kinetic isotope effects in transition metal-catalyzed c-h activation speaker: cheng guijuan apr. 17...
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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
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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
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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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