Organic Syntheses, CV 4, 221
[I. NITROUS ACID METHOD]
Submitted by Hyp J. Dauben, Jr., Howard J. Ringold, Robert H. Wade, David L. Pearson, and Arthur G. Anderson, Jr.
1.
Checked by Arthur C. Cope, Warren N. Baxter, and Robert J. Cotter.
1. Procedure
A solution of
sodium ethoxide is prepared by adding 57.5 g. (2.5 g. atoms) of clean sodium to 1.2 l. of absolute ethanol (Note
2) in a
3-l. three-necked flask equipped with an Allihn reflux condenser fitted with a drying tube, a large sturdy sealed Hershberg stirrer, and a dropping funnel. After the
sodium has dissolved, the solution is cooled to 40° and the condenser is replaced by a
thermometer extending into the liquid. A mixture of
245.5 g. (258.5 ml., 2.5 moles) of redistilled cyclohexanone and
198 g. (175 ml., 3.25 moles) of redistilled nitromethane (Note
3) is added dropwise with vigorous stirring over the course of about 3 hours at a rate that maintains an internal temperature of 45 ± 3° (Note
4). After addition is complete, the white, pasty mass is stirred for an additional 3 hours without cooling or heating and then is allowed to stand overnight. The resulting suspension is cooled with an
ice bath, and the white
sodium salt of 1-(nitromethyl)cyclohexanol is collected on a
25-cm. Büchner funnel and dried by suction for about 1 hour (Note
1). The sodium salt cake is broken up and transferred to a
4-l. beaker equipped with a Hershberg stirrer and immersed in an ice bath. A cold solution of
184 g. (175 ml., 3 moles) of glacial acetic acid in 1250 ml. of water is added in a single portion, and the mixture is stirred for 10–30 minutes to complete dissolution. The oily layer of
1-(nitromethyl)cyclohexanol is separated, and the aqueous layer is extracted with three
100-ml. portions of ether. The
ether extracts and the
1-(nitromethyl)cyclohexanol are combined, dried briefly over
magnesium sulfate, and concentrated by distillation from a
steam bath with a
water aspirator at 20–35 mm. to remove
ether and excess
nitromethane. The crude, undistilled
1-(nitromethyl)cyclohexanol (Note
5) is dissolved in
450 ml. of glacial acetic acid in a 2-l. externally cooled
stainless-steel hydrogenation bottle (Note
6). Three heaping teaspoonfuls of
W-4 Raney nickel catalyst2 are added, and the mixture is shaken with
hydrogen at 40–45 p.s.i., with cooling to maintain the temperature below 35°, until about
90% of the theoretical amount (
7.5 moles) is taken up and absorption ceases (Note
7). The catalyst is separated by filtration with suction through Filter-Cel, and the filtrate (sometimes green or tan) containing the
1-(aminomethyl)cyclohexanol is used directly in the next step (Note
8).
The filtrate is transferred to a
5-l. round-bottomed flask, immersed in an ice-salt mixture and equipped with a Hershberg stirrer, a thermometer, and a dropping funnel. The solution is diluted with 2.3 l. of ice water; then an ice-cold solution of
290 g. (4.2 moles) of sodium nitrite in 750 ml. of water is added dropwise during a period of about 1 hour with stirring and cooling (
ice-salt bath) to maintain the temperature at −5°. The mixture is stirred for an additional period of 1 hour and then allowed to come to room temperature overnight as the ice in the cooling bath melts. The
acetic acid in the reaction mixture is neutralized by the addition of small portions of
solid sodium bicarbonate, and the neutral (to litmus paper) solution is then steam-distilled until about 2 l. of distillate is collected. The oily
cycloheptanone layer is separated, the aqueous layer is extracted with three
100-ml. portions of ether, and the combined organic layers are dried briefly over
magnesium sulfate. Most of the
ether is removed by distillation through a
17 by 2.5 cm. glass helix-packed column at atmospheric pressure (Note
9). The residue is then distilled through the same column, and the fraction boiling at
80–85°/30 mm. is collected. The yield of
cycloheptanone is
112–118 g. (
40–42%),
n25D 1.4600 (Note
10) and (Note
11).
2. Notes
1. It has been reported
3 that when the crude product from the condensation of
2 moles of nitromethane (as the sodium salt in absolute
ethanol) with
1 mole of 1,1,3,3-tetramethylcyclobutane-2,4-dione (dimethylketene dimer) was filtered, and the filter cake was dried on a porous clay plate, a violent explosion occurred upon addition of the dried powder to crushed ice.
This experience suggests that it may be inadvisable to dry completely the
sodium salt of 1-(nitromethyl)cyclohexanol, and that the material should be handled with considerable caution. Also, in other procedures where salts of nitro compounds are involved, and the extent of the reaction and the nature of the products are not known with certainty, the salts probably should not be filtered, but should be neutralized in the reaction mixtures and the free nitro alcohols separated by suitable means.
2. Commercial absolute
ethanol is used without additional drying. The submitters state that the use of absolute
ethanol may be avoided by employment of the alternative condensation procedure of Wood and Cadorin
4 using
5 mole per cent of sodium hydroxide in aqueous methanol at 15–20° for 6 hours, but the yield of
1-(nitromethyl)cyclohexanol is appreciably lower (
51%).
3.
Cyclohexanone is dried over
magnesium sulfate or
calcium sulfate (Drierite) for 1 day and distilled; the fraction boiling at
152.5–154° (uncor.) is used.
Nitromethane is dried in the same manner and distilled; small quantities of acidic impurities are removed in the fore-run, and the fraction boiling at
101.5–102.5° (uncor.) is used. Drying is frequently unnecessary when
good grades of cyclohexanone and nitromethane are used.
4. Efficient stirring of the pasty reaction mixture is necessary to obtain maximum yield.
5. Removal of residual amounts of
acetic acid in the crude product is unnecessary; their presence is actually preferable to the presence of traces of bases, such as any
sodium bicarbonate remaining from neutralization, which reverse the condensation on attempted distillation of
1-(nitromethyl)cyclohexanol.
4 The submitters state that, in preparations conducted on twice the scale specified, fractional distillation of the residue yielded
620–670 g. (
78–84%) of
1-(nitromethyl)cyclohexanol, b.p.
129–132°/19 mm.,
n25D 1.4835.
6. A
Pyrex bottle can be used; it must be enclosed to prevent possible injury by fragments of glass in case of explosion.
7. Catalytic hydrogenation of
1-(nitromethyl)cyclohexanol in
acetic acid solvent is a markedly exothermic reaction, and, unless the temperature is moderated to about 35°, low yields of
1-(aminomethyl)cyclohexanol result owing to hydrogenolysis and deactivation of the catalyst. Cooling can be accomplished by running cold water through a copper coil surrounding the hydrogenation bottle or by periodically adding ice to the container in which the bottle is placed. Considerable cooling is necessary during initial stages of the hydrogenation, but cooling below 25° greatly retards the reduction. Absorption of
hydrogen is usually complete in 15–18 hours under these conditions, but longer times may be required, depending on the temperature and pressure and on the amount and activity of the catalyst.
8.
1-(Aminomethyl)cyclohexanol can be isolated as its acetic acid salt by the addition of
2 volumes of ether to the
acetic acid solution or to the residue after removal of the
acetic acid under reduced pressure, followed by trituration and refrigeration overnight. After filtration of the first crop of crystals, m.p.
118–121°, a second crop of the salt, m.p.
113–116°, is obtained on removal of the dissolved
nickel from an aqueous solution of the concentrated filtrate by saturation with
hydrogen sulfide, concentration, and treatment with
ether. Total yields of the air-dried crude
acetic acid salt of 1-(aminomethyl)cyclohexanol obtained from
100–350 g. lots of 1-(nitromethyl)cyclohexanol in this manner ranged from
69% to 94%.
9. Distillation of the product from a
modified Claisen flask and collection of the fraction boiling at
67–77°/20 mm. (largely 69–72°) gave
140–149 g. of impure
cycloheptanone,
n25D 1.4570–1.4590, containing about equal amounts
(10–15 g.) of lower-boiling and higher-boiling (mainly 1-(nitromethyl)cyclohexanol) contaminants, which were separated by distillation through the
glass helix-packed column.
10. The submitters state that the yields of
cycloheptanone obtained from
60- to 700-g. quantities of the crude
acetic acid salt of 1-(aminomethyl)cyclohexanol (isolated by the procedure of ((Note
8)) were
57–65%.
[II. DIAZOMETHANE METHOD]
Submitted by Th. J. de Boer and H. J. Backer
10.
Checked by James Cason, John B. Rogan, and Wm. G. Dauben.
1. Procedure
Caution!
Diazomethane is very toxic; therefore the operations must be carried out in a
well-ventilated hood. (See
p. 250.)
In a
500-ml. round-bottomed flask, provided with a mechanical stirrer (Note
1), a
thermometer, and a
dropping funnel, are placed
49 g. (0.5 mole) of cyclohexanone (Note
2),
125 g. (0.58 mole) of p-tolylsulfonylmethylnitrosamide (p. 943),
150 ml. of 95% ethanol, and 10 ml. of water (Note
3). The nitroso compound is largely undissolved. The stirrer is adjusted so that only the upper portion of solution is stirred and the precipitate moves slightly. The
thermometer bulb is placed in the liquid.
The reaction mixture is cooled to about 0° with an ice-salt bath; then with gentle stirring a solution of
15 g. of potassium hydroxide in
50 ml. of 50% aqueous ethanol is added dropwise very slowly from the dropping funnel. After the addition of 0.5–1 ml. of the alkaline solution a brisk evolution of
nitrogen commences and the temperature rises. The rate of addition is adjusted so that the temperature is maintained at 10–20° (Note
4). The addition of the alkali requires about 2 hours, during which the nitroso compound gradually disappears. The orange-yellow solution is stirred for an additional 30 minutes, then
2N hydrochloric acid (about 50 ml.) is added until the solution is acidic to litmus paper.
A solution of
100 g. of sodium bisulfite (Note
5) in 200 ml. of water is added as stirring is continued. After a few minutes a thick precipitate separates. The mixture is stirred or preferably shaken mechanically at room temperature with exclusion of air for 10 hours. The bisulfite addition product is separated by suction filtration, washed with
ether until colorless, and decomposed in a flask with a lukewarm solution of
125 g. of sodium carbonate in 150 ml. of water. The ketone layer is separated, the aqueous layer is extracted with four
25-ml. portions of ether, and the combined organic layers are dried over
anhydrous sodium sulfate. Most of the
ether is removed by distillation at atmospheric pressure, and the residual oil is distilled at reduced pressure (Note
6).
After a few drops of fore-run, practically all the liquid distils at
64–65°/12 mm. The yield of
cycloheptanone is
18.5–20.2 g. (
33–36%) (Note
6).
2. Notes
1. If it is desired to determine the amount of
nitrogen evolved, then it is necessary to use a sealed stirrer and a discharge tube for the
nitrogen; however, observing the amount of
nitrogen evolved affords no particular advantage. The temperature exerts sufficient control on the reaction rate, and dissolution of the nitroso compound indicates the progress of the reaction.
4. In some experiments, the temperature was allowed to rise temporarily to 35° without mishap, but the lower temperature is preferred for reasons of safety.
5.
Cycloöctanone, which is a by-product, is removed at this stage since it does not form an adduct with bisulfite.
6. The checkers found it desirable to distil the product through a
fractionating column in order to effectively remove the small fore-run and a smaller after-run. The pattern obtained in a
50-cm. column of the simple Podbielniak type follows: fraction 1, 1.13 g., b.p. up to
63°/12 mm.,
n25D 1.4549; fraction 2, 19.44 g., b.p.
63–64°/12 mm.,
n25D 1.4592; fraction 3, 0.55 g., b.p. >
64°/12 mm.,
n25D 1.4604. A center cut of fraction 2 had
n25D 1.4590.
3. Discussion
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