Stereochemistry: an introduction - UCLA

1 stereochemistry : an introduction Chem 30A fall 2002. Grazia Piizzi, Steve Hardinger stereochemistry of Tetrahedral Carbons We need: one Carbon sp3-hybridized, at least to represent molecules as 3D objects For example: H. H 2D drawing H C Cl H C Cl Not appropriate for Stereochem Br Br H H. 3D drawing C. H Cl H Cl Appropriate for Stereochem Br Br 2. Let's consider some molecules . First pair H Br same molecular formula (CH2 BrCl). same atom connectivity H H. Br Cl H superposable Cl A B identical (same compound). Second pair H F same molecular formula (CHFBrCl). same atom connectivity F Cl H Cl nonsuperposable Br Br C D stereoisomers (two different compounds). 3. Thus, we can define . Stereoisomers: Stereoisomers isomers that have same formula and connectivity but differ in the position of the atoms in space stereochemistry : stereochemistry chemistry that studies the properties of stereoisomers 4.

2 Historical perspective Christiaan Huygens (1629-1695). Dutch astronomer, mathematician, and physicist. He discovers plane polarized light: Normal light Horizontally (nonpolarized) polarized light Light completely blocked Horizontal Vertical Direction of filter filter light 5. Historical perspective Carl Wilhelm Scheele (1742-1786). Oh, how happy I am! No care for eating or drinking or dwelling, no care for my pharmaceutical business, for this is mere play to me. But to watch new phenomena this is all my care, and how glad is the enquirer when discovery rewards his diligence; then his heart rejoices". In 1769, he discovers Tartaric HO CO2H. Acid from tartar (the potassium salt of tartaric acid, deposited HO CO2H. on barrels and corks during fermentation of grape juice). Tartaric Acid 6. Historical perspective Jean Baptiste Biot (1774-1862). In 1815, he notes that certain natural organic compounds (liquids or solutions) rotate plane polarized light (Optical Activity).

3 IN molecule OUT. l ec ule m oleculele mo moleculelecu moleculemo tube containing plane plane a liquid organic polarized polarized compound or light light solution 7. Definitions Optically Active: Active the ability of some compounds to rotate plane polarized light. Dextrorotatory (+): (+) an optically active compound that rotates plane polarized light in a clockwise direction. Levorotatory (-): an optically active compound that rotates plane polarized light in a counterclockwise direction. H H. N. (-)-Nicotine N CH3. CH3 H3C H. N. (+)-Methamphetamine 8. Historical perspective In 1819, Racemic Acid was HO CO2H. discovered. Later shown to have the same formula as Tartaric Acid. HO CO2H. In 1832, Biot notes that Tartaric Acid from grape juice fermentation rotates plane polarized light in a clockwise direction: IN OUT. HO CO2H. HO CO2H HO CO2H. HO CO2H. HO CO2H. HO CO2H HO CO2H. HO CO2H. plane tube containing plane polarized light, polarized solution of rotated clockwise light Tartaric Acid (TA) TA is dextrorotatory 9.

4 Historical perspective In 1819, Racemic Acid was HO CO2H. discovered. Later shown to have the same formula as Tartaric Acid. HO CO2H. In 1838, Biot notes that Racemic Acid does not rotate plane polarized light: IN OUT. HO CO2H. HO CO2H HO CO2H. HO CO2H. HO CO2H. HO CO2H HO CO2H. HO CO2H. plane tube containing plane polarized light, polarized solution of unchanged light Racemic Acid (RA) RA is not optically active 10. Historical perspective Louis Pasteur (1822-1895). In 1847, he repeats earlier work on Racemic Acid. Crystallization of sodium ammonium salt gives mirror image crystals that he separated by hand. Equimolar solutions of separated crystals have equal but opposite optical activity: HO CO2 Na D]=D=+ [ + (+)-Tartaric Acid separate (dextrorotatory, natural). crystals HO CO2 NH4 ]D= (-)-Tartaric Acid [ . (levorotatory, unnatural). Racemic acid salt 11. Historical perspective In 1853, Pasteur studies Mesotartaric Acid (same formula as Racemic and HO CO2H.)

5 Tartaric Acid) but fails to separate into (+) and (-) crystals. HO CO2H. In 1854, he notes that certain plant mold metabolizes (+)-tartaric acid but not (-)-tartaric acid. 12. Historical perspective Joseph A. Jacobus H. LeBel van't Hoff (1847-1930). In 1874, they propose: (1852-1930). Carbon with 4 attachments is Tetrahedral. A molecule having a tetrahedral carbon with 4. different attachments may exist as a pair of isomers. 13. Therefore .. Stereoisomers: Stereoisomers isomers that differ only in the position of atoms in space, and that cannot be interconverted by rotation around a single bond. Stereocenter: Stereocenter a carbon atom bearing 4. different atoms or group of atoms. H F. C,D are a pair of stereoisomers * *. F Cl H Cl Carbon * is a stereocenter Br Br C D. 14..another example Stereoisomers of 2-chlorobutane A,B are stereoisomers * * Carbons * are stereocenters H Cl Cl H A,B are nonsuperposable A mirror images B.

6 Enantiomers Enantiomers: stereoisomers that are nonsuperposable mirror images. Chiral: any molecule that is nonsuperposable with its mirror image ( A and B are chiral). Achiral: any molecule that is not chiral. Racemic mixture: a 1:1 (equimolar) mixture of two enantiomers. 15. Unsolved Issues HO CO2H. HO CO2H. Mesotartaric Acid could not be separated Joseph A. Jacobus H. into (+) crystals and LeBel van't Hoff (-) crystals (1847-1930) (1852-1930). Carbon with 4 attachments is Tetrahedral. A molecule having a tetrahedral carbon with 4. different attachments may exist as a pair of isomers. 16. In 1877, Hermann Kolbe, one of the best organic chemist of the time wrote: Not long ago, I expressed the view that the lack of general education and of through training in chemistry was one of the reasons of the causes of the deterioration of chemical research in Germany ..Will anyone to whom my worries seem exaggerated please read, if he can, a recent memoir by a Herr van't Hoff on The Arrangement of Atoms in Space , a document crammed to the hilt with the outpouring of childish fantasy This Dr.

7 J. H. van't Hoff, employed by the Veterinary College at Utrecht, has, so it seems, no taste for accurate chemical research. He finds it more convenient to mount his Pegasus (evidently taken from the stables of the Veterinary College) and to announce how, on his bold flight to Mount Parnassus, he saw the atoms arranged in in space.. In 1901 van't Hoff received the first Nobel Prize in Chemistry. In 1877, Hermann Kolbe 17. Take-home problem Stereoisomers of 2-chlorobutane * *. H Cl Cl H. A B. Enantiomers Remember: Enantiomers: stereoisomers that are nonsuperposable mirror images. Racemic mixture: a 1:1 (equimolar) mixture of two enantiomers. Explain why: A and B cannot be physically separated. a racemic mixture of A and B has no optical activity (no rotation of plane polarized light). 18. Summary Stereoisomers: Stereoisomers isomers that have same formula and connectivity but differ in the position of the atoms in space.

8 They possess one or more stereocenters. Stereocenter: Stereocenter a carbon atom bearing 4 different atoms or group of atoms. Chiral: Chiral any molecule that is nonsuperposable with its mirror image. Enantiomers: Enantiomers stereoisomers that are non superposable mirror images. Racemic mixture: mixture a 1:1 (equimolar) mixture of two enantiomers. Optically Active: Active the ability of some compounds to rotate plane polarized light. 19. Configuration of Stereocenters Enantiomers of 2-chlorobutane: The Cahn-Ingold-Prelog (CIP). * * rule assigns R or S. H Cl Cl H configuration to the two A enantiomers. B. 1) Assign the priorities to the groups attached to the stereocenter. Priority is based on the atomic number, H has lower priority than Cl. But methyl and ethyl both are attached to the stereocenter through carbon! In these cases, priority assignments proceed outward, to the next atoms.

9 The Methyl carbon has 3 Hs attached while the Ethyl carbon has 2Hs and and a carbon (the terminal methyl group). Therefore, the latter gets higher priority. 20. Configuration of Stereocenters 2 3 2) Orient the molecule so that the * group of priority four (lowest priority). 4H Cl 1 points away from the observer. A. 2 3 3) Draw a circular arrow from * the group of first priority to the 4H Cl 1 group of second priority. 4) If this circular motion is clockwise, the enantiomer is the R enantiomer. If it is counterclockwise, it is the S enantiomer. Thus, A is the R enantiomer of 2-chlorobutane. 21. Configuration of Stereocenters Ibuprofen, an CO2H. antiinflammatory H3C CH3. agent CH3. Not a Stereocenter! 1 CO2H 1. Not a 3 3 CO2H. Stereocenter! 2 CH 3 H3 C. 2. CH3 * H 4 H * CH3. 4. H3C CH3. R enantiomer S enantiomer 22. Molecules with multiple stereocenters Molecules with 1 stereocenter 2 possible can be R or S stereoisomers Molecules with n stereocenters can have all the possible 2n possible combinations of R and S for stereoisomers each stereocenter 23.

10 Tartaric Acid HO CO2H. *. 4 possible 2 stereocenters stereoisomers HO * CO2H. Mirror H H. D HO CO2H. i Enantiomers HO2C OH D. S R i a s S R a t HO CO2H t s D ia as HO2C OH. e H st D i H t r H e H r o HO CO2H. HO2C OH. m R o e S ? S m r R e HO CO2H. s H. HO2C OH r H s 24. Remember Enantiomers: Enantiomers stereoisomers that are non superposable mirror images. Diastereomers: stereoisomers that are not mirror images. For example: H. not mirror H. HO CO2H HO2C OH. S image S. S R. mirror HO CO2H HO2C OH. H image H. (S, S)-Tartaric acid (S, R)-Tartaric acid DIASTEREOMERS. 25. H H. HO CO2H. mirror HO2C OH. R image S. S R. mirror HO CO2H HO2C OH. H image H. (R, S)-Tartaric acid (S, R)-Tartaric acid Enantiomers ? 26. Why not Enantiomers? H H. HO CO2H HO2C OH. R S. S R. HO CO2H. Same HO2C OH. H compound!!!! H. Enantiomers: same molecular formula same connectivity mirror images X nonsuperposable Superposable Achiral compound 27.