The Williamson Ether Synthesis

The Williamson ether synthesis is the most widely used method to produce ethers. It occurs by an Sj 2 reaction in which a metal alkoxide displaces a halide ion from an alkyl halide. The aUcoxide ion is prepared by the reaction of an alcohol with a strong base such as sodium hydride. 

TABLE 18.1 Comparison of Boiling Points of Ethers and Hydrocarbons 

This acid-catalyzed method is limited to the production of symmetrical ethers from primary alcohols because secondary and tertiary alcohols dehydrate to yield alkenes (Section 17.7). Thus, the method is of little practical value in the laboratory. 

Problem 18.2 Why do you suppose only symmetrical ethers are prepared by the. sulfuric acid-catalyzed dehydration procedure What product(s) would you expect if ethanol and P 1-propanol were allowed to react together In what ratio would the products bo 

Metal alkoxides react with primary alkyl halides and tosylates by an 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. 

A long-standing method for the preparation of ethers is the Williamson ether synthesis. Nucleophilic substitution of an alkyl halide by an aUcoxide gives the carbon-oxygen bond of an e er  

The reaction is most successful with methyl and primary alkyl halides. 

Ethyl iodide Butyl ethyl ether (71%) Sodium iodide 

The reaction is named for Alexander Williamson, a British chemist who used it to prepare diethyl ether in 1850. 

Secondary and tertiary alkyl halides are not suitable, because they react with alkoxide bases by E2 elimination rather than by 8 2 substitution. Whether the alkoxide base is primary, secondary, or tertiary is much less important than the nature of the alkyl halide. Thus benzyl isopropyl ether is prepared in high yield from benzyl chloride, a primary chloride that is incapable of undergoing elimination, and sodium isopropoxide  

Preparation of ethers by the Williamson ether synthesis is most successful when the alkyl halide is one that is reactive toward Sn2 substitution. Methyl halides and primary alkyl halides are the best substrates. 

Write equations describing two different ways in which benzylj 

I ethyl ether could be prepared by a Williamson ether synthesis. 

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. 

The alkoxide is commonly made by adding Na, K, or NaH to the alcohol (Section 11-14). 

Propose a Williamson synthesis of 3-butoxy-l, l-dimethylcyclohexane from 3,3-dimethyl- yclohexanol and butanol. 

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. 

To convert two alcohols to an ether, convert the more hindered alcohol to its alkoxide. Convert the less hindered alcohol to its tosylate (or an alkyl halide). Make sure the tosylate (or halide) is a good Sn2 substrate. 

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Both reactants m the Williamson ether synthesis usually originate m alcohol pre cursors Sodium and potassium alkoxides are prepared by reaction of an alcohol with the appropriate metal and alkyl halides are most commonly made from alcohols by reaction with a hydrogen halide (Section 4 7) thionyl chloride (Section 4 13) or phosphorus tri bromide (Section 4 13) Alternatively alkyl p toluenesulfonates may be used m place of alkyl halides alkyl p toluenesulfonates are also prepared from alcohols as their imme diate precursors (Section 8 14)... 

The Williamson ether synthesis (Sec tion 16 6) An alkoxide ion displaces a halide or similar leaving group in an Sn2 reaction The alkyl halide cannot be one that is prone to elimination and so this reaction is limited to methyl and primary alkyl halides There is no limitation on the alkoxide ion that can be used... 

Base promoted cyclization of vicinal halohydrms (Section 16 10) This reaction is an intramolecu lar version of the Williamson ether synthesis The alcohol function of a vicinal halohydrin is con verted to its conjugate base which then displa ces halide from the adjacent carbon to give an epoxide... 

Outline the steps in the preparation of each of the constitutionally isomeric ethers of molec ular formula C4H10O starting with the appropriate alcohols Use the Williamson ether synthesis as your key reaction... 

Ethers are formed under conditions of the Williamson ether synthesis Methyl ethers of carbohydrates are efficiently prepared by alkylation with methyl iodide m the presence of silver oxide... 

Alkylation (Section 25 22) Alkyl halides react with carbohydrates to form ethers at the available hydroxyl groups An application of the Williamson ether synthesis to carbohydrates... 

The most versatile method of preparing ethers is the Williamson ether synthesis, particularly in the preparation of unsymmetrical alkyl ethers (12,13). The reaction of sodium alcoholates with halogen derivatives of hydrocarbons gives the ethers ... 

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). 

Reinhoudt, de Jong and Tomassen have explored the use of metallic fluorides as bases in the Williamson ether synthesis of crowns. They found that the efficacy order for the metal cations they examined was Cs" > Rb > > Na Li . This order was... 

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 ... 

A variant of the Williamson ether synthesis uses thallium alkoxides. The higher reactivity of these can be of advantage in the synthesis of ethers from diols, triols and hydroxy carboxylic acids, as well as from secondary and tertiary alcohols on the other hand however thallium compounds are highly toxic. 

The most generally useful method of preparing ethers is by the Williamson ether synthesis, in which analkoxido ion reacts with a primary alkyl halide or tosylate in an S 2 reaction. As we saw earlier in Section 17.2, thealkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH. 

This is not a new reaction. This is just an Sn2 reaction. We are simply using the alkoxide ion (ethoxide in this case) to function as the attacking nucleophile. But notice the net result of this reaction we have combined an alcohol and an alkyl halide to form an ether. This process has a special name. It is called the Williamson Ether Synthesis. This process relies on an Sn2 reaction as the main step, and therefore, we must be careful to obey the restrictions of Sn2 reactions. It is best to use a primary alkyl halide. Secondary alkyl halides cannot be used because elimination will predominate over substitution (as seen in Sections 10.9), and tertiary alkyl halides certainly cannot be used. 

In their efforts to construct stimuli-responsive, supramolecular amphiphiles, Frechet et al. [126-129] reported the synthesis of a novel series of AB and ABA block copolymers via the Williamson ether synthesis (e.g., 47, Fig. 21). Polyethylene glycols (PEGs) of different lengths were used as the linear hydrophilic B block while polyaryl ether dendrons of different sizes were used as the hydro-phobic A block. These copolymers were characterized by optical microscopy,... 

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

The ether linkage is a major structural motif found in a broad range of natural and unnatural structures. Due to the biomedical and industrial importance of these molecules, the efficient and selective construction of ether bonds has been a topic of long-standing interest. While numerous etherification processes have been developed ever since the discovery of the Williamson ether synthesis,1 an increasingly large number of examples have employed transition... 

The Williamson ether synthesis is a general method for producing both symmetric and asymmetric (R R ) ethers. This is an S,j2 process following the general procedure in Figure 3-30. The process involves the reaction of an alk-oxide ion with an alkyl halide. 

Alkyl ethers of ttigitoxigenin. The Williamson ether synthesis fails when applied to digitoxigenin (1). In fact, only three successful methods arc known for preparation of the 3 alkyl ethers. The 3-melhyl ether can he obtained in 66, yield... 

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