The Grignard Reaction
Synthesis of a Tertiary Alcohol

[adapted from Smith, D.H. J. Chem. Ed. 1999 , 76 , 1427-8]

Introduction

The Grignard reaction is one of the most important carbon-carbon bond forming reactions in organic chemistry. We have covered the reaction of Grignard reagents with aldehydes and ketones in lecture and now you will perform the synthesis of a tertiary alcohol in lab. In this lab you will use an alkyl bromide and an aryl ketone to synthesize a tertiary alcohol. The three steps in the reaction are illustrated below using 2-bromopropane to generate the Grignard reagent and acetophenone as the ketone. You will isolate your product by extraction and evaporation and confirm its identify by IR and NMR.

Possible alkyl bromides:

Possible ketones:

Pre-Lab

Type up your normal introduction. You will be assigned an alkyl bromide and the letter of an unknown ketone. Use a generic acetophenone structure when writing up your reactions and mechanisms. Look up the physical properties for one of the methyl acetophenones and one of the methoxy acetophenones for your table of reagents. Calculate the quantities (either by volume or weight) that you will need of alkyl bromide, ketone, and magnesium before coming to class. Those numbers go in your table of reagents.

Experimental

NOTE: Grignard reagents are extremely strong bases and will react with water. All of your glassware in parts 1 and 2 must be dry (get them out of the oven). We will be using a sonicator which will alleviate some of the problems with wet solvents and reagents

1. Generating the Grignard reagent

• Add 0.010 mol of magnesium ribbon to a 6” test tube (label it A ). Add 0.010 mol of your bromide and 3.1 mL of ethyl ether to a similar test tube (label it B ). Mix the contents of B well. Note the level of liquid in tube B and place a line on tube A at the same height. Use a Pasteur pipet to add enough of the bromide/ether solution to tube A to partially cover the magnesium. Place tube A into a water-filled (you don't need that much water) beaker in the ultrasonic bath and begin sonicating. You can share beakers. Caution: make sure the tube points away from other people.
• When the liquid in the tube turns gray or white, remove it. The ether should begin to boil. If it does not, put the tube back into the ultrasonic bath. When the reaction starts boiling spontaneously, remove the tube. Add about 0.5 mL of pure ethyl ether. When the initial boiling has slowed, add more bromide/ether solution at a rate to keep the reaction going moderately well. You may need to add a little more ether to make up for evaporation loss. If the reaction goes too vigorously, place tube A in cool water.
• After adding all of the bromide/ether solution, add enough pure ether to keep the liquid level to the mark on the test tube. When the reaction slows and almost all of the magnesium has reacted, sonicate the mixture for a few minutes more. Remove tube A from the ultrasonic bath and pipet the solution into a dry 50-mL Erlenmeyer flask. Rinse the test tube once with 0.5 mL of ether and add the rinsings to the Erlenmeyer flask. Don't worry about any unreacted magnesium. Cool the Erlenmeyer flask in an ice bath.

2. Reaction of the Grignard reagent with the ketone

• Measure out 0.009 mol (by weight or volume; assume an average weight or density for the ketone--you looked these numbers up for your table of reagents!) of your ketone into a test tube (label it C ). Add approximately 3 mL of ether to tube C and mix well (be sure any solid ketone is dissolved). Cool tube C in your ice bath for at least 10 minutes. When both your Erlenmeyer flask and tube C are cool, slowly add the ketone/ether solution to the Grignard reagent using a Pasteur pipet. Swirl the reaction occasionally. If the reaction becomes vigorous, stop adding ketone. Only resume adding ketone when the reaction has subsided.
• After the addition of ketone is complete, remove the Erlenmeyer flask from the ice bath and swirl for about 10 minutes.

3. Protonating the salt to form the tertiary alcohol and isolating/purifying the alcohol

• Place the Erlenmeyer flask back in the ice bath. Slowly add ~5 mL of 1 M sulfuric acid dropwise. Separate the organic layer and place it into a 25-mL Erlenmeyer flask (add some more ether if you can't distinguish the layers). Extract the remaining aqueous layer in the 50-mL Erlenmeyer with an additional 4 mL of ether. Combine the ether layers in the 25-mL Erlenmeyer and wash them with 3 mL of saturated NaHCO₃. Dry the ether layer over anhydrous MgSO₄ for 5 min and then pour the ether solution away from the drying agent into a 50-mL beaker. Carefully boil off the ether in a warm water bath.

Obtain IR and NMR spectra of your product.

Clean your test tubes and 50-mL Erlenmeyer flask and put them back into the oven.

For your discussion, see the model lab report for a concise and organized way of presenting spectroscopic evidence to support the identity of a product. You also need to discuss ways of improving the percent yield (I know you didn't figure one out) and the purity. Make sure you write out the mechanism of the reaction.