DIRECT IODINATION AND BROMINATION OF AROMATIC COMPOUNDS WITH SUBSTITUENTS OF THE SECOND TYPE IN THE PRESENCE OF A NITRIC–SULFURIC NITRATING MIXTURE

A. N. NOVIKOV

According to the literature, m-iodo and m-bromo derivatives of certain aromatic compounds with substituents of the second type can be obtained:

1) from benzoic acid, nitrobenzene, or benzaldehyde through nitroamino-diazonium compounds (average yield 20–30%); 2) by the action on benzoic acid, nitrobenzene, or benzaldehyde [1–3] of iodine or bromine in the presence of silver sulfate and concentrated sulfuric acid, with corresponding yields of 75, 60, and 12% (for iodo derivatives); 3) from benzoic acid, iodine or bromine in the presence of fuming nitric acid saturated with sulfuric anhydride [4]—yield 50%; 4) by bromination of benzoic acid or nitrobenzene [5] in the presence of catalysts—iron or ferric chloride. m-Iodobenzoic acid [6] is also prepared from phthalimide through anthranilic and 5-iodoanthranilic acids, and m-iodonitrobenzene from 4-iodo-2-nitroaniline. Considering the opinion of a number of chemists [7–11] that, for successful iodination, it is necessary to remove the hydrogen iodide liberated in the reaction, which acts in a dehalogenating manner on the iodine-containing substance obtained (for which purpose silver sulfate, fuming acids, sulfuric and nitric acids, and other strong oxidants have been proposed), to be of little justification, the author believes that the iodination of the above-mentioned substances, just like bromination, should be carried out in the presence of catalysts that activate the molecule of the aromatic substance and iodine.

For economic reasons, loss of the hydrogen iodide liberated in the iodination reaction is undesirable. Therefore, the author used as the iodination catalyst an ordinary nitrating mixture composed of nitric acid of specific gravity 1.38–1.4 and sulfuric acid of specific gravity 1.84. With this mixture the molecules of the organic substance and iodine are activated, and hydrogen iodide is oxidized to iodine.

Benzoic acid, nitrobenzene, benzaldehyde, m-dinitrobenzene, and benzophenone were subjected to direct iodination in the presence of a nitric–sulfuric mixture; benzoic acid and nitrobenzene were brominated. As a result, the following were obtained: m-iodobenzoic acid (yield 75.0%, m.p. 185–187°), m-bromobenzoic acid (yield 60.4%, m.p. 154–155°), m-iodonitrobenzene (yield 60.0%, m.p. 34–36°), m-bromonitrobenzene—(yield 33.4%, m.p. 55°), and a mixture of iodo derivatives of benzophenone, from which a crystalline substance with m.p. 130° was isolated (yield 10%). By its halogen content this was diiodobenzophenone. Its structure has not been established; it has not been described in the literature. m-Dinitrobenzene was not iodinated under the conditions studied. From benzaldehyde, upon iodination in the presence of urea, which

was added in order to eliminate the oxidizing property of the nitrating mixture; m-iodobenzaldehyde was obtained in 20% yield.

The probable scheme of the mechanism of iodination and bromination is as follows:

\[ \mathrm{J_2 + HNO_3 \rightleftarrows HJ + J\cdot + NO_3'} \]

or

\[ \mathrm{2J_2 + H_2SO_4 \rightleftarrows 2HJ\cdot + 2J\cdot + SO_4''}, \]

other routes of formation of the iodo cation are possible. Then

\[ \mathrm{H_2SO_4 + HNO_3 \rightleftarrows O{=}N{=}O \;\cdots\cdots\cdots\; HOSO_2OH \rightleftarrows} \]
\[ \begin{gathered} \phantom{\mathrm{O{=}N{=}O}} \\ \mathrm{\ \ \ \ \ \ \ \ \ \ \ \ \ |} \\ \mathrm{\ \ \ \ \ \ \ \ \ \ \ \ OH} \end{gathered} \]

\[ \mathrm{ \rightleftarrows \left[ \begin{array}{c} \mathrm{\ \ \ OH}\\[-2mm] \mathrm{O{=}N<}\\[-2mm] \mathrm{\ \ \ OH} \end{array} \right]^{\cdot} + (HSO_4)' \rightleftarrows H_2O + [O{=}N{=}O]' + (HSO_4)'. } \]

Benzoic acid has the greatest electron-donor properties in the m-position, owing to the specific influence of the carboxyl group (a substituent of the second kind). The complex of nitric and sulfuric acids, or the nitronium cation, is electrostatically attracted to this position by its positive charge,

\[ \begin{array}{c} \text{benzoic acid with the activated hydrogen in the }m\text{-position} \end{array} \quad +(\mathrm{NO_2})^{\cdot} \rightleftarrows \quad \begin{array}{c} \text{activated complex at the }m\text{-position} \end{array} \]

as a result of which the bond between the hydrogen and carbon atoms is weakened. When such an activated molecule encounters an iodo cation, the hydrogen atom is replaced by the latter and m-iodobenzoic acid is formed:

\[ \begin{array}{c} \text{activated complex of benzoic acid} \end{array} +\mathrm{J}^{\cdot} \rightarrow \begin{array}{c} m\text{-iodobenzoic acid} \end{array} +\mathrm{H}^{\cdot}+(\mathrm{NO_2})^{\cdot}. \]

Experimental Part

The experiments were carried out according to the following general procedure.

In a three-necked flask with ground-glass joints for a mercury seal, fitted with a stirrer, condenser, and dropping funnel, iodine, the solvents, the starting organic substance, and sulfuric acid (specific gravity 1.84) were mixed. The flask was...

was placed in a sulfuric-acid bath (a glass one, so that it would be possible to observe the changes occurring in the reaction mixture), which was heated by an electric hot plate connected to the mains through a thermoregulator. When the temperature of the bath reached the specified value, nitric acid of specific gravity 1.4, or a mixture of nitric and sulfuric acids, was gradually introduced from a dropping funnel with mechanical stirring (over approximately 1 hour). The heating was then continued for the required time. The reaction was accompanied by abundant evolution of nitrogen oxides (except for experiments involving urea) and by a change in the color of the solution; in some experiments the reaction mixture became decolorized. Separation into a solid substance and a liquid, or into two liquids, was observed. The changes and the subsequent work-up of the mixture, for the purpose of isolating the reaction products, depended mainly on the initial organic product and then on the reaction conditions.

Iodination of benzoic acid

The iodination reaction of benzoic acid was accompanied by a change in the color of the solution, often by its complete decolorization, and also by the appearance and separation in the mixture of crystals of iodobenzoic acid.

After the reaction was complete, the reaction mixture was diluted with water in order to obtain additional separation of iodobenzoic acid crystals from the solution. The cooled solution was filtered, and the crystals were washed first with cold and then with hot water to remove completely sulfuric, nitric, and benzoic acids and, in part, isomers of m-iodobenzoic acid. Then, for further purification, the m-iodobenzoic acid was crystallized two or three times from 50 percent aqueous ethyl alcohol. m-Iodobenzoic acid with a melting point of 185–187° was obtained. The qualitative test for nitrogen was negative.

Determination of iodine by the Stepanov method

Found iodine ............................ 1) 50.6%, 2) 50.8%,
calculated for m-iodobenzoic acid .... 51.17%.

The iodobenzoic acid was assigned to the meta series on the basis of the melting point obtained, 185–187° (literature value, 185–188°), and on the well-known general rule of substitution, according to which substances exhibiting an electron-acceptor function and acting on aromatic compounds with substituents of the second type cause the formation of a meta-substituted product.

Forty-four experiments were carried out on the iodination of benzoic acid. The influence on the yield of m-iodobenzoic acid of various factors was established: the amounts of sulfuric acid, nitric acid, their ratio, iodine, solvents; the duration and temperature of the reaction; and the method of mixing the components. As a result, m-iodobenzoic acid was obtained in a yield of 75%.

Influence of the amount of nitric acid in a mixture with sulfuric acid

$C_6H_5COOH$ 6.1 g, $J_2$ 6.35 g, $H_2SO_4$ 5.6 ml, glacial $CH_3COOH$ 15 ml, $CCl_4$ 4 ml, reaction temperature 85°, duration of synthesis 5 hours.
$HNO_3$ 1.7 ml — yield of m-iodobenzoic acid 43.3%.

$HNO_3$ 2.4 ml — yield of m-iodobenzoic acid 51.3%
$HNO_3$ 3.4 ml — ”                                     ”                             65.0%
$HNO_3$ 6.9 ml — ”                                     ”                             67.5%
$HNO_3$ 10.3 ml — ”                                    ”                             68%

Effect of the amount of sulfuric acid in the mixture with nitric acid

$C_6H_5COOH$ 6.1 g, $J_2$ 6.35 g, $HNO_3$ 3.4 ml, glacial $CH_3COOH$ 15 ml, $CCl_4$ 4 ml, reaction time 5 hours, temperature 85°.

$H_2SO_4$ 2.8 ml—yield of m-iodobenzoic acid 14.0%
” 4.2 ml— ” ” ” 42.5%
” 5.6 ml— ” ” ” 65.0%
” 7.0 ml— ” ” ” 60.1%
” 8.4 ml— ” ” ” 55.8%

Effect of the ratios of nitric and sulfuric acids in their mixture

$C_6H_5COOH$—6.1 g (0.05 mole), $J_2$ 6.35 g (0.025 mole), glacial $CH_3COOH$ 15 ml, $CCl_4$ 4 ml, duration of experiments 4 hours, reaction temperature 85°.

$H_2SO_4$ 0.075 mole, $HNO_3$ 0.075 mole,—yield of m-$JC_6H_4COOH$ 58.2%
” 0.0875 ” ” 0.0625 ” ” ” 66.3%
” 0.1 ” ” 0.05 ” ” ” 74.0%
” 0.1125 ” ” 0.0375 ” ” ” 69.2%
” 0.125 ” ” 0.025 ” ” ” 63.6%

Effect of the amount of the $H_2SO_4 + HNO_3$ mixture

$C_6H_5COOH$ 18.3 g, $J_2$ 19.04 g, glacial $CH_3COOH$ 50 ml, temperature 125°, time 4 hours.

$H_2SH_4$ 8.3 ml, $HNO_3$ 10.3 ml—yield of m-$JC_6H_4COOH$ 50.0%
$H_2SO_4$ 16.7 ml, $HNO_3$ 20.7 ml— ” ” 48.0%
$H_2SO_4$ 33.4 ml, $HNO_3$ 41.3 ml— ” ” 35.1%
$H_2SO_4$ 50.1 ml, $HNO_3$ 62.0 ml— ” ” 0.0%

Effect of the duration of synthesis

$C_6H_5COOH$ 6.1 g, $J_2$ 4 6.35 g, $H_2SO_4$ 5.6 ml, $HNO_3$ 3.4 ml, glacial $CH_3COOH$ 15.0 ml, $CCl_4$ ml, reaction temperature 85°.

2 h—yield of m-$JC_6H_4COOH$ 36.1%; 3 h—58.5%;
4 h—63.0%; 5 h—65%; 6 h—69.4%;
7 h—74.0%; 8 h—71.6%.

Effect of reaction temperature

$C_6H_5COOH$ 6.1 g, $J_2$ 6.35 g, $H_2SO_4$ 4.2 ml, $HNO_3$ 5.2 ml, glacial $CH_3COOH$ 15 ml, $CCl_4$ 4 ml, time 4 hours.

Temperature 75°—yield of m-$JC_6H_4COOH$ 38.5%; 85°—56.2%;
100°—46.0%; 125°—24.5%.

It was found that addition of iodine to a mixture of benzoic acid, solvents, $H_2SO_4$, $HNO_3$ under the optimal conditions found lowers the yield of m-iodobenzoic acid. Addition of the sulfonitric nitrating mixture has the same effect. One should add nitric acid alone to the mixture of $C_6H_5COOH$, $J_2$, solvents, and $H_2SO_4$. Instead of glacial acetic acid, which was used as the solvent, it is possible to use 80-percent-

acetic acid, increasing the amount of sulfuric and nitric acids. According to the optimal conditions found, the reaction must be carried out at 85°. At this temperature, in the presence of acetic acid alone as the solvent, the iodination process almost does not occur, since iodine sublimes, deposits on the walls of the apparatus, and leaves the reaction zone. To avoid this, another solvent—carbon tetrachloride, with a boiling point of 75°—was additionally added in small amount. The vapors of carbon tetrachloride washed the sublimed iodine from the walls of the apparatus, and thanks to this it was introduced again into the reaction mixture. As the experiments performed showed, benzoic acid with only CCl₄, without acetic acid, is not iodinated.

Bromination of benzoic acid

C₆H₅COOH 6.1 g (0.05 mol), Br₂—2.0 ml (0.0375 mol), H₂SO₄ 11.1 ml (0.2 mol), HNO₃ 6.9 ml (0.1 mol), glacial acetic acid 20 ml. Nitric acid was added gradually over 1 hour with mechanical stirring to the mixture of the remaining starting materials at a temperature of 63°. Reaction time 4.5 hours.

The reaction products were transferred to a beaker, diluted with water; the precipitate was separated by filtration and washed with cold and hot water. The crude m-bromobenzoic acid was crystallized twice from aqueous alcohol. Its melting point was 154–155°. Yield 64.5% of theory.

A synthesis carried out at 50° did not give an appreciable amount of m-bromobenzoic acid. An experiment carried out with the following amounts of nitric and sulfuric acids: 3.4 ml (0.05 mol) and 5.8 ml (0.1 mol), led to a 25 percent yield of m-BrC₆H₄COOH.

Iodination of nitrobenzene

Nitrobenzene 10.3 ml (0.1 mol), iodine 12.59 g (0.05 mol), sulfuric acid 22.2 ml (0.4 mol), glacial CH₃COOH 15 ml, CCl₄ 3 ml were taken. At 100°, over 1.5 hours, nitric acid (17.4 ml) was added. Reaction time 15 hours. The oily product (a mixture of iodonitrobenzene and nitrobenzene) was treated with 20 percent sodium sulfite solution to remove iodine, then dried with calcium chloride. After distillation in vacuo, 13.85 g (60.4%) of m-iodonitrobenzene with melting point 34–36° was obtained.

Bromination of nitrobenzene

To a mixture of nitrobenzene 5.1 ml (0.05 mol), bromine 1.3 ml (0.025 mol), sulfuric acid 11.14 ml (0.2 mol), glacial acetic acid (15 ml), nitric acid 6.9 ml (0.1 mol) was added at 83°. Duration of the synthesis: 4.5 hours. The reaction mixture was a two-layer liquid; upon cooling, the lower layer crystallized (crude m-bromonitrobenzene).

M—BrC₆H₄N₄O₂ after washing with hot water to neutral reaction was purified by precipitation from a dilute alcoholic solution with water under vigorous stirring. Yield 33.4% (3.4 g); melting point 54–55°.

Iodination of benzophenone

Benzophenone 9.11 g (0.05 mol), iodine 6.35 g (0.025 mol), sulfuric acid 11.1 ml (0.2 mol), nitric acid 6.9 ml (0.1 mol), glacial acetic acid 5 ml, carbon tetrachloride 2 ml. Nitric acid was added

acid at 85°. Reaction time 30 minutes. The reaction mixture was a colorless, two-layer liquid. From the lower oily layer, a solid product was isolated by crystallization from alcohol. Its melting point was 131°. Yield 10%. The principal reaction product was an oily substance. The qualitative reaction for nitrogen of the crystalline product was negative. On the basis of its iodine content it may be assigned to the diiodo derivatives of benzophenone. Not all possible diiodobenzophenones have been described in the literature. Attempts to establish the structure of the substance obtained by alkaline fusion did not give positive results.

Iodination of m-dinitrobenzene

m-Dinitrobenzene 4.2 g (0.025 mole), iodine 3.17 g, sulfuric acid 11.9 ml, nitric acid 11.4 ml, glacial CH₃COOH—15 ml, CCl₄—7 ml. Reaction temperature 125°, time—8 hours. The reaction product was unchanged m-dinitrobenzene.

Iodination of benzaldehyde

Benzaldehyde 10.1 g, iodine 12.69 g, sulfuric acid 16.7 ml, nitric acid 20.7 ml, glacial acetic acid 30 ml, carbon tetrachloride 8 ml, urea 8.0 g. Experimental temperature 80–82°. Time—6 hours. During the reaction, nitrogen oxides were not evolved. Formation of hydrogen iodide was observed.

After the experiment had been stopped, the reaction mixture was diluted with water. The solid lower layer was subjected to steam distillation to remove the residual iodine; it was then dissolved in ether and treated with a solution of soda, in order to remove benzoic and iodobenzoic acids. After removal of the ether, the precipitate (crude m-iodobenzaldehyde) was twice precipitated from an alcoholic solution with water and dried in a vacuum desiccator to constant weight. The melting point was then determined and the phenylhydrazone was prepared. Yield 20%. Melting point 58°.

Conclusions

1. Meta-iodo derivatives of aromatic compounds with substituents of the second type were obtained by the reaction of direct iodination with iodine in the presence of a sulfuric–nitric nitrating mixture.

2. Using the bromination of benzoic acid and nitrobenzene as examples, the possibility was shown of preparing the m-bromo derivatives of the same substances by direct bromination in the presence of a sulfuric–nitric nitrating mixture.

3. A probable mechanism was proposed for the reaction of direct iodination and bromination of aromatic compounds with meta-directing substituents in the presence of a mixture of sulfuric and nitric acids.

Monovalent positive iodine and bromine cations, formed from elemental iodine and bromine under the action of a mixture of sulfuric and nitric acids, carry out iodination and bromination. The halogen cations act on molecules of the aromatic compound activated by the sulfuric–nitric mixture, as a result of which iodo- and bromo-substituted products are formed.

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