anhydrous diethyl ether

The Grignard Reaction:  Preparation of Benzoic Acid

Prior reading: Bruice, Chapter 12, section 12.11

Prelab Exercise

Prepare a flow sheet for the preparation of benzoic acid.  Through knowledge of the physical properties of the solvents, reactants, and products, show how the products are purified.  Indicate which layer in separations should contain the product. 

Background

In 1912, Victor Grignard received the Nobel Prize in chemistry for his work on the reaction that bears his name, a carbon-carbon bond-forming reaction by which almost any alcohol may be formed from appropriate alkyl halides and carbonyl compounds.  The Grignard reagent is easily formed by reaction of an alkyl halide, in particular a bromide, with magnesium metal in anhydrous diethyl ether. Although the reaction can be written and thought of as simply,

                                                               

it appears that the structure of the material in solution is rather more complex.  There is evidence that dialkylmagnesium is present, that is,

and that the magnesium atoms, which have the capacity to accept two electron pairs from donor molecules to achieve a four-coordinated state, are solvated by the unshared pairs of electrons on ether.  The solubility results from the solvation of the organometallic compound by the ether.  

                                                                 

Hydrocarbon solvents are not useful in the preparation of Grignard agents because they cannot solvate the product.

 

The Grignard reagent is a strong base and a strong nucleophile.  As a base, it will react with all protons that are more acidic than those found on alkenes and alkanes.  Thus Grignard reagents react readily with water, alcohols, amines, thiols, etc., to regenerate the alkane, as shown below. 

 

R-MgBr  +  H₂O  ®  R-H  +  MgBrOH

 

R-MgBr  +  R’OH  ®  R-H  +  MgBrOR’

 

R-MgBr  +  R’NH₂  ®  R-H  +  MgBrNHR’

 

This means that the starting material for preparing the Grignard reagent must not contain any acidic protons.  The reactants and apparatus must all be completely dry; otherwise, the reaction will not start. 

The reaction proceeds satisfactorily only if the reagent and the apparatus are scrupulously dry.  If the solvent is "wet" (i.e. contains traces of water), the Grignard reagent is destroyed as fast as it is formed.

 

Organometals such as Grignard reagents and the organolithiums are very widely used reagents in organic synthesis.  This experiment illustrates the method used to prepare a Grignard reagent as well as its reaction with carbon dioxide to form a carboxylic acid.

The great versatility of this reaction lies in the wide range of reactants that undergo reaction with the Grignard reagent. 

 

 

Preparation of Benzoic Acid

In the present microscale experiment we shall carry out another common type of Grignard reaction, the formation of a carboxylic acid from 1 mole of the reagent and 1 mol. of carbon dioxide, according to: 

 

C₆H₅MgBr  +  CO₂(s)  ®  C₆H₅COO^-MgBr⁺

 

The primary impurity in the present experiment is biphenyl, formed by the reaction of phenylmagnesium bromide with unreacted bromobenzene.  The most effective way to lessen this side reaction is to add the bromobenzene slowly to the reaction mixture so that it will react with the magnesium and not be present in high concentration to react with previously formed Grignard reagent.  The impurity is easily eliminated, since it is much more soluble in hydrocarbon solvents than benzoic acid.  

Subsequent acidic hydrolysis of the salt will produce benzoic acid, according to:

C₆H₅COO^-MgBr⁺ +  H₃O⁺  ®  C₆H₅COOH  +  H₂O  +  Mg²⁺  +  Br^-

 

 

Step 1 – Preparation of Phenylmagnesium Bromide (Phenyl Grignard Reagent)

 

• Advance Preparation: **It is imperative that all equipment and reagents be absolutely dry**. One lab period before you plan to run the reaction, you should place the glassware to be used-two reaction tubes, two short vials, and a stirring rod-can be dried in a 110 °C oven to dry, along with the magnesium turnings. Use anhydrous ether as solvent. Rinse syringe and needle in dry anhydrous ether. If it appears to be dirty, obtain an unused syringe needle and syringe from stockroom. Alternatively, if the glassware, syringe, septa, and magnesium appear to be perfectly dry, they can be used without special drying. The plastic and rubber-ware should be rinsed with anhydrous ether prior to use. Do not place plastic ware in the oven. New, sealed packages of syringes can be used without prior drying. The ether used throughout this reaction must be absolutely dry.  However, ether extractions of aqueous solutions can be carried out with the wet ether.

• Ether is extremely flammable; do not work with this solvent near flames.

• To remove ether from a septum-capped bottle, inject a volume of air into the bottle equal to the amount of ether being removed. Pull more ether than needed into the syringe, and then push the excess back into the bottle before removing the syringe. Try not to hold the syringe in your warm hands as this will cause the ether to vaporize and squirt out of the syringe. As the fluid gets lower in the bottle, the short needle may not reach the fluid.  In this case, turn the bottle upside down.

• Remove a reaction tube from the oven and immediately cap it with a septum. In the operations that follow, keep the tube capped except when it is necessary to open it. After it cools to room temperature, add about 2 mmol (about 50 mg) of magnesium turnings. Record the weight of magnesium used to the nearest milligram. We will make it the limiting reagent by using a 5% molar excess of bromobenzene (about 2.1 mmol.). (See below.)

• Using a dry syringe, add to the magnesium by injection through the septum 0.5 mL of anhydrous diethyl ether. Your laboratory instructor can demonstrate transfer from the storage container used in your laboratory.

• Into an oven-dried short vial weigh about 2.1 mmol (about 330 mg) of dry (stored over molecular sieves)

bromobenzene. Using a syringe, add to this vial 0.7 mL anhydrous diethyl ether, and immediately, with the same syringe, remove all the solution from the via l.  This can be done virtually quantitatively so you do not need to rinse the vial. Immediately cap the empty vial to keep it dry for later use. Inject about 0.1 mL of the bromobenzene-ether mixture into the reaction tube and mix the contents by flicking the tube.  Pierce the septum with another needle for pressure relief.

• Once the reaction has started, the bromobenzene-ether solution is added slowly from the syringe.  The empty needle is for pressure relief, but if condensation is complete (aided by the damp pipe cleaner), it will not be needed.  Once the reaction slows down, stir it with the magnetic stirring bar.  The solution is often turbid and gray due to impurities in the magnesium.     • If the reaction does not start at this point, remove the septum, syringe, and empty syringe needle and crimp or bend the magnesium turnings with a dry stirring rod.  The magnesium metal, in the form of metallic turnings, has a coat of oxide on the outside. A fresh surface can be exposed by gently bending or crimping the turnings under the absolutely dry ether in the presence of the organic halide with a glass stirring rod.

Be careful not to break the stirring rod.  Reaction will begin at the exposed surface, as evidenced by a slight turbidity in the solution and evolution of bubbles.  Once the exothermic reaction starts, it proceeds easily, soon begins to boil as the magnesium metal reacts with the bromobenzene to form the Grignard reagent, phenylmagnesium bromide.

• If the reaction does not start within 1 min, begin again with completely different, dry equipment (syringe, syringe needle, reaction tube, etc.).  Once the Grignard reaction starts, it will continue.  To prevent the ether from boiling away, wrap a pipe cleaner around the top part of the reaction tube.  Dampen this with water or, if the room temperature is very hot, with alcohol.

 

• To the refluxing mixture add slowly and dropwise over a period of several minutes the remainder of the solution of bromobenzene in ether at such a rate that the reaction remains under control at all times.  After all the bromobenzene solution is added, spontaneous boiling of the diluted mixture may be slow or become slow.  At this point, add a 1/2 " magnetic stirring bar to the reaction tube and stir the reaction mixture with a magnetic stirrer.  If the rate of reaction is too fast, slow down the stirrer.  The reaction is complete when none or a very small quantity of the metal remains.  Check to see that the volume of ether has not decreased.  If it has, add more anhydrous diethyl ether.  Since the solution of the Grignard reagent deteriorates on standing, the next step should be started at once.

• Step 2 - Preparation: Benzoic Acid

 

• Wipe off the surface of a small piece of dry ice with a dry towel to remove the frost, and place it in a dry 30-mL beaker. 

Use 2 mmol of the phenylmagnesium bromide you prepared in Step 1.  Remove the pressure-relief needle on the reaction tube, and then insert a syringe through the septum, turn the tube upside down, and draw into the syringe as much of reagent solution as possible.  Gently squirt this solution onto the piece of dry ice.  Then, using a clean needle, rinse out the reaction tube with 1 mL of anhydrous diethyl ether and squirt this onto the dry ice.  Allow excess dry ice to sublime. 

 

• Hydrolyze the intermediate bromo magesium salt by the addition of 2 mL of 3 M hydrochloric acid.  Cork and shake mixture thoroughly.  Two homogeneous layers of approximately equal volume should result. Add more of acid or ordinary (not anhydrous) diethyl ether if necessary.  Remove the aqueous layer.  Shake the ether layer with 1mL of water, which is removed and discarded.   Then extract the benzoic acid by adding to the ether layer 0.7 mL of 3 M sodium hydroxide solution, shaking the mixture thoroughly.  Withdraw the aqueous layer and place it in a small beaker or vial.  The extraction is repeated with another 0.5-mL portion of base and finally 0.5 mL of water.  Now that the extraction is complete, the ether, which can be discarded, contains primarily diphenyl, the byproduct formed during the preparation of the phenylmagnesium bromide.

• The combined aqueous extracts are heated gently and briefly to about 50 °C to drive off dissolved ether from the aqueous solution.  Add concentrated hydrochloric acid to make the solution acidic (test with indicator paper – the pH should be around 3-4).  Cool the mixture thoroughly in an ice bath.  Collect the benzoic acid on the Hirsch funnel, and wash it with about 1 mL of ice-cold water while on the funnel.  A few crystals of this crude material are saved for a melting-point determination, and the remainder of the product is recrystallized from boiling water.

• Recrystallization: The solubility of benzoic acid in water is 68 g/L at 95 °C and 1.7 g/L at 0 °C.  Dissolve the acid in very hot water.  Let the solution cool slowly to room temperature; then cool it in ice for several minutes before collecting the product by vacuum filtration on the Hirsch funnel.  Use the ice-cold filtrate in the filter flask to complete the transfer of benzoic acid from the reaction tube.  Turn the product out onto a piece of filter paper, squeeze out excess water, and allow it to dry thoroughly.  Once dry, weigh it, calculate the percentage yield, and determine the melting point along with the melting point of the crude material.  Obtain an IR (KBr pellet) of your product and compare it with a reference IR.  Place your product in a neatly labeled vial with your name(s) and submit to your instructor. 

 

Cleaning Up: Combine all aqueous layers, dilute with a large quantity of water, and flush the slightly acidic solution down the drain.

 

 

Post lab Questions

1. Suggest an alternate synthesis that can be used to make benzoic acid from readily available starting materials.

2. In the synthesis of benzoic acid, benzene is often detected as an impurity. How does this come about?

3. If the ethyl ether used in the Grignard reaction is wet, what byproduct would be formed?

4. The primary impurity in the present experiment is biphenyl.  Show how it is produced. 

5. Analyze the IR spectrum of benzoic acid which you obtained in the laboratory.

Optional:

6. Analyze the ¹³C NMR spectra of benzoic acid. 

7. Analyze the mass spectrum of bromobenzene shown below and specifically answering the following:
a) The molecular weight of bromobenzene is 157 amu.  Explain the appearance of the m/e 156 and 158 signals of about equal intensity.  b) Suggest a structure for the cation responsible for the m/e 77 signal.