Mechanistic Studies on the Wacker Oxidationstoltz2.caltech.edu/seminars/2008_Tadross2.pdf ·...

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–

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:



Smidt, Wacker Chemie, 1959:

Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42–

2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O





2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O





2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O

C2H4 + 1/2 O2 CH3CHO

Net Result: Air oxidation of ethylene to acetaldehyde!





2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O



! 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!





2 CuCl + 1/2 O2 + 2 HCl 2 CuCl2 + H2O



! 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

[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.

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




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


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





PdCl

Cl

OH2

–OH

PdCl

Cl CH2CH2OH

OH2

–Outer-sphere hydroxide attack:

Predicted to be 103 times faster

than diffusion controlled process


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





PdCl

Cl

OH2

PdCl

Cl

OH2

–OH

PdCl

Cl CH2CH2OH

OH2




H2O

PdCl

Cl CH2CH2OH

OH2

–

+ H+Outer-sphere water attack:Predicted to occur by an antihydroxypalladation mechanism


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





PdCl

Cl

OH2

PdCl

Cl

OH2

PdCl

Cl

OH2

–OH

PdCl

Cl CH2CH2OH

OH2




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

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.


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


–



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.



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




anti pathway has decomposition as the slow step

syn pathway has hydroxypalladation as the slow step



PdH2O

Cl Cl

PdHO

Cl Cl–

+ H2O PdH2O

Cl Cl

CH2CH2OH

–

+ H+

+ H2O PdH2O

Cl Cl

CH2CH2OH

–

O

HH3C

–H++H+

slowfast






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

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



PdCl

Cl

H2O

Na2CO3

PdCl

Cl

HO

CO O

O

anti hydroxypalladation



PdCl

Cl

H2O

Na2CO3

PdCl

Cl

HO

CO 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



PdCl

Cl

H2O

Na2CO3

PdCl

Cl

HO

CO O

O


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




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.

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.



PdH2O

Cl Cl

[Cl–] < 1 M[CuCl2] < 1 M

[Cl–] > 3 M[CuCl2] > 2.5 M

H3C

O

H


information

+

ClOH

CH3CHOstereochemical

information retained (maybe)


Soc. 1979, 101, 2411.



PdH2O

Cl Cl

[Cl–] < 1 M[CuCl2] < 1 M

[Cl–] > 3 M[CuCl2] > 2.5 M

H3C

O

H


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].


Soc. 1979, 101, 2411.



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].



Soc. 1979, 101, 2411.

PdH2O

Cl ClPd

H2OCl Cl

–

+ H++ H2O

D


H DOH

D HD2 CuCl2

Cl OH

H DD H



Soc. 1979, 101, 2411.

PdH2O

Cl ClPd

H2OCl Cl

–

+ H++ H2O

D


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



Soc. 1979, 101, 2411.

PdH2O

Cl ClPd

H2OCl Cl

–

+ H++ H2O

D


H DOH

D HD2 CuCl2

Cl OH

H DD H

PdH2O

Cl ClPd

H2OCl Cl

–

+ H++ H2O

D


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.

Bäckvall's Stereochemical StudiesAn Apparent Contradiction with KIE Studies


PdH2O

Cl Cl

PdHO

Cl Cl–

+ H2O PdH2O

Cl Cl

CH2CH2OH

–

+ H+

+ H2O PdH2O

Cl Cl

CH2CH2OH

–

O

HH3C

–H++H+

slowfast


innter-sphere syn hydroxypalladation




fast slow

Bäckvall's Stereochemical StudiesReconciling Stereochemical Results with Kinetic Data


Soc. 1979, 101, 2411.

PdH2O

Cl ClPd

H2OCl Cl

CH2CH2OH

–

+ H++ H2O



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



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.

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




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.


–d[C2H4]

dt

k [PdCl42–] [olefin]

[Cl–]2 [H+]==Rate




HO OH

PdII

HOH2O + PdCl42– +

oxidation products

k1

k–1

k–1

k1

k2



H

H

H

D D

D

D

H

H H

H H D D


–d[C2H4]

dt


[Cl–]2 [H+]==Rate




HO OH

PdII

HOH2O + PdCl42– +

oxidation products

k1

k–1

k–1

k1

k2



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

Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Isomerization Conditions



HO OH

PdII

HOH2O + PdCl42– +

oxidation products

k1

k–1

k–1

k1

k2



H

H

H

D D

D

D

H

H H

H H D D

[Cl–] = 3.3 M

–d[C2H4]

dt


[Cl–]==Rate

Only isomerization observed.

HO OH

PdII

oxidation products

k2



H H D D

Evidence for Syn HydroxypalladationThe Isomerization of Allyl Alcohol Under Isomerization Conditions


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


[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.

Anti Hydroxypalladation at High [Cl–]

Henry's Proposed Pathway


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


PdCl

Cl Cl

CH

2–

CH2OH

CD2OH+ H+

PdCl

Cl Cl

–OH

HH + H2O

D

D

Reinterpreting Bäckvall's ResultsHenry's Proposed Pathway

Gregor, N.; Zaw, K.; Henry, P. M. Organometallics 1984, 3, 1251.

PdCl

Cl Cl

–

+ Cl–


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–

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




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




2– +

oxidation products

F3C

H3C

H

F3C CD3

CF3F3C

H3C

H


H PdII

OHH3C

OHCD3

k1

k–1

k–1

k1

–d[C2H4]

dt


[Cl–]2 [H+]==Rate

–d[C2H4]

dt


[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




2– +

oxidation products

F3C

H3C

H

F3C CD3

CF3F3C

H3C

H


H PdII

OHH3C

OHCD3

k1

k–1

k–1

k1

–d[C2H4]

dt


[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




2– +

oxidation products

F3C

H3C

H

F3C CD3

CF3F3C

H3C

H


H PdII

OHH3C

OHCD3

k1

k–1

k–1

k1

–d[C2H4]

dt


[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



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



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



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



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



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–]



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–]

Chirality Transfer Studies

Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745.

H

R1

H

HHO

R2

(R), Zreactive

conformation



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)



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



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

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–]



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



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–]



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.

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


– H2O

–

1

[Cl–]inhibition

1

[Cl–]inhibition

1

[H+]inhibition+ CuCl2

+ O2

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



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



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



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

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


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


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.

Bäckvall's Model

PdCl Cl–

OH

O

H+ Pd(0) + HCl

β-hydride eliminationfrom oxygen

OPdIIClH

H3C


4-membered TS: 36.3 kcal/mol Cl-mediated reductive elimination TS: 18.7 kcal/mol

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.

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

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


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+


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!


Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071.

Moritani, 1973:

O–Na+


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


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

Stereochemistry of Oxidative Cyclizations

OHR

PdLn

OR

PdLn

ORanti

oxypalladation!-hydride

elimination

O

RO

RPdLn

ORsyn

oxypalladation!-hydride

elimination

PdLn

H

H

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


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

EE


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

EE



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

+

EE



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

EE



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

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

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

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

DPd




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

DPd




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

DPd




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

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)

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.

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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