The formation of ethers from alcohols under acidic conditions

1 THE FORMATION OF ETHERS FROM ALCOHOLS UNDER ACIDIC CONDITIONS 

Diethyl ether (EtzO) can be prepared by heating ethanol with sulphuric acid at about 140 °C, and adding more alcohol as the ether distils out of the reaction medium. A similar continuous etherification process is used industrially. A more general procedure for the preparation of symmetrical ethers from primary alcohols (e.g. dibutyl ether, Expt 5.70) is to arrange for the water formed in the reaction to be removed azeotropically. 

Excessive heating of the reaction mixture must be avoided otherwise an alkene-forming elimination reaction is induced this is particularly the case with secondary and especially tertiary alcohols. 

Tetrahydropyranyl ethers are readily prepared from the alcohol and 2,3-tetrahyd ropy ran in the presence of acid, and the reaction is widely used as a method of protection of hydroxyl groups. Preparative procedures and the methods of deprotection are given in Section 5.4.6, p. 551). 

The synthesis of dichloromethyl methyl ether has been included because of its usefulness as a reagent for the preparation of aromatic aldehydes (Expt 6.115). It is readily obtained by the reaction of phosphorus pentachloride in admixture with phosphorus oxychloride with methyl formate (Expt 5.71). 

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The formation of ethers from alcohols under acidic conditions (Expts 5.70 and 5.71). 

Symmetrical aliphatic ethers (C -Ci,) are prepared by the removal of water from alcohols under acidic conditions. Thus, in the preparation of diisoamyl ether, the alcohol is heated with concentrated sulfuric acid or p-toluenesulfonyl chloride in a flask equipp>ed with a condenser and a water sep>arator. The top layer of alcohol and ether is returned to the reaction flask until water no longer separates. Any alcohol remaining in the ether is converted to the higher-boiling triisoamyl borate, and the ether is purified by fractional distillation. Several suitable water separators have been described. High reaction temperatures must be avoided to prevent the formation of unsaturated hydrocarbons (cf. method 19). 

When alcohols are added to the reaction mixture, unsymmetrical ether products may be obtained. Starting with a mixture of aldehydes can also give rise to the formation of unsymmetrical ethers. These ether products are formed under conditions different from those used in the formation of ethers directly from alcohols. Thus, it is postulated that the reaction sequence that leads from the carbonyl substrate to the ether involves the intermediate formation of hemiacetals, acetals, or their protonated forms and alkoxycarbenium ions, which are intercepted and reduced to the final ether products by the organosilicon hydrides present in the reaction mix. The probable mechanistic scheme that is followed when Brpnsted acids are present is outlined in Scheme 2.311-327 328... 

Under certain conditions, the trifluoroacetic acid catalyzed reduction of ketones can result in reductive esterification to form the trifluoroacetate of the alcohol. These reactions are usually accompanied by the formation of side products, which can include the alcohol, alkenes resulting from dehydration, ethers, and methylene compounds from over-reduction.68,70,207,208,313,386 These mixtures may be converted into alcohol products if hydrolysis is employed as part of the reaction workup. An example is the reduction of cyclohexanone to cyclohexanol in 74% yield when treated with a two-fold excess of both trifluoroacetic acid and triethylsilane for 24 hours at 55° and followed by hydrolytic workup (Eq. 205).203... 

Essentially the same route is followed for the synthesis of the triphenylethylene nitromifene (8-5). The sequence starts with Friedel-Crafts acylation of the alkylation product (8-1) from phenol and 1,2-dibromoethane with the acid chloride from anisic acid (8-2). The displacement of bromine in the product (8-3) with pyrrolidine leads to the formation of the basic ether and thus (8-4). Condensation of that product with benzylmagnesium bromide gives the tertiary alcohol (8-5). This product is then treated with a mixture of nitric and acetic acids. The dehydration products from the first step almost certainly consist of a mixture of the E and Z isomers for the same reasons advanced above. The olefin undergoes nitration under reaction conditions to lead to nitromifene (8-6) as a mixture of isomers [8] the separated compounds are reported to show surprisingly equivalent agonist/antagonist activities. 

Further Reduction to a Hydrocarbon. In the reduction of benzo-phenone with aluminum ethoxide the formation of 7% of diphenyl-methane was observed. When benzohydrol was treated with aluminum ethoxide under the same conditions, 28% reduction to diphenylmethane occurred.12 In these reactions acetic acid, rather than acetaldehyde,-was formed from the ethoxide. Aluminum isopropoxide does not give this type of undesirable reaction with this reagent, pure benzohydrol is easily obtained in 100% yield from benzophenone.6 37 However, one case of reduction of a ketone to the hydrocarbon has been observed with aluminum isopropoxide.17 When 9, 9-dimethylanthrone-10 (XU) was reduced in xylene solution, rather than in isopropyl alcohol, to avoid formation of the ether (see p. 190), the hydrocarbon XUII was formed in 65% yield. The reduction in either xylene or isopropyl alcohol was very slow, requiring two days for completion. 

The mechanism of the formation of the tetrahydropyranyl ether (see Figure 23.1) is an acid-catalyzed addition of the alcohol to the double bond of the dihydropyran and is quite similar to the acid-catalyzed hydration of an alkene described in Section 11.3. Dihydropyran is especially reactive toward such an addition because the oxygen helps stabilize the carbocation that is initially produced in the reaction. The tetrahydropyranyl ether is inert toward bases and nucleophiles and serves to protect the alcohol from reagents with these properties. Although normal ethers are difficult to cleave, a tetrahydropyranyl ether is actually an acetal, and as such, it is readily cleaved under acidic conditions. (The mechanism for this cleavage is the reverse of that for acetal formation, shown in Figure 18.5 on page 776.)... 

The trimethylsilyl group was the first to be developed and is widely used for the protection of serine and threonine (Table 6). Chlorotrimethylsilane, l,14 3,3,3-hexamethyldisilazane, and A(0-bis(trimethylsilyl)acetamide are commercially available reagents used for the conversion of alcohols into the corresponding trimethylsilyl derivatives.Furthermore, trimethylsilyl cyanide has been used to protect the side chains of serine, threonine, and ty-rosine.f This silyl protection allows the formation of A -carboxyanhydrides from H-Ser(TMS)-OH and H-Thr(TMS)-OH, and their application in peptide synthesis in the aqueous phase.f l The TMS group can be removed under various conditions, depending on the kind of functional group to which it is bound the TMS ethers are more stable than related amino or carboxy derivatives.These differences in stability allow the direct application of completely silylated hydroxy amino acids in peptide synthesis.b ... 

The success of the method employing Li/MeNH2 again arises from the formation of the aldehyde in a protected form. In this case it is the amino alcohol salt (2 Scheme 2). As shown in Scheme 2, the reaction mixture is quenched with saturated aqueous ammonium chloride and may then be extracted with pentane, to yield an imine, or with ether and washed with acid to give the aldehyde. The imine is clearly not the protected form of the aldehyde, as it is reduced to the corresponding secondary amine under the conditions of the reaction. The reaction succeeds for aliphatic saturated acids, and also for one example... 

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