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ATROPINE

PART TWO. Structure of Tropic Acid. ATROPINE. AN INTRODUCTION TO CLASSICAL METHODS OF CHEMICAL STRUCTURE PROOF. Professor Richard Willstatter. Universities of Zurich, Berlin, Munich. . RICHARD WILSTATTER (1872 - 1942 ). Most of the early work on the structure

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ATROPINE

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  1. PART TWO Structure of Tropic Acid ATROPINE AN INTRODUCTION TO CLASSICAL METHODS OF CHEMICAL STRUCTURE PROOF

  2. Professor Richard Willstatter Universities of Zurich, Berlin, Munich .. RICHARD WILSTATTER (1872 - 1942 ) Most of the early work on the structure of atropine was done by: .. Nobel Prize 1930 w/ Hans Fischer (Heme and hemoglobin structures) He was essentially forced by the Nazis to resign his professorship in Munich in 1927. He was Jewish. * Keep in mind, however, that the work was highly competitive and several other research groups were also working on the structure of this compound during the same period.

  3. STRUCTURE PROOF CLASSICAL METHODS

  4. CLASSICAL METHODS The work on the structure of atropine was done from 1895 - 1903. Keep in mind that the following techniques had not yet been invented: INFRARED SPECTROSCOPY NUCLEAR MAGNETIC RESONANCE MOST FORMS OF CHROMATOGRAPHY MASS SPECTROSCOPY X-RAY CRYSTALLOGRAPHY “Classical” methods were used.

  5. CLASSICAL METHODS WHAT DID THEY USE ? Encyclopedic Knowledge of Reactions and Compounds Carbon and Hydrogen Analysis Chemical Conversions oxidation reduction degradation Chemical Tests for Functional Groups Comparison and Mixed Melting Points Chemical Logic and Deduction Chemical Intuition

  6. CHEMICAL CLASSIFICATION TESTS CAN BE USED TO DISCOVER FUNCTIONAL GROUPS (remember Chem 355 ?) white ppt implies labile halide (3o, etc.) silver mirror means aldehyde turns green if aldehyde or 1o or 2o alcohol CrO3 H2SO4 AgNO3 ethanol Ag(NH3)2OH (Tollens) unknown compound 2,4-dinitrophenyl hydrazine NaOH I2 (Iodoform) Br2 CCl4 yel-red ppt means an aldehyde or ketone yel ppt means Me-ketone decolorization implies double bond

  7. CLASSICAL COMBUSTION ANALYSIS 10-20 mg weighed sample furnace 600 -800oC O2 from tank drying agent (MgClO4) strong base (Ascarite) ABSORBS H2O ABSORBS CO2 REMOVE AND WEIGH TUBES TO OBTAIN THE AMOUNTS OF H2O AND CO2 PRODUCED CALCULATE CALCULATE FORMULA %C % H %O by difference other elements obtained by different procedures

  8. A CORRECT MOLECULAR FORMULA CAN DETERMINE WHAT CHANGE HAS HAPPENED IN A REACTION - H2 C6H12O - C5H10O + C H2 + C2H2O Subtraction of the two formulas shows a difference of CH2 , this shows addition of a methyl group. Note that one H was already there. - H2O - OH + Br

  9. CHEMICAL DEGRADATION PROCEDURE ORIGINAL MOLECULE (unknown structure) “DEGRADE” 1) break apart chemically 3) working backwards reassemble the larger molecule (mentally) by using logic and intuition 2) determine identities (structures) of the smaller pieces

  10. ATROPINE

  11. ISOLATION (typical) Dried plant is chopped or crumbled to fine powder Several kilograms extract soxhlet CHCl3 CHCl3 alkaloids several liters fatty substances add pet ether CHCl3 pet ether fatty substances redissolve & alkaloids precipitate (alkaloids-NH+)2 SO4- crystallize from aqueous H2SO4 by adding acetone multiple (20-50) fractional crystallizations until sharp const. melting point NaOH, H2O Na2SO4 aq NaOH (atropine-NH+)2 SO4- other alkaloids CHCl3 a few grams atropine CHCl3

  12. 20 [a]D = - 72o (c = 0.5, H2O) 20 [a]D = + 72o (c = 0.5, H2O) DIFFICULT ASPECTS OF THE ISOLATION (-)-hyoscyamine mp 108-11o C recombine with tropine C17H23NO3 racemizes during workup very careful workup (-)-tropic acid (+/-)-atropine mp 127o resolution via the quinine salt C17H23NO3 mp 114-116o hydrolysis (+)-tropic acid tropine (+/-)-tropic acid + mp 107o C8H15NO C9H10O3 (INACTIVE) (RACEMIC)

  13. R S Q: S S R QH+ QH+ S S S R QH+ QH+ S S RESOLUTION WITH QUININE Racemic mixture of enantiomers (+)-tropic acid (-)-tropic acid + COOH COOH add quinine to form salt COO- COO- Diastereomers + COO- COO- regenerate regenerate separate by crystallization (-)-tropic acid (+)-tropic acid

  14. THE TROPIC ACID PIECE

  15. WE WILL BEGIN WITH THE TROPIC ACID FRAGMENT (+/-)-atropine C17H23NO3 • Contains no N • Chiral hydrolysis tropine (+/-)-tropic acid + C8H15NO C9H10O3 (INACTIVE) (RACEMIC) Since it is a carboxylic acid its “equivalent weight” could be obtained by titration with NaOH. MW = 166

  16. CHEMICAL TESTS AND DEGRADATION ON THE TROPIC ACID FRAGMENT (+/-)-tropic acid KMnO4 H2SO4 C9H10O3 or CrO3 / H2SO4 KOH atropic acid + C9H8O2 H2 Br2/CCl4 acetic anhydride Pd C9H8O2Br2 C9H10O2 C11H12O4 acetate ester ATROPIC ACID TROPIC ACID C6H5 C2H2 CO2H C6H5 C2H4O CO2H

  17. STRUCTURE OF ATROPIC ACID ATROPIC ACID PUTTING THE PIECES TOGETHER THERE ARE ONLY C6H5 C2H2 CO2H TWO POSSIBLE STRUCTURES known compound cinnamic acid both cis and trans known mptrans = 133o atropic acid mp 106-107o

  18. STRUCTURE OF TROPIC ACID TROPIC ACID THIS LEADS TO …... TWO POSSIBLE STRUCTURES FOR TROPIC ACID SINCE TROPIC ACID LOSES WATER TO FORM ATROPIC ACID C6H5 C2H4O CO2H tropic acid atrolactic acid mp 127o known compound - H2O - H2O mp 88-90o atropic acid

  19. FINAL STRUCTURE FOR (+/-)-TROPIC ACID - H2O (+/-)-tropic acid atropic acid chiral, as required R,S has not been determined yet ….. we will show how this was determined later NEXT TIME : WHAT IS THE STRUCTURE OF THE TROPINE FRAGMENT ?

  20. SYNTHESIS OF TROPIC AND ATROPIC ACIDS

  21. SYNTHETIC CONFIRMATION OF THE RESULTS The structure proofs of tropic and atropic acid were based on a few chemical results and the rigorous application of chemical logic. In the late 19th and early 20th centuries, this kind of a proof was not considered unambiguous. It did not “prove” the structure. What would convince fellow chemists was a synthesis of the compound using standard “unambiguous” chemical reactions that were easily understood. Even today, with the wealth of spectroscopic structure-proof techniques, a synthesis may be required in order to prove a complicated structure. As a result Willstatter (and others) worked out syntheses for these compounds to establish “beyond doubt” the structures of these new compounds. Their methods follow.

  22. SYNTHESIS OF ATROPIC ACID .. .. H+ .. + atropic acid .. :

  23. SYNTHESIS OF TROPIC ACID HELL-VOLHARD-ZELINSKY P, Br2 Reformatsky reagent a-bromoester like a Grignard but uses an a-bromoester and zinc .. - H3O+ (+/-)-tropic acid

  24. ASSIGNMENTS Gold Problem Due in one week

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