Stereochemistry & Polarimetry notes

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1 Reminder: These notes are meant to supplement, not replace, the laboratory manual. Stereochemistry & Polarimetry notes History Application: Approximately 25% of all drugs are marketed as either racemates (mixtures of two enantiomers) or mixtures of diastereomers i. The orientation around a chiral center can have a dramatic impact on the pharmacological response of that drug in the human body. A worst case scenario is one which the non-desired stereoisomer causes serious toxicity. The drug Thalidomide, was prescribed to millions of European women to suppress morning sickness associated with pregnancy during the late 50 s early 60 s. Horrible birth defects ii, including missing limbs, resulted. The cause of these birth defects was assigned to the S-(-)-enantiomer of the drug, which did not undergo clinical trials. This drug was close to being allowed into the US. A new woman FDA reviewer, Dr. Frances Kelsey questioned the supporting evidence, did not yield to pressure from the pharmaceutical manufactures, blocked its introduction into US markets iii. Dr. Kelsey received a Presidential award from JFK for her actions that saved tens of thouss of babies in the United States. This tragedy brought about severe tightening in the laws surrounding the testing introduction of new drugs into the US. Chiral synthesis purification is a crucial aspect of all successful drug manufacture. Thalidomide Safety considerations for this experiment: In this experiment aqueous sugar solutions will be prepared their optical rotations will be measured. The solutions are nontoxic the polarimeters have no special hazards. Stard good lab practice of wearing goggles lab coats applies. Terminology. Chiral: A material which is not superimposable on its mirror image. Chirality center: A tetradedral atom having four different groups attached. This is also known as a stereocenter. Cahn-Ingold-Prelog system: A system of prioritization of groups around a carbon center, placement of the lowest priority in the back, then sequencing of the remaining groups. Clockwise is defined as R, counterclockwise is defined as S iv. R & S: Orientation around a chirality center as defined by the Cahn-Ingold-Prelog system. Enantiomers: a pair of nonsuperimposible mirror images. Diastereomers: stereoisomers that are not mirror images of one another.

2 Meso: A compound with 2 or more chirality centers that is achiral (superimposable on its mirror image) due to presence of an internal plane or point of reflective symmetry. v Stereoisomers: Two or more molecules with the same empirical formula, the same atomic connectivity but different spatial orientations. Constitutional isomers: Two or more molecules with the same empirical formula but different atomic connectivity. These two molecules will have different names. Plane Polarized Light: electromagnetic radiation in which the orientation of the electric fields are perfectly aligned. Racemates: A mixture composed of equal amounts of R S enantiomers. Optically active: A material which will rotate plane polarized light. + -: The direction in which an optically active material will rotate light. If the light is rotated clockwise it is defined as +. There is absolutely no correlation between R & S + -. A given R compound may be + or -. In a pair of enantiomers, one compound will rotate plane polarized light in the + direction the other compound will rotate the light by the same amount, in the opposite direction. There is no way to theoretically determine if a compound will rotate light + or -. The direction of rotation must be experimentally determined. Specific Rotation, [ ]: A fixed physical property describing the rotation of plane polarized light by a chiral compound. Other physical properties include melting point boiling point. The specific rotation describes how far in what direction a stard solution (1.00 g/ml solution) of that material in a stard tube (1.00 dm) will rotate light. A [ ] of means that a pure enantiomer made up into a 1.00 g/ml solution in a 1.00 dm tube will rotate light in the clockwise manner by 87.6 degrees. Observed Rotation, obs : This is the experimentally obtained rotation of a compound. This value is dependent upon the way the experiment was carried out including the solution concentration the length of tube. If the tube length the solution concentration is known, the observed rotation may be converted to specific rotation. 1. Chiral molecules have an asymmetrical center which responds to light as a lens rotates light. The ability to rotate light is termed optical activity. Enantiomeric compounds rotate light by exactly the same amount but in opposite direction. The degree to which a substance rotates light may be used to determine a) the identity of the substance, b) the enantiomeric purity of a known substance or c) the concentration of a known substance in a solution. In today s experiment optical rotation will be used to determine the identity of unknown substances. 2. Chiral molecules synthesized in the lab are notoriously expensive. For this experiment we are using chiral molecules synthesized by mother nature. Each of the molecules is a type of naturally occurring sugar.

3 Name (other names) D- Fructose (D-Levulose) Structure (Fisher Haworth) Specific Rotation [ ] -86 D-Glucose +98 D- Galactose + 82 D-Allose +15 Sucrose glucose-fructose Maltose glucose-glucose The glassware which is selected to measure a volume has a large impact on the accuracy precision of the measured volume. Glassware Error of Measurement Cost per unit 50 ml Beaker ± 3 ml $ ml Grad. Cylinder ± 0.2 ml $ ml Volumetric Flask ± 0.02 ml $30.07

4 Volumetric flasks are ten times more precise than 50mL graduated cylinders more than 100 times more precise than beakers. In today s lab it is very important to know the concentration of the solution precisely. The accuracy precision of the volume mass measurements will have a direct significant effect on the correct identification of the unknown. Volumetric flasks will be used to precisely accurately measure ml. (The last two zeros here are important significant.) 4. Volumetric flasks are good for measuring one volume only. The solvent has to be added until the meniscus is exactly on the line. If the meniscus is slightly below the line, add more solvent. If too much solvent is added the meniscus is above the line, there is no fix. The entire solution must be disposed of, the container rinsed the entire procedure repeated. 5. Remember CHEM 1010 Module 4, learning goal 7 how to properly make solutions from pure compounds water. Step 1. Measure out the amount of solute which you need. Step 2. Put approximately one half of the water needed into the container. Step 3. Add the substance from Step 1 into the water in Step 2 mix until all is dissolved. Step 4. Add water until the total volume to be made is obtained. Be careful when using volumetric flasks. Do not add too much solvent. Step 5. Mix the solution. If made in a volumetric flask, cap invert to mix. 6. In order to observe rotation, the light which is passed through the solution must be plane polarized. Ordinary light has waves which are oriented in all directions. Plane polarized light is made up of waves which are oriented parallel to a defined plane. Ordinary light Plane Polarized Light 7. When a beam of plane polarized light passes through a solution of optically active material the light will rotate. 8. Each pure chiral material has a set specific rotation [ ] which is a fixed physical characteristic for that material. The enantiomer will rotate the plane of polarized

5 light by exactly the same amount but in the opposite direction. If an S compound has an [ ] of +87.6, then the R enantiomer will have an [ ] of Some R compounds rotate light in the + direction, some R compounds rotate light in the direction. There is no relationship between R/S +/-. Racemic mixtures (equal parts of two enantiomers) will have no net rotation because the equal but opposite rotations cancel each other. 9. The specific rotation ([ ]) of a compound is a fixed physical property of that compound (as is its boiling point or melting point or density). The observed rotation ( obs ) depends on the concentration of the sample in solution (c) in grams per milliliter, the length of the cell (l) in decimeters as well as the specific optical rotation of the compound [ ] Doubling the concentration of a material in a solution will double the observed rotation. Cutting the cell length in half will half the observed rotation. The specific rotation [ ] takes the concentration cell length into account hence remains the same. 10. The observed rotation measurement will be taken using one of four Atago Polax-2L polarimeters available for organic students. The image on the left, shows the machine in the closed position ready to take a reading. The machine on the right is open showing the polarimeter sample cell resting on the support. 11. If a material was made up into a solution at other than 1.00 g/ml concentration, tested in a tube other than 1.00 dm in length, that observed rotation can easily be normalized back to specific rotation conditions by utilizing the above formula. 12. A mixture of R S enantiomers will rotate light in the direction of the enantiomer present in excess to a degree related to the amount of that excess. This is described by the following equation.

6 e.e. = R-S / (R+S) * 100%= [ ] [ ] * 100% If the amount of the two enantiomers are known, the observed rotation may be calculated from the enatiomeric excess. For example, if a pure R material has a specific rotation of , what will be the specific rotation of a mixture of 40% R 60% S? This means there is a (60%-40%) 20% enantiomeric excess of S. Using basic algebra, the 20% e.e. is then divided by 100 to result in 0.20, multiplied by the absolute value of [ ] pure of or to show this mixture will rotate light by Knowing that the R material rotates in the negative direction, knowing that this mixture has an excess of the S enantiomer, means that this material will rotate light in the positive or clockwise direction by 3.35 degrees. e.e. = R-S / (R+S) * 100%= /(60 +40) *100% = 20% 20% of = 3.35, an excess of S means 3.35 o clockwise. 13. Of more practical use is the calculation of the enantiomeric excess given a specific rotation of a mixture a specific rotation for a pure enantionmer. If a mixture of this R S has a specific rotation [ mix of +3.97, pure R has a specific rotation of ([ R= -16.7) then the composition of the mixture may be determined as follows. The overall rotation is positive, the specific rotation of pure R was stated as 16.70, therefore this mixture has an excess of the S enationmer. Deciding which enantiomer is in excess needs no calculations should be done first. Using the above equation the amount of excess of one entionmer can be calculated e.e.= [ ] [ ] * 100% = ] * 100%=23.8%. This means that there is 23.8 excess S enationmer. This also means the rest of the material ( = 76.2%) is equally divided between the R S. Therefore in the balanced material there is or 38.1% R material, 38.1% S. The total composition of S is the amount of excess 23.8% plus the amount from the balanced, 38.1% or a total of (23.8% +38.1%=) or 61.9% S material. The total mixture composition is then R = 38.1%, S= 61.9%. Always double check by adding these two together, the result should be 100 %. 61.9% (S) % (R) = %, the difference between the two ( ) is 23.8%, the amount of excess. Revised October 21, 2014 S. L. Weaver

7 References. i Hutt, A. J., Grady, J. O., J.Antimicrobial Chemotherapy, 1996, 37, 7-32 ii Chemical & Engineering News, Thalidomide (October 5, 2011) iii (October 21, 2014) iv David Klein, Organic Chemistry, Wiley New York, 2012, pp v Ibid pp