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Home , Bromobenzene, Grignard reaction, Grignard reagent, Phenylmagnesium bromide

Experiment 4: Preparation of

INTRODUCTION

This experiment is designed both as a preparative and an investigative project. Two outcomes are expected: preparation of benzoic acid from and analysis of the by-products of a , an integral part of the synthetic procedure. GC/MS analysis of the organic layer, generated in the reaction of a with CO2, will provide experimental evidence for the nature of the by-products. The mechanism of the Grignard reaction has been provided in this hand-out, and students will provide the structure of the by-products in the Pre-Lab assignment. Additionally, students will propose refinements of the experimental procedure designed to minimize the amount of by-products. The knowledge of the side products will help students understand how side reactions affect the yield of the desired material. For example, if you are an R&D scientist in a company, you would want to minimize the amount of by- products. The latter reduce the yield of desired compound, therefore increasing the cost of the product. By-products may contaminate the final material, thus further increasing cost due to need for additional purification steps.

PART 1: SYNTHETIC PROCEDURE

The experiment begins with the preparation of a Grignard reagent, (1), from bromobenzene and metal using diethyl (“ether”) as the solvent under anhydrous conditions [equation (1)]. The use of an ether, such as , as a solvent for the preparation of Grignard reagents is of key importance because the lone pairs of electrons on oxygen help stabilize the partial positive charge on magnesium in the Grignard reagent and thus facilitate its formation. Grignard reagents do not form in most other “inert” solvents. In general, like diethyl ether or (THF) work well as solvents in many reactions because the ether is unreactive with most reactants.

Br MgBr anhydrous ether + Mg (1)

bromobenzene phenyl , 1

Phenyl magnesium bromide will then be allowed to react with CO2, followed by , to give benzoic acid [equation (2)].

1 O O MgBr H O MgBr (2) + CO2 OH

benzoic acid

The carbon-containing portion of Grignard reagent, 1, has two characteristics: (1) as a that serves as a for its reaction with , and (2) as a strong base that reacts with acidic hydrogen atoms. These characteristics are illustrated by the structure of the reagent that bears a strongly polar covalent bond between carbon and magnesium.

! ! Ar MgBr represented as ArMgBr (where "Ar" is short for aromatic ring)

A. Grignard Reagents as : Benzoic Acid

Of major synthetic interest is the use of Grignard reagents as nucleophiles to form new carbon-carbon bonds, a process that is termed nucleophilic addition. For example, Grignard reagents add to to produce secondary , to to produce tertiary alcohols, to carbon dioxide to form carboxylic acids, and to epoxides to form alcohols. Two moles of the reagent add to and acid chlorides to form tertiary alcohols. As a nucleophile, the Grignard attacks the carbon atom in a because that carbon atom has electrophilic character owing to the polarity of the C=O group. The carbon atom bears some partially positive charge because it is attached to the more electronegative oxygen atom. ! ! C O

The synthetic use of the Grignard reagent, phenylmagnesium bromide, in this experiment is its addition to carbon dioxide to produce, after hydrolysis, benzoic acid [equation (2)]. The mechanism for this reaction is provided in equation (3). A convenient source of CO2 is Dry-Ice (solid CO2) which will be used in this experiment.

2 O O MgBr O + O MgBr H C OH + Mg2+ + Br (3) O benzoic acid

B. Grignard Reagents as Strong Bases

Any compound with an acidic hydrogen — such as H2O, an (ROH), a (RCOOH), or any acid — will donate a proton to a Grignard reagent such as phenyl magnesium bromide and destroy it by forming a new C–H bond. To avoid this undesired side reaction, Grignard reagents are prepared under anhydrous conditions. All apparatus and all reagents (magnesium metal, bromobenzene, and the ether solvent) must be free from traces of moisture. Thus, the apparatus is dried by heating, and anhydrous reagents can usually be purchased commercially. Once dried and assembled, the apparatus used for preparing the Grignard reagent is protected from moisture by attaching a drying tube containing anhydrous calcium chloride, which absorbs moisture from air entering the system. Even so, the procedures used in this synthesis minimize the presence of moisture but do not completely exclude it.

C. Isolation and Purification of Benzoic Acid

After phenyl magnesium bromide is prepared, it is poured over powdered Dry-Ice

(solid CO2) to obtain the bromomagnesium salt of benzoic acid. Additional ether is added and the resulting mixture is made distinctly acidic by the addition of aqueous hydrochloric acid. The HCl protonates the benzoate ion present as the bromomagnesium salt and also dissolves any basic magnesium salts and any unreacted magnesium metal 2+ - + - that may be present. Inorganic ions, such as Mg , Br , H3O , and Cl , remain in the aqueous layer. The ether layer is removed from the aqueous layer, and the ether is then extracted with several portions of aqueous NaOH solution. This converts the benzoic acid into its water-soluble sodium salt, which is now contained in the basic aqueous layer. Several NaOH extractions are done to help ensure complete removal of benzoic acid from the ether layer, and the other organic by-products. Note that you must retain the organic (ether) layer for the optional Part II of this experiment. The combined aqueous layers are then boiled gently to remove traces of ether, which is slightly soluble in water. If the basic solution is not boiled before acidification, traces of ether will be present in the aqueous layer and thus dissolve some of the benzoic acid. If the benzoic acid stays dissolved, it will not fully crystallize upon acidification that would then decrease the amount of benzoic acid

3 recovered. Decolorizing charcoal is added before boiling to remove any colored impurities that may be present. The basic solution is then cooled and made distinctly acidic with HCl to precipitate benzoic acid. Upon protonation of the anion, the ionic sodium salt becomes an uncharged organic compound, insoluble in a polar solvent like water. After cooling this mixture in an ice bath, the benzoic acid is collected by vacuum filtration and allowed to air dry. If your instructor desires, it may be recrystallized from hot water. [Note: The ether layer may be analyzed by gas chromatography and mass spectral analysis for the presence of by-products. See Part II for this discussion.]

REAGENT/PRODUCT TABLE:

Reagents MW (g/mol) MP (ºC) BP (ºC) Density bromobenzene 157.02 -31 156 1.491 Mg 24.3 Dry Ice (CO2) Used in Excess - not the limiting reagent diethyl ether 74.12 -166 34.6

Product MW (g/mol) MP (ºC) BP (ºC) benzoic acid 122.12 122-123 249

EXPERIMENTAL PROCEDURE:

Preparation of Phenyl Magnesium Bromide 1. Obtain the following items that have been pre-dried in an oven for you: 1 small sample vial and cap, 1 large sample vial and cap, one 5" Pasteur pipette, one Claisen adapter, and one 5 mL conical vial without cap containing a spin vane. 2. Weigh approximately 75 mg of magnesium turnings. Record amount used in notebook. Use tweezers to handle magnesium turnings. Transfer the Mg turnings to the 5-mL conical vial containing the spin vane. 3. Obtain a drying tube packed with indicating silica gel desiccant pellets, and set up the apparatus as described in Section A.5 and shown in Figure A.5A. Place the vial in the aluminum block on the stirring hot plate. 4. Take the large, dry sample vial to your instructor who will fill it about two-thirds full of anhydrous ether. Tightly cap it, and label it as “ether vial”. 5. (a) For use in Step 6, clean the syringe in the Microscale Kit by drawing several portions of into it (with needle attached). Carefully remove the plunger and place the barrel end of the syringe over the heavy-walled tubing

4 attached to the house vacuum, and pull air through the syringe for a minute to remove the acetone. Carefully reinsert the plunger. (b) Place 0.34 mL of bromobenzene (density = 1.491 g/mL) in a small, dry preweighed sample vial, and then reweigh to determine the weight of bromobenzene you have added. Add 2 mL of anhydrous ether to this vial from the “ether vial”, cap it, and shake it gently to dissolve the bromobenzene in the ether. Label this small vial as “bromobenzene–ether.” 6. Using the clean, dry syringe (Step 5a), transfer all the bromobenzene–ether mixture to the conical vial containing the Mg turnings. This may be done by drawing the bromobenzene–ether mixture into the syringe, inserting the needle through the rubber septum on the reaction apparatus, and injecting the mixture. It will be necessary to refill the syringe several times to get all the bromobenzene–ether mixture into the conical vial, and this should be done as quickly as possible. 7. Turn on the magnetic stirrer (no heat), and stir the mixture gently. The reaction has started when the solution turn light yellow (or darker) color; another indication that the reaction has started is the formation of a brownish-gray, cloudy solution and sometimes even a trace of white precipitate (magnesium hydroxide). If none of these changes are observed after 5–10 min, consult your instructor.

8. As soon as the reaction has started, use the syringe and add about 1 mL of ether1 from the “ether vial” to the conical vial. If the reaction becomes too vigorous, as evidenced by vigorous boiling, place the conical vial in a beaker of cold tap water until the boiling has subsided some but do not cool it until the boiling stops. The volume of the reaction mixture should be about 4 mL that can be estimated from the volume markings on the conical vial. If not, add more ether from the “ether vial” to the reaction mixture using the syringe so the volume is at least 4 mL. 9. Allow the reaction mixture to stir for an additional 5–10 min, during which time most or all of the magnesium metal should be gone. If traces of Mg metal are left, they will dissolve when HCl is added in Step 11. of Phenyl Magnesium Bromide; Hydrolysis of Reaction Mixture 10. Allow the reaction mixture to cool to room temperature. Take a clean, dry 30- or 50-mL small beaker to your instructor to get Dry-ice. Do not weigh the Dry-ice, as you will be given an excess of it. Remove the conical vial from the rest of apparatus attached to it, and immediately carefully pour its contents onto the Dry-Ice. (Be

1For adding this 1-mL of ether, you may use the syringe without cleaning and drying it.

5 prepared – this is a strong nucleophile and a reactive – the force of the reaction will surprise you.) Rinse the conical vial with about 1-mL of anhydrous ether and add it to the beaker. 11. Hydrolyze the reaction mixture by slowly adding about 3 mL of 6 M HCl to the beaker, swirling to remove the remnants of Dry-ice. The beaker will be very cold and may need to warm back to room temperature to dissolve all the unreacted Dry- ice. Add an additional 8-10 mL of ether to beaker, and stir the mixture with a stirring rod. (The HCl converts the bromomagnesium salt of benzoic acid to benzoic acid and dissolves any excess Mg metal.) You should now have two distinct layers— an aqueous layer containing inorganic salts and HCl, and an ether layer containing benzoic acid and neutral organic compounds. Both layers should be clear, and the ether layer is typically light yellow in color. If any solid is present, add an additional 2-mL of 6 M HCl and stir again. 12. Pour the contents of the beaker into a clean large sample vial. To rinse the beaker, add 1–2 mL of ether to the beaker, swirl it, and transfer it to the vial.

Isolation of Benzoic Acid 13. Turn on the hot plate to a setting of about 4 for use later. 14. Cap the vial (from Step 12) and invert it gently several times to mix the layers. Vent several times by loosening and re-tightening the cap. 15. Allow the layers to separate. Remove the lower aqueous layer with a pipette, and leave the upper ether layer in the vial. The separation will require you to hold the vial at a slight angle to aid in removal of the entire lower layer. Put the aqueous layer in a small beaker (mark it as “acid layer”) but don't discard any layers until you are certain you have obtained benzoic acid. 16. Add about 4 mL of 5% NaOH solution to the ether layer in the vial, cap it, and shake it gently; vent it several times by loosening and re-tightening the cap. Allow the layers to separate, and remove the lower aqueous layer with a pipette. Save this layer in a different 30- or 50- mL beaker labeled “basic layer-product”. 17. Repeat Step 16 two more times with 4 mL portions of 5% NaOH. Combine all the NaOH extracts in the same beaker. Save the upper ether layer remaining in a vial labeled “ether layer”.

18. Add a little decolorizing charcoal2 to the beaker containing the basic NaOH layers and heat it gently on the hot plate, with stirring or swirling, for about 2 minutes to

2The charcoal removes any colored impurities that might be present.

6 remove traces of ether dissolved in the aqueous layer. The solution does not have to, and should not boil, although the bubbles of escaping ether fumes will be observed initially. 19. Using a glass funnel and filter paper, gravity filter the contents of the beaker into another clean, small beaker. Add about 2 mL of water to this beaker that contained the NaOH layers from Step 18, swirl around, rinsing the inside of the beaker as best as possible. Pour this through the filter paper as well. The filter funnel does not have to be pre-warmed because the product is contained in solution as its water- soluble sodium salt and thus will not crystallize in the funnel. 20. Cool the beaker containing the filtrate from Step 19 to room temperature by placing it on the bench for a couple minutes. With stirring, add about 4 mL of 6 M HCl to the beaker. This converts sodium benzoate into benzoic acid, and you should observe the formation of a white precipitate of benzoic acid. Use pH paper to determine that the solution is pH ~ 1. (Check the pH by adding a drop of solution on the tip of a stirring to a piece of pH paper. DO NOT dip the pH paper in the solution.) If the solution is not pH 1, add HCl dropwise and with stirring until the solution is the proper acidity. 21. Cool the beaker in an ice–water bath. Collect the benzoic acid by vacuum filtration on a Hirsch funnel (Section A.2, Figure A.2). Add 1 mL of ice water to the beaker, swirl to rinse, and pour over the solid on the funnel. Repeat with a second 1 mL portion of ice-water. Support the funnel in a beaker and allow it to dry until the next lab period.3 22. Transfer the dry benzoic acid to a dry, pre-weighed sample vial, and determine the weight and percent yield of the product. Determine the mp range (reported mp of benzoic acid: 122°C) and hand in the product in properly labeled vial.

OPTIONAL ANALYSIS OF THE BY-PRODUCTS: 23. Add a small amount of anhydrous magnesium sulfate to the ether layer that was saved from Step 17. Gently swirl the contents of the vial. Continue adding small amounts of magnesium sulfate until it does not appear to stick to the sides or bottom of the vial when swirled. When the ether layer is sufficiently dried, the

3If instructed to do so, the benzoic acid may be recrystallized from a minimum volume of hot water.

7 magnesium sulfate in the vial should appear to “drift” like snow in a liquid. Do not add so much that you no longer have any visible liquid in your vial! 24. Gravity filter the dried ether layer through a clean, dry glass funnel with fluted filter paper into a clean and dry sample vial. Label the new vial as “dried ether layer” with your name and course section number. 25. Fill the GC vial that has been provided for you at least half full with a sample of the dried ether layer and submit it to your instructor.

WASTE DISPOSAL

1. Place the acid layer from Step 15 and the filtrate from Step 21 in the “aqueous acid waste” bottle. 2. Place the organic layer remaining in the large vial (Step 17) in the “organic waste” container. 3. Filter paper and other paper waste belong in the trash can.

Part II: OPTIONAL GC/MS ANALYSIS OF BY-PRODUCTS IN THE ORGANIC LAYER The mechanism for the formation of a Grignard reagent, and of some of the by- products, is shown below. Notice that the reaction is initiated at the surface of the metal by an electron transfer to the . This reduction process results in the formation of a bromide anion and a phenyl radical, a highly energetic, reactive intermediate. This molecule results when the bromide anion is removed from the 2 bromobenzene radical anion. The resulting unpaired electron remains in the vacant sp hybrid orbital. This free-radical is very similar to the familiar radical such as 3 methyl, with an unpaired electron in the sp orbital. It is the phenyl radical that reacts +1 with Mg to generate phenyl magnesium cation that then traps a bromide anion to form the Grignard reagent, 1. Phenyl radical may undergo side reactions typical of organic radicals, such as reaction with another phenyl radical. This occurs when the localized concentration of radicals is too high. The resulting possible by-products will be identified by the GC/MS analysis of the ether layer saved from Step 17, which was used in Steps 23-25. Recall that the Pre-Lab exercise asked that you make some suggestions as to the nature of these by-products based on your understanding of radical reactions. Now you can use GC/MS data to validate or refute your previous hypothesis. Note that the

8 understanding of these side reactions will help you in planning your experimental synthetic procedure. Obviously, minimizing the former will increase the yield of the desired Grignard reagent and ultimately the desired product.

- Br Br + Mg+1

radical anion

By-Product A + Br + Mg+1

phenyl radical

O MgBr H2O CO By-Product B 2 OH

phenyl magnesium bromide, 1 desired benzoic acid

The results of the GC/MS analysis will be given to you in either of two ways: as a chromatogram file, stored on one of the NT Windows computers as described in the general hand-out for the discovery-based experiments, or as an output of the GC/MS instrument. In the latter case, you will receive a gas chromatogram printout of the GC/MS with mass spectra of each of the by-products.

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5 -0 4000 3500 3000 2500 2000 1500 1000 Wavenumbers (cm-1)

Date: Wed Dec 16 11:11:33 2009 (GMT-05:00) bromobenzene

Scans: 4

Resolution: 4.000 O

OH

0.07 0.14 0.21 10 8 6 4 2 0 PPM