2008 Tadross2

2 CuICl 2 Cl +2 CuIICl2 PdIICl42 O Pd0 H3C + HCl H
C2H4
Cl
Mechanistic Studies on the Wacker Oxidation

H PdIICl H
PdIICl3 H2O
O H3C
H+, Cl
Pamela Tadross
Stoltz Group Literature Presentation December 8, 2008 8 PM, 147 Noyes HO PdIICl H3C PdIICl OH Cl
OH
PdIICl2
Cl Cl Pd H2O
+ H2O
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.

F. C. Phillips, 1894:
PdCl42 + C2H4 + H2O

Smidt, Wacker Chemie, 1959:
Pd(0) + CH3CHO + 2 HCl + 2 Cl
Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + 1/2 O2 + 2 HCl
2 CuCl + PdCl42 2 CuCl2 + H2O
PdCl42 + C2H4 + H2O Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + 1/2 O2 + 2 HCl
Pd(0) + CH3CHO + 2 HCl + 2 Cl 2 CuCl + PdCl42 2 CuCl2 + H2O
PdCl42 + C2H4 + H2O Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + 1/2 O2 + 2 HCl C2H4 + 1/2 O2
Pd(0) + CH3CHO + 2 HCl + 2 Cl 2 CuCl + PdCl42 2 CuCl2 + H2O 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!
! 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).
Early Kinetic Studies

Conditions: [PdII] = 0.005 - 0.04 M ] = 0.1 - 1.0 M [Cl [H+] = 0.04 -1.0 M Rate = d[C2H4] dt = k [PdCl42] [C2H4] [Cl]2 [H+] ! 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.

Chloride Inhibition
Source of Chloride Inhibition: 2 1 [Cl]
Cl Cl Pd Cl Cl
+ C2H4
Cl Pd Cl Cl
+ Cl
inhibition
Cl Pd Cl Cl
+ H2O
Cl Pd Cl OH2
+ Cl
1 [Cl]
inhibition

Proton Inhibition
Cl Pd Cl OH2
OH
Cl CH2CH2OH Pd Cl OH2
Outer-sphere hydroxide attack: Predicted to be 103 times faster than diffusion controlled process

Proton Inhibition
Cl Pd Cl OH2
OH
Cl Pd Cl OH2
H2O
+ H+
Outer-sphere water attack: Predicted to occur by an anti hydroxypalladation mechanism

Proton Inhibition
Cl Pd Cl OH2
OH
Cl Pd Cl OH2
H2O
+ H+
Outer-sphere water attack: Predicted to occur by an anti hydroxypalladation mechanism
Cl Pd Cl OH2
Cl Pd Cl OH
+ H+
Inner-sphere hydroxyl attack: Predicted to occur by a syn hydroxypalladation mechanism
Kinetic Isotope Effects

Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism
D D H H D + PdCl42 + H2O D H + PdCl42 + H2O H H3C D3C O + Pd(0) + 2 HCl + 2 Cl H O + Pd(0) + 2 HCl + 2 Cl D
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.

D D H H D + PdCl42 + H2O D H + PdCl42 + H2O H H3C D3C O + Pd(0) + 2 HCl + 2 Cl H O + Pd(0) + 2 HCl + 2 Cl D
kH kD = 1.07
KIE for decomposition step determined by competitive isotope effect experiment: H-shift
O DH2C D
kH kD
D H
D + PdCl42 + H2O H HO
D H
D Pd(OH2)Cl2 H
= 1.70
O
D-shift
HD2C

KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition.
outer-sphere anti hydroxypalladation
Cl Cl Pd H2O
+ H2O
Cl Cl Pd H2O CH2CH2OH
+ H+
O
+H+ H+
H3C + H2O
Cl Cl Pd HO
inner-sphere syn hydroxypalladation

Cl Cl Pd H2O
+ H2O
fast
+ H+
slow
O
+H+ H+
H3C + H2O
slow
Cl Cl Pd HO
fast
anti pathway has decomposition as the slow step syn pathway has hydroxypalladation as the slow step

Cl Cl Pd H2O
+ H2O
+ H+
O
+H+ H+
H3C + H2O
slow
Cl Cl Pd HO
fast
Early Stereochemical Studies

Stille's Work Suggests Anti Hydroxypalladation Mechanism
OH
H2O Na2CO3
Cl Pd Cl
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.

OH
H2O Na2CO3
Cl Pd Cl
Pd
Cl Cl
CO
O O
Key: CO insertion proceeds with retention of stereochemistry at the migrating stereocenter.
HO OH Cl Pd Cl
CO CO
O O
Cl Pd Cl
O O
anti hydroxypalladation
syn hydroxypalladation

HO
H2O Na2CO3 CO
Cl Pd Cl
Pd
Cl Cl
O O

HO
H2O Na2CO3 CO
Cl Pd Cl
Cl Pd Cl
O O
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

HO
H2O Na2CO3 CO
Cl Pd Cl
Cl Pd Cl
O O
HO
H2O
CO
HO H D
H PdLn H
O O D H D
D H
D PdCl2 H
2
PdLn
O O
H2O
O PdLn O H D D H H
HO H D
PdLn D H
CO
HO H D D

HO
H2O Na2CO3 CO
Cl Pd Cl
Cl Pd Cl
O O
HO
H2O
CO
HO H D
H PdLn H
O O D H D
D H
D PdCl2 H
2
PdLn
O O
H2O
O PdLn O H D D H H
HO H D
PdLn D H
CO
HO H D D

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.
HO
H2O
CO
HO H D
H PdLn H
O O D H D
D H
D PdCl2 H
2
PdLn
O O
H2O
O PdLn O H D D H H
HO H D
PdLn D H
CO
HO H D D
Bckvall's Stereochemical Studies

Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation
[Cl] < 1 M [CuCl2] < 1 M
O H3C H
loss of stereochemical information
C2H4 + PdCl42
H2O
Cl Cl Pd H2O
Bckvall, J.-E.; kermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bckvall, J.-E.; kermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411.

[Cl] < 1 M [CuCl2] < 1 M
O H3C H
C2H4 + PdCl42
H2O
Cl Cl Pd H2O
[Cl] > 3 M [CuCl2] > 2.5 M
Cl
CH3CHO + OH
stereochemical information retained (maybe)

[Cl] < 1 M [CuCl2] < 1 M
O H3C H
C2H4 + PdCl42
H2O
Cl Cl Pd H2O
[Cl] > 3 M [CuCl2] > 2.5 M
Cl
Two Key Assumptions:
CH3CHO + OH
stereochemical information retained (maybe)
! 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].

+ H+
Cl Cl Pd H2O
+ H2O
decomposition
2 CuCl2
Cl
OH + 2 CuCl
CH3CHO
! Chloride displacement of Pd occurs with inversion of stereochemistry at carbon. ! Chlorohydrin formation requires both high [Cl] and high [CuCl2].

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

+ H+
2 CuCl2
H D Cl
D H OH
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

+ H+
2 CuCl2
H D Cl
D H OH
Cl Cl Pd H2O D
D + H2O
H D Cl Cl Pd H2O OH H D
syn hydroxypalladation Control Experiments:
+ H+
2 CuCl2
H D Cl
H D OH
! Z/E isomerization is < 1% under the reaction conditions.

! Cofirmed that cleavage of CPd bond with CuCl2 occurs with inversion at carbon. ! Confirmed that chlorohydrin does not arise from an intermediate epoxide.

An Apparent Contradiction with KIE Studies
Cl Cl Pd H2O
+ H2O
fast
+ H+
slow
O
+H+ H+
H3C + H2O
slow
Cl Cl Pd HO
fast
innter-sphere syn hydroxypalladation

Reconciling Stereochemical Results with Kinetic Data
Cl Cl Pd H2O + H2O Cl Cl Pd H2O CH2CH2OH + H+

Cl Pd H2O CH2CH2OH
slow
+ Cl
H Cl Cl Pd H2O OH

Cl Pd H2O CH2CH2OH
slow
+ Cl
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
Cl Pd H OH H2O C CH3 H3C
O H
Evidence for Syn Hydroxypalladation

The Isomerization of Allyl Alcohol Under Wacker Conditions
OH + PdCl 2 + H O 4 2
k1 k1 k1
H2O + PdCl42 + HO PdII HO OH
k1
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.

OH + PdCl 2 + H O 4 2
k1 k1 k1
H2O + PdCl42 + HO PdII HO OH
k1
k2 If hydroxypalladation is anti, isomerization should occur since hydroxypalladation is required to be an equilibrium process. If hydroxypalladation is syn, isomerization should not occur since hydroxypalladation is rate limiting.
oxidation products
Rate =
d[C2H4] dt
k [PdCl42] [olefin] [Cl]2 [H+]

H H H OH + PdCl 2 + H O 4 2 D D
k1 k1 k1
H H2O + PdCl42 + HO H H
k1
D D
PdII HO OH
H H D D
oxidation products
Rate =
d[C2H4] dt
k [PdCl42] [olefin] [Cl]2 [H+]

k1 k1 k1
k1
D D
PdII HO OH
H H D D
oxidation products
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!

The Isomerization of Allyl Alcohol Under Isomerization Conditions
k1 k1 [Cl] = 3.3 M k1
k1
D D
PdII HO OH
H H D D
oxidation products
Rate =
d[C2H4] dt
k [PdCl42] [olefin] [Cl]
Only isomerization observed.

The Isomerization of Allyl Alcohol Under Isomerization Conditions
k1 k1 [Cl] = 3.3 M k1
k1
D D
PdII HO OH
Reactions at high and low chlorideH notD D do H proceed through the same mechanism. k Formation of aldehyde and chlorohydrin2does not occur through a common 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
Only isomerization observed.
Anti Hydroxypalladation at High [Cl]

Henry's Proposed Pathway
2
Cl Cl Pd Cl Cl
OH D D + H2O
Cl Cl Pd Cl D
OH D
+ Cl
Cl Cl Pd Cl D
OH D
Cl Cl CD2OH Pd Cl CH CH2OH
+ H+
+ H+
Cl Cl Pd Cl H D H D
OH
+ H2O
Anti Hydroxypalladation at High [Cl]

2
Cl Cl Pd Cl Cl
OH D D + H2O
Cl Cl Pd Cl D
OH D
+ Cl
Cl Cl Pd Cl D
OH D
+ H+
+ H+
Cl Cl Pd Cl H D H D
OH
+ H2O
Reinterpreting Bckvall's Results

PdCl4
2
+ C2H4
Cl Cl Pd Cl
+ Cl
Cl ligand loss prevented by high concentration of Cl.
Cl Cl Pd Cl + Cl
H2O
Cl Cl Pd Cl CH2CH2OH
Excess Cl prevents this intermediate from undergoing decomposition to oxidation products.
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.

A New Stereochemical and Kinetic Probe
H F3C OH + PdCl42 + H2O H2O + PdCl42 + F3C HO H3C
Required Properties: ! Substrate cannot undergo oxidation; can only isomerize.
H CF3 CD3
H3C F3C CD3
oxidation products
! Substrate whose RLS is hydroxypalladation. ! Substrate possesses stereochemistry that can be used to distinguish between syn and anti hydroxypalladation.
oxidation products
Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498.

k1 k1 k1 k1
H CF3 CD3
H3C F3C CD3
H PdII oxidation products F3C H3C OH CF3 CD3 OH oxidation products
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.

k1 k1 k1 k1
H CF3 CD3
H3C F3C CD3
H PdII oxidation products F3C H3C

For syn hydroxypalladation: d[C2H4] dt k [PdCl42] [olefin] [Cl]2 [H+]
CF3 OH CD3 OH
For anti hydroxypalladation: d[C2H4] dt
oxidation products
Rate =
Rate =
Proton inhibition term must result from an equilibrium that occurs before the rate-limiting hydroxypalladation step.
Proton inhibition term does not show up in the exchange rate because it results from this exchange equilibrium.

k1 k1 k1 k1
H CF3 CD3
H3C F3C CD3

For syn hydroxypalladation: d[C2H4] dt k [PdCl42] [olefin] [Cl]2 [H+]
CF3 OH CD3 OH
oxidation products
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.
Rate =
Proton inhibition term must result from an equilibrium that occurs before the rate-limiting hydroxypalladation step.

k1 k1 k1 k1
H CF3 CD3
H3C F3C CD3

Observed Kinetics under High [Cl] Conditions: ! Rate expression had no first order proton inhibition term. ! Rate expression was identical to what Bckvall observed at high [Cl]. ! Consistent with anti hydroxypalladation mechanism.
CF3 OH CD3 OH
For anti hydroxypalladation: d[C2H4] dt
oxidation products
Rate =
Proton inhibition term does not show up in the exchange rate because it results from this exchange equilibrium.

anti H+
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O
CF3 D3C H OH CF3 CH3
(R), Z CD3 CH3 H (R), E CF3 PdCl42 H2O
F3C HO

anti H+
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O
F3C HO
H+
F3C HO PdII
CD3
CH3 CF3 OH
CD3
+ H+ PdII H2O
F3C H (S), E
CH3 CF3 OH
syn

anti H+
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O

product substrate config R R S S % ee 100 100 100 100 [Cl] 0.10 0.05 0.10 0.05 [catalyst] PdCl42 PdCl42 PdCl42 PdCl42 % isomerization 30 48 25 50
F3C HO
%S 32.5 50.0 72.5 50.0
%R 67.5 50.0 27.5 50.0
H+
F3C HO PdII
CD3
CH3 CF3 OH
CD3
+ H+
F3C H (S), E
syn
PdII H2O
CH3 CF3 OH

anti H+
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O

product substrate config R R S S % ee 100 100 100 100 [Cl] 0.10 0.05 0.10 0.05 [catalyst] PdCl42 PdCl42 PdCl42 PdCl42 % isomerization 30 48 25 50
F3C HO
%S 32.5 50.0 72.5 50.0
%R 67.5 50.0 27.5 50.0
H+
F3C HO PdII
CD3
CH3 CF3 OH
CD3
+ H+ PdII H2O
F3C H (S), E
CH3 CF3 OH
syn

anti H+
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O

substrate config R R S S % ee 100 100 100 100 [Cl] 2.0 3.5 2.0 3.5 product % isomerization % Z 31 27 35 45 30 25 32 45 %S 0.0 0.0 100 100 %R 100 100 0.0 0.0
F3C HO
H+
F3C HO PdII
CD3
CH3 CF3 OH
CD3
+ H+
F3C H (S), E
syn
PdII H2O
CH3 CF3 OH

anti H+
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O

substrate config R R S S % ee 100 100 100 100 [Cl] 2.0 3.5 2.0 3.5 product % isomerization % Z 31 27 35 45 30 25 32 45 %S 0.0 0.0 100 100 %R 100 100 0.0 0.0
F3C HO
H+
F3C HO PdII
CD3
CH3 CF3 OH
CD3
+ H+
F3C H (S), E
syn
PdII H2O
CH3 CF3 OH

anti H+ high [Cl]
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O

Conclusions: ! At low [Cl] (Wacker conditions), syn hydroxypalladation is operative. ! At high [Cl] (Bckvall's conditions), anti hydroxypalladation is operative.
F3C HO
low [Cl] H+
F3C HO PdII
CD3
CH3 CF3 OH
CD3
+ H+
F3C H (S), E
syn
PdII H2O
CH3 CF3 OH

anti H+ high [Cl]
F3C HO PdII
CD3 OH CF3 H CH3

+ H+ PdII H2O
(R), Z
Criticism:
F3C HO H
CD3 CH3 CF3 PdCl42 H2O
! 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.
(R), E
low [Cl] H+
F3C HO PdII
CD3
CH3 CF3 OH
CD3
+ H+ PdII H2O
F3C H (S), E
CH3 CF3 OH
syn
Chirality Transfer Studies
HO R2 H
H R1 H
(R), Z reactive conformation
Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.

[Cl] > 2 M
R2 H H H (S), Z R2 OH R1
anti H+
HO R2 PdII
H OH H H R1
PdII H2O
[Cl] = 0.1 M
O H (S)
OH R1
HO R2 H
H R1 H PdCl42 H2O
Pd0 H+

[Cl] > 2 M
anti H+
HO R2 PdII
H OH H H R1
PdII H2O
[Cl] = 0.1 M
O H (S) H
OH R1
HO R2 H
H R1 H PdCl42 H2O
Pd0 H+

H+
[Cl]
>2M PdII
R2
R1
HO R2 PdII
H R1 OH
H2O
H OH (R), E R2
syn
[Cl] = 0.1 M H+ Pd0
R1
OH (R)

[Cl] > 2 M
anti H+
HO R2 PdII
H OH H H R1
PdII H2O
[Cl] = 0.1 M
O H (S) H
OH R1
HO R2 H
H R1 H PdCl42 H2O
Pd0 H+

H+
[Cl]
>2M PdII
R2
R1
HO R2 PdII
H R1 OH
H2O
H OH (R), E R2
syn
[Cl] = 0.1 M H+ Pd0
R1
OH (R)

Me
[Cl] > 2 M
H H H (S), Z Me
Ph Me
anti H+
HO Me PdII
H Ph H H Me
PdII H2O
[Cl]
= 0.1 M
O H (S) H
Ph Me
HO Me H
H Me H PhPdCl MeOH
Pd0 H+

H+
[Cl]
>2M PdII
Me
Me
HO Me PdII
H2O
Me
H Ph (R), E Me
syn
Ph
[Cl] = 0.1 M Pd0
Me
H+
Ph (R)

Me
[Cl] > 2 M
H H H (S), Z Me
Ph Me
anti H+
HO Me PdII
H Ph H H Me
PdII H2O
[Cl]
= 0.1 M
O H (S) H
Ph Me
HO Me H
H Me H PhPdCl MeOH
PhPdCl must add syn regardless of the [Cl]
Pd0 H+

H+
[Cl]
>2M PdII
Me
Me
HO Me PdII
H2O
Me
H Ph (R), E Me
syn
Ph
[Cl] = 0.1 M Pd0
Me
H+
Ph (R)

Me
[Cl] > 2 M
H H H (S), Z Me
OH Et
anti H+
HO Me PdII
H OH H H Et
PdII H2O
[Cl]
= 0.1 M
O H (S) H
OH Et
HO Me H
H Et H PdCl42 H2O
Pd0 H+

H+
[Cl]
>2M PdII
Me
Et
HO Me PdII
H Et OH
H2O
H OH (R), E Me
syn
[Cl]
= 0.1 M Pd0
Et
H+
OH (R)

Me
[Cl] > 2 M
H H H (S), Z Me
OH Et
anti H+
HO Me PdII
H OH H H Et
PdII H2O
[Cl]
= 0.1 M
O H
OH Et
HO Me H
H Et H PdCl42 H2O
Pd0 H+ the stereochemistry of hydroxypalladation (S) must be different at high and low [Cl] [Cl]
H
>2M PdII

H+
Me
Et
HO Me PdII
H Et OH
H2O
H OH (R), E Me
syn
[Cl]
= 0.1 M Pd0
Et
H+
OH (R)

Me
[Cl] > 2 M
H H H (S), Z Me
OH Et
anti H+
HO Me PdII
H OH H H Et
PdII H2O
[Cl]
= 0.1 M
O H (S)
OH Et
HO Me H
H Et H PdCl42 H2O
Pd0 ! Excess Cl prevents syn hydroxypalladation by H+ prohibiting the ligation of water. Cl

H+
! Excess prevents "-hydride elimination to oxidation products by prohibiting the necessary dissociation H of a Cl ligand. ] > 2 M [Cl Et Me
HO Me PdII
H Et OH
H2O
PdII
H OH (R), E Me
syn
[Cl]
= 0.1 M Pd0
Et
H+
OH (R)
Mechanism for Oxidation of Olefins under Wacker Conditions

1 [Cl] inhibition 1 [Cl] inhibition
Cl Cl Pd Cl Cl O H3C Cl H Cl
H2C CH2 Cl
Cl Cl Pd Cl
+ H2O Cl
Cl Cl Pd H2O
+ CuCl2 + O2
1 [H+]
inhibition
H+
Pd
H2O
OH
Cl Cl Pd H2O
+ H2O
OH
Cl Cl Pd HO
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] inhibition 1 [Cl] inhibition
Cl Cl Pd Cl Cl O H3C Cl H Cl
H2C CH2 Cl
Cl Cl Pd Cl
+ H2O Cl
Cl Cl Pd H2O
+ CuCl2 + O2
1 [H+]
inhibition
H+
Pd
H2O
OH
Cl Cl Pd H2O
+ H2O
OH
Cl Cl Pd HO
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 OH
Cl Cl Pd H
!-hydride elimination
O OH H
dissociation tautomerize
OH
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. Bckvall, J.-E.; kermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411. Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246.

Moiseev's Mechanism:
Cl
Pd
Cl OH
Cl Cl Pd H
O OH H
dissociation tautomerize
OH
D D H H
D + PdCl42 + H2O D H + PdCl42 + D2O H H3C D3C
O + Pd(0) + 2 HCl + 2 Cl D O + Pd(0) + 2 DCl + 2 Cl H
lack of proton incorporation from solvent means that tautomerization mechanism is invalid

Henry's Model
H H Cl Cl Pd OH H H
H Cl Pd
H H H
O H
+ Pd(0) + HCl
Cl
PdII-assisted hydride shift

Henry's Model
H H Cl Cl Pd OH H H
H Cl Pd
H H H
O H
+ Pd(0) + HCl
Cl
PdII-assisted hydride shift
Bckvall's Model
Cl
Pd
Cl OH
Cl Cl Pd H
Cl
Pd
Cl OH
OH
reinsertion
O H
+ Pd(0) + HCl
!-hydride elimination from oxygen

Computational Studies
Bckvall's Model
Cl
Pd
Cl OH
O H PdIICl H3C
O H
+ Pd(0) + HCl
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.

Bckvall's Model
Cl
Pd
Cl OH
O H PdIICl H3C
O H
+ Pd(0) + HCl
4-membered TS: 36.3 kcal/mol


Bckvall's Model
Cl
Pd
Cl OH
O H PdIICl H3C
-hydride elimination from oxygen
O H
+ Pd(0) + HCl
4-membered TS: 36.3 kcal/mol
Cl-mediated reductive elimination TS: 18.7 kcal/mol
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 = CuCl22H2O (10 mol%) or p-benzoquinone
Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241. Tsuji, J. Synthesis 1984, 369.

Preparations of Methyl Ketones from Terminal Olefins
Clement, 1964: PdCl2 (10 mol%) oxidant H2O (12-17%), O2 DMF oxidant = CuCl22H2O (10 mol%) or p-benzoquinone
OH MeO O O MeO
Zearalenone
H O O H
H H
19-Nortestosterone
intermediate to Dichroanone
H O O O O O
Nootkatone Brevicomin
OTHP
intermediate to Coriolin
Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241. Tsuji, J. Synthesis 1984, 369.

Oxidative Cyclizations Give Access to Heterocyclic Compounds
Moritani, 1973: PdCl2(PhCN)2 (1 equiv)
R ONa+
PhH
R O
Hosokawa, T.; Maeda, K.; Koga, K.; Moritani, I. Tetrahedron Lett. 1973, 10, 739.

R ONa+
PhH
R O
Pd(dba)2 (5 mol%) KHCO3 (1.1 equiv)
Pd(OAc)2 (2 mol%) Cu(OAc)2H2O (1 equiv)
air, DMSO, H2O 60 C no co-oxidant!
OH
air, DMF, 100 C
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.

R ONa+
PhH
R O
Pd(dba)2 (5 mol%) KHCO3 (1.1 equiv)
Pd(OAc)2 (2 mol%) Cu(OAc)2H2O (1 equiv)
air, DMSO, H2O 60 C no co-oxidant!
OH
air, DMF, 100 C
Pd(TFA)2 (10 mol%) ligand (20 mol%)
O i-Pr N O N 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.

Boc N O MeO2C O H O H BnO BnO OBn H O H
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
O PdLn
H R O PdLn O
syn oxypalladation
O PdLn

Stoltz Group Studies
Pd(TFA)2 (5 mol%) pyridine (20 mol%) Na2CO3 (2 equiv)
OH
MS3, 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.

Pd(TFA)2 (5 mol%) pyridine (20 mol%) Na2CO3 (2 equiv)
OH
MS3, O2 (1 atm) PhCH3, 80 C
O
95% yield
O O
O NTs O
CO2Et
O NOBn
90% yield
88% yield
63% yield
82% yield
87% yield
93% yield
62% yield
Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892.

E [PdII] H OH HO E D O E D E [PdII] H OE E D
anti oxypalladation
CO2Et CO2Et
E H E O [PdII] D
syn oxypalladation
E H H E O [Pd] D
E H OE
Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.

E [PdII] H OH HO E D O E D E [PdII] H OE E D
anti oxypalladation
O D
+
CO2Et CO2Et
CO2Et CO2Et
CO2Et CO2Et
E H E O [PdII] D
syn oxypalladation
E H H E O [Pd] D
E H OE

E [PdII] H O HO O OH E D O O E D E [PdII] H O OE E D
anti oxypalladation
CO2Et CO2Et
E H O E O [PdII] D
syn oxypalladation
E H H O E O [Pd] D O
E H OE

E [PdII] H O HO O OH E D O O E D O O E [PdII] H O OE E D
anti oxypalladation
CO2Et CO2Et
CO2Et CO2Et
E H O E O [PdII] D
syn oxypalladation
E H H O E O [Pd] D O
E H OE

Hayashi Group Studies
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
H O B D
O A
OH
A:B:C:D = 16:46:29:9
syn oxypalladation
O C
O D
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.

Hayashi Group Studies
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
H O B D
O A
OH
A:B:C:D = 16:46:29:9
syn oxypalladation
O C
O D
H D
PdCl2(MeCN)2 (10 mol%) Na2CO3 (2 equiv) LiCl (2 equiv) benzoquinone (1 equiv) THF, 65 C, 24 h
H O B D D
O A
OH
A:B:C:D = 6:5:7:82
anti oxypalladation
O C
O D
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.

Stahl Group Studies
Ts N H
anti aminopalladation
LnPd D
Ts N
DPd H
Ts N D H Ts N
NHTs D LnPd D
syn aminopalladation
Ts N D Ts N HPd D Ts N D Ts N
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.

Stahl Group Studies
Ts N H
LnPd D
Ts N
DPd H
Ts N D H Ts N
NHTs D LnPd D
No additive: 2:1 ratio syn:anti aminopalladation products
Ts N D Ts N Ts N D
Ts N
HPd D

Stahl Group Studies
Ts N H
LnPd D
Ts N
DPd H
Ts N D H Ts N
NHTs D LnPd D
CF3CO2H Additive: 1:2 ratio syn:anti aminopalladation products
Ts N D Ts N Ts N D
Ts N
HPd D

Stahl Group Studies
Ts N H
LnPd D
Ts N
DPd H
Ts N D H Ts N
NHTs D LnPd D
NaOAc or Na2CO3 Additive: exclusively syn aminopalladation products
Ts N D Ts N Ts N D
Ts N
HPd D
Conclusions
Pd Source and Ligands
Additive Effects (co-oxidant, acid, base, salts) syn vs. anti heteropalladation or carbopalladation
Solvent Effects (H2O, ROH, DMSO, etc.)
Olefin Sterics and Electronics
Nucleophile Sterics and Electronics
The Wacker Oxidation

One-Stage Process
purge C2H4
Reactor C2H4, O2 PdCl2, CuCl2, HCl 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. CH3CHO
Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120.
Separation Equipment
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. ! Operates at 90-100 C, 10 atm. ! Yields >95% acetaldehyde. C2H4 Oxidation Reactor PdCl2, CuCl2, HCl + CH3CHO CH3CHO
PdCl2, (CuCl)2, HCl
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.
Separation Equipment

2008 Tadross2

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

2008 Tadross2

Uploaded by

Copyright:

Available Formats

2 CuICl 2 Cl +2 CuIICl2 PdIICl42 O Pd0 H3C + HCl H

Mechanistic Studies on the Wacker Oxidation

Origins of the Wacker Oxidation

PdCl42 + C2H4 + H2O

Pd(0) + CH3CHO + 2 HCl + 2 Cl

Origins of the Wacker Oxidation

PdCl42 + C2H4 + H2O

Pd(0) + CH3CHO + 2 HCl + 2 Cl

Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + 1/2 O2 + 2 HCl

2 CuCl + PdCl42 2 CuCl2 + H2O

Origins of the Wacker Oxidation

PdCl42 + C2H4 + H2O Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + 1/2 O2 + 2 HCl

Pd(0) + CH3CHO + 2 HCl + 2 Cl 2 CuCl + PdCl42 2 CuCl2 + H2O

Origins of the Wacker Oxidation

Pd(0) + CH3CHO + 2 HCl + 2 Cl 2 CuCl + PdCl42 2 CuCl2 + H2O CH3CHO

Net Result: Air oxidation of ethylene to acetaldehyde!

Origins of the Wacker Oxidation

Pd(0) + CH3CHO + 2 HCl + 2 Cl 2 CuCl + PdCl42 2 CuCl2 + H2O CH3CHO

Net Result: Air oxidation of ethylene to acetaldehyde!

Origins of the Wacker Oxidation

Pd(0) + CH3CHO + 2 HCl + 2 Cl 2 CuCl + PdCl42 2 CuCl2 + H2O CH3CHO

Net Result: Air oxidation of ethylene to acetaldehyde!

Early Kinetic Studies

Early Kinetic Studies

Source of Chloride Inhibition: 2 1 [Cl]

Early Kinetic Studies

Early Kinetic Studies

Outer-sphere water attack: Predicted to occur by an anti hydroxypalladation mechanism

Early Kinetic Studies

Outer-sphere water attack: Predicted to occur by an anti hydroxypalladation mechanism

Inner-sphere hydroxyl attack: Predicted to occur by a syn hydroxypalladation mechanism

Kinetic Isotope Effects

Kinetic Isotope Effects

Kinetic Isotope Effects

outer-sphere anti hydroxypalladation

inner-sphere syn hydroxypalladation

Kinetic Isotope Effects

outer-sphere anti hydroxypalladation

inner-sphere syn hydroxypalladation

Kinetic Isotope Effects

outer-sphere anti hydroxypalladation

inner-sphere syn hydroxypalladation

Early Stereochemical Studies

Key: CO insertion proceeds with retention of stereochemistry at the migrating stereocenter.

Early Stereochemical Studies

Key: CO insertion proceeds with retention of stereochemistry at the migrating stereocenter.

Early Stereochemical Studies

Early Stereochemical Studies

Early Stereochemical Studies

Early Stereochemical Studies

Early Stereochemical Studies

Bckvall's Stereochemical Studies

loss of stereochemical information

Bckvall's Stereochemical Studies

loss of stereochemical information

stereochemical information retained (maybe)

Bckvall's Stereochemical Studies

loss of stereochemical information

stereochemical information retained (maybe)

Bckvall's Stereochemical Studies

Bckvall's Stereochemical Studies

Bckvall's Stereochemical Studies