SYNTHESIS OF SOME ESTERS OF 4(5)-HYDROXYMETHYLIMIDAZOLE

L. P. KULEV and A. E. ONISHCHUK

At the basis of the numerous derivatives of imidazole, which have varied and broad application, lies imidazole itself, or glyoxaline,

\[ \mathrm{HC} \begin{matrix} & \mathrm{NH}-\mathrm{CH}\\ \diagup & \ \ \Vert\\ & \mathrm{N}-\mathrm{CH} \end{matrix} \]

The mechanism of the reaction for the formation of imidazole from glyoxal, formaldehyde, and ammonia was elucidated as early as 1882 by Lyubavin \([1,2,3]\), who deserves credit for developing a preparative method for obtaining this substance. However, in none of the later works by foreign authors devoted to these same questions is the name of the Russian scientist mentioned, although the considerations he expressed found reflection in their investigations.

One of the principal intermediate products in the synthesis of β-imidazolylethylamine, or histamine, is 4(5)-hydroxymethylimidazole:

\[ \mathrm{HC} \begin{matrix} & \mathrm{NH}-\mathrm{CH}\\ \diagup & \ \ \Vert\\ & \mathrm{N}-\mathrm{C}-\mathrm{CH_2OH} \end{matrix} \]

Very considerable attention has been devoted to developing methods for obtaining this substance, but only a few of them can have practical significance. The most interesting in this respect are methods for obtaining 4(5)-hydroxymethylimidazole based on the use of monosaccharides as starting materials. Thus, a number of investigators used fructose, oxidizing it with a copper-ammonia solution \([6,7,8,9,10]\). Dankova, Sidorova, and Preobrazhenskii \([4]\) replaced fructose with sorbose, obtained through the action of sorbose bacteria on sorbitol, which in turn is produced on an industrial scale by catalytic reduction of glucose. We \([5]\) proposed a method for obtaining 4(5)-hydroxymethylimidazole from invert sugar, which has significant advantages over other methods in terms of the availability of the starting material.

Imidazolylcarbinol is of interest not only because it is an important link in the synthesis of histamine. By using it, one can obtain certain new derivatives of glyoxaline, among which, one may suppose, there may prove to be representatives with properties no less interesting than those of β-imidazolylethylamine, which has found fairly broad application in medicine.

It seemed advisable to us to begin the investigation with esters of 4(5)-hydroxymethylimidazole, i.e., compounds of the type

\[ \mathrm{HC} \begin{matrix} & \mathrm{NH}-\mathrm{CH}\\ \diagup & \ \ \Vert\\ & \mathrm{N}-\mathrm{C}-\mathrm{CH_2}-\mathrm{O}-\mathrm{R} \end{matrix} \qquad \mathrm{HC} \begin{matrix} & \mathrm{NH}-\mathrm{CH}\\ \diagup & \ \ \Vert\\ & \mathrm{N}-\mathrm{C}-\mathrm{CH_2}-\mathrm{O}-\mathrm{CO}-\mathrm{R} \end{matrix} \]

about which there is almost no information in the literature.

The choice of a method for obtaining ethers is determined by certain specific features of 4(5)-hydroxymethylimidazole. Thus, the use of catalytic methods for dehydrating the alcohol with sulfuric acid or aluminum oxide is impossible because of the instability of the heterocycle at high temperature. It also does not seem possible to carry out the reaction between the alcoholate of hydroxymethylimidazole and an alkyl halide, since imidazolylcarbinol does not react with metallic sodium at ordinary temperature, while on heating to the melting point of the solid alcohol the reaction proceeds so violently that it is accompanied by complete decomposition of the organic substance.

Attempts to slow the reaction by cooling gave no positive results, just as did the use of solvents indifferent to sodium, since 4(5)-hydroxymethylimidazole itself dissolves only in water and alcohol. It proved much more convenient to conduct the synthesis in the reverse order, i.e., instead of alkyl halides to use the alcoholates of the corresponding alcohols, and to replace the alcoholate of 4(5)-hydroxymethylimidazole by 4(5)-chloromethylimidazole:

\[ \mathrm{ \begin{array}{c} \mathrm{HC}\!\!\diagup\!\mathrm{NH}-\mathrm{CH}\\[-2pt] \mathrm{\ \ \ \diagdown N}-\mathrm{C}-\mathrm{CH_2Cl} \end{array} +\mathrm{NaOR} \;\longrightarrow\; \begin{array}{c} \mathrm{HC}\!\!\diagup\!\mathrm{NH}-\mathrm{CH}\\[-2pt] \mathrm{\ \ \ \diagdown N}-\mathrm{C}-\mathrm{CH_2-O-R} \end{array} +\mathrm{NaCl} } \]

The starting substances are readily soluble in lower monohydric alcohols, and under these conditions the reaction is accompanied by a comparatively small evolution of heat.

Experimental Part

The alcoholates required for the synthesis of the ethers were obtained by dissolving metallic sodium in an excess of alcohol and were then used as solutions, without isolation in the free state. 4(5)-Chloromethylimidazole was obtained by Pyman’s method [11], by the action of phosphorus pentachloride on 4(5)-hydroxymethylimidazole, with certain modifications in the procedure proposed by the author. In particular, it proved possible to use, instead of the base 4(5)-hydroxymethylimidazole, its hydrochloride, i.e.,

\[ \mathrm{ HCl\cdot \begin{array}{c} \mathrm{NH}-\mathrm{CH}\\[-2pt] \mathrm{HC}\!\!\diagup\!\!\diagdown\\[-2pt] \mathrm{N}-\mathrm{C}-\mathrm{CH_2OH} \end{array} } \]

with which the reaction proceeds just as well, while the synthesis is simplified by one operation.

To obtain the ethers, an alcoholic solution of the alcoholate is added, with constant vigorous stirring, to an alcoholic solution of 4(5)-chloromethylimidazole hydrochloride. The former is taken in a considerable excess, usually in twice the amount calculated. After the solutions have been combined, the mixture is heated on a water bath at 40–50° for 30 minutes and left for several hours. The excess alcoholate is decomposed by adding dilute hydrochloric acid until the reaction to Congo red is weakly acidic. The precipitate of sodium chloride is filtered off, and picric acid is added to the filtrate. The separated picrate of the 4(5)-hydroxymethylimidazole ether is collected on a Büchner funnel and washed several times with water, alcohol, and ether. To isolate the free ethers, the picrates are decomposed with hydrochloric acid.

Methyl Ether of 4(5)-Hydroxymethylimidazole

The synthesis of the ether is carried out by the interaction of sodium methylate with 4(5)-chloromethylimidazole hydrochloride:

\[ \begin{aligned} &\mathrm{HCl}\cdot \begin{matrix} \mathrm{NH{-}CH}\\[-2pt] \mathrm{HC}\!\!\diagup \quad \|\\[-2pt] \mathrm{N{-}C{-}CH_2Cl} \end{matrix} + 2\mathrm{NaOCH_3} \;\longrightarrow\; \begin{matrix} \mathrm{NH{-}CH}\\[-2pt] \mathrm{HC}\!\!\diagup \quad \|\\[-2pt] \mathrm{N{-}C{-}CH_2{-}O{-}CH_3} \end{matrix} + 2\mathrm{NaCl} + \mathrm{CH_3OH}. \end{aligned} \]

Since the starting substances are very sensitive to water, the reaction is carried out under conditions excluding access of moisture from the air. Before the experiment, 4(5)-chloromethylimidazole is dried in a vacuum desiccator for several days, and the methyl alcohol is carefully made absolute. The sodium methylate required for the reaction is obtained by dissolving 1 g of metallic sodium in 20 ml of methanol in a flask equipped with a reflux condenser and a calcium chloride tube. To the cooled solution of alcoholate, with stirring, 2.1 g of 4(5)-chloromethylimidazole hydrochloride in 20 ml of anhydrous \(\mathrm{CH_3OH}\) are added dropwise. The ether-formation reaction, the external sign of which is the separation of a NaCl precipitate, proceeds almost instantaneously. The liquid is filtered, treated with dilute hydrochloric acid, filtered again, neutralized with a solution of caustic soda, and a solution of picric acid saturated at room temperature is added to it. The yellow flocculent precipitate is suction-filtered on a Büchner funnel and washed several times with water, alcohol, ether, or benzene. The picrate of the methyl ether of 4(5)-hydroxymethylimidazole, dried in a vacuum desiccator, is a yellow powder with m.p. 115–116°. It is sparingly soluble in cold water, somewhat better in hot water. It is insoluble in benzene, chloroform, and ether, but dissolves fairly well in 60% aqueous acetone. On adding an excess of water or acetone to such a solution, a yellow flocculent precipitate of the picrate is deposited.

Analysis of the picrate of the methyl ether of 4(5)-hydroxymethylimidazole by Liebig.

1. 0.1328 g of picrate give 0.1896 g \(\mathrm{CO_2}\) and 0.1962 g \(\mathrm{H_2O}\).
2. 0.1166 g „ „ „ 0.1664 „ „ 0.1612 „ „.

Found:

\[ \begin{aligned} \mathrm{C} &= 38.96 \text{ and } 38.71\%,\\ \mathrm{H} &= 4.03 \text{ and } 3.74\%. \end{aligned} \]

Calculated for \(\mathrm{C_{11}H_{11}O_8N_5}\)

\[ \begin{aligned} \mathrm{C} &= 38.71\%,\\ \mathrm{H} &= 3.25\%. \end{aligned} \]

Analysis of the picrate for nitrogen by Dumas.

1. 0.1266 g of picrate give 23.3 ml of nitrogen,
2. 0.1030 g „ „ 19.0 „ „.
   Pressure \(P = 754\) mm, temperature \(t^\circ = 25^\circ\mathrm{C}\).

Found nitrogen:

\[ \begin{aligned} \mathrm{N_1} &= 20.53,\\ \mathrm{N_2} &= 20.58. \end{aligned} \]

Calculated for \(\mathrm{C_{11}H_{11}O_8N_5}\)

\[ \mathrm{N} = 20.52\%. \]

To obtain the hydrochloride and the free methyl ether of 4(5)-oxymethylimidazole, 2 g of the picrate are added to a mixture consisting of 8 ml of water, 3 ml of concentrated hydrochloric acid, and 18 ml of benzene. The picric acid liberated in this process passes into the benzene layer, while the ether hydrochloride remains in the aqueous acid layer. The benzene solution is carefully separated by means of a separatory funnel; the residue is treated with fresh portions of benzene and, finally, with ether to remove traces of picric acid. The liquid is boiled with animal charcoal, filtered, and evaporated in a vacuum desiccator. The hydrochloride of the methyl ether of 4(5)-oxymethylimidazole is an oil which, on standing in a vacuum desiccator, solidifies to a glassy mass having no sharply defined melting point. It is readily soluble in water and alcohol and only with great difficulty in other organic solvents. It is very hygroscopic. To obtain the free base, the hydrochloride of the methyl ether of 4(5)-oxymethylimidazole is dissolved in water, the solution is neutralized with solid potassium bicarbonate, the liquid is evaporated in vacuo, and the residue is treated with absolute alcohol. After removal of the solvent, the free ether is obtained in the form of a thick oil, which slowly solidifies to a solid mass.

Both the free ether and its hydrochloride give a cherry-red coloration with diazotized sulfanilic acid, but somewhat less intense than that given by 4(5)-oxymethylimidazole.

Determination of the molecular weight of the free ether by the cryoscopic method gave the following results:
0.1126 g of substance lower the freezing point \(t^0\) of 10 g of water by \(0.19^\circ\).

Found:

\[ M = 111.4. \]

Calculated for \(C_5H_8ON_2\): \(M = 112.13\).

Ethyl ether of 4(5)-oxymethylimidazole

\[ \begin{array}{c} \mathrm{HC}\!\begin{matrix} & \mathrm{NH{-}CH}\\[-2pt] \diagup & \ \ \Vert\\[-2pt] \mathrm{N{-}C{-}CH_2{-}O{-}CH_2{-}CH_3} \end{matrix} \end{array} \]

To obtain this ether, 4.2 g of the hydrochloride of 4(5)-chloromethylimidazole were taken in 40 ml of absolute ethyl alcohol and sodium ethylate, prepared by dissolving 2.5 g of metallic sodium in 40 ml of \(C_2H_5OH\). Since a considerable amount of heat is liberated when the solutions are mixed, the flask is cooled, not allowing the temperature inside it to rise above \(40\text{–}45^\circ\). The further treatment of the reaction products is analogous to that which we used in obtaining the methyl ether of 4(5)-oxymethylimidazole. Isolation of the free ethyl ether of imidazolylcarbinol was carried out with the aid of picric and oxalic acids. The picrate is a yellow powder with \(t^0_{\mathrm{melt.}}\) 145°, poorly soluble in water and completely insoluble in ordinary organic solvents (with the exception of acetone).

Analysis of the picrate

a) For the carbon and hydrogen content by Liebig’s method.

1. 0.1198 g of substance give 0.1768 g of \(CO_2\) and 0.4196 g of \(H_2O\).

Found: \(C = 40.27\%\),

\[ H = 3.98\%. \]

1. 0.1236 g of substance gave 0.1830 g of CO₂ and 0.4584 g of H₂O.

Found: C = 40.40%,
   H = 4.15%.

Calculated for C₁₂H₁₃O₈N₅:
   C = 40.57%,
   H = 3.69%.

b) for nitrogen content by Dumas.

1. 0.1040 g of substance gave 21.1 ml of nitrogen.
      P = 755 mm, t° = 23°.

Found: N = 19.87%.

1. 0.1200 g of substance gave 21.1 ml of nitrogen.
      P = 757 mm, t° = 23°.

Found: N = 19.60%.

Calculated for C₁₂H₁₃O₈N₅: N = 19.71%.

The free ethyl ester of 4(5)-hydroxymethylimidazole is obtained as a thick, oily liquid of dark-brown color, which solidifies on standing in a vacuum desiccator over sulfuric acid to a glassy solid mass, readily triturated to a powder. The ester greedily absorbs moisture from the air and is very readily soluble in water and absolute alcohol. With strong mineral and organic acids it forms salts. Its hydrochloride is also obtained as a glassy mass, readily soluble in water and alcohol. With AuCl₃ and H₂PtCl₆ it gives yellow double salts that are sparingly soluble in water.

Analysis of these salts gave the following results.

1. 0.0964 g of substance gave 0.0406.

Found: Au = 42.12%.

Calculated for C₆H₁₀ON₂HAuCl₄: Au = 42.30%.

1. 0.1026 g of substance gave 0.0374 g Pt.

Found: Pt = 36.45%.

Calculated for C₆H₁₀ON₂·H₂PtCl₆: Pt = 36.68%.

The oxalate of the ethyl ester of 4(5)-hydroxymethylimidazole is obtained by adding a saturated aqueous solution of oxalic acid to an alcoholic solution of the free ester. The mixture is heated on a water bath and left for slow crystallization until the next day. The precipitate of the oxalate is filtered off and washed several times with small amounts of cold water. After recrystallization of the salt from hot water and subsequent cooling of the solution, a finely crystalline precipitate of the oxalate is obtained, which is then decomposed with baryta water. The free ester obtained from the oxalate is completely analogous to the ester isolated from the picrate.

Determination of the molecular weight by the cryoscopic method gives the following results: 0.1060 g of substance lowers the freezing point of 10 g of water by 0.16°.

Found: M = 123.

Calculated for C₆H₁₀ON₂: M = 126.1.

The ethyl ester of 4(5)-hydroxymethylimidazole, under the name 4(5)-ethoxymethylimidazole, was described by Pyman in 1911. However, the author’s data, ex-

raise doubts as to the authenticity of the product obtained by him. Pyman isolated a substance to which he assigns the formula

\[ \begin{array}{c} \mathrm{HC{-}NH}\\[-2mm] \| \ \ \ \ \diagdown\\[-1mm] \mathrm{C_2H_5{-}O{-}CH_2C{-}N} \ \diagup \ \mathrm{CH_3} \end{array} \]

after prolonged boiling of an alcoholic solution of 4(5)-chloromethylimidazole with potassium cyanide. The reaction under these conditions may proceed in many directions, and it is very unlikely that it proceeded chiefly toward the formation specifically of the ethyl ether of 4(5)-oxymethylimidazole. In our case, on the contrary, there can hardly be any doubt that the interaction between chloromethylimidazole and sodium alcoholate would be complicated by any side reactions and was not directed almost exclusively toward replacement of chlorine by an ethoxy group. In addition, the carefully performed analyses by us of the picrate and double salts of the imidazole derivative, the composition of which is very close to that theoretically calculated, confirm our considerations concerning the nature of the compound obtained. It should also be pointed out that, according to Pyman himself, the substance isolated by him was of no interest to him and was not subjected to further investigation.

Propyl ether of 4(5)-oxymethylimidazole

\[ \begin{array}{c} \mathrm{NHCH}\\[-2mm] \mathrm{HC}\diagup \ \ \|\\[-1mm] \ \ \mathrm{N{-}C{-}CH_2{-}O{-}CH_2{-}CH_2{-}CH_3} \end{array} \]

To remove water and other impurities, propyl alcohol is heated with calcium oxide; it is treated with metallic sodium and distilled with a dephlegmator. Upon repeated distillation it is possible to collect a fraction boiling exactly at \(97^\circ\), which corresponds to the boiling point of pure \(\mathrm{CH_3{-}CH_2{-}CH_2OH}\). The conditions for preparing the propyl alcoholate, carrying out the reaction between 4(5)-chloromethylimidazole hydrochloride, and isolating the picrate are the same as in the cases described above.

The picrate of the propyl ether of 4(5)-oxymethylimidazole is a yellow powder with melting point \(131\text{--}134^\circ\). It is insoluble in water, alcohol, ether, benzene, and chloroform, but dissolves fairly well in acetone.

Analysis of the picrate

a) for carbon and hydrogen by Liebig’s method.

1. \(0.1346\ \mathrm{g}\) of substance give \(0.2096\ \mathrm{g}\ \mathrm{CO_2}\) and \(0.4964\ \mathrm{g}\ \mathrm{H_2O}\).

Found: \( \mathrm{C} = 42.53\% \).

\[ \mathrm{H} = 4.13\%. \]

1. \(0.1168\ \mathrm{g}\) of substance give \(0.1816\ \mathrm{g}\ \mathrm{CO_2}\) and \(0.4374\ \mathrm{g}\ \mathrm{H_2O}\).

Found: \( \mathrm{C} = 42.43\% \).

\[ \mathrm{H} = 4.19\%. \]

Calculated for \(\mathrm{C_{13}H_{15}O_8N_5}\)

\[ \begin{aligned} \mathrm{C} &= 42.28\%,\\ \mathrm{H} &= 4.09\%. \end{aligned} \]

b) for nitrogen by Dumas.

1. 0.1132 g of substance gives 20.4 ml of nitrogen.

\[ P = 754 \text{ mm}, \quad t^\circ = 24. \]

Found: \(N = 19.26\%\).

1. 0.1214 g of substance gives 20.8 ml of nitrogen.

\[ P = 751 \text{ mm}, \quad t^\circ = 24^\circ. \]

Found: \(N = 19.12\%\).

Calculated for \(C_{13}H_{15}O_8N_5\): \(N = 18.97\%\).

The free propyl ester is obtained upon decomposition of the picrate with hydrochloric acid in the form of a dark-brown oil, which upon prolonged standing in a vacuum desiccator over sulfuric acid solidifies to a hard amorphous mass. Aqueous solutions of both the free ester and its hydrochloride are colored the characteristic cherry-red by the action of diazotized sulfanilic acid. In hydrochloric acid solution, chloroauric acid precipitates a yellowish-brown chloroaurate, which blackens on heating to \(300^\circ\).

Analysis of the chloroaurate of the propyl ester of 4(5)-hydroxymethylimidazole.

0.1010 g of substance gives 0.0408 g Au.

Found: \(Au = 41.21\%\).

Calculated for \(C_7H_{12}ON_2 \cdot HAuCl_4\)

\[ Au = 41.06\%. \]

Determination of the molecular weight of the ester by the cryoscopic method.
0.1272 g of substance lowers the freezing temperature of 10 g of water by \(0.165^\circ\).

Found: \(M = 143\).

Calculated for \(C_7H_{12}ON_2\): \(M = 140.182\).

Butyl ester of 4(5)-hydroxymethylimidazole

\[ \begin{array}{c} \mathrm{NH{-}CH} \\ \mathrm{HC}\!\begin{array}{c} / \\[-0.3em] \backslash \end{array}\!\begin{array}{c} \\[-1.0em] \\[-0.3em] \end{array} \begin{array}{c} \\[-1.0em] \mathrm{N{-}C{-}CH_2{-}O{-}CH_2{-}CH_2{-}CH_2{-}CH_3} \end{array} \end{array} \]

Primary butyl alcohol \(CH_3{-}CH_2.CH_2{-}CH_2OH\) with \(t^\circ_{\text{boil.}} 117^\circ\) was taken for the work. Its purification and all the remaining operations necessary for obtaining the corresponding ester are analogous to the preceding ones. From the reaction mixture the ester is isolated in the form of a picrate with an indistinctly expressed melting point \((137—142^\circ)\). It is very poorly soluble in cold water and somewhat better in hot water.

Analysis of the picrate

a) for carbon and hydrogen by Liebig.

1. 0.1404 g of substance gives 0.2254 g \(CO_2\) and 0.5810 g \(H_2O\).

Found: \(C = 43.81\%\).

\[ H = 4.63\%. \]

1. 0.1288 g of substance gives 0.2076 g \(CO_2\) and 0.5502 g \(H_2O\).

Found: \(C = 43.98\%\).

\[ H = 4.78\%. \]

Calculated for \(\mathrm{C}_{15}\mathrm{H}_{17}\mathrm{O}_{8}\mathrm{N}_{5}\): \(\mathrm{C} = 43.86\) and \(\mathrm{H} = 4.47\%\).

b) Nitrogen by Dumas.

1. \(0.1026\) g of substance gives \(16.8\) ml of nitrogen
   \[ P = 755\ \mathrm{mm}, \quad t^\circ = 23^\circ . \]
   Found: \(\mathrm{N} = 18.39\%\).

2. \(0.1196\) g of substance gives \(19.6\) ml of nitrogen
   \[ P = 755\ \mathrm{mm}, \quad t = 23^\circ . \]
   Found: \(\mathrm{N} = 18.41\%\).

Calculated for \(\mathrm{C}_{17}\mathrm{H}_{17}\mathrm{O}_{8}\mathrm{N}_{5}\): \(\mathrm{N} = 18.27\%\).

Determination of molecular weight

\(0.1236\) g of substance lowers the freezing point of \(10\) g of water by \(0.15^\circ\).

Found: \(\mathrm{M} = 153\).

Calculated for \(\mathrm{C}_{8}\mathrm{H}_{14}\mathrm{ON}_{2}\): \(\mathrm{M} = 154.208\).

The free butyl ether of 4(5)-hydroxymethylimidazole and its hydrochloride are dark-brown viscous liquids, which solidify with difficulty upon prolonged standing in a vacuum desiccator.

Isoamyl Ether of 4(5)-Hydroxymethylimidazole

\[ \begin{array}{c} \mathrm{HC}\!\left( \begin{array}{c} \mathrm{NH{-}CH}\\[-2mm] \parallel\\[-2mm] \mathrm{N{-}C} \end{array} \right)\!{-}\mathrm{CH}_{2}{-}\mathrm{O}{-}\mathrm{CH}_{2}{-}\mathrm{CH}_{2}{-}\mathrm{CH}(\mathrm{CH}_{3}){-}\mathrm{CH}_{3} \end{array} \]

As the starting material for obtaining this ether, crude isoamyl alcohol from fermentation was used. After treatment with dilute sulfuric acid and heating with slaked lime, it was subjected to fractional distillation with a high dephlegmator; as a result, a fraction with b.p. \(130^\circ\) was isolated, which corresponds to pure

\[ \mathrm{CH}_{3}{-}\mathrm{CH}(\mathrm{CH}_{3}){-}\mathrm{CH}_{2}{-}\mathrm{CH}_{2}\mathrm{OH}. \]

Because of the poor solubility of 4(5)-chloromethylimidazole in cold isoamyl alcohol, dissolution is carried out at \(65\text{--}70^\circ\). In all other respects the procedure is the same as in the preparation of the ethers described above.

Unlike the other ethers obtained by us, the isoamyl ether of 4(5)-hydroxymethylimidazole gives a picrate with a low melting point \((82\text{--}85^\circ)\) and with a content of water of crystallization in the ratio \(1:1\).

Analysis of the picrate

a) Determination of water of crystallization: \(1.3640\) g of picrate loses \(0.0580\) g of \(\mathrm{H}_{2}\mathrm{O}\) in a desiccator.

Found: \(\mathrm{H}_{2}\mathrm{O} = 4.25\%\).

Calculated for \(\mathrm{C}_{15}\mathrm{H}_{19}\mathrm{O}_{8}\mathrm{N}_{5}\cdot\mathrm{H}_{2}\mathrm{O}\): \(\mathrm{H}_{2}\mathrm{O} = 4.34\%\).

b) Carbon and hydrogen by Liebig.

1. \(0.1128\) g of substance gives \(0.1888\) g of \(\mathrm{CO}_{2}\) and \(0.5000\) g of \(\mathrm{H}_{2}\mathrm{O}\).

Found:
\[ \begin{aligned} \mathrm{C} &= 45.67\%,\\ \mathrm{H} &= 4.96\%. \end{aligned} \]

1. \(0.1388\) g of substance gives \(0.2330\) g of \(\mathrm{CO}_{2}\) and \(0.6314\) g of \(\mathrm{H}_{2}\mathrm{O}\).

Found:
\[ \begin{aligned} \mathrm{C} &= 45.81\%,\\ \mathrm{H} &= 5.09\%. \end{aligned} \]

Calculated for \(\mathrm{C}_{15}\mathrm{H}_{19}\mathrm{O}_{8}\mathrm{N}_{5}\):
\[ \begin{aligned} \mathrm{C} &= 45.34\%,\\ \mathrm{H} &= 4.82\%. \end{aligned} \]

c) Nitrogen by Dumas.

\(0.1298\) g of substance gives \(20.8\) ml \(\mathrm{N}_{2}\)
\[ P = 760\ \mathrm{mm}, \quad t^\circ = 23^\circ . \]

Found: \(\mathrm{N} = 18.12\%\).

Calculated for \(\mathrm{C}_{15}\mathrm{H}_{19}\mathrm{O}_{8}\mathrm{N}_{5}\): \(\mathrm{N} = 17.63\%\).

The free base of the isoamyl ester of 4(5)-hydroxymethylimidazole, obtained by decomposition of the picrate, has the form of a semi-liquid brown mass that solidifies on storage in a vacuum desiccator. It gives reactions characteristic of this group of compounds with paradiazobenzenesulfonic acid, silver nitrate, and cuprammonium solution.

Determination of the molecular weight of the free ester

0.1290 g of the substance lowers the freezing point of 10 g of water by 0.145°.
Found: \(M = 165\).
Calculated for \(C_9H_{16}ON_2\): \(M = 168.234\).

Acetic ester of 4(5)-hydroxymethylimidazole

\[ \begin{array}{c} \mathrm{HC}\!\begin{array}{c} \diagup \mathrm{NH}-\mathrm{CH}\\[-2pt] \diagdown \mathrm{N}-\mathrm{C}-\mathrm{CH_2}-\mathrm{O}-\mathrm{CO}-\mathrm{CH_3} \end{array} \end{array} \]

Attempts to obtain the ester by the action of glacial acetic acid and acetic anhydride were unsuccessful, since in the cold the reaction with these acetylating agents apparently does not proceed, while at elevated temperature complete destruction of the molecule of 4(5)-hydroxymethylimidazole occurs. The most convenient for this purpose is acetyl chloride, which has a low boiling point. When acetyl chloride is added to 4(5)-hydroxymethylimidazole hydrochloride, a reaction immediately begins, accompanied by the evolution of hydrogen chloride. On heating the mixture to the boiling point of acetyl chloride (56°), the reaction proceeds more vigorously and is completed after one and a half hours, the crystals of 4(5)-hydroxymethylimidazole hydrochloride dissolving completely. On cooling, the mixture separates into two layers. The lower layer, on standing, rapidly crystallizes into a solid mass, which is the hydrochloride of the acetic ester of 4(5)-hydroxymethylimidazole. After washing the product with benzene and chloroform, in which it is completely insoluble, it is dried in a vacuum desiccator over caustic sodium. The substance obtained has m.p. 143–144°, is very readily soluble in ether, benzene, chloroform, and acetone. It is not hygroscopic. The free ester is liberated from its hydrochloride by the action of a saturated aqueous soda solution. After evaporation of the liquid, extraction with anhydrous ether, and distillation of the solvent, a white fine-crystalline powder is obtained, m.p. 110–111°. The free ester dissolves in water, alcohol, ether, and acetone and gives a red coloration with diazotized sulfanilic acid.

Analysis of the hydrochloride of the acetic ester of 4(5)-hydroxymethylimidazole

a) For carbon and hydrogen by Liebig’s method.

1. 0.1262 g of the substance gives 0.1880 g \(CO_2\) and 0.5954 g \(H_2O\).
   Found:
   \[ \begin{aligned} C &= 40.65\%,\\ H &= 5.28\%. \end{aligned} \]

2. 0.1138 g of the substance gives 0.1698 g \(CO_2\) and 0.5450 g \(H_2O\).
   Found:
   \[ \begin{aligned} C &= 40.72\%,\\ H &= 5.36\%. \end{aligned} \]

Calculated for \(C_6H_9O_2N_2Cl\):
\[ \begin{aligned} C &= 40.80\%,\\ H &= 5.16\%. \end{aligned} \]

b) For nitrogen by Dumas’ method

1. 0.1094 g of the substance gives 15.8 ml \(N_2\)
   \[ P = 754\ \text{mm}, \quad t^\circ = 24^\circ. \]

Found: \(N = 16.12\%\).

1. \(0.1408\) g of substance gave \(20.2\) ml

\[ P = 754\ \text{mm}, \qquad t^\circ = 24^\circ . \]

Found: \(N = 16.01\%\).

Calculated for \(C_6H_9O_2N_2Cl\): \(N = 15.86\%\).

Thus, of the derivatives of 4(5)-hydroxymethylimidazole that we obtained, only the acetic ester is a well-crystallizing compound, whereas the simple ethers were isolated only in the form of thick syrups, which, on standing in a vacuum desiccator, slowly solidified to a brittle glassy mass.

Poor crystallizing ability is characteristic not only of the simple ethers studied by us. A large number of imidazole derivatives have been described in the literature which were also isolated as thick, oil-like liquids. These include, above all, alkyl derivatives of imidazole that contain no active groups in their composition, for example, \(-NH_2\), \(-OH\), \(-COOH\), etc. Even some of the simplest homologs of imidazole have not been obtained in the crystalline state, and the number of such substances increases considerably on passing to compounds of higher molecular weight. For a long time, for example, 4(5)-methyl- and 4,5-dimethylimidazoles were known as noncrystallizing compounds:

\[ \begin{array}{cc} \begin{array}{c} \mathrm{HC}\!\left<\begin{array}{c} \mathrm{NH{-}CH}\\[-2pt] \mathrm{N{-}C{-}CH_3} \end{array}\right. \end{array} & \begin{array}{c} \mathrm{HC}\!\left<\begin{array}{c} \mathrm{NH{-}C{-}CH_3}\\[-2pt] \mathrm{N{-}C{-}CH_3} \end{array}\right. \end{array} \end{array} \]

for which crystallization conditions were found many years after their discovery.

To this day, 4(5)-ethylimidazole has not been obtained in the crystalline state; isolated in the form of thick, syrupy liquids are:

4(5)-methyl-4(4)-propylimidazole

\[ \mathrm{HC}\!\left<\begin{array}{c} \mathrm{NH{-}C{-}CH_3}\\[-2pt] \mathrm{N{-}C{-}CH_2{-}CH_2{-}CH_3} \end{array}\right. \]

4(5)-methyl-5(4)-isopropylimidazole

\[ \mathrm{HC}\!\left<\begin{array}{c} \mathrm{NH{-}C{-}CH_3}\\[-2pt] \mathrm{N{-}C{-}CH{-}CH_3}\\[-2pt] \phantom{\mathrm{N{-}C{-}}}\vert\\[-2pt] \phantom{\mathrm{N{-}C{-}}}\mathrm{CH_3} \end{array}\right. \]

4(5)-methyl-5(4)-ethylimidazole

\[ \mathrm{HC}\!\left<\begin{array}{c} \mathrm{NH{-}C{-}CH_3}\\[-2pt] \mathrm{N{-}C{-}CH_2{-}CH_3} \end{array}\right. \]

and many other analogous compounds.

Replacement of alkyl groups by alkoxy groups apparently does not exert a substantial influence on the change in the physical properties of compounds with a glyoxaline ring and does not enhance their ability to crystallize. Therefore the simple ethers of 4(5)-hydroxymethylimidazole obtained by us are not exceptional in this respect.

For the characterization of noncrystallizing imidazole derivatives, use is usually made of their ability to form salts with mineral and organic-

...with acids, as well as sparingly soluble complex compounds with salts of heavy metals. The application of these methods to the simple ethers of 4(5)-hydroxymethylimidazole does not give positive results, since the hydrochlorides of these ethers also could not be obtained in the crystalline state, and the double salts with gold and platinum chlorides do not have a clearly expressed melting point, i.e., in turn, they cannot be compared with one another. More definite data are obtained with the picrates of the simple ethers of imidazolylcarbinol. Their melting points vary in the following order.

Table 1

Consequently, with increasing complexity of the hydrocarbon radical the melting point of the picrate rises on passing from the methyl ether to the isoamyl ether. An exception is the picrate of the isoamyl ether, whose melting point lies considerably lower than that of the simplest of the ethers obtained by us.

Conclusions

1. By the interaction of alcoholates of alcohols with 4(5)-chloromethylimidazole, the simple ethers of imidazolylcarbinol were obtained: methyl, ethyl, propyl, butyl, and isoamyl. The properties of the free ethers, their hydrochlorides, and picrates were studied.

2. The acetic ester of 4(5)-hydroxymethylimidazole was obtained. In contrast to the simple ethers, both the free acetic ester and its hydrochloride are readily crystallizing substances that are not hygroscopic.

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