ON THE USE OF PHOSPHORUS TRICHLORIDE IN THE ACYLATION REACTION OF AROMATIC AMINES

R. N. GIREVA

The acylation reaction of aromatic amines is of great industrial importance both for obtaining important intermediate products and for no less important finished substances: pharmaceutical preparations, dyes, insectofungicides, etc.

As is known, the acylation reaction of amino compounds can be carried out with the aid of various acylating agents: free carboxylic acids, their anhydrides, acid chlorides, and, in some cases, other acid derivatives, such as, for example, amides and esters.

Of the acids used for the acylation of amino compounds, the simplest are employed: formic, acetic, less often benzoic and oxalic acids [1]. Of the acid anhydrides, acetic anhydride, sulfuric anhydride (most often in the form of a compound with some tertiary amine), sulfuryl chloride, phthalic anhydride, and, less often, benzoic anhydride are used for the same purpose [1].

The most active and most commonly used acylating agents are acid chlorides, obtained from the corresponding acids by treating them chiefly with acid chlorides of inorganic acids \((\mathrm{PCl}_5, \mathrm{PCl}_3, \mathrm{SOCl}_2, \mathrm{COCl}_2)\) [1].

For obtaining arylamides of hydroxycarboxylic aromatic acids, acylation is most often carried out by treating a mixture of a hydroxycarboxylic acid and an aromatic amine in a suitable solvent (toluene, xylene, chlorobenzene) with phosphorus trichloride under heating [2].

In this case, evidently, the acid chloride of the hydroxycarboxylic acid is first formed, which then reacts with the amine. Thus, various azotols are usually obtained from aromatic amines and hydroxycarboxylic aromatic acids.

\[ 3\,\mathrm{Ar} \begin{matrix} \mathrm{OH}\\[-2pt] \backslash\\[-2pt] \mathrm{COOH} \end{matrix} + 2\mathrm{PCl}_3 \longrightarrow 3\,\mathrm{Ar} \begin{matrix} \mathrm{OH}\\[-2pt] \backslash\\[-2pt] \mathrm{COCl} \end{matrix} + \mathrm{P}_2\mathrm{O}_3 + 3\mathrm{HCl} \]

\[ \mathrm{Ar} \begin{matrix} \mathrm{OH}\\[-2pt] \backslash\\[-2pt] \mathrm{COCl} \end{matrix} + \mathrm{H}_2\mathrm{N}-\mathrm{Ar}' \longrightarrow \mathrm{Ar} \begin{matrix} \mathrm{OH}\\[-2pt] \backslash\\[-2pt] \mathrm{CONH}-\mathrm{Ar}' \end{matrix} + \mathrm{HCl}. \]

This method of acylating amines with acids with the participation of acid chlorides of inorganic acids \((\mathrm{PCl}_3, \mathrm{SOCl}_2 + \mathrm{AlCl}_3)\), which form the corresponding acid chlorides of aromatic carboxylic acids in the course of the synthesis, although described [3], is not widely used. In practice, for acylation with aromatic acids it is preferred to use ready-made acid chlorides, although this entails an additional expenditure of time for obtaining and purifying the acid chloride. Because of the simplicity of execution, the method of acylating amines with aromatic acids in the presence of \(\mathrm{PCl}_3\) represents—

is of definite practical interest; therefore we carried out a series of experiments on the preparation of several anilides of aromatic acids. The anilides of benzoic, o-, m-, and p-nitrobenzoic, and o- and p-chlorobenzoic acids were obtained. The anilides of all these acids have been described in the literature, but all of them are obtained by other methods. Thus, benzanilide is obtained by prolonged heating of benzoic acid with an excess of aniline [4]. The method is distinguished by considerable complexity and gives an 80–84% yield of the technical product. Benzanilide can also be obtained by heating sodium benzoate and aniline in a sealed tube, from benzoic anhydride and aniline, from benzoyl chloride and aniline, and by a whole series of other methods [5].

The isomeric nitrobenzanilides are obtained from aniline and the corresponding nitrobenzoyl chlorides, from aniline and nitrobenzoic acids on heating, and by other methods [5].

Chlorobenzanilides may be obtained from chlorobenzoyl chlorides and aniline, and also by the action of \( \mathrm{PCl_5} \) on \(\alpha\)-(-chlorobenzophenone oximes) [5].

Acylation of aniline with aromatic acids, carried out by the usual method for obtaining azotoles [6], in the presence of \( \mathrm{PCl_3} \), makes it possible to obtain the above-named anilides in fairly good yield and with sufficient purity.

It proved possible to apply this method successfully to the acylation of other amines, including heterocyclic ones.

Like other acylation methods, the method of acylating amines in the presence of \( \mathrm{PCl_3} \) is unsuitable for the preparation of arylamides of aromatic aminocarboxylic acids. When aniline is heated with aminobenzoic acids in the presence of \( \mathrm{PCl_3} \), not only does the acylation reaction of aniline proceed, but also acylation of the amino group of the aminobenzoic acid, leading to the formation of more complex, infusible products. The process occurring in the example of anthranilic acid may be represented as follows:

\[ 3\,\mathrm{H_2N{-}C_6H_4{-}COOH} + \mathrm{PCl_3} \longrightarrow 3\,\mathrm{H_2N{-}C_6H_4{-}COCl} + \mathrm{P_2O_3} + 3\,\mathrm{HCl} \]

\[ \mathrm{H_2N{-}C_6H_4{-}COCl} + \mathrm{H_2N{-}C_6H_5} \longrightarrow \mathrm{H_2N{-}C_6H_4{-}CONH{-}C_6H_5} + \mathrm{HCl} \]

\[ \mathrm{H_2N{-}C_6H_4{-}CONH{-}C_6H_5} + \mathrm{H_2N{-}C_6H_4{-}COCl} \longrightarrow \mathrm{C_6H_5NHCO{-}C_6H_4{-}NHCO{-}C_6H_4{-}NH_2} \]

The possibility is not excluded that the amino group is acylated in this product as well, and in the next one, etc. It is quite natural that such a complex product proves to be infusible and insoluble in ordinary solvents.

Experimental Part

Anilide of benzoic acid

Equimolecular amounts of aniline and benzoic acid, dissolved in a 20-fold (relative to aniline) amount of solvent (carefully dried and distilled xylene or benzene\(^1\)), were placed in a three-necked round-bottom flask equipped with a mechanical stirrer, a dropping funnel, and a reflux condenser closed with a calcium chloride tube with a tube for removal of the hydrogen chloride evolved. The mixture was heated

\(^1\) Aniline and the solvents were purified by distillation; benzoic acid was recrystallized.

in an oil bath (in the experiments with benzene, in a water bath) to gentle boiling, and, with good mechanical stirring, a solution of 1.3 moles of phosphorus trichloride in an organic solvent (xylene or benzene), taken in a twofold amount relative to aniline, was added dropwise from a dropping funnel. Vigorous evolution of hydrogen chloride took place; the latter, passing through a condenser and a calcium chloride tube, was absorbed by water. The strongest evolution of hydrogen chloride occurred during the addition of phosphorus trichloride. On further heating of the reaction mixture, the evolution of hydrogen chloride decreased, but did not cease altogether even upon heating for many hours (8–10 hours). After completion of the reaction, the cooled reaction mixture was neutralized with a 10% soda solution to a weakly alkaline reaction toward litmus; the solvent and the aniline that had not entered into the reaction were distilled off with steam. The anilide remaining in the distillation flask after removal of the solvent was filtered off, washed with water, air-dried, weighed, and recrystallized from alcohol. The melting point of the technical and recrystallized product was determined. In most cases, a single recrystallization from alcohol was sufficient to obtain a product with a constant melting point, i.e., \(161^\circ\). The results of experiments on the acylation of aniline with benzoic acid are given in Table 1.

Table 1

It is evident from this that benzanilide can be obtained in fairly good yield by acylating aniline with benzoic acid in the presence of \(PCl_3\) at \(80^\circ\) (in boiling benzene) for 4 hours. Raising the reaction temperature (experiments in xylene) leads to the formation of a less pure product.

Anilide of p-nitrobenzoic acid

To a mixture of 5 g of aniline and 8.4 g of pure p-nitrobenzoic acid, obtained by oxidation of p-nitrotoluene with chromic mixture [8], in xylene solution at gentle boiling, a xylene solution of 9 g of PCl₃ was added dropwise. The reaction mixture was heated from 1 hour to 8, after which it was treated in the usual manner. The results of the experiments are given in Table 2.

Table 2

As is evident from the results of the experiments, the acylation of aniline with p-nitrobenzoic acid in the presence of PCl₃ proceeds completely in 1 hour, and further heating of the reaction mixture leads to the formation of a dirtier product.

Anilide of m-nitrobenzoic acid

To a mixture of 5 g of aniline and 8.4 g of pure m-nitrobenzoic acid, obtained by nitration of benzoic acid [6], in xylene solution at gentle boiling, PCl₃ (9 g), dissolved in xylene, was added dropwise. The reaction mixture was heated from 30 minutes to 4 hours. The results of the acylation are given in Table 3.

Table 3

From the table it is evident that the acylation reaction in this case proceeds completely within 1 hour.

Anilide of o-nitrobenzoic acid

To a xylene solution of 2 g of aniline and 3.5 g of pure o-nitrobenzoic acid, obtained by oxidation of o-nitrotoluene with nitric acid [8], heated to boiling, a solution of 3 g of PCl₃ in xylene was added dropwise. The reaction mixture was heated for 1 and 2 hours. With one-hour heating, the yield of the reaction product was 96%, m.p. 154° (the pure product melts at 155°). With two-hour acylation, a resinous product was obtained.

Anilide of p-Chlorobenzoic Acid

To a mixture of 2.4 g of aniline and 4 g of pure p-chlorobenzoic acid, obtained by oxidation of p-chlorotoluene [8], in xylene solution, with gentle boiling, a solution of 4.6 g of PCl₃ in xylene was added dropwise. The reaction mixture was heated for 3 hours and then worked up in the usual way. The yield of anilide was 86.3%; m.p. 194° (the pure product melts at 194–195°).

With more prolonged heating of the reaction mixture, a product with a lower melting point is obtained.

Anilide of o-Chlorobenzoic Acid

To a mixture of 2 g of aniline and 3.4 g of pure o-chlorobenzoic acid, obtained from anthranilic acid by diazotization and subsequent decomposition of the diazo compound [8], in xylene solution, with gentle boiling, a xylene solution of 3.8 g of PCl₃ was added dropwise. The reaction mixture was heated for 3 hours and then worked up in the usual way. The yield of anilide was 80.3%; m.p. 112° (the pure product melts at 114°). With more prolonged heating of the reaction mixture, the yield of the reaction product increases, but the anilide obtained is less pure (m.p. 107°).

Conclusions

1. It has been shown that the method of acylating amines with aromatic acids in the presence of phosphorus trichloride is fully suitable not only for obtaining arylamides of oxycarbonic acids, but also of other carboxylic acids, in particular benzoic, nitrobenzoic, and chlorobenzoic acids.

2. The use of this acylation method in most cases simplifies the method of obtaining an arylamide, since the stage of formation of the acid chloride is eliminated.

3. Carrying out the acylation reaction with isomeric nitrobenzoic acids shows that the introduction of a nitro group into the molecule of benzoic acid greatly increases its acylating ability.

4. The method of acylating amines in the presence of PCl₃ is unsuitable for aminobenzoic acids, which under these conditions themselves undergo acylation with the formation of complex, infusible products.

Literature

1. N. N. Vorozhtsov. Fundamentals of the Synthesis of Intermediates and Dyes. Goskhimizdat, 569, 570, 1950.

2. W. Vaughan A. E. AKP, 3, 11, 1933.

3. Belg. patent 375883, Zbl., II, 1765, 1933.

4. Syntheses of Organic Preparations. Collection edited by Gilman, Adams, and others, Moscow, I, 80, 1949.

5. Beilsteins Handbuch der Organischen Chemie, Bd. XII, 262, 266, 267, 268.

6. V. M. Rodionov, S. V. Bogoslovskii, B. M. Fedorov, A. M. Laboratorskoe rukovodstvo po khimii promezhutochnykh produktov i krasitelei, Goskhimizdat, 72, 26, 1948.

7. A. M. Berkengeim. Practicum in Synthetic Medicinal and Fragrant Substances and Photoreagents. State Scientific-Technical Publishing House of Chemical Literature. M.–L., 58, 1942.

8. L. Vanino. Präparative Chemie, II Band, Stuttgart, 567, 566, 564, 1923.