is essential to complex stability. Complexes are stable to pH 3 and the ligands can be used as simultaneous proton and metal ion buffers. The low extractibility of the complexes was applied in a membrane transport system which is a formal model of primary active transport. 

The central reaction is, of course, the Williamson ether synthesis. Early reports on the preparation of tartaric acid ethers [11], suggested that the base thallous ethoxide, (TlOEt), was essential to avoid epimerization of the chiral centers. The first syntheses thus utilized this base in dimethyformamide (DMF), and oligo-ethylenglycol diiodides for the preparation of di- and tetra-carboxylate crown ethers [4, 12]. More recently, we found that by strict control of stoichiometry, sodium hydride could be used successfully to displace tosylate without loss of chiral integrity [5]. Scheme 1 shows a recent synthesis of an 18-crown-6 hexaacid from three units of (H-)tartaric acid [13]. This route illustrates all the key features in the syntheses of polycarboxylate crown ethers. 

Most important for the laboratory synthesis of unsymmetric ethers is the Williamson synthesis, named after the British chemist who devised it. This method has two steps, both of which we have already discussed. In the first step, an alcohol is converted to its alkoxide by treatment with a reactive metal (sodium or potassium) or metal hydride (review eqs. 7.12 and 7.13). In the second step, an 5 2 displacement is carried out between the alkoxide and an alkyl halide (see Table 6.1, entry 2). The Williamson synthesis is summarized by the general equations... 

An alternative method for the preparation of an epoxide reacts a halohydrin (Chapter 10, Section 10.4.2) with a base such as sodium hydride. The resulting alkoxide undergoes an intramolecular Williamson ether synthesis. Draw the product expected when 2-bromo-l-hexanol reacts with NaH in THF. Based on the two carbons of the epoxide, is this transformation a net oxidation or a reduction ... 

Nevertheless, this procedure is significantly easier than the traditional Williamson ether synthesis which requires prior generation of the alkoxide salt, usually by reaction of the alcohol with a strong base such as sodium hydride, sodamide, or sodium metal. 

It is notable that tosylate 87, derived from isomeric epoxide 86, available in turn by epoxidation of 82 in diethyl ether rather than dichloromethane, is also disposed to undergo fragmentation to 72. Unfortunately, when 87 was subjected to sodium hydride, a Williamson ether synthesis (87 —> 88) became competitive -with the desired fragmentation. Sometimes the best laid plans are undercut by nature. Regardless, the Syntex-Zoecon synthesis remains one of the least obvious, yet creative and successful, routes to Cecropia Juvenile Hormone. 

The Williamson ether synthesis is the most widely used method to produce ethers. It occurs by an Sj 2 reaction in which a metal alkoxide displaces a halide ion from an alkyl halide. The aUcoxide ion is prepared by the reaction of an alcohol with a strong base such as sodium hydride. 

Protection of Alcohols. The inherent stability of the MPM ether, coupled with a large repertoire of methods for its removal under mild conditions that do not normally effect other functional groups, makes it a particularly effective derivative for the protection of alcohols. The most common method for its introduction is by the Williamson ether synthesis. A number of bases can be used to generate the alkoxide, but Sodium Hydride in DMF (eq 1) or THF (eq 2) is the most common. Other bases such as n-Butyllithium, Potassium Methylsulfinyl-methylide (dimsylpotassium) (eq 3), and Sodium Hydroxide under phase-transfer conditions are also used. From these results, it is clear that protection can be achieved without interference from Payne rearrangement, and considerable selectivity can be obtained. In the ribose case, selectivity is probably achieved because of the increased acidity of the 2 -hydroxy group. The additive Tetra-n-butylammonium Iodide is used for in situ preparation of the highly reactive p-methoxybenzyl iodide, thus improving the protection of very hindered alcohols. Selective monoprotection of diols is readily occasioned with 0-stannylene acetals. ... 

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