mechanistic studies on the wacker oxidationstoltz2.caltech.edu/seminars/2008_tadross2.pdf ·...
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Mechanistic Studies on the Wacker Oxidation
Pamela TadrossStoltz Group Literature Presentation
December 8, 2008
8 PM, 147 Noyes
PdIICl42–
PdIICl3–
PdIICl2–
OH
PdIICl
OHPdIICl
H3C
HO
PdIICl
HO
H3C H
H3C
O
H
Pd0
2 Cl– + 2 CuIICl2
2 CuICl
+ HCl
C2H4
Cl–
H2O
H+, Cl–
Cl–
PdH2O
Cl Cl+ H2O Pd
HO
Cl Cl–
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Origins of the Wacker Oxidation
F. C. Phillips, 1894:
PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Phillips, F. C. Am. Chem. J. 1984, 16, 255-277. Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
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Origins of the Wacker Oxidation
F. C. Phillips, 1894:
PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Phillips, F. C. Am. Chem. J. 1984, 16, 255-277. Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
Smidt, Wacker Chemie, 1959:
Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42–
2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O
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Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Phillips, F. C. Am. Chem. J. 1984, 16, 255-277. Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42–
2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O
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Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Phillips, F. C. Am. Chem. J. 1984, 16, 255-277. Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42–
2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O
C2H4 + 1/2 O2 CH3CHO
Net Result: Air oxidation of ethylene to acetaldehyde!
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Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Phillips, F. C. Am. Chem. J. 1984, 16, 255-277. Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42–
2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O
C2H4 + 1/2 O2 CH3CHO
Net Result: Air oxidation of ethylene to acetaldehyde!
! First organopalladium reaction applied on industrial scale.
! First rendered commercial in 1960.
! At one point was responsible for the production of over 2 billion pounds per year of acetaldehyde!
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Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Phillips, F. C. Am. Chem. J. 1984, 16, 255-277. Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42–
2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O
C2H4 + 1/2 O2 CH3CHO
Net Result: Air oxidation of ethylene to acetaldehyde!
! First organopalladium reaction applied on industrial scale.
! First rendered commercial in 1960.
! At one point was responsible for the production of over 2 billion pounds per year of acetaldehyde!
! Prior acetaldehyde production: a) Oxymercuration of acetylene b) Dehydrogenation of ethanol
! Wacker process eventually replaced because of more efficient ways of producing acetic acid (i.e. Monsanto process).
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Early Kinetic Studies
Conditions:
[PdII] = 0.005 - 0.04 M
[Cl–] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
–d[C2H4]
dt
k [PdCl42–] [C2H4]
[Cl–]2 [H+]==Rate
! First order in PdII
! Second order Cl– inhibition
! First order acid inhibition
Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246. Jira, R.; Sedlmeier, J.; Smidt, J. Liebigs Ann. Chem. 1966, 693, 99. Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140.
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Early Kinetic StudiesChloride Inhibition
Conditions:
[PdII] = 0.005 - 0.04 M
[Cl–] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
–d[C2H4]
dt
k [PdCl42–] [C2H4]
[Cl–]2 [H+]==Rate
! First order in PdII
! Second order Cl– inhibition
! First order acid inhibition
Source of Chloride Inhibition:
PdCl
Cl Cl
Cl
2–
+ C2H4 PdCl
Cl
Cl
–
+ Cl–PdCl
Cl
Cl
–
+ H2O PdCl
Cl
OH2
+ Cl–1
[Cl–]inhibition
1
[Cl–]inhibition
Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246. Jira, R.; Sedlmeier, J.; Smidt, J. Liebigs Ann. Chem. 1966, 693, 99. Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140.
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Early Kinetic StudiesProton Inhibition
Conditions:
[PdII] = 0.005 - 0.04 M
[Cl–] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
–d[C2H4]
dt
k [PdCl42–] [C2H4]
[Cl–]2 [H+]==Rate
! First order in PdII
! Second order Cl– inhibition
! First order acid inhibition
Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246. Jira, R.; Sedlmeier, J.; Smidt, J. Liebigs Ann. Chem. 1966, 693, 99. Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140.
PdCl
Cl
OH2
–OH
PdCl
Cl CH2CH2OH
OH2
–Outer-sphere hydroxide attack:
Predicted to be 103 times faster
than diffusion controlled process
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Early Kinetic StudiesProton Inhibition
Conditions:
[PdII] = 0.005 - 0.04 M
[Cl–] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
–d[C2H4]
dt
k [PdCl42–] [C2H4]
[Cl–]2 [H+]==Rate
! First order in PdII
! Second order Cl– inhibition
! First order acid inhibition
Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246. Jira, R.; Sedlmeier, J.; Smidt, J. Liebigs Ann. Chem. 1966, 693, 99. Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140.
PdCl
Cl
OH2
PdCl
Cl
OH2
–OH
PdCl
Cl CH2CH2OH
OH2
–Outer-sphere hydroxide attack:
Predicted to be 103 times faster
than diffusion controlled process
H2O
PdCl
Cl CH2CH2OH
OH2
–
+ H+Outer-sphere water attack:Predicted to occur by an antihydroxypalladation mechanism
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Early Kinetic StudiesProton Inhibition
Conditions:
[PdII] = 0.005 - 0.04 M
[Cl–] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
–d[C2H4]
dt
k [PdCl42–] [C2H4]
[Cl–]2 [H+]==Rate
! First order in PdII
! Second order Cl– inhibition
! First order acid inhibition
Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246. Jira, R.; Sedlmeier, J.; Smidt, J. Liebigs Ann. Chem. 1966, 693, 99. Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140.
PdCl
Cl
OH2
PdCl
Cl
OH2
PdCl
Cl
OH2
–OH
PdCl
Cl CH2CH2OH
OH2
–Outer-sphere hydroxide attack:
Predicted to be 103 times faster
than diffusion controlled process
H2O
PdCl
Cl CH2CH2OH
OH2
–
+ H+Outer-sphere water attack:Predicted to occur by an antihydroxypalladation mechanism
PdCl
Cl
OH
–
+ H+ PdCl
Cl CH2CH2OH
OH2
– Inner-sphere hydroxyl attack: Predicted to occur by a syn hydroxypalladation mechanism
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Kinetic Isotope EffectsEarly Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
D
D D
D
+ PdCl42– + H2O
O
DD3C+ Pd(0) + 2 HCl + 2 Cl–
H
H H
H
+ PdCl42– + H2O
O
HH3C+ Pd(0) + 2 HCl + 2 Cl–
kH
kD
= 1.07
Henry, P. M. J. Org. Chem. 1973, 38, 2415. Kosaki, M.; Isemura, M.; Kitaura, K.; Schinoda, S.; Saito, Y. J. Mol. Catal. 1977, 2, 351. Saito, Y.; Schinoda, S. J. Mol. Catal. 1980, 9, 461.
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Kinetic Isotope EffectsEarly Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
D
D D
D
+ PdCl42– + H2O
O
DD3C+ Pd(0) + 2 HCl + 2 Cl–
H
H H
H
+ PdCl42– + H2O
O
HH3C+ Pd(0) + 2 HCl + 2 Cl–
kH
kD
= 1.07
KIE for decomposition step determined by competitive isotope effect experiment:
H
D D
H
+ PdCl42– + H2O
D
H H
D
Pd(OH2)Cl2HO
H-shift
D-shift
O
DDH2C
O
HHD2C
kH
kD
= 1.70
Henry, P. M. J. Org. Chem. 1973, 38, 2415. Kosaki, M.; Isemura, M.; Kitaura, K.; Schinoda, S.; Saito, Y. J. Mol. Catal. 1977, 2, 351. Saito, Y.; Schinoda, S. J. Mol. Catal. 1980, 9, 461.
–
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Kinetic Isotope EffectsEarly Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
Henry, P. M. J. Org. Chem. 1973, 38, 2415. Kosaki, M.; Isemura, M.; Kitaura, K.; Schinoda, S.; Saito, Y. J. Mol. Catal. 1977, 2, 351. Saito, Y.; Schinoda, S. J. Mol. Catal. 1980, 9, 461.
PdH2O
Cl Cl
PdHO
Cl Cl–
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
+ H+
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
O
HH3C
–H++H+
outer-sphere anti hydroxypalladation
inner-sphere syn hydroxypalladation
KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition.
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Kinetic Isotope EffectsEarly Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
Henry, P. M. J. Org. Chem. 1973, 38, 2415. Kosaki, M.; Isemura, M.; Kitaura, K.; Schinoda, S.; Saito, Y. J. Mol. Catal. 1977, 2, 351. Saito, Y.; Schinoda, S. J. Mol. Catal. 1980, 9, 461.
PdH2O
Cl Cl
PdHO
Cl Cl–
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
+ H+
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
O
HH3C
–H++H+
slow
slow
fast
fast
outer-sphere anti hydroxypalladation
inner-sphere syn hydroxypalladation
KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition.
anti pathway has decomposition as the slow step
syn pathway has hydroxypalladation as the slow step
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Kinetic Isotope EffectsEarly Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
Henry, P. M. J. Org. Chem. 1973, 38, 2415. Kosaki, M.; Isemura, M.; Kitaura, K.; Schinoda, S.; Saito, Y. J. Mol. Catal. 1977, 2, 351. Saito, Y.; Schinoda, S. J. Mol. Catal. 1980, 9, 461.
PdH2O
Cl Cl
PdHO
Cl Cl–
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
+ H+
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
O
HH3C
–H++H+
slowfast
outer-sphere anti hydroxypalladation
inner-sphere syn hydroxypalladation
KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition.
anti pathway has decomposition as the slow step
syn pathway has hydroxypalladation as the slow step
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Early Stereochemical StudiesStille's Work Suggests Anti Hydroxypalladation Mechanism
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
PdCl
Cl
H2O
Na2CO3
PdCl
Cl
OH
CO O
O
Key: CO insertion proceeds with retention of stereochemistryat the migrating stereocenter.
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Early Stereochemical StudiesStille's Work Suggests Anti Hydroxypalladation Mechanism
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
PdCl
Cl
H2O
Na2CO3
PdCl
Cl
OH
CO O
O
Key: CO insertion proceeds with retention of stereochemistryat the migrating stereocenter.
PdCl
Cl
HO
CO O
O
PdCl
Cl
OH
CO O
O
anti hydroxypalladation syn hydroxypalladation
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Early Stereochemical StudiesStille's Work Suggests Anti Hydroxypalladation Mechanism
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
PdCl
Cl
H2O
Na2CO3
PdCl
Cl
HO
CO O
O
anti hydroxypalladation
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Early Stereochemical StudiesStille's Work Suggests Anti Hydroxypalladation Mechanism
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
PdCl
Cl
H2O
Na2CO3
PdCl
Cl
HO
CO O
O
anti hydroxypalladation
Criticism:
! Olefin is unable to rotate into the square plane of the PdCl2 making syn hydroxypalladation impossible
! Ligand exchange to give Pd(cod)(H2O)Cl would result in a cationic intermediate and is unlikely
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Early Stereochemical StudiesStille's Work Suggests Anti Hydroxypalladation Mechanism
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
PdCl
Cl
H2O
Na2CO3
PdCl
Cl
HO
CO O
O
anti hydroxypalladation
D
H H
D
PdCl2
2
H2O
H2O HO PdLn
D DH H
HO
PdLnD
D
H
H
CO
CO
HO
D DH H
HO
D
D
H
H
O
PdLn
PdLn
O
O
D DH H
O
O
D HH D
O
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Early Stereochemical StudiesStille's Work Suggests Anti Hydroxypalladation Mechanism
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
PdCl
Cl
H2O
Na2CO3
PdCl
Cl
HO
CO O
O
anti hydroxypalladation
D
H H
D
PdCl2
2
H2O
H2O HO PdLn
D DH H
HO
PdLnD
D
H
H
CO
CO
HO
D DH H
HO
D
D
H
H
O
PdLn
PdLn
O
O
D DH H
O
O
D HH D
O
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Early Stereochemical StudiesStille's Work Suggests Anti Hydroxypalladation Mechanism
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
anti hydroxypalladation
D
H H
D
PdCl2
2
H2O
H2O HO PdLn
D DH H
HO
PdLnD
D
H
H
CO
CO
HO
D DH H
HO
D
D
H
H
O
PdLn
PdLn
O
O
D DH H
O
O
D HH D
O
Criticism:
! Solvent is acetonitrile not water.
! Might proceed through a dimeric Pd complex.
! CO (3 atm) is very coordinating and might occupy coordination sites prohibiting the ligation of water necessary for syn hydroxypalladation.
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Bäckvall's Stereochemical StudiesFurther (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
C2H4 + PdCl42– H2O
PdH2O
Cl Cl
[Cl–] < 1 M[CuCl2] < 1 M
H3C
O
H
loss of stereochemical
information
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
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Bäckvall's Stereochemical StudiesFurther (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
C2H4 + PdCl42– H2O
PdH2O
Cl Cl
[Cl–] < 1 M[CuCl2] < 1 M
[Cl–] > 3 M[CuCl2] > 2.5 M
H3C
O
H
loss of stereochemical
information
+
ClOH
CH3CHOstereochemical
information retained (maybe)
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
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Bäckvall's Stereochemical StudiesFurther (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
C2H4 + PdCl42– H2O
PdH2O
Cl Cl
[Cl–] < 1 M[CuCl2] < 1 M
[Cl–] > 3 M[CuCl2] > 2.5 M
H3C
O
H
loss of stereochemical
information
+
ClOH
CH3CHOstereochemical
information retained (maybe)
Two Key Assumptions:
! Chlorohydrin and acetaldehyde form from the same intermediate (i.e., [Pd(CH2CH2OH)(H2O)Cl2]–).
! The steric course of the reaction is not affected by conditions containing high [Cl–] and high [CuCl2].
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
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Bäckvall's Stereochemical StudiesFurther (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
PdH2O
Cl ClPd
H2OCl Cl
CH2CH2OH
–
+ H++ H2O2 CuCl2
OHCl
+ 2 CuCl
decomposition
CH3CHO
! Chloride displacement of Pd occurs with inversion of stereochemistry at carbon.
! Chlorohydrin formation requires both high [Cl–] and high [CuCl2].
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Bäckvall's Stereochemical StudiesFurther (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
PdH2O
Cl ClPd
H2OCl Cl
–
+ H++ H2O
D
anti hydroxypalladation
H DOH
D HD2 CuCl2
Cl OH
H DD H
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Bäckvall's Stereochemical StudiesFurther (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
PdH2O
Cl ClPd
H2OCl Cl
–
+ H++ H2O
D
anti hydroxypalladation
H DOH
D HD2 CuCl2
Cl OH
H DD H
PdH2O
Cl ClPd
H2OCl Cl
–
+ H++ H2O
D
syn hydroxypalladation
H DOH
H DD2 CuCl2
Cl OH
H HD D
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Bäckvall's Stereochemical StudiesFurther (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
PdH2O
Cl ClPd
H2OCl Cl
–
+ H++ H2O
D
anti hydroxypalladation
H DOH
D HD2 CuCl2
Cl OH
H DD H
PdH2O
Cl ClPd
H2OCl Cl
–
+ H++ H2O
D
syn hydroxypalladation
H DOH
H DD2 CuCl2
Cl OH
H HD D
Control Experiments:
! Z/E isomerization is < 1% under the reaction conditions.
! Cofirmed that cleavage of C–Pd bond with CuCl2 occurs with inversion at carbon.
! Confirmed that chlorohydrin does not arise from an intermediate epoxide.
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Bäckvall's Stereochemical StudiesAn Apparent Contradiction with KIE Studies
Henry, P. M. J. Org. Chem. 1973, 38, 2415. Kosaki, M.; Isemura, M.; Kitaura, K.; Schinoda, S.; Saito, Y. J. Mol. Catal. 1977, 2, 351. Saito, Y.; Schinoda, S. J. Mol. Catal. 1980, 9, 461.
PdH2O
Cl Cl
PdHO
Cl Cl–
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
+ H+
+ H2O PdH2O
Cl Cl
CH2CH2OH
–
O
HH3C
–H++H+
slowfast
outer-sphere anti hydroxypalladation
innter-sphere syn hydroxypalladation
KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition.
anti pathway has decomposition as the slow step
syn pathway has hydroxypalladation as the slow step
fast slow
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Bäckvall's Stereochemical StudiesReconciling Stereochemical Results with Kinetic Data
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
PdH2O
Cl ClPd
H2OCl Cl
CH2CH2OH
–
+ H++ H2O
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Bäckvall's Stereochemical StudiesReconciling Stereochemical Results with Kinetic Data
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
PdH2O
Cl ClPd
H2OCl Cl
CH2CH2OH
–
+ H++ H2O
PdH2O
Cl ClCH2CH2OH
–Pd
H2OCl
CH2CH2OH + Cl–
PdH2O
Cl Cl
–
OH
H
slow
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Bäckvall's Stereochemical StudiesReconciling Stereochemical Results with Kinetic Data
Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411.
PdH2O
Cl ClPd
H2OCl Cl
CH2CH2OH
–
+ H++ H2O
PdH2O
Cl ClCH2CH2OH
–Pd
H2OCl
CH2CH2OH + Cl–
PdH2O
Cl Cl
–
OH
H
PdH2O
ClCH2CH2OH Pd
H2OCl H
–
OHPd
H2OCl H
C
CH3
OH
H3C H
O
slow
fast
Since decomposition occurs after the rate-limiting stepa primary isotope effect would not be predicted.
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Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Wacker Conditions
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
OH + PdCl42– + H2O
HO OH
PdII
HOH2O + PdCl42– +
oxidation products
k1
k–1
k–1
k1
k2
Oxidation of allyl alcohol is directed by the hydroxyl group
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Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Wacker Conditions
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
OH + PdCl42– + H2O
HO OH
PdII
HOH2O + PdCl42– +
oxidation products
k1
k–1
k–1
k1
k2
If hydroxypalladation is anti,isomerization should occur since hydroxypalladation is required tobe an equilibrium process.
If hydroxypalladation is syn,isomerization should not occursince hydroxypalladation is ratelimiting.
Oxidation of allyl alcohol is directed by the hydroxyl group
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]2 [H+]==Rate
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Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Wacker Conditions
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
OH + PdCl42– + H2O
HO OH
PdII
HOH2O + PdCl42– +
oxidation products
k1
k–1
k–1
k1
k2
If hydroxypalladation is anti,isomerization should occur since hydroxypalladation is required tobe an equilibrium process.
If hydroxypalladation is syn,isomerization should not occursince hydroxypalladation is ratelimiting.
H
H
H
D D
D
D
H
H H
H H D D
Oxidation of allyl alcohol is directed by the hydroxyl group
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]2 [H+]==Rate
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Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Wacker Conditions
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
OH + PdCl42– + H2O
HO OH
PdII
HOH2O + PdCl42– +
oxidation products
k1
k–1
k–1
k1
k2
If hydroxypalladation is anti,isomerization should occur since hydroxypalladation is required tobe an equilibrium process.
If hydroxypalladation is syn,isomerization should not occursince hydroxypalladation is ratelimiting.
Isomerization product was < 3% of the total deuteratedallyl alcohol when the reaction was stopped after
one half-life.
Hydroxypalladation is NOT an equilibrium process!
H
H
H
D D
D
D
H
H H
H H D D
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Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Isomerization Conditions
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
OH + PdCl42– + H2O
HO OH
PdII
HOH2O + PdCl42– +
oxidation products
k1
k–1
k–1
k1
k2
If hydroxypalladation is anti,isomerization should occur since hydroxypalladation is required tobe an equilibrium process.
If hydroxypalladation is syn,isomerization should not occursince hydroxypalladation is ratelimiting.
H
H
H
D D
D
D
H
H H
H H D D
[Cl–] = 3.3 M
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]==Rate
Only isomerization observed.
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HO OH
PdII
oxidation products
k2
If hydroxypalladation is anti,isomerization should occur since hydroxypalladation is required tobe an equilibrium process.
If hydroxypalladation is syn,isomerization should not occursince hydroxypalladation is ratelimiting.
H H D D
Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Isomerization Conditions
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
OH + PdCl42– + H2O HOH2O + PdCl4
2– +
k1
k–1
k–1
k1
H
H
H
D D
D
D
H
H H
[Cl–] = 3.3 M
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]==Rate
Only isomerization observed.
Reactions at high and low chloride do not proceed through the same mechanism.
Formation of aldehyde and chlorohydrin does not occur through a common hydroxypalladation intermediate.
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Anti Hydroxypalladation at High [Cl–]
Henry's Proposed Pathway
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
PdCl
Cl Cl
Cl PdCl
Cl Cl
–
+ Cl–
2–
OH+
PdCl
Cl Cl
CH
2–
CH2OH
CD2OH
OH
+ H+
D D DD
PdCl
Cl Cl
–OH
DD
+ H2O
outer-sphere anti hydroxypalladation
PdCl
Cl Cl
CH
2–
CH2OH
CD2OH+ H+
PdCl
Cl Cl
–OH
HH + H2O
D
D
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Anti Hydroxypalladation at High [Cl–]
Henry's Proposed Pathway
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
PdCl
Cl Cl
Cl PdCl
Cl Cl
–
+ Cl–
2–
OH+
PdCl
Cl Cl
CH
2–
CH2OH
CD2OH
OH
+ H+
D D DD
PdCl
Cl Cl
–OH
DD
+ H2O
outer-sphere anti hydroxypalladation
PdCl
Cl Cl
CH
2–
CH2OH
CD2OH+ H+
PdCl
Cl Cl
–OH
HH + H2O
D
D
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Reinterpreting Bäckvall's ResultsHenry's Proposed Pathway
Gregor, N.; Zaw, K.; Henry, P. M. Organometallics 1984, 3, 1251.
PdCl
Cl Cl
–
+ Cl–
outer-sphere anti hydroxypalladation
PdCl42– + C2H4
Excess Cl– prevents this intermediate
from undergoing decomposition to
oxidation products.
Cl– ligand loss prevented by high
concentration of Cl–.
Assumption that oxidation productsand chlorohydrin arise from a commonintermediate is NOT valid.
PdCl
Cl Cl
–
+ Cl– PdCl
Cl Cl
CH2CH2OH
2–H2O
CuCl2
ClOH
PdCl
Cl Cl
CH2CH2OH
2–
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
OH + PdCl42– + H2O H2O + PdCl4
2– +
oxidation products
F3C
H3C
H
F3C CD3
CF3F3C
H3C
H
Required Properties:
! Substrate cannot undergo oxidation; can only isomerize.
! Substrate whose RLS is hydroxypalladation.
! Substrate possesses stereochemistry that can be used to distinguish between syn and anti hydroxypalladation.
oxidation products
CD3
HO
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
OH + PdCl42– + H2O H2O + PdCl4
2– +
oxidation products
F3C
H3C
H
F3C CD3
CF3F3C
H3C
H
oxidation productsF3C CF3
H PdII
OHH3C
OHCD3
k1
k–1
k–1
k1
Exchange is completely symmetric,thus the rate of isomerization depends only
on the rate of formation of the hydroxypalladateand not on its equilibrium concentration.
CD3
HO
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
OH + PdCl42– + H2O H2O + PdCl4
2– +
oxidation products
F3C
H3C
H
F3C CD3
CF3F3C
H3C
H
oxidation productsF3C CF3
H PdII
OHH3C
OHCD3
k1
k–1
k–1
k1
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]2 [H+]==Rate
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]==Rate
For anti hydroxypalladation:For syn hydroxypalladation:
Proton inhibition term must result from anequilibrium that occurs before the rate-limitinghydroxypalladation step.
Proton inhibition term does not show up in the exchange rate because it results from thisexchange equilibrium.
HOCD3
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
OH + PdCl42– + H2O H2O + PdCl4
2– +
oxidation products
F3C
H3C
H
F3C CD3
CF3F3C
H3C
H
oxidation productsF3C CF3
H PdII
OHH3C
OHCD3
k1
k–1
k–1
k1
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]2 [H+]==Rate
For syn hydroxypalladation:
Proton inhibition term must result from anequilibrium that occurs before the rate-limitinghydroxypalladation step.
Observed Kinetics under Wacker Conditions:
! Rate expression had a first order proton inhibition term.
! Rate expression was identical to the Wacker rate expression.
! Consistent with syn hydroxypalladation mechanism.
CD3
HO
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
OH + PdCl42– + H2O H2O + PdCl4
2– +
oxidation products
F3C
H3C
H
F3C CD3
CF3F3C
H3C
H
oxidation productsF3C CF3
H PdII
OHH3C
OHCD3
k1
k–1
k–1
k1
–d[C2H4]
dt
k [PdCl42–] [olefin]
[Cl–]==Rate
For anti hydroxypalladation:
Proton inhibition term does not show up in the exchange rate because it results from thisexchange equilibrium.
Observed Kinetics under High [Cl–] Conditions:
! Rate expression had no first order proton
inhibition term.
! Rate expression was identical to what
Bäckvall observed at high [Cl–].
! Consistent with anti hydroxypalladation
mechanism.
HOCD3
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
antiOH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
– H+
anti
syn
OH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
CD3F3C
HO
PdII
H
+ H+
– PdII
– H2O
CD3
H
F3C
(S), E
OH
CF3
CH3
OH
CF3
CH3
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
– H+
anti
syn
OH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
CD3F3C
HO
PdII
H
+ H+
– PdII
– H2O
CD3
H
F3C
(S), E
OH
CF3
CH3
OH
CF3
CH3
substrate
config % ee [Cl–] [catalyst]
%isomeriz-
ation % S % R
product
R
R
S
S
100
100
100
100
0.10
0.05
0.05
0.10
PdCl42–
PdCl42–
PdCl42–
PdCl42–
30
48
25
50
32.5
50.0
72.5
50.0
67.5
50.0
27.5
50.0
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
– H+
anti
syn
OH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
CD3F3C
HO
PdII
H
+ H+
– PdII
– H2O
CD3
H
F3C
(S), E
OH
CF3
CH3
OH
CF3
CH3
substrate
config % ee [Cl–] [catalyst]
%isomeriz-
ation % S % R
product
R
R
S
S
100
100
100
100
0.10
0.05
0.05
0.10
PdCl42–
PdCl42–
PdCl42–
PdCl42–
30
48
25
50
32.5
50.0
72.5
50.0
67.5
50.0
27.5
50.0
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
– H+
anti
syn
OH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
CD3F3C
HO
PdII
H
+ H+
– PdII
– H2O
CD3
H
F3C
(S), E
OH
CF3
CH3
OH
CF3
CH3
substrate
config % ee [Cl–] % Z% isomerization % S % R
product
R
R
S
S
100
100
100
100
2.0
3.5
3.5
2.0
30
25
32
45
31
27
35
45
0.0
0.0
100
100
100
100
0.0
0.0
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
– H+
anti
syn
OH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
CD3F3C
HO
PdII
H
+ H+
– PdII
– H2O
CD3
H
F3C
(S), E
OH
CF3
CH3
OH
CF3
CH3
substrate
config % ee [Cl–] % Z% isomerization % S % R
product
R
R
S
S
100
100
100
100
2.0
3.5
3.5
2.0
30
25
32
45
31
27
35
45
0.0
0.0
100
100
100
100
0.0
0.0
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
– H+
anti
syn
OH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
CD3F3C
HO
PdII
H
+ H+
– PdII
– H2O
CD3
H
F3C
(S), E
OH
CF3
CH3
OH
CF3
CH3
Conclusions:
! At low [Cl–] (Wacker conditions), syn hydroxypalladation is
operative.
! At high [Cl–] (Bäckvall's conditions), anti hydroxypalladation is
operative.
high [Cl–]
low [Cl–]
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Evidence for Syn HydroxypalladationA New Stereochemical and Kinetic Probe
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
PdCl42–
H2OH
CH3
CF3
CD3F3C
HO
– H+
– H+
anti
syn
OH
CD3F3C
HO
CF3CH3
PdII
H
(R), E
+ H+
– PdII
– H2O
OH
CF3
CF3CH3
H
D3C
(R), Z
CD3F3C
HO
PdII
H
+ H+
– PdII
– H2O
CD3
H
F3C
(S), E
OH
CF3
CH3
OH
CF3
CH3
Criticism:
! Trisubstituted alkenes are not standard Wacker substrates.
! Substrate cannot undergo oxidation.
! Would be best to study a substrate that can undergo both
oxidation and isomerization under both low and high [Cl–]
concentrations.
high [Cl–]
low [Cl–]
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
R1
H
HHO
R2
(R), Zreactive
conformation
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PdCl42–
H2OH
R1
H
HHO
R2
– H+
antiOH
HHO
R2
R1
HPdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
OH
R2
R1
HH
H
(S), Z
– Pd0
– H+
[Cl–] = 0.1 M OH
R2
R1
H
O
(S)
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PdCl42–
H2OH
R1
H
HHO
R2
– H+
– H+
anti
syn
OH
HHO
R2
R1
HPdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
OH
R2
R1
HH
H
(S), Z
HHO
R2
PdII
H
(R), E
OH
R1H
– Pd0
– H+
– PdII
– H2O
– Pd0
– H+
[Cl–] > 2 M
[Cl–] = 0.1 M
[Cl–] = 0.1 M
H
H
R2
OH
R1
H
OH
R2
R1
H
O
(S)
(R)
R2
O
OH
R1
H
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PdCl42–
H2OH
R1
H
HHO
R2
– H+
– H+
anti
syn
OH
HHO
R2
R1
HPdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
OH
R2
R1
HH
H
(S), Z
HHO
R2
PdII
H
(R), E
OH
R1H
– Pd0
– H+
– PdII
– H2O
– Pd0
– H+
[Cl–] > 2 M
[Cl–] = 0.1 M
[Cl–] = 0.1 M
H
H
R2
OH
R1
H
OH
R2
R1
H
O
(S)
(R)
R2
O
OH
R1
H
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PhPdCl
MeOHH
Me
H
HHO
Me
– H+
– H+
anti
syn
Ph
HHO
Me
MeH
PdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
Ph
Me
MeHH
H
(S), Z
HHO
Me
PdII
H
(R), E
Ph
MeH
– Pd0
– H+
– PdII
– H2O
– Pd0
– H+
[Cl–] > 2 M
[Cl–] = 0.1 M
[Cl–] = 0.1 M
H
H
Me
Ph
MeH
Ph
Me
MeH
O
(S)
(R)
Me
O
Ph
MeH
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PhPdCl
MeOHH
Me
H
HHO
Me
– H+
– H+
anti
syn
Ph
HHO
Me
MeH
PdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
Ph
Me
MeHH
H
(S), Z
HHO
Me
PdII
H
(R), E
Ph
MeH
– Pd0
– H+
– PdII
– H2O
– Pd0
– H+
[Cl–] > 2 M
[Cl–] = 0.1 M
[Cl–] = 0.1 M
H
H
Me
Ph
MeH
Ph
Me
MeH
O
(S)
(R)
Me
O
Ph
MeH
PhPdCl must add
syn regardless of
the [Cl–]
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PdCl42–
H2OH
Et
H
HHO
Me
– H+
– H+
anti
syn
OH
HHO
Me
EtH
PdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
OH
Me
EtHH
H
(S), Z
HHO
Me
PdII
H
(R), E
OH
Et
H
– Pd0
– H+
– PdII
– H2O
– Pd0
– H+
[Cl–] > 2 M
[Cl–] = 0.1 M
[Cl–] = 0.1 M
H
H
Me
OH
EtH
OH
Me
EtH
O
(S)
(R)
Me
O
OH
EtH
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PdCl42–
H2OH
Et
H
HHO
Me
– H+
– H+
anti
syn
OH
HHO
Me
EtH
PdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
OH
Me
EtHH
H
(S), Z
HHO
Me
PdII
H
(R), E
OH
Et
H
– Pd0
– H+
– PdII
– H2O
– Pd0
– H+
[Cl–] > 2 M
[Cl–] = 0.1 M
[Cl–] = 0.1 M
H
H
Me
OH
EtH
OH
Me
EtH
O
(S)
(R)
Me
O
OH
EtH
the stereochemistry of hydroxypalladation
must be different at high and low [Cl–]
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Chirality Transfer Studies
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
PdCl42–
H2OH
Et
H
HHO
Me
– H+
– H+
anti
syn
OH
HHO
Me
EtH
PdII
H
(R), Zreactive
conformation
[Cl–] > 2 M
– PdII
– H2O
OH
Me
EtHH
H
(S), Z
HHO
Me
PdII
H
(R), E
OH
Et
H
– Pd0
– H+
– PdII
– H2O
– Pd0
– H+
[Cl–] > 2 M
[Cl–] = 0.1 M
[Cl–] = 0.1 M
H
H
Me
OH
EtH
OH
Me
EtH
O
(S)
(R)
Me
O
OH
EtH
! Excess Cl– prevents syn hydroxypalladation by
prohibiting the ligation of water.
! Excess Cl– prevents "-hydride elimination to oxidation
products by prohibiting the necessary dissociation
of a Cl– ligand.
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Mechanism for Oxidation of Olefins under Wacker Conditions
Henry, P. M. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons, Inc.: New York, 2002; Vol. 1, p 2119.
PdCl
Cl Cl
Cl
2–
PdCl
Cl Cl–
PdH2O
Cl Cl
PdHO
Cl Cl–
PdCl Cl
–
OHH2OPd
Cl Cl–
OH
H3C H
O
H2C CH2
– Cl–+ H2O
– Cl–
– H+
+ H2O
syn hydroxypalladation
– H2O
–
1
[Cl–]inhibition
1
[Cl–]inhibition
1
[H+]inhibition+ CuCl2
+ O2
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Mechanism for Oxidation of Olefins under Wacker Conditions
Henry, P. M. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons, Inc.: New York, 2002; Vol. 1, p 2119.
PdCl
Cl Cl
Cl
2–
PdCl
Cl Cl–
PdH2O
Cl Cl
PdHO
Cl Cl–
PdCl Cl
–
OHH2OPd
Cl Cl–
OH
H3C H
O
H2C CH2
– Cl–+ H2O
– Cl–
– H+
+ H2O
syn hydroxypalladation
– H2O
–
1
[Cl–]inhibition
1
[Cl–]inhibition
1
[H+]inhibition+ CuCl2
+ O2
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Mechanism for Decomposition to Oxidation Products
Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80. Moiseev, I. I.; Warhaftig, M. N.; Sirkin, J. H. Doklady Akad. Nauk UdSSR 1960, 130, 820. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411. Henry, P. M. J. Am.
Chem. Soc. 1964, 86, 3246.
Moiseev's Mechanism:
PdCl Cl–
OHPd
HCl Cl
–
OHOH
O
H!-hydride
elimination dissociation tautomerize
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Mechanism for Decomposition to Oxidation Products
Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80. Moiseev, I. I.; Warhaftig, M. N.; Sirkin, J. H. Doklady Akad. Nauk UdSSR 1960, 130, 820. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411. Henry, P. M. J. Am.
Chem. Soc. 1964, 86, 3246.
Moiseev's Mechanism:
PdCl Cl–
OHPd
HCl Cl
–
OHOH
O
H!-hydride
elimination dissociation tautomerize
D
D D
D+ PdCl4
2– + H2OO
DD3C+ Pd(0) + 2 HCl + 2 Cl–
H
H H
H+ PdCl4
2– + D2OO
HH3C+ Pd(0) + 2 DCl + 2 Cl–
lack of proton incorporation from solvent means that tautomerization mechanism is invalid
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Mechanism for Decomposition to Oxidation Products
Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80. Moiseev, I. I.; Warhaftig, M. N.; Sirkin, J. H. Doklady Akad. Nauk UdSSR 1960, 130, 820. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411. Henry, P. M. J. Am.
Chem. Soc. 1964, 86, 3246.
Henry's Model
PdCl Cl
–
OHH H
H H
HPd
OH
HHH
Cl
Cl
O
H
+ Pd(0) + HCl
PdII-assistedhydride shift
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Mechanism for Decomposition to Oxidation Products
Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80. Moiseev, I. I.; Warhaftig, M. N.; Sirkin, J. H. Doklady Akad. Nauk UdSSR 1960, 130, 820. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411. Henry, P. M. J. Am.
Chem. Soc. 1964, 86, 3246.
Henry's Model
Bäckvall's Model
PdCl Cl
–
OHH H
H H
HPd
OH
HHH
Cl
Cl
O
H
+ Pd(0) + HCl
PdCl Cl–
OHPd
HCl Cl
–
OH!-hydride
elimination
PdII-assistedhydride shift
PdCl Cl
–
reinsertionOH
O
H
+ Pd(0) + HCl !-hydride eliminationfrom oxygen
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Mechanism for Decomposition to Oxidation ProductsComputational Studies
Keith, J. A.; Oxgaard, J.; Goddard, W. A., III J. Am. Chem. Soc. 2006, 128, 3132. Keith, J. A.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III J. Am. Chem.
Soc. 2007, 129, 12342.
Bäckvall's Model
PdCl Cl
–
OH
O
H
+ Pd(0) + HCl
!-hydride eliminationfrom oxygen
O
PdIICl
H
H3C
Goddard's Computations
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Mechanism for Decomposition to Oxidation ProductsComputational Studies
Keith, J. A.; Oxgaard, J.; Goddard, W. A., III J. Am. Chem. Soc. 2006, 128, 3132. Keith, J. A.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III J. Am. Chem.
Soc. 2007, 129, 12342.
Bäckvall's Model
PdCl Cl
–
OH
O
H
+ Pd(0) + HCl
!-hydride eliminationfrom oxygen
O
PdIICl
H
H3C
Goddard's Computations
4-membered TS: 36.3 kcal/mol
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Mechanism for Decomposition to Oxidation ProductsComputational Studies
Keith, J. A.; Oxgaard, J.; Goddard, W. A., III J. Am. Chem. Soc. 2006, 128, 3132. Keith, J. A.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III J. Am. Chem. Soc. 2007, 129, 12342.
Bäckvall's Model
PdCl Cl–
OH
O
H+ Pd(0) + HCl
β-hydride eliminationfrom oxygen
OPdIIClH
H3C
Goddard's Computations
4-membered TS: 36.3 kcal/mol Cl-mediated reductive elimination TS: 18.7 kcal/mol
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From Industrial Process to Synthetic MethodPreparations of Methyl Ketones from Terminal Olefins
Clement, 1964:
PdCl2 (10 mol%)oxidant
H2O (12-17%), O2DMF
O
oxidant = CuCl2•2H2O (10 mol%) or p-benzoquinone
Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241. Tsuji, J. Synthesis 1984, 369.
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From Industrial Process to Synthetic MethodPreparations of Methyl Ketones from Terminal Olefins
Clement, 1964:
PdCl2 (10 mol%)oxidant
H2O (12-17%), O2DMF
O
O
OMeO
MeO O
Zearalenone
O
O
Nootkatone
intermediate to Dichroanone
OH
H H
H H
O
19-Nortestosterone
O
O
Brevicomin
H
H OTHP
O
O
intermediate toCoriolin
Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241. Tsuji, J. Synthesis 1984, 369.
oxidant = CuCl2•2H2O (10 mol%) or p-benzoquinone
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From Industrial Process to Synthetic MethodOxidative Cyclizations Give Access to Heterocyclic Compounds
Hosokawa, T.; Maeda, K.; Koga, K.; Moritani, I. Tetrahedron Lett. 1973, 10, 739.
Moritani, 1973:
O–Na+
PdCl2(PhCN)2 (1 equiv)
PhH O
RR
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From Industrial Process to Synthetic MethodOxidative Cyclizations Give Access to Heterocyclic Compounds
Roshchin, A. I.; Kel'chevski, S. M.; Bumagin, N. A. J. Organomet. Chem. 1998, 560, 163. Larock, R. C.; Wei, L.; Hightower, T. R. Synlett 1998, 522.
Moritani, 1973:
O–Na+
PdCl2(PhCN)2 (1 equiv)
PhH O
RR
OH OO
Pd(OAc)2 (2 mol%)Cu(OAc)2•H2O (1 equiv)
air, DMF, 100 °C
Pd(dba)2 (5 mol%)KHCO3 (1.1 equiv)
air, DMSO, H2O60 °C
no co-oxidant!
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From Industrial Process to Synthetic MethodOxidative Cyclizations Give Access to Heterocyclic Compounds
Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071.
Moritani, 1973:
O–Na+
PdCl2(PhCN)2 (1 equiv)
PhH O
RR
OH OO
Pd(OAc)2 (2 mol%)Cu(OAc)2•H2O (1 equiv)
air, DMF, 100 °C
Pd(dba)2 (5 mol%)KHCO3 (1.1 equiv)
air, DMSO, H2O60 °C
no co-oxidant!
OH
Pd(TFA)2 (10 mol%)ligand (20 mol%)
p-benzoquinone(4 equiv)
MeOH, 60 °C
O
96% ee
N
O
N
O
i-Pri-Pr
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From Industrial Process to Synthetic MethodOxidative Cyclizations Give Access to Heterocyclic Compounds
Hosokawa, T.; Murahashi, S.-I. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons: New York, 2002; Vol. 2, pp 2169-2192.
O
N
O
Boc
MeO2C OH H
O
BnO OBn
BnO
H H
O
O
OOO
O
NH
NH
NTs
NTs
N
O
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Stereochemistry of Oxidative Cyclizations
OHR
PdLn
OR
PdLn
ORanti
oxypalladation!-hydride
elimination
O
RO
RPdLn
ORsyn
oxypalladation!-hydride
elimination
PdLn
H
H
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Stereochemistry of Oxidative CyclizationsStoltz Group Studies
Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892.
OH
Pd(TFA)2 (5 mol%)pyridine (20 mol%)Na2CO3 (2 equiv)
MS3Å, O2 (1 atm) PhCH3, 80 °C
O
95% yield
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Stereochemistry of Oxidative CyclizationsStoltz Group Studies
Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892.
OH
Pd(TFA)2 (5 mol%)pyridine (20 mol%)Na2CO3 (2 equiv)
MS3Å, O2 (1 atm) PhCH3, 80 °C
O
O O
O
O
95% yield
NTs
O
NOBn
OCO2Et
O O O
90% yield 88% yield 63% yield 82% yield
87% yield 93% yield 62% yield
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EE
Stereochemistry of Oxidative CyclizationsStoltz Group Studies
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
D
HO
CO2Et
CO2Et
E
OHD
H
E
E
OD
H
[PdII]
O D
H
E [PdII]
E
E
O
D
[PdII]E
O D
H
E
E
E
O
H
[Pd]
H
antioxypalladation
synoxypalladation
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EE
Stereochemistry of Oxidative CyclizationsStoltz Group Studies
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
D
HO
CO2Et
CO2Et
E
OHD
H
E
E
OD
H
[PdII]
O D
H
E [PdII]
E
E
O
D
[PdII]E
O D
H
E
E
E
O
H
[Pd]
H
antioxypalladation
synoxypalladation
HCO2Et
CO2Et
O
HCO2Et
CO2Et
O
D
+
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EE
Stereochemistry of Oxidative CyclizationsStoltz Group Studies
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
D
HO
CO2Et
CO2Et
E
OHD
H
E
E
OD
H
[PdII]
O D
H
E [PdII]
E
E
O
D
[PdII]E
O D
H
E
E
E
O
H
[Pd]
H
antioxypalladation
synoxypalladation
O
O
O
O
O
O
O
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EE
Stereochemistry of Oxidative CyclizationsStoltz Group Studies
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
D
HO
CO2Et
CO2Et
E
OHD
H
E
E
OD
H
[PdII]
O D
H
E [PdII]
E
E
O
D
[PdII]E
O D
H
E
E
E
O
H
[Pd]
H
antioxypalladation
synoxypalladation
O
O
O
O
O
O
O
DCO2Et
CO2Et
O
O
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Stereochemistry of Oxidative CyclizationsHayashi Group Studies
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
OH
D
Pd(MeCN)4(BF4)2 (5 mol%)(S,S)-ip-boxax (Pd/L* = 1/2)
benzoquinone (4 equiv)MeOH, 40 °C, 4 h
O
H
O
H
OO
D
D D
A B
DC
A:B:C:D = 16:46:29:9
synoxypalladation
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Stereochemistry of Oxidative CyclizationsHayashi Group Studies
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
OH
D
Pd(MeCN)4(BF4)2 (5 mol%)(S,S)-ip-boxax (Pd/L* = 1/2)
benzoquinone (4 equiv)MeOH, 40 °C, 4 h
O
H
O
H
OO
D
D D
A B
DC
A:B:C:D = 16:46:29:9
OH
D PdCl2(MeCN)2 (10 mol%)Na2CO3 (2 equiv)
LiCl (2 equiv)
benzoquinone (1 equiv)THF, 65 °C, 24 h
O
H
O
H
OO
D
D
A B
DC
A:B:C:D = 6:5:7:82D
synoxypalladation
antioxypalladation
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DPd
Stereochemistry of Oxidative CyclizationsStahl Group Studies
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
antiaminopalladation
synaminopalladation
D
NHTs
TsN
D
LnPd
TsN
D
LnPd
TsN
H
TsN
D
HPd
TsN
H
TsN
H
D
TsN
D
TsN
D
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DPd
Stereochemistry of Oxidative CyclizationsStahl Group Studies
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
antiaminopalladation
synaminopalladation
D
NHTs
TsN
D
LnPd
TsN
D
LnPd
TsN
H
TsN
D
HPd
TsN
H
TsN
H
D
TsN
D
TsN
D
No additive:
2:1 ratio syn:antiaminopalladation products
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DPd
Stereochemistry of Oxidative CyclizationsStahl Group Studies
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
antiaminopalladation
synaminopalladation
D
NHTs
TsN
D
LnPd
TsN
D
LnPd
TsN
H
TsN
D
HPd
TsN
H
TsN
H
D
TsN
D
TsN
D
CF3CO2H Additive:
1:2 ratio syn:antiaminopalladation products
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DPd
Stereochemistry of Oxidative CyclizationsStahl Group Studies
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
antiaminopalladation
synaminopalladation
D
NHTs
TsN
D
LnPd
TsN
D
LnPd
TsN
H
TsN
D
HPd
TsN
H
TsN
H
D
TsN
D
TsN
D
NaOAc or Na2CO3 Additive:
exclusively synaminopalladation products
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Conclusions
syn vs. antiheteropalladation
or carbopalladation
Pd Sourceand
Ligands
SolventEffects
(H2O, ROH, DMSO, etc.)
NucleophileSterics and Electronics
OlefinSterics and Electronics
Additive Effects(co-oxidant, acid, base,
salts)
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The Wacker OxidationOne-Stage Process
Reactor
PdCl2, CuCl2, HCl
Se
pa
rati
on
Eq
uip
me
nt
Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120.
C2H4, O2
purge
C2H4, CH3CHO
C2H4
CH3CHO
! Required brick and rubber-lined reactors and titanium pipes.
! Requires an O2 plant.
! Operates at 60-70 °C, 3 atm, and pH between 0.8 and 3.0.
! Yields >95% acetaldehyde.
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The Wacker OxidationTwo-Stage Process
Oxidation Reactor
Se
pa
rati
on
Eq
uip
me
nt
Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120.
RegenerationReactor
CH3CHO
PdCl2, (CuCl)2, HCl
+ CH3CHO
C2H4
PdCl2, CuCl2, HCl
N2
air
PdCl2, (CuCl)2, HCl
! Required brick and rubber-lined reactors and titanium pipes.
! Uses ambient air as O2 source and impure mixtures of ethylene.
! Operates at 90-100 °C, 10 atm.
! Yields >95% acetaldehyde.
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