CHEMISTRY

R. G. KOSTYANOVSKII

THE REACTION OF ETHYLENIMINE WITH FORMALDEHYDE

(Presented by Academician I. L. Knunyants, 6 VIII 1960)

There are only a few scattered reports in the literature in which the interaction of ethylenimine with aldehydes and ketones is touched upon directly or indirectly. In the reaction (mole for mole) in the cold, crystalline products of undetermined structure are isolated, corresponding to the composition of the initial mixture ($^1$). An analogous interaction on heating leads to the corresponding 2-mono- (or di-) substituted oxazolidines ($^2$). When aldehydes or ketones are treated with ethylenimine (one mole per 2 moles, respectively), compounds have been obtained that were described (without proof of structure) as $N,N'$-alkylidene-bis-ethylenimines ($^1$). As a result of saturating solutions of ethylenimine in ketones with hydrogen sulfide, 2,2-disubstituted thiazolidines are formed ($^3$).

An attempt to carry out the reaction of ethylenimine with formaldehyde was undertaken only in aqueous solution, and polymeric products of undetermined structure were obtained ($^4$).

In the present communication, the results are given of an investigation of the reaction of ethylenimine with formaldehyde in organic solvents. The principal reaction and the transformations of the products are presented in the scheme:

\[ \begin{gathered} \ce{ \underset{\text{Na/alcohol}}{\overset{}{\triangle NH + O=CH2}} ->[\ ] \triangle N-CH2-OH\ (I) }\\ \ce{ \triangle NH + O=CH2 -> \triangle N-CH2-N\triangle\ (II) }\\ \ce{ (I) ->[\ce{H2S}] [\begin{matrix} \ce{CH2-NH-CH2}\\ \ce{CH2-SH\ HO} \end{matrix}] -> \underset{(III)}{\ce{HN1CCSC1}} } \end{gathered} \]

$N$-Methylol­ethylenimine (I) and $N,N'$-methylene-bis-ethylenimine (II), which we have named zinimine and azirizine, respectively, are colorless, transparent, mobile liquids with a formaldehyde odor (I) and a weak amine odor (II). The products are readily soluble in water and in organic solvents. I (m.p. 19.1°) is stable when stored in the crystalline state, but at room temperature gradually turns into a viscous liquid that does not crystallize on cooling. During distillation in vacuum at a bath temperature of 160–180°, I partially decomposes with liberation of formaldehyde and formation of II (from 8.75 g of I, 1.85 g of II was obtained). II does not change when stored in the absence of moisture. Under the action of atmospheric moisture, I and II at room temperature polymerize in 1–3 days into hard, colorless, completely transparent ethylenimine–formaldehyde resins (polyzines), insoluble in water and in organic solvents, resistant to the action of concentrated alkalis and soluble in mineral acids. In contrast to the polyzines, the polymers ($^4$) obtained by heating ethylenimine with 30% formalin are soluble in water.

With an excess of hydrogen sulfide, I is smoothly converted into thiazolidine III. The known ease of cleavage of the ethylenimine ring by hydrogen sulfide makes it possible to suppose that III is the product of intramolecular condensation of the intermediate $\beta$-mercaptoethylmethylolamine. The reaction,

apparently, can be extended to the preparation of various 4,5-substituted thiazolidines.

On treatment with sodium in alcohol under the reduction conditions of Bouveault and Blanc (the ethylenimine ring is stable to such action) (⁵), ethylenimine was obtained. This hydrogenolysis reaction serves as proof of the presence of an ethylenimine ring in I.

Fig. 1. Infrared spectra of N-methylolethylenimine (I) and N,N′-methylene-bis-ethylenimine (II)

The structures of I and II are confirmed by IR spectra (Fig. 1)*. The latter correspond to the spectra of N-alkylated derivatives of ethylenimine (ring deformation vibrations: 1247–1186, 868–862, 826–812, 740–710 cm⁻¹; vibrations of the exocyclic C—N bond: 1271–1264 cm⁻¹; stretching-vibration frequencies of the ring C—H bonds, elevated in comparison with ordinary aliphatic compounds: the region of 3000 cm⁻¹ (⁶,⁷)); moreover, in the spectra of I there are sharp bands of O—H and C—O bond vibrations (3205 and 1110–1070 cm⁻¹).

Changing the conditions for the interaction of ethylenimine with formaldehyde affects the ratio of the yields of I and II (Table 1). The character of the dependence makes it possible to adopt a two-stage reaction mechanism:

\[ \begin{aligned} (1)\quad &\ce{(ethylenimine)N-H + CH2=O -> (ethylenimine)N-CH2-OH} \\ &\ce{(ethylenimine)N-H + HO-CH2-N(ethylenimine) -> (ethylenimine)N-CH2-N(ethylenimine) + H2O} \end{aligned} \]

* I express my gratitude to Doctor of Chemical Sciences Yu. N. Sheinker for recording the spectra.

Direct proof of reaction (2) was obtained by carrying out the condensation of I with ethyleneimine.

The ethyleneiminomethylation reaction, apparently, can also be extended to other compounds containing mobile hydrogen.

Comparing the data obtained with a number of other studies \((^{1-3})\), it may be assumed that the interaction of ethyleneimine with the carbonyl group of aldehydes and ketones proceeds according to the following general scheme:

\[ \begin{array}{c} \text{ethyleneimine } N\!-\!H + {>}C{=}O \\ \downarrow \\ \text{ethyleneimine-}N{-}C(OH)\text{ intermediate} \;\longrightarrow\; \begin{array}{c} \text{oxazolidine derivative} \\ \text{thiazolidine derivative (with }H_2S\text{)} \end{array} \end{array} \]

We were unable to observe isomerization of I into oxazolidine. This is evidently explained by the instability of unsubstituted oxazolidine; the latter is not known in the free state \((^8)\).

Compounds I and II are of interest as potential physiologically active agents. Ethyleneimine \((^9)\) and its derivatives are highly active mutagens; at present ethyleneimine is widely used in agricultural and industrial (antibiotic-producing strains) breeding \((^{10})\). Ethyleneimine derivatives possess antitumor action \((^{11})\), with bifunctional compounds being the most active. The latter, together with bis-β-chloroethylamines, have found the widest application in oncological practice.

I and II are the simplest bifunctional derivatives of ethyleneimine. In zinimine I the second functional group is \(N\)-methylol. It is of interest that a number of \(N\)-methylolamides possess antitumor activity \((^{12})\).

In order to determine the general character of the physiological action of the compounds obtained, we studied their acute toxicity. The experiments were carried out on black mice of the \(C_{14}\) line. On intraperitoneal administration, \(LD_{100}\) for I was 40 mg/kg, and for II 30 mg/kg. At absolutely lethal and higher doses, intoxication develops after a latent period (death on days 3–5), characteristic of the action of radiomimetic substances \((^{13})\). Together with I. A. Rapoport, the mutagenic activity of I and II was investigated on Drosophila: the percentage of sex-linked lethal mutations was 8.4 and 11.1, respectively.

Experimental Part

N-Methylolethyleneimine I and NN′-methylene-bis-ethyleneimine II. Ethyleneimine (6–20 g) was dissolved in dry ether or benzene (30–100 ml, respectively). A stream of formaldehyde, obtained by thermal depolymerization of paraform (calculated as one mole of formaldehyde per mole of ethyleneimine), was passed through the solution. The temperature of the mixture was maintained within the intervals indicated in Table 1. After removal of the solvent (when the reaction was carried out in ether, the residue was subjected to azeotropic drying with benzene), two products were obtained: \(N\)-methylolethyleneimine, m.p. 19.1°; b.p. 45–48°/1 mm, 55–56°/2 mm, 65–66°/3–5 mm; \(n_D^{20}\) 1.4548; \(d_{20}^{20}\) 1.050; \(MR\) found 18.99, calculated 19.32 (as is known \((^7)\), the strain of the ethyleneimine ring does not affect the value of \(MR\)).

\[ \begin{aligned} &\text{Found, \%:}\quad &&C\ 49.18;\ 49.38;\quad H\ 9.38;\ 9.45;\quad N\ 18.95;\ 19.12 \\ &\mathrm{C_3H_7ON}.\ \text{Calculated, \%:}\quad &&C\ 49.29;\quad H\ 9.65;\quad N\ 19.16 \end{aligned} \]

N,N′-methylene-bis-ethyleneimine, b.p. 110–113°/1 mm, 125–126°/2 mm;
\(n_D^{20}\) 1.4914; \(d_{20}^{20}\) 1.000; \(MR\) found 28.45, calculated 28.77.

Found, %: C 61.22; 61.44; H 10.18; 10.40; N 28.16; 28.49
\(\mathrm{C_5H_{10}N_2}\). Calculated, %: C 61.19; H 10.27; N 28.54

Product II was also obtained by condensation of I with ethyleneimine: to a solution of 4 g (0.055 mole) of I in 10 ml of dry benzene, 2.36 g (0.055 mole) of ethyleneimine was added (self-heating to 40°), and the mixture was heated at 70° for 30 min. After removal of the solvent, 3.1 g of product was obtained, yield 59.6%.

Table 1

Ratio of yields of I and II as a function of the reaction conditions of ethyleneimine with formaldehyde

* The products partially polymerize during distillation.

Upon addition of a mixture of 2 g (0.027 mole) of I with 4.1 g (0.055 mole) of abs. n-butyl alcohol to 1.26 g (0.055 mole) of finely divided metallic sodium in 10 ml of toluene, 0.5 g of ethyleneimine was obtained, yield 42.5%; b.p. 56°; \(n_D^{20}\) 1.4136 (literature data \(^{7}\)): b.p. 55–56°; \(n_D^{20}\) 1.4130.

Thiazolidine (III). Abs. methyl alcohol (150 ml) was saturated with hydrogen sulfide to a gain in weight of 13 g and at −55° was treated with a solution of 5.6 g of N-methylolethyleneimine I in 20 ml of methyl alcohol. After stirring for 1 hour with cooling, the mixture was left overnight at room temperature. 6.5 g of III was obtained, yield almost quantitative; b.p. 45–46°/1.5–2 mm; \(n_D^{20}\) 1.5520.

Found, %: N 15.40; 15.60
\(\mathrm{C_3H_7NS}\). Calculated, %: N 15.73

Treatment of III with hydrogen chloride in ether gave the hydrochloride of III, m.p. 180–182° (with decomposition). The melting point of a mixed sample with an authentic thiazolidine hydrochloride \(^{14}\) showed no depression.

Received
3 VIII 1960

CITED LITERATURE

1. A. Dornow, W. Schacht, Ber., 82, 464 (1949).
2. J. B. Doughty, C. L. Lazzell, A. R. Collett, J. Am. Chem. Soc., 72, 2866 (1950).
3. G. Bestian, Ann., 566, 210 (1950).
4. H. Ulrich, Am. pat., 2272489 (1942); Chem. Abstr., 36, 3593²; Am. pat., 2296225 (1942): Chem. Abstr., 37, 1210⁶.
5. D. S. Tarbell, D. K. Fukushima, J. Am. Chem. Soc., 68, 2499 (1946).
6. H. T. Hoffman, G. E. Evans, G. Glockler, J. Am. Chem. Soc., 73, 3028 (1951).
7. Yu. N. Sheinker, E. M. Peresleni, G. I. Braz, ZhFKh, 29, 518 (1955).
8. E. D. Bergmann, Chem. Rev., 53, 309 (1953).
9. I. A. Rapoport, Bull. Exp. Biol. Med., 23, 3 (1947).
10. S. I. Alikhanyan, S. Yu. Gol’dat, F. S. Klepikova, S. Z. Mindlina, Antibiotiki, 2, 33 (1957).
11. V. A. Chernov, Med. prom. SSSR, No. 4, 17, No. 5, 6 (1959).
12. J. A. Hendry, F. L. Rose, A. L. Walpole, Brit. J. Pharmacol., 6, 201 (1951).
13. R. G. Kostyanovskii, S. P. Yarmonenko, DAN, 127, 1294 (1959).
14. S. Ratner, H. T. Clarke, J. Am. Chem. Soc., 59, 200 (1937).