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ATROPINE

PART THREE. Structure of Tropine. ATROPINE. AN INTRODUCTION TO CLASSICAL METHODS OF CHEMICAL STRUCTURE PROOF. TROPINE. GENERAL FEATURES. NOW WE WILL LOOK AT THE TROPINE PIECE. (+/-)-atropine. C 17 H 23 NO 3. Contains N Not chiral Basic due to N. hydrolysis. tropine.

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ATROPINE

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  1. PART THREE Structure of Tropine ATROPINE AN INTRODUCTION TO CLASSICAL METHODS OF CHEMICAL STRUCTURE PROOF

  2. TROPINE GENERAL FEATURES

  3. NOW WE WILL LOOK AT THE TROPINE PIECE (+/-)-atropine C17H23NO3 • Contains N • Not chiral • Basic due to N hydrolysis tropine (+/-)-tropic acid + C8H15NO C9H10O3 C8H18 (INACTIVE) (RACEMIC) C8H19NO mp 63o, bp 233o - C8H15NO [a]D = 0o H4 pKa = 3.80 (pKb = 9.20) = 2 units unsat 2

  4. IMPLIES CHEMICAL TESTING reacts once IMPLIES 3o amine C9H18NOI CH3-NH2 KOH fusion methiodide salt methylamine +CH3I CH3I dil NaOH 1 2 Tropine 5 3 H2SO4 HOAc C8H15NO acetic anhydride 4 +CH2CO -H2O CrO3 HOAc Tropidine C10H17NO2 acetate ester C8H13N IMPLIES IMPLIES IMPLIES Tropinone secondary alcohol 3o N can’t acetylate! C8H13NO b-hydrogen ketone (2,4-DNP)

  5. KOH FUSION This was a pretty standard investigative technique used by early alkaloid chemists. Potasssium hydroxide was ground to a fine powder using a mortar and pestle. The compound was added and the mixture was ground some more. This operation had to be done in the absence of atmospheric moisture since KOH is hygroscopic. The mixture was placed in a distillation apparatus and heated until the mixture “fused” (became molten or liquid). THIS IS A BRUTAL PROCEDURE it tears the comound apart but many basic amine fragments survive Any small amines that are produced are distilled, collected and identified. The amine piece ripped out in this fashion gives some structural information about the environment around the nitrogen.

  6. KOH FUSION (continued) If a small piece like methylamine or ethylamine is obtained it tells you only that somewhere in the molecular skeleton there is an N-methyl or an N-ethyl group, nothing else. CH3-NH2 Occasionally, bigger amines are found, such as pyridine or 3-methylpyridine. These would imply a six-membered nitrogen- containing heterocyclic ring is a part of the structure. However, the double bonds could be artifacts (produced in the reaction). This technique probes the environment of the nitrogen atom.

  7. FORMATION OF METHIODIDE SALTS REACTION WITH CH3I and dil NaOH PRIMARY AMINES REACT THREE TIMES 3 CH3I .. SN2 NaOH all electron pairs and hydrogens are replaced methiodide salt SECONDARY AMINES REACT TWICE 2 CH3I .. .. NaOH TERTIARY AMINES REACT ONCE 1 CH3I .. NaOH .. .. ALSO CALLED “EXHAUSTIVE METHYLATION”

  8. TROPINE TROPIDINE TROPINONE PARTIAL STRUCTURES We can begin to assemble tentative structures from the features that were found by doing the chemical tests and reactions. -H2O [O]

  9. TROPINONE TROPINONE THE KETONE ENVIRONMENT IN TROPINONE C8H13NO C7H6O + C7H6 O + C7H6 O C22H25NO3 C8H13NO C22H21NO - H2 O NaOH dibenzylidene derivative - H2 O C22H21NO OH- HENCE: : -H2O aldol condensation corrected structure

  10. TROPINONE TROPINE AN ACCOUNTING OF WHERE WE ARE atoms in the part structure = C6H7NO the missing elements are 2 units unsat C8H13NO C8H13NO - C6H7 NO C8H15NO C2H6 3 units unsat … and don’t forget the two units of unsaturation that we showed were in tropine. Tropinone has three!

  11. INVESTIGATION OF THE RINGS HOFMANN DEGRADATIONS

  12. HOFMANN ELIMINATION RECALL? Hofmann found that when the leaving group was -N(CH3)3+ E2 elimination reactions gave the least-substituted alkene. BULKY LEAVING GROUPS! Hofmann 95% 5% Zaitsev 31% 69%

  13. THE HOFMANN DEGRATION COMBINES EXHAUSTIVE METHYLATION AND THE HOFMANN ELIMINATION in a chain .. 1) CH3I + changes iodide to hydroxide, Ag2O is essentially Ag(OH) 2) Ag2O 3) D an alkene distill + : + nitrogen is removed as trimethylamine ALL THREE STEPS COMPRISE ONE DEGRADATION SEQUENCE

  14. HOFMANN DEGRADATIONS DISCOVERING THE NITROGEN RING ENVIRONMENT It takes more than one Hofmann sequence to remove nitrogen from an amine if the nitrogen atom is in a ring (two required) or if it is located at a ring junction (three required). Using this method alkaloid chemists could determine if a nitrogen atom was in a chain, in a ring, or at the junction of two rings. .. .. 1 2 3 1 2 3 .. in a ring SEQUENCE ONE SEQUENCE TWO breaks the first bond to the nitrogen breaks the second bond to the nitrogen

  15. WORK THIS ONE THROUGH YOURSELF 1 2 3 1 2 3 1 2 3 .. .. three complete sequences are required ring junction CAUTION: This reaction is carried out in hot NaOH, which sometimes causes the double bonds to rearrange after they first form, especially if they can become conjugated! Sometimes a fourth step is added. In this modification each double bond is hydrogenated (Pd / H2) right after it is formed. This strategem avoids all confusion due to rearranged bonds.

  16. Tropine Tropilene Tropidine Tropilidene HOFMANN DEGRADATION OF TROPINE achiral 2,4-DNP (+) C8H15NO Pd H2 C7H12O -H2O 1) xs CH3I / NaOH 2) Ag2O 3) D KOH C9H15N C7H10O + (CH3)2NH + H2O 1) 2) 3) C8H13N chiral C7H8 + (CH3)3N + H2O cycloheptane C7H14 look how few hydrogens ! Pd 3H2 4 units of unsaturation two sequences implies two rings What kind of structure can fit this?

  17. Tropilidene Tropilene POSSIBLE RING STRUCTURES FOR TROPILIDENE C7H8 toluene 4 units unsat known compound not a cycloheptane What else would fit ? C7H10O 3 units unsat

  18. PUTTING IT ALL TOGETHER Remember, we started the Hofmann Degradations with tropidine which already had a double bond and is chiral. Each Hofmann sequence broke a bond to nitrogen and removed a ring. MOST LIKELY NO! NO! achiral chiral Bredt Rule We need to prove our choice…... aziridine not likely, small ring achiral, but small ring chiral

  19. achiral achiral HYPOTHESIS ! tropine CrO3 -H2O H2SO4 heat tropinone tropidine chiral

  20. Tropine KUHN-ROTH OXIDATION OF TROPINE PROOF AT LAST ! KMnO4 Tropinic Acid a diacid H2SO4 C8H15NO C8H13NO4 1) CH3I, NaOH 2) Ag2O 3) D 4) H2 / Pd CrO3 Kuhn Roth H2SO4 1) CH3I, NaOH 2) Ag2O 3) D 4) H2 / Pd PROVES 5-RING PROVES 7-RING pimelic acid N-methylsuccinimide (known compound) (known compound)

  21. THE ANSWER IS OBTAINED BY SUPERIMPOSING THE TWO RINGS CH3 N not chiral COOH 5 + 7 COOH tropine squiggly lines are used to indicate that the stereochemistry is not known

  22. EXPLANATION OF THE OXIDATION REACTIONS In the Kuhn-Roth oxidation it is known that tertiary H’s oxidize first. 3o > 2o > 1o KMnO4 H2SO4 CrO3 H2SO4 KMnO4 cleaves ketones by a-hydroxylation, then the diketone is formed, and finally the diketone is cleaved into two carboxylic acids. 1) 2) 3) 1) 2) 3) two Hofmann sequences remove the nitrogen bridge

  23. THE STRUCTURE OF ATROPINE tropine tropic acid atropine is racemic here next to C=O This was the end of the classical structure work. Notice that the early chemists could not establish the absolute stereochemistry at three points. * * * In the next set of slides we will show how that was accomplished. an ester ! atropine

  24. See assignments page for actual dates. ASSIGNMENTS Gold Problem Gray Problem Already assigned Due in one week Blue Problem and Green Problem and Pink Problem Due in two weeks

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