Williamson synthesis, phenols

Higher alkyl ethers are prepared by treating the sodium derivative of the phaiol (made by adding the phenol to a solution of sodium ethoxide in ethyl alcohol) with the alkyl iodide or bromide (Williamson synthesis), for example ... 

For the classical Williamson synthesis an alcohol is initially reacted with sodium or potassium to give an alkoxide, e.g. 1. Alternatively an alkali hydroxide or amide may be used to deprotonate the alcohol. Phenols are more acidic, and can be converted to phenoxides by treatment with an alkali hydroxide or with potassium carbonate in acetone. ... 

WILLIAMSON SYNTHESIS. An organic method for preparing ethers by the interaction of an alkylhalide with a sodium alcoholate (or phenolate). 

Answer Procedure XIH> which requires a diazonium salt and procedure VIl-I, which is the Williamson synthesis. Procedure VII-1 when applied to aromatic alkyl systems requires the sodium salt of a phenol and the appropriate alkyl halide. Since we are concerned with the synthesis of phenols in this chapter let us use procedure VII-I which requires the phenoxide salt A and n-butyl bromide. OCHjCHj... 

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.). 

Solution Treating a phenol with base in the presence of an alkyl halide is representative.of the Williamson synthesis. The reaction produces phenolic ethers by an S 2... 

This azo compound contains a phenolic hydroxyl group and therefore it may undergo a Williamson synthesis. Ethyl sulfate is an alkylating reagent which reacts with the phenoxide ion to produce an ethyl ether. 

Even carbowax (a chemically and thermally stable poly(ethylene glycol), when adsorbed on an inorganic salt with no other solid support, may act as a very efficient gas-solid phase-transfer catalyst. This system has been employed, for example, in the Williamson synthesis of ethers and thioethers, starting from alkyl halides and phenols or thiols in the presence of potassium carbonate as a base Gas-solid PTC shows the advantage that pure products are obtained directly, due to the absence of aqueous and organic solvents. 

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). 

Alkyl-aryl ethers are often synthesized by carefully controlling solubility. Both the alkyl halide and phenol are dissolved in dichloromethane then the solution is mixed with an aqueous solution of sodium hydroxide. Phenol, a poor nucleophile, reacts with sodium hydroxide in the aqueous phase to form the phenoxide ion, a good nucleophile. Alkyl-aryl ethers can be synthesized by treating the sodium salt of a phenol with an alkyl halide. The following example illustrates the Williamson synthesis of allyl-aryl ethers. The Bu N+Br is used to facilitate reaction between the polar phenoxide salt and the hydrophobic alkyl halide in the mixed solvent. 

Hydroaryloxylation of terminal alkenes RCH=CH2 with phenols ArOH can be catalysed by the pincer-iridium complex (133) at 150 °C to afford the corresponding Markovnikov ethers RCH(OAr)-CH3 as an attractive alternative to the Williamson synthesis. The reaction is believed to proceed via alkene insertion into an iridium-alkoxide bond, followed by the rate-determining C-H reductive elimination. ... 

Inspection of the structures of both the starting material and the product reveals three structural modifications (1) An amino group is introduced into the benzene core, suggesting a nitration-reduction sequence (Section 16-5) that relies on the ortho-directing effect of the hydroxy substituent (2) the phenol function is etherified, best done by Williamson synthesis (Section 22-5) (3) the carboxy function is esterified with the appropriate amino alcohol (Section 20-2). What is the best sequence in which to execute these manipulations To answer this question, consider the possible interference of the various functions with the suggested reaction steps. 

Anisole.—The prepaiation of anisole fiom phenol is analogous to Williamson s synthesis of the ethers (see p. 236), luit the etheis of phenol cannot be obtained by the action of tire alcohol on the phenol in presence of sulphuric acid. This reaction c.an, howet er, be effected In the case of the naphthdls (see p 316). 

Unlike the acid-catalyzed ether cleavage reaction discussed in the previous section, which is general to all ethers, the Claisen rearrangement is specific to allyl aryl ethers, Ar—O—CH2CH = CH2. Treatment of a phenoxide ion with 3-bromopropene (allyl bromide) results in a Williamson ether synthesis and formation of an allyl aryl ether. Heating the allyl aryl ether to 200 to 250 °C then effects Claisen rearrangement, leading to an o-allylphenol. The net result is alkylation of the phenol in an ortho position. 

Alternatively, the Sn2 nucleophilic substitution reaction between alcohols (phenols) and organic halides under basic conditions is the classical Williamson ether synthesis. Recently, it was found that water-soluble calix[n]arenes (n = 4, 6, 8) containing trimethylammonium groups on the upper rim (e.g., calix[4]arene 5.2) were inverse phase-transfer catalysts for alkylation of alcohols and phenols with alkyl halides in aqueous NaOH solution to give the corresponding alkylated products in good-to-high yields.56... 

Hydroxyl Group. Reactions of the phenolic hydroxyl group include the formation of salts, esters, and ethers. The sodium salt of the hydroxyl group is alkylated readily by an alkyl halide (Williamson ether synthesis). Normally, only alkylation of the hydroxyl is observed. However, phenolate ions are ambident nucleophiles and under certain conditions, ring alkylation can also occur. Proper choice of reaction conditions can produce essentially exclusive substitution. Polar solvents favor formation of the ether nonpolar solvents favor ring substitution. 

Phenols do not undergo intermolecular dehydration. Although aryl halides cannot be used as substrates in typical Williamson syntheses, they do undergo a modified Williamson-type synthesis at higher temperature in the presence of Cu. 

Phenols attached to insoluble supports can be etherified either by treatment with alkyl halides and a base (Williamson ether synthesis) or by treatment with primary or secondary aliphatic alcohols, a phosphine, and an oxidant (typically DEAD Mitsu-nobu reaction). The second methodology is generally preferred, because more alcohols than alkyl halides are commercially available, and because Mitsunobu etherifications proceed quickly at room temperature with high chemoselectivity, as illustrated by Entry 3 in Table 7.11. Thus, neither amines nor C,H-acidic compounds are usually alkylated under Mitsunobu conditions as efficiently as phenols. The reaction proceeds smoothly with both electron-rich and electron-poor phenols. Both primary and secondary aliphatic alcohols can be used to O-alkylate phenols, but variable results have been reported with 2-(Boc-amino)ethanols [146,147]. 

The coordination of Cr(CO)3 does not activate aryl chloride sufficiently for Williamson diaryl ether formation to occur. Smooth formation of aryl ether 222 proceeds by reacting the easily prepared arene-Ru complex 220 of the highly functionalized aryl chloride with phenol 219. Decomplexation of 221 by irradiation gives 222, and the product is used for the synthesis of the BCF rings of ristocetin A [57],... 

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 would use the Williamson ether synthesis to prepare the following ethers. You may use any alcohols or phenols as your organic starting materials. 

Much of the chemistry of phenols is like that of aliphatic alcohols. For example, phenols can be acylated to give esters, and phenoxide ions can serve as nucleophiles in the Williamson ether synthesis (Section 14-5). Formation of phenoxide ions is particularly easy because phenols are more acidic than water aqueous sodium hydroxide deproto-nates phenols to give phenoxide ions. 

The anethole ring has two functional groups - an ether and a hydrocarbon side chain with a double bond. The ether is synthesized first - by a Williamson ether synthesis from phenol and CH3I. The hydrocarbon side chain results from a Friedel-Crafts acylation of the ether. Reduction of the ketone, bromination and dehydrohalogenation are used to introduce the double bond. 

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. 

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