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Avg # of students per office hour: Dr. Dong: 4-5 students Ian: 1-3 students

Attendance from last week:. 116 students attended discussion last week (60% of the class). 4. 2. 10. 8. 15. 12. 15. 25. 25. Avg # of students per office hour: Dr. Dong: 4-5 students Ian: 1-3 students En- wei : 0 students Ray: 1 student.

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Avg # of students per office hour: Dr. Dong: 4-5 students Ian: 1-3 students

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  1. Attendance from last week: 116 students attended discussion last week (60% of the class) 4 2 10 8 15 12 15 25 25 • Avg # of students per office hour: • Dr. Dong: 4-5 students • Ian: 1-3 students • En-wei: 0 students • Ray: 1 student Please take advantage of discussion section and office hours! 9 office hours per week!!!!

  2. Closed loop of p orbitals • Parallel p orbitals • Pi electrons described by 4n+2 (Huckel’s Rule)

  3. Conditions for aromaticity: • Closed loop of p orbitals • Parallel p orbitals • Pi electrons described by 4n+2 (Huckel’s Rule)

  4. mirror Pegasus Stereochemistry Part 1Lecture Supplement page 59

  5. Stereochemistry: What is It? Isomers: Molecules with same chemical formula but different spatial arrangement of atoms • Jöns Jakob Berzelius, 1830 Urea CH4N2O Ammonium cyanate CH4N2O Constitutional isomers: Isomers that differ in sequence of atom connectivity

  6. rotate around C2-C3 bond Stereochemistry: What is It?Isomers Conformational isomers • Same sequence of connectivity; can be interconverted by rotation around a single bond Butane C4H10 Staggered conformation Butane C4H10 Eclipsed conformation • Are other isomer types possible? Tetrahedral carbon...

  7. light beam Iceland spar crystal (natural CaCO3) Historical BackgroundTimeline A: Light 1678: Christiaan Huygens discovers plane-polarized light many vibrational planes nonpolarized light one vibrational plane plane-polarized light

  8. plane-polarized light tube of liquid organic polarization plane shifted compound or solution Historical BackgroundTimeline A: Light 1815: Jean Baptiste Biot notes some natural substances rotate plane-polarized light Optically active: Rotates plane-polarized light Optically inactive: Does not rotate plane-polarized light

  9. (+)-Methamphetamine (-)-Nicotine Historical BackgroundTimeline A: Light Optical activity Dextrorotatory: Rotates plane-polarized light in a clockwise direction (+) Levorotatory: Rotates plane-polarized light in a counterclockwise direction (-)

  10. Historical BackgroundTimeline B: Tartaric Acid Isomers Prior to 1847: Three tartaric acid isomers... Origin Wine fermentation Synthesis in lab Substance Tartaric acid Tartar: wine precipitate Racemic acid Latin racemus: bunch of grapes Mesotartaric acid Optical activity (+) Inactive Inactive Structure Isomers Isomers

  11. Ammonium sodium racemate optically inactive Historical BackgroundTimeline B: Tartaric Acid Isomers 1847: Louis Pasteur separates racemic acid ammonium sodium salt into (+) and (-)-tartaric acids (+)-Tartaric acid optically active Quantity: Equal Optical activity: Equal but opposite separate crystals (-)-Tartaric acid optically active Conclusion: Racemic acid is a 1:1 mixture of two optically-active substances

  12. Historical BackgroundTimeline B: Tartaric Acid isomers 1853: Pasteur cannot separate mesotartaric acid into (+) and (-) forms • Pasteur says he lacks the skill to achieve this separation • 1854: Pasteur notes a plant mold metabolizes (+)-tartaric acid but not (-)-tartaric acid • Tartaric acid isomers have different biological properties

  13. A molecule having a tetrahedral carbon atom with four unequal attachments exists as a pair of isomers. Historical BackgroundTimeline C: Tetrahedral Carbon 1874: Joseph Achille Le Bel (age 27) and Jacobus Henricus van’t Hoff (age 22) propose:

  14. Historical BackgroundTimeline C: Tetrahedral Carbon Example: 2-Chlorobutane Constitutional isomers? Same atom connectivity sequence Conformational isomers? Cannot be made superposable by bond rotation Verify with models Identical? Not superposable Verify with models Configurational isomers (stereoisomers): Isomers that differ by the position of atoms in space, but are not constitutional or conformational isomers.

  15. mirror } Verify with models Historical BackgroundTimeline C: Tetrahedral Carbon The 2-chlorobutane stereoisomers have another relationship: Observations: Mirror images Nonsuperposable Enantiomers: Stereoisomers that are nonsuperposable mirror images

  16. Historical BackgroundTimeline C: Tetrahedral Carbon Other useful stereochemistry vocabulary Stereocenter: An atom bearing three or more different attachments whose exchange leads to stereoisomers. • Usually (but not always) a carbon atom bearing four different attachments. Attachments: CH3, CH3, Cl, H This carbon is not a stereocenter Attachments: CH3, CH3CH2, Cl, H This carbon is a stereocenter Chiral: Any object that is not superposable on its mirror image. Example: Your hands Not same meaning as enantiomers Achiral: Any object that is not chiral. Mirror

  17. Common misconception Just because a molecule has “dashed” and “wedged” arrows does not automatically mean it is chiral. Chiral molecules have a stereocenter (an atom bearing three or more different attachments) achiral chiral chiral achiral Klein, Chapter 7

  18. Historical BackgroundTimeline C: Tetrahedral Carbon At first the “stereoisomer theory” was not well accepted... 1877: Hermann Kolbe comments on The Arrangement of Atoms in Space (van’t Hoff’s Ph.D. thesis) “Not long ago, I expressed the view that the lack of general education and of thorough training in chemistry was one of ... the causes of the deterioration of chemical research in Germany..”

  19. Pegasus Historical BackgroundTimeline C: Tetrahedral Carbon “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. J. H. van’t Hoff, employed by the Veterinary College at Utrecht [Netherlands], has, so it seems, no taste for accurate chemical research. He finds it more convenient to mount his Pegasus (evidently taken from the stables at the Veterinary College) and announce how, on his bold flight to Mount Parnassus, he saw the atoms arranged in space. Mount Parnassus: Home of the Muses in Greek legend Nobel Prize in Chemistry 1901: J. H. van’t Hoff for his studies of chemical dynamics and osmotic pressure

  20. Historical BackgroundTimeline C: Tetrahedral Carbon Why tetrahedral carbon stereoisomer theory not accepted at first? • All physical properties of enantiomers identical • Exception: Direction of plane-polarized light rotation • Physical properties used to separate substances (bp, solubility, etc.) • Enantiomers could not be separated, so their existence was questioned

  21. Example: 2-chlorobutane H = 1 C = 6 Cl = 17 Equal priority? Highest priority (1) Lowest priority (4) Stereocenter Nomenclature Absolute configuration: Spatial arrangement of groups at stereocenter • Stereocenter can have only two absolute configurations Verify with models • Therefore need only two stereocenter designators Cahn-Ingold-Prelog System Step 1: Assign priorities based on atomic number of atoms attached to stereocenter:  atomic number =  priority

  22. H, H, H C, H, H Stereocenter Nomenclature When atoms are of equal priority, move out to next set of atoms • Select highest priority atom in each set Priorities 3 2 4 1 Highest priority (1) Lowest priority (4) C > H so CH3CH2 > CH3

  23. 2 3 1 4 Stereocenter Nomenclature Step 2: View with lowest priority group in the back Movie: “lowest priority moves back.mov”

  24. Stereocenter Nomenclature Step 3: Assign absolute configuration • Priorities decrease clockwise: Absolute configuration = R (Latin rectus, to the right) • Priorities decrease counterclockwise: Absolute configuration = S (Latin sinister, to the left) (S)-2-chlorobutane or (R)-2-chlorobutane

  25. Stereocenter Nomenclature How to handle double and triple bonds Multiple bonds: Add phantom atoms Assign priorities Priorities decrease clockwise 2 2 View with lowest priority group in back Assign absolute configuration 1 4 1 3 3 (R)-(-)-glyceraldehyde Verify with a model CHO versus CH2OH H, O, O versus H, H, O X X O > H so HC=O > CH2OH Based on our own convention (Cahn-Ingold-Prelog system) Based on experiment (rotates plane-polarized light counterclockwise)

  26. Stereocenter Nomenclature Avoid this common misconception: “R/S (absolute configuration) and +/- (optical rotation) are related” 3 2 1 2 1 3 (S)-(+)-Methamphetamine (S)-(-)-Nicotine • There is no easily predictable relationship between R/S and +/- • Enantiomer of (S)-(-) is (R)-(+) Practice: Verify absolute configurations. Use models. Klein, Chapter 7 (start with 7.1-7.3)

  27. An Idea to Consider Consider for next lecture... • Was Pasteur right about tartaric acid and mesotartaric acid? • More than one stereocenter: How many stereoisomers are possible?

  28. Note to instructor: • Part 1: bring 2-chlorobutane enantiomer models to lecture • Part 2: Bring 2 tartaric acid models, gloves, and carvones

  29. Stereochemistry Part 2Lecture Supplement page 71

  30. Stereocenter: Carbon with four different attachments (usually). mirror levorotatory absolute configuration (Cahn-Ingold-Prelog) Summary of Part 1 Stereoisomers: Isomers differing in the position of atoms in space, but are not constitutional or conformational isomers. Example: (R)-(-)-2-chlorobutane (S)-(+)-2-chlorobutane Verify with models Enantiomers: Nonsuperposable mirror image molecules • Most physical properties identical, except direction of rotation of plane-polarized light

  31. Ibuprofen analgesic * * Ascorbic acid vitamin C Deoxyribofuranose in DNA * * * Molecules with Multiple Stereocenters More stereocenters = more stereoisomers possible One stereocenter R or S Two stereoisomers * Two stereocenters R,RR,SS,RS,S Four stereoisomers Three stereocenters Eight stereoisomers

  32. * Tartaric acid * } Three stereoisomers Molecules with Multiple Stereocenters General rule: Molecule with n stereocenters has up to 2n stereoisomers Number of stereocenters = 2 22 = up to 4 stereoisomers Consistent with Pasteur’s observations? (+)-Tartaric acid (-)-Tartaric acid Mesotartaric acid

  33. enantiomers enantiomers R S R S mirror mirror diastereomers diastereomers S R R S diastereomers Molecules with Multiple StereocentersStereoisomers of tartaric acid Create enantiomer by inverting all stereocenters Invert stereocenter by switching position of any two groups (example: OH and COOH) stereoisomers but not enantiomers Diastereomers: Stereoisomers that are not enantiomers X Create diastereomer by inverting at least one, but not all, stereocenters

  34. yes no S R R S Molecules with Multiple Stereocenters(2S,3R) and (2R,3S)-tartaric acid mirror mirror X Enantiomers are nonsuperposable mirror images These molecules are identical • Meso compound: A molecule with stereocenters that is superposable on its mirror image. • Achiral and therefore optically inactive • Internal mirror plane

  35. mirror Molecules with Multiple StereocentersA meso compound has stereocenters but is not optically active??? This half rotates +Xo This half rotates -Xo Total rotation 0o • Rotation of plane-polarized light cancelled by internal symmetry

  36. (+)-(2R,3R)-tartaric acid (-)-(2S,3S)-tartaric acid (2R,3S)-tartaric acid Molecules with Multiple StereocentersPasteur got it right Tartaric acid has only three stereoisomers: mesotartaric acid 1:1 mixture = racemic acid

  37. Properties causes Biological effects Biological Significance of Stereoisomers Structure Stereochemistry Example: Pasteur’s plant mold metabolized (+)-tartaric acid but not (-)-tartaric acid

  38. Biological Significance of StereoisomersThalidomide • Marketed in 50 countries 1956-1962 • Sedative for pregnant women • Antiemetic to combat morning sickness • Caused thousands of birth defects • Teratogen: Causes fetal abnormalities * One stereocenter • Sold as racemic mixture: 1:1 mixture of enantiomers • R enantiomer = antiemetic (not teratogenic) • S enantiomer = teratogenic (not antiemetic) • Single-enantiomer drug not useful; quickly racemizes in body

  39. enantiomers (R)-(-)-carvone (S)-(+)-carvone Biological Significance of StereoisomersAnother biological effect: Odor smells like spearmint smells like caraway Mirror image molecules do not have “mirror image effects”

  40. Biological Significance of StereoisomersOf hands, gloves, and biology Why do stereoisomers have different biological properties? • Many biological effects involve interaction with a pocket in enzyme or receptor • Good fit to pocket (i.e., strong binding) triggers enzyme or receptor • Enzymes and receptors are proteins; built from amino acids: • Most amino acids are chiral (R ≠ H), so pocket is also chiral • Metaphor: Stereoisomer = left hand or right hand • Protein pocket = left glove or right glove • Left hand fits left glove but not right glove • Left hand triggers “left hand protein” but not “right hand protein” • (R)-carvone triggers spearmint smell receptor but not caraway smell receptor

  41. Separation of Stereoisomers Why is separation necessary? • Mixtures from natural sources or synthesis • Example: Thalidomide manufactured as racemic mixture • Extra stereoisomers may have undesirable effects • How is separation achieved? • Physical properties: Boiling point, solubility, etc. • Chemical properties: One stereoisomer reacts faster or slower than others • Separation of diastereomers • Diastereomers have different physical properties • Separation methods on solubility, boiling point, etc.

  42. * All reactants achiral Product has 1 stereocenter  2 enantiomers Separation of Stereoisomers Separation of enantiomers • No difference in physical properties except direction of rotation of plane-polarized light Example: Manufacture of (S)-(+)-methamphetamine • Thermodynamic restriction: Achiral reactants  optically inactive product or product mix • Therefore product mixture must be racemic • Optically inactive • 1:1 mixture of enantiomers (R)-(-)-methamphetamine: Weaker CNS stimulant • (S)-(+)-methamphetamine: Stronger CNS stimulant

  43. Separation of Stereoisomers Resolution: Separation of enantiomers Resolution strategy Key issue: Enantiomers not easily separated but diastereomers are Step 1: Convert enantiomers into diastereomers Step 2: Separate diastereomers Step 3: Reverse diastereomer formation to give separated enantiomers

  44. + • Product mixture • racemic • Ph = benzene ring • amine = base • (2R,3R)-Tartaric acid • an acid react to form Separation of Stereoisomers Methamphetamine Resolution Step 1: Convert enantiomers into diastereomers (S,R,R) Diastereomers (R,R,R) Salts

  45. (S,R,R) (S,R,R) salt in flask A separate salts (R,R,R) (R,R,R) salt in flask B Mixture of salts (one flask) Separation of Stereoisomers Methamphetamine Resolution Step 2: Separate diastereomers

  46. H3O+ Flask A Pure (S)-(+)-methamphetamine Pure (S,R,R) salt Two separate flasks H3O+ Flask B Pure (R)-(-)-methamphetamine Pure (R,R,R) salt Separation of Stereoisomers Methamphetamine Resolution Step 3: Recover enantiomers from diastereomers

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