Experiment 4: Preparation of Benzoic Acid INTRODUCTION This experiment is designed both as a preparative and an investigative project. Two outcomes are expected: preparation of benzoic acid from bromobenzene and analysis of the by-products of a Grignard reaction, an integral part of the synthetic procedure. GC/MS analysis of the organic layer, generated in the reaction of a Grignard reagent 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, phenylmagnesium bromide (1), from bromobenzene and magnesium metal using diethyl ether (“ether”) as the solvent under anhydrous conditions [equation (1)]. The use of an ether, such as diethyl ether, 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, ethers like diethyl ether or tetrahydrofuran (THF) work well as solvents in many nucleophilic addition reactions because the ether functional group is unreactive with most reactants. Br MgBr anhydrous ether + Mg (1) bromobenzene phenyl magnesium bromide, 1 Phenyl magnesium bromide will then be allowed to react with CO2, followed by hydrolysis, 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 carbanion that serves as a nucleophile for its reaction with carbon dioxide, 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 Nucleophiles: 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 aldehydes to produce secondary alcohols, to ketones to produce tertiary alcohols, to carbon dioxide to form carboxylic acids, and to epoxides to form alcohols. Two moles of the reagent add to esters and acid chlorides to form tertiary alcohols. As a nucleophile, the Grignard attacks the carbon atom in a carbonyl group 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 alcohol (ROH), a carboxylic acid (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 sodium hydroxide 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 acetone 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.