Org. Synth. 1926, 6, 92
DOI: 10.15227/orgsyn.006.0092
THYMOQUINONE
Submitted by Edward Kremers, Nellie Wakeman, and R. M. Hixon.
Checked by H. T. Clarke and C. R. Noller.
1. Procedure
(A) Nitrosothymol.—To a solution of 100 g. (0.66 mole) of thymol in 500 cc. of 95 per cent ethyl alcohol is added 500 cc. of concentrated hydrochloric acid. This mixture is cooled to 0° in a 2-l. beaker set in an ice-salt bath, and to it is added 72 g. (1 mole) of commercial sodium nitrite in portions of about 5 g. each.
The mixture is stirred well after each addition (Note 1). The solution first becomes brown in color, and a green precipitate soon begins to form. After 35 g. of nitrite has been added, the mixture becomes pasty; the intervals between the additions must now be lengthened and the stirring made more vigorous. When all has been added, the bulk of the product is transferred to a 12-l. flask containing 8 l. of cold water, and the remainder washed in with water. The product, after agitation with water, is now a light-yellow, fluffy solid; it is filtered off by suction and washed well with water (Note 2).
(B) Aminothymol.—The crude, wet nitrosothymol so obtained is worked up with a mixture of 900 cc. of 28 per cent aqueous ammonia (sp. gr. 0.90) and 1600 cc. of water; the brown solution is filtered free of a little resinous matter, and hydrogen sulfide is passed into it. The brown color disappears and a white precipitate of aminothymol forms. The passage of hydrogen sulfide is continued for thirty minutes longer (Note 3), when the base is filtered and washed well with cold water, contact with air being avoided as far as possible (Note 4).
(
C)
Thymoquinone.—The wet
aminothymol thus prepared is immediately dissolved in
110 cc. of concentrated sulfuric acid diluted to 4 l. and contained in a 12-l. flask. To this solution is added
150 g. (2.08 moles) of sodium nitrite, in 5–10 g. portions, with shaking after each addition. The resulting mixture is heated to 60° on a
steam bath, with occasional shaking, for one-half hour
(Note 5), and is then distilled in a current of steam, by means of the apparatus described on
p. 479 (Note 6). All the
thymoquinone passes over with the first 3 l. of distillate; it solidifies on cooling, and is filtered with suction
(Note 7), washed, and dried at room temperature. The yield is
80–87 g. (
73–80 per cent of the theoretical amount) of bright yellow crystals, melting at
43–45° (Note 8).
2. Notes
1.
No
nitrous acid escapes from the mixture, since it is converted into
ethyl nitrite which in turn reacts with the
thymol.
2.
The crude
nitrosothymol may be purified by drying and subsequent recrystallization from
2 l. of benzene, from which it separates as a pale yellow solid, melting at
160–164°. A small second crop is obtained on concentrating the mother liquor, which contains in addition an orange-colored resinous impurity. The yield is
103 g. (
87 per cent of the theoretical amount).
3.
If the base is filtered off without passing in the excess of
hydrogen sulfide, it immediately assumes a purple color on exposure to air.
4.
The free base tends to become oxidized in the air but may be preserved as the hydrochloride. This is prepared by transferring it as soon as possible to 1500 cc. of distilled water containing
100 cc. of concentrated hydrochloric acid. The sparingly soluble hydrochloride separates at once. It is recrystallized from the mixture with the use of a little
decolorizing carbon, whereupon it separates as colorless needles. A further crop is obtained on concentrating the mother liquor under reduced pressure to about 200 cc. The yield is
110 g. (
82.1) per cent of the theoretical amount).
5.
The greater part of the
oxides of nitrogen escapes during this treatment; the small amount that passes over with the
thymoquinone does not harm the product.
6.
If an ordinary condenser is employed for the steam distillation, care must be taken that the distilled product does not crystallize in the condenser tube and clog it.
7.
The watery filtrate contains about
0.5 g. of dissolved
thymoquinone; this can be recovered by distilling over 500 cc. of it and filtering the distillate.
8.
The melting point is not appreciably raised by recrystallization from
petroleum ether (b.p.
60–80°).
3. Discussion
Thymoquinone can be prepared directly from
thymol by sulfonating and oxidizing the sulfonation mixture with
manganese dioxide1 or
potassium dichromate;
2 the same process has been successfully employed with
carvacrol.
3 The oxidation of
salts of aminothymol with dichromate,
4 ferric chloride,
5 or
nascent bromine6 leads to satisfactory yields of
thymoquinone, as does prolonged refluxing of
nitrosothymol with dilute
hydrochloric acid.
7 The procedure described is based on the observation
8 that the
diazonium salt obtained from aminothymol is almost quantitatively converted into
thymoquinone on warming in the presence of excess
nitrous acid.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
oxides of nitrogen
petroleum ether
salts of aminothymol
nascent bromine
diazonium salt obtained from aminothymol
ethyl alcohol (64-17-5)
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
ammonia (7664-41-7)
Benzene (71-43-2)
hydrogen sulfide (7783-06-4)
sodium nitrite (7632-00-0)
nitrous acid (7782-77-6)
nitrite (14797-65-0)
decolorizing carbon (7782-42-5)
manganese dioxide (1313-13-9)
ferric chloride (7705-08-0)
ethyl nitrite (109-95-5)
potassium dichromate (7778-50-9)
Thymoquinone (490-91-5)
Nitrosothymol (2364-54-7)
thymol (89-83-8)
Aminothymol
carvacrol (499-75-2)
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