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Wacker's process

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2 CuICl
Cl–
2
+2
C2H4
CuIICl2
PdIICl42–
Cl–
O
Pd0
H3C
H
+ HCl
Mechanistic Studies on
the Wacker Oxidation
H2O
H
O
H3C
PdIICl3–
H+, Cl–
PdIICl
Pamela Tadross
H
PdIICl2–
HO
PdIICl
OH
H3C
PdIICl
Cl
Cl
Pd
H2O
OH
Stoltz Group Literature Presentation
December 8, 2008
8 PM, 147 Noyes
+ H2O
Cl–
Cl
Cl
Pd
HO
–
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.
Origins of the Wacker Oxidation
F. C. Phillips, 1894:
PdCl42– + C2H4 + H2O
Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Smidt, Wacker Chemie, 1959:
Pd(0) + 2 CuCl2 + 2 Cl–
2 CuCl + 1/2 O2 + 2 HCl
2 CuCl + PdCl42–
2 CuCl2 + H2O
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.
Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O
Pd(0) + CH3CHO + 2 HCl + 2 Cl–
Pd(0) + 2 CuCl2 + 2 Cl–
2 CuCl + PdCl42–
2 CuCl + 1/2 O2 + 2 HCl
2 CuCl2 + H2O
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.
Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O
Pd(0) + CH3CHO + 2 HCl + 2 Cl–
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!
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.
Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O
Pd(0) + CH3CHO + 2 HCl + 2 Cl–
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!
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.
Origins of the Wacker Oxidation
PdCl42– + C2H4 + H2O
Pd(0) + CH3CHO + 2 HCl + 2 Cl–
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.
! Prior acetaldehyde production:
a) Oxymercuration of acetylene
b) Dehydrogenation of ethanol
! First rendered commercial in 1960.
! At one point was responsible for the
production of over 2 billion pounds per
year of acetaldehyde!
! Wacker process eventually replaced
because of more efficient ways of
producing acetic acid (i.e. Monsanto
process).
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.
Early Kinetic Studies
Conditions:
[PdII]
= 0.005 - 0.04 M
–
[Cl ] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
! First order in PdII
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [C2H4]
[Cl–]2
[H+]
! 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.
Early Kinetic Studies
Chloride Inhibition
Conditions:
! First order in PdII
[PdII]
= 0.005 - 0.04 M
–
[Cl ] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [C2H4]
[Cl–]2
[H+]
! Second order Cl– inhibition
! First order acid inhibition
Source of Chloride Inhibition:
2–
Cl
Cl
Pd
Cl
Cl
–
+ C2H4
Cl
Pd
Cl
Cl
+ Cl–
–
Cl
Pd
Cl
Cl
+ H2O
Cl
Pd
Cl
OH2
+ Cl–
1
[Cl–]
1
[Cl–]
inhibition
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.
Early Kinetic Studies
Proton Inhibition
Conditions:
! First order in PdII
[PdII]
= 0.005 - 0.04 M
–
[Cl ] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
Cl
Pd
Cl
OH2
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [C2H4]
[Cl–]2
[H+]
! Second order Cl– inhibition
! First order acid inhibition
–OH
–
Cl
CH2CH2OH
Pd
Cl
OH2
Outer-sphere hydroxide attack:
Predicted to be 103 times faster
than diffusion controlled process
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.
Early Kinetic Studies
Proton Inhibition
Conditions:
! First order in PdII
[PdII]
= 0.005 - 0.04 M
–
[Cl ] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
Cl
Pd
Cl
OH2
Cl
Pd
Cl
OH2
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [C2H4]
[Cl–]2
[H+]
! First order acid inhibition
–OH
–
Cl
CH2CH2OH
Pd
Cl
OH2
H2O
! Second order Cl– inhibition
–
Cl
CH2CH2OH
Pd
Cl
OH2
+ H+
Outer-sphere hydroxide attack:
Predicted to be 103 times faster
than diffusion controlled process
Outer-sphere water attack:
Predicted to occur by an anti
hydroxypalladation mechanism
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.
Early Kinetic Studies
Proton Inhibition
Conditions:
! First order in PdII
[PdII]
= 0.005 - 0.04 M
–
[Cl ] = 0.1 - 1.0 M
[H+] = 0.04 -1.0 M
Cl
Pd
Cl
OH2
Cl
Pd
Cl
OH2
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [C2H4]
[Cl–]2
! First order acid inhibition
–OH
–
Cl
CH2CH2OH
Pd
Cl
OH2
H2O
! Second order Cl– inhibition
[H+]
–
Cl
CH2CH2OH
Pd
Cl
OH2
+ H+
Outer-sphere hydroxide attack:
Predicted to be 103 times faster
than diffusion controlled process
Outer-sphere water attack:
Predicted to occur by an anti
hydroxypalladation mechanism
–
–
Cl
Pd
Cl
OH2
Cl
Pd
Cl
OH
+ H+
Cl
CH2CH2OH
Pd
Cl
OH2
Inner-sphere hydroxyl
attack: Predicted to
occur by a syn
hydroxypalladation
mechanism
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.
Kinetic Isotope Effects
Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
D
D
O
+ PdCl42– + H2O
D
H
D
D3C
H
H
D
kH
kD
O
+ PdCl42– + H2O
H
+ Pd(0) + 2 HCl + 2 Cl–
= 1.07
+ Pd(0) + 2 HCl + 2 Cl–
H3C
H
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.
Kinetic Isotope Effects
Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
D
D
O
+ PdCl42– + H2O
D
H
D
D3C
H
D
kH
kD
O
+ PdCl42– + H2O
H
+ Pd(0) + 2 HCl + 2 Cl–
H
= 1.07
+ Pd(0) + 2 HCl + 2 Cl–
H3C
H
KIE for decomposition step determined by competitive isotope effect experiment:
O
H-shift
DH2C
D
D
D
+ PdCl42– + H2O
H
H
–
D
HO
D
kH
Pd(OH2)Cl2
H
kD
H
= 1.70
O
D-shift
HD2C
H
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.
Kinetic Isotope Effects
Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
outer-sphere anti hydroxypalladation
Cl
Cl
Pd
H2O
+ H2O
KIE 1.07 and competitive KIE of 1.70
indicates that the slow step occurs
before decomposition.
Cl
Cl
Pd
H2O
CH2CH2OH
–
+ H+
O
+H+
–H+
H3C
Cl
Cl
Pd
HO
–
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
H
–
inner-sphere syn hydroxypalladation
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.
Kinetic Isotope Effects
Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
outer-sphere anti hydroxypalladation
Cl
Cl
Pd
H2O
KIE 1.07 and competitive KIE of 1.70
indicates that the slow step occurs
before decomposition.
Cl
Cl
Pd
H2O
CH2CH2OH
+ H2O
–
+ H+
fast
slow
O
+H+
–H+
H3C
Cl
Cl
Pd
HO
–
slow
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
inner-sphere syn hydroxypalladation
–
H
fast
anti pathway has decomposition as the
slow step
syn pathway has hydroxypalladation as
the slow step
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.
Kinetic Isotope Effects
Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
outer-sphere anti hydroxypalladation
Cl
Cl
Pd
H2O
KIE 1.07 and competitive KIE of 1.70
indicates that the slow step occurs
before decomposition.
Cl
Cl
Pd
H2O
CH2CH2OH
+ H2O
–
+ H+
O
+H+
–H+
H3C
Cl
Cl
Pd
HO
–
slow
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
inner-sphere syn hydroxypalladation
–
H
fast
anti pathway has decomposition as the
slow step
syn pathway has hydroxypalladation as
the slow step
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.
Early Stereochemical Studies
Stille's Work Suggests Anti Hydroxypalladation Mechanism
OH
Cl
Pd
Cl
H2O
Na2CO3
Pd
Cl
Cl
CO
O
O
Key: CO insertion proceeds with retention of stereochemistry
at the migrating stereocenter.
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
Early Stereochemical Studies
Stille's Work Suggests Anti Hydroxypalladation Mechanism
OH
Cl
Pd
Cl
H2O
Pd
Na2CO3
Cl
Cl
O
CO
O
Key: CO insertion proceeds with retention of stereochemistry
at the migrating stereocenter.
HO
OH
Cl
Pd
Cl
CO
O
Cl
Pd
Cl
CO
O
O
anti hydroxypalladation
O
syn hydroxypalladation
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
Early Stereochemical Studies
Stille's Work Suggests Anti Hydroxypalladation Mechanism
HO
Cl
Pd
Cl
H2O
Na2CO3
Pd
Cl
Cl
CO
O
O
anti hydroxypalladation
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
Early Stereochemical Studies
Stille's Work Suggests Anti Hydroxypalladation Mechanism
HO
Cl
Pd
Cl
H2O
Na2CO3
Cl
Pd
Cl
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
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
Early Stereochemical Studies
Stille's Work Suggests Anti Hydroxypalladation Mechanism
HO
Cl
Pd
Cl
H2O
Na2CO3
O
CO
Cl
Pd
Cl
O
anti hydroxypalladation
HO
H2O
D
H
D
D
D
H
CO
HO
H
PdLn
D
O
H
O
PdLn
D
O
H
D
H
D
PdCl2
H
H
O
2
H2O
HO
H
D
PdLn
D
H
CO
O
HO
H
D
PdLn
D
H
O
H
D
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
D
H
Early Stereochemical Studies
Stille's Work Suggests Anti Hydroxypalladation Mechanism
HO
Cl
Pd
Cl
H2O
Na2CO3
O
CO
Cl
Pd
Cl
O
anti hydroxypalladation
HO
H2O
D
H
D
D
D
H
CO
HO
H
PdLn
D
O
H
O
PdLn
D
O
H
D
H
D
PdCl2
H
H
O
2
H2O
HO
H
D
PdLn
D
H
CO
O
HO
H
D
PdLn
D
H
O
H
D
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
D
H
Early Stereochemical Studies
Stille's Work Suggests Anti Hydroxypalladation Mechanism
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.
anti hydroxypalladation
HO
H2O
D
H
D
D
D
H
CO
HO
H
PdLn
D
O
H
O
PdLn
D
O
H
D
H
D
PdCl2
H
H
O
2
H2O
HO
H
D
PdLn
D
H
CO
O
HO
H
D
PdLn
D
H
O
H
D
Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239.
D
H
Bäckvall's Stereochemical Studies
Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
[Cl–] < 1 M
[CuCl2] < 1 M
O
H3C
C2H4 + PdCl42–
H2O
H
loss of
stereochemical
information
Cl
Cl
Pd
H2O
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.
Bäckvall's Stereochemical Studies
Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
[Cl–] < 1 M
[CuCl2] < 1 M
O
H3C
C2H4 + PdCl42–
H2O
H
loss of
stereochemical
information
Cl
Cl
Pd
H2O
[Cl–] > 3 M
[CuCl2] > 2.5 M
Cl
CH3CHO
+
OH
stereochemical
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.
Bäckvall's Stereochemical Studies
Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
[Cl–] < 1 M
[CuCl2] < 1 M
O
H3C
C2H4 + PdCl42–
H2O
H
loss of
stereochemical
information
Cl
Cl
Pd
H2O
[Cl–] > 3 M
[CuCl2] > 2.5 M
Cl
CH3CHO
+
OH
stereochemical
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.
Bäckvall's Stereochemical Studies
Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Cl
Cl
Pd
H2O
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
–
+
H+
2 CuCl2
Cl
OH
+ 2 CuCl
decomposition
CH3CHO
! Chloride displacement of Pd
occurs with inversion of
stereochemistry at carbon.
! Chlorohydrin formation requires
both 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.
Bäckvall's Stereochemical Studies
Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Cl
Cl
Pd
H2O
D
D
+ H2O
D H
Cl
Cl
Pd
H2O
OH
H D
–
+ H+
2 CuCl2
H
D
Cl
D
H
OH
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.
Bäckvall's Stereochemical Studies
Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Cl
Cl
Pd
H2O
D
+ H2O
D
D H
Cl
Cl
Pd
H2O
OH
H D
–
+ H+
2 CuCl2
H
D
D
H
Cl
OH
anti hydroxypalladation
Cl
Cl
Pd
H2O
D
D
+ H2O
H D
Cl
Cl
Pd
H2O
OH
H D
–
+ H+
2 CuCl2
H
D
Cl
H
D
OH
syn 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.
Bäckvall's Stereochemical Studies
Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
Cl
Cl
Pd
H2O
D
+ H2O
D
D H
Cl
Cl
Pd
H2O
OH
H D
–
+ H+
2 CuCl2
H
D
D
H
Cl
OH
anti hydroxypalladation
Cl
Cl
Pd
H2O
D
D
+ H2O
H D
Cl
Cl
Pd
H2O
OH
H D
–
+ H+
2 CuCl2
H
D
Cl
H
D
OH
syn hydroxypalladation
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.
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.
Bäckvall's Stereochemical Studies
An Apparent Contradiction with KIE Studies
outer-sphere anti hydroxypalladation
Cl
Cl
Pd
H2O
KIE 1.07 and competitive KIE of 1.70
indicates that the slow step occurs
before decomposition.
Cl
Cl
Pd
H2O
CH2CH2OH
+ H2O
–
+ H+
fast
slow
O
+H+
–H+
H3C
Cl
Cl
Pd
HO
–
slow
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
innter-sphere syn hydroxypalladation
–
H
fast
anti pathway has decomposition as the
slow step
syn pathway has hydroxypalladation as
the slow step
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.
Bäckvall's Stereochemical Studies
Reconciling Stereochemical Results with Kinetic Data
Cl
Cl
Pd
H2O
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
–
+ H+
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.
Bäckvall's Stereochemical Studies
Reconciling Stereochemical Results with Kinetic Data
Cl
Cl
Pd
H2O
Cl
Cl
Pd
H2O
CH2CH2OH
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
–
–
+ H+
Cl
Pd
H2O
CH2CH2OH
+ Cl–
slow
–
H
Cl
Cl
Pd
H2O
OH
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.
Bäckvall's Stereochemical Studies
Reconciling Stereochemical Results with Kinetic Data
Cl
Cl
Pd
H2O
Cl
Cl
Pd
H2O
CH2CH2OH
+ H2O
Cl
Cl
Pd
H2O
CH2CH2OH
–
–
+ H+
Cl
Pd
H2O
CH2CH2OH
+ Cl–
slow
–
H
Cl
Cl
Pd
H2O
OH
Since decomposition occurs after the rate-limiting step
a primary isotope effect would not be predicted.
–
Cl
Pd
H2O
CH2CH2OH
fast
Cl
H
Pd
H2O
OH
O
Cl
Pd H OH
H2O
C
CH3
H3C
H
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.
Evidence for Syn Hydroxypalladation
The Isomerization of Allyl Alcohol Under Wacker Conditions
OH + PdCl 2– + H O
4
2
H2O + PdCl42– + HO
k1
k–1
PdII
k–1
HO
k1
OH
k2
oxidation products
Oxidation of allyl alcohol is directed by the hydroxyl group
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
Evidence for Syn Hydroxypalladation
The Isomerization of Allyl Alcohol Under Wacker Conditions
OH + PdCl 2– + H O
4
2
H2O + PdCl42– + HO
k1
k–1
PdII
k–1
HO
k1
OH
k2
If hydroxypalladation is anti,
isomerization should occur since
hydroxypalladation is required to
be an equilibrium process.
oxidation products
If hydroxypalladation is syn,
isomerization should not occur
since hydroxypalladation is rate
limiting.
Oxidation of allyl alcohol is directed by the hydroxyl group
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [olefin]
[Cl–]2 [H+]
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
Evidence for Syn Hydroxypalladation
The Isomerization of Allyl Alcohol Under Wacker Conditions
H
H
H
OH + PdCl 2– + H O
4
2
H
H2O + PdCl42– + HO
k1
D D
k–1
PdII
k–1
HO
H H
D
D
k1
OH
H H D D
k2
If hydroxypalladation is anti,
isomerization should occur since
hydroxypalladation is required to
be an equilibrium process.
oxidation products
If hydroxypalladation is syn,
isomerization should not occur
since hydroxypalladation is rate
limiting.
Oxidation of allyl alcohol is directed by the hydroxyl group
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [olefin]
[Cl–]2 [H+]
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
Evidence for Syn Hydroxypalladation
The Isomerization of Allyl Alcohol Under Wacker Conditions
H
H
H
OH + PdCl 2– + H O
4
2
H
H2O + PdCl42– + HO
k1
D D
k–1
PdII
k–1
HO
H H
D
D
k1
OH
H H D D
k2
If hydroxypalladation is anti,
isomerization should occur since
hydroxypalladation is required to
be an equilibrium process.
oxidation products
If hydroxypalladation is syn,
isomerization should not occur
since hydroxypalladation is rate
limiting.
Isomerization product was < 3% of the total deuterated
allyl alcohol when the reaction was stopped after
one half-life.
Hydroxypalladation is NOT an equilibrium process!
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
Evidence for Syn Hydroxypalladation
The Isomerization of Allyl Alcohol Under Isomerization Conditions
H
H
H
OH + PdCl 2– + H O
4
2
H
H2O + PdCl42– + HO
[Cl–] = 3.3 M
k1
D D
k–1
PdII
k–1
H H
D
D
k1
HO
OH
H H D D
k2
If hydroxypalladation is anti,
isomerization should occur since
hydroxypalladation is required to
be an equilibrium process.
oxidation products
Rate =
–d[C2H4]
dt
=
If hydroxypalladation is syn,
isomerization should not occur
since hydroxypalladation is rate
limiting.
k [PdCl42–] [olefin]
[Cl–]
Only isomerization observed.
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
Evidence for Syn Hydroxypalladation
The Isomerization of Allyl Alcohol Under Isomerization Conditions
H
H
H
OH + PdCl 2– + H O
4
2
H
H2O + PdCl42– + HO
[Cl–] = 3.3 M
k1
D D
k–1
PdII
k–1
HO
H H
D
D
k1
OH
H Dproceed
D
Reactions at high and low chlorideHdo not
through the same mechanism.
k2does not occur through a common
Formation of aldehyde and chlorohydrin
hydroxypalladation intermediate.
If hydroxypalladation is anti,
If hydroxypalladation is syn,
isomerization should occur since
isomerization should not occur
hydroxypalladation is required to
since hydroxypalladation is rate
be an equilibrium process.
oxidation products
limiting.
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [olefin]
[Cl–]
Only isomerization observed.
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
Anti Hydroxypalladation at High [Cl–]
Henry's Proposed Pathway
2–
Cl
Cl
Pd
Cl
Cl
OH
+
D D
Cl
Cl
Pd
Cl
D
Cl
Cl
Pd
Cl
D
+ Cl–
D
2–
–
OH
–
OH
+ H2O
D
Cl
Cl CD2OH
Pd
Cl
CH
+ H+
CH2OH
outer-sphere anti hydroxypalladation
OH
2–
Cl
Cl CD2OH
Pd
Cl
CH
CH2OH
+ H+
Cl
Cl
Pd
Cl
H
D
H
D
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
–
+ H2O
Anti Hydroxypalladation at High [Cl–]
Henry's Proposed Pathway
2–
Cl
Cl
Pd
Cl
Cl
OH
+
D D
Cl
Cl
Pd
Cl
D
Cl
Cl
Pd
Cl
D
+ Cl–
D
2–
–
OH
–
OH
+ H2O
D
Cl
Cl CD2OH
Pd
Cl
CH
+ H+
CH2OH
outer-sphere anti hydroxypalladation
OH
2–
Cl
Cl CD2OH
Pd
Cl
CH
CH2OH
+ H+
Cl
Cl
Pd
Cl
H
D
H
D
Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681.
–
+ H2O
Reinterpreting Bäckvall's Results
Henry's Proposed Pathway
–
PdCl4
2–
Cl
Cl
Pd
Cl
+ C2H4
Cl– ligand loss prevented by high
concentration of Cl–.
+ Cl–
–
Cl
Cl
Pd
Cl
+
H2O
Cl–
2–
Cl
Cl
Pd
Cl
CH2CH2OH
Excess Cl– prevents this intermediate
from undergoing decomposition to
oxidation products.
outer-sphere anti
hydroxypalladation
2–
Cl
Cl
Pd
Cl
CH2CH2OH
CuCl2
Cl
OH
Assumption that oxidation products
and chlorohydrin arise from a common
intermediate is NOT valid.
Gregor, N.; Zaw, K.; Henry, P. M. Organometallics 1984, 3, 1251.
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
H
F3C
H
OH
+ PdCl42– + H2O
H2O + PdCl42– +
F3C
HO
H3C
H3C F3C CD3
CF3
CD3
Required Properties:
! Substrate cannot undergo oxidation; can only isomerize.
oxidation products
! Substrate whose RLS is hydroxypalladation.
! Substrate possesses stereochemistry that can be used to
distinguish between syn and anti hydroxypalladation.
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
oxidation products
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
H
F3C
H
OH
+ PdCl42– + H2O
H2O + PdCl42– +
F3C
HO
H3C
H3C F3C CD3
k1
CF3
CD3
k–1
k–1
k1
H PdII
oxidation products
F3C
H3C
CF3
OH
CD3
OH
Exchange is completely symmetric,
thus the rate of isomerization depends only
on the rate of formation of the hydroxypalladate
and not on its equilibrium concentration.
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
oxidation products
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
H
F3C
H
OH
+ PdCl42– + H2O
H2O + PdCl42– +
F3C
CF3
HO
H3C
H3C F3C CD3
k1
CD3
k–1
k–1
k1
H PdII
oxidation products
F3C
H3C
For syn hydroxypalladation:
Rate =
–d[C2H4]
dt
=
oxidation products
CF3
OH
CD3
OH
For anti hydroxypalladation:
k [PdCl42–] [olefin]
[Cl–]2 [H+]
Proton inhibition term must result from an
equilibrium that occurs before the rate-limiting
hydroxypalladation step.
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [olefin]
[Cl–]
Proton inhibition term does not show up in the
exchange rate because it results from this
exchange equilibrium.
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
H
F3C
H
OH
+ PdCl42– + H2O
H2O + PdCl42– +
F3C
HO
H3C
H3C F3C CD3
k1
CF3
CD3
k–1
k–1
k1
H PdII
oxidation products
F3C
H3C
For syn hydroxypalladation:
Rate =
–d[C2H4]
dt
=
CF3
OH
oxidation products
CD3
OH
Observed Kinetics under Wacker Conditions:
k [PdCl42–] [olefin]
[Cl–]2 [H+]
Proton inhibition term must result from an
equilibrium that occurs before the rate-limiting
hydroxypalladation step.
! Rate expression had a first order proton
inhibition term.
! Rate expression was identical to the Wacker
rate expression.
! Consistent with syn hydroxypalladation
mechanism.
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
H
F3C
H
OH
+ PdCl42– + H2O
H2O + PdCl42– +
F3C
CF3
HO
H3C
H3C F3C CD3
k1
CD3
k–1
k–1
k1
H PdII
oxidation products
F3C
H3C
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.
oxidation products
CF3
OH
CD3
OH
For anti hydroxypalladation:
Rate =
–d[C2H4]
dt
=
k [PdCl42–] [olefin]
[Cl–]
Proton inhibition term does not show up in the
exchange rate because it results from this
exchange equilibrium.
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
– H+
F3C
HO
PdII
CD3
CF3
OH
CF3
H CH3
+ H+
– PdII
– H2O
D3C
OH
H
CF3
CH3
(R), Z
CD3
F3C
HO
H
CH3
PdCl42–
CF3
H2O
(R), E
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
– H+
F3C
HO
PdII
CD3
CF3
OH
CF3
H CH3
+ H+
D3C
– PdII
– H2O
OH
H
CF3
CH3
(R), Z
CD3
F3C
HO
H
CH3
PdCl42–
CF3
H2O
(R), E
–
H+
syn
F3C
HO
PdII
CD3
H
CH3
CF3
OH
CD3
+ H+
– PdII
– H2O
F3C
H
(S), E
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
CH3
CF3
OH
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
F3C
HO
PdII
– H+
CD3
CF3
+ H+
OH
CF3
H CH3
D3C
OH
– PdII
– H2O
CF3
CH3
H
(R), Z
product
CD3
F3C
CH3
HO
H
CF3
substrate
PdCl42–
config
% ee
[Cl–]
[catalyst]
%
isomerization
R
100
0.10
PdCl42–
30
32.5
67.5
R
100
0.05
PdCl42–
48
50.0
50.0
S
100
0.10
PdCl42–
25
72.5
27.5
S
100
0.05
PdCl42–
50
50.0
50.0
H2O
(R), E
–
H+
syn
F3C
HO
PdII
CD3
H
CH3
CF3
OH
%S
%R
CD3
+
H+
– PdII
– H2O
F3C
H
(S), E
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
CH3
CF3
OH
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
F3C
HO
PdII
– H+
CD3
CF3
+ H+
OH
CF3
H CH3
D3C
OH
– PdII
– H2O
CF3
CH3
H
(R), Z
product
CD3
F3C
CH3
HO
H
CF3
substrate
PdCl42–
config
% ee
[Cl–]
[catalyst]
%
isomerization
R
100
0.10
PdCl42–
30
32.5
67.5
R
100
0.05
PdCl42–
48
50.0
50.0
S
100
0.10
PdCl42–
25
72.5
27.5
S
100
0.05
PdCl42–
50
50.0
50.0
H2O
(R), E
–
H+
syn
F3C
HO
PdII
CD3
H
CH3
CF3
OH
%S
%R
CD3
+ H+
– PdII
– H2O
F3C
H
(S), E
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
CH3
CF3
OH
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
F3C
HO
PdII
– H+
CD3
CF3
+ H+
OH
CF3
H CH3
D3C
OH
– PdII
– H2O
H
CF3
CH3
(R), Z
CD3
F3C
HO
H
product
substrate
CH3
PdCl42–
CF3
H2O
config
% ee
[Cl–]
R
100
2.0
31
R
100
3.5
S
100
S
100
(R), E
–
H+
syn
F3C
HO
PdII
% isomerization % Z
%S
%R
30
0.0
100
27
25
0.0
100
2.0
35
32
100
0.0
3.5
45
45
100
0.0
CD3
H
CH3
CF3
OH
CD3
+
H+
– PdII
– H2O
F3C
H
(S), E
Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832.
CH3
CF3
OH
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
F3C
HO
PdII
– H+
CD3
CF3
+ H+
OH
CF3
H CH3
D3C
OH
– PdII
– H2O
H
CF3
CH3
(R), Z
CD3
F3C
HO
H
product
substrate
CH3
PdCl42–
CF3
H2O
config
% ee
[Cl–]
R
100
2.0
31
R
100
3.5
S
100
S
100
(R), E
–
H+
syn
F3C
HO
PdII
% isomerization % Z
%S
%R
30
0.0
100
27
25
0.0
100
2.0
35
32
100
0.0
3.5
45
45
100
0.0
CD3
H
CH3
CF3
OH
CD3
+
H+
– PdII
– H2O
F3C
H
(S), E
Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832.
CH3
CF3
OH
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
– H+
high
[Cl–]
F3C
HO
PdII
CD3
CF3
OH
CF3
H CH3
+ H+
D3C
– PdII
– H2O
OH
CF3
CH3
H
(R), Z
CD3
F3C
HO
H
Conclusions:
CH3
PdCl42–
CF3
H2O
! At low [Cl–] (Wacker conditions), syn hydroxypalladation is
operative.
! At high [Cl–] (Bäckvall's conditions), anti hydroxypalladation is
operative.
(R), E
low [Cl–]
–
H+
syn
F3C
HO
PdII
CD3
H
CH3
CF3
OH
CD3
+
H+
– PdII
– H2O
F3C
H
(S), E
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
CH3
CF3
OH
Evidence for Syn Hydroxypalladation
A New Stereochemical and Kinetic Probe
anti
– H+
high
[Cl–]
F3C
HO
PdII
CD3
CF3
OH
CF3
H CH3
+ H+
D3C
– PdII
– H2O
OH
CF3
CH3
H
(R), Z
Criticism:
CD3
F3C
! Trisubstituted alkenes are not standard Wacker substrates.
CH3
HO
H
CF3
PdCl42–
! Substrate cannot undergo oxidation.
H2O
! Would be best to study a substrate that can undergo both
oxidation and isomerization under both low and high [Cl–]
concentrations.
(R), E
low [Cl–]
–
H+
syn
F3C
HO
PdII
CD3
H
CH3
CF3
OH
CD3
+ H+
– PdII
– H2O
F3C
H
(S), E
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.
CH3
CF3
OH
Chirality Transfer Studies
H
HO
R1
R2
H
H
(R), Z
reactive
conformation
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
Chirality Transfer Studies
[Cl–] > 2 M
anti
– H+
HO
R2
PdII
HO
R2
H
R1
PdCl42–
H
H2O
H
– PdII
– H2O
H
H H
OH
H
H
(S), Z
OH
R1
R1
R2
[Cl–] = 0.1 M
H
R2
O
OH
– Pd0
– H+
(R), Z
reactive
conformation
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
(S)
R1
Chirality Transfer Studies
[Cl–] > 2 M
anti
– H+
HO
R2
PdII
H
H
R1
PdCl42–
H
H2O
R1
H
(S), Z
R1
H H
OH
H
OH
R2
O
OH
– Pd0
– H+
H
R2
H
– PdII
– H2O
[Cl–] = 0.1 M
HO
R2
R1
H
(S)
[Cl–]
(R), Z
reactive
conformation
H
>2M
R1
R2
PdII
–
H+
syn
HO
R2
PdII
H
–
– H2O
H
H
OH
(R), E
R1
H
H
R2
OH
[Cl–] = 0.1 M
R1
O
Pd0
–
– H+
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
OH
(R)
Chirality Transfer Studies
[Cl–] > 2 M
anti
– H+
HO
R2
PdII
H
H
R1
PdCl42–
H
H2O
R1
H
(S), Z
R1
H H
OH
H
OH
R2
O
OH
– Pd0
– H+
H
R2
H
– PdII
– H2O
[Cl–] = 0.1 M
HO
R2
R1
H
(S)
[Cl–]
(R), Z
reactive
conformation
H
>2M
R1
R2
PdII
–
H+
syn
HO
R2
PdII
H
–
– H2O
H
H
OH
(R), E
R1
H
H
R2
OH
[Cl–] = 0.1 M
R1
O
Pd0
–
– H+
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
OH
(R)
Chirality Transfer Studies
Me
[Cl–] > 2 M
anti
HO
– H+
Me
PdII
– PdII
– H2O
H
Me
Me
H
= 0.1 M
O
Ph
– Pd0
– H+
H
Me
PhPdCl
H
MeOH
Me
H
(S), Z
Me
H H
Ph
H
Ph
[Cl–]
HO
H
Me
H
(S)
H
[Cl–]
(R), Z
reactive
conformation
>2M
Me
Me
PdII
–
H+
syn
HO
Me
PdII
H
H
H
–
– H2O
H
H
Ph
(R), E
Me
Ph
Me
[Cl–]
= 0.1 M
Me
O
Pd0
–
– H+
Ph
(R)
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
Chirality Transfer Studies
Me
[Cl–] > 2 M
anti
HO
– H+
Me
PdII
– PdII
– H2O
H
Me
Me
H
= 0.1 M
O
Ph
– Pd0
– H+
H
Me
PhPdCl
H
MeOH
Me
H
PhPdCl must add
syn regardless of
the [Cl–]
(S)
H
[Cl–]
(R), Z
reactive
conformation
Me
H
(S), Z
Me
H H
Ph
H
Ph
[Cl–]
HO
H
>2M
Me
Me
PdII
–
H+
syn
HO
Me
PdII
H
H
H
–
– H2O
H
H
Ph
(R), E
Me
Ph
Me
[Cl–]
= 0.1 M
Me
O
Pd0
–
– H+
Ph
(R)
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
Chirality Transfer Studies
Me
[Cl–] > 2 M
anti
HO
– H+
Me
PdII
– PdII
– H2O
H
Me
Me
H
Et
PdCl42–
H
H2O
= 0.1 M
O
OH
– Pd0
– H+
H
Et
H
(S), Z
Et
H H
OH
H
OH
[Cl–]
HO
H
Et
H
(S)
H
[Cl–]
(R), Z
reactive
conformation
>2M
Et
Me
PdII
–
H+
syn
HO
Me
PdII
H
–
– H2O
H
H
OH
(R), E
Et
H
H
OH
Me
[Cl–]
= 0.1 M
Et
O
Pd0
–
– H+
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
OH
(R)
Chirality Transfer Studies
Me
[Cl–] > 2 M
anti
HO
– H+
Me
PdII
– PdII
– H2O
H
Me
Me
H
Et
PdCl42–
H
H2O
= 0.1 M
O
OH
– Pd0
– H+
H
Et
H
(S), Z
Et
H H
OH
H
OH
[Cl–]
HO
H
Et
H
the stereochemistry of hydroxypalladation (S)
must be different at high and low [Cl–]
H
[Cl–]
(R), Z
reactive
conformation
>2M
Et
Me
PdII
–
H+
syn
HO
Me
PdII
H
–
– H2O
H
H
OH
(R), E
Et
H
H
OH
Me
[Cl–]
= 0.1 M
Et
O
Pd0
–
– H+
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
OH
(R)
Chirality Transfer Studies
Me
[Cl–] > 2 M
– PdII
– H2O
H
anti
HO
– H+
Me
PdII
Me
Et
Me
H
H
= 0.1 M
O
OH
– Pd0
! Excess Cl– prevents syn hydroxypalladation
by
– H+
prohibiting the ligation of water.
H
PdCl42–
Et
H
(S), Z
Et
H H
OH
H
OH
[Cl–]
HO
H
Et
H
(S)
Cl–
! Excess
prevents "-hydride elimination to oxidation
products by prohibiting the necessary dissociation
H
of a Cl– ligand.
–
[Cl ] > 2 M
Et
Me
H2O
(R), Z
reactive
conformation
PdII
–
H+
syn
HO
Me
PdII
H
–
– H2O
H
H
OH
(R), E
Et
H
H
OH
Me
[Cl–]
= 0.1 M
Et
O
Pd0
–
– H+
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.
H
OH
(R)
Mechanism for Oxidation of Olefins under Wacker
Conditions
1
[Cl–]
Cl
Cl
Pd
Cl
Cl
O
–
H3C
Cl
H
Pd
H2C CH2
– Cl–
2–
1
inhibition
[Cl–]
Cl
Cl
Pd
Cl
+ H2O
– Cl–
–
1
+ CuCl2
+ O2
[H+]
–
Cl
OH
inhibition
– H2O
Cl
Cl
Pd
H2O
–
OH
Cl
Cl
Pd
H2O
inhibition
+ H2O
– H+
Cl
Cl
Pd
HO
–
syn hydroxypalladation
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.
Mechanism for Oxidation of Olefins under Wacker
Conditions
1
[Cl–]
Cl
Cl
Pd
Cl
Cl
H2C CH2
– Cl–
2–
1
inhibition
[Cl–]
Cl
Cl
Pd
Cl
+ H2O
– Cl–
–
O
–
H3C
Cl
H
Pd
1
+ CuCl2
+ O2
[H+]
–
Cl
OH
inhibition
– H2O
Cl
Cl
Pd
H2O
–
OH
Cl
Cl
Pd
H2O
inhibition
+ H2O
– H+
Cl
Cl
Pd
HO
–
syn hydroxypalladation
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.
Mechanism for Decomposition to Oxidation Products
Moiseev's Mechanism:
Cl
Pd
–
Cl
Cl
Cl
Pd
H
OH
!-hydride
elimination
O
–
OH
OH
H
dissociation
tautomerize
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.
Mechanism for Decomposition to Oxidation Products
Moiseev's Mechanism:
Cl
Pd
–
Cl
Cl
Cl
Pd
H
OH
OH
OH
!-hydride
elimination
D
H
H
H
+ Pd(0) + 2 HCl + 2 Cl–
D3C
D
O
+ PdCl42– + D2O
H
tautomerize
O
+ PdCl42– + H2O
D
H
dissociation
D
D
O
–
+ Pd(0) + 2 DCl + 2 Cl–
H3C
H
lack of proton incorporation from solvent means that tautomerization mechanism is invalid
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.
Mechanism for Decomposition to Oxidation Products
Henry's Model
H H
Cl
Cl
Pd
OH
H H
–
H
H H
Cl Pd
O
H
Cl
H
O
+ Pd(0) + HCl
H
PdII-assisted
hydride shift
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.
Mechanism for Decomposition to Oxidation Products
Henry's Model
H H
Cl
Cl
Pd
OH
H H
–
H
H H
Cl Pd
O
O
H
H
+ Pd(0) + HCl
H
Cl
PdII-assisted
hydride shift
Bäckvall's Model
Cl
Pd
–
Cl
Cl
Cl
Pd
H
OH
Cl
–
OH
!-hydride
elimination
reinsertion
O
+ Pd(0) + HCl
Pd
Cl
–
OH
!-hydride elimination
from oxygen
H
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.
Mechanism for Decomposition to Oxidation Products
Computational Studies
Bäckvall's Model
Cl
Pd
Cl
–
O H
PdIICl
OH
H3C
O
+ Pd(0) + HCl
H
!-hydride elimination
from oxygen
Goddard's Computations
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.
Mechanism for Decomposition to Oxidation Products
Computational Studies
Bäckvall's Model
Cl
Pd
Cl
–
O H
PdIICl
OH
H3C
O
+ Pd(0) + HCl
H
!-hydride elimination
from oxygen
Goddard's Computations
4-membered TS: 36.3 kcal/mol
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.
Mechanism for Decomposition to Oxidation Products
Computational Studies
Bäckvall's Model
Cl
Pd
Cl
–
O H
PdIICl
OH
H3C
O
+ Pd(0) + HCl
H
β-hydride elimination
from oxygen
Goddard's Computations
4-membered TS: 36.3 kcal/mol
Cl-mediated reductive elimination TS:
18.7 kcal/mol
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.
From Industrial Process to Synthetic Method
Preparations of Methyl Ketones from Terminal Olefins
Clement, 1964:
PdCl2 (10 mol%)
oxidant
H2O (12-17%), O2
DMF
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.
O
From Industrial Process to Synthetic Method
Preparations of Methyl Ketones from Terminal Olefins
Clement, 1964:
O
PdCl2 (10 mol%)
oxidant
H2O (12-17%), O2
DMF
oxidant = CuCl2•2H2O (10 mol%) or p-benzoquinone
OH
MeO
O
H
O
MeO
H
O
Zearalenone
O
H
H
intermediate to
Dichroanone
O
19-Nortestosterone
H
O
O
O
O
H
O
Nootkatone
Brevicomin
OTHP
intermediate to
Coriolin
Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241. Tsuji, J. Synthesis 1984, 369.
From Industrial Process to Synthetic Method
Oxidative Cyclizations Give Access to Heterocyclic Compounds
Moritani, 1973:
PdCl2(PhCN)2
(1 equiv)
R
R
O–Na+
PhH
O
Hosokawa, T.; Maeda, K.; Koga, K.; Moritani, I. Tetrahedron Lett. 1973, 10, 739.
From Industrial Process to Synthetic Method
Oxidative Cyclizations Give Access to Heterocyclic Compounds
Moritani, 1973:
PdCl2(PhCN)2
(1 equiv)
R
R
O–Na+
PhH
Pd(dba)2 (5 mol%)
KHCO3 (1.1 equiv)
O
air, DMSO, H2O
60 °C
O
Pd(OAc)2 (2 mol%)
Cu(OAc)2•H2O (1 equiv)
OH
air, DMF, 100 °C
O
no co-oxidant!
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.
From Industrial Process to Synthetic Method
Oxidative Cyclizations Give Access to Heterocyclic Compounds
Moritani, 1973:
PdCl2(PhCN)2
(1 equiv)
R
R
O–Na+
PhH
O
Pd(dba)2 (5 mol%)
KHCO3 (1.1 equiv)
O
air, DMSO, H2O
60 °C
Pd(OAc)2 (2 mol%)
Cu(OAc)2•H2O (1 equiv)
air, DMF, 100 °C
OH
O
no co-oxidant!
O
Pd(TFA)2 (10 mol%)
ligand (20 mol%)
i-Pr
OH
p-benzoquinone
(4 equiv)
MeOH, 60 °C
O
96% ee
Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071.
N
O
N
i-Pr
From Industrial Process to Synthetic Method
Oxidative Cyclizations Give Access to Heterocyclic Compounds
H
Boc
N
MeO2C
O
H
O
BnO
H
O
O
H
BnO
OBn
O
O
O
O
O
O
N
H
NTs
N
H
N
Ts
N
O
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.
Stereochemistry of Oxidative Cyclizations
PdLn
H
R
OH
O
anti
oxypalladation
R
O
PdLn
!-hydride
elimination
R
H
R
O PdLn
O
syn
oxypalladation
R
O
PdLn
!-hydride
elimination
R
Stereochemistry of Oxidative Cyclizations
Stoltz Group Studies
Pd(TFA)2 (5 mol%)
pyridine (20 mol%)
Na2CO3 (2 equiv)
OH
MS3Å, O2 (1 atm)
PhCH3, 80 °C
O
95% yield
Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892.
Stereochemistry of Oxidative Cyclizations
Stoltz Group Studies
Pd(TFA)2 (5 mol%)
pyridine (20 mol%)
Na2CO3 (2 equiv)
MS3Å, O2 (1 atm)
PhCH3, 80 °C
OH
O
95% yield
O
CO2Et
O
O
NTs
90% yield
O
88% yield
O
87% yield
O
NOBn
63% yield
O
93% yield
82% yield
O
O
62% yield
Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892.
Stereochemistry of Oxidative Cyclizations
Stoltz Group Studies
E [PdII]
E [PdII]
E
H
OH
D
O
E
D
OE
D
anti
oxypalladation
HO
D
E
H
CO2Et
CO2Et
E
H
E
O [PdII] D
E H
E
H
E
O [Pd] D
syn
oxypalladation
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
H
OE
Stereochemistry of Oxidative Cyclizations
Stoltz Group Studies
E [PdII]
E [PdII]
E
H
OH
E
H
D
O
E
D
OE
D
anti
oxypalladation
HO
O
O
D
+
D
CO2Et
H
CO2Et
E
H
E
O [PdII] D
CO2Et
H
CO2Et
E H
CO2Et
CO2Et
E
H
E
O [Pd] D
syn
oxypalladation
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
H
OE
Stereochemistry of Oxidative Cyclizations
Stoltz Group Studies
E [PdII]
E [PdII]
E
H
O
HO
D
OH
E
H
D
O
O
E
D
D
O
OE
anti
oxypalladation
O
CO2Et
CO2Et
E H
E
H
O
E
O [PdII] D
E
H
O
E
O [Pd] D
syn
oxypalladation
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
H
O
OE
Stereochemistry of Oxidative Cyclizations
Stoltz Group Studies
E [PdII]
E [PdII]
E
H
O
HO
D
OH
E
H
D
O
O
E
D
D
O
anti
oxypalladation
O
OE
O
O
CO2Et
CO2Et
D
CO2Et
E H
E
H
O
E
O [PdII] D
CO2Et
E
H
O
E
O [Pd] D
syn
oxypalladation
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
H
O
OE
Stereochemistry of Oxidative Cyclizations
Hayashi Group Studies
H
H
D
Pd(MeCN)4(BF4)2 (5 mol%)
(S,S)-ip-boxax (Pd/L* = 1/2)
OH
benzoquinone (4 equiv)
MeOH, 40 °C, 4 h
O
A
D
O
B
A:B:C:D = 16:46:29:9
syn
oxypalladation
O
D
C
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
O
D
D
Stereochemistry of Oxidative Cyclizations
Hayashi Group Studies
H
H
D
Pd(MeCN)4(BF4)2 (5 mol%)
(S,S)-ip-boxax (Pd/L* = 1/2)
benzoquinone (4 equiv)
MeOH, 40 °C, 4 h
OH
O
A
D
O
B
A:B:C:D = 16:46:29:9
syn
oxypalladation
D
O
D
O
C
D
H
D
PdCl2(MeCN)2 (10 mol%)
Na2CO3 (2 equiv)
LiCl (2 equiv)
benzoquinone (1 equiv)
THF, 65 °C, 24 h
OH
O
A
H
D
O
B
D
A:B:C:D = 6:5:7:82
anti
oxypalladation
O
D
C
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
O
D
Stereochemistry of Oxidative Cyclizations
Stahl Group Studies
Ts
N
H
anti
aminopalladation
LnPd
Ts
N
D
DPd
Ts
N
H
D
Ts
N
H
NHTs
Ts
N
D
LnPd
D
D
Ts
N
HPd
Ts
N
D
syn
aminopalladation
Ts
N
D
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
Stereochemistry of Oxidative Cyclizations
Stahl Group Studies
Ts
N
H
anti
aminopalladation
LnPd
Ts
N
D
DPd
Ts
N
H
D
Ts
N
H
No additive:
NHTs
2:1 ratio syn:anti
aminopalladation products
D
LnPd
D
Ts
N
D
Ts
N
HPd
Ts
N
D
syn
aminopalladation
Ts
N
D
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
Stereochemistry of Oxidative Cyclizations
Stahl Group Studies
Ts
N
H
anti
aminopalladation
LnPd
Ts
N
D
DPd
Ts
N
H
D
Ts
N
H
CF3CO2H Additive:
NHTs
1:2 ratio syn:anti
aminopalladation products
D
LnPd
D
Ts
N
D
Ts
N
HPd
Ts
N
D
syn
aminopalladation
Ts
N
D
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
Stereochemistry of Oxidative Cyclizations
Stahl Group Studies
Ts
N
H
anti
aminopalladation
LnPd
Ts
N
D
DPd
Ts
N
H
D
Ts
N
H
NaOAc or Na2CO3 Additive:
NHTs
exclusively syn
aminopalladation products
D
LnPd
D
Ts
N
D
Ts
N
HPd
Ts
N
D
syn
aminopalladation
Ts
N
D
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
Conclusions
Pd Source
and
Ligands
Additive Effects
(co-oxidant, acid, base,
salts)
Solvent
Effects
(H2O, ROH, DMSO, etc.)
syn vs. anti
heteropalladation
or carbopalladation
Olefin
Sterics and Electronics
Nucleophile
Sterics and Electronics
The Wacker Oxidation
One-Stage Process
purge
Reactor
C2H4, O2
PdCl2, CuCl2, HCl
C2H4, CH3CHO
Separation
Equipment
C2H4
! 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.
CH3CHO
Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120.
The Wacker Oxidation
Two-Stage Process
! Required brick and rubber-lined reactors and titanium pipes.
! Uses ambient air as O2 source and impure mixtures of
ethylene.
CH3CHO
! Operates at 90-100 °C, 10 atm.
C2H4
PdCl2, (CuCl)2, HCl
Oxidation
Reactor
+ CH3CHO
PdCl2, CuCl2,
HCl
Separation
Equipment
! Yields >95% acetaldehyde.
PdCl2, (CuCl)2, HCl
N2
Regeneration
Reactor
air
Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120.
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