New version page

Mechanistic Study in the MacMillan Group

This preview shows page 1-2-3-4-5-6 out of 18 pages.

View Full Document
View Full Document

End of preview. Want to read all 18 pages?

Upload your study docs or become a GradeBuddy member to access this document.

View Full Document
Unformatted text preview:

1A Thought Exercise - Mechanistic Study in the MacMillan GroupWhy (and When) do we do mechanistic studies?Initial IncidentClimaxConclusionNew Reaction DiscoveryReach Optimal ConditionsPublish or Present! Aid with reaction development! Explain exceptional results! Is the mechanistic study itself ever the climax?Mechanistic StudyHouk/Martinelli Ergot Alkaloid OxidationsDFT and experimental studies reveal important basis for selectivity2High Selectivity in Ergot EpoxidationNRO! Kornfeld-Woodward ketone! Widely used in ergot alkaloid synthesisHNNMeO OHHKornfeld, Woodward et al.J. Am. Chem. Soc. 1956, 78, 3087.! Often converted to 2-keto isomerHLeanna, M. R.; Martinelli, M. J.; Varie, D. L.; Kress, T. J. Tetrahedron Lett. 1989, 30, 3935.NRONRNRONROHHHHNaBH4H3O+mCPBAorBr2/NaOHLewisacidNRHmCPBACHCl3NRHONRHOBr2wet DMSOthen, NaOH99 : 1 dr 98 : 2 drSteric Arguments are MinimalLeanna, M. R.; Martinelli, M. J.; Varie, D. L.; Kress, T. J. Tetrahedron Lett. 1989, 30, 3935.NBzH2axH3ax! Axial hydrogen atoms are conflictingFO! Electronic nature of diastereoselectivityle NobleHOJerinaJ. Am. Chem. Soc. 1982, 104, 1972J. Org. Chem. 1989, 54, 997HoukJ. Am. Chem. Soc. 1981, 103, 24383Torsional Effects on Transition StatesCaramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc. 1981, 103, 2438.! Inherent barrier to rotation around propene: 1.58 kcal/mol! Barrier to rotation is significantly larger in transition state! Consider addition to opposite faces of same rotamerH1H2H3HH2CH3H1H2HH2CH3H1H2HH2CEclipsing TS". . . the stereochemical rule found here can be stated. . . to be a result of magnified torsional effects occuringin the transition states of addition reactions."Houk/Martinelli Home Run ExperimentMartinelli, M. J.; Peterson, B. C.; Khau, V. V.; Hutchinson, D. R.; Leanna, M. R.; Audia, J. E.; Houk, K. N. J. Org. Chem. 1994, 59, 2204HHNBSthen, NaOHNBSthen, NaOHHOHODiffer by one –CH2– unit99:1 dr 98:2 dr! No change in axial H! Opposite torsional steering4Torsional Effects - A Word of CautionMartinelli, M. J.; Peterson, B. C.; Khau, V. V.; Hutchinson, D. R.; Leanna, M. R.; Audia, J. E.; Droste, J. J. J. Org. Chem. 1994, 59, 2204MeMeOmCPBA1:1 drPhtBumCPBA1:1 drPhtBuO! No torsional bias! Equal and opposite torsional biasPhPhstaggeredstaggeredeclipsedeclipsed"These results provide powerful examples ofthe magnitude of torsional steering upon thestereoselectivities of additions to !-bonds."The NIH ShiftUnderstanding the molecular basis of carcinogenicity5In-Situ Reaction Monitoring - Historic MethodsGuroff, G.; Daly, J. W.; Jerina, D. M.; Renson, J.; Witkop, B.; Udenfriend, S. Science 1967, 157, 1524.HOONH2O2, H+phenylalaninehydroxylaseHOONH2OH! First phenolase discovered 1955Mason, H. S.; Fowlks, W. L.; Peterson, E. J. Am. Chem. Soc. 1955, 77, 2914.! Oxygen atom from 18O2! How to direcly measure kinetics?HOONH2O2, H+phenylalaninehydroxylaseHOONH2OHTTOHHOONH2OHHOHT! Minute amounts of tritium can be measured in aliquots"NIH-Shift"Mechanistic Basis of Carcinogenicity! NIH ShiftHOONH2OHHOHT! Cancer of chimney sweeps! "K-region" of highest toxicity! Biological conjugatesOHSGlutathioneKOArene OxidesJerina, D. M.; Daly, J. W. Science, 1974, 185, 573.6NIH Shift – Pinacol RearrangementHOONH2TGuroff, G.; Daly, J. W.; Jerina, D. M.; Renson, J.; Witkop, B.; Udenfriend, S. Science, 1967, 157, 1524.phenylalainehydroxylaseHOONH2TOPinacolHOONH2OH TLargeKIE! Compare arene vs. oxide ! Compare arene series ! Compare arene isomersOOHOHOOOOOO'Goldilocks' Postulate for CarcinogenicityJerina, D. M.; Daly, J. W. Science, 1974, 185, 573.Oxide stabilityOxide reactivityOOOOSpontaneousisomerizationOHNon-enzymaticnucleophiletrappingOHOHOHS-Glutathione! Lifetime of highly reactive oxides too short for high carcinogenicity! K-region oxides reactive enough to alkylate important biomolecules! K-region oxides stable enough to require enzymatic degredationO7Halpern Mechanism for HydrogenationExperimental proof of an important catalysis conceptCurtin-Hammett PrincipleCurtin, D. Y. Rec. Chem. Prog. 1954 , 15, 111.I1I2P2P1! A kinetic (mathematical) concept! If I1/I2 interconversion is rapid, selectivity is determined by I to P transition state! To what extent would this affect important catalytic systems?8Knowles' Hydrogenation of EnamidesKnowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 1445.Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946.OOHRhL3Cl3, H2PMePhPrL = (–)OOHMe15% ee(60% ee ligand)! Knowles' original system! Finalized systemRhLLPPMeOOMePPMeMe(R,R)–DiPAMP(R,R)–CHIRAPHOSHNMeOMeOORh(cod)(DiPAMP)BF450 ºC, 3 atm H2HNMeOMeOO96% ee! Requires multi-point binding! Z-olefin much more selectiveOriginal Mechanistic StudiesBrown, J. M.; Chaloner, P. A. Tetrahedron Lett. 1978, 21, 1877.! Widely accepted mechanismRhPPsolventkbindkbind–1CO2MeHNRhPPSSRhPPOMeH2kox.addnCO2MeHNRhPPOMeHHkinsertMeCO2MeHNRhPPOMeHsolventSkred.elimNHAcOMeOMeRDS isoxidative additionBrown, J. M.; Chaloner, P. A. Chem. Commun. 1978, 321.Brown, J. M.; Chaloner, P. A. Chem. Commun. 1980, 344.! NMR shows 10:1 to >20:1selectivity in olefin binding". . diastereospecificity in binding may be studiedby NMR without the necessity for resolution"Upon addition of H2 at –50 ºC only minor diastereomer in NMR reacts9Halpern's X-Ray Structurekbindkbind–1CO2EtHNRhPPSSRhPPOMeH2kox.addnCO2EtHNRhPPOMeHHkinsertBnCO2EtHNRhPPOMeHsolventSkred.elimNHAcOEtOBnHalpern, J. Science, 1982, 217, 401.PhPhPPMeMePhAcHNOOEt! Halpern solves structure of related complexNot formedNHAcOEtOBnMajor product>95% eeCurtin-Hammett Principle – RevisitedHalpern, J. Science, 1982, 217, 401.I1I2P2P1CO2EtHNRhPPOMePhEtO2CHNRhPPOMePhCO2EtHNRhPPOMeHHPhEtO2CHNRhPPOMeHHPh! Predicted effect of increasing pH2?! Eventually, outcompete isomerizationpH2(atm)%ee (S,S-BPPM)15205010084622158! Inverse temperature effectsSinou, D. Tetrahedron Lett. 1981 , 22, 2987.10Olah's Structure of Non-Classical CarbocationsDifficult mechanistic question forces new technique developmentSymposium-In-Print"The Great Carbocation Problem"Joseph F. Bunnett, editor-in-cheif of Accounts"Inductivity and Bridging in Carbocations"Cyril A. Grob"The Energy of the Transition States and the IntermediateCation in the Ionization of 2-Norbornyl Derivatives.Where is the Nonclassical Stabilization Energy?Herbert C. Brown"Conclusion of the Classical-Nonclassical Ion ControversyBased on the Structural Study of the 2-Norbornyl Cation"George A. Olah, G. K.


Loading Unlocking...
Login

Join to view Mechanistic Study in the MacMillan Group and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Mechanistic Study in the MacMillan Group and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?