Checked by Arthur C. Cope, William F. Gorham, and Roscoe A. Pike.
1. Procedure
In a
1-l. three-necked round-bottomed flask equipped with a
Hershberg stirrer, a
thermometer, and a
250-ml. dropping funnel are placed
80 g. (0.67 mole) of acetophenone,
60 ml. of ether, and 100 ml. of water. The apparatus is assembled in a
well-ventilated hood, the flask is surrounded by an
ice-salt bath, and
82 g. (1.67 moles) of granulated sodium cyanide is added all at once with vigorous stirring. When most of the
sodium cyanide has dissolved and the temperature of the mixture has fallen to 5°,
140 ml. (1.7 moles) of concentrated hydrochloric acid is added from the dropping funnel at such a rate that the temperature remains between 5° and 10°. The addition requires about 1.7 hours. After all the acid has been added, the cooling bath is removed and vigorous stirring is continued for 2 hours. The mixture is allowed to settle, and the liquid portion is decanted into a
1-l. separatory funnel. The water layer is returned to the reaction flask, and 100 ml. of water is added to dissolve the salts. The aqueous solution is extracted with four
50-ml. portions of ether, and the original
ether layer and extracts are combined in a
500-ml. round-bottomed flask. The
ether is distilled at 20–30 mm. pressure (water aspirator) (Note
1), and the residual oil is poured slowly with stirring into
160 ml. of concentrated hydrochloric acid in a 1-l. round-bottomed flask. The mixture then is saturated with
hydrogen chloride gas in the hood (Note
2) and (Note
3) and allowed to stand overnight.
Part of the excess
hydrogen chloride is removed by blowing (or drawing) air through the solution for 1 hour. The solution then is made alkaline by the slow addition of
50% aqueous sodium hydroxide. (Note
4) with mechanical stirring and cooling in an ice bath. Solid
sodium hydroxide (24 g.) is added, and the mixture is steam-distilled until no more
ammonia and
acetophenone pass into the distillate (Note
5). About 3–4 l. of distillate is collected (Note
6).
Water is added to the residue if necessary to make the volume 700 ml., and the solution is treated with
2 g. of Norit and filtered with suction (Note
7). The filtrate is extracted with
100 ml. of ether (which is discarded), and acidified by the addition of
80 ml. of concentrated hydrochloric acid. After thorough chilling, preferably overnight in a
refrigerator, the precipitated
atrolactic acid is collected on a
suction filter (Note
8) and air-dried at a temperature not exceeding 65°.
The crude product weighs somewhat more than 70 g. and contains water and
sodium chloride. It is dissolved in
500 ml. of boiling benzene, the solution is filtered by gravity, and the solid in the flask and funnel is rinsed with
50 ml. of boiling benzene. The filtrate is concentrated by distillation until no more water collects in the distillate, and the residual solution (300–400 ml.) is cooled. The
atrolactic acid which crystallizes is collected on a suction filter and washed with
25 ml. of cold benzene and
25 ml. of commercial pentane (b.p.
30–40°). After air-drying, the cream-colored product amounts to
42.9–43.5 g., m.p.
88–90° with shrinking at 82° (Note
9) and (Note
10). It is pure enough for most purposes but is intermediate in composition between the anhydrous acid and hemihydrate and contains about
3% sodium chloride. This product is dissolved in 200 ml. of boiling water and treated with
10 g. of Norit. The solution is filtered and cooled overnight at 0–5°. The pure, colorless crystals of
atrolactic acid hemihydrate that separate are collected on a suction filter and air-dried. The yield is
33.5–34.7 g. (
29–30%), m.p.
88–90° with softening beginning at 75°. The anhydrous acid can be obtained by drying the hemihydrate at 55°/1–2 mm.; m.p.
94.5–95°.
2. Notes
1. By maintaining ebullition with a capillary air inlet and cooling the
receiver in a
bath containing Dry Ice and trichloroethylene, the distillation can be completed in 1 hour or less.
2. The solution becomes homogeneous when it is nearly saturated. An exothermic reaction begins within a few minutes, and some
hydrogen chloride gas escapes.
3. The preparation should be carried to this point in 1 day; the time required is about 8 hours. All the operations must be conducted in a well-ventilated hood.
5. The distillation flask should be heated so as to maintain a liquid volume of 600–700 ml.
6.
Acetophenone (15–16.5 g., b.p. 92–94°/20 mm.) can be recovered by extracting the distillate with
100 ml. of pentane (b.p.
30–40°). The extract is dried over
sodium sulfate, concentrated, and distilled.
7. Only a small amount of solid, in addition to the
Norit, should be retained by the filter. If a copious precipitate of
sodium atrolactate forms, it should be dissolved by the addition of more water.
9. If the yield is low, the mother liquors should be concentrated to a volume of 50 ml. A second crop of crystals can sometimes be obtained in that way.
10. The submitters have obtained the same yields in preparations on five times this scale.
3. Discussion
The synthesis of
atrolactic acid through
acetophenone cyanohydrin was first described by Spiegel
12 and has since been used by several other investigators.
6,13,14,15,16,17 The above preparation is adapted from the methods of McKenzie and Clough
15 and Freudenberg, Todd, and Seidler.
17
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