Irving Allan Kaye
Brooklyn College The City University of New York
Brooklyn
11
Student Laboratory Preparation of Cis- and rmns-4-f-Butyl~y~lohe~anol~
The sequence of experiments described in this paper' has been used over the past two years with first year graduate students in a laboratory course in synthetic organic chemistry. I t should be suitable for advanced undergraduates as well. The experiments were designed to prepare students for research in organic chemistry by introducing them to laboratory techniques which are not usually taught in the introductory organic chemistry course Furthermore, since the products are conformationally homogeneous systems (employed extensively in recent studies on conformational equilibria and energy) (I-S), the student's knowledge of stereoisomerism and conformational analysis may be augmented by assigning a number of related problems based on some of the numerous recent publications in these areas In the first experiment, a mixture of the stereoisomenc 4-t-butylcyclohexanols is prepared by hydrogenating 4&butyIcyclohexanone2 or 4f-butylpheno12 in the presence of Raney nickel4 or rhodium-on-alumina5 respectively Since the nickel catalyst is mexpensive, and the reduction is quite rapid, we have had most of the students in each laboratory section prepare a cis-rich mixture of the alcohols by reducing the ketone with Raney nickel at room temperature. One or two students usually are assigned the reduction of the phenol and a similar number the preparation of a trans-rich mixture of the alcohols by hydrogenating the ketone in the presence of nickel at 80° This A more detailed description of the experiments and topics mentioned in this paper may be obtained from the author. Obtained from the Dow Chemical Co., Midland, Mich. a Obtained from the Chemicals Division of Union Carbide Corm. New Ynrk. - ~-~~~ Obtained as no. 28 Raney active nickel catalyst in water from the Oilman Paint and Varnish Division of W. R.Grace and Co., Chattanooga, Tenn. ~
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is the first experience of most students in conducting a moderate-pressure catalytic hydrogenation and in transferring, filtering, and disposing of a pyrophoric substance (the catalyst). The danger of fires in the filtration of the reduced catalysts is minimized by using methylcne chloride as wash-solvent. Also new to most students in this experiment is the technique of distilling a low-melting solid, pulverizing a congealed product, and handling a solid which readily acquires a static electrical charge. In addition we require each student to analyze his product qualitatively by thinlayer chromatography and quantitatively by obtaining an infrared spectrum and comparing it with the spectra of mixtures of known composition. If time permits, he is also expected to analyze his product by gas-liquid chromatography (2'). In a subsequent experiment trans-4-t-butylcyclohexanol is isolated as its hydrogen phthalate ester from the trans-rich mixture prepared by the student or a classmate, hut also available c~mmercially.~ The ester, purified by recrystallization from a solvent mixture, is saponified. The free alcohol is isolated by direct steam distillation and dried by vacuum-sublimation. I n the final experiment the cis-isomer is isolated from a cis-rich mixture of the alcohols by elution chromatography, in an automatic recycling apparatus (4),' and crystallized from pentane. This chromatographic procedure has received little attention hitherto but is admirably adapted to this separation, and many others, with considerable savings in solvent, time, and attention. The progess of the elution may he followed readily by thin-layer chromatography of each fraction. Stereoisomeric 4-f-Butylcyclohexanols
(a) Using distilled water to effect the transfer, IV; level teaspoons of Raney nickel catalyst* is transferred to a hydrogenation bottle. After removing the super-
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natant water by aspiration, 15.43 g (0.100 mole) of 4i-b~tylcyclohexanone,~ 40 ml of methanol, and 3.5 ml of triethylamine are added and the mixture reduced in a Parr-Burgess hydrogenator a t an initial pressure of 60 psi. The hydrogenation is con~pletein about 30 min. The mixture is filtered through a mat of a diatomaceous earth and the catalyst washed repeatedly with a total of 100 ml of methylene chloride. The colorless filtrate is washed with 100 ml of 1 M hydrochloric acid and then dried over sodium sulfate. After removing the solvent on a steam bath, the residue is distilled rapidly from a 50 ml distilling flask and the product collected in a test tube attached to the sidearm of the distilling flask by a grooved cork. Yield: 14.82 g (95%), bp: 215-219". The distillate quickly solidifies in the receiver and is pulverized easily by the following procedure. The white solid is partially melted by heating the test tube until the solid floats freely in its own melt; the tube is then quickly inverted and the product caught on a large piece of aluminum foil. After cooling, the mixture is wrapped well in foil and paper and pounded, at first with a heavy weight and then with a mallet. A little of the powder is dissolved in 1-2 drops of benzene and the solution applied to a layer of unactivated silica gel G on a microscope slide. The chromatogram is developed with benzeneether (1 :2; v/v) and visualized by spraying with 0.1 N potassium permanganate in sodium carbonate solution. The isomeric alcohols appear as yellow spots against a purple background. The product is readily soluble in nujol, and an infrared spectrum of the solution, prepared between salt plates, compared with the peaks in the 7.5-12.2~ regions of the spectra of mixtures of known composition, affords a convenient method of analysis, accurate to about ±3 Gas-liquid chromatographic analyses were carried out with an F and M Model 500 instrument equipped with a thermal conductivity detector. Using a 10-ft column of 1/4-~ncopper tubing packed with 60-80 mesh Chromosorb P containing 20% diethylene glycol succinate a t 155O and a helium flow of 60 ml/min, the retention times of the cis- and transisomers were found to be 19.8 and 24.0 min, respectively. (6) A mixture of 15.02 g (0.100 mole) of p-i-bntylphen01,~'3 3.5 g of 5% rhodium-on-alumina,= and 25 ml of 95% ethanol is hydrogenated a t an initial pressure of 55-60 psi. The theoretical amount of hydrogen is absorbed in about 2 hr. The procedure for isolating the product is identical with the foregoing. Yield: 14.51 g (93%). On infrared analysis (vide supra), the composition of a product prepared by this method was found to be identical with that obtained by the previous procedure, namely 60% cis-isomer (literature results, for the high-pressure hydrogenation of p-t-butylphenol in the presence of rhodium-onalumina: 60% cis-isomer) (5). (c) Nine level teaspoons of Raney nickel are transferred to a hydrogenation bottle and washed three times with 100-ml portions of isopropyl alcohol. Then 60.1 g (0.400 mole) of p-i-butylphennl and 100 ml of isopropyl alcohol are added and the mixture hydrogenObtained from Engelhard Industries, Inc , Newark, N. J. 6Availahle from Matheson Scientific, Inc , Chicago, 111.
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ated at 80' and an initial pressure of 55-60 psi. Reduction is complete in 2-3 hr and the product is isolated by the procedure described in (a). Yield: 53.9 g (86%); bp 215-220". Infrared analysis of a product prepared by this procedure indicated that it contained 80% of the trans-isomer. A mixture of 8.40 g of 4-t-butylcyclohexanol (rich in the trans-isomer), 8.40 g of phthalic anhydride and, 10 ml of dry pyridine is heated in a steam bath or in an electrically heated oil bath at a bath temperature of 99-102' for 90 min. After chilling in an ice bath for at least 15 min, a little ether is added to lower the viscosity of the mixture and the solution transferred to a 250-ml separately funnel. One hundred ml of ether is added and the colorless solution washed with 125 ml of an ice-cold saturated salt-hydrochloric acid solution (prepared by dissolving 220 g of sodium chloride and 90 ml of con hydrochloric acid in 710 ml of water). The ether layer is then washed with 125 ml of ice-cold saturated aqueous sodium chloride. The aqueous washings are each extracted separately with 50 ml of ether and the ether layers are combined and dried by passage through a column of anhydrous granular sodium sulfate. The dried ether solution is heated to boiling on a steam bath, and hexane is added dropwise to the boiling solution at a rate sufficient to maintain the volume at 100-125 ml. A thermometer should be supported in the neck of the flask during this process to indicate the temperature of the escaping vapor. When the first signs of crystals are noted in the solution, the addition of hexane is discontinued, the vapor temperature noted (usually 53-59'), and the solution quickly removed from the steam bath and left at room temperature until crystallization seems complete. After an additional hour at O0, the product is separated by filtration and washed three times with an ice-cold hexane-ether solution.' This is prepared by adding ether slowly to 70 ml of boiling hexane until the vapor temperature is the same as that of the solution just before it was removed from the steam bath. Recrystallization is repeated in the same manner until the melting point is constant (2-5 recrystallizations); mp: 144-145' (literature value: 146-147') (2). The pure ester is then suspended in water (70 ml/g of ester), and saturated aqueous sodium hydroxide (1.32 ml/g) added. The mixture is heated to boiling in an apparatus set up for simple distillation and distilled until the distillate is clear (36.5 ml/g). The alcohol, which is separated by filtering the chilled distillate, air-dried for 1-2 days, and dried further by sublimation at a bath temperature of 94-95' and a vacuum of 2 mm, is obtained in almost quantitative yield from the ester; mp: 80.2-80.9' (literature value 80.5-81') (2). The absence of cis-isomer from the product should be confirmed by TLC, infrared, and, if possible, glc analysis. A solution of 1.20 g of 4t-butylcyclohexanol (rich Tram-4-t-Biitylcyclohexyl hydrogen phthalate is a stemuator as a dry powder Transfers of the product in this state should he conducted in a fume hood
in the cis-isomer) in 20 ml of pentane is added to a column of 36 g of alumina which has an activity slightly greater than I l i a (6'),%prepared under pentane. The column is then set up for automatic recycling (4) and eluted with pentane, at a rate of about 900 ml per hr, for a period of 3 hr. This first fraction is examined by thin-layer chromatography for the presence of trans-isomer. If none is found present, elution is continued for another 30 min. Fractions are then collected at 30-n~inintervals until the trans-isomer appears in the eluate; this usually occurs after 4 hr of elution under these conditions. [The column may then be eluted continuously with ether (solvent grade) Ahunina of this activity may be prepared by adding 36 ml of e of commercial alumina of activity 11. After shakcater to 500 ing and leaving a t room temperature for a t least 2 hr, the adsorbent may be used. I t is advisable to cheek its iictivity before use with the dye solutions of I T . Brockmann and H. Schodder Bpi., 74, 73 (1941).
for about 3 hrs to recover the remainder of the starting material, which contains about 90% of the transisomer.] The residue, which was left after evaporating the solvent from the combined extracts containing only the cis-isomer, is recrystallized once from 5 ml of pentane. Yield: 0.475 g; mp: 81.1-81.5' (literature value 81-8Z0) ( 2 ) . An additional 0.085 g of product may be obtained by subliming in vacua the residue recovered from the filtrat,e,mp: 79-80', Literature Cited
ELIEL,K. l;.,
ET AL., "Conformational Analysis," Interscience Publishers, (division of John Wile? & Sons, Inc.), New York, 1965,pp. 64,66,74,146, and 188. ( 2 ) ELIEL,E. I,., A N D SCHKUETER, S. lI., J. Am. Chem. Soc., 87, 5031 (1965). ( 3 ) HADEIC, C. l'., J . A m . Chem. Soc., 88,1713 (1966). (4) KAYE,I. A,, Mikrochim. Acts, in press. (5) KICKBOKN, B., A N D QUAII'I'L'CCI, J., J. Org. Chem., 29, 2476 (1964). (6) H E I ~ A N D E It., Z ,I~EKSANDEZ, TI., JK., AND AXELI~OD, L. R., Anal. (Them., 33,370 (1961).
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