t wilson
TRANSCRIPT
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