Preparation of ethers

Ethers can be prepared by using an alcohol or its conjugate base, an alkoxide ion. as the nucleophile. A general equation for the reaction with alkoxide ion is 

When an alkoxide ion is used as the nucleophile, the reaction is called a Williamson ether synthesis. Because the basicity of an alkoxide ion is comparable to that of hydroxide ion, much of the discussion about the use of hydroxide as a nucleophile also applies here. Thus, alkoxide ions react by the SN2 mechanism and are subject to the usual Sn2 limitations. They give good yields with primary alkyl halides and sulfonate esters but are usually not used with secondary and tertiary substrates because elimination reactions predominate. 

The alkoxide ion nucleophile is often prepared from the alcohol by reaction with sodium metal, as shown in the following equation for the formation of ethoxide ion from ethanol  

Because phenols are stronger acids than alcohols, nucleophilic phenoxide ions can be prepared by reacting the phenol with bases such as hydroxide ion or carbonate ion. 

Several examples of the Williamson ether synthesis are given in the following equations  

4-Methoxyphenyl ethers can be cleaved by mild oxidants (Entry 10, Table 7.8). Because many acid-labile linkers are also readily oxidized, care must be taken when applying this deprotection strategy. Benzyl ethers have been removed from Tentagel-or PEGA-bound carbohydrates by catalytic hydrogenation using palladium nanoparticles [112], 

Ethers are widely used in solid-phase synthesis, either as linkers for alcohols or as target compounds. Almost all reported solid-phase syntheses of ethers are O-alkyla-tions or O-arylations of alcohols, which differ only in the type of alkylating/arylating agent used and in the precise reaction conditions. This section covers mainly syntheses of acyclic ethers. Preparations of cyclic ethers are considered in Chapter 15. 

Diethyl ether is prepared industrially via the acid-catalyzed dehydration of ethanol. The mechanism of this process is believed to involve an Sivf2 process. 

A molecule of ethanol is protonated and then attacked by another molecule of ethanol in an S(sj2 process. As a final step, deprotonation generates the product. Notice that a proton is used 

This process has many limitations. For example, it only works well for primary alcohols (since it proceeds via an Sj,j2 pathway), and it produces symmetrical ethers. As a result, this process for preparing ethers is too limited to be of any practical value for organic synthesis. 

Ethers can be readily prepared via a two-step process called a Williamson ether synthesis. 

We learned both of these steps in the previous chapter. In the first step, the alcohol is deproton-ated to form an alkoxide ion. In the second step, the alkoxide ion functions as a nucleophile in an Sn2 reaction (Mechanism 14.1). 

Simple ethers can be prepared by acid-catalyzed intermolecular dehydration of alcohols. 

An ether can also be prepared by the nucleophilic substitution of an alkyl halide by an alkoxide. The reaction is an example of Sj 2 reaction. The reaction is called Williamson ether synthesis (Sample reaction 25-2). 

It is best to use primary alkyl halides in this type of reaction. Other halides most likely undergo elimination rather than substitution reaction. 

Ethers are cleaved when reacted with hydrogen halides to form alkyl halides and water. A sample reaction is shown  

Only symmetrical ethers can be obtained from these reactions proceeding in the presence of an acid catalyst. 

Because they are widely used as solvents, many simple dialkyl ethers are commercially available. Diethyl ether and dibutyl ether, for example, are prepared by acid-catalyzed condensation of the corresponding alcohols, as described earlier in Section 15.7. 

In general, this method is limited to the preparation of symmetrical ethers in which both alkyl groups are primary. Isopropyl alcohol, however, is readily available at low cost and gives high enough yields of diisopropyl ether to justify making (CH3)2CHOCH(CH3)2 by this method on an industrial scale. 

Acid-catalyzed addition of alcohols to alkenes is sometimes used. Indeed, before its use as a gasoline additive was curtailed, billions of pounds of r -butyl methyl ether (MTBE) were prepared by the reaction  

Small amounts of tert-h xiy methyl ether increase the octane rating of gasoline. Before environmental concerns placed limits on its use, the demand for MTBE exceeded the supply. 

In media such as water and alcohols, fluoride ion is strongly solvated by hydrogen bonding and is neither very basic nor very nucleophilic. On the other hand, the poorly solvated, or naked, flnoride ions that are present when potassium fluoride dissolves in benzene in the presence of a crown ether are better able to express their anionic reactivity. Thus, alkyl halides react with potassium fluoride in benzene containing 18-crown-6, thereby providing a method for the preparation of otherwise difficultly accessible aUcyl fluorides. 

No reaction is observed when the process is carried ont under comparable conditions bnt with the crown ether omitted. 

The reaction proceeds in the direction indicated because a C—F bond is much stronger than a C—Br bond. 

In general, this method is limited to the preparation of symmetrical ethers in which both alkyl groups are primary. 

The mechanism for the formation of diethyl ether from ethanol under conditions of acid catalysis was shown in Mechanism 15.1. 

The most important commercial ether is diethyl ether. It is prepared from ethanol and sulfuric acid. 

Note that ethanol can be dehydrated by sulfuric acid to give either ethylene (eq. 7.17) or diethyl ether (eq. 8.8). Of course, the reaction conditions are different in each case. These reactions provide a good example of how important it is to control reaction conditions and to specify them in equations. 

Although it can be adapted to other ethers, the alcohol-sulfuric acid method is most commonly used to make symmetric ethers from primary alcohols. 

PROBLEM 8.9 Write an equation for the synthesis of propyl ether from 1-propanol. 

The commercial production of f-butyl methyl ether has become important in recent years. In 2002, worldwide consumption of MTBE was about 7 billion gallons. With an octane value of 110, it is used as an octane number enhancer in unleaded gasolines. It is prepared by the acid-catalyzed addition of methanol to 2-methyl-propene. The reaction is related to the hydration of alkenes (Sec. 3.7.b). The only difference is that an alcohol, methanol, is used as the nucleophile instead of water. 

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The ethereal extracts are then united, dried with a suitable drying agent and filtered. The filtrate is then cautiously distilled, the ether being first distilled and finally the organic compound if volatile if the compound is solid, the crude residue is purified by recrystallisation. Very great care must be taken on all occasions when ether is distilled because of the risk of fire or of an explosion full experimental details for this operation are given, both on p. 8o (Preparation of Ether) and on p. 164 (Pre-... 

The preparation of ether is described here because this is chemically its logical position. It is advisable, however, for students to defer its preparation... 

Note that this is only a particular case of Williamson s general method for the preparation of ethers. 

The following procedures may be used for the preparation of ethereal solutions of diazomethane containing ethyl alcohol they differ slightly according to as to whether large or small quantities are required. The presence of alcohol is not harmful for many appUcatioiis of diazomethane. (It may be pointed out that ethereal diazomethane solution prepared from nitrosomethylurea is free from alcohol.)... 

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

Preparation of ethers by the Williamson ether synthesis is most successful with methyl and primary alkyl halides... 

Weak acid (Section 1 16) An acid that is weaker than 1130" Weak base (Section 1 16) A base that is weaker than HO Williamson ether synthesis (Section 16 6) Method for the preparation of ethers involving an Sfj2 reaction between an alkoxide ion and a primary alkyl halide... 

The modified Williamson synthesis with NaOH and chloroacetic acid or monochlorosodium acetate for the preparation of ether carboxylates is very old [3-8] and is suitable for batch production of different types of ethercarboxylates. 

Table 9. Preparation of ethers, esters and alcohols by non-Kolbe electrolysis of carboxylates 00... 

Diazomethane Follow essentially Aldrich Chemical Company s procedure for the Preparation of ethereal-alcoholic solution of diazomethane A 25-mL volume of ethanol is added to a solution of 5 g of potassium hydroxide in 8 mL of water in a 100-mL distillation flask fitted with a dropping funnel and a distillation condenser. The lower end of the condenser extends through and just below the neck of a 250-mL Erlenmeyer receiving flask, the latter being cooled in an ice-bath. The distillation flask containing the alkaline solution is heated in a water-bath to 65 °C and the contents of the flask are agitated with a magnetic stirrer. A solution of... 

The use of trichloroimidates for the preparation of ethers is an effective method for O-alkylation of alcohols [27]. This method has found widespread use in the protection of alcohols as benzyl ethers since the corresponding trichlorobenzylimi-date is inexpensive and commercially available. The mechanism involves activation of the imidate with a catalytic amount of a strong acid (typically TfOH) which leads to ionization of the electrophile and the formation of carbocation which is rapidly trapped by an alcohol. For the preparation of sec-sec ethers, this protocol has been limited to glycosidation reactions, due to the SN1 nature of the reaction which often leads to diastereomeric mixtures of products [26],... 

In carbohydrate chemistry, the preparation of ethers that are stable in the presence of acids, bases, and aqueous alkali is an important analytical and synthetic tool. The methods used for the etherification of hydroxyl groups51 generally employ reactions of unprotected sugars and glycosides with methyl, allyl, benzyl, triphenylmethyl, and alkylsilyl halides in the presence of a variety of aqueous and nonaqueous bases. 

Table 4.14. Preparation of ethers by intermolecular O-H insertion of electrophilic carbene complexes.

The method is suitable for the preparation of ethers having primary alkyl groups only. The alkyl group should be unhindered and the temperature be kept low. Otherwise the reaction favours the formation of alkene. The reaction follows S l pathway when the alcohol is secondary or tertiary about which you will learn in higher classes. However, the dehydration of secondary and tertiary alcohols to give corresponding ethers is unsuccessful as elimination competes over substitution and as a consequence, alkenes are easily formed. 

Preparation of ethers by acid dehydration of secondary or tertiaiy alcohols is not a suitable method. Give reason. 

Addition of alcohols to alkenes acid catalysed. Preparation of ethers... 

Williamson ether synthesis preparation of ether The sodium or potassium alkoxides are strong bases and nucleophiles. Alkoxides (RO ) can react with primary alkyl halides to produce symmetrical or unsymmetrical ethers. This is known as Williamson ether synthesis. The reaction is limited to primary alkyl halides. Higher alkyl halides tend to react via elimination. For example, sodium ethoxide reacts with ethyl iodide to produce diethyl... 

Methyllithium in ethyl ether from Ventron Corporation was used. Directions for the preparation of ethereal methyllithium from methyl bromide are also available [see G. Wittig and A. 

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