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Week V: Stereochemical Resolution of Ibuprofen

Pre-Lab Work

1. Fill in the Table of Physical Constants.

2. Read Chapters 4.2, 7.4, 7.7 in Hornback and 14.1-14.5 in Mohrig.

Introduction
The process by which the enantiomers of a racemic compound are separated is called stereochemical resolution. In 1848, Louis Pasteur performed the first stereochemical resolution of an organic compound. While observing crystals of tartaric acid under a microscope, he noted that they appeared to be mirror images of each other. By looking at the crystals under a microscope and physically separating the crystals which looked different, Pasteur isolated (+) and (-) tartaric acid from the racemic mixture of the two, and showed that the two samples rotated plane-polarized light in opposite directions. Today, chiral chromatography, in which the stationary phase preferentially retains one enantiomer over the other, is a preferred method of stereochemical resolution. Enzymatic resolution is another method of stereochemical resolution.  Certain enzymes will preferentially react with one enantiomer in a racemic mixture, creating a new product through functional group conversion; the new chiral molecule can then be separated by conventional chromatography from the starting material.

In this lab, ibuprofen (a carboxylic acid) will be reacted with (S)-1-phenylethanamine, as shown in Scheme 1, below, to produce two diastereomeric salts, only one of which is water soluble. The salts will be separated by filtration and the enantiomers of ibuprofen will be recovered by an acid base reaction, as indicated in Scheme 2.

scheme 1

Scheme1. Formation of diastereomeric salts from racemic ibuprofen.

scheme 2

Scheme 2. Regeneration of ibuprofen from its (S)-1-phenylethanamine salt.

Table of Physical Constants (TPC)

Compound Formula Molecular Weight Moles Used Grams or mL Used

MP or BP °C

Density g/mL Solubility
Ibuprofen              
Potassium Hydroxide              

(S)-1-phenylethanamine

             
Hydrochloric acid              
Isopropanol              

Experimental Procedure1

Formation of the diastereomers:

  1. Work in teams of two people. Weigh 2.4 g of racemic ibuprofen and transfer to a 100 mL round bottom flask. Add 24 mL of 0.25 M KOH. Set up a reflux apparatus using an air condenser, a heating mantle connected to a Variac, and a magnetic stirrer. Place a magnetic stir bar in the flask and begin stirring the reagents. Heat the reagents to 75-85°C and adjust the Variac to maintain this temperature range. The temperature can be measured by removing the condenser and placing a thermometer into the reaction mixture. You can do this occasionally, but it is not recommended or necessary that you monitor the temperature continuously. There will be a small amount of vapor in the condenser but the reagents should not be allowed to boil.2
  2. When the temperature of the reagents has reached 75°C and most of the ibuprofen has dissolved, remove the condenser and add 0.75 mL (S)-1-phenylethanamine, dropwise, using a plastic measuring pipet. (Adding this reagent slowly prevents the mixture from cooling so much that the ibuprofen solidifies.) Replace the condenser and continue to heat and stir for 1 hour, maintaining a temperature of 75-85°C.
  3. Cool the mixture to room temperature and vacuum-filter, using a Buchner funnel to collect the insoluble phenylethanamine salt of ibuprofen. Use a 500 mL filter flask as there will be a large volume of foam produced. Dry the salt for 10 minutes on the filter with the vacuum running before proceeding to the next steps.

Regeneration of (R)-and (S)-ibuprofen:

  1. To recover a sample of (S)-ibuprofen, transfer approximately 1/3 to 1/2 of the insoluble salt from the Buchner funnel to a 50 mL beaker. Add 5% HCl, with stirring, until pH paper shows that the mixture is acidic. Chill the mixture in an ice bath, and vacuum filter, collecting the solid on a Hirsch funnel. Wash with ice water and let dry for 15 minutes. Alternatively, you can use a ceramic tile to dry it more quickly. Spread your sample on the tile, then spread and scrape it with a metal spatula until the crytals look dry and crumbly. Use all of your sample to make a solution in absolute ethanol for polarimetry. Optional: Reserve a portion of your sample to obtain a melting point.
  2. To recover (R)-ibuprofen from the soluble phenylethanamine-ibuprofen salt in the filtrate, gravity filter into a 100 mL beaker, using a stemless funnel and fluted filter paper. Add 5% HCl, with stirring, until pH paper shows that the mixture is acidic. Chill the mixture in an ice bath, and vacuum filter, collecting the solid on a Buchner funnel. Wash with ice water and let dry for 15 minutes. Alternatively, you can use a ceramic tile to dry it more quickly. Spread your sample on the tile, then spread and scrape it with a metal spatula until the crytals look dry and crumbly. Use all of your sample to make a solution in absolute ethanol for polarimetry. Optional: Reserve a portion of your sample to obtain a melting point.

Recrystallization of the insoluble phenylethanamine-ibuprofen salt:

Safety Note: Use caution when heating flammable isopropanol with a hot plate. Monitor carefully and use just enough heat to dissolve the diastereomeric salt.
  1. Transfer the remaining phenylethanamine-ibuprofen salt from the Buchner funnel filter to a preweighed 50 mL beaker. Determine the weight of the salt and add 16 mL isopropanol per gram of salt. Cover the beaker with a watch glass and add a boiling stick. Carefully, heat the mixture on a hot plate at a low setting (start with setting #2) until the solid dissolves. If the isopropanol is boiling and all solid has not dissolved, add additional isopropanol, up to 3 mL. When all solid has dissolved, remove the solution from the hot plate and cool to room temperature in the hood. Crystals should form upon cooling. Chill the sample in an ice bath for 10 minutes and collect the recrystallized salt on a Buchner funnel. Wash the crystals with 2 mL of ice cold isopropanol. Recover (S)-ibuprofen from the salt using the procedure outlined in step 4. Prepare a solution in absolute ethanol for polarimetry. Optional: Dry the rest of the sample in your tote overnight and obtain a melting point.

(1) Adapted from McCullagh, James V., J. Chemical Education, Vol. 85, No. 7, July 2008, pp. 941-943.

(2) As an alternative to the reflux apparatus, the reaction can also be carried out in a 125 mL Erlenmeyer flask using a magnetic stirring hot plate.


Post-lab Work

  1. Calculate the enantiomeric excess of your resolved samples, using a literature value of +57 for the specific rotation of (R)-ibuprofen.
  2. Write equations for all of the acid-base reactions which you and your partner carried out.
  3. For your sample of (S)-ibuprofen, calculate the amount of (R)-ibuprofen present.
  4. Use ChemDraw to make models of the two enantiomers of ibuprofen. Identify the active enantiomer.

Special Waste Disposal
Dispose of the products in their respective containers. Neutralize leftover acids and bases and flush down the drain with plenty of water.