Williamson’s synthesis of ethers

In addition to its uses in photography and medicine, iodine and its compounds have been much exploited in volumetric analysis (iodometry and iodimetry, p. 864). Organoiodine compounds have also played a notable part in the development of synthetic organic chemistry, being the first compounds used in A. W. von Hofmann s alkylation of amines (1850), A. W. Williamson s synthesis of ethers (1851), A. Wurtz s coupling reactions (1855) and V. Grignard s reagents (1900). 

Additional reactions which need to be highlighted are the reductive alkylation of alcohols and amines with aldehydes leading to the green synthesis of ethers and amines. These reactions are generally catalyzed by palladium [35]. This reaction can replace the classical Williamson s synthesis of ethers which requires an alcohol and an alkyl halide together with a base, and always results in the concomitant production of salt. The choice of Pd/C as catalyst is due to the low efficiency of this metal for the competitive carbonyl reduction. Analysis of the... 

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). 

Mixed ethers may be prepared by the interaction of an. alkyl halide and a sodium alkoxide (Williamson s synthesis), for example ... 

Many of the crown ether syntheses with which we are concerned in this book are one form or another of the Williamson ether synthesis. Although the simplest example of such a reaction would involve an co-haloethylene glycol oligomer which undergoes intramolecular cyclization, it is more common for two new bonds to be formed in crown syntheses. An early example of the formation of a crown by a double-Williamson can be found in Dale s synthesis of 18-crown-6. The rather obvious chemical steps are shown in Eq. (2.1). 

Write the names of reagents and equations for the preparation of the following ethers by Williamson s synthesis ... 

Williamson s S3mthesis.—This reaction is known as Williamson s synthesis because, in 1851, he showed, by it, the true constitution of ether, and made possible the explanation of its preparation from alcohol and sulphuric acid as given a little later on. The reaction is similar to the Wurtz reaction between sodium and an alkyl halide by which a hydrocarbon is formed. 

Treatment of a thiol with a base, such as NaH, gives the corresponding thioiate ion, RS , which undergoes reaction with a primary or secondary alkyl halide to give a sulfide. The reaction occurs by an Sn2 mechanism, analogous to the Williamson synthesis of ethers (Section 18.3). Thioiate anions are among the best nucleophiles known, and product yields are usually high in these S>j2 reactions. 

Williamson s synthesis A method for the preparation of mixed ethers by nucleophilic substitution. A haloalkane is refluxed with an alcoholic solution of sodium alkoxide (from sodium dissolved in alcohol) ... 

Williamson s synthesis 1. A method of preparing simple ethers by dehydration of alcohols with concentrated sulfuric acid. The reaction is carried out at 140 C under reflux with an excess of the alcohol 2ROH ROR + H2O The concentrated sulfuric acid both catalyzes the reaction and displaces the equilibrium to the right. Also the ether may be distilled off during the reaction (in which case it is called Wilkinson s continuous process). The product, ether, is termed simple , because the R groups are identical. There are two possible mechanisms for the process, depending on the nature of the alcohol. In the case of primary alcohols, there is a hydrogensulfate formed. For example, with ethanol ... 

The answer, Meyer thought, lies in the kinetic theory of heat and matter. This physical theory had been given explicit chemical meaning by Williamson s inference from studies of the synthesis of diethyl ether that atoms in chemical compounds must be continually changing places.56 Molecules are not empty boxes in translation or rotation but little Pandora-like boxes filled with active entities. The goal of chemistry must be the understanding of chemical phenomena using theories of motion, not just theories of species or types. 

Direct reduction of an aldehyde or ketone to the corresponding ether could potentially telescope two reactions, reduction and protection, into one step. S. Chandrasekhar of the Indian Institute of Chemical Technology, Hyderabad, reports (Tetrahedron Lett. 2004,45,5497) that in the present of polymethylhydrosiloxane (PMHS) and catalytic B(C6F,), TMS ethers of alcohols will convert aldehydes to the corresponding dialkyl ethers. The reaction works well for both saturated and benzylic alcohols. This may prove to be a useful alternative to Williamson synthesis for the preparation of complex ethers. 

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. 

This agrees with the constitution of ether as established by its synthesis from sodium ethylate and ethyl iodide, Williamson s s mthesis, or from ethyl iodide and silver oxide (p. 106). 

Metal alkoxides react with primary alkyl halides and tosylates by an S>j2 pathway to yield ethers, a process known as the Williamson ether synthesis. Discovered in 1850, the Williamson synthesis is still the best method for the preparation of ethers, both symmetrical and unsymmetrical. 

Williamson ether synthesis (Section 16.6) Method for the preparation of ethers involving an S 2 reaction between an alkoxide ion and a primary alkyl halide ... 

Two months later (June 1855) Wurtz announced the successful synthesis of five novel mixed or asymmetric hydrocarbons (ethyl-butyl, ethyl-amyl, butyl-amyl, butyl-caproyl, and methyl-caproyl), all produced by the reaction of iodides of the radicals with sodium metal— e.g., ethyl iodide and butyl iodide react with sodium to yield, inter alia, the new substance ethyl-butyl. This is precisely what Hofmann and Brodie had tried but failed to accomplish, pursuing Williamson s "mixed ether" strategy, in December 1850. It is a testament to Wurtz s experimental artistry that he succeeded. ... 

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. 

Ba(OH)2 is known to cattdyze several base-catalyzed organic reactions in the solid form, Of the reactions, aldol condensation is the most common. In recent years, several organic reactions besides aldol condensation have been found to be effectively catalyzed by Ba(OH)2. These reactions are the Claisen-Schmidt reaction, esterification of acid chlorides, Williamson s ether synthesis, benzil-benzilic acid rearrangement, the synthesis of A -pyrazolines by the reaction of a,/3-unsaturated ketone with PhNHNHz Wittig-Homer reaction, and Michael addition. For these reactions, the Ba(OH)2 catalyst prepared from Ba(0H)2-8H20 by cidcination at 473 K shows the highest activity. 

Firstly, we examined the esterification with metal acetate, benzyl bromide, and catalyst 9c, 15, or 16. The reaction proceeded in the presence of these catalysts, but not in the absence of them. Therefore, their catalytic activity is apparent. The rate constants remained in the same range for all runs. Moreover, the reaction was slow (k=10 — 10 s ) because of the low nucleophilicity of acetate ion. Since the substitution by acetate did not give much information on their catalytic activity, we chose the Williamson ether synthesis with phenol, benzyl bromide, metal hydroxide, and catalyst (see Equation 1), because phenolate has high nucleophilicity and hydrophobicity [24]. In fact, the difference of their catalytic activities clearly appeared in this case as shown in Table III. Catalysts made the reaction markedly faster than that without them. In carbon tetrachloride as a nonpolar solvent, the catalytic activity of 9c increased remarkably when larger ions were used and the maximum rate constant was recorded in the RbOH system. This behavior of 9c resembles that of calix[6]arene derivative 16 because both 9c and 16 have the same affinity for large ions. The other experiments were performed in... 

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

---