J. Hodge Markgraf
Williams College Williarnstown, Massachusetts
Stereochemical Correlations in the Camphor Series
A
corollary of teaching organic chemistry at the undergraduate level from the mechanistic approach is the increased emphasis on such concepts as molecular geometry and the influence of structure on reactivity. Although the presentation of these topics has been discussed frequently in THIS JOURNAL and elsewhere, the choice of suitable experiments to illustrate such concepts has been limited. This paper presents a series of experiments which require the student to interpret the effect of structure on the steric course of an oxidation and a reduction in a bicyclic system. The outcome of each reaction is not specified in the laboratory manual, and the student must therefore obtain quantitative data that are the basis for his interpretations. The reactions involved are the oxidation of isoborneol(1) with the Jones reagent, a competitive rate of oxidation of isoborneol and borneol(II), and the reduction of camphor(II1) with borohydride. The chemiral reduction of camphor affords a hicyelir
alcohol(1V) whose stereochemistry (i.e., I and/or 11) is to be deduced by the student. The apparat.us used in these reactions is quite simple, but the manipulation of small quantities in a variety of operations is required. The use of modern synthetic procedures is an added point of interest. Before the experiment, the student is expected to review the theory of vacuum sublimation, chromic acid oxidation of alcohols ( I ) , and hydride reductions of ketones (1). Infrared spectra of the starting materials and products permit identification of the function groups involved and also afford a semiquantitative measure of the extent of the reactions. Analysis of the reaction products is best accomplished, however, by vapor phase chromatography(VPC). The preparation of camphor by the oxidation of isoborneol is very well known, but the use of the Jones reagent in this capacity has not previously been reported. The yields are good, and the product is uncontaminated by starting material. The competitive oxidat.ion of the epimeric akohols is carried out by treat36
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Journal o f Chemical Education
ing equivalent amounts of I and I1 with only one equivalent of oxidizing agent, and the crude reaction mixture is analyzed directly by VPC for the relative amounts of unreacted alcohols. Interestingly, the results with the Jones reagent (47% isoborneol, 53% borne01 remaining aft,er oxidation) showed less discrimination than was expect#edfrom the work of Icwart and Francis (Z). An alternate procedure was then employed using the same CrOa/acetic acid reagent as the kinetic study (2). The results (42% isoborneol, 58% borneol remaining) were a clearer demonstration of the effect of struct,ure on reactivity. The interpretation of these data is reasonably complex for the student. He is referred first to the work of Westheimer et al. (3) who established the mechanism of the oxidation, and then to the discussion of Icwart and Francis (Z), who assessed the relative importance of st,ereoelect.ronicand strain relief effect-s. The borohydride reduction of camphor is carried out only to the point where the crude product is analyzed by VPC. Methanol as solvent proved to be superior to 2-propanol, in accordance with the same observation by Russo and Ricca (4). The interpretation of the data (84Y0 isoborneol, 16% borneol as reduced product; some camphor also present) is more straightforward in this case. References are given first to the concepts of st,eric approach versus product development control (5) and t,hen to recent applications of these concepts to a series of bicyclic ketones (6-9). The project is completed by a laboratory report in whirh each student presents his data and discusses the results. For the report, a series of questions is posed which requires the application of the above principles to related reactions and systems. Two afternoon laboratory periods are sufficient for completion of the experimental work. For large sections i t is convenient to post infrared spectra and VPC traces of the three compounds for comparison purposes. The present series of experiments can be contracted by omitting the competitive rate st,udy or expanded (in duration and degree of difficulty) by comparing the stereospecificity oI several reducing agents [e.g., lithium trialkoxyaluminohydrides (7, 8 ) , dissolving metal reductions (lo), hydrohoration ( l l ) ] , t,he reduction of several bicyclic ketones [e.g., norcamphor (67,camphenilone, fenchone], or the competit,iveoxidation of other bicyrlir alcohols [e.g., norborneol (2), fenrhyl alcohol]. The Experiment
The Oxidation o.fIsobo7%eol to Camphor (12). Prepare a solution of the Jones reagent by dissolving chromic anhydride (26.7 g, 0.267 mole) in 50 ml of distilled wat.er in a 100-ml volumetric flash and cautiously ad-
ding 23 ml of conc. H2S04with swirling. (Cool, if necessary.) Dilute the solution to the mark with additional water. Dissolve isoborneol (1.23 g, 8.0 mmoles) in 5 ml of acetone (reagent grade) in a 25-ml Erlenmeyer flask and cool the solution in an ice bath. To the manually swirled, chilled solution, add dropwise 2 ml of the Jones reagent from a volumetric pipet over a period of 10 min.' Green salts of Cr(II1) precipitate during the course of the reaction. Allow the mixture to warm to room temperature. If the characteristic orange color of the reagent persists, add isopropyl alcohol dropwise to quench the excess chromic acid. Decant the mixture into a separatory funnel containing 30 ml of water, using a small additional portion of acetone to rinse the gelatinous green salts. Ext,ract the system with three 10-ml portions of et,hyl ether. Wash the combined extract once each with 10-ml portions of saturated NaCl solution, saturated NaHC03 solution, and the NaCl solution; dry the ethereal solution with anhydrous MgSo,.2 Concentrate the ether solution to a few milliliters by distillation of the solvent, using all the usual precautions. Transfer the residual solution by capillary pipet to the lower portion of a vacuum sublimation apparatus, and carefully remove the final portions of solvent with a stream of air.3 Assemble the apparatus and sublime the product at reduced pressure (water aspirator) and elevated temperature (steam bath). Yield: ca. 0.90-0.95 g, 74-78%. Obtain the infrared spectra and determine the retention times for samples of isoborneol and ~ a m p h o r . ~ Competitive Oxidation of Isoborneol and Borneo1 ( I S ) . Dissolve isoborneol (1.23 g, 8.0 mmoles) and borneol (1.23 g, 8.0 mmoles) in 10 ml of glacial AcOH in a 25ml Erlenmeyer flask. To the manually swirled, icecooled solution add dropwise from a capillary pipet during a 15-min period a solution of CrOJ (0.80 g,
' The use of a magnetic stirrer and an internal thermometer is not. necessary; the temperature of the reactim solution remains helow 15' C with this rate of addition. VPC analysis of the ethweal salntion demonstrates the absence of koborneol in the crude prodoct. *The last traces of ether are removed at reduced pressure, which must be accomplished slowly to avoid spattering of the solid onto the cold finger. & T h e following conditions are satisfactory far the \'PC analyses using an Aerograph, Model A-90-P instntment: helium at 50 ml/min and a Frft. column of 5% Carbowax 4000 on aeidwashed firebrick operated at 110"; thk-compoundr may be intrrlduced as solutions in ethyl ether, chloroform, etc. characteristic retention times for III, I, and IS are 6, 10, and 12 min, respectively
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8.0 rnmoles) in aqueous acetic acid (2 ml H 2 0 3 ml AcOH).' Allow the reaction solution to warm to room temperature, pour i t into a separatory funnel containing 75 ml of water, and extract the system with two 10-ml portions of ethyl ether. Wash the combined extract as before (two portions of t,he NaHCOJ solution may be necessary to neutralize the acidity). Use a sample (1 WL)of the dried ethereal solution directly for VPC analysis. Prior to this, determine the retention time of borneol. Ident,ify the peaks from the analysis oi the mixture and calculate the relative amounts of the epimeric alcohols from the areas under the curves. Sodium Borohydride Reduction of Camphor. Dissolve camphor (0.50 g, 3.3 mmoles) in 5 ml of methanol in a 25-ml flask, and add NaBH4 (0.15 g, 4.0 mmoles) in one portion. Reflux the solution (steam bath) for 15 min, and then pour it ont,o 10 g of cracked ice. Collect the product; wash it with water; and air dry it. Yield: 0.45 g, 90%. Dissolve a small amount of the material in ether for VPC analysis. Calculate the relat,ive amounts of the reduced products in the usual manner. Literalure Cited (1) HOUSE, H . O., "Modern Synthetic Reactions," W. A. Benjamin, Inc., New York, 1965, Chaps. 2, 4. (2) KwaRT, H.. AND FRa~crs.P. S., J . Am. Chem. Soc.,. 81,2116 (1959). (:3) WESTHEIMER, F. H., AND NICOLAIUES, N., J . Am. Chem. So?., 71, 25 (1949); HOLL~WAY, F., COHEN,M., AND WESTHEIMER, F. H., J. Am. Chenc. Soc., 73, 65 (1951); ~
COHEN, M., AND WESTHEIMER, F. I
(12) Adapted from the procedore of MEINWALD, J., ANDERSON, P., AND TUFARIELLO, J. J., J. Am. C h m . Soc., 88, 1301 (1966); a180 see EI~ENBRATJN, E. J., Org. Synlh., 4 5 , 28 (1965) aud MEINWALD, J., CRANDALL, J., AND HYMANS, W. E., Org. Syizlh., 45, 77 (1966). (13) MOSHER, W. A., AND L.*NGERAK, E. O., J. Am. Chem. Soc., 73, 1302 (1951).
Volume 44, Number 7 , lonuory 1967
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