Practical I: Resolution of 1-Phenylethylamine

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1 Practical I: Resolution of 1-Phenylethylamine Reference: Adapted from Ault, A. J. Chem. Educ. 1965, 42, 269. Readings: rganic Chemistry by David Klein, Chapter 5 Summary In this experiment (S)-( )-1-phenylethylamine will be isolated. Racemic (1)- phenylethylamine will be reacted with enantiomerically pure (2R,3R)-(+)-tartaric acid to form diastereoisomeric salts which can be resolved by selective crystallization from methanol. The isolated salt will be converted to the optically active free base by treatment with sodium hydroxide. A polarimeter will be used to determine the optical rotation of the product, from which we can determine enantiomeric excess and evaluate the efficiency of our resolution. Introduction An object that has a non-superimposable mirror image is referred to as being chiral (from the Greek chiros meaning handed). Examples of such objects include many organic and inorganic molecules, of which many occur naturally. These two nonsuperimposible stereoisomers are referred to as enantiomers. An equimolar mixture of two enantiomers is known as a racemic mixture (or racemate). Enantiomers have identical physical properties (e.g. melting point, boiling point, and solubility in methanol). owever, the isolation of a single enantiomer from a racemic mixture can sometimes be accomplished by a process known as chiral resolution. Mirror plane N 2 2 N (R)-(+)-1-phenylethylamine (S)-(-)-1-phenylethylamine (2R,3R)-(+)-tartaric acid Non-superimposable bject - image ENANTIMERS (R)-1-Phenylethylamine (depicted above) cannot be superimposed with its mirror image. When a racemic mixture (a 1:1 ratio of enantiomers) of 1-phenylethylamine is reacted with a single enantiomer of tartaric acid, 1 two diastereomeric salts form (in a 1:1 ratio). These complexes are not mirror images of one another since only a single enantiomer of tartaric acid is used in the reaction. Thus, (R)-amine, (R, R)-tartaric acid salt and (S)- amine, (R, R)-tartaric acid salt are formed. 1 Tartaric acid occurs naturally and is widely available as it is a byproduct in the wine making industry.

2 RACEMATE (1:1 mixture) N 2 2 N + (R)-(+)-1-phenylethylamine (S)-(-)-1-phenylethylamine (2R,3R)-(+)-tartaric acid DIASTEREMERIC SALTS N 3 (R)-1-phenylethylammonium (2R,3R)-tartrate 3 N (S)-1-phenylethylamine (2R,3R)-tartrate More soluble (stays in solution) Less soluble (crystallizes from solution) owever, unlike enantiomers, diastereomers (generally) have different physical properties, so we would expect that the above complexes should have different solubilities in methanol. In fact these two diastereomeric complexes have a significant solubility difference in methanol. The (R)-amine:(R, R)-tartaric acid salt is more soluble in methanol than the (S)-amine:(R, R)-tartaric acid salt. This difference permits the isolation of one of the diastereomeric salts by selectively crystallizing out the (S)-amine, (R, R)-tartaric acid salt from a methanolic solution. nce the solid (S)-amine, (R, R)- tartaric acid complex is isolated, treatment with excess aqueous sodium hydroxide will convert the salt to the free amine (organic soluble) and disodium tartrate (aqueous soluble). Drawing on your acid/base extraction skills, you soon will have a sample of 1- phenylethylamine that should predominantly consist of (S)-( )-1-phenylethylamine. Now let s discuss how to analyze the enantiomeric composition of your sample. 3 N (S)-1-phenylethylamine (2R,3R)-tartrate Na 2 N Na (S) (-)-1-phenylethylamine (Dichloromethane soluble) Na (2R,3R)-tartrate Enantiomers do not interact with plane-polarized light in the same way, a phenomenon that chemists have made good use of. Recall that light is a wave that

3 consists of oscillating electric and magnetic fields. A regular beam of light has electric (and magnetic) fields that oscillate in all directions perpendicular to the direction of beam travel. A beam of light with an electric field oscillating in only a single plane is called plane-polarized light, or more simply polarized light. When regular light is passed through a polarizer (imagine this as functioning like a slit) only light that oscillates parallel to this slit can pass through it and as a result the light that emerges from the polarizer only oscillates in one direction. When plane-polarized light is passed through a single enantiomer of a chiral molecule (more commonly a solution of a single enantiomer of a chiral molecule), the plane of polarization is rotated. When the opposite enantiomer is used, the plane of polarization is rotated in an equal and opposite direction. Samples that rotate polarized light are said to be optically active. The magnitude of this rotation,, is reported in degrees by a device called a polarimeter. A schematic of a polarimeter is shown below. If the light has been rotated in a clockwise direction, the is assigned a positive (+) value; if the light has been rotated in a counterclockwise direction, the is assigned a negative ( ) value.

4 For a given enantiomer the degree of rotation is dependent on the concentration of the compound (c), the path length of the sample cell (l), and the wavelength of light that is used. Typically, the yellow light of a sodium lamp (the D line of Na, wavelength = 589 nm) is used as a light source. If you have ever spilled salt on a gas burner the flame will burn yellow this is due to emission at 589 nm. The equation below can be used to calculate the specific rotation, sample, which is a constant for a single enantiomer of a chiral compound in a given solvent at a given temperature and wavelength. For neat samples, the concentration (c) is taken to be the density of the compound.. = Specific rotation = observed rotation c = concentration (g/ml) l = pathlength (dm (1 dm = 10 cm)) D = sodium D-line (589 nm) t = temperature of sample It is usually reported in the following format: #.## (c #.#, solvent) A racemic mixture will not rotate polarized light and is said to be optically inactive. Achiral molecules also do not rotate plane-polarized light. Any excess of one enantiomer over the other will result in the rotation of polarized light, with the maximum rotation occurring when the sample consists of a single enantiomer. The enantiomeric excess (ee) of a compound can be calculated using the equation below. The ee of a racemic mixture is 0% while the ee of a single enantiomer is 100%. ee = % of the major enantiomer - % of the minor enantiomer. By comparing the specific rotation of a sample prepared in the laboratory with the published specific rotation of an enantiomerically pure sample, one can calculate the optical purity of the sample. If the relationship between concentration and rotation is linear, then optical purity = %ee. ptical purity. 100% Procedure Place 7.8 g of (L)-(+)-tartaric acid and 125 ml of methanol in a 250 ml Erlenmeyer flask. eat this mixture on a hot plate until the solution is nearly boiling. Slowly add 6.25 g of racemic α-methylbenzylamine to this hot solution. Allow the contents to cool, and then cover the top of the flask with aluminum foil and let stand overnight. The crystals that form should be prismatic. If needles form, they will not be optically pure enough to give a sufficient resolution of isomers -- they must be prisms! Needles should be redissolved (by careful heating) and cooled to slowly crystallize again (if this

5 is necessary, your TA will take care of this between periods). When you recrystallize in this fashion you can seed the reaction with a prismatic seed. If you have a mixture of prisms and needles, you can heat until most of the solid is dissolved. Usually the needles will dissolve faster than the prisms in this case. (If you get the incorrect crystals, your TA will check during the week and redissolve/seed as necessary). Continue from here during next lab period nce you have obtained the correct type of crystals, you should isolate them by vacuum filtration. The crystals can be washed with a small portion (~ 5 ml) of cold methanol. Partially dissolve the crystalline salt in 25 ml of water and treat with 4 ml of 50% Na. The resultant solution is extracted with 3 x 10 ml of dichloromethane. The organic layers are combined in a stoppered flask and dried with 1 gram of anhydrous sodium sulfate for about 10 minutes. Decant the dichloromethane into a preweighed 100 ml round bottom flask and by simple distillation (use a steam bath). Avoid transferring any of the white solid. Calculate the percent yield of the resolved amine based upon the amount of racemate you started with. Prior to determining the optical rotation, allow the TA to examine your sample and to check the mass of the material obtained. btain the optical rotation by dissolving your sample in (use 1.00 g in 10 ml). If you have less than 1 g, use what you have, but you must record the mass accurately your TA will provide details on how to use the polarimeter. Literature Data (S)-( )-1-phenylethylamine: D = 30, c = 0.1 g/ml in Et; density = g/ml Cleanup The sodium hydroxide solution should be disposed of in the Basic Aqueous Waste. MgS4, filter paper, and excess tartaric acid should be put in the Solid Waste. The phenylethylamine, methanol, and ether go in the Non-halogenated rganic Waste.