Williamson synthesis aryl ethers

Methyl chloride can be converted iato methyl iodide or bromide by refluxing ia acetone solution ia the presence of sodium iodide or bromide. The reactivity of methyl chloride and other aUphatic chlorides ia substitution reactions can often be iacteased by usiag a small amount of sodium or potassium iodide as ia the formation of methyl aryl ethers. Methyl chloride and potassium phthalimide do not readily react to give /V-methy1phtha1imide unless potassium iodide is added. The reaction to form methylceUulose and the Williamson synthesis to give methyl ethers are cataly2ed by small quantities of sodium or potassium iodide. 

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. 

Selected examples of the catalysed Williamson synthesis of aryl ethers... 

Williamson synthesis of an aryl alkyl ether requires the Ar to be part of the nucleophile ArO and not the halide, since ArX does not readily undergo 5 2 displacements. Note that since ArOH is much more acidic than ROH, it is converted to ArO" by OH instead of by Na as required for ROH. 

The so-called Williamson synthesis of ethers is by far the most important ether synthesis because of its versatility it can be used to make unsymmetrical ethers as well as symmetrical ethers, and aryl alkyl ethers as well as dialkyl ethers. These reactions involve the nucleophilic substitution of alkoxide ion or phenoxide ion for halide (equation 70).26°... 

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 following methods are generally used for the laboratory preparation of ethers. (The Williamson synthesis is used for the preparation of aryl alkyl ethers industrially, as well.)... 

The most common preparative method to prepare the aryl allyl ether is the Williamson s ether synthesis [la,b]. Typically, aryl allyl ethers can be obtained from phenol derivatives and allylic halide under basic conditions (KjCOj) in refluxing acetone. This method is convenient for the preparation of simple allyl aryl ethers. However, some side reactions such as a competitive C-allylation (Sn2 type reaction) often accompany the formation of undesired byproducts. Mitsunobu reaction of phenol derivatives with allylic alcohols instead of allylic halides can be used under mild conditions [13]. In particular, when the allyl halide is unstable, this procedure is effective instead of the Williamson s ether synthesis. This method is also useful for the preparation of chiral allyl aryl ether from chiral allylic alcohol with inversion at the chiral center. Palladium catalyzed O-allylation of phenols is also applicable, but sometimes a lack of site-selectivity with unsymmetrical allylic carbonate [14] may be a problematic issue. 

The compounds whose preparations are described in Experiments [Ilk], [22B], [22C], and [22D] are alkyl aryl ethers. The general method of preparation is the Williamson synthesis, an Sn2 reaction spedficaUy between a phe-noxide ion (ArO ) nucleophile and an aUcyl halide. This reaction is often used for the synthesis of symmetrical and unsymmetrical ethers where at least one of the ether carbon atoms is primary or methyl, and thus amenable to an Sn2 reaction. Elimination (E2) is generally observed if secondary or tertiary halides are used, since phenoxide ions are also bases. 

Alkyl-aiyl ethers can be prepared from a phenoxide salt and an alkyl halide (the Williamson synthesis, Section 11.4A). They cannot be prepared from an aryl halide and alkoxide salt, however, because aryl halides are unreactive under the conditions of Williamson synthesis they do not undergo nucleophilic displacement by either an Sjjl or Sjj2 mechanism. 

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. 

Phenoxides can be used in a Williamson ether synthesis by reaction with alkyl halides (Sjj2 process) to create aUg l-aryl ethers. 

One of the most popular approaches to the laboratory scale synthesis of ethers is the addition of alkoxides and phenoxides to a suitable substrate such as an alkyl bromide. This reaction is known as the Williamson ether synthesis. For primary substrates, this approach tended to work quite well, and a host of ethers have been prepared using this method. The chemistry is less straightforward when secondary or tertiary alkyl halides were used due to competing elimination processes. As a representative example, the successful synthesis of an alkyl aryl ether is shown in Example 2.2 [14]. The reaction was carried out in acetone using allyl bromide and a functionalized phenol as the substrates and potassium carbonate as the base. While many bases have been used in Williamson ether syntheses, a mild base was critical for this work since it was needed to deprotonate the phenol without deprotonating the alkyne. This was critical for the success of the chemistry as the alkyne was needed for later steps in the reaction. In related work, potassium carbonate promoted the synthesis of photo-activatable fluorescein derivatives through a Williamson ether synthesis (Scheme 2.11) [15]. It also promoted the synthesis of a morphine precursor as well (Example 2.3) [16]. 

Formation of a symmetrical sulphide (a) (e.g. dipropyl sulphide, Expt 5.204), is conveniently effected by boiling an alkyl halide (the source of carbocations) with sodium sulphide in ethanolic solution. Mixed sulphides (b) are prepared by alkylation of a thiolate salt (a mercaptide) with an alkyl halide (cf. Williamson s ether synthesis, Section 5.6.2, p. 583). In the case of an alkyl aryl sulphide (R-S Ar) where the aromatic ring contains activating nitro groups (see Section 6.5.3, p. 900), the aryl halide is used with the alkyl thiolate salt. The alternative alkylation of a substituted thiophenol is described in Section 8.3.4, p. 1160. The former procedure is illustrated by the preparation of isobutyl 2,4-dinitrophenyl sulphide (Expt 5.205) from l-chloro-2,4-dinitrobenzene and 2-methylpropane-1-thiol. 

Ethers are compounds that have two organic groups bonded to the same oxygen atom, ROR. The organic groups can be alkyl, vinylic, or aryl, and the oxygen atom can be in a ring or in an open chain. Ethers are prepared by either the Williamson ether synthesis, which involves Sf t2 reaction of an alkoxide ion with a primary alkyl halide, or the alkoxymercuration reaction, which involves Markovnikov addition of an alcohol to an alkene. 

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... 

Figure 7.10 The first concave 1,10-phenanthrolines with aryl bridgeheads were synthesized from a tetraphenollc precursor applying a quadruple Williamson ether synthesis (X = polymethylene or polyethylene glycol). The alternative product, a bis-metacyclophane (sometimes called earmuff, shown on the right), was not formed. The bimacrocyclic structure of the concave 1,10-phenanthroline was confirmed by X-ray analyses ...

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