Chemistry 350 Laboratory - Fall Semester 2010 – Professor T. Nalli, Winona State University

Expt #4. Resolution of a Racemic Amine

Relevant textbook readings - Mohrig, Chapter 8 (especially 8.2-8.4), Chapter 14.

Overview - You will isolate the levorotatory enantiomer from a sample of racemic α-phenylethylamine. This will be accomplished through fractional crystallization of the (+)-tartrate salt of the (−)-amine.

Background - Tartaric acid is a natural product that occurs naturally as the (+) enantiomer. It will be used as a resolving agent for racemic α-phenylethylamine, which it reacts with in acid/base fashion (eq 1). This reaction forms diasteromeric salts, (+)-amine (+)-tartrate and (−)-amine (+)-tartrate. The (−)-amine (+)-tartrate is less soluble than the other salt and can be crystallized out of methanol solution. The obtained crystals are then converted back to (−)-α-phenylethylamine by reaction with aqueous sodium hydroxide (eq 2).

You will use both polarimetry and NMR to measure the enantiomeric excess of your final product. Ideally, the obtained final product would be enantiomerically pure (−)-α-phenylethylamine (ee = 100%). However, in practice, resolution of racemic mixtures rarely gives such a result. Thus, you can expect an ee of somewhat less than 100%.

Procedures

Running the reaction. Weigh out 7.5 g of (+)-tartaric acid and add it to a 250-mL Erlenmeyer flask. Add 120 mL methanol and heat on a hot plate to about 60°C. To the hot solution, slowly add 6.4 mL of α-phenylethylamine. Stopper the flask, label it thoroughly, and let it stand in the designated area in the lab until next week.

Week 2 – Check your flask for crystals. If you have no crystals then either borrow a crystal from another group and add it to your flask as a seed crystal or use a glass rod to scratch the inside of the flask to induce crystal growth. For best results the crystals that form should be prismatic rather than needle-like. If your crystals appear to be mostly needles with some prisms present, you may want to heat until most of the solid is dissolved and then cooling slowly. (The needles should dissolve quickly leaving behind a few prismatic crystals, which can then act as seeds for the growth of more prisms.)

Work-up procedures.

· Collect the crystals by vacuum filtration on a pre-weighed Buchner funnel and wash them with two 5-mL portions of ice cold methanol.

· Weigh the funnel with crystals and calculate the yield and percent yield of (−)-α-phenylethylamine tartrate.

· Add the crystals to 25 mL H₂O in a 100-mL Erlenmeyer and add 4 mL 50% NaOH(aq). Swirl to mix the contents and note your observations.

· Transfer the solution to a separatory funnel (Chapter 8) and extract with 10-mL dichloromethane (DCM). Drain the lower, organic layer to a clean dry flask labeled “DCM extracts”. Extract the aqueous solution in the separatory funnel with an additional 10-mL DCM and again drain the lower layer into the labeled flask. Repeat this process once more. Discard the remaining aqueous layer.

· Add about 1 g anhydrous Na₂SO₄ to the DCM extracts and allow the solution to dry for at least ten minutes. (See Chapter 8.8-8.11).

· Transfer the dried solution to a small pre-weighed round-bottom flask and heat gently with a hot water bath to evaporate the solvent. Use a stream of nitrogen from a pipet blown on the surface of the liquid to expedite the evaporation process. Once the volume of liquid is down to about 2-3 mL then discontinue this process and place the flask under vacuum for a few minutes to remove remaining solvent. (Heating the amine in the absence of solvent is likely to promote the reaction of carbon dioxide in the air with it. This reaction forms a white solid, which interferes with the polarimetry measurements, so we are attempting to avoid it by not evaporating all of the solvent with heat.)

· Weigh the flask with amine product and calculate the yield and percent yield of (−)-α-phenylethylamine.

Determination of enantiomeric excess (ee).

¹H NMR Method. The two enantiomers of α-phenylethylamine have identical NMR spectra as do any pair of enantiomers. Therefore, a chiral resolving agent must be used to allow the detection and quantitation of each compound separately. We will use (S)-acetylmandelic acid (AMA) as the chiral resolving agent. This is very simply accomplished by adding AMA to the NMR tube along with the amine and the NMR solvent (see procedures below). An acid/base reaction occurs to form diasteromeric salts (eq 3). These salts have somewhat different ¹H NMR spectra, so NMR can be used to estimate the relative amount of each and, thus, the ee.

· Place 5 mg of the product into a small test tube. Keep the test tube corked as much as possible to prevent reaction of the amine with carbon dioxide in the atmosphere.

· Weigh out 10 mg of (S)-O-acetylmandelic acid and add it to the test tube.

· Add about 0.25 mL CDCl₃ and mix the solution so as to dissolve the contents completely.

· Add the mixture to an NMR tube and add enough CDCl₃ to bring the level of liquid up to that necessary for good shimming (~ 5 cm).

· Obtain the ¹H NMR spectrum.

· Integrate the NMR spectrum and use the integration values to help identify as many of the peaks as you can. Pay special attention to the pair of doublets at 1.0-1.3 ppm because these are the resonances of the methyl protons of the amine. Literature values of these chemical shifts are 1.23 ppm for the R-(+) amine salt and 1.12 ppm for the S-(−) amine salt. Thus the relative integrations of these two doublets provide a measurement of ee for your product. (Convert the relative integrations to percents and then calculate ee by simple subtraction.)

Polarimeter Method. Measure the specific rotation, [α], of the product using a polarimeter and a 10-mL graduated cylinder (see procedures below). Also, look up the literature value of [α] for pure (−)-α-phenylethylamine. Use the two values of [α] to determine the optical purity of the sample (Chapter 14.5)

· Weigh a 10-mL graduated cylinder that has a glass (rather than plastic) base. We need the bottom of the cylinder to be transparent because we will be using it as a polarimeter tube.

· Add all of your amine product (after having taken a sample for the NMR determination of ee) to the graduated cylinder.
Weigh again to get the mass (m) of amine.

· Measure the volume (v) of liquid in the cylinder using the gradations on the cylinder.

· Measure the height of the column of liquid in the cylinder. This is the polarimeter tube length (l).

· Place the graduated cylinder in the polarimeter and measure the rotation to the nearest degree. Do three trials and average the result.

· Use the standard polarimetry equation (Chapter 14.4) to calculate [α].

Report

Please try to integrate the answers to the assigned questions into your results and conclusions section for this report (rather than answering each sequentially).

Assigned Questions:

1. What is the reaction that occurs between the amine and carbon dioxide? Do some literature research to find the answer and draw the structure of the product.

2. Discuss the advantages and disadvantages of each method for determination of enantiomeric excess.