Submitted by Margaret K. Seikel
Checked by H. R. Snyder and A. B. Spradling.
1. Procedure
A.
3,5-Dichlorosulfanilamide. In a
2-l. round-bottomed flask, fitted with a
two-holed stopper carrying a
mechanical stirrer and a
thermometer, are placed
50 g. (0.29 mole) of sulfanilamide and 500 ml. of water. About
50 ml. of a 500-ml. portion (approximately 6 moles) of pure concentrated hydrochloric acid is added, and the mixture is stirred until a clear solution results (Note
1). The remainder of the
500 ml. of hydrochloric acid is then added. If the internal temperature does not rise to 45°, the stirred solution should be warmed gently with a free flame until this temperature is reached. At this point
65 g. (59 ml., 0.58 mole) of 30% hydrogen peroxide (sp. gr. 1.108) is added and rapid stirring is initiated (Note
2). The heat of reaction causes a progressively faster rise in temperature. After 5 minutes the solution fills with a white precipitate which increases rapidly in amount and becomes delicately colored. When the temperature has reached 60°, about 10 minutes after adding the peroxide (Note
3), any further rise is preferably prevented by judicious cooling (Note
4). The reaction is allowed to proceed for 15 minutes more at 60°, and then an
ice bath is raised about the flask while stirring is continued. When the temperature has fallen to 25–30°, the mixture is filtered at once. The yield of
3,5-dichlorosulfanilamide is
45–50 g. (
65–71%), and the crude dusky pink product melts over a range of 1–2° in the region 200–205° (Note
5).
C.
3,5-Dibromosulfanilamide. The bromination of
sulfanilamide is carried out in much the same way as the chlorination. The stirrer must be more efficient (Note
9); a glass stirrer with two sets of blades is satisfactory if run at high speed. Fifty grams
(0.29 mole) of sulfanilamide is dissolved in a mixture of 850 ml. of water (Note
9) and
100 ml. (0.68 mole) of 40% hydrobromic acid (Note
10). The solution is heated as above, but to 70–75°, and
65 g. (59 ml., 0.58 mole) of 30% hydrogen peroxide is added (Note
2) and (Note
11). A precipitate settles in 2–3 minutes, and the solution becomes yellow. The heat of reaction causes the internal temperature to rise without further application of heat to a maximum of 85–90° after 10 minutes; by the end of the reaction time the temperature will have fallen to about 70° (Note
12). After a total reaction time of 30 minutes (Note
13), during which the mixture has become almost solid and is very difficult to stir, the material is filtered hot (Note
14). The yield of
3,5-dibromosulfanilamide is
85–90 g. (
90–94%), and the crude tan product (Note
15) melts over a range of 1–2° in the region 230–237° (Note
16).
2. Notes
1. Solution of
sulfanilamide is more readily obtained in this way than by treating the amide at once with 6
N acid for, in the latter case, the salt precipitates at first and redissolves only slowly. If acid stronger than 6
N is used, a larger volume is required to dissolve the
sulfanilamide hydrochloride, and the product is partly held in solution as
dichlorosulfanilamide hydrochloride unless the solution is diluted. If 4
N acid is used, the reaction is much slower without any worthwhile decrease in the color of the product.
2. Equivalent quantities of
sulfanilamide and
hydrogen peroxide are used in order to minimize the cost since no better yields are obtained with either in excess. If
sulfanilamide is in excess, the product is tinged more orange-tan than pink and never becomes red from subsequent oxidation. If
hydrogen peroxide is in excess, the reaction is faster but rapid oxidation giving dark-colored materials occurs toward the end.
3. When smaller amounts of reactants are employed, it is necessary to apply heat to reach and maintain a temperature of 60°.
4. Without cooling, the temperature rises above 70° and the precipitate becomes deep rose from oxidation by-products. The color, however, does not seem to affect the yield or purity of the
dichloroaniline to any great extent.
5. The color of the product varies; higher temperatures, larger excesses of peroxide, longer reaction times, higher acidity, and higher concentrations of the reactants lead to the formation of more deeply colored materials. The color may be removed by several recrystallizations from glacial
acetic acid with
decolorizing carbon. As a preparative method for
dichlorosulfanilamide, when a pure product is desired, the following procedure is recommended. For each
10 g. (0.058 mole) of sulfanilamide, 200 ml. of water,
200 ml. of concentrated hydrochloric acid, and
24 ml. (0.23 mole or 2 equivalents) of 30% hydrogen peroxide are used and the reaction is run at 25° for not more than 2 hours. A practically white product is obtained in
45–60% yield. It may be recrystallized from a very large volume of water, from
95% ethanol, or from
glacial acetic acid; the recrystallized product melts at
205–205.5°.
6. Desulfonamidation is brought about faster by
75% sulfuric acid, but the yield is lower. The reaction is inconveniently slow with
65% sulfuric acid.
7. This bend prevents the mechanical carry-over of dark materials from the spray rising from the boiling dark solution. A distilling flask is not employed because dark oil creeps out the side arm.
8. It is difficult to measure the yield accurately; the material must be air-dried on account of its low melting point; the substance volatilizes to a significant extent on standing.
9. The larger amount of product obtained requires a more dilute initial solution coupled with violent stirring to maintain sufficient agitation.
10. Speedier reactions can be run at lower temperatures, producing lighter-colored crude materials if the amount of
hydrobromic acid is doubled (30 minutes at 45°) or quadrupled (20 minutes at 25°); the use of the minimum quantity recommended above (approximately 1.15 times the required amount) produces as high yields of as high-melting materials with an attendant reduction in cost.
11. The use of excess peroxide in the bromination also causes the formation of
tribromoaniline.
1,2,3,4 If only
0.29 mole of hydrogen peroxide is used, the monobromo derivative is obtained.
12. When small runs are made, it is necessary to use a bath to attain and maintain an internal temperature of 80–85° during the reaction time of 30 minutes.
13. The reaction is considered complete when a sudden increase in or appearance of the brownish yellow color of free
bromine is noted. This may or may not be evident under the above conditions, for the solution is deeply colored because of the high temperature and a very slight excess of
hydrobromic acid is used; it is clearly evident whenever the excess is greater or the temperature lower.
14. Hot filtration removes traces of the monobromo compound, which is soluble in water and acids.
15. When the reaction is run at lower temperature with excess
hydrobromic acid, the crude product is lighter colored. However, it melts no higher and is purified with no greater ease and with only slightly better recovery.
16. The purification of the crude material is effected by recrystallization from glacial
acetic acid or, preferably,
95% ethanol (25 ml./g.), using
decolorizing carbon; colorless needles, which melt at 239–240°, are obtained after two recrystallizations.
17. The crude material to be used for desulfonamidation should be tested for absence of
sym-tribromoaniline by ascertaining its solubility in 1
N alkali. A clear, though colored, solution should result. If the solution is cloudy, purification of the impure material by dissolving it in alkali, filtering the solution, and reprecipitating the amide is essential.
18. Fifty-gram lots seem to be the maximum size if consistently high-melting pure material is to be obtained under the conditions employed. If a very pure product is desired, less starting material should be used.
19. The use of a current of steam in the desulfonamidation of the dibromo compound as recommended by earlier investigators
1,3,5 was found to be absolutely necessary in this instance. Without the steam, considerable amounts of
sym-tribromoaniline are formed;
6 superheated steam is not necessary. The purity of the crude product varies directly with the ratio of the amount of steam to the size of the reaction mixture; the current of steam should be very rapid or the amount of material in a single operation should be small.
20. One and a half liters of distillate was collected in the time given.
21. If the crude product melts lower, it contains too much
tribromoaniline to permit satisfactory purification. Recrystallization effects no separation; repeated fractional steam distillation is very slowly effective.
3. Discussion
2,6-Dichloroaniline was prepared by Beilstein
7 and by Körner
8 by reduction of
2,6-dichloronitrobenzene. A better method, more recently reported,
9 involves the chlorination of
sulfanilic acid in
1% solution with free chlorine, subsequent evaporation of the solution, and desulfonation as above. The present method (reported earlier in slightly different form and for small amounts
10), although requiring more expensive raw materials, is more convenient and gives higher yields.
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