J. Hodge Markgraf and Pak-Tong Leung Williams College Williamstown, Massachusetts 01267
I
Stereochemical Correlations
(
in the Norbornc~neSystem
I
A n advanced organic experiment
I n connection with our continuing interest in developing experiments which require the student to deduce stereochemical relationships ( I ) , we have devised a series of reactions in the norbornane system suitable for an advanced undergraduate organic chemistry laboratory. I n this experiment 2norbornanone (I) is converted to the epimeric 2-methyl2-norbornanols by two routes: (1) reaction with methylmagnesium iodide to yield 2-exo-methyl-2-endonorbornanol (11) and (2) conversion to 2-methylenenorbornane (111) followed by hydration to give 2-endomethyl-2-exo-norbornanol (IV) .
1.Hg(OAc),, H,O, T H F 2NaBH.NaOH
III
Identification of the epimeric alcohols can be accomplished by spectroscopic methods and by preparation of derivatives. The infrared spectra of I1 and IV differ markedly in the 7.5-11.5 p region and can serve as the basis for differentiation, if copies of the two spectra are posted. An alternate method is by nuclear magnetic resonance. The difference in the chemical shifts of the hydroxylic protons in DRISO-de is sufficiently large (4 Hz) to permit resolution; the endo alcohol (11) appears at lower field.' Vapor phase chromatography is not useful in the present case, since separations of I1 and IV have only been accomplished on capillary column^.^ A standard alcohol derivative, such as the 3,5-dinitro-benzoate ester, is also satisfactory for differentiati~n.~ I n the post-laboratory discussion the student is led from the correct identification of the isomeric products to the consideration of the following useful generalizations. I n conformationally rigid systems it is often observed that reagents attack from a specific direction. Thus with the norbornane system reagents tend to react preferentially from the exo direction, regardless of the mechanistic classification of the r e a ~ t i o n . Pre~ sumably steric factors control this preference with the ethano bridge more effectively blocking endo approach than the methano bridge does exo approach. As a consequence the atom or function which is introduced first appears as the endo substituent and that which is introduced second ends up on the exo position. The following transformations constitute another example.
AOH IV
I n the laboratory instructions for the student the structural assignments of the products are not specified, but must be determined from comparisons of various physical properties. A variety of reactions (Grignard, Wittig, oxymercuration-demercuration), reagents (butyllithium, methylenetriphenylphosphorane, mercuric acetate, sodium borohydride) and techniques (vacuum distillation and sublimation) are utilized. The reactions are conducted on a small scale, a t times semimicro, and are adapted for use with the standard-taper glassware kits now widely available. The Grignard and Wittig reactions are discussed in most intr~duct~ory textbooks, although references to more detailed commentaries are provided. The conversion of I11 to IV is effected by a recently reported procedure which involves oxymercurationdemercuration ( 2 ) . The reaction is mild, rapid, and completely stereospecific; the net result corresponds to Markovnikov addition. Intermediate carbonium ions are not involved, however, and rearrangements, which may frequently occur (especially with norbornyl cations) during acid-catalyzed hydration of double bonds, do not occur under these conditions. The oxymercuration step, in which mercuric acetate reacts as an electrophile toward the olefinic bond, has been studied in detail (3, 4). I n the demercuration step the -CH2HgX linkage is reduced to a methyl group.
Spectra were obtained on a Varian T-60 instrument. Dimethylsulfoxide-ds was the only suitable solvent found (e.g., 11, 6 4.17; IV, 6 4.10); acetonitrile-d3, acetone-&, carbon tetrachloride, chloroform-d, and pyridine were ineffectual. The methyl groups were of no help; a CClr solution of I1 and IV showed a single peak even a t 100 MHz. Prof. H. C. Brown and associates (Purdue University) used a 0.01 in. X 150 f t column coated with 5 to 7.5% Quadrol [N, N, N', N'-tetrakis (2-hydroxypropyl) ethylenediamine] a t 100°C. Dr. R. Teranishi and T. R. Mon (Western Utilization Laboratory, USDA) observed partial separation on a 0.02 in. X 700 f t column coated with OV-210 [trifluoropropylmethyl silicone oil] a t 100°C; no separation was obtained on similar columns with Carbowax 20M, Apiezon L, and silicone oils SF 96(50), OV-17, and OV-225. 3 This derivative of IV exhibits interesting properties. At the melting point partial vaporization occurs, the residue solidifies with increasing temperature and then re-melts a t 205OC (3,5dinitrobenzoic acid: mp 204-205°C). Analysis (VPC) of the condensed vapors from the upper portion of the mp tube established the presence of 2-methylenenorbornane (111) and Zmethylnorbornene by comparison with authentic samples. Similar behavior was not observed with the same derivative of 11. Exceptions have been reported in which substantial amounts of products were derived from endo attack (5, 6). Volume 47, Number 10, October 7 970
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707
oxymercuration demercuration
tional ether portion.6 Transfer the colorless filtrate to a separatory funnel, wash twice with water, dry with MgSO4, and filter by gravity. Remove the solvent (as above) and use the residual liquid directly in the next step.'
oxidation
H
4 0
Oxymercuration-Demercuration o f 2-Methylenenorbornane
reduction hydride
*
&H
OH
Hence, by controlling the order in which atoms are introduced it is possible to prepare either isomer. The Experiment Reaction o f 2-Norbornanone with Methylmagnesium Iodide
Carry out the reaction in a dry 50-ml, r.b. flask fitted with a reflux condenser and CaClz drying tube. Prepare the Grignard reagent from magnesium turnings (1.2 g, 0.050 g-atom), methyl iodide (7.1 g, 0.050 mole), and anhydrous diethyl ether (10 rnl) by initially treating all the Mg with a small portion of the ethereal CH31 solution. Once the exothermic reaction has commenced, add the balance of the solution down the condenser in small portions from a capillary pipet to maintain gentle reflux. After the addition is complete gently reflux the mixture on the steam bath for an additional 10 min and allow to cool. To the reaction mixture a t room temperature add portionwise down the condenser a solution of 2-norbornanone (2.74 g, 0.025 mole) in 10 ml of anhydrous ether; use an additional small portion of ether to complete the transfer. Reflux the mixture 15 min, chill briefly, and pour the mixture into a separatory funnel containing ice (20 g) and a solution of NH4C1 (4 g) in water (10 ml). Separate the ether layer, and extract the aqueous phase twice with ether; wash the combined extract with water, dry with MgSOa and filter by gravity. Remove the solvent by distillation a t atmospheric pressure on a steam bath using a 25-ml, r.b. flask, Claisen adapter fitted with an addition funnel and distillation head, thermometer, condenser, and adapter. Replace the funnel with a narrow capillary and vacuum distill the residual oil; a water aspirator and steam bath are satisfactory conditions for the vacuum distillation, if the distilling flask is immersed in the steam bath. I t is convenient to omit the water condenser for this step, since the product is a solid below room temperature. Cool the receiver with an ice bath after the residual traces of solvent are removed; no forerun is obtained. Yield of 11: 2 g, 41%; bp 73-74OC (15 mm); m p 2g°C. Obtain the infrared spectrum, prepare the 3,s-dinitrobenzoate ester, and determine the mp of the recrystallized derivative (mp 131-132OC).
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Preparation o f 2-Methylenenorbornane
Prepare the Wittig reagent in a dry 250-ml, r.b. flask fitted with a serum stopper on the side tubulation and a reflux condenser with CaClz drying tube. To the manually swirled flask containing methyltriphenylphosphonium bromide (5.57 g, 0.0156 mole) and anhydrous EtzO (50 ml) add dropwise from a syringe through the serum stopper a solution of n-butyllithium (10 ml, 15.2% in hexane, d 0.68 g/ml; 1.03 g, 0.016 mole reagent). (CAUTION: the use of the n-butyllithium solution can be hazardous; consult with the laboratory instructor regarding the proper flushing, use and cleaning of the hypodermic syringe.) Reflux the mixture for 15 min on a steam bath with occasional swirling and use directly in the next step. Temporarily remove from the steam bath the flask containing the methylenetriphenylphosphorane and add in one portion down the condenser a solution of 2-norbornanone (1.31 g, 0.0120 mole) in 5 ml anhydrous EtzO; complete the transfer with a small portion of ether. Gently reflux the reaction mixture on a steam bath with occasional swirling for one additional hour. Chill the orange mixture in a n ice bath and filter by suction on a Biichner funnel with Filter-Cell to remove the precipitated solids. Complete the transfer and wash the collected solids with an addi-
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Journal o f Chemical Education
Add to a 50-ml Erlenmeyer flask in the following order mercuric acetate (3.19 g, 0.010 mole), water (10 ml), and tetrahydrofuran (10 ml). To the solution a t room temperature add 2-methylenenorbornane (1.08 g, 0.010 mole), swirl the mixture 5 min, then add 10 ml 3 M NaOH, followed by 10 ml of a solution of 0.5 M NaBH, in 3 M NaOH. Saturate the aqueous phase with NaCl and permit the mercury to settle.8 Carefully withdraw the organic phase with a capillary pipet; dry, filter, and partially concentrate it on a steam bath. Transfer the residual solution to the lower portion of a sublimation apparatus and evaporate the remaining traces of solvent with a gentle air stream. Purify the residual solid by vacuum sublimation.9 Yield of IV: 0.3 g, 20% overall from I ; mp 78-80°C. Obtain the infrared spectrum, prepare the 3,s-dinitrobenzoate ester, and determine the mp of the recrystallized derivative (mp 137-138OC dec). Acknowledgment
The authors are grateful to Professor Herbert C. Brown, Dr. I
