The Mechanistic Studies of theWacker Oxidation

Tyler W. WilsonSED Group Meeting

11.27.2007

Introduction

• Oxidation of ethene by Pd (II) chloride solutions (Phillips, 1894)-First used as a test for alkenes (Pd black was the indicator)C2H4 + Pd(II)Cl2 + H2O → C2H4O + Pd(0) + 2HCl

• Later Smidt and co-workers employed cupric chloride toregenerate the Pd (0) catalyst (Smidt, 1962)

• What made Smidt’s process applicable to large scale production was thefinal recycling of CuCl back to Cu(II)Cl2 by air

C2H4 + Pd(II)Cl2 + H2O → C2H4O + Pd(0) + 2HCl Pd(0) + 2CuCl2 → Pd(II)Cl2 + 2CuCl

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

Introduction

PdCl42- + C2H4 + H2O → Pd(0) + CH3CHO +2 HCl + 2 Cl- (1)Pd(0) + 2 CuCl2 + 2 Cl- → PdCl42- + 2 Cu(I)Cl (2)2 Cu(I)Cl + 2 HCl + 1/2 O2 → 2 Cu(II)Cl2 + H2O (3)

Net: C2H4 + 1/2 O2 → CH3CHO (4)

• Adding up the three reactions gives the Wacker Oxidation Reaction :

Wacker Oxidation Reaction

• Why is it called the Wacker Oxidation?-Smidt and co-workers discovered the reaction at Consortium Fur Elecktrochemie Industrie G.M.BH., Munich, Germany (a subsidiary of WackerChemie)

• Industrial Importance:- Plants with production capacity of 15,000 tons of acetaldehyde per yearhave been developed

Introduction

Chloride Inhibition:

Proton Inhibition:

PdCl

Cl

OH2

H2C

CH2 PdCl

Cl

OH2

PdCl

Cl

OH2

OH

OH

H2O

PdCl

Cl

OH

H2C

CH2H

Ka

H

Slow

H2O

K

CH3CHO

Slow

Fast

PdCl42- + C2H4

K1PdCl3(C2H4)1- + Cl1-

PdCl3(C2H4)1- + H2OK2

PdCl2(C2H4)(H2O) + Cl1-

1/[Cl-] term

1/[Cl-] term

outer sphere (trans)

inner sphere (cis)

-d[olefin]

dt=

k [ PdCl4-2 ] [olefin]

[ H+ ] [ Cl - ]2Rate =

Rate Equation: -First order in Pd and alkene-Chloride squared inhibition term-Proton inhibition term

C2D4 + PdCl42- + H2O CD3CDO + Pd(0) + 2 HCl + 2 Cl-

C2H4 + PdCl42- + H2O CH3CHO + Pd(0) + 2 HCl + 2 Cl-

kD

kH

Observed KIE = kH / kD = 1.07

+ PdCl42- + H2O

H H

D DH+

H2OC C

D D

H HOHCl2(OH2)Pd

CH2DCDO

CHD2CHOCompetitive isotope effect = kH / kD = 1.9

Early Evidence for Inner-Sphere Mechanism: KIEs

• Observed Kinetic Isotope Effects

• Competitive isotope effect:

• No deuterium incorporation is observed when reaction is run in D2O

GROUPEXERCISE

PdCl

Cl

OH2

H2C

CH2 PdCl

Cl

OH2

PdCl

Cl

OH2

OH

OH

H2O

PdCl

Cl

OH

H2C

CH2H

Ka

H

RDS

H2O

K

CH3CHO

RDS

Fast

inner sphere (cis)

Proton Inhibition

Proton Inhibition

Early Evidence for Inner-Sphere Mechanism: KIEs

• Inner-sphere was initially proposed based on observed kinetics in combinationwith kinetic isotope effect (circa 1964)

• Outer-sphere was disfavored because RDS is after hydroxypalladationreasonable to assume a KIE would be observed• Stereochemical probe of the reaction is needed

Pd Cl

ClHO Pd

Cl 2

C

O

O

H2O

Na2CO3

CO

H

DD

HPdCl2

2

NaOAc

CH3CNH2O

HO

PdH

D

DH

Cl

2

HO

HD

DH

COPdL3

OO

HD

DH

CO

retentiveinsertion

Trans stereochemistry confirmed by1H-NMR

coupling constant

Evidence For Outer-Spere Addition: Stille Study

• Trapping hydropalladated intermediate with CO

Problem: Sterically, syn addition would be disfavored with a chelating diolefin

Problems:-Solvent is CH3CN not water-Previous studies have shown that dimeric Pd(II)complexes were prone to anti addition-Strong CO binds Pd strongly and could preventcoordination of H2O

H2C CH2 PdCl42-+

[Cl-] < 1M

[Cl-] > 3 M

[CuCl2] > 2.5 M

HOCl

CH3CO

CH3CO

PdCl

Cl

OH2

H2C

CH2H2O

O2

O2

Stereochemistry is lost

Stereochemistry is retained(potentially)

[CuCl2] < 1M

Evidence for Outer-Spere: Backvall Study

• Product distribution depends on chloride and CuCl2 concentrations:

• Major Assumptions:-Chlorohydrin and ethanal are formed from the same intermediate:(PdCl2(H2O)(C2H4))- Steric course of the reaction is not altered by running at higher chloride andcupric chloride concentrations

D

D

H

H

C CD

H D

H

Pd OH2Cl

Cl

OH

HDL3Pd

D H OH

HD

Cl

HD

threo

CuCl2

LiCl

H2O

"trans"

PdCl42-

"inversion"

D

D

H

H

PdCl42- C C

D

H D

H

Pd OH

Cl

Cl OH

DH

L3Pd

D H

OH

HDCl

HD

erythro

CuCl2

LiCl

H2O

"cis""inversion"

(E)-d2-ethene

D

H

D

H

(Z)-d2-ethene erythro

D

H

D

H

(Z)-d2-ethene threo

"trans" OH

HDCl

HD

OH

HD

Cl

HD"cis"

Evidence for Outer-Spere: Backvall Study

• Stereochemical course of trans-addition (outer-sphere):

• Stereochemical course of cis-addition (inner-sphere):

Similarly,

H

HD

D

HO

DH HgCl

HD Cl

HD

HO

HD

PdCl4-2

"retention"

CuCl2

LiCl

HO

DH PdL3

HD

Hg(NO3)2

AcOH

H2O

40% yield> 96% threo

HO

DH PdL3

HD O

D HH D

Cl

HDHO

HD

erythro

CuCl2

LiCl

Evidence for Outer-Spere: Backvall Study

• Control experiments:(1) (Z)/(E) isomerization was less than 1%(2) Confirmed cleavage of 1° palladium-carbon bond by CuCl2-LiCl proceeded with

inversion(3) Confirmed chlorohydrin was not being obtained from an epoxide intermediate

-Stereochemistry predicted for chlorohydrin via epoxide intermediate

-Independent preparation of a hydroxypalladated ethene

DHC CHD (gas)

0.033 M PdCl2 (aq.)

2.7 M CuCl2 (aq.),

3.3 M LiCl (aq.)

5 kg/cm2 , 20-40 h, 20 °C ClOH

D

D(E or Z)

6 M NaOH

O

D D

O

D D

And/or

Evidence for Outer-Spere: Backvall Study

Model for anti addition predicts: (E)-ethene-d2 → (Z)-ethylene oxide-d2

(Z)-ethene-d2 → (E)-ethylene oxide-d2

• Results clearly indicate that under these reactions conditions an outer-sphere mechanismis operative

PdCl

Cl

OH2

H2C

CH2 PdCl

Cl

OH2

OH

H2O HK3 OH

PdCl

OH2

RDS

14 e- complex

fast

PdCl

H

OH2

CH2

OH

PdCl

H

OH2

CH2

OH

Cl

16 e- complex

18 e- complex!"Hydride Elimination

RDS

X

OH2

PdCl

OH

Me

O

H CH3

2 3

4

PdCl42- C2H4

H2O - 2 [Cl-] 1

Evidence for Outer-Spere: Backvall Study

• Backvall Outer-Sphere Mechanism:

Experimental observations1. Chloride inhibition2. Proton inhibition3. Very low KIE4. No D-incorporation

from D2O

Reevaluation of Inner and Outer Sphere Mechansims

• Kinetically, the main difference between the mechanisms is the position of therate-determining step:

-Outer-sphere: Trans-hydroxypalladation is in equilibrium (proton inhibition) and RDSoccurs downstream of this step-Inner-sphere: Proton inhibition results from Acid/Base equilibrium prior to cis-hydroxypalladation and the RDS is the hydroxypalladation

PdCl

Cl

OH2

H2C

CH2 PdCl

Cl

OH2

PdCl

Cl

OH2

OH

OH

H2O

PdCl

Cl

OH

H2C

CH2H

Ka

H

H2O

K

CH3CHO

RDS

Fast

outer sphere (anti)

inner sphere (syn)

RDS

• Distinguishing the mechanisms requires an olefin that will undergo anexperimentally observable change if the hydroxypalladation is in equilibrium

OHD

D H HPdCl4

-2 H2O

HO

D D

Pd(II)

OH

H H

HO H

HDDPdCl4

-2H2O

1a 1b

k2

k1

k-1

k1

k-1

Oxidation Products

H

Evidence for Inner-Sphere: Isomerization of Allylic Alcohol

• Isomerization of deuterated allyl alcohol

Inner-sphere mechanism:• k2 >> k-1

• At early conversion very littleisomerization will be observed

Outer-sphere mechanism:• k2 << k-1

• At early conversionisomerization will be observed

Experimental Predictions

Evidence for Inner-Sphere: Isomerization of Allylic Alcohol

OH

Me PdCl42-

PdCl42-

Me

O

Me OMe

H

90% 10%(Markovnikov) (Anti-Markovnikov)

O

H

OHMe

O

OH

40%12%

Me OH

Me OH

PdII

OH

Me OH

OH

PdII

PdCl42-

Me

O

OH

OMe

OH H

Me

O

OH

2.6%

49% 39%

(Markovnikov) (Anti-Markovnikov)

• Directing influence of hydroxyl group

OHD

D H HPdCl4

-2 H2O

[H+] =0.4 M[Cl-] = 0.4 M

Oxidation Productsstd. kinetic rxn

conditionsHenry, P. M. et. al. J. Mol. Cat. 1982, 16, 81-87

Less 3% isomerization observered in recoverd starting material after

oxidation had preceeed to 50% conversion

Evidence for Inner-Sphere: Isomerization of Allylic Alcohol

Control Experiments:-No detectable isomerization observed in the absence of Pd (II)-Kinetic study revealed that the oxidation of allyl alcohol obeyed the samerate expression as observed for ethene (eqn 1)

Initial Result:

Evidence for Inner-Sphere: Isomerization of Allylic Alcohol

Kinetic Data for Isomerization

Oxidation rate is 2xisomerization rateIsomerization rate is5x Oxidation rate

OHD

D H HPdCl4

-2

1a

-d[olefin]

dt=

kox [ PdCl4-2 ] [olefin]

[ H+ ] [ Cl - ]2(1)Rate =

-d[olefin]

dt=

ki [ PdCl4-2 ] [olefin]

[ Cl - ](2)Rate =

[ LiCl] = 0.2-3.3 M[HClO4] = 0.2- 2.0 M[PdCl4

2-] = 0.01-0.10 M

Quinone, H2O

HO H

HDD

O

H OH

Me

isomerization oxidation

Rate expresion for oxidation

Rate expresion for isomerization

Evidence for Inner-Sphere: Isomerization of Allylic Alcohol

• Question: Why is isomerization the predominate process at high [Cl-]?

PdCl Cl

Cl

CH2OH

PdCl Cl

Cl CH2OH

HOH2C

PdCl Cl

Cl CH2OHH2O H2O

+ H+

2- 1-1-

PdCl

Cl

OH2

H2C

CH2 PdCl

Cl

OH2

PdCl

Cl

OH2

OH

OH

H2O

PdCl

Cl

OH

H2C

CH2

H

SlowH2O

K

1- 1-

1-

CH3CHO

CH3CHO

Labile coordination site

Pd

Cl

Cl CH2OH

HOH2C 1-

Cl-

Unfavorable at high [Cl-]

• Compare to proposed wacker intermediates that lead to oxidation

Evidence for Inner-Sphere: Kinetic Probe

• Design a kinetic probe in which RDS is hydroxypalladation

Assumption:-Exchange is completely symmetric then k1 = k-1’ and k-1 = k-1’, then the rate ofisomerization only depends on the rate of formation of 3, not on its equilibrium conc.

Prediction:-Kinetics will follow rate equation (1) if syn hydroxypalladation is operative (b/c protonequilibrium is prior to RDS)-Kinetics will follow rate equation (3) if trans hydroxypalladation is operative

O16HF3C

CH3 CF3

CD3PdCl4

-2 H218O

H16O

H3C CF3

Pd(II)18OH

CF3

CD3

H18O CD3

CF3CH3F3C

PdCl4-2H2

16O

k1

k-1

k1'

k-1'H

=ki [ PdCl4

-2 ] [olefin]

[ Cl - ]2 [H + ]

2a 2b

3

Rate (1) =ki [ PdCl4

-2 ] [olefin]

[ Cl - ]2Rate (3)

Evidence for Inner-Sphere: Kinetic Probe

Results:Kinetic Data

-Kinetic data shows clear inversedependence on [H+]-The value of ki was calculated fromeqn 1 and remains fairly constant overrange of Pd, Cl and H concentrations

=ki [ PdCl4

-2 ] [olefin]

[ Cl - ]2 [H + ]Rate (1)

=ki [ PdCl4

-2 ] [olefin]

[ Cl - ]2Rate (3)

• Kinetic data is consistent with syn hydoxypalladation, what about stereochemistry ofisomerization

Evidence for Inner Sphere: Kinetic Probe

• Prediction on stereochemical outcome of the isomerization

-Syn should lead to inversion and Anti should give retention

Isomerization Results:

• Stereochemistry of isomerzation is alsoconsistent with a syn hydroxypalladation• Downside this alkene is not a goodmodel of an actual Wacker substrate

Evidence for Inner Sphere: Transfer of Chirality

• Chirality Transfer to study modes of addition

• Study stereochemistry of products at both high and low chlorideconcentrations• Anti-addition at low chloride will give the opposite absolutestereochemistry

C CC

H

R

H

H

R2

HO PdII

X

R

S H

R2 H

C

X

R1

H

(S)-(E)-1a

R

O X

R1

H

(S)-5, 5' or 5''

or

C CC

H

Me

H

H

Me

HO(R)-Z-3a(53% ee)

MeOH

Li2PdCl4, NEt3CuCl2, PhHgCl

Me

O

Ph

Me H

(R)-2

Low Chloride84% yield30% ee

Me PhMe H

(S)-Z-3a''High Chloride

70% yield68% ee

(S)-Z-3a(74% ee)

Similarily,

Evidence for Inner Sphere: Transfer of Chirality

Controls:

1. Test a nucleophile whose mode of addition is known to be syn regardless ofchloride concentration

Results:

• Results suggest a syn hydroxypalladation at low chloride concentrations and an antihydroxypalladation at high chloride concentrations

Computational Study of the Wacker Oxidation

• Combined catalytic cycles of the Wacker Oxidation

Wacker Conditions:LL conditions (Industria): Low[Cl-] (< 1M) and low [CuCl2](< 1M) yield only aldehyde viainternal syn addition (rate eqn 1)HH conditions: high [Cl-] (> 3 M)and high [CuCl2] (> 2.5M) yieldboth aldehyde and chlorohydrinvia external anti addition (rateeqn 2)HL conditions: yield no oxidationproductsLH conditions: yield syn and antiproducts, and obey a combinedrate law

• Employed computational models (hybrid density functional theory andimplicit solvation methods) to investigate relevant steps in cycle

Goddard, W. A. et. al. J. Am. Chem. Soc. 2007, 129, 12342-12343

Computational Study of the Wacker Oxidation

Key Results (Syn pathway):1. For the syn manifold, the calculated barrier

for the deprotonation from 3 (5.8 kcal/mol)to 4 (15.3 kcal/mol) is plausible under thestandard conditions (pH 0-2)

2. The calculated barrier for 4 to 5 is ΔG** =33.4 kcal/mol and is far to high to befeasible for the Wacker process (ΔG**expt =22.4 kcal/mol)

Overall for syn: 1→ 2 → TS-ALE1 → 3 → TS-INT → 10 → TS-ISO (RDS) → 6 → product

Computational Study of the Wacker OxidationKey Results (anti-pathway):

-Overall for anti: 1→ 2 → TS-EXT (RDS) → 9-H → TS-ALE2 → 10 → TS-ISO → 6 →product-Since anti obeys rate equation 2 there is no proton inhibition so TS-EXT being the RDSis consistent with rate law

Computational Study of Wacker Oxidation

Results: Role of CuCl2

Stabilizing Interactions:CuCl2 stabilizes both TS-ISO (by -6.0 kcal/mol) and TS-EXT (by -1.9 kcal/mol)Destabilizing Interactions:CuCl2 destabilizes TS-ALE1 (by + 2.7 kcal/mol)-Predicts at HH anti pathway is strongly favored

Conclusions

• Mechanism of the Wacker oxidation is dependent on the reaction conditionsand is best described by two competing processes

Inner-SpereHydroxypalladation

-Occurs at low [Cl-] andlow [CuCl2]-Rate is best describedby eqn 1-RDS is still debated

Outer-SphereHydroxypalladation

-Occurs at high [Cl-] andhigh [CuCl2]-Rate is best describedby eqn 2-RDS is still debated

• Kinetic and stereochemical models have been well studied and future workmay need to relay more heavily on computational models

References

Excellent Reviews:(1) P. M. Henry, Palladium Catalyzed Oxidation of Hydrocarbons; D. Reidel, Dordrecht:

Holland, 1980, p. 41.(2) P. M. Henry, In Handbook of Organopalladium Chemistry for Organic Synthesis;

Negishi, E., Ed.; Wiley & Sons: New York, 2001; p. 209Initial Kinetic Studies:(1) Smidt, J. et. al. Angew. Chem. Int. Ed. 1962, 1, 80-88(2) Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246-3250.Backvall Study:(1) Backvall, J. E. et. al. J. Am. Chem. Soc. 1979, 101, 2411-2416Computational Studies:(2) Goddard, W. A. et. al. J. Am. Chem. Soc. 2007, 129, 12342-12343(3) Siegbahn, E. M. J. Phys. Chem. 1996, 100, 14672-14680

Additional Comments/Questions

http://en.wikipedia.org/wiki/Patrick_Henry

Patrick Henry“Give me liberty or give me death”

Updated Version“Give me syn or give me death”

Group Exercise

Group Exercise

Given that (1) is an intermediate the reaction, write a mechanism thataccounts for the formation acetaldehyde observed in the KIE studies

C2D4 + PdCl42- + H2O CD3CDO + Pd(0) + 2 HCl + 2 Cl-

C2H4 + PdCl42- + H2O CH3CHO + Pd(0) + 2 HCl + 2 Cl-

kD

kH

Observed KIE = kH / kD = 1.07

+ PdCl42- + H2O

H H

D DH+

H2OC C

D D

H HOHCl2(OH2)Pd

CH2DCDO

CHD2CHOCompetitive isotope effect = kH / kD = 1.9

PdCl

Cl

OH2

OH

CH3CHO?

Reaction run in D2O shows no incorporation

Solution for Group Exercise

PdH2O

Cl H

CH2

OH

PdCl

Cl

OH2

OHPd

H2O

ClOH

Cl-

PdH2O

Cl

OH

CH3

H3C

O

H

• Recent computational workquestions ability to undergo β-Hydride elimination from -OH(see Goddard, W. A. JACS,2006, 128, 3132 and referencetherein)

Backup: Ruling out π-Allyl Pathway

Rate of isomerization isequal to 1/2 rate ofexchange

Rate of exchange isequal to rate ofisomerization

Backup: Schematic for Industrial Wacker Process