CHEM51LC PROJECT DETERMINATION OF DIASTEREOSELCTIVITY USING THERMODYNAMIC VERSUS KINETIC CONTROLLED REDUCTION PROCEDURES: A REDUCTION

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1 CHEM51LC PROJECT DETERMINATION OF DIASTEREOSELCTIVITY USING THERMODYNAMIC VERSUS KINETIC CONTROLLED REDUCTION PROCEDURES: A REDUCTION of 4-tert-BUTYLCYCLOHEXANONE REACTION: Oxidation of an Alcohol, Reductions of a Ketone TECHNIQUES: TLC, Extraction, Extraction, 1 H NMR spectroscopy In this multi week experiment, we will explore the oxidation of a secondary alcohol to a ketone using an oxidizing reagent, sodium hypochlorite, which is a readily available and commonly used household cleaning product. We will use TLC technique to monitor the progress of the oxidation reaction. Reduction of the ketone will be performed under different reaction conditions and the diastereoselectivity will be determined by 1 H NMR spectroscopy. READING ASSIGNMENT:! Background handout (on website)! This handout for procedure.! Technique 11 Extraction in Techniques in Organic Chemistry 3 rd Ed.! Technique 17 Thin Layer Chromatography in Techniques in Organic Chemistry 3 rd Ed.! Technique 20 IR in Techniques in Organic Chemistry 3 rd Ed.! Technique 21 NMR in Techniques in Organic Chemistry 3 rd Ed.! Supplementary information in Janice Gorzynski Smith (2 nd ed), Chapter 12 PRE-LAB ASSIGNMENT:! In your lab notebook make a table of the chemicals you will use in this experiment.! Remember to use an appropriate scale for the reduction reaction based on your yield from the previous week! You need 100 mg of tert-butylcyclohexanone for this experiment, but if you don t have enough left over your TA will provide you with extra.! In your lab notebook create a flow chart for the work up-procedure whenever an extraction is required. IMPORTANT SAFETY INFORMATION 4-tert-butylcyclohexanol and 4-tert-butylcyclohexanone are irritants. Wear gloves and avoid all contact with skin eyes, and clothing. 5.25% Sodium hypochlorite (NaOCl) is commercial bleach. The solution is colorless or slightly yellow with faint chlorine-like odor. Ingestion may cause corrosion of mucouse membranes. Inhalation may produce severe bronchial irritation. Glacial Acetic Acid is an irritant and can cause severe burns. Use in the hood only! Wear gloves and avoid all contact with skin eyes, and clothing. Sodium borohydride and aluminum isopropoxide are harmful and all contact with skin or eyes should be avoided! Sodium Borohydride is also water reactive and may cause fires if exposed to it. Keep away from water unless specifically instructed! Diethyl ether is extremely volatile and flammable! Use it in the hood! Be certain that a hot plate doesn t ignite the vapors, causing a fire.

2 Deuterated chloroform may be fatal if inhaled or swallowed. Possible carcinogen. Readily absorbed through the skin. Acts as a defatting agent in contact with skin. Harmful if splashed into the eye. Chronic exposure may cause liver and kidney damage. PART A: OXIDATION OF 4-TERT-BUTYLCYCLOHEXANOL Procedure: Dissolve 300 mg of 4-tert-butylcyclohexanol in 4 ml of acetone using a 25 ml round bottom-flask equipped with a magnetic stir bar on a magnetic stirrer. Place a 100 ml beaker containing water (50 ml) on a hot plate and heat to maintain the water temperature approximately 50 o C. Put the reaction flask into the warm water bath before adding 0.50 ml of glacial acetic acid, and start the oxidation by adding 4.0 ml of a 5.25% (0.75 M) sodium hypochlorite solution (commercial bleach). Stir the mixture vigorously with the help of a magnetic stir bar. Use TLC technique to monitor the progress of the reaction every 10 minutes. Remove a small sample for TLC analysis (less than 1 drop using Pasteur pipette) from the organic layer if the reaction mixture separates into two layers. (Which one is the organic layer?) Once the conversion is complete and the reaction mixture shows no more starting material by TLC analysis, proceed with the workup of the 4-tert-butylcyclohexanol. A total of 5 ml of 5.25% NaOCl should be more than enough to convert all of the 4-tertbutylcyclohexanol to 4-tert-butylcyclohexanone. However, since NaOCl decomposes rapidly (eq 1), add an additional 0.5 ml of NaOCl solution if there is still starting material after 30 min. NaOCl + NaCl + H2O Cl NaOH (eq 1) Checking Reaction Progress by TLC: The aliquot you removed for analysis might be very concentrated. If it appears that your sample is too concentrated for good TLC analysis, you can dilute the aliquot in a small flask or test tube using acetone as the solvent. Use 35% acetone/65% hexane, which you will need to make, as the TLC solvent. Since neither the starting material nor the product is UV active, visualization in this experiment will be accomplished using a KMnO 4 stain. To stain your plate, submerge your TLC plate in the jar with the stain and quickly remove it. Allow the excess liquid to drain in the jar and then dab the bottom and back of the plate on a paper towel to remove any excess liquid. The plate will come out dark purple and after a few minutes bright yellow spots will appear. If you are not seeing spots you may place the plate into the oven for one minute. What data should you record?

3 Work up: First, test the reaction mixture for excess hypochlorite by placing a drop of the reaction solution on a piece of wet starch-iodide indicator paper. The appearance of blue-black color from the formation of the triiodide-starch complex on the indicator paper signifies the presence of excess hypochlorite. If hypochlorite is present, add 0.5 ml of 2-propanol (isopropyl alcohol), stir the mixture, and again re-test the reaction mixture for the presence of any hypochlorite. If necessary, continue adding 2-propanol in 0.1 ml increments and testing with starch-iodide paper until excess oxidant is completely destroyed. (Why are we using isopropanol here? How does the addition of isopropanol lead to a lack of hypochlorite? Why are we not concerned about any additional products from this process? These should be mentioned briefly in your report!) Transfer the reaction mixture into a 60 ml separatory funnel. Extract the reaction mixture two times, each with 10 ml hexane. (Which layer contains your product water or hexane?) Wash the hexane extracts with 5 ml of 5% sodium bicarbonate solution, then wash with 5 ml of deionized water. Dry the hexane extract with anhydrous sodium sulfate for a few minutes, and transfer the hexane extract to a tared Erlenmeyer flask. Rinse the anhydrous sodium sulfate with 2 ml of hexane and add the rinsed hexane to the hexane extract. Evaporate the hexane in the fume hood using gentle heating on a hot plate or by blowing air to yield an off white or yellow colored residue of crude product. Cool the residue until it becomes a solid. Give your product to your TA in a properly labeled vial. What data should you record? PART B: REDUCTION OF 4-TERT-BUTYLCYCLOHEXANONE FOR DETERMINATION OF DIASTEREO SELECTIVITY AND THERMODYNAMIC VERSUS KINETIC CONTROL Your TA will assign one of the two reduction reactions to you for the second lab period. O NaBH 4, EtOH or H OH + OH H Al(OiPr) 3 iproh Procedure for Sodium Borohydride Reduction Dissolve 100 mg of 4-tert-butylcyclohexanone in 3 ml of ethanol in a 25 ml Erlenmeyer flask equipped with a magnetic stir bar on a magnetic stirplate. Slowly add the appropriate amount of sodium borohydride (3 molar equivalents) to the flask. Each 15 minutes, check the reaction progress using TLC (see instructions for monitoring the reaction progress as described in Exp 5). Once you have determined the reaction is complete, slowly quench the reaction by adding 2 ml of deionized H 2 O drop-wise, followed by drop-wise addition of 3M HCl until no more H 2 gas is evolved. Cool the reaction mixture to room temperature and add 5 ml of Et 2 O. Transfer the solution into a separatory funnel. If there is solid in the bottom of the Erlenmeyer, carefully decant the solution into the separatory funnel leaving any solid behind. Rinse the remaining solids with 2 ml of diethyl ether and add it to the separatory funnel, again leaving the solid behind in the Erlenmeyer. Extract the reaction mixture and separate the layers and set the Et 2 O layer aside. Take the aqueous layer and extract with 5 ml of Et 2 O again. Add the ether layer from the second extraction with the one from the first extraction and pour it back into the separatory funnel. Wash the combined organic layers with 5 ml of deionized water. Dry the organic layer with anhydrous sodium sulfate

4 for a few minutes, and transfer it to a tared Erlenmeyer flask. Rinse the anhydrous sodium sulfate with 2 ml of ether and add the rinsed ethers to the ether extract. Evaporate the ether in the fume hood by heating in a water bath or by blowing air. Cool the residue until it becomes a solid. What data should you record? Prepare an NMR sample by dissolving around 100 mg of synthesized 4-tert-butylcyclohexanol ~0.50 ml deuterated chloroform to dissolve the solid. Consult with your TA if you have significantly less than 100 mg of product. Once all of the solid is dissolved, transfer the solution to an NMR tube and cap the tube. Be sure to label your NMR sample. NOTE: If it is possible to perform both reduction reactions simultaneously then this could be a time saving technique. You should decide whether you feel capable of completing both reactions in a single lab period. Procedure for Meerwein-Pondorff-Verley Reduction In a 10 ml round bottom flask equipped with a stirbar and a condenser, 4.0 ml of isopropyl alcohol, 0.40 ml of acetone, 100 mg of 4-tert-butylcyclohexanone and 1.0 g of aluminum isopropoxide were combined. The solution was heated to reflux for one hour. After cooling, transfer the reaction mixture to a separatory funnel. Add 20 ml water, then extract the mixture with two 10 ml portions of ether. Wash the combined ether layers with two 10 ml portions of H 2 O to remove most of the isopropyl alcohol that remains dissolved in the ether layer. Dry the combined ether layers over anhydrous MgSO 4, filter, and remove the solvent by air stream. What data should you record? Prepare an NMR sample by dissolving around 100 mg of synthesized 4-tert-butylcyclohexanol ~0.50 ml deuterated chloroform to dissolve the solid. Consult with your TA if you have significantly less than 100 mg of product. Once all of the solid is dissolved, transfer the solution to an NMR tube and cap the tube. Be sure to label your NMR sample. NOTE: If it is possible to perform both reduction reactions simultaneously then this could be a time saving technique. You should decide whether you feel capable of completing both reactions in a single lab period. REPORT REMINDERS Introduction: Write a coherent introduction that describes the goals of this four-week project. Theory: Results: Include an overview of the oxidation and reduction reactions. Include a discussion of the mechanisms for both reactions and any appropriate stereochemistry considerations. Summarize the results you obtained in each part of this project. Include all relevant observations and data for all reactions and compounds. Include calculations for

5 cis/trans ratios from spectra of alcohols including commercially purchased starting alcohol mixture (provided on class website), alcohol mixture from sodium borohydride reduction, alcohol mixture from MPV reduction, and alcohol mixture from L- selectride reduction (provided on class website). Discussion: Discuss reaction results as usual. Provide a reasonable explanation for the diastereoselectivity and the outcomes for the reductions conducted under the three different conditions. Evaluate the stereoisomer ratio in the commercially obtained alcohol mixture and determine whether this mixture appears to have been synthesized by any of the three reductions in this experiment.