Chemistry 251 Laboratory -- Spring 2003
Ibuprofen Project Home Page

Go to Lab Syllabus
Updated 4/11/03

Index

Introduction

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.

Synthesis of Ibuprofen from 4-Isobutylacetophenone

Reference: Cleij, M.; Archelas, A.; Furstoss, R. J. Org. Chem. 1999, 64, 5029-5035.

Reaction of 4-isobutylacetophenone with the sulfur ylide produced by deprotonation of trimethylsulfonium iodide yields the epoxide 1 in good yield. (You should look this reaction up in an advanced organic text, e.g. the one by Jerry March.) In the JOC article listed above they found that the epoxide could be converted to Ibuprofen by reduction to the alcohol 2 using H2/Pd followed by oxidation of the resulting alcohol to the acid using KMnO4. Several years ago we found that the epoxide 1 could be readily converted to the aldehyde 3 by BF3Et2O catalyzed rearrangement of the epoxide. Some preliminary attempts at oxidizing this aldehyde to Ibuprofen have been explored, but we need to find a reliable method. In order to work out appropriate conditions for this oxidation, we will purchase some 2-phenylpropionaldehyde (aka hydratropaldehyde) that we can use as a model system.


Synthesis of Ibuprofen using "Superbase"

Reference: Faigl, F.; Schlosser, M. Tetrahedron Lett. 1991, 32, 3369-3370.

Last year a couple students found an alternative strategy for synthesizing Ibuprofen. This strategy uses the "superbasic" mixture of butyllithium and potassium tert-butoxide to deprotonate benzylic positions. These anions can then be used as nucleophiles. Using this strategy, p-xylene was sequentially deprotonated and reacted with methyl iodide, isopropyl bromide, and carbon dioxide to yield ibuprofen. I was initially skeptical, but the preliminary results were very good. It looks like we were able to produce ibuprofen, but we need to find a good method for purifying it.



Students Working on This Project

Synthetic Approach Lab Day Name E-mail
Superbase Monday Robin Ziegler rziegler@ups.edu
Superbase Monday Wendy Quinones-Mejia wqmejia@ups.edu
Superbase Tuesday Ryan O'Connor roconnor@ups.edu
Superbase Tuesday Eric Hinderager ehinderager@ups.edu
From 4-Isobutylacetophenone Wednesday Natasha Qaraiski nquraishi@ups.edu
From 4-Isobutylacetophenone Wednesday Brandy Hurd bhurd@ups.edu
From 4-Isobutylacetophenone Thursday Aft. Bryan Brune bbrune@ups.edu
From 4-Isobutylacetophenone Thursday Aft. Evan Los elos@ups.edu
From 4-Isobutylacetophenone Thursday Aft. Tricia Howard phoward@ups.edu
From 4-Isobutylacetophenone Thursday Eve. Maren Buck mbuck@ups.edu
From 4-Isobutylacetophenone Thursday Eve. Kari Nordgren knordgren@ups.edu




Synthesis of Ibuprofen from 4-Isobutylacetophenone

Table of Reagents and Amounts Available for this Project

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
(Click on name to see MSDS)
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
DMSO (Dimethyl sulfoxide)
Anhydrous
Aldrich
Cat. #27,685-5
100 mL TA room Wear gloves when handling DMSO. It is readily absorbed through the skin!
Boron trifluoride diethyl etherate Aldrich
Cat. #21,660-7
10 mL TA room Caution: Toxic, corrosive, moisture sensitive. Dispense under nitrogen in the hood.
Palladium powder Aldrich
Cat. #32,666-6
0.4 g TA room
2-Phenylpropionaldehyde
aka Hydratropaldehyde
Aldrich
Cat. #24,136-9
10 g TA room
Sodium chlorite, tech. 80% Aldrich
Cat. #24,415-5
5 g TA room
Hydrogen peroxide 30% Fisher
Cat. #H325-500
10 mL Cold room (on the left, on the floor) Oxidizer. Wear gloves!



Step 1: Epoxide Formation using Trimethylsulfonium Iodide



Notes and Suggestions
  1. When developing your procedure for Step 1, look at the reports from last year's students. (They are available in a binder in the chemistry library.) Also look at the information on the web pages from last year.
  2. Nobody got this reaction to work the first time, just recovered starting material. I suspected that the old bottle of DMSO might be wet, so we tried a new one. Only one out of 3 groups had success on the second try. The only significant thing that the successful group seemed to do differently was to pump off the residual hexane after the washing step.


Step 2: BF3 Catalyzed Rearrangement



Reference: Garin, D.L.; Gamber, M.; Rowe, B.J. "Epoxidation of Alpha-Methylstyrene and Its Lewis Acid Rearrangement to 2-Phenylpropanal" J. Chem. Educ. 1996, 73, 555.

Notes and Suggestions
  1. See notes form last year.



Step 3: Oxidation of the Aldehyde to the Acid



Notes and Suggestions
  1. See notes form last year.
  2. Brandy and Natasha have located a potentially interesting reference that we should look at: Riley, D.P.; Getman, D.P.; Beck, G.R.; Heintz, R. M. "Selective Metal-Catalyzed Autoxidation of 2-Arylpropionaldehydes. An Improved Synthesis of Ibuprofen" J. Org. Chem. 1987, 52, 287-290.




"Superbase" Synthesis

Table of Reagents and Amounts Available for this Project

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 John Hanson. Also note the "Amount/group" column. This is the total amount of material available for each group to use on the project.

Reagent
(Click on name to see MSDS)
Source Amount/group Location Comments
p-Xylene
Anhydrous
Aldrich
Cat. # 29,633-3
20 g TA room
Iodomethane Malinckrodt
Cat. # 1077
10 g Th 303?
Special storage cabinet
Highly Toxic! Cancer Suspect Agent!
Handle with gloves in a hood.
2-Bromopropane Aldrich
Cat. # B7, 811-4
10 g TA room Flammable Solid, Moisture Sensitive
Butyllithium
1.6 M solution in Hexanes
Aldrich
Cat. # 18,617-1
20 mL TA Room Flammable liquid. Moisture sensitive.
Dispense under nitrogen.
Potassium tertbutoxide Aldrich
Cat. # 15,667-1
10 g TA room Flammable solid. Moisture Sensitive.



Step 1: Alkylation of Xylene


Notes and Suggestions
  1. Iodomethane (aka methyl iodide) is EXTREMELY TOXIC! You must WEAR GLOVES and WORK IN THE HOOD at all times. In addition, this will only be dispensed under the direct supervision of a faculty member. As part of this project you should investigate less toxic alternatives.
  2. When developing your procedure for Step 1, look at the reports from last year's students. (They are available in a binder in the chemistry library.) Also look at the information on the web pages from last year.
  3. Ryan and Eric have found an interesting citation that uses dimethyl sulfate in place of methyl iodide: Bates, R.B.; Ogle, C.A. "Arenes disubstituted with primary alkyl groups from xylylene dianions" J. Org. Chem. 1982, 47, 3949-3952.