B. V. Tronov and L. V. Ladygina.

On the Preparation of Simple Ethers by the Interaction of Alcoholates with Haloid Hydrocarbons

The action of haloid hydrocarbons on potassium and sodium alcoholates was first applied to the preparation of simple ethers by Williamson¹) in 1851. This method proved especially convenient for the preparation of mixed ethers. Cahours²) used it for the synthesis of phenyl ethers. Lippmann³) applied it to the preparation of the first diphenyl ether.

Reboul⁴) studied this reaction in greater detail and elucidated the side process of formation, in it, of unsaturated hydrocarbons and alcohols when ethers with secondary and tertiary radicals are obtained. This second reaction, under certain conditions, proved to be predominant and even the only one.

More complete indications of the most advantageous conditions for attaining the best yields by this method were given by Lippert⁵), who prepared in this way a whole series of ethers. The direction of the reaction toward the formation of unsaturated hydrocarbons occurs as a consequence of the easy dissociation, with liberation of HBr, of secondary and tertiary haloid compounds at high temperature. The iodide derivatives dissociate especially readily.—And Lippert established that, in order to avoid this side reaction, secondary and tertiary radicals are better introduced in the form of alcoholates, and not of haloid derivatives. Of the haloid derivatives it is more advantageous to use bromides, which react sufficiently well and are less subject to dissociation than iodides. The temperature during the reaction in all cases must be as low as possible, never exceeding the boiling point of the haloid derivative. Under these conditions the reaction sometimes lasts many days, but the yields of ethers increase.

With a view to determining the strength of the bond of various hydrocarbon radicals with oxygen, we prepared a series of simple ethers, chiefly with the phenyl radical. Since the reaction between alcoholates and haloid compounds has hitherto been studied rather little, especially from the preparative side, and, in particular, in most works on this question even the yield of the ethers formed is not indicated, we consider it necessary to give the results of some syntheses carried out by us. In many cases, moreover, we used other starting materials, and two of the prepared ethers (phenyl-secondary-butyl and phenyl-hexyl) have not even been described in the literature at all.

In all we obtained 11 phenyl ethers with various fatty radicals and 2 with cyclic radicals (cyclohexyl and benzyl).

Owing to the very low activity of the halogen in the benzene ring, the starting substances in the preparation of phenyl ethers were always sodium or potassium phenolates and haloid derivatives of other radicals.

The phenolates were prepared in alcoholic solution. In most cases absolute ethyl alcohol was used for this purpose. Sodium was dissolved in it and phenol was added to the ethylate obtained. Or

¹) Al. Williamson, A. 77, 37, 1851; 81, 73, 1852.
²) A. Cahours, C. r. 32, 61; A. 78, 227, 1851.
³) E. Lippmann, C. r. 68, 1269, 1869; J. 1869, 438.
⁴) E. Reboul, C. r. 108, 39, 162, 1889.
⁵) W. Lippert, A. 276, 148–198, 1893.

the same alcohol was mixed with phenol, and sodium was dissolved already in the mixture. Potassium phenolates were prepared by adding phenol to a solution of KOH in ethyl alcohol. In the preparation of some ethers, absolute isopropyl alcohol was used as the solvent.

The halogenated hydrocarbon was poured into the alcoholic solution of the phenolate. The mixture was left for several days at ordinary temperature in a flask with a reflux condenser fitted with a calcium chloride tube. The course of the reaction during this time could be judged from the increase in the precipitate of sodium or potassium halide that appeared at the bottom of the flask. After a more or less prolonged standing in the cold, the flask was heated for several hours on a water bath, and then sometimes also on a salt bath.

To isolate the ether formed, the entire contents of the flask were poured into water, whereby the halide salt of the alkali metal dissolved. The whole was shaken in a separatory funnel with ordinary ether. The separated lower layer, containing an aqueous solution of the halide salt and alcohol, was removed. The upper ethereal layer was washed several times with alkali solution and distilled water to purify it from phenol and alcohol, and was dried over calcium chloride. After removal of the ethyl ether, the phenyl ether was isolated by fractional distillation.

This method was applied for the preparation of all the phenyl ethers obtained, with the slight modifications indicated in individual cases. Thus the following were prepared:

1) $C_6H_5 \cdot O \cdot CH_2 \cdot CH_2CH_3$

2) $C_6H_5 \cdot O \cdot CH(CH_3)_2$

3) $C_6H_5 \cdot O \cdot CH_2 \cdot CH{=}CH_2$

4) $C_6H_5 \cdot O \cdot CH_2 \cdot CH_2 \cdot CH_2 \cdot CH_3$

5) $C_6H_5 \cdot O \cdot CH_2 \cdot CH(CH_3)_2$

6) $C_6H_5 \cdot O \cdot CH(CH_3) \cdot CH_2 \cdot CH_3$

7) $C_6H_5 \cdot O \cdot CH_2 \cdot CH_2 \cdot CH(CH_3)_2$

8) $C_6H_5 \cdot O \cdot CH_2 \cdot CH_2 \cdot CH_2 \cdot CH_2 \cdot CH_2 \cdot CH_3$

9)

$$ C_6H_5 \cdot O \cdot CH{-}CH_2{-}CH_2 $$

$$ \phantom{C_6H_5 \cdot O \cdot {}}\big| \qquad\qquad \big| $$

$$ \phantom{C_6H_5 \cdot O \cdot {}}CH_2{-}CH_2{-}CH_2 $$

10) $C_6H_5 \cdot O \cdot CH_2 \cdot C_6H_5$

11) $C_6H_5 \cdot O \cdot CH_2 \cdot O \cdot C_6H_5$

12) $C_6H_5 \cdot O \cdot CH_2 \cdot CH_2 \cdot O \cdot C_6H_5$

13) $C_6H_5 \cdot O \cdot CH_2 \cdot CH_2 \cdot CH_2 \cdot O \cdot C_6H_5$

Propyl phenyl ether, obtained by Cahours¹ from potassium phenolate and propyl iodide at 100–110°, was prepared by us by the action of propyl bromide and potassium phenolate. The reaction was carried out for 13 days in the cold and then with heating on a water bath for 9 hours. From 30 g of bromide and potassium phenolate, prepared from 13 g of caustic potash and 22 g of phenol in ethyl alcohol, there were formed 22 g of propyl phenyl ether with b.p. 190°. Yield 78% of theoretical. (Not reported in the literature.)

The preparation of isopropyl phenyl ether from isopropyl iodide and sodium phenolate was described in detail by Silva². He carried out the reaction in sealed long-necked flasks with heating to

110–120° or in a flask with a reflux condenser on a salt bath, but did not indicate the yield of ether.

We took the same starting materials. On reacting for 4 days in the cold and with 29-hour heating, first on a water bath and then on a salt bath, they gave a 50% yield of ether. We obtained 10 g of isopropyl phenyl ether with b.p. 176° from 25 g of isopropyl iodide, 3.5 g of sodium, and 14 g of phenol in alcoholic solution.

Allyl phenyl ether was first obtained by Henry¹) from sodium phenolate and allyl bromide, but under what conditions the reaction proceeded and with what yield is unknown. Perkin²) prepared it by heating allyl iodide with phenol and sodium ethylate on a water bath; and Claisen³)—from allyl bromide, potash, and phenol in acetone, but likewise without indication of the yield.

We prepared a mixture of 41 g of allyl bromide and sodium phenolate from 8 g of sodium and 33 g of phenol in ethyl alcohol. It stood for 11 days in the cold, during which an abundant precipitate of NaBr fell out, and the liquid acquired a dark color. After 8-hour heating on a water bath, the ether was isolated in the usual manner. On distilling off ordinary ether with a rise in temperature, the liquid in the flask turned dark violet. It was possible to distill off only 13 g of ether with b.p. 190–195°, i.e. 29% of the theoretical amount. Apparently, on heating, a rearrangement of allyl phenyl ether into ortho-allylphenol occurred, as studied in detail by Claisen⁴).

Butyl phenyl ether was prepared by Pinette⁵), by heating phenol with solid caustic potash and butyl iodide.

We prepared it in the usual way from 29 g of butyl bromide, 21 g of phenol, and 5 g of sodium in ethyl alcohol. The process went for a week in the cold and 22 hours with heating. Twenty-four grams of ether with b.p. 209–210° were isolated—78% of the theoretical.

Isobutyl phenyl ether was first obtained by Ramberger⁶) from isobutyl iodide and then by Riess⁷) from isobutyl bromide, phenol, and an alcoholic solution of caustic potash, but again it is unknown with what yield.

The reaction was carried out by us for 5 days in the cold and 39 hours with heating on a water bath and then on a salt bath. Under these conditions 23 g of bromide, 16 g of phenol, and 9 g of caustic potash in alcoholic solution gave 12.5 g of ether with b.p. 199–202°—50% of the theoretical yield.

There is no information in the literature on secondary butyl phenyl ether. This ether was obtained by us from secondary butyl bromide and sodium phenolate in absolute ethyl alcohol. We took 65 g of bromide not purified from alcohol, 11 g of sodium, and 55 g of phenol in 30 g of ethyl alcohol. The reaction proceeded at ordinary temperature for 11 days. By this time a large precipitate of NaBr had collected at the bottom of the flask. To isolate the ether, the entire contents of the flask were shaken with water in a separatory funnel. Two layers gradually separated. The lower, lighter-colored one was separated. After the usual washing and drying over CaCl₂, a fraction (8 g) boiling at 140–220° was isolated from it by distillation. From the upper layer an ether extraction was made,

¹) L. Henry, B. 5, 455, 1872.
²) Perkin, Soc. 69, 1225, 1896.
³) L. Claisen, A. 418, 70, 78; C. 1919, I, 1015.
⁴) L. Claisen, B. 45, 3157, 1912; A. 401, 21, 1913, 442, 210, 1925, 449, 81, 1926; B. 58, 275, 1925, 59, 2344, 1926.
⁵) I. Pinette, A. 243, 32, 36, 1886.
⁶) E. Ramberger, B. 19, 1820, 1866.
⁷) I. Riess, B. 3, 780, 1870.

also washed and dried. From it 5 g of liquid boiling between 150° and 220° was distilled off. Both fractions were mixed and, after standing over metallic sodium to remove impurities, upon distillation gave 5.37 g of pure sec-butyl phenyl ether, boiling at 191–196°. The completely pure ether boiled at 195–196° at 763 mm pressure. Determination of the specific gravity with a pycnometer gave the following results: \(d^{10}_{4}=0.9505,\ d^{15}_{4}=0.9456,\ d^{20}_{4}=0.9415\).

Isoamyl phenyl ether is described among the first phenyl ethers by Cahours¹. He synthesized it in sealed tubes from isoamyl iodide and potassium phenolate at 110–120°.

As starting materials we used isoamyl chloride and sodium phenolate. From 19 g of isoamyl chloride, 19 g of phenol, and 4 g of sodium in alcoholic solution, after standing in the cold for 3 days and heating for 37 hours on a water and salt bath, 14 g of isoamyl phenyl ether with b.p. 215–220° was formed—47% of the theoretical amount.

Hexyl phenyl ether was found by Braun² in a mixture with hexylene phenyl ether, which is obtained by the action of sodium on \(\mathrm{J(CH_2)_6\cdot O\cdot C_6H_5}\), along with the formation of a large quantity of dodecamethylene glycol diphenyl ether. Braun confined himself to determining the elemental composition of the mixture.

We carried out the synthesis of this ether from 35 g of hexyl bromide and sodium phenolate, obtained by dissolving 5 g of sodium in a mixture of 22 g of phenol and 50 g of absolute isopropyl alcohol. The process proceeded for 2 days at ordinary temperature and for 12 hours with heating on a water bath. From the cooled mixture, after shaking with water in a separatory funnel, the main mass of ether separated as the upper layer. For complete extraction an ether extract was made and, as always, washed and dried. After distilling off the simple ether, the liquid was left standing over metallic sodium. Its distillation gave 22.4 g of ether with a constant boiling point of 243–243.5° at 739 mm pressure and \(d^{10}_{4}=0.9271,\ d^{15}_{4}=0.9225,\ d^{20}_{4}=0.9189\). Yield 59%.

Regarding cyclohexyl phenyl ether, there is a statement in the literature that it was obtained by Eykman³ as a by-product in the action of HBr on crude cyclohexanol containing phenol. He isolated it from benzene in the form of crystals melting at 121°, insoluble in water and alkalis.

The melting point indicated, improbably high for this ether, leads one to doubt that the substance obtained by Eykman was cyclohexyl phenyl ether, since even diphenyl ether melts only at 26.9–27° and is often liquid at ordinary temperature. Evidently Eykman obtained an entirely different substance, which is quite possible when working with crude alcohol. There is a statement⁴ that N. I. Kursanov⁵ studied the isomerization of this ether, but we do not know in what way the ether was prepared.

We synthesized cyclohexyl phenyl ether by acting with cyclohexyl bromide on sodium phenolate in a solution of absolute isopropyl alcohol. 19 g of sodium were dissolved in 150 g

isopropyl alcohol while heating on a water bath, and 90 g of phenol was added. After cooling, 140 g of bromoform was poured in. The mixture was left at ordinary temperature for 6 days, during which an abundant precipitate of NaBr accumulated at the bottom of the flask. After 8 hours of heating, the ether was extracted from the mixture and purified as the preceding one. Fractional distillation was carried out over calcium oxide, in order to bind any traces of HBr that might be present, which at high temperature can cause rearrangement into p-cyclohexylphenol¹). 5.29 g of ether were distilled off, boiling at 252–257°. The entirely pure ether boiled at 252–254° at 744 mm pressure. Determination of the specific gravity with a pycnometer gave the following values: \(d^{10}_{4} = 0.9882\), \(d^{15}_{4} = 0.9830\), \(d^{20}_{4} = 0.9795\).

The preparation of benzyl phenyl ether was carried out by us analogously to the method described by Lauth and Grimaux²), from benzyl chloride and potassium phenolate in alcoholic solution.

A mixture of 27 g of benzyl chloride, 23 g of phenol, and 12 g of caustic potash was heated on a water bath for 7 hours. Then the alcohol was distilled off, and the ether was washed with warm alkali solution and water. On cooling it solidified. Since its isolation by distillation is accompanied by losses, it was obtained in pure form by recrystallization from alcohol. M.p. 39°, yield 18 g, 45% of theory.

Methylene diphenyl ether was prepared by Henry³) from methylene bromide and by Arnhold⁴) from methylene chloride and potassium phenolate, but their quantitative results are unknown.

We left to react for 5 months at ordinary temperature an alcoholic solution of 30 g of methylene chloride, 33 g of phenol, and 8 g of sodium in a flask closed with a stopper fitted with a calcium chloride tube. Finally, the mixture was heated for 10 hours. 6 g of ether were obtained, boiling at 290–294°.

Ethylene diphenyl ether. Lippmann⁵) obtained it by the action of potassium phenolate on ethylene bromide while heating on a water bath.

By this same method we obtained 18 g of ether with m.p. 98° after 10 hours’ heating of a mixture of 35 g of ethylene bromide, 35 g of phenol, and 21 g of caustic potash in ethyl alcohol. Yield 45%.

Trimethylene diphenyl ether was prepared by us analogously to the preceding. Lohman⁶) and Solonina⁷), who obtained it from sodium phenolate and trimethylene bromide, and Henry⁸), who used trimethylene chloride, do not indicate the yield.

We obtained 20 g of ether from 28 g of trimethylene bromide, 23 g of phenol, and 5.5 g of sodium in ethyl alcohol. M.p. of the ether 61°. Yield 55%.

¹) Ibid.

²) Lauth, Grimaux, A. 143, 81, 1867.

³) L. Henry A. ch [5], 30, 269, 1883.

⁴) M. Arnhold, A 240, 197, 201, 1887.

⁵) E. Lippmann, C. r. 68, 1269, 1869; J. 1869, 438.

⁶) Lohman, B. 24, 2632, 1891.

⁷) V. Solonina, Zh. R. Kh. O. 30, 828.

⁸) L. Henry, Bl [3], 15, 1221.

1. A. Cahours, C. r. 32, 61. 1851. ↩↩

2. J. v. Braun, Müller, B. 39, 4113, 1906; 42, 4542, 1909. ↩↩

3. J. T. Eykman, C. 1909, II, 2146. ↩

4. P. P. Shorygin, “Advances in Organic Chemistry,” p. 214, 1928. ↩

5. N. I. Kursanov, “Investigations in the Field of Cyclic Compounds,” Moscow, 1915. ↩