A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Page
GO
GO
?
^
Top
Org. Synth. 1966, 46, 48
DOI: 10.15227/orgsyn.046.0048
3-HYDROXYGLUTARONITRILE
[Glutaronitrile, 3-hydroxy-]
Submitted by F. Johnson and J. P. Panella1.
Checked by A. G. Anastassiou and B. C. McKusick.
1. Procedure
A mixture of 493 g. (2.00 moles) of magnesium sulfate heptahydrate and 700 ml. of tap water is stirred for 5 minutes and filtered into a 2-l. three-necked flask equipped with a mechanical stirrer and an alcohol thermometer that dips into the solution. The flask is immersed in a cooling bath (Note 1), the stirrer is started, and the solution is cooled to 10°. To the solution is added, in one portion, 143 g. (2.20 moles) of potassium cyanide (Caution! Toxic), and stirring is continued for 45 minutes at 8–12° (Note 2). The solution is maintained at this temperature while 102 g. (1.10 moles) of epichlorohydrin (Note 3) is added dropwise with stirring over a period of 1 hour (Note 4). The mixture is allowed to come to room temperature and is stirred for an additional 24 hours at this temperature.
The dark red-brown reaction mixture is stirred and extracted continuously with 1 l. of ethyl acetate for 48 hours (Note 5). The extract is dried over anhydrous magnesium sulfate for 18 hours (Note 6), filtered, and the filtrate is concentrated under reduced pressure on a steam bath. The residual dark-brown oil (about 90 g.) is distilled from a Claisen flask; the distillation must be rapid to minimize decomposition. About 20 g. of fore-run consisting of 4-chloro-3-hydroxybutyronitrile and 4-hydroxycrotononitrile is collected at 90–115° (0.4 mm.). 3-Hydroxyglutaronitrile is collected at 155–160° (0.4 mm.), yield 65–75 g. (54–62%), n23D 1.4634. This pale yellow distillate is sufficiently pure for most purposes. Further purification can be effected with only 3–5% loss by distillation of the material through a 15-cm. Vigreux column and collection of the portion boiling at 154–156° (0.2 mm.), n23D 1.4632 (Note 7).
2. Notes
1. The bath contained a mixture of trichloroethylene and solid carbon dioxide kept at −20°.
2. At this point the mixture has an opaque milky-white appearance caused by precipitation of a little magnesium hydroxide.
3. Epichlorohydrin (white label brand) supplied by Eastman Organic Chemicals was used without further purification.
4. The reaction is exothermic. If the temperature of the reaction mixture is allowed to rise above 30°, the reaction is likely to get out of control.
5. The checkers found that a stirred extractor2 was much more efficient than an unstirred one for this operation.
6. This extensive drying period is necessary to allow precipitation of traces of basic salts that have been carried over during the extraction procedure. Failure to remove these salts results in extensive decomposition of the product during the distillation step.
7. The submitters have obtained the same yield working on 10 times this scale.
3. Discussion
3-Hydroxyglutaronitrile has been prepared by the action of potassium cyanide on 1,3-dichloro-2-propanol3,4,5 or on 4-chloro-3-hydroxybutyronitrile.6,7 More recently it has been prepared from epichlorohydrin using essentially the present method.8
4. Discussion
This is a much more convenient and satisfactory synthesis of 3-hydroxyglutaronitrile than earlier ones.3,4,5,6,7 The method can be applied to other epichlorohydrins; 2-methylepichlorohydrin and 2-ethylepichlorohydrin have been converted to the corresponding hydroxydinitriles in 71% and 77% yields, respectively.8 The hydroxydinitriles undergo cyclizations to heterocyclic compounds not easily prepared in other ways. Thus hydrogen bromide at 0° converts 3-hydroxyglutaronitrile to 2-amino-6-bromopyridine in 70% yield.9
The reaction probably proceeds as follows:8

References and Notes
  1. The Dow Chemical Company, Eastern Research Laboratory, Wayland, Massachusetts.
  2. G. Billek, this volume p. 627
  3. M. Simpson, Ann., 133, 74 (1865).
  4. O. Morgenstern and E. Zerner, Monatsh., 31, 777 (1910).
  5. G. Braun, J. Am. Chem. Soc., 52, 3167 (1930).
  6. R. Lespieau, Bull. Soc. Chim. France, [4] 33, 725 (1923).
  7. R. Legrand, Bull. Soc. Chim. Belges, 53, 166 (1944).
  8. F. Johnson, J. P. Panella, and A. A. Carlson, J. Org. Chem., 27, 2241 (1962).
  9. F. Johnson, J. P. Panella, A. A. Carlson, and D. H. Hunneman, J. Org. Chem., 27, 2473 (1962).

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

2-methylepichlorohydrin

2-ethylepichlorohydrin

ethyl acetate (141-78-6)

Epichlorohydrin (106-89-8)

hydrogen bromide (10035-10-6)

potassium cyanide (151-50-8)

carbon dioxide (124-38-9)

magnesium hydroxide

1,3-dichloro-2-propanol (96-23-1)

magnesium sulfate (7487-88-9)

trichloroethylene (79-01-6)

3-Hydroxyglutaronitrile,
Glutaronitrile, 3-hydroxy- (13880-89-2)

magnesium sulfate heptahydrate (10034-99-8)

4-chloro-3-hydroxybutyronitrile

4-hydroxycrotononitrile

2-amino-6-bromopyridine