Determination of the Relative J. Barry Laboratorie d e Synthsse Asymktrique, Bat. 4.20 Universitk Paris-Sud 91405 Orsoy, France
and Absolute Configurations of (-)Menthol
and (+)Neomenthol
An introductory stereochemistry experiment
This experiment which takes only one afternoon is used a s part of a course in the Facult6 des Sciences d'Orsay in order t o familiarize students with t h e stereochemistry and conformational analysis of cyclohexane systems.' Molecular models are made available t o the students. Principle (-) menthol a n d (+) neomenthol aie two stereoisomers having I a s their planar formula. Students are asked t o determine the relative stereochemistry a n d absolute configuration of these alcohols. An easy reaction-the reduction of (-1 menthone I1 by KBHl in a n aqueous medium2
affords a mixture of these two alcohols a n d demonstrates t h a t (-) menthol a n d (+) neomenthol are epimeric by t h e configurations of their hydroxyl group. With the added information t h a t t h e asymmetric carbon bearing t h e methyl group in (-1 menthone I1 has t h e absolute configuration R, t h e student has t o establish, in a first step, the ahsolute configuration a t t h e second asymmetric center in (-) menthone. For this purpose, a sample of (-) menthone is equilibrated in acid medium with its epimer, (+) isomenthone. Glc shows t h e predominance of (-) menthone in the equilibrated mixture. With the hypothesis t h a t t h e ring is chair and t h a t suhstituents have a n equatorial preference, the student can attribute, with t h e help of molecular models, formula V for (-) menthone. Thus t h e absolute configuration a t the carbon atom hearing the isopropyl group is S for (-) menthone, R in t h e (+) isomenthone.
boH 6, bOH A
m
A
N
7,
V
In order t o determine the configuration a t the asymmetric carbon substituted by the hydroxyl groups in the alcohols, a known mixture of (-) menthol a n d (+) neomentho1 is treated by a less t h a n equivalent quantity of phthalic anhydride. After removal of the monophthalates by basic washing, t h e residue in the ether extraction is analyzed by glc. It appears t h a t menthol reacted more easily t h a n its epimer. Knowing t h a t the reaction is under 292
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Journal of Chemical Education
steric control, the student can deduce t h a t the hydroxyl group is equatorial in t h e menthol, due t o its greater reactivity. III is thus t h e formula of (-) menthol and IV represents (+) neomenthol. T h e equatorial a n d axial character of the hydroxyl groups i n menthol and neomenthol, respectively, is confirmed by the retention time in glc (on a polar column): t h e neomenthol is first eluted since the axial hydroxyl is more hindered. Experimental
1. Menthone Equilibration: A solution of (-) menthone (0.5 g), acetic acid (2.5 ml), and 1 N HC1 (2.5 ml) is refluxed for 30 min (the equilibration is assumed to he realized) and allowed to cool. The mixture is then neutralized with 1 N NaOH and extracted with ether. 2. Menthone Reduction; Potassium horohydride (70 mg) is added slowly with stirring and cooling to a solution of (-) menthone (0.5 g) in methanol (5 ml). After 15 min at room temperature, the mixture is neutralized with 1 N HCI and extracted with ether. 3. Reaction of Phthalic Anhydride with the Menthol (7%)Neomenthol (25%) Sample: Dry pyridine (2.5 ml) and phthalic anhydride (475 mg-Yz equivalent) are added quickly to the menthol-neamenthol sample (0.5 g). The solution is heated 45 min and allowed to cool. Ether (25 ml) and 1 N HCI (50 ml) are added and the mixture is extracted. The ethereal phase is washed twice with 1NNaOH (50 ml) and finally with water (10 ml). 4. Gle Analysis: The ethereal phases are dried over sodium sulfate and the solvent is evaporated. The five samples: menthone, the mixture resulting from its equilibration, and the three mixtures menthol-neomenthol (from reduction of menthone in 2, before and after esterification in 3) are diluted with the same weight of benzene and analyzed by glc at 125T on a 95 ft column (10% Carbowax-1OM) on Gas Q 80-100 Mesh. (luestions Asked to Students 1. Identify by glc the menthone in the mixture resulting from its equilibration. Measure the retention times of these two ketones and the composition of this mixture. Find the stable chair forms for (-)menthane and (+)isomenthone and deduce the absolute configurations about C-2. Explain the mechanism of the menthone-isomenthone transformation. 2. Identify menthol and neomenthol in the three samples by glc. Measure the retention times of these two diastereoisomeric alcohols and the campwitions of these samples. Find the stable chair forms for menthol and neomenthol. Which one has the most hindered hydroxyl group? Give the stereoformulas and absolute configurations at C-1 for (-)menthol and (+)neomenthol. Account for the difference in retention times of these alcohols.
See also, Dunatban, H., J. CHEM. EDUC., 40,205 (1963). ZIf reduction with KBHn is performed in anhydrous alcohol some epimwinarion occur; f ~ r i tin , presrnre of water this rpimcrirnlinn i i inh:l,itrd. Harh. V.. Fryherg. E. C. and McDonald. E.. Torrahrdron Lorr., 2629 r1971,. 1
