Kinetic Isotope Effects in Transition Metal-catalyzed C-H Activation

Speaker: CHENG GuijuanApr. 17th, 2014

PrefacePreface

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Tools of physical organic chemistry

crossover experiments

kinetic studies

isotope labeling

linear free-energy relationships (LFER)

kinetic isotope effect (KIE)

computational chemistry

…

KIE provide important information about which bonds are broken or formed at different stages of a reaction.

computationcomputation experimentexperimentKIE

OutlineOutline

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Introduction what’s KIE origin of KIE magnitude of the observed KIEs

KIE in transition metal-catalyzed C-H activation measurement of KIE interpretation of KIE mechanistic study employing KIE

Summary

IntroductionIntroduction

44

Kinetic isotope effect (KIE): the change in the rate of a chemical

reaction upon substitution of an atom in the reactants with one of its

isotopes.

HkkLKIE

The ratio of rate constants for the reactions involving the light (kL) and the heavy (kH) isotopically substituted reactants.

Deuterium KIE:  kH/kD

 kH/kD =1, no isotope effect

 kH/kD >1, normal KIE

Primary KIE: deuterated C-H bond breaks in the RDS (rate-determing step)

 kH/kD <1, inverse KIE

Secondary KIE: deuterated C-H bond does not break in RDS but changes in hybridization (sp3 to sp2, sp2 to sp, and the reverse).

Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.

IntroductionIntroduction

55

Origin of isotope effect Morse potential

Stretching vibration

Zero-point energy

The isotope effects origins from the difference in ZpEs between unlabeled (C-H) and labeled (C-D) bonds.

Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.

IntroductionIntroduction

66

Origin of kinetic isotope effect---primary KIE

According to Eyring equation:

Isotopic ZpE difference remains in the transition state

the C−H activation energy (AEH) is smaller than the C−D activation energy (AED), leading to a faster reaction (kH/kD > 1).

Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.

IntroductionIntroduction

77

Magnitude of the observed KIEs---primary KIEs

According to Eyring equation:

the maximum kH/kD: 6.5~7 (at 298 K)

experimental kH/kD values are affected by

the geometrythe degree of bond breaking−bond making in the TS the position of the transition state in the reaction coordinate (early TS, late TS or centered TS)

Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.

IntroductionIntroduction

88

Magnitude of the observed KIEs---secondary KIEs

maximum theoretical value is 1.4 Typical experimental values: 1.1~1.2

Typical experimental values: 0.8~0.9

Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Observation of primary KIE

Observation of primary KIE

C-H activation is the rate-determing step

C-H activation is the rate-determing step

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Measurement of KIE---common KIE experiments

provides conclusive information on whether the C-H bond cleavage occurs during the RDS or not.Absolute rate measurements are rarely sufficiently precise.

Simple to conduct, give precise dateNo isotope effect: C-H activation is not rate-determing stepPrimary KIE: cannot conclude C-H activation is rate-determing step

H

RC-H funtionalization

rate constant= kH

FG

R

D

RC-D funtionalization

rate constant= kD

FG

R

KIE = kH/kD

A) KIE determined by two parallel reactions

B) KIE determined from an intermolecular competitionH

RC-H funtionalization FG

R

D

RC-D funtionalization FG

R

KIE = [PH]/[PD]

RH

RD

PH

PD

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Measurement of KIE---common KIE experiments

Simple to conduct, give precise dataNo isotope effect: C-H activation is not rate-determing stepPrimary KIE: cannot conclude C-H activation is rate-determing step

rate-determing step (RDS)

product-determing step (selectivity-determing step)

an elementary reaction which determines the overall rate

an irreversible step that determines the product distribution

Although the product-determining step can also be the rate-determining step, the product-determining step does not need to be the rate-determining step

C) KIE determined from an intramolecular competition

HC-H or C-D

funtionalization

DGD

KIE = [PH]/[PD]

FGDG

D HDG

FG

PH PD

Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 1: the C-H bond cleavage step is irreversible and is the RDS of the overall process

Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

H

R

D

R

H

R

D

R

RH

RD

HDG

D

A B C

KIE = kH/kD KIE = [PH]/[PD] KIE = [PH]/[PD]

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 2: the C-H bond cleavage step is irreversible but it occurs after the RDS

C-H cleavage is the product-determing step

for experiments B and C but is not

rate-determing step.

Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

H

R

D

R

H

R

D

R

RH

RD

HDG

D

A B C

KIE = kH/kD KIE = [PH]/[PD] KIE = [PH]/[PD]

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 2:

Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

General Mechanism for the Palladium-Catalyzed Direct Arylation of Simple Arenes

RDS: ligand dissociation or reductive elimination from a metal complex, or oxidative addition of C-X

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 3: the C-H bond cleavage step is irreversible but it occurs after the RDS

Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

H

R

D

R

H

R

D

R

RH

RD

HDG

D

A B C

KIE = kH/kD KIE = [PH]/[PD] KIE = [PH]/[PD]

C-H cleavage is the product-determing step

for experiment C.

Substrate-binding is the product-determing step

for experiment B.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 3: the C-H bond cleavage step is irreversible but it occurs after the RDS

formation of π complex

C-H activation

H

H

H

H

H

H

+

D

D

D

D

D

DKIE=1.0

D

DD

KIE=3.2

intermolecular KIE---B

intramolecular KIE---C

Bhalla, G.; Liu, X. Y.; Oxgaard, J.; Goddard, W. A., III; Periana, R. A. J. Am. Chem. Soc. 2005, 127, 11372.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 4: the C-H bond cleavage step is reversible and occurs before the RDS of the overall process

Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

H

R

D

R

H

R

D

R

RH

RD

HDG

D

A B C

KIE = kH/kD KIE = [PH]/[PD] KIE = [PH]/[PD]

No large primary KIE will be observed for anyof three experiments.

k1 an k-1 are affected by isotope substitution.

Potential KIE could be observed for these three experiments.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 4:

Nicholas R. Deprez; Melanie S. Sanford; J. Am. Chem. Soc.  2009, 131, 11234.

C-H activation

oxidative addition

reductive elimination

N

5 mol % Pd(OAc)2

1.1 equiv [Ph2I]BF4

AcOH, 100°CN

Ph

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 4:

Nicholas R. Deprez; Melanie S. Sanford; J. Am. Chem. Soc.  2009, 131, 11234.

N

5 mol % Pd(OAc)2

1.1 equiv [Ph2I]BF4

AcOH, 100°C

N

Ph

D

D

H

D

D

H/D

D

D

D

N

5 mol % Pd(OAc)2

2 equiv [Ph2I]BF4

AcOH, 100°C

N

Ph

N

5 mol % Pd(OAc)2

2 equiv [Ph2I]BF4

AcOH, 100°C

N

Ph

D

D

D

D

D

D

D

D

D

versus

 KIE =2.5±0.2

 kH/kD =1

C-H cleavage is not the rate-determining step.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Case 5: the C-H bond cleavage step is reversible and occurs after the RDS of the overall process

Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

H

R

D

R

H

R

D

R

RH

RD

HDG

D

A B C

KIE = kH/kD KIE = [PH]/[PD] KIE = [PH]/[PD]

No large primary KIE will be observed.

A small isotope effect could be observed fromexperiments B and C.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Mechanistic study employing KIE---example 1

N

H

X Pd(OAc)2, MeB(OH)2

Ag2O, benzoquinoneN

Me

X

N

H

cyclopalladation N

D

Pd OAc

2

Ag2O, benzoquinone

MeB(OH)2

H/D

N

Me

H/D

KIE= 7.3

N

H

Pd(OAc)2, MeB(OH)2

Ag2O, benzoquinoneN

Me

D H

N

Me

D

+ KIE= 6.7

C-H cleavage is the rate-determining step.

Chen, X.; Goodhue, C. E.; Yu, J-Q.  J. Am. Chem. Soc. 2006, 128, 12634.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Mechanistic study employing KIE---example 1

the C-H bond cleavage step is irreversible and is the RDS of the overall process

Chen, X.; Goodhue, C. E.; Yu, J-Q.  J. Am. Chem. Soc. 2006, 128, 12634.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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Mechanistic study employing KIE---example 2

O Cl

ClR

Pd2dba2, R1B(OH)2

DPEphos, CsF-Cs2CO3

dioxane

RO

R1

O Cl

Cl

Pd2dba2, R1B(OH)2

DPEphos, CsF-Cs2CO3

dioxane

OAr

D H

OAr

D

+

a)

4 : 1

b)O Cl

Cl

Pd2dba2, R1B(OH)2

DPEphos, CsF-Cs2CO3

dioxane

OAr

OAr +

O Cl

ClH H[D5]

[D4]+

1 : 1

C-H cleavage is not the rate-determining step.

Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 2010, 5563.

KIE in Transition Metal-catalyzed C-H ActivationKIE in Transition Metal-catalyzed C-H Activation

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O Cl

ClR R

OCl

O Cl

PdR

Cl

O Cl

PdR

RO

R1

oxidativeaddition

reductiveelimination

C-H activation

the C-H bond cleavage step is irreversible but it occurs after the RDS

Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 2010, 5563.

C-H cleavage is the product-determing step

for experiment C.

Substrate-binding is the product-determing step

for experiment B.

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Take-home MessageTake-home Message KIE is an import tool in physical organic chemistry.

KIE in Transition Metal-catalyzed C-H Activation

computationcomputation experimentexperimentKIE

H

RC-H funtionalization

rate constant= kH

FG

R

D

RC-D funtionalization

rate constant= kD

FG

R

KIE = kH/kD

A) Parallel reactions B) Intermolecualr competitionH

RC-H funtionalization FG

R

D

RC-D funtionalization FG

R

KIE = [PH]/[PD]

RH

RD

PH

PD

C) Intramolecular competition

HC-H or C-D

funtionalization

DGD

KIE = [PH]/[PD]

FGDG

D HDG

FG

PH PD

The observation of a primary KIE in experiments B and C do not indicate that C-H activation must involves in rate-determing step.

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