Checked by E. J. Corey and Barbara Kaski.
1. Procedure
In a
3-l. three-necked flask, equipped with a
mercury-sealed Hershberg stirrer, a
dropping funnel, and a
reflux condenser protected with a
calcium chloride tube, is placed
67 g. (0.5 mole) of powdered anhydrous aluminum chloride. The flask is cooled in an
ice bath,
500 ml. of dry ether is slowly added from the dropping funnel, and the mixture is stirred for a few minutes. Meanwhile
5.5 g. of powdered lithium aluminum hydride (Note
1) is placed in a
1-l. flask fitted with a condenser, and
140 ml. of dry ether is added slowly from the top of the condenser with caution while the flask is kept cooled in ice. The mixture is gently refluxed for 30 minutes to effect, as far as possible, solution of the hydride. It is then cooled, and the resulting slurry (which consists of a suspension of
lithium aluminum hydride in its solution) is transferred to the dropping funnel of the previous setup and is added to the ethereal solution of
aluminum chloride with stirring within 10 minutes. After the addition is complete, the reaction mixture is stirred for an additional 30 minutes without cooling to complete the formation of the "mixed hydride."
A solution of
77.2 g. (0.5 mole) of 4-t-butylcyclohexanone (Note
2) in
500 ml. of dry ether is then placed in the dropping funnel and slowly added to the "mixed hydride" solution without much cooling so that gentle refluxing is maintained (Note
3) After addition of the ketone over a period of 45–60 minutes the reaction mixture is refluxed for 2 hours more to complete the reduction. The excess hydride is destroyed by the addition of
10 ml. of dry t-butanol, and the mixture is refluxed for an additional 30 minutes.
4-t-Butylcyclohexanone (3 g.) in
20 ml. of dry ether is then added to the reaction mixture, which is refluxed for 4 hours more and allowed to stand overnight (Note
4), (Note
5). The reaction mixture is cooled in an ice bath and decomposed by successive additions of 100 ml. of water and
250 ml. of 10% aqueous sulfuric acid. The ethereal layer is separated and the aqueous layer extracted once with
150 ml. of ether. The combined
ether extracts are washed once with water and dried over anhydrous
magnesium sulfate. The extract is filtered from
magnesium sulfate and the
ether removed by distillation on a
steam bath. The residue, weighing
85–87 g., solidifies in the flask and on gas chromatographic analysis (see (Note
5)) is found to contain 96%
trans alcohol, 0.8%
cis alcohol, and 3.2% ketone.
The crude white product is dissolved in
150 ml. of hot petroleum ether (b.p.
60–70°). On cooling, it forms a solid cake which is transferred to a
Buchner funnel and rinsed with small portions of cooled
petroleum ether. The yield of product, m.p.
75–78° (Note
6), is
57–61 g. (
73–78%). It has an approximate composition of 99.3%
trans alcohol, 0.3%
cis alcohol, and 0.4% ketone. A further crop of
12 g. is obtained by concentration of the mother liquor. It contains less than 1% of the
cis alcohol and the ketone and is sufficiently pure for most preparative purposes (Note
7).
2. Notes
1. The
lithium aluminum hydride was obtained from Metal Hydrides Incorporated and was more than 95% pure. For calculation of the quantity of hydride required it was assumed that the purity was 95%.
3. The continuance of gentle refluxing as the last portion of the ketone is added assures that there is an excess of "mixed hydride" present.
4. It is not necessary to allow the reaction mixture to stand overnight, and it may be decomposed at this stage without any loss in purity.
5. At this stage the attainment of equilibrium can be checked by removing a 5-ml. aliquot from the reaction product and working it up in the same way as described in the preparation. The product is then analyzed by gas-liquid chromatography using a 20% Carbowax 20M on
firebrick column at 150°. The features to note in the chromatogram are almost complete absence (less than 1%) of the
cis isomer (second peak, disregarding initial solvent and
t-butanol peaks) and the presence of some
4-t-butylcyclohexanone (first peak). The
trans isomer constitutes the third peak with longest retention time.
6. The melting point of a highly purified sample
2 of
trans alcohol is
82.5–83°.
7. Since the alcohol has a relatively high solubility in
petroleum ether, the yield from the crystallization depends on the volume of solvent used. However, by concentrating the mother liquor the overall yield from the first and second crops of crystals varies from
74% to 94%.
3. Discussion
4. Merits of the Preparation
The procedure employs a readily available starting material and produces the pure
trans isomer in high yield. The method described is an improvement on that used by Eliel and Rerick
2 in that it is not necessary to use a clear solution of
lithium aluminum hydride in ether for the preparation of the "mixed hydride." It is not necessary to know the precise amount of
lithium aluminum hydride used so long as a slight excess is present. The excess hydride is destroyed by adding
t-butanol; the excess
t-butanol has no effect on the subsequent equilibration and purification. The equilibration of the
4-t-butylcyclohexanol is effected by adding a small amount of
4-t-butylcyclohexanone.
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