Handout Grignard reaction PDF

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Grignard Reaction – Synthesis of Benzoic acid Watch the following videos: ➔ Grignard Reaction – Organic Chemistry (https://youtu.be/ExC9kPQNVaM) This video was created so you can see the whole process while not performing it yourself in the lab due to the pandemic. Grignard Reaction (https://youtu.be/19KRl1jdAWw) Drawing Solvent in a Needle from a bottle capped with a septum (https://www.youtube.com/watch?v=Z_oWPZV1kIc) Recrystallization – microscale (www.youtube.com/watch?v=IOodrXFvpoA&feature=youtu.be) - No hot filtration will be done in this lab. Microscale Vacuum Filtration (www.youtube.com/watch?v=bhLEfPWGwtY&feature=youtu.be) TLC chromatography (www.youtube.com/watch?v=Z7Dd4ZaIaXA&feature=youtu.be) TLC – SMART video (www.youtube.com/watch?v=462CmolEFhc) Melting Point determination (https://www.youtube.com/watch?v=bV9VfjdQJBo) - you are not performing the experiment shown in the video but you will perform one melting point measurement with the final product of the reaction.

Read the following chapters in the OER textbook: “Organic Chemistry Laboratory Techniques” from Lisa Nichols, 2nd edition (https://open.umn.edu/opentextbooks/textbooks/369): 1.1.F Drying Glassware 1.4.D Suction Filtration 1.4.F Pipette Filtration 2.2 Thin Layer Chromatography (TLC) Chapter 3: Crystallization (especially 3.4 and 3.5) Chapter 4: Extraction (especially 4.3 and 4.7) 6.1 Melting Point And whatever you need to review to perform this experiment successfully.

Background: The formation of a carbon-carbon bond is one important objective in organic synthesis. One of the reactions that accomplish this goal is the Grignard reaction, an organometallic chemical reaction. The Grignard reagent is formed by reaction of an alkyl halide with magnesium metal in anhydrous diethyl ether.

Formation of the Grignard reagent:

. . . Mg

-

.

. .

The bond between in the Grignard reagent is not only highly polarized but has a significant ionic character with a negatively charged carbon atom. The reason for that is the large difference in electronegativity of the two elements. The Grignard reagent is very reactive and will react as a . Any acidic protons will immediately react with the Grignard reagent in an acid base reaction. If that happens, the purpose of the Grignard reagent to react with a carbonyl carbon and form a new carbon-carbon bond cannot be fulfilled. Therefore it is very important to exclude water from the reaction and work under absolute dry conditions. . The first reaction is the formation of the Grignard reagent (see above). The second reaction is the nucleophilic attack of the phenylmagnesium bromide (the Grignard reagent) with carbon dioxide. Formation of the carbon-carbon bond:

. .

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Make sure you include the overall reaction AND the reaction mechanism in your notebook BEFORE you come to the lab. (The overall reaction is NOT given here!) Most likely you will have the side products benzene and biphenyl in the ether layer that will be analyzed via HPLC, you NEED to include the reaction mechanism of the formation of these side products either in your introduction or discussion (if you don’ have them already in your lab note book). You can draw the structures by hand scan it and include it in your word document (or hand in a hardcopy on the due date of the lab report). You can also draw the structures/mechanism with a drawing program (e.g. Accelrys or ChemDraw – the programs are on the computer/s in the computer lab across Einstein Corner) and include them in your word document that you submit through Moodle/Turnitin. DON’T just copy/paste the equations from any source. You will find more information on the background and the mechanism of the Grignard reaction in the Klein textbook 2nd edition Chapter 13.6 (page 596 – 599).

Additional information about this experiment can be obtained by reading Chapter 38 (pages 490 to 505) of Williamson/Masters: Macro and Micro Experiments in Organic Chemistry, 6 edition, other Org. Chem. laboratory textbooks or from online resources.

Procedure:

Unfortunately, due to the pandemic we cannot let you do the synthesis part of the experiment in the lab. In our experience student need a lot of help to close the septum, get the reaction started, … As you know we need to stay 6 feet apart from each other and therefore we won’t be able to provide you with the help you might need. However, we produced a video of the experiment. The parts that is not done by you is printed in italic in the following procedure. You need to have these parts of the procedure (reaction and HPLC chromatogram) in your lab report as if you have done the experiment yourself. At the beginning of the lab (BEFORE you get an introduction from your instructor!!!) rinse out a clean microscale reaction tube and a vial with 0.5 mL acetone and place it in the preheated oven. DO NOT place the vial lid and the septum in the oven! You will find a dry syringe, needle, stir bar, and septum in the desiccators. They were dried for at least 12 hours. After heating the glassware for about 20 minutes at 120°C all water molecules should be removed. Take the reaction tube and the vial out of the oven – WEAR GLOVES while doing so otherwise you will burn your fingers! IMMEDIATELY after removing the reaction tube from the oven close it with the septum and the vial with a lid. If the glassware stays open while cooling down, atmospheric water will condense on the glass and the heating process needs to be repeated. Grind Magnesium with a mortar to remove at least some of the magnesium oxide layer and maybe produce fresh cut pieces of magnesium. Weigh 2 mmol of small pieces of magnesium on a weighing boat/weighing paper. Calculate the milligrams BEFORE you come to the lab. Since magnesium is the limited reagent in this reaction you need to record the exact weight to the nearest milligram. After the reaction tube has been cooled down to room temperature, add the magnesium and a stir bar. Be fast! Don’t leave the tube open for a long time. Have the magnesium and the stir bar ready, open the septum, add the magnesium and the stir bar, and close the septum. Use the syringe provided at the diethyl ether bottle, add 0.5 mL anhydrous diethyl ether through the septum. (The anhydrous diethyl ether is in the bottle with the septum. The septum is used to protect the ether from humidity in the air. Only puncture the middle of the septum with the needle. NEVER push the needle so deep in the septum that the bigger part of the needle would touch the septum. NEVER remove the septum.) Draw 2.1 mmol dry bromobenzene (stored over molecular mole sieves) in a dry syringe (provided in the desiccator). Calculate the milliliters BEFORE you come to the lab! Place 0.7 mL dry diethyl ether (again drawn with the syringe provided with the dry diethyl ether bottle) in the dry vial and immediately draw the ether in the syringe with the bromobenzene. Mix the two liquids in the syringe by swirling the syringe. Make sure the reaction mixture is mixed well.

Pierce the septum of the reaction tube with a needle for pressure relief. Push the needle of the syringe that holds the bromobenzene-diethyl ether solution also through the septum. Inject about 0.1 mL of the bromobenzene-ether solution into the reaction tube. (DO NOT add more bromobenzene-ether solution yet.) You can put the reaction tube in an Erlenmeyer flask or a beaker and place it on top of a stirrer. Start the stirrer without applying heat. After about 2 to 5 minutes, the solution should get cloudy, bubbles should appear, and the reaction mixture should get warm. If that is not the case, ask your instructor or learning assistant for help. If the solution gets cloudy and warm the Grignard reaction started. Do not let it stop! Add the bromobenzene-ether solution dropwise over a period of several minutes. You have to add enough to let the reaction continue but don’t add too much. Otherwise, the reaction might be too violent. To prevent diethyl ether from boiling away, wrap a pipe cleaner around the top part of the reaction tube and dampen the pipe cleaner with water. Make sure no water will enter the reaction tube through the pressure relief needle. While adding the bromobenzene-ether solution make always sure that the reaction mixture stirs well and keeps reacting. After all, bromobenzene solution is added the reaction has to continue until no magnesium is left over. You might need to heat the solution in a water bath. Check the volume of the ether. If a lot of ether evaporated, add that amount of anhydrous diethyl ether with a syringe. If no magnesium is left over in the reaction tube, get fresh prepared dry ice (solid carbon dioxide) from your instructor/learning assistant in a 30 mL beaker. Remove all needles from the septum, remove the septum and IMMEDIATELY pour the mixture (phenylmagnesium bromide in ether – the Grignard reagent) over the dry ice. Stir with a dry glass rod, allow excess dry ice to sublime. Then hydrolyze the salt by adding 2 mL of 3 M hydrochloric acid. Transfer the mixture to a reaction tube. Rinse out the beaker twice with about 0.5 mL tert-butyl methyl ether (Do not use the dry diethyl ether here. It is not necessary to use dry ether anymore - you already added water to the reaction mixture.) Make sure you get as much as possible of the white/yellow precipitate (This is your product!) Add the rinse to the reaction tube. You might want to use a pipette to do so or simply pour it if you are confident to not spill it. Cork the tube and shake it thoroughly. Two layers should result with about 1.5 mL tert-butyl methyl ether as the top layer. Don’t continue unless you provided 10 L of the ether solution for a HPLC analysis. (Skip providing a sample. However, you will be provided with an HPLC chromatogram of a reaction mixture from a reaction from an experiment from the past. The HPLC chromatogram, the interpretation and discussion need to be included in your lab report as if it were the sample of the Grignard Reaction you performed.) If that is done, remove the aqueous layer and extract the ether layer with 1 mL of water. Remove the water layer and discard it. (Even though the water layer can be discarded, it is a good habit to not through anything out before the experiment is done. If you do not get product because you mixed up the layers you might be able to go back to these solutions and save your product.) Then extract the benzoic acid from the ether layer by adding 0.7 mL of 3 M sodium hydroxide solution to the ether layer. Shake the solution thoroughly. Withdraw the aqueous layer and place it in a clean vial. Repeat the extraction with 0.7 mL 3 M sodium hydroxide (combine this layer with the previous basic extract) and finally with 0.5 mL water (add this layer to the precious two basic extractions). Now that the extraction is complete, the ether contains

primarily biphenyl (the byproduct formed during the preparation of phenylmagnesium bromide) and benzene (formed by the reaction of phenylmagnesium bromide with water) and can ultimately be discarded. (But again, it is a good habit to keep all solutions until the product is isolated.) The combined aqueous basic extracts are heated briefly to about 50°C to drive off dissolved tert-butyl methyl ether from the aqueous solution. Do not leave it unattended! Add concentrated hydrochloric acid to make the solution acetic. (Test with indicator paper – DON’T dip the paper in the solution. Use a glass rod to take one drop of the solution and place it on the indicator paper.) Cool the mixture in an ice bath and collect the crystalized benzoic acid via vacuum filtration with a Hirsch funnel. Wash the crystals with about 1 mL ice cold water while on the funnel. (Preparation of ice-cold water: Add DI water in a reaction tube and place the tube in an ice bath.) The product is recrystallized from boiling water. (www.youtube.com/watch?v=IOodrXFvpoA&feature=youtu.be – no hot filtration is necessary here. In addition to watching the video, read the chapters about recrystallization in the OER textbook.) Perform a TLC on your purified product with hexanes/ethyl acetate: 7/3. Watch the videos www.youtube.com/watch?v=Z7Dd4ZaIaXA&feature=youtu.be and www.youtube.com/watch?v=462CmolEFhc and read the Chapter about TLC in the textbook. Once the TLC is developed you ask your instructor or LA to provide the UV. Take a picture of the TLC plate while the UV light makes the sample spot visible. Keep the purified product on your lab place in a tared vial that is covered with a kimwipe. Make sure the vial is labeled with your full name and the word “Grignard”. Next time you will be in the lab, all water should be evaporated from the sample and you can determine the weight of the product and the melting point. You will be provided with an NMR and IR of the product. The spectra, the correct notation of the spectra and their interpretation need to be included in the lab report.

Cleaning up:

Pour all solutions in one glass container (beaker or Erlenmeyer flask) and leave it on your lab space labeled with “Waste”....