6-Chloro-3-hydroxy-(1)-benzoic acid
Abstract Generated abstract
This paper compares three preparative routes to 6-chloro-3-hydroxybenzoic acid, required as an intermediate for planned condensations in the anthracoumarin dye series. The authors experimentally examine chlorination and saponification of ethyl m-hydroxybenzoate, a modified route from chlorinated m-cresol using phosphorous acid ester protection during oxidation, and a newly proposed sequence from anthranilic acid through chloro-nitro, chloro-amino, and diazotized intermediates. They find the Mazzarra ester route unsuitable for preparative work because of difficult isomer separation and low saponification yields, while the modified m-cresol route is faster but limited by starting-material availability. The anthranilic acid route is presented as constitutionally persuasive and simple in principle, although the final diazotization and hydroxylation step gives low yields and requires further study.
Full Text
Prof. V. I. Minaev and K. M. Ripper.
6-Chloro-3-oxy-(1)-benzoic acid.
(From the Laboratory of Chemical Technology of Fibrous and Dye Substances of the Tomsk Technological Institute).
Subject. 6-Chloro-3-oxy-(1)-benzoic acid was needed by us as one of the components for condensations of certain derivatives in the anthracoumarin series. One of us, assuming in advance that in the anthracoumarin series new compounds with the properties of vat dyes might be synthesized, outlined in this direction a certain series of experimental investigations. To carry out the latter it was necessary to possess a sufficiently convenient preparative method for obtaining 6-chloro-3-oxy-(1)-benzoic acid.
For obtaining the named acid, on the basis of literature data, two schemes (1 and 2) of work could be compiled; in addition, from theoretical considerations, it seemed to us quite feasible and, apparently, more practical to use a new route for obtaining 6-chloro-3-oxy-benzoic acid, represented by the 3rd scheme.
According to the first scheme, starting from m-oxybenzoic (or, correspondingly, from benzoic¹) acid, it is proposed, according to the experimental data of Mazzarra²), to chlorinate the ethyl ester of m-oxybenzoic acid with sulfuryl chloride \((\mathrm{SO_2Cl_2})\) and, from the resulting mixture of chlorinated isomeric esters, by saponification and separation of the isomeric acids, to isolate the 6-chloro-3-oxy-benzoic acid required by us. Apart from the fact that this method is to a sufficient degree complicated and troublesome, as was also confirmed in practice, it leads to the formation of two products, of which we need only one; consequently, this in itself decreases the yield of the required product, counting from the starting material.
In the literature, Peratoner describes another method for obtaining the same acid, where the starting substance is m-cresol³). m-Cresol, on treatment with sulfuryl chloride, is converted in good yield into 6-chloro-3-oxy-1-methylbenzene. The author of this method, subsequently, in order to protect the OH group during oxidation of the \(\mathrm{CH_3}\) group into the \(\mathrm{COOH}\) group, resorts to alkylation \((\mathrm{OH \rightarrow O.CH_3})\); we, modifying the proposed method, proceed through the monoester of phosphoric acid⁴). This route for obtaining the acid required by us, appearing, in comparison with the first, preparatively simpler, has the obvious drawback that the starting material here is m-cresol, which practically cannot be considered readily accessible.
Starting from considerations of the greatest availability of the starting material and, as far as possible, the greatest simplicity of experimentation, we for the first time propose a theoretically correctly substantiated route for obtaining 6-chloro-3-oxybenzoic acid from anthranilic acid according to scheme 3.
The present work, therefore, was undertaken precisely with the aim of establishing, by experimental means, the simplest method for obtaining
¹) The conversion of benzoic acid by sulfonation and alkaline fusion into m-oxybenzoic acid is described in A. 280 (1894), 6–8.
²) Mazzarra, Gazetta Chimica Italiana XXIX (1899), 371.
³) Peratoner, Gazetta Chim. It. XXIX (1898), 213.
⁴) Heymann and Königs, B. XIX (1886), 3304. The method proposed by the named authors and successfully applied by them in the oxidation of other phenols is now likewise successfully extended by us to the case of oxidation of chlorinated m-cresol.
Scheme 1)
\[ \begin{array}{c} \text{[benzene ring with } \mathrm{COOH}\text{ substituent]}\\ \longrightarrow \text{[ring bearing } \mathrm{SO_3H},\ \mathrm{COOH}\text{]}\\ \longrightarrow \text{[ring bearing } \mathrm{OH},\ \mathrm{COOH}\text{]}\\ \stackrel{\mathrm{SOCl_2}}{\longrightarrow} \begin{cases} \text{[ring bearing } \mathrm{OH},\ \mathrm{Cl},\ \mathrm{COOC_2H_5}\text{]} & \text{solid ester},\\ \text{[ring bearing } \mathrm{OH},\ \mathrm{Cl},\ \mathrm{COOC_2H_5}\text{]} & \text{liquid ester}. \end{cases} \end{array} \]
Scheme 2)
\[ \begin{array}{c} \text{[ring bearing } \mathrm{OH},\ \mathrm{Cl}\text{]}\\ \stackrel{\mathrm{CO_2C_2H_5}}{\longrightarrow} \text{[ring bearing } \mathrm{OH},\ \mathrm{Cl}\text{]}\\ \longrightarrow \text{[ring bearing } \mathrm{Cl},\ \mathrm{COOH},\ \mathrm{O\!-\!P(O)(OH)_2}\text{]}\\ \longrightarrow \text{[ring bearing } \mathrm{OH},\ \mathrm{Cl},\ \mathrm{COOH}\text{]} } \end{array} \]
\[ (6\text{-chloro-3-hydroxybenzoic acid}) \]
Scheme 3)
\[ \begin{array}{c} \text{[ring bearing } \mathrm{COOH}\text{]}\\ \longrightarrow \text{[ring bearing } \mathrm{NO_2},\ \mathrm{Cl},\ \mathrm{COOH}\text{]}\\ \longrightarrow \text{[ring bearing } \mathrm{NH_2},\ \mathrm{Cl},\ \mathrm{COOH}\text{]}\\ \longrightarrow \text{[ring bearing } \mathrm{OH},\ \mathrm{Cl},\ \mathrm{COOH}\text{]} } \end{array} \]
\[ (6\text{-chloro-3-hydroxybenzoic acid}) \]
*) This substance, [[unclear: ester]], was isolated and characterized by [[unclear]].
6-chloro-3-hydroxybenzoic acid would, moreover, be accompanied by the maximum yield of product. Only a parallel execution of reactions according to three schemes, leading to one and the same final compound, gives material for conclusions and inferences in the sense indicated above.
Experimental Part
1. The first method, which consists in the chlorination1 of the ethyl ester of m-hydroxybenzoic acid, the separation of the two isomers obtained, and the final saponification of the ethyl ester of 6-chloro-3-hydroxybenzoic acid, was carried out in its essential features according to the data of Mazzarra. In doing so, however, a certain discrepancy was observed in the quantitative ratio of liquid ester to solid; namely, according to Mazzarra this ratio was expressed by the figures 21 : 12, whereas with us it was 18 : 12, i.e. the yield of the liquid ester (the one required for our purposes) decreased. However, we cannot ascribe this decrease in yield wholly to the experiment; the matter here lies in the circumstance that both substances can for a long time be in mutual solution, and for the separation of the solid ester from the liquid isomer certain suitable temperature conditions are needed. Owing to the extraordinary viscosity of the liquid ester, suction filtration of it, even in a vacuum filter, in our laboratory at \(+5^\circ C\)2 from the solid white crystalline ester proceeded very slowly and imperfectly. The liquid ester separated in this way solidified completely overnight and thus became, contrary to Mazzarra’s opinion, crystalline. This circumstance again indicates that complete separation of our two isomeric esters by the indicated route is almost impossible; unfortunately, other working conditions did not allow us at that moment to apply, for the separation of the esters, the method of fractional distillation under reduced pressure. However, the separation of the named esters is not necessary, since both isomeric acids obtained after the corresponding saponification can be conveniently separated on the basis that 2-chloro-3-hydroxybenzoic acid is readily soluble in boiling benzene, whereas the 6-chloro-3-hydroxybenzoic acid required by us remains insoluble.
Thus, the result of this experiment is a correction to Mazzarra’s data concerning the ethyl ester of 6-chloro-3-hydroxybenzoic acid, which at a somewhat lowered temperature (about \(+5^\circ C\)) solidifies, being liquid only at ordinary room temperature.
With regard to the method under consideration for obtaining 6-chloro-3-hydroxybenzoic acid, it must be said that the saponification reaction of the esters is accompanied by very small yields; perhaps for this reason Mazzarra, while everywhere giving exact data on the yield of intermediate products, does not indicate the yield of the free (final) acids in relation to the quantities of esters taken for saponification. The yields of the chlorosubstituted m-hydroxybenzoic acid obtained by us were very low—namely, 17% for 6-chloro-3-hydroxybenzoic acid and 27% for the isomeric 2-chloro acid. Undoubtedly, to study in greater detail the saponification reaction of these esters in the direction of improving the yield of both acids is of interest, but in general the route for obtaining 6-chloro-3-hydroxybenzoic acid indicated by the 1st scheme must be recognized as unsuitable for preparative work.
2. The second method in the isomerization proposed by us,3 as indicated above, gives generally good results.
whereby the temperature of the reaction mass was kept below \(50^\circ\) throughout the entire course of the reaction.
\[ \begin{array}{ccc} \text{\(o\)-aminobenzoic acid} & \longrightarrow & \text{\(o\)-chlorobenzoic acid} \longrightarrow \text{6-chloro-3-nitro-(1)-benzoic acid} \\ \begin{matrix} \mathrm{COOH}\\[-2pt] \mathrm{NH_2} \end{matrix} && \begin{matrix} \mathrm{COOH}\\[-2pt] \mathrm{Cl} \end{matrix} \qquad \begin{matrix} \mathrm{NO_2}\\[-2pt] \mathrm{COOH}\\[-2pt] \mathrm{Cl} \end{matrix} \end{array} \]
6-Chloro-3-nitro-(1)-benzoic acid\(^1\) is obtained in a yield of \(73\%\) from the isomeric 2-chloro-3-nitrobenzoic acid; it is separated owing to its ready ability to crystallize in the form of the potassium salt.
The reduction of the latter to 6-chloro-3-amino-benzoic acid was carried out by Hübner’s method,\(^2\) whereby, in order to moderate the reducing action and to preserve the chlorine located in the nucleus, instead of tin and hydrochloric acid\(^3\) we used stannous chloride \((\mathrm{SnCl_2\cdot 2H_2O})\), as a result of which the yield of the amino acid rose from \(62\%\) to \(81\%\). The reaction of our reduction may be expressed by the following equation:
\[ \mathrm{ C_6H_3 \begin{matrix} Cl\\[-2pt] NO_2\\[-2pt] COOH \end{matrix} + 3\,SnCl_2 + 7\,HCl \longrightarrow C_6H_3 \begin{matrix} Cl\\[-2pt] NH_2\cdot HCl\\[-2pt] COOH \end{matrix} + 3\,SnCl_4 + 2\,H_2O } \]
The reaction was carried out in the following manner: 6-chloro-3-nitro-(1)-benzoic acid (\(6\) g) was gradually introduced into a solution of \(\mathrm{SnCl_2}\) (\(30\) g) in concentrated hydrochloric acid (\(75\) cu. cm), with continuous shaking at \(45^\circ\mathrm{C}\), the reaction proceeding by itself quite perceptibly, but not violently. The nitro acid was added to the indicated solution of the acid reducing agent in small portions at intervals of such duration that during this time the evolution of vapors completely ceased. After completion of the reaction, the reaction mass was heated for \(1/2\) hour on a water bath and for another \(1/2\) hour over an open flame, and then the transparent solution, faintly colored yellow, was subjected to evaporation.
To obtain the amino acid in the pure state, it was, according to Hübner, converted by means of sodium acetate and copper acetate salts into the copper salt, from which the amino acid was again obtained in the free state and recrystallized from water. In agreement with Bamberger,\(^4\) who established Hübner’s error, we too found the melting point of the recrystallized amino acid to be \(185\)—\(186^\circ\mathrm{C}\).
The diazotization of 6-chloro-3-amino-(1)-benzoic acid had been undertaken only once by Hübner, whereby the diazo product obtained in hydrochloric-acid solution was converted into dichlorobenzoic acid. For replacement of the amino group by hydroxyl (\(-\mathrm{OH}\)), the diazotization was conducted by us in sulfuric-acid solution, and it was observed that the sulfuric-acid salt of 6-chloro-3-aminobenzoic acid is capable of being diazotized only upon heating to a temperature of \(30\)—\(40^\circ\mathrm{C}\) (!), whereas the hydrochloric-acid salt, as usual, can be diazotized only with cooling by ice.
The diazotization reaction was carried out by us in the following manner: to a solution of the amino acid (\(1\) g) in dilute sulfuric acid, warmed to \(30\)—\(40^\circ\mathrm{C}\), an aqueous solution of nitrite was added dropwise (\(0.5\) g \(\mathrm{NaNO_2}\) in \(5\) cu. cm water). The solution of the resulting diazonium salt was then dropwise
\(^1\) That 6-chloro-3-nitro-(1)-benzoic acid possesses precisely this constitution, ascribed to it here, was proved by Hübner (A. 222, 195), Montagne (Rec. Trav. Chim. Pays-Bas, 1900, XIX, 46), and especially by Holleman and De-Bruyn (Rec. Trav. Chim. Pays-Bas, 1901, XX, 206), as well as by Purgotti and Cantardi (Gaz. Chim. Ital. 1902, XXXII, I, S. 526).
\(^2\) A. 222 (1883), 198.
\(^3\) A. 222 (1883), 198, Hübner.
\(^4\) B. 35 (1902), 3703.
is introduced into water acidified with sulfuric acid (50 cubic cm) at a temperature of 90–95° C, each subsequent drop being introduced only after the evolution of \(N_2\) gas from the previously introduced drop of diazo-compound solution has ceased. On evaporation and cooling, shiny crystals with an admixture of red-colored resin separate from the solution. After repeated crystallization from water it was possible to obtain only a small quantity (0.1 g) of 6-chloro-3-hydroxy-(1)-benzoic acid with m.p. 176–177° C.
\[ \begin{array}{ccc} \begin{array}{c} \mathrm{NH_2}\\[-2mm] \chemfig{*6(-=-(-Cl)-(-COON)=-)} \end{array} & \longrightarrow & \begin{array}{c} \mathrm{OH}\\[-2mm] \chemfig{*6(-=-(-Cl)-(-COOH)=-)} \end{array} \end{array} \]
In the literature\(^{1}\) there are indications of a general character that the hydroxylation of diazo compounds under known conditions is possible without resinification and without significant losses (owing to the formation of an azo dye from the phenol that is partially formed and the diazo compound that has not yet decomposed). Thus, despite the almost negative literature data, we undertook the hydroxylation of our diazo compound and achieved a certain success, although our method still requires further development in the sense of increasing the yield of the product.
The melting point of the chloro-hydroxycarboxylic acid obtained in this way, almost coinciding with the m.p. of the product obtained by method (2), together with other evidentiary circumstances, fully establishes the identity of both products, i.e. the 6-chloro-3-hydroxy-(1)-benzoic acid sought by us. The low yield of product, naturally, leaves much to be desired, but for the time being, despite numerous experiments, we have not succeeded in raising the yield. Under suitable, more favorable conditions the investigation of this reaction should be resumed.
Conclusion.
1) The first method for obtaining 6-chloro-3-hydroxy-(1)-benzoic acid (Mazzarra) is difficult and complicated.
2) Both chlorinated isomeric ethyl esters—the normal and the unsymmetrical one (see scheme)—contrary to Mazzarra’s observation, proved to be solid [[unclear: substances]].
3) The second method for obtaining 6-chloro-3-hydroxy-(1)-benzoic acid (according to Pfitzinger) is considerably improved by the use of phosphorous-acid esters for protecting the OH group during the oxidation of chlorinated \(m\)-cresol into the corresponding derivative of \(m\)-hydroxybenzoic acid (the Hübner and Königs reaction, extended by us to the present case with good success).
4) Although the execution of the second method is connected with large losses of substance—precisely owing to the ready solubility of 6-chloro-3-hydroxybenzoic acid in water, from which it had to be recrystallized—nevertheless this route leads to the desired product most rapidly. A substantial drawback of this method is the limited availability of the starting \(m\)-cresol.
5) The new (third) route proposed by us is, in principle, very simple, and by the indisputability of its scheme is quite evidential for the accepted constitutional formula of 6-chloro-3-hydroxybenzoic acid.
6) The peculiarities of the diazotization of 6-chloro-3-aminobenzoic acid in sulfuric-acid solution are of special interest, and therefore the study of this reaction deserves particular attention for the sake of increasing the yield of the product.
\(^{1}\) A. 253 (1889), 280–283.