Experiment 2. Sodium Borohydride Reduction_Experimental Procedure - REVISED W24

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Feb 20, 2024

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Experiment 2: NaBH 4 Reduction of Aryl Ketones Introduction: Hydride reducing agents such as LiAlH 4 (lithium aluminum hydride) and NaBH 4 (sodium borohydride) react with ketones to produce 2° alcohol products, or with aldehydes to produce 1° alcohols. Both reagents were discovered by Schlesinger and Brown in the 1940s and are routinely used in organic synthesis. 1 NaBH 4 is a milder reducing agent than LiAlH 4 and can be used in protic solvents, such as ethanol. Conversely, LiAlH 4 must always be used in aprotic solvents, such as tetrahydrofuran, and under rigorously anhydrous (moisture-free) conditions. LiAlH 4 also requires a separate acidic work up step, while reduction with NaBH 4 does not (if conducted in a protic solvent). Reaction Scheme: Note the stoichiometry of the reaction. Each molecule of NaBH 4 can reduce up to 4 carbonyl groups since the reagent can potentially deliver 4 hydrides per NaBH 4 molecule. Objective: In Part 1 (Session 1) of this experiment, you will carry out the reduction of 9-fluorenone with NaBH 4 . Your objective for Part 2 (Session 2) of this experiment is to explore the influence of ketone structure on reactivity towards NaBH 4 . To achieve this goal, you will formulate a hypothesis about the relationship between structure and reactivity, and then design an experiment to test this hypothesis. IMPORTANT NOTE: You should complete the Experimental Design Worksheet after your first lab session; this is due two days after the day of your first lab session for Experiment 2. 1 Schlesinger, H.I.; Brown, H.C. et.al. J. Am. Chem. Soc. 1952 , 75 , 186. 9-fluorenone O Part 1 NaBH 4 Ethanol 9-fluorenol OH Part 2 NaBH 4 Ethanol O R R = H, OCH 3 , Br, Cl, CH 3 OH R reactivity hypothesis?

Procedure: Table 1. Reagents used in this experiment – this is not complete – look up what you need for part 2 Reagent CAS Number Molecular Weight (g/mol) Concentration or density m.p or b.p ( o C) SAFETY NOTES 9-fluorenone 486-25-9 180.206 – 84 (m.p) Toxic, irritant Sodium Borohydride 16940- 66-2 37.83 – – Flammable, reacts with water 9-fluorenol 1689-64- 1 182.22 – 152–155 (mp) Toxic, irritant Ethanol 64-17-5 46.069 0.789 g/mL 78 (bp) Toxic, flammable Before the week 1 lab session, be sure to use Reaxys, SDBS, or other databases to find the literature melting point value, and IR and NMR spectra from the literature that you can use for comparison to the data you obtain from your product. You should include this information in your pre-lab writeup. See the Notebook Page Assignment Description for details. Part 1 (Lab Session 1) – In a disposable reaction vial, dissolve 0.1 g of 9-fluorenone in 2 mL of 95% ethanol, and cool the solution in ice (you may observe a fine suspension rather than a homogeneous solution – this is fine). Add to this solution or suspension 20 mg of sodium borohydride (a large excess; remember all 4 H’s are active!). If you have a suspension the suspended ketone solid will dissolve. The reaction mixture may warm up and it may be necessary to add more ethanol if it has evaporated. After 15 minutes, add 1 mL of water and heat the solution to the boiling point. Dilute the hot solution with hot water (1-2 mL) to the point of saturation indicated by cloudiness. Cool the mixture to room temperature, then collect the crystalline precipitate using vacuum filtration. Obtain the mass of your crude product. Purify by recrystallization (you will need to determine the best solvent mixture, but a combination of ethanol and water usually works). Collect the pure crystallized solid by vacuum filtration. Pull air through the solid for 5-10 minutes (as time allows), then measure the mass of your product and characterize your product by TLC, IR, NMR, and Melting Point. Be sure to graphically annotate your IR and NMR spectra once you print them out or transfer them to your computer/tablet/etc. Note: An amber bottle containing NaBH 4 is stored in a larger jar containing a desiccant. Take care not to add desiccant to your reaction by mistake. The NaBH 4 is a powder with small particle size. The desiccant has a much larger particle size (pebbles rather than powder).

Characterization: Calculate percent yield. Determine the purity of the product using TLC . For TLC analysis, determine and report the appropriate solvent mixture to use as eluent; be sure to report the visualization method you use (UV light for this experiment). Be sure to run a TLC of the crude product to determine if starting material was consumed. Characterize the product by m.p. , IR spectroscopy , and 1 H NMR spectroscopy . Part 1 Analysis Questions (page limit: one sentence per question – these are Yes/No questions, but please write a complete sentence so it is clear which question you are answering). (a) Do all the key signals in the literature NMR spectrum of your desired product appear in your acquired NMR spectrum of the product you made in lab? Sample Answer: Yes, all key signals from the literature NMR spectrum of my product can be seen in the NMR that I acquired. (b) Do you see additional signals in your acquired NMR spectrum that are not present in the literature NMR spectrum? (c) Do all the key stretches in the literature IR spectrum of your desired product appear in your acquired IR spectrum for the product you made in lab? (d) Does the TLC of your crude product show one or more spots that are not your starting material? (e) Does the TLC of your crude product show complete consumption of the starting material(s)? (f) Does the melting point you measured match the literature value for your product? Part 1 Reflection Questions (page limit: ½ page; no more than a few sentences may be needed) (a) What aspect of the experiment that you did today was the most challenging (where could you make improvements for part 2)? (b) What do you plan to do differently for part 2 of this experiment to make the challenging part easier or to improve whatever did not go as well as planned? Design your experiment for Part 2 during/after your lab session (the Experimental Design Worksheet is due 2 days after your first lab session). Here are a few important things to keep in mind: 1. You should design your experiment during the lab period, or right after. It won’t take a ton of time, and it is easier/more efficient to do this while all group members are together (rather than having to meet at some later time/location). 2. Each group member should run a reaction, that is different from reactions that other group members are running. Each reaction will become one of your group’s data points that you will analyze to assess the validity of your hypothesis. 3. Work smarter not harder! The key to productive experimentation is good preparation. The more thought you put into it the better the feedback your GSI can give you. There are many important things to consider when designing your experiment. How many reaction trials will you run and why? How will you

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ensure reproducibility between the reaction trials? How will you assign work within your group (i.e. who will do which reaction trial)? 4. Do your best to ensure that this is a fair experiment. In other words, you should take care to change only one variable; everything else should be kept constant. For example, although you will be using different ketones, you should keep all other aspects of the reaction the same for each reaction trial including temperature, quantity and concentration of reagents, and method of monitoring the reaction. Take care that your dependent variable is something you can measure. 5. Note that the purification method that works in the procedure above may not work the same for a modified procedure. A modified isolation procedure is provided below if needed. 6. Flexibility and communication are essential. Be prepared to make alterations to your experimental plan in real time in the lab. 7. A failed experiment does not mean a failing grade! Your lab grade will be evaluated based on your understanding of the experiments you design and implement and on your understanding of the results you do obtain. You will not be penalized for experimental errors made by another group member. 8. Take care to share the results of your part of the experiment with the other members of your group before you leave the lab. Likewise, make sure the other members of your group do the same. Available ketones (acetophenone derivatives): Ketones that are available in the Chemistry 216 laboratory are shown below. It isn’t necessary to test all of the compounds. Rather, you should select a set of 3-4 (one per group member) that you think will demonstrate a range of reactivity based on electronic differences that result from structural variations (different substituents on the aromatic ring). Keep in mind that a small change in the structure of each compound can have a significant impact on reactivity, but it could also influence the solubility and other physical properties of both the ketone starting material and the alcohol product, so you may need to make adjustments to your procedure in the lab in real time to troubleshoot problems.. Note: you will need to look up the molecular weight and melting point of these ketones and should also check for safety data (i.e. toxic, irritant, flammable, etc.). The Aldrich catalog is a good place to look, but there are other sources where this information can be found as well. Before the week 2 lab session, be sure to use Reaxys, SDBS, or other databases to find the literature melting point value, and IR and NMR spectra from the literature that you can use for comparison to the data you obtain from your product (the one you personally will make – each group member will run a different reaction). You should include this information in your pre-lab writeup.

You only need to include information in your pre-lab for the reaction you personally run. You do not need to include all of the information for reactions run by your lab partners. Part 2 (Lab Session 2) – Use the procedure on the previous page (the one you used during session 1) for the reduction of the acetophenone derivative you have selected based on your group’s experimental design. If you do not obtain a solid, or if your expected product is a liquid, after you have cooled the mixture to room temperature (the last step before recrystallization for Part 1), transfer your liquid solution (mixture of ethanol, water, and product) to a separatory funnel. Extract the mixture 3 times with 5 mL portions of ether. The ether will be the top layer, and the aqueous will be the bottom. It is fine to add another 1-2 mL of water if the layers are hard to see after you add the first portion of ether. Combine the three ether extracts in one Erlenmeyer flask. Add solid MgSO 4 to dry (swirl the contents). Vacuum filter to remove the solid MgSO 4 ; the product is in the ether solution. Gently blow air or nitrogen over the ether solution to dry. Essentially all of the liquid should evaporate to leave a thin film. Characterization: Determine the mass of your product. Obtain TLC, product m.p., an IR spectrum, and a 1 H NMR spectrum of your product. Be sure to include annotated copies of your IR and NMR spectra when you upload your notebook pages! Part 2 Analysis Questions (page limit: 1 page; nothing more will be graded): The easiest way to answer these questions is to simply talk about your data. (a) Did the reaction you conducted produce the expected product? How do you know? (b) Was the product you isolated pure, or were there also impurities, and how did you know? (c) If you obtained less than 100% yield, briefly explain why (common explanations are losses during purifications, incomplete reactions, etc.). If you obtained more than 100% yield, briefly explain why (what impurities may be present in your isolated product, or did you make a weighing/measuring error of some sort?). Part 2 Discussion (page limit 2 pages hand-written; 1 page typed) (a) Complete and include the tables below (you will need to get information from your teammates to do this – it is best to do this right after the lab session before everyone leaves the room); these do not count towards page limits. (b) Restate your hypothesis (copy the hypothesis you wrote on the experimental design worksheet). (c) Briefly answer the following question: Do these results your group obtained support your hypothesis or rule out your null hypothesis? Why or why not? Student #, Name Ketone (name or structure) Result of Experiment (% yield, reaction time, etc.) Student 1 [Enter Name] Student 2 [Enter Name] Student 3 [Enter Name] Student 4 [Enter Name]

Group Experiment Peer Review Form Please rate your group members in the space provided below. Your GSI will use this to calculate your group participation points for the experimental design portion of this experiment. Group Member 1 Name: Rate this group member on their overall contribution to this experiment including worksheet A preparation and contribution during the lab session (circle one): 0 = didn’t contribute 1-2 = minimal contribution 3 = average contribution 4 = good contribution 5 = outstanding contribution Briefly explain your rating: Group Member 2 Name: Rate this group member on their overall contribution to this experiment including worksheet A preparation and contribution during the lab session (circle one): 0 = didn’t contribute 1-2 = minimal contribution 3 = average contribution 4 = good contribution 5 = outstanding contribution Briefly explain your rating: Group Member 3 Name:_ Rate this group member on their overall contribution to this experiment including worksheet A preparation and contribution during the lab session (circle one): 0 = didn’t contribute 1-2 = minimal contribution 3 = average contribution 4 = good contribution 5 = outstanding contribution Briefly explain your rating:

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