Symmetrical ethers

Formation of, -dinitrobenzoates. Aliphatic ethers are broken up by heating with ZnClg, and a 3,5--dinitrobenzoate of the residue can then be prepared. This is suitable only for symmetrical ethers. 

In general this method is limited to the preparation of symmetrical ethers m 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... 

Ethers are compounds of the general formula Ar—O—Ar, Ar—O—R, and R—O—where Ar is an aryl group and R is an alkyl group. If the two R or Ar groups are identical, the compound is a symmetrical ether. Examples of symmetrical ethers are (di)methyl ether, CH OCH, and (di)phenyl ether,... 

Simple ethers derive their name from the two groups attached to the oxygen followed by the word ether, eg, diethyl ether, CH3CH2OCH2CH3. Eor symmetrical ethers the "di" prefix is often omitted. If one group has no simple name, the compound may be named as an alkoxy derivative, eg, 2-ethoxyethanol, CH3CH2OCH2CH2OH. 

This reaction, which is named after W. Williamson, is the most important method for the synthesis of unsymmetrical ethers 3. For this purpose an alkoxide or phenoxide 1 is reacted with an alkyl halide 2 (with R = alkyl, allyl or benzyl). Symmetrical ethers can of course also be prepared by this route, but are accessible by other routes as well. 

Diethyl ether and other simple symmetrical ethers are prepared industrially by the sulfuric acid-catalyzed dehydration of alcohols. The reaction occurs by SN2 displacement of water from a protonated ethanol molecule by the oxygen atom of a second ethanol. Unfortunately, the method is limited to use with primary alcohols because secondary and tertiary alcohols dehydrate by an El mechanism to yield alkenes (Section 17.6). 

Problem 18.2 Why do you suppose only symmetrical ethers are prepared by the sulfuric add-catalyzed dehydration procedure What product(s) would you expect if ethanol and 1-propanol were allowed to react together In what ratio would the products be formed if the two alcohols were of equal reactivity ... 

This Is such a simple strategy that it is worth solving the problem of removing one carbonyl group. The best way turns out to be to reduce (10) all the way to the symmetrical ether (11) and then to add one carbonyl group after condensation to (12) has made the molecule sufficiently unsymmetrical. 

Ethers are unaffected by sodium and by acetyl (or benzoyl) chloride. Both the purely aliphatic ethers e.g., di-n-butyl ether (C4H, )30 and the mixed aliphatic - aromatic ethers (e.g., anisole C3HSOCH3) are encountered in Solubility Group V the purely aromatic ethers e.g., diphenyl ether (C,Hj)20 are generally insoluble in concentrated sulphuric acid and are found in Solubility Group VI. The purely aliphatic ethers are very inert and their final identification may, of necessity, depend upon their physical properties (b.p., density and/or refractive index). Ethers do, however, suffer fission when heated with excess of 67 per cent, hydriodic acid, but the reaction is generally only of value for the characterisation of symmetrical ethers (R = R ) ... 

However, pMBCl 42 has a thermal stability issue and is expensive (Aldrich price 25 g for 69.90 the largest bottle). On the other hand, pMBOH 43 is stable and economically viable (Aldrich price 500 g for 84.90 the largest bottle). It was found that mono-N-alkylation of 36 proceeded well by slow addition (over 3 h) of 43 to a solution of 36 in acetonitrile in the presence of a catalytic amount of acid (p-TsOH) at 70 °C, as shown in Scheme 1.16. Slow addition of alcohol 43 minimized the self-condensation of 43 to form symmetrical ether 44, which was an equally effective alkylating agent. The product 41 was then directly crystallized from the reaction mixture by addition of water and was isolated in 90% yield and in >99% purity. A toluene solution of 41 can be used for the next reaction without isolation but the yield and optical purity of the asymmetric addition product were more robust if isolated 41 was used. In general, the more complex the reaction, the purer the starting materials the better. 

The reduction of aldehydes with the combination Et3SiH/BF3 OEt2 gives both the alcohol and the symmetrical ether,70 as do the Et3SiH/TFA (and other acids) combinations.313 Addition of boron trifluoride etherate to a mixture of 1-octanal and triethylsilane leads to the formation of di-n-octyl ether in 66% yield and //-octyl alcohol in 34% yield (Eq. 155).74... 

Reductive Etherification. As indicated earlier, aldehydes as well as ketones often give very good yields of ethers when they are treated with Br0nsted acids or other electrophilic species in the presence of organosilicon hydrides (Eq. 172). In the absence of added alcohols, symmetrical ethers are obtained. 

They offer the advantage that reductions can be effected under conditions that permit the conversion of substrates that may be adversely sensitive to the presence of strong Brpnsted acids. For example, in the presence of a 10% excess of triethylsilane, addition of one-half equivalent of boron trifluoride etherate to octanal results, within one hour, in the formation of a 66% yield of dioctyl ether after a basic hydrolytic workup. Benzaldehyde provides a 75% yield of dibenzyl ether under the same reaction conditions. The remainder of the mass is found as the respective alcohol.70 Zinc chloride is also capable of catalyzing this reaction. With its use, simple alkyl aldehydes are converted into the symmetrical ethers in about 50% yields.330... 

The use of trimethylsilyl-based electrophilic catalysts with organosilicon hydrides also promotes the conversion of aldehydes into ethers and avoids the need to employ the potentially hazardous trityl perchlorate salt.314,334,338 One reagent pair that is particularly effective in the reductive conversion of aldehydes into symmetrical ethers is a catalytic amount of trimethylsilyl triflate combined with either trimethylsilane, triethylsilane, PMHS,334 or 1,1,3,3-tetramethyldisiloxane (TMDO, 64) as the reducing agent (Eq. 179).314 Either... 

Similar treatment of a trifluoroacetic acid solution of p-tolualdehyde with triethylsilane gives only a 20% yield of /7-xylene after 11 hours reaction time followed by basic workup. Use of 2.5 equivalents of dimethylphenylsilane enhances the yield to 52% after only 15 minutes. This reaction proceeds stepwise through the formation of a mixture of the trifluoroacetate and the symmetrical ether. These intermediates slowly form the desired /7-xylene product along with Friedel-Crafts side products under the reaction conditions (Eq. 192).73 Addition of co-solvents such as carbon tetrachloride or nitromethane helps reduce the amount of the Friedel-Crafts side products.73... 

In the preparation of iodides, but not bromides, PMHS may be substituted for the TMDO. Chlorides can be obtained if thionyl chloride and zinc iodide are added to suppress the formation of symmetrical ethers.314 An example of this type of reductive chlorination is shown by the TMDO-mediated conversion of p-tolualdehyde into p-methylbenzyl chloride (Eq. 201).313 To obtain chlorides from aldehydes having electron-withdrawing groups such as nitro or carbomethoxy, the initial reaction is first carried out at —70° and the mixture is then heated to reflux in order to reduce the formation of symmetrical ether by-products. Zinc chloride is substituted for zinc iodide for the synthesis of chlorides of substrates with electron-donating groups such as methoxy and hydroxy.314... 

Dibenzyl Ether [Brpnsted Acid Promoted Reduction of an Aldehyde to a Symmetrical Ether].311 To a stirred solution of benzaldehyde (5.4 g, 0.05 mol) and TFA (11.4 g, 0.1 mol) under argon was added dropwise, with cooling, Et3SiH (8.1 g, 0.07 mol) at a rate such that the temperature of the reaction mixture did not exceed 40°. The solution turned a crimson color that gradually disappeared. Analysis by GLC showed the complete absence of the aldehyde immediately after addition of all of the silane. The products were separated by vacuum distillation at 20 Torr, collecting the fractions up to 125°. Dibenzyl ether was obtained from the residue by freezing out 4 g (0.02 mol, 80%) mp 3-6° nD25 1.5608. 

Dicyclohexyl Ether [Brpnsted Acid Promoted Reduction of a Ketone to a Symmetrical Ether].313 Cyclohexanone (3.92 g, 40 mmol) and tri(n-butyl) silane (1.78 g, 20 mmol) were placed in a round-bottomed flask. TFA (75 mmol) was added slowly over a one-hour period to the reaction mixture, which was held at —35°. After complete addition, the reaction flask was placed in a freezer at —15° for 70 hours. Direct distillation gave dicyclohexyl ether 2.91 g (16 mmol, 80%) bp 119-121718 Torr. 

Di-w -pentyl Ether [TMSI-Catalyzed Reduction of an Aldehyde to a Symmetrical Ether].314 A mixture of sodium iodide (0.15 g, 1 mmol), 1-pentanal (1.06 mL, 10 mmol), and trimethylsilyl chloride (2.0 mL, 15.4 mmol) was stirred in MeCN (5.0 mL) at room temperature for 10 minutes, after which 1,1,3,3-tetramethyldisiloxane (TMDO, 1.79 mL, 10 mmol) was added. When the exothermic reaction had ended (30 minutes), a solution of 2.5 N HF in MeOH (30 mL) was added to the reaction mixture, which was then refluxed for 5 minutes. Work-up was carried out by diluting the solution with CH2CI2 (40 mL), washing with water (30 mL) and saturated aqueous NaHC03 solution (20 mL), drying, and evaporating the solvents. Crude di-n-pentyl ether was purified by distillation 0.65 g (84%) bp 185-1897760 Torr. 

Dibenzyl ether [Brpnsted acid promoted reduction of aldehyde to symmetrical ether], 122... 

Dicyclohexyl ether [Brpnsted acid promoted ketone reduction, symmetrical ether], 123 Diels-Alder cycloaddition-cycloreversion pathway, alkene to alkane reductions, trisubstituted alkenes, 39-40 3,5-Dimethyl-1 -cyclohexen-1 -yl... 

Saturated aliphatic 53C—O— 1150-1060 (vs) 1140-900 (s) Two peaks may be observed for branched chain, usually 1140-1110 cm-1. Usually 930-900 cm-1 may be absent for symmetric ethers... 

Symmetric ethers (R = R ) can be prepared by the acid-catalyzed dehydration of primary alcohols. However, this reaction competes with the acid-catalyzed dehydration of the alcohol to form an alkene. Lower temperatures favor ether formation over alkene formation. Secondary and tertiary alcohols favor alkene formation. The general reaction is shown in Figure 3-29. 

---