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)
C
2
H
4
+ Pd(II)Cl
2
+ H
2
O ! C
2
H
4
O + Pd(0) + 2HCl
Later Smidt and co-workers employed cupric chloride to
regenerate the Pd (0) catalyst (Smidt, 1962)
What made Smidt!s process applicable to large scale production was the
nal recycling of CuCl back to Cu(II)Cl
2
by air
C
2
H
4
+ Pd(II)Cl
2
+ H
2
O ! C
2
H
4
O + Pd(0) + 2HCl
Pd(0) + 2CuCl
2
! Pd(II)Cl
2
+ 2CuCl
2 CuCl + 1/2 O
2
+ 2 HCl

! 2CuCl
2
+ H
2
O
Introduction
PdCl
4
2-
+ C
2
H
4
+ H
2
O ! Pd(0) + CH
3
CHO +2 HCl + 2 Cl
-
(1)
Pd(0) + 2 CuCl
2
+ 2 Cl
-
! PdCl
4
2-
+ 2 Cu(I)Cl (2)
2 Cu(I)Cl + 2 HCl + 1/2 O
2
! 2 Cu(II)Cl
2
+ H
2
O (3)
Net: C
2
H
4
+ 1/2 O
2
! CH
3
CHO (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 Wacker
Chemie)
Industrial Importance:
- Plants with production capacity of 15,000 tons of acetaldehyde per year
have been developed
Introduction
Chloride Inhibition:
Proton Inhibition:
Pd
Cl
Cl
OH
2
H
2
C
CH
2
Pd
Cl
Cl
OH
2
Pd
Cl
Cl
OH
2
OH
OH
H
2
O
Pd
Cl
Cl
OH
H
2
C
CH
2
H
K
a
H
Slow
H
2
O
K
CH
3
CHO
Slow
Fast
PdCl
4
2-
+ C
2
H
4
K
1
PdCl
3
(C
2
H
4
)
1-
+ Cl
1-
PdCl
3
(C
2
H
4
)
1-
+ H
2
O
K
2
PdCl
2
(C
2
H
4
)(H
2
O) + Cl
1-
1/[Cl
-
] term
1/[Cl
-
] term
outer sphere (trans)
inner sphere (cis)
-d[olefin]
dt
=
k

[ PdCl
4
-2
] [olefin]
[ H
+
] [ Cl
-
]
2
Rate =
Rate Equation:
-First order in Pd and alkene
-Chloride squared inhibition term
-Proton inhibition term
C
2
D
4
+ PdCl
4
2-
+ H
2
O
CD
3
CDO + Pd(0) + 2 HCl + 2 Cl
-
C
2
H
4
+ PdCl
4
2-
+ H
2
O
CH
3
CHO + Pd(0) + 2 HCl + 2 Cl
-
k
D
k
H
Observed KIE = k
H
/ k
D
= 1.07
+ PdCl
4
2-
+ H
2
O
H H
D D
H
+
H
2
O
C C
D D
H H
OH Cl
2
(OH
2
)Pd
CH
2
DCDO
CHD
2
CHO
Competitive isotope effect = k
H
/ k
D
= 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 D
2
O
GROUP
EXERCISE
Pd
Cl
Cl
OH
2
H
2
C
CH
2
Pd
Cl
Cl
OH
2
Pd
Cl
Cl
OH
2
OH
OH
H
2
O
Pd
Cl
Cl
OH
H
2
C
CH
2
H
K
a
H
RDS
H
2
O
K
CH
3
CHO
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 combination
with kinetic isotope effect (circa 1964)
Outer-sphere was disfavored because RDS is after hydroxypalladation
reasonable to assume a KIE would be observed
Stereochemical probe of the reaction is needed
Pd Cl
Cl
HO
Pd
Cl 2
C
O
O
H
2
O
Na
2
CO
3
CO
H
D D
H
PdCl
2
2
NaOAc
CH
3
CN
H
2
O
HO
Pd
H
D
D
H
Cl
2
HO
H
D
D
H
COPdL
3
O
O
H
D
D
H
CO
retentive
insertion
Trans stereochemistry
confirmed by
1
H-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 diolen
Problems:
-Solvent is CH
3
CN 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 H
2
O
H
2
C CH
2
PdCl
4
2-
+
[Cl
-
] < 1M
[Cl
-
] > 3 M
[CuCl
2
] > 2.5 M
HO
Cl
CH
3
CO
CH
3
CO
Pd
Cl
Cl
OH
2
H
2
C
CH
2
H
2
O
O
2
O
2
Stereochemistry
is lost
Stereochemistry
is retained
(potentially)
[CuCl
2
] < 1M
Evidence for Outer-Spere: Backvall Study
Product distribution depends on chloride and CuCl
2
concentrations:
Major Assumptions:
-Chlorohydrin and ethanal are formed from the same intermediate:
(PdCl
2
(H
2
O)(C
2
H
4
))
- Steric course of the reaction is not altered by running at higher chloride and
cupric chloride concentrations
D
D
H
H
C C
D
H D
H
Pd OH
2
Cl
Cl
OH
H
D
L
3
Pd
D
H
OH
H
D
Cl
H
D
threo
CuCl
2
LiCl
H
2
O
"trans"
PdCl
4
2-
"inversion"
D
D
H
H
PdCl
4
2-
C C
D
H D
H
Pd OH
Cl
Cl
OH
D
H
L
3
Pd
D
H
OH
H
D
Cl
H
D
erythro
CuCl
2
LiCl
H
2
O
"cis"
"inversion"
(E)-d
2
-ethene
D
H
D
H
(Z)-d
2
-ethene
erythro
D
H
D
H
(Z)-d
2
-ethene
threo
"trans" OH
H
D
Cl
H
D
OH
H
D
Cl
H
D "cis"
Evidence for Outer-Spere: Backvall Study
Stereochemical course of trans-addition (outer-sphere):
Stereochemical course of cis-addition (inner-sphere):
Similarly,
H
H D
D
HO
D
H
HgCl
H
D
Cl
H
D
HO
H
D
PdCl
4
-2
"retention"
CuCl
2
LiCl
HO
D
H
PdL
3
H
D
Hg(NO
3
)
2
AcOH
H
2
O
40% yield
> 96% threo
HO
D
H
PdL
3
H
D
O
D H
H
D
Cl
H
D
HO
H
D
erythro
CuCl
2
LiCl
Evidence for Outer-Spere: Backvall Study
Control experiments:
(1) (Z)/(E) isomerization was less than 1%
(2) Conrmed cleavage of 1 palladium-carbon bond by CuCl
2
-LiCl proceeded with
inversion
(3) Conrmed 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 PdCl
2

(aq.)
2.7 M CuCl
2

(aq.),
3.3 M LiCl
(aq.)
5 kg/cm
2
, 20-40 h, 20 C
Cl
OH
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-d
2
! (Z)-ethylene oxide-d
2
(Z)-ethene-d
2
! (E)-ethylene oxide-d
2
Results clearly indicate that under these reactions conditions an outer-sphere mechanism
is operative
Pd
Cl
Cl
OH
2
H
2
C
CH
2
Pd
Cl
Cl
OH
2
OH
H
2
O H
K
3
OH
Pd
Cl
OH
2
RDS
14 e
-
complex
fast
Pd
Cl
H
OH
2
CH
2
OH
Pd
Cl
H
OH
2
CH
2
OH
Cl
16 e
-
complex
18 e
-
complex
!"Hydride Elimination
RDS
X
OH
2
Pd
Cl
OH
Me
O
H CH
3
2
3
4
PdCl
4
2-
C
2
H
4
H
2
O - 2 [Cl
-
] 1
Evidence for Outer-Spere: Backvall Study
Backvall Outer-Sphere Mechanism:
Experimental observations
1. Chloride inhibition
2. Proton inhibition
3. Very low KIE
4. No D-incorporation
from D
2
O
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 cis-
hydroxypalladation and the RDS is the hydroxypalladation
Pd
Cl
Cl
OH
2
H
2
C
CH
2
Pd
Cl
Cl
OH
2
Pd
Cl
Cl
OH
2
OH
OH
H
2
O
Pd
Cl
Cl
OH
H
2
C
CH
2
H
K
a
H
H
2
O
K
CH
3
CHO
RDS
Fast
outer sphere (anti)
inner sphere (syn)
RDS
Distinguishing the mechanisms requires an olen that will undergo an
experimentally observable change if the hydroxypalladation is in equilibrium
OH D
D
H
H
PdCl
4
-2
H
2
O
HO
D
D
Pd(II)
OH
H
H
HO H
H
D
D
PdCl
4
-2
H
2
O
1a
1b
k
2
k
1
k
-1
k
1
k
-1
Oxidation Products
H
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol
Isomerization of deuterated allyl alcohol
Inner-sphere mechanism:
k
2
>> k
-1
At early conversion very little
isomerization will be observed
Outer-sphere mechanism:
k
2
<< k
-1
At early conversion
isomerization will be observed
Experimental Predictions
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol
OH
Me
PdCl
4
2-
PdCl
4
2-
Me
O
Me O
Me
H
90% 10%
(Markovnikov)
(Anti-Markovnikov)
O
H
OH Me
O
OH
40% 12%
Me OH
Me OH
Pd
II
OH
Me OH
OH
Pd
II
PdCl
4
2-
Me
O
OH
O Me
OH H
Me
O
OH
2.6%
49% 39%
(Markovnikov)
(Anti-Markovnikov)
Directing inuence of hydroxyl group
OH D
D
H
H
PdCl
4
-2
H
2
O
[H
+
] =0.4 M
[Cl
-
] = 0.4 M
Oxidation Products
std. kinetic rxn
conditions
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
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:
Evidence for Inner-Sphere: Isomerization of Allylic Alcohol
Kinetic Data for Isomerization
Oxidation rate is 2x
isomerization rate
Isomerization rate is
5x Oxidation rate
OH D
D
H
H
PdCl
4
-2
1a
-d[olefin]
dt
=
k
ox
[ PdCl
4
-2
] [olefin]
[ H
+
] [ Cl
-
]
2
(1)
Rate =
-d[olefin]
dt
=
k
i
[ PdCl
4
-2
] [olefin]
[ Cl
-
]
(2)
Rate =
[ LiCl] = 0.2-3.3 M
[HClO
4
] = 0.2- 2.0 M
[PdCl
4
2-
] = 0.01-0.10 M
Quinone, H
2
O
HO H
H
D
D
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
-
]?
Pd
Cl Cl
Cl
CH
2
OH
Pd
Cl
Cl
Cl
CH
2
OH
HOH
2
C
Pd
Cl
Cl
Cl
CH
2
OH
H
2
O H
2
O
+ H
+
2-
1-
1-
Pd
Cl
Cl
OH
2
H
2
C
CH
2
Pd
Cl
Cl
OH
2
Pd
Cl
Cl
OH
2
OH
OH
H
2
O
Pd
Cl
Cl
OH
H
2
C
CH
2
H
Slow
H
2
O
K
1- 1-
1-
CH
3
CHO
CH
3
CHO
Labile coordination site
Pd
Cl
Cl
CH
2
OH
HOH
2
C
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 k
1
= 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
O
16
H F
3
C
CH
3
CF
3
CD
3
PdCl
4
-2
H
2
18
O
H
16
O
H
3
C CF
3
Pd(II)
18
OH
CF
3
CD
3
H
18
O CD
3
CF
3
CH
3
F
3
C
PdCl
4
-2
H
2
16
O
k
1
k
-1
k
1
'
k
-1
'
H
=
k
i
[ PdCl
4
-2
] [olefin]
[ Cl
-
]
2
[H
+
]
2a
2b
3
Rate (1) =
k
i
[ PdCl
4
-2
] [olefin]
[ Cl
-
]
2
Rate (3)
Evidence for Inner-Sphere: Kinetic Probe
Results:
Kinetic Data
-Kinetic data shows clear inverse
dependence on [H
+
]
-The value of k
i
was calculated from
eqn 1 and remains fairly constant over
range of Pd, Cl and H concentrations
=
k
i
[ PdCl
4
-2
] [olefin]
[ Cl
-
]
2
[H
+
]
Rate (1)
=
k
i
[ PdCl
4
-2
] [olefin]
[ Cl
-
]
2
Rate (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
C C
C
H
R
H
H
R
2
HO
Pd
II
X
R
S
H
R
2
H
C
X
R
1
H
(S)-(E)-1a
R
O X
R
1
H
(S)-5, 5' or 5''
or
C C
C
H
Me
H
H
Me
HO
(R)-Z-3a
(53% ee)
MeOH
Li
2
PdCl
4
, NEt
3
CuCl
2
, PhHgCl
Me
O
Ph
Me
H
(R)-2
Low Chloride
84% yield
30% ee
Me Ph
Me
H
(S)-Z-3a''
High Chloride
70% yield
68% 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 of
chloride concentration
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 [CuCl
2
]
(< 1M) yield only aldehyde via
internal syn addition (rate eqn 1)
HH conditions: high [Cl
-
] (> 3 M)
and high [CuCl
2
] (> 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 "G** =
33.4 kcal/mol and is far to high to be
feasible for the Wacker process ("G**
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 CuCl
2
Stabilizing Interactions:
CuCl
2
stabilizes both TS-ISO (by -6.0 kcal/mol) and TS-EXT (by -1.9 kcal/mol)
Destabilizing Interactions:
CuCl
2
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
-Occurs at low [Cl
-
] and
low [CuCl
2
]
-Rate is best described
by eqn 1
-RDS is still debated
Outer-Sphere
Hydroxypalladation
-Occurs at high [Cl
-
] and
high [CuCl
2
]
-Rate is best described
by eqn 2
-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
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 that
accounts for the formation acetaldehyde observed in the KIE studies
C
2
D
4
+ PdCl
4
2-
+ H
2
O
CD
3
CDO + Pd(0) + 2 HCl + 2 Cl
-
C
2
H
4
+ PdCl
4
2-
+ H
2
O
CH
3
CHO + Pd(0) + 2 HCl + 2 Cl
-
k
D
k
H
Observed KIE = k
H
/ k
D
= 1.07
+ PdCl
4
2-
+ H
2
O
H H
D D
H
+
H
2
O
C C
D D
H H
OH Cl
2
(OH
2
)Pd
CH
2
DCDO
CHD
2
CHO
Competitive isotope effect = k
H
/ k
D
= 1.9
Pd
Cl
Cl
OH
2
OH
CH
3
CHO
?
Reaction run in D
2
O shows no incorporation
Solution for Group Exercise
Pd
H
2
O
Cl H
CH
2
OH
Pd
Cl
Cl
OH
2
OH
Pd
H
2
O
Cl
OH
Cl
-
Pd
H
2
O
Cl
OH
CH
3
H
3
C
O
H
Recent computational work
questions ability to undergo #-
Hydride elimination from -OH
(see Goddard, W. A. JACS,
2006, 128, 3132 and reference
therein)
Backup: Ruling out $-Allyl Pathway
Rate of isomerization is
equal to 1/2 rate of
exchange
Rate of exchange is
equal to rate of
isomerization
Backup: Schematic for Industrial Wacker Process