Organic Syntheses, Coll. Vol. 3, p.523 (1955); Vol. 21, p.74 (1941).
A. α-Bromoisocaproic acid. Five hundred grams (4.3 moles) of commercial isocaproic acid
is mixed with 250 ml. of benzene
in a 2-l. round-bottomed flask
, and the water and benzene
are removed by distillation through a short column
until the temperature of the vapors reaches 100°. The temperature rises rapidly as soon as the last of the benzene
is removed. The residual acid is cooled to room temperature, 743 g. (4.65 moles, 243 ml.) of dry bromine (Note 1)
is added, and the flask is fitted with a long condenser
and placed in an oil bath
. The top of the condenser is connected to an empty 500-ml. Erlenmeyer flask
which acts as a safety flask, and this in turn leads to a gas-absorption trap (Note 2)
. Ten milliliters of phosphorus trichloride
is added to the mixture through the top of the condenser, and the flask is heated to 80–85°. The bromination proceeds smoothly at this temperature and is allowed to continue for 8–15 hours until the dark red color of bromine
disappears from the condenser. When it has, the temperature is raised to 100–105° and kept there 2 hours. The contents of the flask are transferred to a 1-l. modified Claisen flask
or a flask attached to a Widmer column
and distilled. The fraction boiling at 125–131°/12 mm.
is collected. The yield amounts to 530–550 g
). The low-boiling fraction is mainly isocaproic acid (Note 3)
. To 1.5 l. of technical ammonium hydroxide
(sp. gr. 0.90) in a 3-l. round-bottomed flask
is added 300 g. (1.56 moles) of α-bromoisocaproic acid
. A rubber stopper
is wired in, and the flask is allowed to stand for a week at room temperature. The crude leucine
from four such flasks is collected on a filter and washed with 400 ml. of ethanol
. This crop amounts to about 300 g.
is removed from the filtrate by heating the solution in a 12-l. flask
on a steam cone overnight. The solution is concentrated under reduced pressure until vigorous bumping occurs (about 2.5 l.). The mixture is then cooled to about 15° and filtered. The precipitate is washed with 250 ml. of cold water and 250 ml. of 95% ethanol
. The total yield of crude leucine
in the two fractions is 440–460 g.
The amino acid is recrystallized by dissolving all the crude material in 12.5 l. of water heated to 95° on a steam cone. The hot solution is treated with 20 g. of Norit
for 30 minutes and filtered hot. An equal volume of 95% ethanol
is added immediately, and the flask is placed in the ice chest
overnight. The crystalline material is collected on a filter and washed with 200 ml. of 95% ethanol
. The yield of pure leucine
in this fraction is 290–300 g.
An additional crop is obtained by evaporating the mother liquors under reduced pressure until considerable solid separates (liquid volume about 1 l.), adding an equal volume of ethanol
, and cooling. This crop is washed with 100 ml. of cold water and then with 200 ml. of ethanol
; it amounts to 60–65 g.
The total yield of pure leucine
is 350–365 g.
). It decomposes at 290–292°
(uncor.) in a sealed capillary (Note 4)
The low-boiling fractions (105–115 g.
) may be combined with the next portion of acid to be brominated, or several such fractions may be collected and brominated together. If this last is done only two-thirds as much bromine
is used as in the original run.
The amino nitrogen content of leucine
prepared in this way checks with the theoretical value.
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