The Williamson Synthesis

This reaction is usually called the Williamson synthesis of ethers. In a modification of it, the alkyl halide may be replaced by a sulfonic ester or a dialkyl sulfate. 

Undoubtedly the transformation is a displacement reaction which normally proceeds by an Sn2 mechanism  

Thus the reaction of sodium eugenoxide with various alkyl iodides in dry alcohol solution was shown to be in accord with second-order kinetics.1 The reaction of sodium ethoxide with optically active 2-bromo or 2-chlorooctane proceeded with complete inversion,2 and etherification of ethanol containing O18 with diethyl sulfate and alkali indicated that the ethyl group came from the sulfuric ester and that the alkoxide fragment was derived from the alcohol.8 

Although the Williamson synthesis usually proceeds by Sn2, halides are known whose rate of etherification is independent of the concentration of alkoxide ion in a solution of the corresponding alcohol. Tri-phenylmethyl chloride and a-phenylethyl chloride are examples (p. 83). 

Again it is clear that if we are to apply the general principles of displacement reactions to making predictions about the Williamson synthesis (p. 85), we must know whether the reaction proceeds by S l, by Sn2, or by the simultaneous operation of both processes. 

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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. 

The conversion of chlorohydrins into epoxides by the action of base is an adaptation of the Williamson synthesis of ethers. In the presence of hydroxide ion, a small proportion of the alcohol exists as alkoxide, which displaces the chloride ion from the adjacent carbon atom to produce a cycHc ether (2). 

A useful variation of the Williamson synthesis involves silver oxide, Ag20, as a mild base rather than NaH. Under these conditions, the free alcohol reacts directly with alkyl halide, so there is no need to preform the metal alkoxide intermediate. Sugars react particularly well glucose, for example, reacts with excess iodomethane in the presence of Ag20 to generate a pentaether in 85% yield. 

Because the Williamson synthesis is an S 2 reaction, it is subject to all the usual constraints, as discussed in Section 11.2. Primary halides and tosylates work best because competitive E2 elimination can occur with more hindered substrates. Unsymmetrical ethers should therefore be synthesized by reaction between the more hindered alkoxide partner and less hindered halide partner rather than vice versa. For example, terf-butyl methyl ether, a substance used in the 1990s as an octane booster in gasoline, is best prepared by reaction of tert-butoxide ion. with iodomethane rather than by reaction of methoxide ion with 2-chloro-2-methylpropane. 

How would you prepare ethyl phenyl ether Use whichever method you think is more appropriate, the Williamson synthesis or the alkoxymercuration reaction. 

Strategy Draw the target ether, identify the two groups attached to oxygen, and recall the limitations of the two methods for preparing ethers. The Williamson synthesis uses an Sn2 reaction and requires that one of the two groups attached to oxygen be either... 

Rank the following halides in order of their reactivity in the Williamson synthesis (a) Bromoethane, 2-bromopropanc, bromobenzene 1 (b) Chloroethane, bromoethane, 1-iodopropene... 

Treatment of a thiol with a base, such as NaH, gives the corresponding thiolate 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 18.2). Thiolate anions are among... 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

In fact, the reaction of alkoxides with alkyl halides or alkyl sulfates is an important general method for the preparation of ethers, and is known as the Williamson synthesis. Complications can occur because the increase of nucleo-philicity associated with the conversion of an alcohol to an alkoxide ion always is accompanied by an even greater increase in eliminating power by the E2 mechanism. The reaction of an alkyl halide with alkoxide then may be one of elimination rather than substitution, depending on the temperature, the structure of the halide, and the alkoxide (Section 8-8). For example, if we wish to prepare isopropyl methyl ether, better yields would be obtained if we were to... 

This involves the direct nucleophilic displacement of halogen in an alkyl halide by an alkoxide ion (the Williamson synthesis) (Expt 5.72), and the method is particularly useful for the preparation of mixed ethers. For an unsymmetrical ether [e.g. t-butyl ethyl ether (7)], the disconnection approach suggests two feasible routes. 

The selection of reagents is governed by availability, cost, and, more importantly, the possible intrusion of side reactions. Thus in the above example, the action of the strongly basic ethoxide ion on t-butyl bromide would give rise to extensive alkene formation on the other hand little or no elimination would occur by the alternative reaction route. In general therefore, secondary or tertiary alkyl groups can only be incorporated into ethers by the Williamson synthesis by way of the corresponding alkoxide ions in reaction with a primary halide. 

Examples of the preparation of alkyl benzyl ethers by the Williamson synthesis are included in Section 5.6.2, p. 583. An example of an alkyl phenyl ether is provided by the synthesis of phenacetin (Expt 6.109) where p-aminophenol is first converted into its Af-acetyl derivative by reaction with slightly more than one equivalent of acetic anhydride. Treatment of the product with ethanolic sodium ethoxide solution followed by ethyl iodide then yields the ethyl ether of AT-acetyl-p-phenetidine (phenacetin). This compound is biologically active and has been widely employed for example as an antipyretic and analgesic however, owing to undesirable side reactions, its use is now restricted. 

Both reactions would be successful. This synthesis of ethers is called the Williamson synthesis (see Sec. 8.5). 

The Williamson synthesis, using a sodium phenoxide and allyl bromide in methanol solution, is more rapid than the procedure using acetone and potassium carbonate and gives good results.16-36 441 66 Aqueous acetone also has been used as the reaction medium with allyl bromide and sodium hydroxide this method likewise is rapid and sometimes leads to better yields than the procedure using potassium carbonate and acetone.34 Allylation of 2-hydroxy-l,4-naphthoquinone has been carried out by treating the silver salt, in benzene, with allyl bromide 84 some C-alkylation as well as O-alkylation was observed. 

The ether linkage ( C—0—C ) is normally prepared by one of the three following procedures. The Williamson synthesis is the most general method, while the diazomethane procedure and the epoxide formation procedure are useful for specific types of... 

Cleavage 1 would require the tertiary Br, A, while cleavage 2 would require the primary Br, D. Since the Williamson synthesis works best if the alkyl halide is primary rather than tertiary, cleavage 2 is the method of choice. 

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... 

A student wanted to use the Williamson ether synthesis to make (R)-2-ethoxybutane. He remembered that the Williamson synthesis involves an SN2 displacement, which takes place with inversion of configuration. He ordered a bottle of (S)-butan-2-ol for his chiral starting material. He also remembered that the SN2 goes best on primary halides and tosylates, so he made... 

We have already seen most of the common methods for synthesizing ethers. We review them at this time, looking more closely at the mechanisms to see which methods are most suitable for preparing various kinds of ethers. The Williamson ether synthesis (Section 11-14) is the most reliable and versatile ether synthesis. This method involves the Sn2 attack of an alkoxide ion on an unhindered primary alkyl halide or tosylate. Secondary alkyl halides and tosylates are occasionally used in the Williamson synthesis, but elimination competes, and the yields are often poor. 

Show how the following ethers might be synthesized using (1) alkoxymercuration-demercuration and (2) the Williamson synthesis. (When one of these methods cannot be used for the given ether, point out why it will not work.)... 

Strategy Use the Williamson synthesis when one of the ether components can be a primary or benzylic halide. Use alkoxymercuration when one or both components are branched. 

This reaction is similar to the Williamson synthesis of ethers (method 115). Otthofotmates in which the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and isoamyl have been prepared from chloroform. The yield of ethyl orthoformate is 45%. Mixed esters are obtained from a mixture of sodium alkoxides and chloroform. Benzotrichloride, C,HjCClj, is converted to methyl orthobenzoate in 86% yield by sodium methoxide in methanol, ... 

Chemical Properties.—Chemically the ethers are not very active nor do they lead to important derivatives. Chlorine forms substitution products in which, as in methyl ether, one to six hydrogens of the alkyl radicals are substituted. The halogen acids, especially hydriodic acid, form an alcohol by a reaction analogous to the reversion of the Williamson synthesis. 

These ethers are usually formed by the reaction of an alcoholate with an ester of a halogen acid, the reaction being analogous to the Williamson synthesis of ether. 

With the increasing availability of suitable monomers and the desire for polymers having improved heat resistance combined with higher levels of mechanical properties, displacement (or substitution ) reactions have become of increased interest for polycondensation. A suitable example with monofunctional reactants would be the Williamson synthesis of ethers... 

The Williamson synthesis, using a sodium phenoxide and allyl bromide in methanol solution, is more rapid than the procedure using acetone and potassium carbonate and gives good results. - Aqueous ace-... 

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.)... 

In the laboratory, the Williamson synthesis of ethers is important 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. 

In the Williamson synthesis an alkyl halide (or substituted alkyl halide) is allowed to react with a sodium alkoxide or a sodium phenoxide ... 

The Williamson synthesis involves nucleophilic substitution of alkoxide ion or phenoxide ion for halide ion it is strictly analogous to the preparation of alcohols by treatment of alkyl halides with aqueous hydroxide (Sec. 15.7). Aryl halides cannot in general be used, because of their low reactivity toward nucleophilic substitution. 

Problem 17.4 (a) On what basis could you have predicted that methyl sulfate would be a good methylating agent in reactions like those presented above (Hint What is the leaving group See Sec. 14.6.) fb) Can you suggest another class of compounds that might serve in place of alkyl halides in the Williamson synthesis ... 

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