The Mechanistic Studies of the
Wacker Oxidation
Tyler W. Wilson
SED 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 to
regenerate the Pd (0) catalyst (Smidt, 1962)
C2H4 + Pd(II)Cl2 + H2O
Pd(0) + 2CuCl2
→ C2H4O + Pd(0) + 2HCl
→
Pd(II)Cl2 + 2CuCl
• What made Smidt’s process applicable to large scale production was the
final recycling of CuCl back to Cu(II)Cl2 by air
2 CuCl + 1/2 O2 + 2 HCl →
2CuCl2 + H2O
Introduction
• Adding up the three reactions gives the Wacker Oxidation Reaction :
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)
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 Wacker
Chemie)
• Industrial Importance:
- Plants with production capacity of 15,000 tons of acetaldehyde per year
have been developed
Introduction
Rate Equation:
-First order in Pd and alkene
-d[olefin]
=
Rate =
dt
k [ PdCl4-2 ] [olefin]
[
H+ ]
[ Cl
- ]2
-Chloride squared inhibition term
-Proton inhibition term
Chloride Inhibition:
PdCl42-
+
PdCl3(C2H4)1- +
K1
C2H4
K2
H 2O
PdCl3(C2H4)1- + Cl1-
1/[Cl-] term
PdCl2(C2H4)(H2O) + Cl1-
1/[Cl-] term
Proton Inhibition:
Cl
H 2C
Pd CH2
Cl
OH2
K
H2O
OH
Cl
Pd
OH2
Cl
outer sphere (trans)
H
Slow
Ka
Cl
Cl
CH3CHO
H 2C
Pd
CH2
OH
Slow
H
H 2O
Cl
OH
Pd
OH
Cl
2
inner sphere (cis)
Fast
Early Evidence for Inner-Sphere Mechanism: KIEs
• Observed Kinetic Isotope Effects
C2D4
+
PdCl42- +
H2O
CD3CDO + Pd(0) + 2 HCl + 2 Cl-
kD
C2H4
+
PdCl42- +
H 2O
CH3CHO + Pd(0) + 2 HCl + 2 Cl-
kH
Observed KIE = kH / kD = 1.07
• Competitive isotope effect:
D
D
+ PdCl4
H
H
2-
+
H2O
H+
H2O
D
D
Cl2(OH2)Pd C C OH
H
H
Competitive isotope effect = kH / kD = 1.9
• No deuterium incorporation is observed when reaction is run in D2O
GROUP
EXERCISE
CH2DCDO
CHD2CHO
Early Evidence for Inner-Sphere Mechanism: KIEs
• Inner-sphere was initially proposed based on observed kinetics in combination
with kinetic isotope effect (circa 1964)
Cl
H2C
Pd CH2
Cl
OH2
Proton
Inhibition
Cl
Cl
K
H2O
Proton
Inhibition
OH
Cl
Pd
OH2
Cl
H
RDS
Ka
CH3CHO
H 2C
Pd
CH2
OH
RDS
H
H2O
Cl
OH
Pd
OH2
Cl
inner sphere (cis)
Fast
• Outer-sphere was disfavored because RDS is after hydroxypalladation
reasonable to assume a KIE would be observed
• Stereochemical probe of the reaction is needed
Evidence For Outer-Spere Addition: Stille Study
• Trapping hydropalladated intermediate with CO
O
H2O
Pd Cl
Cl
Na2CO3
C
CO
HO
Pd
Cl
O
2
Problem: Sterically, syn addition would be disfavored with a chelating diolefin
D
D
PdCl2
H
H
H2O
2
NaOAc
CH3CN
H
D
HO
Cl
Pd
H
D
2
CO
retentive
insertion
H
D
HO
COPdL3
HD
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 prevent
coordination of H2O
H
D H
D
O
O
Trans stereochemistry
confirmed by1H-NMR
coupling constant
Evidence for Outer-Spere: Backvall Study
• Product distribution depends on chloride and CuCl2 concentrations:
[Cl-] < 1M
[CuCl2] < 1M
H2C CH2 +
PdCl42-
H 2O
Cl
Cl
H 2C
Pd
O2
CH2
OH2
CH3CO
Stereochemistry
is lost
[Cl-] > 3 M
[CuCl2] > 2.5 M
CH3CO
O2
HO
• Major Assumptions:
Cl
Stereochemistry
is retained
(potentially)
-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 and
cupric chloride concentrations
Evidence for Outer-Spere: Backvall Study
• Stereochemical course of trans-addition (outer-sphere):
H
H
D
PdCl4
2-
D
H
(E)-d2-ethene
C C
D
H2O
D
H
Cl Pd OH2 "trans"
Cl
DH
L3Pd
OH
H
D
CuCl2
LiCl
"inversion"
Cl
OH
H
D
D
H
threo
• Stereochemical course of cis-addition (inner-sphere):
H
D
D
H
PdCl4
2-
H
C C
D
H2O
D
H
Cl Pd OH
Cl
"cis"
DH DH
OH
L3Pd
D
Cl
CuCl2
H
OH
D
erythro
LiCl
"inversion"
Similarly,
D
D
H
H
(Z)-d2-ethene
"trans"
Cl
D
H
D
OH
erythro
H
D
D
H
H
(Z)-d2-ethene
"cis"
H
Cl
OH
H
D
D
H
threo
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
-Independent preparation of a hydroxypalladated ethene
D
H
H
D
Hg(NO3)2
AcOH
H 2O
HO
D
H
PdCl4-2
HO
D
H
CuCl2
HO
H
D
HgCl
"retention"
H
D
PdL3
LiCl
H
H
D
D
H
PdL3
O
H
D
D
H
CuCl2
LiCl
HO
D
D
H
40% yield
> 96% threo
-Stereochemistry predicted for chlorohydrin via epoxide intermediate
HO
Cl
D
H
H
Cl
D
erythro
Evidence for Outer-Spere: Backvall Study
DHC CHD (gas)
(E or Z)
0.033 M PdCl2 (aq.)
2.7 M CuCl2 (aq.),
3.3 M LiCl (aq.)
5
kg/cm2
O
D
, 20-40 h, 20 °C
Model for anti addition predicts:
OH
Cl
6 M NaOH
D
D
D
And/or
O
D
D
(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 mechanism
is operative
Evidence for Outer-Spere: Backvall Study
• Backvall Outer-Sphere Mechanism:
OH
PdCl42H 2O
Cl
C 2H 4
- 2 [Cl-]
RDS
X
1
!"Hydride Elimination
H 2C
Pd CH2
Cl
OH2
Cl
K3
H 2O
2
OH
Cl
Pd
OH2
Cl
16 e- complex
H
RDS
3
H
CH2
Cl
OH2
18 e complex
Pd
OH
Cl
Pd
OH2
14 e- complex
fast
Experimental observations
1.
OH
Chloride inhibition
2.
Proton inhibition
3.
Very low KIE
4.
No D-incorporation
from D2O
OH
O
H
Cl
CH3
Pd Me
OH2
H
Cl
Pd
4
CH2
OH2
Reevaluation of Inner and Outer Sphere Mechansims
• Kinetically, the main difference between the mechanisms is the position of the
rate-determining step:
-Outer-sphere: Trans-hydroxypalladation is in equilibrium (proton inhibition) and RDS
occurs downstream of this step
-Inner-sphere: Proton inhibition results from Acid/Base equilibrium prior to cishydroxypalladation and the RDS is the hydroxypalladation
Cl
H 2C
Pd CH2
Cl
OH2
K
H2O
OH
Cl
Pd
OH2
Cl
outer sphere (anti)
H
RDS
Ka
Cl
Cl
CH3CHO
H 2C
Pd
CH2
OH
H
RDS
H 2O
Cl
OH
Pd
OH2
Cl
inner sphere (syn)
Fast
• Distinguishing the mechanisms requires an olefin that will undergo an
experimentally observable change if the hydroxypalladation is in equilibrium
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol
• Isomerization of deuterated allyl alcohol
D
OH
D
H H
1a
PdCl4-2
H2O
k1
k-1
PdCl4-2
H 2O
HO
Pd(II)
OH
k1
HO
D D
k-1
H
H
H
1b
D DH H
k2
Oxidation Products
Experimental Predictions
Inner-sphere mechanism:
Outer-sphere mechanism:
• k2 >> k-1
• k2 << k-1
• At early conversion very little
isomerization will be observed
• At early conversion
isomerization will be observed
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol
• Directing influence of hydroxyl group
O
Me
PdCl42-
H
Me
Me
90%
(Markovnikov)
10%
(Anti-Markovnikov)
O
OH
PdCl42-
H
OH
Me
(Markovnikov)
12%
O
OH
(Anti-Markovnikov)
40%
O
OH
Me
Me
OH
OH
OH
2.6%
PdII
Me
Me
O
PdCl42PdII
Me
Me
OH
OH
O
OH
49%
Me
O
OH H
39%
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 same
rate expression as observed for ethene (eqn 1)
Initial Result:
D
OH
D
H H
PdCl4-2
H 2O
[H+] =0.4 M
[Cl-] = 0.4 M
std. kinetic rxn
conditions
Oxidation Products
Henry, 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
D
OH
D
H H
1a
[ LiCl] = 0.2-3.3 M
[HClO4] = 0.2- 2.0 M
[PdCl42-] = 0.01-0.10 M
PdCl4-2
Quinone, H2O
HO
H
D D H
isomerization
O
Me
H
OH
oxidation
Kinetic Data for Isomerization
Oxidation rate is 2x
isomerization rate
Isomerization rate is
5x Oxidation rate
kox [ PdCl4-2 ] [olefin]
-d[olefin]
=
Rate =
dt
[ H+ ] [ Cl - ]2
-d[olefin]
=
Rate =
dt
ki [ PdCl4-2 ] [olefin]
[ Cl
-]
(1)
Rate expresion for oxidation
(2)
Rate expresion for isomerization
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol
• Question: Why is isomerization the predominate process at high [Cl-]?
CH2OH
Cl
Cl
Pd
HOH2C
1- H O
2
Cl
Cl
Cl
Pd
2-
Cl
H2O
CH2OH + H+
1Cl
Cl
Pd
Cl
CH2OH
Unfavorable at high [Cl-]
HOH2C
Cl
Pd
1CH2OH
Cl-
Cl
• Compare to proposed wacker intermediates that lead to oxidation
Cl
Cl
Cl
Cl
H 2C
Pd
CH2
OH2
H2C
Pd
K
CH2
OH
H2O
1-
Slow
H 2O
Cl
Pd
OH2
Cl
OH
1H
CH3CHO
1Cl
OH
Pd
OH2
Cl
Labile coordination site
CH3CHO
Evidence for Inner-Sphere: Kinetic Probe
• Design a kinetic probe in which RDS is hydroxypalladation
F 3C
O16H
CD3
CH3 CF3
2a
PdCl4
-2
H2
18O
k1
k-1
PdCl4-2
H216O
H16O
Pd(II)
18OH
H3C CF3 CFCD3
3
3
H18O
k1'
H
CD3
F3C CH CF
3
3
2b
k-1'
Assumption:
-Exchange is completely symmetric then k1 = k-1’ and k-1 = k-1’, then the rate of
isomerization 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 proton
equilibrium is prior to RDS)
-Kinetics will follow rate equation (3) if trans hydroxypalladation is operative
Rate =
ki [ PdCl4-2 ] [olefin]
[ Cl
- ]2 [H + ]
(1)
Rate =
ki [ PdCl4-2 ] [olefin]
[ Cl
- ]2
(3)
Evidence for Inner-Sphere: Kinetic Probe
Results:
Kinetic Data
-Kinetic data shows clear inverse
dependence on [H+]
-The value of ki was calculated from
eqn 1 and remains fairly constant over
range of Pd, Cl and H concentrations
Rate =
Rate =
ki [ PdCl4-2 ] [olefin]
[ Cl
- ]2 [H + ]
ki [ PdCl4-2 ] [olefin]
[ Cl - ]2
(1)
(3)
• Kinetic data is consistent with syn hydoxypalladation, what about stereochemistry of
isomerization
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 also
consistent with a syn hydroxypalladation
• Downside this alkene is not a good
model 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 chloride
concentrations
• Anti-addition at low chloride will give the opposite absolute
stereochemistry
X
H
R2
S
C
C H
R C
R
II
HO H Pd
X
O
X
H
R
R1
(S)-5, 5' or 5''
or
H
C H
R1
R2
H
(S)-(E)-1a
Evidence for Inner Sphere: Transfer of Chirality
Controls:
1. Test a nucleophile whose mode of addition is known to be syn regardless of
chloride concentration
Me H C C H
C
Me
H
HO
(R)-Z-3a
(53% ee)
Li2PdCl4, NEt3
CuCl2, PhHgCl
MeOH
O Me H
Me
Ph
(R)-2
Low Chloride
84% yield
30% ee
Similarily,
(S)-Z-3a
(74% ee)
Me
Ph
Me H
(S)-Z-3a''
High Chloride
70% yield
68% ee
Results:
• Results suggest a syn hydroxypalladation at low chloride concentrations and an anti
hydroxypalladation 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 via
internal syn addition (rate eqn 1)
HH conditions: high [Cl-] (> 3 M)
and high [CuCl2] (> 2.5M) yield
both aldehyde and chlorohydrin
via external anti addition (rate
eqn 2)
HL conditions: yield no oxidation
products
LH conditions: yield syn and anti
products, and obey a combined
rate law
• Employed computational models (hybrid density functional theory and
implicit 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 the
standard conditions (pH 0-2)
2.
The calculated barrier for 4 to 5 is ΔG** =
33.4 kcal/mol and is far to high to be
feasible 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 Oxidation
Key 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 RDS
is 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 conditions
and is best described by two competing processes
Inner-Spere
Hydroxypalladation
Outer-Sphere
Hydroxypalladation
-Occurs at low [Cl-] and
low [CuCl2]
-Occurs at high [Cl-] and
high [CuCl2]
-Rate is best described
by eqn 1
-Rate is best described
by eqn 2
-RDS is still debated
-RDS is still debated
• Kinetic and stereochemical models have been well studied and future work
may 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. 209
Initial 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, 2411-2416
Computational 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
Patrick Henry
“Give me liberty or give me death”
Updated Version
“Give me syn or give me death”
http://en.wikipedia.org/wiki/Patrick_Henry
Group Exercise
Group Exercise
Given that (1) is an intermediate the reaction, write a mechanism that
accounts for the formation acetaldehyde observed in the KIE studies
OH
Cl
Pd
OH2
Cl
?
CH3CHO
C2D4
+
PdCl42- +
H2O
CD3CDO + Pd(0) + 2 HCl + 2 Cl-
kD
C2H4
+
PdCl42- +
H 2O
CH3CHO + Pd(0) + 2 HCl + 2 Cl-
kH
Observed KIE = kH / kD = 1.07
D
D
+ PdCl4
H
H
2-
+
H2O
H+
H2O
D
D
Cl2(OH2)Pd C C OH
H
H
Competitive isotope effect = kH / kD = 1.9
Reaction run in D2O shows no incorporation
CH2DCDO
CHD2CHO
Solution for Group Exercise
• Recent computational work
questions ability to undergo βHydride elimination from -OH
(see Goddard, W. A. JACS,
2006, 128, 3132 and reference
therein)
OH
OH
Cl
Pd
OH2
Cl
Cl
OH
Cl-
Pd
H2O
H2O Pd
Cl
CH2
H
OH
O
H3C
H2O Pd
H
Cl
CH3
Backup: Ruling out π-Allyl Pathway
Rate of exchange is
equal to rate of
isomerization
Rate of isomerization is
equal to 1/2 rate of
exchange
Backup: Schematic for Industrial Wacker Process