Highlights of the Career of Robert G. Bergman

Transcription

1 ighlights of the Career of obert G. Bergman Vy M. Dong MacMillan Group Meeting May 17, 2002 Career Sketch of obert G. Bergman 1963 B.S. Carleton College 1966 h.d. in Chemistry from University of Wisconsin, advisor: Jerome A. Berson ostdoctoral Fellow at Columbia University with onald Breslow 1968 to 1977 rofessor, California Institute of Technology 1977 to present rofessor, University of California, Berkeley Trained as an organic chemist Ventured into organometallic chemistry (1970's) Synthesis and chemistry of several types of organotransition metal complexes and the understanding of their mechanisms

2 Selected Topics for Discussion from the Career of Bergman I. Bergman Cyclization a. Significance in chemistry and biology II. Activation of C- Bonds a. Stoichiometric eactions: ighlights on study of mechanism, kinetics and selectivity III. Chemo- and enantioselective reactions of metal heteroatom bonds with organic molecules a. Zirconocene Imido Complexes with Allenes: Study of selectivity and mechanism I. The Bergman Cyclization

3 Bergman Cyclization In the pursuit of physical organic chemistry and theoretically interesting molecules adical 1,4 dehydrobenzene: important molecule in field of reactive intermediates and aromaticity D 200 o C D D D gas phase Evidence for the structure of the molecule D! = 14 kcal/mol! = 32 kcal/mol D CCl 4 Cl heat heat Cl Bergman,. G. Acc. Chem. es. 1973, 6, 25. Bergman Cyclization and the Mechanism of DA Damage Base Base 1) 2 Base 2) Base Base reduction Bergman cylization is the reaction nature uses to generate lethal fragents to DA!

4 Bergman Cyclization and the Mechanism of DA Damage Base Base Base 1) 2 2) Base Base reduction Bergman cylization is the reaction nature uses to generate lethal fragents to DA! icolaou, K. C. et al. ACIEE 1991, 30, Structures of the Enediyne Anticancer Antibiotics DA cleaving molecules MeSSS calicheamicin C 2 Me Me neocarzinostatin chromaphore dynemicin A 1980's: Attracted much attention due to their unique molecular structure and fascinating mode of action

5 Calicheamicin's Mode of Action C 2 Me 1) ucleophilic attack C 2 Me S S -sugar 2) Conjugate addition S -sugar MeS glutathione C 2 Me DA Bergman Cyclization C 2 Me DA cleavage S -sugar S -sugar II. The Activation of C- Bonds of ydrocarbons

6 Structures of the Enediyne Anticancer Antibiotics DA cleaving molecules MeSSS calicheamicin C 2 Me Me neocarzinostatin chromaphore dynemicin A 1980's: Attracted much attention due to their unique molecular structure and fascinating mode of action II. The Activation of C- Bonds of ydrocarbons

7 Selective Transformations of C- Bonds of Alkanes a "holy grail" in synthetic organic chemistry Importance most ubiquitous chemical linkage in nature fundamental understanding of chemical reactivity abundant and inexpensive Challenges lack of reactivity: C- bond energy: kcal/mol C- bond acidity: pka = free radical reaction, super acids (George lah, obel prize) lack of selectivity: ability to selectively attack one type of C- bond over another ability to convert the alkane into a functionalized product without having the product undergo an even faster reaction than the alkane C 4 C 3 C 2 2 Intriguing otential Solution use of transition metal chemistry ndtsen, B.A.; Bergman,.G.; Mobley, T.A.; eterson, T.. Acc. Chem. es. 1995,28,154 Background on C- Activation Goal: A soluble complex capable of intermolecular oxidative addition M - -M- (formal 2 e- oxidation of the metal) Many examples of intramolecular C- oxidative addition were known for over a decade: (h 3 ) 3 Cl (h 3 ) 2 (Cl) h 2 orthometallation L 2 t C 2 CMe 3 C 2 CMe 3 -CMe 3 L 2 t C 3 C 3 Bergman,.G. Science 1984, 223, 902

8 First Examples of ydrocarbon Activation early 1980's by Bergman Me3 M hv - 2 [Cp*M(Me 3 )] Me3 M M = h, = c-hexyl, n-propyl, neopentyl C C hv -C [Cp*C] C = c-hexyl, n-propyl, neopentyl The 16-electron Cp*ML fragments believed to be responsible for hydrocarbon oxidative addition were not directly observable. Janowicz, A..; Bergman.G., JACS,1982,104,352. Mechanistic Studies Me 3 c-c6 12 C 6 D o C c-c 6 12 Me 3 D C6 D 5 thermally induced C- activation first order in the loss of cyclohexane selective for intermolecular process Me 2 C2 not observed Janowicz, A..; Bergman.G., JACS,1983,105,3929.

9 Free Energy Diagram Selectivity in C- Activation!!G!G 1 M + +'!G 2 M '!G o =!G 1 -!G 2 -!!G M ' Kinetic Selectivity versus Thermodynamic selectivity elative Kinetic Selectivities For Different Types of C- bonds C C hv -C [Cp*(Me 3 )] ' C General trends observed: > normal alkanes smaller cycloalkanes > larger cycloalkanes > This latter observation provided one of the strongest arguments against primary C- bonds > secondary C- bonds > tertiary C- bonds

10 Thermodynamic Selectivities Toward C- Bond Activation Me 3 hv pentane Me 3 Me o C Me 3 Me 3 Me 3 Strong preference for less hindered primary bonds over more hindered primary bonds and preference for primary over secondary bonds Suggests that a combination of protolysis followed by thermal equilibratin will allow exclusive functionalization of primary linear alkanes Wax, M.J.; Stryker, J.M.; buchanan, J.M.; Kovac, C.A.; Bergman,.G. JACS, 1984, 106, 1121 Functionalization of the ydrido Alkyl Insertion roducts Treatment with reagents such as ZnBr 2, 2 2, Br 2, BF 4 or 2 results in reductive elimination of. Solution was to replace the hydride ligand with bromide: Me 3 n-pentyl CBr 3 Me 3 Br neopentyl FS 3 D 1-deuteriopentane gcl 2 neopentyl bromide > 98% M yield Br 2 -g-cl Me 3 Cl Br Janowicz, A..; Bergman,.G. JACS, 1983, 105, 3929

11 Stereochemistry of xidative Addition of C- Bonds Examination of the rearrangement of a gem-dimethylcyclopropane adduct h *Cp Me3 h *Cp Me3 S h *Cp Me3 h *Cp Me3 Inversion of the carbon center was effected by way of isomerization to an alkane sigma complex which rearranged to a second complex before reinserting into the C- bond Mobley, T. A.; Bergman,.G. JACS, 1995, 117, 7822 ecent Example of C- Activation with Asymmetric Induction hv h Me 2 h Me 2 1:1 Me 2 hv 150 o C benzene Me 2 only Differences reflect kinetic selectivities due to the greater steric demands of the cyclohexane ring Mobley, T.A.; Bergman,.G. JACS, 1998, 120, 3253

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14 Annulation of omatic Imines via Directed C- Activation Bn X n x = C 2, n = 0,1 1) 5 mol% (h 3 ) 3 hcl or 150 o C, toluene n 3 2) 1 Cl (aq) X 50 to 79% yields 1 1 X n 3 71% yield, 4 h 59% yield, 16 h 50% yield, 22 h 50% yield, 3 h 50% 1:1 ratio 48 h 65% yield, 8 h Thalji,.K.; Ahrendt,.G.; Bergman,.G.; and Ellman, J.A. JACS, 2002,123,9692 utlook on the Activation and Functionalization of C- Bonds In past decade, chemistry of the catalytic functionalization of C bonds has rapidly expanded C-/ olefin, C-/acetylene, C-/C/olefin couplings ydroacylations of olefins and acetylenes to provide ketones Transition metal-catalyzed aldol and Michael additon reactions (enantioselective and diastereoselective). Kakiuchi, F.; Murai, S. Topics in rganometallic Chemistry 1999, 48 egioselective and Catalytic Functionalization Achieved: 5 mol% B B Cp*h(C 2 4 ) 2 Bin 150 o C 84% yield, 5hr artwig, J.F. et. al. Science, 2000, 1995 Field is still young and exciting new discoveries expected in the next decade

15 Addition of C- Bonds Across M=X Bonds Ziconium-nitrogen double bond - C3 85 o C - C 4 = C 6 6 h TF o reactions with alkanes have yet been reported Walsh,.J.; ollander, F.J.; Bergman,.G. JACS, 1988, 110, 8729 III. Chemistry of Zirconocene Imido Complexes rganometallics 1993, 12, 3705 JACS 1998, 110, 8729 ACIEE 2000, 39, 233 9

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18 Equimolar eaction of Enantiopure Imido Complex with acemic 1,2 Cyclononadiene C C C + TF + C C C TF acemic 1.0 equiv (,) Enantiopure 1.0 equiv (S) (,) Expected: 0.5 equiv 0.5 equiv 0.5 equiv Found: 1.0 equiv 0 equiv 0 equiv C C C C C C + C C C (S) () ossible Mechanism for Allene Stereoinversion : C C C (S), = [ (C 2 ) 6 ] + or Zwitterion (or diradical)!-allyl complex C C C () Allene chirality is destroyed in forming the intermediate

19 robing the Stepwise Mechanism eaction of the achiral == and ptically Active Allene Cp 2 Concerted TF C C C enantioenriched Stepwise Stepise mechanism should result in racemization of the starting allene esults Depend Dramatically on the Allene Substituents C C C (S), 86% ee Al 2 3 (C 2 ) 6 optically inactive C C C acemic h C C C h (), 98% ee Al 2 3 h C C C h h h () optically active 93% ee

20 Thermal Metallacycle earrangement bserved * C 3 60 C 1 ( 2 ) C 3 2 C b a C 3 a 1,4 ydrozirc. C 3 1,2-ydrozirc. C b C b * C C 3 Could rapid!-elimination be the mechanistic explanation? The!-Elimination athway Accounts For the uzzling bservations (a) acemization in the reaction of alkyl- but not arylallenes with Cp 2 Z=: (b) Formation of azadiene complexes: C' fast C' slow C' C 2 ' (c) Inversion of configuration in the (EBTI) + 1,3 dialkylallene reactions: C C C unstable stable

21 Use of Enantiopure Diphenylallene to esolve Imidozirconium Complexes (S,S) h h C C C (S) h (S,S,) h 86% ee 61 %yield 0.60 eq -10 to 25 o C = 2,5 Me 2 C 6 3 > 95 % ee 44% yield (,) (,) esolved imido complex cleanly separated by wasing with cold Et 2 obert G. Bergman esearch Best known for: 1972 Discovery of thermal rearrangement ofcis-1,5-hexadiyne-3-enes to 1,4-dehydrobenzenes, the "Bergman cyclization" 1982 Discovery of the first soluble organometallic complexes that undergo intermolecular insertion of transition metals into C- bonds of alkanes Major eas of Current esearch ew Stoichiometric and Catalytic C- activation and Si- activation Methods Stoichiometric and Catalytic Chemistry of Group IV Imido Complexes Fundamental Chemistry of Late Metal Alkoxo and Amido Complexes ew Catalytic Ligands for Use in Aysymmetric Carbene Transfer eactions ver 350 publications