Highlights of the Career of

Robert G. Bergman

Vy M. Dong

MacMillan Group Meeting

May 17, 2002

Career Sketch of Robert G. Bergman

1963 B.S. Carleton College

1966 Ph.D. in Chemistry from University of Wisconsin, advisor: Jerome A. Berson

1966-67 Postdoctoral Fellow at Columbia Universitywith Ronald Breslow

1968 to 1977 Professor, California Institute of Technology

1977 to present Professor, University of California, Berkeley

Ventured into organometallic chemistry (1970's)

Trained as an organic chemist

Synthesis and chemistry of several types of organotransition metal complexes and the understanding of their mechanisms

II. Activation of C-H Bonds

I. Bergman Cyclization

III. Chemo- and enantioselective reactions of metal heteroatom bonds withorganic molecules

Selected Topics for Discussion from the Career of Bergman

a. Significance in chemistry and biology

a. Stoichiometric Reactions: Highlights on study of mechanism, kinetics and selectivity

a. Zirconocene Imido Complexes with Allenes: Study of selectivity and mechanism

I. The Bergman Cyclization

Bergman Cyclization

D

D

D

D

H

H

D

D

200 oC

gas phase

! H = 14 kcal/mol

! H = 32 kcal/mol

Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.

H

H

Cl

Cl

RH CCl4

heat heat

Radical 1,4 dehydrobenzene: important molecule in field of reactive intermediates and aromaticity

Evidence for the structure of the molecule

In the pursuit of physical organic chemistry and theoretically interesting molecules

Base

O

O

PO O

O

Bergman Cyclization and the Mechanism of DNA Damage

H

O H

PO O

OBase

O

O

PO O

O

O

PO O

O Base

O

O

PO O

O

O O

PO O

Base

O

O

PO O

O

O H

PO O

OBase

O

O

PO O

O

O H

OH

Nicolaou, K. C. et al. ACIEE 1991, 30, 1387.

Bergman cylization is the

reaction nature uses to generatelethal fragents to DNA!

1) O2

2) H

HO

reduction

O

H

PO O

OH

HO

Base

O

O

PO O

O

Bergman Cyclization and the Mechanism of DNA Damage

H

O H

PO O

OBase

O

O

PO O

O

O

PO O

O Base

O

O

PO O

O

O O

PO O

Base

O

O

PO O

O

O H

PO O

OBase

O

O

PO O

O

O H

OH

Nicolaou, K. C. et al. ACIEE 1991, 30, 1387.

Bergman cylization is the

reaction nature uses to generatelethal fragents to DNA!

1) O2

2) H

HO

reduction

O

H

PO O

OH

HO

Structures of the Enediyne Anticancer Antibiotics

O

O

O

O

O

O

O

O

MeNHHO

OH

neocarzinostatin chromaphore

HO

O

OR

calicheamicin

HNHO

HO

O

O OH

H

O

CO2H

OMe

dynemicin A

1980's: Attracted much attention due to their unique molecular structure and fascinating mode of action

DNA cleaving molecules

MeSSS

II. The Activation of C-H Bonds of Hydrocarbons

Calicheamicin's Mode of Action

HO

O

NHCO2Me

S

S

MeS

O-sugar

glutathione

1) Nucleophilic attack

2) Conjugate addition

HO

O

NHCO2Me

S O-sugar

Bergman

Cyclization

HO

O

NHCO2Me

S O-sugar

DNA

DNA cleavage

HO

O

NHCO2Me

S O-sugar

Structures of the Enediyne Anticancer Antibiotics

O

O

O

O

O

O

O

O

MeNHHO

OH

neocarzinostatin chromaphore

HO

O

OR

calicheamicin

HNHO

HO

O

O OH

H

O

CO2H

OMe

dynemicin A

1980's: Attracted much attention due to their unique molecular structure and fascinating mode of action

DNA cleaving molecules

MeSSS

II. The Activation of C-H Bonds of Hydrocarbons

Selective Transformations of C-H Bonds of Alkanesa "holy grail" in synthetic organic chemistry

Importancemost ubiquitous chemical linkage in nature

fundamental understanding of chemical reactivity

abundant and inexpensive

Challenges

lack of reactivity: C-H bond energy: 90-100 kcal/mol

free radical reaction, super acids (George Olah, Nobel prize)

lack of selectivity: ability to selectively attack one type of C-H bond over another

ability to convert the alkane into a functionalized product without having

CH4 CH3OH CO2 H2O

C-H bond acidity: pKa = 45-60

the product undergo an even faster reaction than the alkane

Arndtsen, B.A.; Bergman, R.G.; Mobley, T.A.; Peterson, T.H. Acc. Chem. Res. 1995,28,154

Intriguing Potential Solutionuse of transition metal chemistry

Background on C-H Activation

Many examples of intramolecular C-H oxidative addition were known for over a decade:

(PPh3)3IrCl (PPh3)2(Cl)IrH

Ph2P

orthometallation

L2PtCH2CMe3

CH2CMe3

-CMe3L2Pt

CH3

CH3

Bergman, R.G. Science 1984, 223, 902

Goal: A soluble complex capable of intermolecular oxidative addition

M R-H R-M-H (formal 2 e- oxidation of the metal)

First Examples of Hydrocarbon Activation

IrCOOC

MHMe3P

hv RH

MHMe3P

M = Rh, Ir R = c-hexyl, n-propyl, neopentyl

H R

Janowicz, A.H.; Bergman R.G., JACS,1982,104,352.

[Cp*M(PMe3)]

-H2

hv RH

IrHOC

R

[Cp*IrCO]

-CO

early 1980's by Bergman

The 16-electron Cp*ML fragments believed to be responsible for hydrocarbon oxidativeaddition were not directly observable.

R = c-hexyl, n-propyl, neopentyl

IrHMe3P

c-C6H12

C6D6

110oC

IrDMe3P

C6D5

c-C6H12

Janowicz, A.H.; Bergman R.G., JACS,1983,105,3929.

Mechanistic Studies

first order in the loss of cyclohexane IrHMe2P

CH2selective for intermolecular process

not observed

thermally induced C-H activation

Selectivity in C-H Activation

Kinetic Selectivity versus Thermodynamic selectivity

MR

HR'H

RH MR'

H

M + RH +R'H

!Go = !G1-!G2-!!G

!!G

!G1

!G2

Free Energy Diagram

Relative Kinetic Selectivities For Different Types of C-H bonds

> normal alkanes smaller cycloalkanes > larger cycloalkanes>

primary C-H bonds > secondary C-H bonds > tertiary C-H bonds

General trends observed:

This latter observation provided one of the strongest arguments against

IrCOOC

hv RH

IrHOC

R

[Cp*Ir(PMe3)]

-CO

Bergman, R. G. Science, 1984, 223, 902

R'H

Thermodynamic Selectivities Toward C-H Bond Activation

IrHMe3P

H

hv

pentane

IrMe3P

H

IrMe3P

H

IrMe3P

H

IrMe3P

HIr

Me3P

H

110 oC

Strong preference for less hindered primary bonds over more hindered primary bondsand preference for primary over secondary bonds

Wax, M.J.; Stryker, J.M.; buchanan, J.M.; Kovac, C.A.; Bergman, R.G. JACS, 1984, 106, 1121

Suggests that a combination of protolysis followed by thermal equilibratin will allow exclusive functionalization of primary linear alkanes

Functionalization of the Hydrido Alkyl Insertion Products

IrHMe3P

n-pentyl

Treatment with reagents such as ZnBr2, H2O2, Br2, HBF4 or O2 results in reductive

elimination of RH.

Solution was to replace the hydride ligand with bromide:

CHBr3

IrBrMe3P

neopentyl

FSO3D1-deuteriopentane

HgCl2

R-Hg-Cl IrBrMe3P

Cl

neopentyl bromide

> 98% NMR yield

Br2

Janowicz, A.H.; Bergman, R.G. JACS, 1983, 105, 3929

Stereochemistry of Oxidative Addition of C-H Bonds

Rh

H

*CpPMe3 H

Rh*Cp

PMe3H

H

Rh*Cp

PMe3H

HRh

H

*CpPMe3 H

Examination of the rearrangement of a gem-dimethylcyclopropane adduct

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-H bond

Mobley, T. A.; Bergman, R.G. JACS, 1995, 117, 7822

R S

R R

Recent Example of C-H Activation with Asymmetric Induction

Ir H

HPMe2

hv

hv

Ir H

PhPMe2

Ir Ph

HPMe2

Ir HPMe2

1:1

only

150oC

benzene

Mobley, T.A.; Bergman, R.G. JACS, 1998, 120, 3253

Differences reflect kinetic selectivities due to the greater steric demands of the cyclohexane ring

Annulation of Aromatic Imines via Directed C-H Activation

X

R2

R3

BnN R1

n

1) 5 mol% (Ph3)3RhCl

125 or 150 oC, toluene

2) 1 N HCl (aq) X

O

n

R2

R3

R1

X

O R1R1

R3

n

x = CH2, O NR

n = 0,150 to 79% yields

Thalji, R.K.; Ahrendt, R.G.; Bergman, R.G.; and Ellman, J.A. JACS, 2002,123,9692

O

O

O

N

O H

71% yield, 4 h 59% yield, 16 h 50% yield, 3 h

O

O H

50% yield, 22 h

O

65% yield, 8 h

O O

50%1:1 ratio48 h

Kakiuchi, F.; Murai, S. Topics in Organometallic Chemistry 1999, 48

C-H/ olefin, C-H/acetylene, C-H/CO/olefin couplings

Hydroacylations of olefins and acetylenes to provide ketones

Transition metal-catalyzed aldol and Michael additon reactions (enantioselective anddiastereoselective).

In past decade, chemistry of the catalytic functionalization of CH bonds has rapidly expanded

Regioselective and Catalytic Functionalization Achieved:

O

B

O

B

O

O

Cp*Rh(C2H4)2BPin

150oC

5 mol%

84% yield, 5hr

Hartwig, J.F. et. al. Science, 2000, 1995

Outlook on the Activation and Functionalization of C-H Bonds

Field is still young and exciting new discoveries expected in the next decade

Addition of C-H Bonds Across M=X Bonds

Cp2Zr=NRZrCH3

NH-R 85 oC

- CH4

ZrN

R

O

ZrNH

R

PhC6H6

THF

Ziconium-nitrogen double bond

No reactions with alkanes have yet been reported

Walsh, P.J.; Hollander, F.J.; Bergman, R.G. JACS, 1988, 110, 8729

III. Chemistry of Zirconocene Imido Complexes

Organometallics 1993, 12, 3705

JACS 1998, 110, 8729

ACIEE 2000, 39, 2339

Equimolar Reaction of Enantiopure Imido Complex with Racemic 1,2 Cyclononadiene

RCH C CHR

Racemic

1.0 equiv

ZrN

THF

Ar

+

Enantiopure

1.0 equiv

(R,R)

N

Zr

R

Ar

R

H

H+ C C C

H

R

H

R

ZrN

THF

Ar

(S) (R,R)

Expected: 0.5 equiv 0.5 equiv 0.5 equiv

Found: 0 equiv1.0 equiv 0 equiv

RCH C CHR C C C

H

H

(S)

C C C

H

H

+

(R)

NZr

Ar

R

R

H

H

+ NZr

Ar

R

R

H

H

+ N

Zr

Ar

R

R

H

H

or

N

Zr

Ar

R

R

H

H

or

NZr

Ar

CC

C

R

HR

H

(S)

:

R, R = [ (CH2)6 ]R, R = [ (CH2)6 ]

Zwitterion(or diradical)

Zwitterion(or diradical) !-allyl complex!-allyl complex

N

Zr

H

Ar

RR

HN

Zr

H

Ar

RR

H

C C C

R

H

H

R

(R)

C C C

R

H

H

R

C C C

R

H

H

R

(R)

Possible Mechanism for Allene Stereoinversion

Allene chirality is destroyed in forming the intermediate

Probing the Stepwise Mechanism

Reaction of the achiral Cp2Zr=N=R and Optically Active Allene

NAr

Zr

THF

Cp2

C C C

H

RR

H

enantioenriched

N

Cp2Zr

Ar

H

R

R H

N

Cp2Zr

Ar

H

R

H R

NH

H

R

R

Ar

Cp2Zr

Concerted

Stepwise

Stepise mechanism should result in racemization of the starting allene

Cp2ZrN

OCp2Zr

N

O

C C C

H

H

(S), 86% ee

HC C CH

Racemic

Cp2Zr

N

Ar

H

H (CH2)6

optically inactive

Al2O3

C C C

H

H

(S), 86% ee

HC C CH

Racemic

HC C CH

Racemic

Cp2Zr

N

Ar

H

H (CH2)6

optically inactive

Cp2Zr

N

Ar

H

H (CH2)6

optically inactive

Al2O3Al2O3

CH

PhC C

H

Ph

(R), 98% ee Al2O3C

H

PhC C

H

Ph

(R)

93% ee

Cp2Zr

N

Ar

H

Ph

HPh

optically active

CH

PhC C

H

Ph

(R), 98% ee Al2O3Al2O3C

H

PhC C

H

Ph

(R)

93% ee

CH

PhC C

H

Ph

(R)

93% ee

Cp2Zr

N

Ar

H

Ph

HPh

optically active

Cp2Zr

N

Ar

H

Ph

HPh

optically active

Results Depend Dramatically on the Allene Substituents

Cp2Zr

N

Ar

H2

H H1 (H2)

CH3Cp2Zr

N

Ar

H2

H H1 (H2)

CH3

N

Cp2Zr

H

CH3

CH2H1

Ar

H2

N

Cp2Zr

H

CH3

CH2H1

Ar

H2

60°C60°C

Cp2Zr

N

Ar

H2

H

CH3

H1

H

CH3N

Cp2ZrH1

Ar

H2

1,2-Hydrozirc.

1,4Hydrozirc.

N

Cp2ZrH

CH3

CH2

Ar

H2H1

a

b

b

a

Cp2Zr

N

Ar

H2

H

CH3

H1Cp2Zr

N

Ar

H2

H

CH3

H1

H

CH3N

Cp2ZrH1

Ar

H2

H

CH3N

Cp2ZrH1

Ar

H2

1,2-Hydrozirc.1,2-Hydrozirc.

1,4Hydrozirc.

1,4Hydrozirc.

N

Cp2ZrH

CH3

CH2

Ar

H2H1

a

b

N

Cp2ZrH

CH3

CH2

Ar

H2H1

a

b

bb

aa

*

b

N

Cp2Zr

H

CH3

H2

Ar

CH2

H1

*

bb

N

Cp2Zr

H

CH3

H2

Ar

CH2

H1

N

Cp2Zr

H

CH3

H2

Ar

CH2

H1

*

Thermal Metallacycle Rearrangement Observed

Could rapid !-elimination be the mechanistic explanation?

NCp2Zr

Ar

H

RH

RH

NCp2Zr

Ar

H

R

R

H

NCp2Zr

Ar

H

R

H H

R

(a) Racemization in the reaction of alkyl- but not arylallenes with Cp2Z=NR:

NCp2Zr

Ar

H

RH

RH

NCp2Zr

Ar

H

R

R

H

NCp2Zr

Ar

H

R

H H

R

NCp2Zr

Ar

H

RH

RH

NCp2Zr

Ar

H

RH

RH

NCp2Zr

Ar

H

R

R

H

NCp2Zr

Ar

H

R

R

H

NCp2Zr

Ar

H

R

H H

R

NCp2Zr

Ar

H

R

H H

R

(a) Racemization in the reaction of alkyl- but not arylallenes with Cp2Z=NR:

(b) Formation of azadiene complexes:

slowNCp2Zr

Ar

CHR'

R

H

NCp2Zr

HR

CHR'

Ar

NCp2Zr

R

CH2R'

Ar

fast

NCp2Zr

Ar

CHR'

RH

H

(b) Formation of azadiene complexes:

slowslowslowNCp2Zr

Ar

CHR'

R

H

NCp2Zr

Ar

CHR'

R

H

NCp2Zr

HR

CHR'

Ar

NCp2Zr

HR

CHR'

Ar

NCp2Zr

R

CH2R'

Ar

NCp2Zr

R

CH2R'

Ar

fastfast

NCp2Zr

Ar

CHR'

RH

H

NCp2Zr

Ar

CHR'

RH

H

(c) Inversion of configuration in the (EBTHI)Zr + 1,3 – dialkylallene reactions:

NZr

H

H

Ar

R

R

NZr

Ar

R

H

H

R

C C C

R

H

H

R

unstable stable

NZr

H

H

Ar

R

RH

(c) Inversion of configuration in the (EBTHI)Zr + 1,3 – dialkylallene reactions:

NZr

H

H

Ar

R

R

NZr

H

H

Ar

R

R

NZr

Ar

R

H

H

R

NZr

Ar

R

H

H

R

C C C

R

H

H

R

C C C

R

H

H

R

unstableunstable stablestable

NZr

H

H

Ar

R

RH

NZr

H

H

Ar

R

RH

The !-Elimination Pathway Accounts For the Puzzling

Observations

Use of Enantiopure Diphenylallene to Resolve Imidozirconium Complexes

Zr NAr

O

Zr NAr

O

C C CH

PhH

PhN

Zr

Ar

Ph

Ph H

(S,S)

(R,R)

(S)

0.60 eq

-10 to 25 o C

(S,S,R)

(R,R)

Zr NAr

O

86% ee61 %yield

> 95 % ee

44% yieldAr = 2,5 Me2C6H3

Resolved imido complex cleanly separated by wasing with cold Et2O

Robert G. Bergman Research

New Stoichiometric and Catalytic C-H activation and Si-H activation Methods

Stoichiometric and Catalytic Chemistry of Group IV Imido Complexes

Fundamental Chemistry of Late Metal Alkoxo and Amido Complexes

New Catalytic Ligands for Use in Aysymmetric Carbene Transfer Reactions

1972 Discovery of thermal rearrangement ofcis-1,5-hexadiyne-3-enes to 1,4-dehydrobenzenes, the "Bergman cyclization"

Major Areas of Current Research

1982 Discovery of the first soluble organometallic complexes that undergointermolecular insertion of transition metals into C-H bonds of alkanes

Best known for:

Over 350 publications