CH421 Experiment 3

CH421 Experiment 3 A Guided Inquiry: Using the Grignard Reaction to Prepare an Alcohol and Determining Reaction Conversion

Reading: Organic Chemistry by John McMurry, 8e, Chapter sections 10.6 and 17.5

Techniques: TLC, extraction, NMR

Introduction Grignard reagents are organomagnesium halides (RMgX), and they are one of the most synthetically useful and versatile classes of reagents available to the organic chemist to generate carbon‐carbon bonds. A Grignard reagent is generated by treating an organic halide with magnesium metal in an ethereal solvent (e.g., diethyl ether or tetrahydrofuran). The reaction proceeds via a free radical mechanism as illustrated below. The organic halide reacts with magnesium metal to yield an alkyl or aryl free radical and magnesium halide radical, which then combine to yield the Grignard reagent. The carbon‐magnesium bond is covalent but highly polarized so that the carbon has significant anionic character. This carbanion is both a strong base and a good nucleophile. The Grignard reagent is capable of reacting with many different substrates, including carbonyl compounds, alkyl halides, and other organometallic reagents. One of the most important and synthetically useful reactions involving Grignard reagents is their addition to carbonyl compounds such as aldehydes, ketones, and esters to furnish the corresponding secondary and tertiary alcohols.

Grignard reagents (like organolithiums) are extremely strong bases that can react violently with hydroxylic compounds, such as water or alcohols; thus protic solvents cannot be used with Grignard reagents. Even solvents that are not rigorously dry will partially quench a Grignard reagent. The metal hydroxide (or alkoxide) formed in the above reaction is an insoluble white solid in ethereal solvents. Therefore, if you see significant white precipitate during the formation of a Grignard reagent, you may need to start the reaction over with dry glassware. In the laboratory, initiation of the Grignard reaction is sometimes very slow. In the presence of air, a thin coating of magnesium oxide forms on the surface of the metal turnings. This coating must be removed or the reaction will not initiate. A sonicator — which produces ultrasonic waves — helps to physically removes the coating. This will be the method used during today’s experiment. Other methods for initiating Grignard formation include adding a small crystal of iodine or a drop of ethylene dibromide. If the magnesium turnings have been properly treated and the reaction still fails to initiate, a few drops of a preformed Grignard reagent may initiate the reaction. Today’s experiment includes two steps. In the first step, you will prepare the Grignard reagent, phenylmagnesium bromide. During the second part of the experiment, you will react your Grignard with a substituted aldehyde: either 4‐ chlorobenzaldehyde, 4‐methoxybenzaldehyde (p‐anisaldehyde), or 4‐methylbenzaldehyde (p‐tolualdehyde).

Experiment 3: The Grignard Reaction: Preparation of an Alcohol

Oftentimes in organic synthesis, reactions do not always proceed to completion, and some starting material still remains unreacted. This can be due to numerous factors, including poor reagent quality, lab technique, or even that the reaction being performed is not a highly favorable or clean reaction. As Grignard reagents are strong nucleophiles and bases, they can be particularly challenging to handle without quenching the reagent. For example, small amounts of moisture on glassware, in impure reactants, or in transfer pipets can react with and therefore destroy your Grignard reagent. In today’s experiment, the Grignard addition to your aldehyde will work to some extent, but it is highly likely that the reaction will not go to completion (i.e. some aldehyde will be left over). While part of the purpose of the experiment is to generate and use a Grignard reagent, another important learning objective is to have you analyze your crude product mixture and determine the extent of reaction (in this case we will use % conversion). Determining % Conversion 1. We will use TLC to qualitatively determine the extent of reaction (i.e. we can see whether or not a spot still exists for the aldehyde starting material). Note that this is only a qualitative answer: starting material is gone (100% conversion), or there is still some left (less than 100% conversion). 2. We will also obtain a 1H NMR spectrum of your crude product. From this spectrum, you will be able to quantitatively determine the % conversion using integration. Here’s how: a. In the crude product 1H NMR, choose an appropriate peak(s) that you can unambiguously assign to your aldehyde starting material; then integrate that peak(s). The NMR spectra of all aldehyde starting materials are given for reference at the end of this lab document. b. Next, in the crude product 1H NMR, choose an appropriate peak(s) that you can unambiguously assign to your alcohol product; then integrate that peak(s). c. To determine % conversion, you use the normalized ratio of the integration values for your starting material and product peaks to determine the % of each component. Your instructor will help you with this calculation during the lab. Safety Precautions Diethyl ether is extremely flammable. Sulfuric acid is corrosive and will cause burns if left in contact with skin for a period of time. Bromobenzene is a mild irritant, and the aldehydes are odorous. Avoid skin and eye contact with all chemicals in this lab and wear gloves and appropriate clothing. Pre‐Lab Notebook (to be completed prior to the start of lab)  

Enter date, experiment number and title on notebook page and in TOC with corresponding page number. Copy the reaction and the reaction table below (in your own writing) into your notebook and complete all empty cells in the table. Calculate the masses for all three aldehydes, but leave the product row blank. Your instructor will assign your group’s aldehyde in lab, after which you can calculate your specific product data. Make sure to check your calculations with your instructor before starting the experiment.


Name

formula

MW (g/mol)

mass (g)

mmol

equiv

d (g/mL)

vol (mL) mp (°C)

bp (°C)

157.07 0.942 6.00 1.5 1.50 0.63 ____ 156 bromobenzene C6H5Br 24.31 1.5 ____ ____ ___ ____ Mg turnings C4H6O3 4‐chloro‐ 140.57 1.0 ____ ____ 45‐50 ____ benzaldehyde C7H5ClO 4‐methyl‐ benzaldehyde C8H8O 120.15 1.0 ____ ____ ____ 204 (p‐tolualdehyde) 4‐methoxy‐ 136.15 1.0 ____ ____ ____ 248 benzaldehyde C8H8O2 (p‐anisaldehyde) alcohol product ____ ____ ____ ____ ___ Procedure Preparation of Phenylmagnesium Bromide As explained in the introduction, your glassware must be thoroughly dry or the Grignard reaction will not initiate. Your instructor will give you two clean, dry test tubes for the reaction. Make sure your small graduated cylinder is not wet; if it is wet, rinse it with a small amount of acetone, then rinse it again with diethyl ether prior to use. First, weigh out 6 mmol of magnesium turnings, record the mass, and place them in one test tube (NOTE: it’s best to cut the larger pieces with scissors into smaller ones). Next, use the provided syringe to measure 6 mmol of bromobenzene into the other test tube, record the volume, and then dilute the bromobenzene with approximately 1 mL of anhydrous diethyl ether (approximately 2/3 of a Pasteur pipet). Use a Pasteur pipet to transfer enough of the bromobenzene/ether mixture to just cover the magnesium in the other test tube. Cover this test tube with a small piece of foil. Place the test tube containing the magnesium/bromobenzene/ether mixture into the sonicator and turn the sonicator on. After 1‐2 minutes, check your reaction for progress. If the liquid is brown, the reaction has begun, and you are ready to continue. If not, let it go for another 2 minutes and check again. If it has still not turned brown, you may be able to add a small crystal of iodine to start the reaction – check with your instructor.

Experiment 3: The Grignard Reaction: Preparation of an Alcohol Remove the tube of brown‐colored Grignard reagent from the sonicator and return to your hood. Add about 1 mL of ether to the tube that contains the bromobenzene/ether mixture, and then carefully add a few drops of this mixture to the magnesium/bromobenzene/ether tube. Keep adding the bromobenzene/ether mixture at a rate which keeps the reaction proceeding, as evidenced by bubbling, a brown color, and production of heat. It should take 10‐15 minutes to add all of the bromobenzene mixture. (While you are waiting, your partner can begin dissolving the aldehyde in ether as directed in the next section.) After all of the bromobenzene/ether is added, monitor the reaction for loss of solvent and for signs of continued reaction. If the volume drops below 2 mL, add a little fresh diethyl ether to the test tube. (Your instructor will have a test tube marked with the proper volume for reference.) Once the reaction stops, as evidenced by no more bubbling and the disappearance of almost all of the magnesium, put the reaction tube back into the sonicator for 2 minutes. Your Grignard reagent is now ready to use in the second part of the experiment. Addition of the Grignard to Your Aldehyde Carefully weigh out 4 mmol of your assigned aldehyde into a clean, dry 25 or 50 mL Erlenmeyer flask, record the mass, add a magnetic stir bar, and dissolve the aldehyde in about 4 mL of anhydrous diethyl ether. Clamp the Erlenmeyer flask in a versatile clamp and place in an ice‐bath over a stirring motor. Stir the aldehyde solution slowly, and then use a Pasteur pipet to slowly transfer the Grignard reagent to the cold aldehyde solution. Be sure to add it slowly, in a drop wise fashion, and be sure to leave any unreacted magnesium behind in the test tube. Once the addition of the Grignard reagent is complete, remove the flask from the ice bath and let it stir at room temperature for about 5‐10 minutes (during this time you should begin to chill 5 mL of 5% H2SO4 for the next step of the experiment). To quench the reaction, slowly add 5 mL of chilled 5% H2SO4 (aq.) to the reaction flask (continue to stir, if possible). Swirl the flask until the mixture is nearly free of undissolved solids (the basic magnesium salts are converted into water‐ soluble salts, and the alcohol product dissolves in the ether layer). Transfer the mixture to your separatory funnel, leaving behind any undissolved solids. Rinse the flask with a small amount of ether and add this rinse to the separatory funnel. If there are not two obvious layers in the separatory funnel, add a little more ether (total volume should be ca. 10 mL). Shake the funnel, allow the layers to separate, and then drain off the lower aqueous layer. Wash the ether layer with 3 mL of 5% H2SO4, drain the lower aqueous layer, then wash the ether layer with 3 mL of saturated aqueous sodium chloride. Collect the ether solution, dry it over anhydrous sodium sulfate, decant the solution into a clean filter flask (sidearm flask), and rinse the Na2SO4 with ca. 1 mL of ether. The ether solution should contain your alcohol product, any unreacted starting materials, and reaction byproducts (principally biphenyl). Qualitative Test of Conversion Using TLC. Create a TLC solution of your aldehyde starting material by dissolving a very small amount (a few specks if a solid, or a small amount in the tip of a pipet if a liquid) in ca. 1 mL of EtOAc. Mark a TLC plate with 3 tick marks: “sm” on the left (starting material), co‐spot in the center, and “crd” on the right. Spot your aldehyde solution on the left and center tick marks. Then, dip a pipet into the ether solution containing your crude product in the filter flask, and using a spotter, spot your crude reaction solution on the center and right tick marks. Develop the TLC plate in 4:1 hexanes:ethyl acetate. Draw this plate and calculate Rf values for all spots in your Data section.

Experiment 3: The Grignard Reaction: Preparation of an Alcohol Isolating your crude product. First, cap your sidearm flask with a green rubber stopper, clamp it, hook up the vacuum hose to the sidearm, and gently turn on the vacuum. The ether should start to slowly evaporate, as evidence by bubbling and the flask getting cold. Open the vacuum sufficiently for evaporation, but don’t let the bubbling become too vigorous, or the solution may bump into the vacuum hose. Place the sidearm flask in a beaker containing warm tap water to help in the evaporation process. Once the bubbling stops, continue to pull vacuum on the flask for another 10‐ 15 min. Quantitative Test of Conversion Using NMR. Obtain a sample of your crude product for NMR analysis (if the crude is a solid, weigh out ca. 10‐15 mg; if the crude is a liquid, dip a clean pipet tip into the oil and draw some up into the tip), dissolve in CDCl3, and obtain a 1H NMR spectrum with your instructor. Integrate the appropriate protons as described in the Introduction, and use the ratio of integration values to determine the % conversion. Wastes Aqueous Waste: all aqueous layers obtained during the extraction of the reaction mixture, the 5% H2SO4 and saturated aqueous sodium chloride washes. Organic Waste: NMR solution and all acetone rinses (glassware, sidearm flask with crude product, NMR tube, etc.) Solid Chemical Waste: Drying agent (Na2SO4). Data (collect and record in your notebook during the lab)   



Describe crude product (solid or oil, color, etc.) TLC data (draw TLC plate, calculate Rf’s, include mobile phase) Obtain 1H NMR spectrum (CDCl3), staple into notebook, and label as “Name and Name Expt 3 crude in CDCl3.” Draw the structures of your aldehyde starting material and product, and label only the peaks that you are using to determine the % conversion by integration. Show your % conversion calculation.

Conclusion (record in your notebook)  State of the outcome of your reaction (complete conversion or otherwise).  Support your outcome with the results of the qualitative TLC analysis, and include your calculated % conversion (note that this is based on NMR analysis).  State two possible sources of error and any other information deemed necessary and relevant.

The 1H NMR data for the aldehyde starting materials are given below for your reference.


4‐Chlorobenzaldehyde (90 MHz, CDCl3)

4‐Methylbenzaldehyde (p‐tolualdehyde) (90 MHz, CDCl3)

4‐Methoxybenzaldehyde (p‐anisaldehyde) (90 MHz, CDCl3)