Chemistry 251 Laboratory -- Spring 2000
Ibuprofen Project Home Page

Index

• Students working on this project
• Table of Reagents and Amounts Available
• Notes on Step 1

Ibuprofen is the active ingredient in a number of over the counter pain relievers, e.g. Advil, Motrin, and Nuprin. It is one of the top-ten drugs sold worldwide, and, although it has been shown that only the S enantiomer has the desired biological activity, it is currently sold as the racemate. The synthesis begins with reaction of 4-isobutylacetophenone with the sulfur ylide produced by deprotonation of trimethylsulfonium iodide to yield an epoxide. (You should look this reaction up in an advanced organic text, e.g. the one by Jerry March.) The epoxide is then opened reductively by treatment with H₂ and Pd catalyst to give an alcohol that is then oxidized to the acid, Ibuprofen, using KMnO₄.

The table below lists the chemicals that we will have available for this project. If you need something that is not on this list, consult with the mentor for your project. Also note the "Amount/group" column. This is the total amount of material available for each group to use on the project.

Reagent	Source	Amount/group	Location	Comments
4-isobutylacetophenone	Lancaster Cat. # 6284	5 g	TA room
Trimethylsulfonium iodide	Aldrich Cat. #T8,048-9	4 g	TA room	Irritant
Sodium Hydride (60% dispersion in mineral oil)	Aldrich Cat. #45,291-2	5 g	TA room	Flammable Solid, Moisture Sensitive
Methyltriphenylphosphonium bromide	Aldrich Cat. #13,007-9	10 g	TA room	Irritant, Hygroscopic
Butyllithium (1.6 M in Hexanes)	Aldrich Cat. #18,617-1	20 mL	TA room	Flammable Liquid, Moisture Sensitive
DMSO (Dimethyl sulfoxide)			TA room	Wear gloves when handling DMSO. It is readily absorbed through the skin!
Pd, powder, submicron	Aldrich Cat. #32,666-6	0.2 g	TA room

1. The NaH comes as a dispersion in oil. It looks like a grey powder. Be sure not to expose it to air for any significant amount of time. NaH is usually washed with hexane to remove the oil before it is used. Here is a wash procedure that I used when I was doing a reaction that required 2 g of NaH (it was also a 60% dispersion in oil).
   
   
   • A 100 mL pear shaped flask, equipped with a stir bar was flame dried and cooled under nitrogen. The appropriate amount of NaH was weighed into the flask. The NaH was washed 4 x 10 mL with anhydrous hexane. To do the washing, I added the hexane by syringe and then stirred for a few minutes under Nitrogen. I then turned of the stir bar and let the NaH settle. I then removed most of the hexane with a syringe and repeated the process. After the last wash I removed the remaining hexane by placing on a high vacuum pump, but this might not be necessary.
   
   
2. Since the NaH is a 60% dispersion in oil, you will have to weigh out 1.67 times the amount you would need if it was pure.
   
   
3. Is it possible to use NaHMDS instead of NaH? This worked OK, but still some starting material.
   
   
4. Sarah and Jayme got BEAUTIFUL results using 1.5 eq. of NaH, 1.2 eq. of the trimethylsulfonium iodide. They washed the NaH once with hexane, then did the reaction normally. After workup the NMR looked perfect -- no starting material present. No need to do any purification! Click here to see the NMR.