Homework answers / question archive / Study in Diastereoselective Addition of Grignard ReagentQ1-4 to Alpha-Chiral Ketones: In lecture, we have discussed several mechanistic models developed to explain the stereoselectivity observed in reactionsQ9,10 resulting in the formation of new chiral centers

Study in Diastereoselective Addition of Grignard ReagentQ1-4 to Alpha-Chiral Ketones: In lecture, we have discussed several mechanistic models developed to explain the stereoselectivity observed in reactionsQ9,10 resulting in the formation of new chiral centers

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Study in Diastereoselective Addition of Grignard ReagentQ1-4 to Alpha-Chiral Ketones: In lecture, we have discussed several mechanistic models developed to explain the stereoselectivity observed in reactionsQ9,10 resulting in the formation of new chiral centers. Some of these include the famous Cram’s model, the Felkin-Anh model and the Cram chelation model. In this experiment, we will study the reaction between (±)-2-hydroxy-1,2-di(phenyl)ethanone (benzoin, (±)-1) and methylmagnesium iodide. The reaction is expected to result in a racemic mixture of two diastereomersQ5-8, 2a and 2b. HO H Ph Ph Me OH (+)-2a (mp 104 o C) HO H Ph Me Ph OH (+)-2b (mp 94 o C) Once the major stereoisomer isolated is identified, you will use one of the models mentioned above to explain the stereoselectivity achieved in this reaction. In your report, you will clearly draw the structure of the major diastereomer formed (as a racemic mixture) and also provide a clear explanation for the stereoselectivity achieved by including a drawing of the key intermediate or transition state responsible for the stereoselectivity. Experimental Cautions: It is essential that your glassware be clean and dry one week before the day of the Grignard reagent preparation. Diethyl ether is highly volatile and flammable so no open flames will be allowed during the experiment. Do not use hot plates to remove diethyl ether since it has a low flash point. IodomethaneQ11,12 (methyl iodide) is a suspected carcinogen so avoid skin contact and breathing its vapor. Handle this reagent with protective gloves and always handle it and its ether solution in the hood. CHEM 420 – Grignard Experiment – Lab Manual 1 Preparation of Methylmagnesium Iodide: One week before the experiment, make sure that that all necessary glassware is clean and dry. Do NOT wash your glassware on the day of the experiment. Check out an additional drying tubeQ15.1-15.2 from the stockroom. A 1.0 M solution of MeI in anhydrous diethyl ether, provided for you by the stockroom, was added to your addition funnel. Magnesium turningsQ14 (290 mg, 12.0 mmol) and a dry stirring bar were placed in a dry 100-mL one-neck round-bottom flask equipped with a Claisen head adapter which is mounted with a reflux condenser and an addition funnel. Attach a drying tube to both attachments. Transfer the 1.0 M MeI in ether solution (12.0 mL, 12.0 mmol) to the addition funnel. Cover the magnesium metal with about 2 – 3 mL of the 1.0 M MeI in ether solution. Once the Grignard reagent formation has started, the rest of the MeI/ether solution was added slowly over 20 minQ13 from the addition funnel to the magnesium turning with stirring. The suspension was periodically hand-warmed during addition, and the reaction proceeded spontaneously. After addition was complete, the contents of the flask were refluxed using a heating mantle with voltage regulator until most of the Mg metal had reacted and the solution was cloudy gray or white (usually 30 min). If a significant amount of unreacted Mg remained, the mixture was cooled to room temperature and treated with an additional 2 mL of 1.0 M ethereal MeIQ16. The reaction was continued at room temperature and then heated to reflux as before until most of the Mg had reacted. You will use this set up in the next step so do not take it apart. Grignard Reaction of MeMgI with Benzoin; Synthesis of 2Q25: The ethereal MeMgI solution in the 100-mL round-bottom flask used in the reagent preparation above was cooled in an ice-water bath. (+/–)-1 (500 mg, 2.36 mmol) in anhydrous CH2Cl2 (10 mL) was added slowly from the addition funnel over 2–3 min while the mixture was stirred (the solution frothed slightly owing to methane evolutionQ11). After addition was complete, the ice-water bath was removed and the mixture was refluxed for 25 min using a heating mantle. Check the reaction progress by TLC by spotting some of the reaction mixture directly onto a TLC plate with some benzoin already prespottedQ17. (Further heating may be required, depending upon reaction progress.) After cooling to room temperature, the mixture was slowly treated with 10% H2SO4 Q22(50 mL), vigorously swirled for 1–2 min, poured into a separatory funnelQ18-21,24, and the layers separated. The aqueous layer was extracted once with 15 mL of ether. The combined organic layers were dried over anhydrous MgSO4, filtered into a pre-weighed flask, and concentrated on a rotary evaporator to afford 495 mg ((92%, the average yield) of an amber solid (average mp 83–88 °C) or an amber oil, which partially solidified upon cooling. Run a TLC on the crude product against the starting material. Recrystallize the crude product using ca. 5 mL (but not more than about 25 mL) of high-boiling petroleum ether for every 100 mg of crude (+/–)-2 once or twice, taking the melting point after each recrystallization. For each recrystallization, the mother liquorQ23 was decanted away from any undissolved solid and was CHEM 420 – Grignard Experiment – Lab Manual 2 not cooled in an ice-water bath. The purified product (+/–)-2 was obtained as white needles. Weigh the product and calculate an yield. 1H NMR (CDCl3) δ 7.2–7.0 (m, 10 H, Ph), 4.65 (s, 1H, PhCH(OH)); 2.70 (s, 2H, OH, D2O exchangeable), 1.60 (s, 3H, CH3). Report: There will be two parts to the report: An experiment results/data report sheet will be completed outside of the lab. A data analysis report sheet will be completed in lab after the last day of the experiment. CHEM 420 – Grignard Experiment – Lab Manual 3 CHEM 420 – Grignard Experiment – Lab Manual 4 IR of Benzoin Model IR 1,2-diphenyl-1,2-propanediol Name:___________________________________ Report Sheet for the Grignard Experiment (Spring 2021) DUE: Week of May 3-7) (Please be concise and complete! Attach all spectra copies.) 1. Write the balanced equation for the reaction between the methyl Grignard reagent and (+)benzoin (prior to any acid addition). (4 pts.) 2. Write the balanced equation (for the reaction involved in the acid work-up) step between the sulfuric acid solution and the alkoxide formed through the Grignard reaction in question #1. (5 pts.) 3. Calculate the total moles of protons that the sulfuric acid provided in the work up. Also, calculate the total moles of iodomagnesium alkoxide expected to form (if the reaction proceeded at 100% yield) and determine if enough protons were supplied or not to protonate all of the alkoxide expected to form in the experiment. (4pts.) 4. The IR spectrum of the benzoin starting material and a model IR spectrum of the 1,2diphenyl-1,2-propane diol product are posted on the CHEM420-sec01Beachboard site. Compare these two IR Spectra. What features of the Benzoin IR change in going to the IR of the product? (6pts) 5. Draw the structure of the major diastereomer that is expected to form in this experiment if transition state model based on Cram’s Rule (which was discussed in the recorded lecture) is applied to the R enantiomer of Benzoin. Include a clear drawing of the Newman projection of the transition state. (6 pts.) 6. Draw the structure of the major diastereomer that is expected to form in this experiment if the Felkin-Anh transition state model (which we discussed in lecture) is applied to the R enantiomer of Benzoin. Include a clear drawing of the Newman projection of the transition state. (6 pts.) 7. Draw the structure of the major diastereomer that is expected to form in this experiment if the Cram chelation transition state model is applied to the R enantiomer of Benzoin. Include a clear drawing of the chelation transition state complex. (6 pts.) 8. Determine which model, Cram’s Rule, the Felkin-Anh or the Cram-Chelate transition state model, predicts the correct diastereomer formed in this experiment. (3 pt.)