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MORPHINE

Part Two. Structure Proof. MORPHINE. -. +. MeOH. [ a ] D = - 130.9 o. Here is an example of the problems with using morphine. AMINE. CH 3. . N. CH 3. N. CH 3. 1 CH 3 I 2 Ag 2 O. +. morphine. morphine. PHENOL. -. zwitterion (betaine). D. proton removed by base.

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MORPHINE

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  1. Part Two Structure Proof MORPHINE

  2. - + MeOH [a]D = - 130.9o Here is an example of the problems with using morphine. AMINE CH3 .. N CH3 N CH3 1 CH3I 2 Ag2O + morphine morphine PHENOL - zwitterion (betaine) D proton removed by base The Hofmann Degradation does not work, a zwitterion forms that will not react furhter. NO REACTION MUCH OF THE WORK WAS DONE ON CODEINE morphine codeine C17H19NO3 C18H21NO3 MeOH [a]D = - 136.0o mp 254o mp 155o pKa = 8.2 pKa = 8.87

  3. PRELIMINARY WORK codeine

  4. PRELIMINARY RESULTS no FeCl3 test PhNMe3+ OH- morphine codeine C17H19NO3 C18H21NO3 aq FeCl3 Pd H2 CrO3 HOAc u = 9 u = 9 colored solution dihydrocodeine codeinone PHENOL C18H23NO3 C18H19NO3 BrCN von Braun DOUBLE BOND 2o ALCOHOL C18H18NO3 + CH 3Br H3O+ C17H19NO3 + CO2 3o AMINE (N-methyl)

  5. INITIAL TRY AT PART-STRUCTURES The results on the previous slide allow us to draw part-structures for each of the compounds, showing what we have found in each case. MORPHINE CODEINE CODEINONE methoxy- aromatic phenol 2o alcohol ketone double bond double bond N-methyl (3o amine) N-methyl (3o amine)

  6. + . . H H . . C Br + CONTINUED INVESTIGATION CH3I NaOH codeine codeine methiodide C18H21NO3 C19H23NO3+ I- adds once Br2 CCl4 3o AMINE AROMATIC SUBSTITUTION bromocodeine C18H20NO3Br Only one ortho or para position is available. Activated rings like anisole react three times. H2 Pd bromodihydrocodeine bromocodeine still has a double bond C18H22NO3Br 2 atm H2 Pd HYDROGENOLYSIS C18H23NO3 + HBr

  7. CODEINE - THE MISSING OXYGEN nitrogen atom codeine oxygen 1 C18H21NO3 oxygen 2 oxygen 3 CODEINE not identified The third oxygen was thought to be an ether because of its inertness.

  8. HOFMANN DEGRADATIONS Codeine

  9. HOFMANN DEGRADATIONS codeine Two Hofmann sequences were required to eliminiate nitrogen. This implies the nitrogen is in a ring, not in a chain or at a ring junction. C18H21NO3 1. CH3I, NaOH 2. Ag2O 3. heat an isomer strong heating a-codeimethine b-codeimethine C19H23NO3 C19H23NO3 1. CH3I, NaOH 2. Ag2O 3. heat 1. CH3I, NaOH 2. Ag2O 3. heat MYSTERY RESULT should add to 20 carbons methylmorphenol If you do your accounting you will see that two carbons were lost and not accounted for (in fact, C2H4 is lost). = C18H21NO3 C15H10O2 + (CH3)3N + H2O u = 11

  10. METHYLMORPHENOL

  11. METHYLMORPHENOL cleaves ether + + CH3Br negative FeCl3 test positive FeCl3 test H+ Br- HBr D methylmorphenol morphenol C15H10O2 C14H8O2 a phenol Zn dust distillation Zn dust distillation acetic anhydride phenanthrene monoacetate derivative C14H10 identified by ultraviolet spectrum Care must be taken, however, the following rearrangement has been shown to take place. this implies a phenanthrene-like skeleton Zn D

  12. 5 4 log e 3 2 200 220 240 260 280 300 320 340 360 380 mm (nm) ULTRAVIOLET SPECTRA OF AROMATIC SYSTEMS Aromatic ring systems have particularly characteristic ultraviolet spectra. The “fine structure” of a given ring type is very identifiable by the wavelengths of both its maxima and minima. Substituents have little effect on the overall shape of the spectrum. It is easy, for instance to tell the difference between a system with a phenanthrene ring and one with an anthracene ring. Other types of rings are also easy to recognize.

  13. PART STRUCTURE OF METHYLMORPHENOL phenanthrene ring OCH3 methylmorphenol C15H10O2 oxygen 1 oxygen 1 UNKNOWN not identified or located by ordinary chemical reactions OCH3 Because the second oxygen was so inert to chemical change, it was postulated that it was a diaromatic ether (not easily cleaved) located at the notch between the two outer rings. However, diaromatic ethers can be cleaved by the reagent Na/EtOH (next slide)…..

  14. CLEAVING DIAROMATIC ETHERS This can be accomplished by using a dissolving metal reduction. DIAROMATIC ETHERS Na EtOH The standard method of cleaving ethers (conc HI or conc HBr) only works on aliphatic ethers or ethers where one of the groups is aliphatic, preferably primary. It is an SN2 reaction. NOT HERE (sp2 carbon) ALIPHATIC OR HALF-ALIPHATIC ETHERS SN2 at the primary carbon cleaves ether + + CH3Br H+ Br- + CH3Br + Br-

  15. METHYLMORPHENOL TRYING TO FIND THAT DARN OXYGEN-2 FeCl3 (-) FeCl3 (+) conc HBr FeCl3 (+) Na EtOH morphol methylmorphenol methylmorphol C15H10O2 C15H12O2 C14H10O2 acetic anhydride conc HBr a diphenol FeCl3 (+) monoacetyl- morphol KOH 250o morphenol C14H8O2 acetic anhydride CrO3 an acetyl- phenanthraquinone monoacetyl- morphenol CrO3 B an acetyl- phenanthraquinone assumed A

  16. PHENANTHRAQUINONE FORMATION Phenanthrene rings are easily oxidized to phenanthraquinones. The double bond in the middle ring behaves like an ordinary double bond in many reactions, not as if it were aromatic. The 9,10 double bond is very reactive. 10 9 CrO3 1 8 2 7 3 4 5 6 phenanthraquinone Br2 If there is any substituent at either C9 or C10, except OH, then the phenanthraquinone cannot form. Therefore, if a phenanthrene compound forms a phenanthraquinone derivative, there is likely no substituent at either C9 or C10.

  17. IF WE ASSUME THIS STRUCTURE FOR METHYLMORPHENOL THE RESULTS MAKE SENSE. conc HBr Na EtOH OR OR conc HBr acetic anhydride KOH fusion acetic anhydride CrO3 CrO3 or the isomer with the acetyl group on carbon 4. this was targeted for synthesis A B

  18. PSCHORR PHENANTHRENE SYNTHESIS

  19. FIRST A LOOK AT DIAZOTIZATION OF AROMATIC AMINES nitrous acid .. .. .. HCl + : : Cl- .. .. .. .. .. + : .. .. .. .. : : H+ .. .. .. .. .. .. : .. H+ Cl- + .. .. .. .. + : .. .. - H2O

  20. HONO HCl dilute H2SO4 gas Cl- + D Cl- : + : : + HBF4 via carbocation CuCN H3PO2 CuBr KI CuCl Sandmeyer Reaction

  21. THE PSCHORR PHENANTHRENE SYNTHESIS protective group removed later base + aldol condensation Sn / HCl reduction of nitro diazotization HONO + : HCl - N2 loss of nitrogen

  22. OH2 (+) aromatic substitution (+) (+) + (+) + (+) (+) intermediate has lots of resonance (+) (+) carbocation H+ H3O+ heat

  23. OH2 + - CO2 decarboxylation H2 / Pd hydrogenolysis CH3I NaOH from KOH fusion of methylmorphenol both products identical

  24. STRUCTURE OF METHYLMORPHENOL and part-structure of codeine

  25. NOW THAT WE KNOW THE STRUCTURE OF METHYLMORPHENOL WE CAN BEGIN TO FORMULATE THE STRUCTURE OF CODEINE codeine 1 2 3 Hofmanns these groups are in one of these two rings 1 2 3 . . loses nitrogen, oxygen and two carbons -CH2-CH2- N CH3 methylmorphenol OH Codeine H

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