The Stereochemistry of
Harmon C. Dunathan
Haverford College Haverford, Pennsylvania
(-1
Menthol
An organic laboratory experiment
The trend in the first year organic laboratory a t Haverford is to place less emphasis on short preparative experiments and more on longer experiments involving quantitative measurements. I n these experiments the results are sufficiently complex that the student must devote considerable thought to their interpretation. Each student presents his interpretation in a short report answering the questions posed a t the beginning of the experiment. An experiment in the area of stereochemistry which has been quite successful is the determination of the relative configuration of (-) menthol.' In the course of this experiment, the student measures optical rotations, follows the rate of a mutarotation, evaluates the rate constants, and carries out a reaction involving asymmetric induction. The student is given an optically pure sample of (-) menthol (I) and is asked t o determine the conliguration a t Caand C4relative to that a t C, using data from these experiments: 1. (-) Menthol, [ w ] D ~ = ~ -50' is oxidized to (-) menthone(I1) with chromic acid. If this oxidation is carried out carefully, the configuration a t C h remains unchanged. Product rotation is determined. 2. A portion of the (-) menthone is treated with HC1 in ethanol. The rotation is determined after a time t (three students are assigned each time). Each student places his point on a 111 (ao - or.)/(- - WJ versus t plot. The acid concentration is such that the reaction is 90% complete in about three hours. Given that the C4epimer of (-) menthone, (+) isomenthone(III), has a rotation of +91.7', the student is asked to evaluate K.,.,,, k,, and k, for the reaction (-) menthone % (+) isomenthone. The rate constants k, and k, here include [H+]"; this may be separated and n determined if the class is large enough to use different acid concentrations. 3. The remainder of the (-1 menthone is reduced to a mixture of (-) menthol and (+) neomenthol(1V) with sodium borohydride. The rotation of the product mixture is determined. The student is given the rotation of (+) neomenthol, [ a ] =~ +20.7', ~ ~ and is told that reduction of (-) menthone with hydride reagents bulkier than BH4- yields a product mixture of more positive rotation. The reactions involved are as follows ' A discussion of the stereochemistry of menthol is given by R. H., AND NOLLER,C. R. in Gilman, H., "Orgsnio EASTMAN, nn. filR-23~ Chemistrv." " . John Wilev. " , New York., 1953. Vol. -~~4. -..~= This source, however, gives the wrong rotation far (+) isomenJ. CHEM.SOC., 1927,1276. thonc. See READ, WAUBEN,W. G., FONKEN,G. J., AND NOYCE,D. S., J. Am. Chern. Sac., 78,2579 (1956). 'Taken from the procedure in GILMAN,H., ed., Cal. Val. 1, "Organic Syntheses," John Wiley, New York, 1932, p . 340.
.
~
.
I1 (-)
80
b '
I ( - ) Menthol
6""
IV (+) Neomenthol
[=I;&
+20.7"
Menthone
[elb -29.6" I',
I I I ( + ) Isomenthone [a]:% t91.7"
The argument leading to the relative configuration at C involves a straightforward application of the principles of conformational analysis. However, successful assignment of a configuration at Ca depends on the student realizing that the products of the borohydride reduction are kinetically controlled. Even with this realization, the stereochemical arguments are quite s~phisticated.~As a result, the student's interpretation of the data in assigning a configuration at Cais almost always deficient in some respect. After the reports are in, the paper by Dauben, el al.,l is assigned and carefully discussed in class. The difficulties in the interpretation of the data seem not to bother students; rather, they are pleased to face an experiment where the interpretation of results is not trivial. At the begiuning of the experiment the student is given instruction in the operation of the polarimeter and is asked to derive the expression
where a. = initial rotation; n. = rotation at equilibrium; robation at any time 1.
a =
The Experiment
The Om.dalia of (-) Menthol to (-) Menthme.a Prepare a solution of chromic acid by carefully adding 7.2 ml of conc. H2S04to 90 ml of H20 in a 250-ml Erlenmeyer flask and dissolving in the acid solution 15.8 g of sodium dichromate dihydrate. Add menthol, 12.0 g, to the chromic solution, stopper the flask with a sound cork, cover the top with a paper towel, and shake the flask to initiate the reaction. Loosen the cork frequently to relieve any pressure build-up. The temperature of the reaction mixture should rise slowly (ca. 30 min.) to 55' as the flask is shaken vigorously. (If the temperature rises above 55', cool in cold water. If it fails to reach 55', heat gently on a hotplate.) The reaction mixture will remain near 50-55O for 15-20 min before the temperature starts to go down. The flask should be shaken vigorously during this time. Volume 40, Number 4, April 1963
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205
When the flask has cooled to about 40°, cool t o room temperature in an ice bath, extract the reaction mixture with 30 ml of ether, and then wash the ether layer with successive 30-ml portions of 5% NaOH until the ether layer is colorless. Wash the ether layer twice with 30ml portions of water and dry it over anhydrous NazSOa. Remove the ether by distillation from a 50-ml distilling flask using all the usual precautions. When the distillation temperature has risen above 45', remove the hot plate and distill carefully with a microburner until the temperature reaches 180'. (This mixture tends to foam; heat gently on the side of the flask.) At this point turn off your flame, dismantle the condenser and receiver, and dispose of the distilled ether. Now distill without a condenser, collecting fractions in tared test tubes placed over the side arm. Collect the fraction 20P11°; determine weight and optical rotation. The Mutarotation of (-) Menthone. Using an analytical balance, weight out exactly 2.000 g of menthone from the chromic acid oxidation in a 25 ml volumetric flask. Note the time and add in this order: 15 ml of ethanol (swirl), 5 ml of 5.0 N HCI and enough ethanol to fill to the mark. Mix immediately and a t the time assigned you determine the rotation of the solution, again noting the exact time. Calculate the % composition of your mixture at time 1 and place your point on the In (a, - a,)/(a - a,) versus t plot. Sodium Borohydride Reduction of (-) Menthone.
206
/
lournol of Chemicof Education
Dissolve NaBH,, 1.0 g, 0.02 moles, in a mixture of 10 ml H 2 0 and 15 ml MeOH in a round-bottom flask. Fit the flask with a condenser and add a solution of menthone, 4.0 g, 0.03 moles, in 10 ml of MeOH dropwise through the condenser. When the addition is complete, reflux the solution for 45 rnin. After cooling, add 30 ml of 5% NaOH slowly through the condenser and reflux the resulting solution 45 min. Extract the cooled reaction mixture with ether (twice with 30 ml), then extract the combined ether layers with water (twice with 30 ml), dry the ether layer over Ka,SOa and remove the ether by distillation with the usual precautions. The last traces of ether may be removed by using a microburner. When the temperature registers above 100°, stop the distillation and determine the weight and optical rotation of the clear oil remaining in the flask. The time required for this experiment will depend on the number of polarimeters available. Laboratory sections of 15 using one polarimeter should be able to complete the experiment in 10 hr. Average results for the experiment are given below. The rotations were determined at room temperature. Yield of (-1 menthone 65-70% -23" to -20" Specific rotation of ( - 1 methone Equilibrium composition of mutarotation mixture Yield of menthols Composition of reduction mixture
25% (+) 75% ( -) 75-85% 40% ( - ) 607" (+)
isomenthone menthone
menthol neomenthol
