Aryl alkyl ethers Williamson synthesis

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 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 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. 

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. 

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... 

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]. 

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