Kinetic Isotope Effects in Transition
Metal-catalyzed C-H Activation
Speaker: CHENG Guijuan
Apr. 17th, 2014
Preface
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.
KIE
computation
experiment
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Outline
 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
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Introduction
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.
kL
KIE 
kH
The ratio of rate constants for the reactions
involving the light (kL) and the heavy (kH)
isotopically substituted reactants.
Deuterium KIE: kH/kD
Primary KIE: deuterated C-H bond breaks in
kH/kD =1, no isotope effect
kH/kD >1, normal KIE
kH/kD <1, inverse KIE
the RDS (rate-determing step)
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.
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Introduction

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.
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Introduction

Origin of kinetic isotope effect---primary KIE
According to Eyring equation:
the C−H activation energy (AEH) is smaller
than the C−D activation energy (AED),
leading to a faster reaction (kH/kD > 1).
Isotopic ZpE difference remains in the
transition state
Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.
6
Introduction

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 geometry
the 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.
7
Introduction

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.
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KIE in Transition Metal-catalyzed C-H Activation
C-H activation is
the rate-determing step
Observation of
primary KIE
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KIE in Transition Metal-catalyzed C-H Activation

Measurement of KIE---common KIE experiments
A) KIE determined by two parallel reactions
provides conclusive information on
whether the C-H bond cleavage occurs
during the RDS or not.
Absolute rate measurements are rarely
sufficiently precise.
B) KIE determined from an intermolecular competition
Simple to conduct, give precise date
No isotope effect: C-H activation is not ratedeterming step
Primary KIE: cannot conclude C-H activation
is rate-determing step
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KIE in Transition Metal-catalyzed C-H Activation

Measurement of KIE---common KIE experiments
C) KIE determined from an intramolecular competition
Simple to conduct, give precise data
No isotope effect: C-H activation is not
rate-determing step
Primary KIE: cannot conclude C-H
activation is rate-determing step
rate-determing step (RDS)
an elementary reaction which determines the overall rate
product-determing step (selectivity-determing step)
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
Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.
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KIE in Transition Metal-catalyzed C-H Activation

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.
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KIE in Transition Metal-catalyzed C-H Activation

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.
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KIE in Transition Metal-catalyzed C-H Activation

Case 2:
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
Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.
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KIE in Transition Metal-catalyzed C-H Activation

Case 3:
the C-H bond cleavage step is irreversible but
it occurs after the RDS
Substrate-binding is the product-determing step
for experiment B.
C-H cleavage is the product-determing step
for experiment C.
Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.
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KIE in Transition Metal-catalyzed C-H Activation

Case 3:
the C-H bond cleavage step is irreversible but
it occurs after the RDS
formation of π complex
C-H activation
Bhalla, G.; Liu, X. Y.; Oxgaard, J.; Goddard, W. A., III; Periana, R. A. J. Am. Chem. Soc. 2005,
127, 11372.
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KIE in Transition Metal-catalyzed C-H Activation

Case 4:
the C-H bond cleavage step is reversible and
occurs before the RDS of the overall process
No large primary KIE will be observed for any
of three experiments.
Potential KIE could be observed for these three
experiments.
k1 an k-1 are affected by isotope substitution.
Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.
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KIE in Transition Metal-catalyzed C-H Activation

Case 4:
C-H activation
oxidative addition
reductive elimination
Nicholas R. Deprez; Melanie S. Sanford; J. Am. Chem. Soc. 2009, 131, 11234.
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KIE in Transition Metal-catalyzed C-H Activation

Case 4:
KIE =2.5±0.2
kH/kD =1
C-H cleavage is not the rate-determining step.
Nicholas R. Deprez; Melanie S. Sanford; J. Am. Chem. Soc. 2009, 131, 11234.
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KIE in Transition Metal-catalyzed C-H Activation

Case 5:
the C-H bond cleavage step is reversible and
occurs after the RDS of the overall process
No large primary KIE will be observed.
A small isotope effect could be observed from
experiments B and C.
Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.
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KIE in Transition Metal-catalyzed C-H Activation

Mechanistic study employing KIE---example 1
C-H cleavage is the rate-determining step.
Chen, X.; Goodhue, C. E.; Yu, J-Q. J. Am. Chem. Soc. 2006, 128, 12634.
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KIE in Transition Metal-catalyzed C-H Activation

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.
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KIE in Transition Metal-catalyzed C-H Activation

Mechanistic study employing KIE---example 2
C-H cleavage is not the rate-determining step.
Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 2010, 5563.
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KIE in Transition Metal-catalyzed C-H Activation
the C-H bond cleavage step is irreversible but
it occurs after the RDS
Substrate-binding is the product-determing step
for experiment B.
C-H cleavage is the product-determing step
for experiment C.
Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 2010, 5563.
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Take-home Message

KIE is an import tool in physical organic chemistry.
KIE
computation

experiment
KIE in Transition Metal-catalyzed C-H Activation
A) Parallel reactions
B) Intermolecualr competition
C) Intramolecular competition
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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