An Oxidation-Reduction Scheme: Borneol, Camphor and Isoborneol

H C CH3 CH 3 H C CH3 H3C 3 NaOCl 3 NaBH4 CH3COOH H OH H C 3 OH H C H3C 3 O H Borneol Camphor Isoborneol

This experiment will illustrate the use of a "green" oxidizing agent, sodium hypochlo-rite (bleach) in acetic acid, for converting a secondary alcohol (borneol) to a ketone (camphor). This reaction will be followed by TLC to monitor the progress of the oxidation. The camphor is then reduced by sodium borohydride to give the isomeric alcohol, isoborneol. The spectra of borneol, camphor, and isoborneol will be compared to detect structural differences and to determine the extent to which the final step produces an alcohol isomeric with the starting material, borneol.

OXIDATION OF BORNEOL WITH HYPOCHLORITE

Sodium hypochlorite, bleach, can be used to oxidize secondary alcohols to ketones. Because this reaction occurs more rapidly in an acidic environment, it is likely that the actual oxidizing agent is hypochlorous acid, HOC1. This acid is generated by the reaction between sodium hypochlorite and acetic acid.

NaOCl + CH3COOH → HOCl + CH3COONa

Although the mechanism is not fully understood, there is evidence that an alkyl hypochlorite intermediate is produced, which then gives the product via an E2 elimination:

H C CH3 H C CH3 CH 3 3 H3C 3 NaOCl CH COOH H 3 O H3O + Cl H H H C H C H 3 OH 3 O Cl H3C O

REDUCTION OF CAMPHOR WITH SODIUM BOROHYDRIDE

- Metal hydrides (sources of H: ) of the Group III elements, such as lithium aluminum hydride, LiAlH4, and sodium borohydride, NaBH4, are widely used in reducing carbonyl groups. Lithium aluminum hydride, for example, reduces many compounds containing carbonyl groups, such as aldehydes, ketones, carboxylic acids, esters, or amides, whereas sodium borohydride reduces only aldehydes and ketones. The reduced reactivity of borohydride allows it to be used even in alcohol and water solvents, whereas lithium aluminum hydride reacts violently with these solvents to produce hydrogen gas and thus must be used in non-hydroxylic solvents. In the present experiment, sodium borohydride is used because it is easily handled, and the results of reductions using either of the two reagents are essentially the same. The same care need not be taken in keeping sodium

borohydride away from water as is required with lithium aluminum hydride. The mechanism of action of sodium borohydride in reducing a ketone is as follows:

Note in this mechanism that all four hydrogen atoms are available as hydrides (H:-), and thus one mole of borohydride can reduce four moles of ketones. All the steps are irreversible. Usually, excess borohydride is used because there is uncertainty regarding its purity and because some of it reacts with the solvent. Once the final tetraalkoxyboron compound (1) is produced, it can be decomposed (along with excess borohydride) at elevated temperatures as shown:

- + - + (R2CH —O)4 B Na + 4R'OH(i) → 4 R2CHOH + (R'O)4 B Na (1)

The stereochemistry of the reduction is very interesting. The hydride can approach the camphor molecule more easily from the bottom side (endo approach) than from the top side

(exo approach). If attack occurs at the top, a large steric repulsion is created by one of the two

geminal methyl groups. Geminal methyl groups are groups that are attached to the same carbon. Attack at the bottom avoids this steric interaction.

It is expected, therefore, that isoborneol, the alcohol produced from the attack at the least-hindered position, will predominate but will not be the exclusive product in the final reaction mixture. The percentage composition of the mixture can be determined by spectroscopy. It is interesting to note that when the methyl groups are removed (as in 2-norborna-none), the top side (exo approach) is favored, and the opposite stereochemical result is obtained. Again, the reaction does not give exclusively one product.

Special Instructions

The reactants and products are all highly volatile and must be stored in tightly closed containers. The reaction should be carried out in a well-ventilated room or under a hood because a small amount of chlorine gas will be emitted from the reaction mixture.

Suggested Waste Disposal The aqueous solutions obtained from the extraction steps should be placed in the aqueous waste container. Any leftover methanol may be placed in the non-halogenated organic waste container. Methylene chloride may be placed in the halogenated waste container.

Procedure PART A. OXIDATION OF BORNEOL TO CAMPHOR Assemble the Apparatus. To a 50-mL round- bottom flask, add 1.0 g of racemic borneol, ~3 ml of acetone, and 0.8 ml of acetic acid (approx. 10 drops). After adding a magnetic stir bar to the flask, attach a water condenser and place the round-bottom flask in a warm water bath at 50°C, as shown Figure 1. The apparatus should be set up in a good fume hood or in a well-ventilated room because of the potential for evolution of chlorine gas. It is important that the temperature of the water bath remain near 50°C during the entire reaction period. Stir the mixture until the borneol is dissolved. If the borneol does not dissolve, add about 1 ml of acetone. Addition of Sodium Hypochlorite. Measure out 18 ml of 6% sodium hypochlorite solution in a graduated cylinder. Add dropwise 1.5 ml of the hypochlorite solution every 4 minutes through the top of the water-cooled condenser. The addition will take 48 minutes to complete. Continue to stir and heat the mixture during the 48-minute period. Following the addition, heat and stir the mixture for an additional 5 minutes. Allow the reaction mixture to cool to room temperature. Remove the condenser. Monitoring the Oxidation with Thin-Layer Chromatography (TLC). The reaction progress can be monitored by TLC. Remove about 1 mL of reaction mixture with a Pasteur pipet and place it into a centrifuge tube. Add about 1 mL of methylene chloride, cap the tube, and shake the tube for a few minutes. Remove the lower, methylene chloride, layer with a Pasteur pipet in such a way to avoid drawing up any aqueous layer. Place the methylene chloride extract into a dry test tube. Prepare a 30-mm x 70-mm silica gel TLC plate (Whatman Silica Gel plate with aluminum backing. No. 4420-222) that will be spotted with three solutions using micro-pipets. Borneol (2% in methylene chloride) is spotted in lane 1, camphor (2% in methylene chloride) in lane 2, and the reaction mixture dissolved in methylene chloride in lane 3. Spot each solution 2 or 3 times, each time spotting it on top of the previous spot (allow the previous spot to dry before applying the next one). Prepare a developing chamber by using a 400mL beaker and watch glass, using methylene chloride as the solvent. Put the plate into the developing chamber. When the solvent front has traveled about 5 cm, remove the plate, evaporate the solvent, and place the plate into another beaker with a watch glass that contains a few crystals of iodine. Gently, heat the jar on a hotplate. The iodine vapors will visualize the spots. Camphor will have a larger R-value than borneol. Unfortunately, camphor and borneol do not give intense spots with iodine, but you should be able to see them. The relative amounts of borneol and camphor can be determined by the relative intensity of the spots on the plates. The reaction will be judged

to be complete if the borneol spot in lane 3 is not visible. If some borneol remains as determined by the TLC method, reattach the water condenser, reheat the reaction mixture in the round-bottom flask, and then add 3 mL more of sodium hypochlorite solution dropwise to the reaction mixture over a 10- minute period. Check the mixture again using the previous procedure and a new TLC plate. Ideally, borneol should not be visible on the plate, and camphor should be visible.

Extraction of Camphor. When the reaction is complete, allow the mixture to cool to room temperature. Remove the water condenser and transfer the mixture to a separatory funnel using 10 mL of methylene chloride to aid the transfer by rinsing the any remaining Camphor in the round-bottom flask. Shake the separatory funnel remembering the ‘burp’ any methylene chloride vapor. Drain the lower organic layer from the funnel to a beaker. Extract the aqueous layer remaining in the separatory funnel with another 10-mL portion of methylene chloride, combine the two organic layers in the beaker and discard the aqueous layer. Return the organic layer to the separatory funnel and extract the combined methylene chloride with 6 mL of saturated sodium bicarbonate solution, being careful to vent the funnel frequently to release carbon dioxide gas formed from reaction with acetic acid. Drain the lower organic layer and discard the aqueous layer. Return the organic layer to the separatory funnel and extract it with 6 ml of 5% sodium bisulfite solution. Drain the lower organic layer and discard the aqueous layer. Return the organic layer to the separatory funnel and extract it with 6 ml of water. Drain the organic layer into a dry Erlenmeyer flask and add about 2 g of granular anhydrous sodium sulfate to dry the solution. Swirl gently until any cloudiness in the solution is removed. If all the sodium sulfate clumps together when the mixture is stirred with a spatula, add some additional drying agent. Cork the flask, and allow the solution to dry for about 5 minutes.

Isolation of Product. Transfer the dried methylene chloride extracts to a pre-weighed 50-mL Erlenmeyer flask. Evaporate the solvent in the hood with a gentle stream of dry air while heating the Erlenmeyer flask in a water bath at 40-50°C. When all the liquid has evaporated and a solid has appeared, remove the flask from the heat source. If the crystals appear wet with solvent, apply a vacuum for a few minutes to remove any residual solvent.

Analysis of Camphor. Weigh the flask to determine the weight of your product and calculate the percentage yield. At the option of your instructor, determine the melting point of product. The melting point of pure camphor is 174°C, but it is likely that the melting point obtained will be lower than this value because impurities drastically affect the melting behavior of camphor.

Infrared Spectrum. Before proceeding to Part B, you should verify that the oxidation was successful. This can be done by determining the infrared spectrum of camphor product. By examination of the infrared peaks, determine if the borneol (an alcohol OH stretch) is absent, or nearly absent, and if the borneol has been oxidized to camphor (a ketone C=O stretch). For comparison, an infrared spectrum of camphor is shown on page. If your oxidation was not totally successful, consult your instructor for your options. The camphor is reduced in Part B to isoborneol. Store the camphor in a tightly stoppered flask.

PART B. REDUCTION OF CAMPHOR TO ISOBORNEOL

Reduction. The camphor obtained in Part A should not contain borneol. If it does, show your infrared spectrum to your instructor and ask for advice. If the amount of camphor obtained in Part A, is less than 0.25 g, obtain some camphor from the supply shelf to supplement your yield. If the amount is more than 0.25 g, scale up the reagents appropriately from the following amounts. Add 1.5 ml of methanol to the camphor contained in a 50-mL flask. Stir with a

glass stirring rod until the camphor has dissolved. In portions, cautiously and intermittently add 0.25 g of sodium borohydride to the solution with a spatula. When all of the boro-hydride is added, boil the contents of the flask on a warm hot plate (low setting) for 2 minutes.

Isolation and Analysis of Product. Allow the reaction mixture to cool for several minutes and carefully add 10 ml of ice water. Collect the white solid by filtering it on a Hirsch funnel and, by using suction, allow the solid to dry for a few minutes. Transfer the solid to a dry Erlenmeyer flask. Add about 10 ml of methylene chloride to dissolve the product. Once the product has dissolved (add more solvent, if necessary), add about 0.5 g of granular anhydrous sodium sulfate to dry the solution. When dry, the solution should not be cloudy. If the solution is still cloudy, add some more granular anhydrous sodium sulfate. Transfer the solution from the drying agent into a pre-weighed dry flask. Evaporate the solvent in a hood, as described previously. Determine the weight of the product and calculate the percentage yield. At the option of the instructor, determine the melting point; pure isoborneol melts at 212°C. Determine the infrared spectrum of the product by the dry film method used previously with camphor. Compare the spectrum with the infrared spectra for borneol and isoborneol shown in the figures.

If time permits: PART C. PERCENTAGES OF ISOBORNEOL AND BORNEOL OBTAINED FROM THE REDUCTION OF CAMPHOR

Gas Chromatography. The isomer ratio and percentages can also be obtained by gas chromatography. Your instructor will provide instructions for preparing your sample. A Gow-Mac 69- 360 instrument fitted with an 8-ft column of 10% Carbowax 20M, in an oven set at 180°C, and with a 40 mL/min helium flow rate will completely separate isoborneol and borneol from each other. In addition, any residual camphor can be observed. The retention times for camphor, isoborneol, and borneol are 8, 10, and 11 minutes, respectively. Other instrument conditions are provided in the Notes to the Instructor.

Pre-Lab Questions 1. How do you expect to tell the difference between borneol and camphor by IR? 2. How do you expect to tell the difference between borneol and isoborneol at the end of the experiment? 3. The reaction below, proceeds as follows: Why do you think you only get one product instead of two? H O NaBH4 OH

4. Please predict the products of the following reactions: O

OH NaBH4 H

O O

OH LiAlH4 H

O

Post- Lab Questions

1. Interpret the major absorption bands in the infrared spectra of camphor, borneol, and iso-borneol.

2. A sample of iso-borneol prepared by reduction of camphor was analyzed by IR spectroscopy and showed a band at 1750 cm-1. This result is unexpected, why?

3. Why was the methylene chloride layer washed with sodium bicarbonate in the procedure for preparing camphor?

4. Why was the methylene chloride layer washed with sodium bisulfite in the procedure for preparing camphor?

REFERENCES Pavia, D. L., et al. “Experiment 33” Introduction to Organic Laboratory Techniques-A Small Scale Approach 2nd ed, (2005), 272-287. Brown, H. C., and Muzzio, J. "Rates of Reaction of Sodium Borohydride with Bicyclic Ketones." Journal of the American Chemical Society, 88(1966): 2811. Dauben, W. G., Fonken, G. J., and Noyce, D. S. "Stereochemistry of Hydride Reductions." Journal of the American Chemical Society, 78 (1956): 2579. Markgraf, J. H. "Stereochemical Correlations in the Camphor Series." Journal of Chemical Education, 44 (1967): 36