Organic Syntheses, CV 5, 1070
Submitted by C. Ainsworth
1
Checked by B. C. McKusick and B. C. Anderson.
1. Procedure
(Note 1)
A.
1-Formyl-3-thiosemicarbazide.
Four hundred milliliters of 90% formic acid contained in a
2-l. round-bottomed flask is heated on a steam bath for 15 minutes, and then
182 g. (2 moles) of colorless thiosemicarbazide (Note
2) is added. The mixture is swirled until the
thiosemicarbazide dissolves. The heating is continued for 30 minutes, during which time crystalline
1-formyl-3-thiosemicarbazide usually separates. Boiling water (600 ml.) is added, and the milky solution that results is filtered through a fluted filter paper. After standing for 1 hour, the filtrate is cooled in an
ice bath for 2 hours, and the
1-formyl-3-thiosemicarbazide that separates is collected by suction filtration and air-dried overnight. It weighs
170–192 g. (
71–81%) and melts at
177–178° with decomposition.
B.
1,2,4-Triazole-3(5)-thiol. A solution of
178.5 g. (1.5 moles) of 1-formyl-3-thiosemicarbazide and
60 g. (1.5 moles) of sodium hydroxide in 300 ml. of water in a
2-l. round-bottomed flask is heated on a steam bath for 1 hour. The solution is cooled for 30 minutes in an ice bath and then is treated with
150 ml. of concentrated hydrochloric acid. The reaction mixture is cooled in an ice bath for 2 hours, and the
1,2,4-triazole-3(5)-thiol that precipitates is collected by suction filtration. The thiol is dissolved in 300 ml. of boiling water and the solution is filtered through a fluted filter paper. The filtrate is cooled in an ice bath for 1 hour, and the thiol is collected by suction filtration and air-dried overnight. The
1,2,4-triazole-3(5)-thiol weighs
108–123 g. (
72–81%) and melts at
220–222°.
C.
1,2,4-Triazole.
Caution! This preparation should be carried out in a ventilated hood to avoid exposure to noxious fumes.
A mixture of 300 ml. of water,
150 ml. of concentrated nitric acid, and
0.2 g. of sodium nitrite (Note
3) is placed in a
2-l. three-necked flask equipped with a stirrer and a thermometer. The stirred mixture is warmed to 45°, and
2 g. of 1,2,4-triazole-3(5)-thiol is added. When oxidation starts, as indicated by the evolution of brown fumes of
nitrogen dioxide and a rise in temperature, a bath of cold water is placed under the reaction flask to provide cooling and an additional
99 g. (total, 101 g.; 1 mole) of
1,2,4-triazole-3(5)-thiol is added in small portions over the course of 30–60 minutes. The rate of addition and the extent of cooling by the
water bath are so regulated as to keep the temperature close to 45–47° all during the addition. The water bath is kept cold by the occasional addition of ice.
When the addition is completed, the bath is removed and stirring is continued for 1 hour while the reaction mixture gradually cools to room temperature.
Sodium carbonate (100 g.) is added in portions, followed by the cautious addition of
60 g. of sodium bicarbonate (Note
4). The water is removed from the slightly basic solution by heating the solution in a
3-l. round-bottomed flask under reduced pressure on a steam bath. To aid in removing the last traces of water,
250 ml. of ethanol is added to the residue and the mixture is heated under reduced pressure on a steam bath until it appears dry (Note
5).
The residue is extracted twice with
600 ml. of boiling ethanol to separate the triazole from a large amount of inorganic salts. This extract is evaporated to dryness on a steam bath under reduced pressure, and the resulting residue is extracted with two
500-ml. portions of boiling ethyl acetate. The
ethyl acetate extract is evaporated to dryness on a steam bath under reduced pressure. The crude
1,2,4-triazole remaining in the flask is dissolved by heating it with
50 ml. of absolute ethanol, and then
1 l. of benzene is added. The mixture is heated under reflux for 15 minutes, and the hot solution is filtered through a fluted filter paper. This extraction procedure is repeated. The two extracts are combined, cooled in an ice bath for 30 minutes, and filtered to remove colorless crystals of
1,2,4-triazole (m.p.
120–121°), weighing
28–30 g. after being dried in air. About 300 ml. of the filtrate is removed by slow distillation through a Claisen still-head to remove the bulk of the
ethanol. The residual solution is cooled in an ice bath for 30 minutes and filtered to separate an additional
8–10 g. of colorless
1,2,4-triazole, m.p.
119–120°. The total weight of
1,2,4-triazole is
36–40 g. (
52–58% yield).
2. Notes
1. This procedure is no longer regarded as the best available for the preparation of
1,2,4-triazole. See Discussion section.
4. A large flask is used to contain the vigorous effervescence that occurs upon the addition of carbonate. The final pH should be near 7.5, and it is reached after the addition of bicarbonate no longer causes bubbling.
5. Prolonged heating under reduced pressure should be avoided, since
1,2,4-triazole tends to sublime.
3. Discussion
1,2,4-Triazole has been prepared by the oxidation of substituted 1,2,4-triazoles,
5 by the treatment of
urazole with
phosphorus pentasulfide,
6 by heating equimolar quantities of
formylhydrazine and
formamide,
7 by removal of the amino function of
4-amino-1,2,4-triazole,
8 by oxidation of
1,2,4-triazole-3(5)-thiol with
hydrogen peroxide,
3 by decarboxylation of
1,2,4-triazole-3(5)-carboxylic acid,
9 by heating hydrazine salts with
formamide,
10 by rapidly distilling
hydrazine hydrate mixed with two molar equivalents of
formamide,
11 by heating
N,N'-diformylhydrazine with excess
ammonia in an autoclave at 200° for 24 hours,
11 by the reaction of
1,3,5-triazine and
hydrazine monohydrochloride,
12 and by the deamination of
3-amino-1,2,4-triazole with
hypophosphorous acid.
13 In view of the availability of
3-amino-1,2,4-triazole in several grades and from several commercial sources, the last-cited procedure, that of Henry and Finnegan,
13 is considered to be preferable to that described here for the preparation of
1,2,4-triazole itself.
14 The Henry and Finnegan procedure has been found to be useful for the deamination of a wide variety of heteroaromatic amines.
15
Modifications of the present procedure for the preparation of
1,2,4-triazole have been used to prepared 3-aryl-1,2,4-triazoles
16 and 3-alkyl-1,2,4-triazoles.
17
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
hypophosphorous acid
1,2,4-Triazole-3(5)-thiol
1,2,4-triazole-3(5)-carboxylic acid
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
ammonia (7664-41-7)
Benzene (71-43-2)
ethyl acetate (141-78-6)
formamide (75-12-7)
sodium hydroxide (1310-73-2)
sodium bicarbonate (144-55-8)
nitric acid (7697-37-2)
sodium carbonate (497-19-8)
formic acid (64-18-6)
sodium nitrite (7632-00-0)
hydrogen peroxide (7722-84-1)
nitrogen dioxide (10102-44-0)
hydrazine hydrate (7803-57-8)
phosphorus pentasulfide
3-amino-1,2,4-triazole (61-82-5)
4-Amino-1,2,4-triazole (584-13-4)
formylhydrazine (624-84-0)
1,2,4-Triazole,
1H-1,2,4-Triazole (288-88-0)
thiosemicarbazide (79-19-6)
1-Formyl-3-thiosemicarbazide (2302-84-3)
1,3,5-triazine (290-87-9)
urazole (3232-84-6)
hydrazine monohydrochloride (2644-70-4)
N,N'-diformylhydrazine
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