Wacker Oxidation H O + – II H , Cl Pd Cl Pamela Tadross H3C H Stoltz Group Literature Presentation OH December 8, 2008 8 PM, 147 Noyes Pdiicl – HO 2 OH Pdiicl

2 CuICl C2H4 – II 2 Cl + 2 Cu Cl2

II 2– Pd Cl4 Cl– O Pd0 H3C H PdIICl – + HCl 3

Mechanistic Studies on H2O the Wacker Oxidation H O + – II H , Cl Pd Cl Pamela Tadross H3C H Stoltz Group Literature Presentation OH December 8, 2008 8 PM, 147 Noyes PdIICl – HO 2 OH PdIICl

H3C Cl– PdIICl Cl Cl – Pd Cl Cl + H2O Pd H2O HO Origins of the Wacker Oxidation

F. C. Phillips, 1894:

2– – PdCl4 + 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. Origins of the Wacker Oxidation

F. C. Phillips, 1894:

2– – PdCl4 + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl

Smidt, Wacker Chemie, 1959:

– 2– Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + PdCl4

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

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. Origins of the Wacker Oxidation

2– – PdCl4 + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl – 2– Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + PdCl4

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

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. Origins of the Wacker Oxidation

2– – PdCl4 + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl – 2– Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + PdCl4

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

C2H4 + 1/2 O2 CH3CHO

Net Result: Air oxidation of ethylene to acetaldehyde!

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. Origins of the Wacker Oxidation

2– – PdCl4 + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl – 2– Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + PdCl4

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

C2H4 + 1/2 O2 CH3CHO

Net Result: Air oxidation of ethylene to acetaldehyde!

! 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!

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. Origins of the Wacker Oxidation

2– – PdCl4 + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl – 2– Pd(0) + 2 CuCl2 + 2 Cl 2 CuCl + PdCl4

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

C2H4 + 1/2 O2 CH3CHO

Net Result: Air oxidation of ethylene to acetaldehyde!

! First organopalladium reaction applied on ! Prior acetaldehyde production: industrial scale. a) Oxymercuration of acetylene b) Dehydrogenation of ethanol ! First rendered commercial in 1960. ! Wacker process eventually replaced ! At one point was responsible for the because of more efficient ways of production of over 2 billion pounds per producing acetic acid (i.e. Monsanto year of acetaldehyde! process).

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. Early Kinetic Studies

Conditions: ! First order in PdII 2– –d[C2H4] k [PdCl ] [C H ] [PdII] = 0.005 - 0.04 M Rate = = 4 2 4 – – 2 + ! Second order Cl inhibition [Cl–] = 0.1 - 1.0 M dt [Cl ] [H ] + [H ] = 0.04 -1.0 M ! 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 Studies Chloride Inhibition

Source of Chloride Inhibition:

2– – 1 Cl Cl Cl – inhibition Pd + C2H4 Pd + Cl – Cl Cl Cl Cl [Cl ]

– 1 Cl + H O Cl + Cl– inhibition Pd 2 Pd [Cl–] Cl Cl Cl OH2

– – OH Outer-sphere hydroxide attack: Cl Cl CH CH OH Pd Pd 2 2 Predicted to be 103 times faster Cl OH2 Cl OH2 than diffusion controlled process

H2O – Cl Cl CH CH OH Outer-sphere water attack: Pd Pd 2 2 + H+ Predicted to occur by an anti Cl OH2 Cl OH2 hydroxypalladation mechanism

– – OH Outer-sphere hydroxide attack: Cl Cl CH CH OH Pd Pd 2 2 Predicted to be 103 times faster Cl OH2 Cl OH2 than diffusion controlled process

H2O – Cl Cl CH CH OH Outer-sphere water attack: Pd Pd 2 2 + H+ Predicted to occur by an anti Cl OH2 Cl OH2 hydroxypalladation mechanism

– – Inner-sphere hydroxyl Cl Cl Cl CH CH OH Pd Pd + H+ Pd 2 2 attack: Predicted to Cl OH Cl OH Cl OH occur by a syn 2 2 hydroxypalladation mechanism

D D O 2– – + PdCl4 + H2O + Pd(0) + 2 HCl + 2 Cl D D D3C D kH = 1.07 k H H O D 2– – + PdCl4 + H2O + Pd(0) + 2 HCl + 2 Cl H H H3C H

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. Kinetic Isotope Effects Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism

D D O 2– – + PdCl4 + H2O + Pd(0) + 2 HCl + 2 Cl D D D3C D kH = 1.07 k H H O D 2– – + PdCl4 + H2O + Pd(0) + 2 HCl + 2 Cl H H H3C H

KIE for decomposition step determined by competitive isotope effect experiment:

H-shift O

DH2C D

D D D D – k 2– H + PdCl4 + H2O HO Pd(OH2)Cl2 = 1.70 k H H H H D

D-shift HD2C H

KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs outer-sphere anti hydroxypalladation before decomposition.

– Cl Cl Cl Cl Pd Pd + + H2O + H H2O H2O CH2CH2OH

O +H+ –H+

H3C H

– – Cl Cl Cl Cl Pd + H O Pd HO 2 H2O CH2CH2OH

inner-sphere syn hydroxypalladation

KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs outer-sphere anti hydroxypalladation before decomposition.

– Cl Cl Cl Cl Pd Pd + + H2O + H H2O H2O CH2CH2OH fast slow

O +H+ –H+

H3C H

fast – slow – Cl Cl Cl Cl Pd + H O Pd HO 2 H2O CH2CH2OH

inner-sphere syn hydroxypalladation anti pathway has decomposition as the slow step

syn pathway has hydroxypalladation as the slow step

KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs outer-sphere anti hydroxypalladation before decomposition.

– Cl Cl Cl Cl Pd Pd + + H2O + H H2O H2O CH2CH2OH

O +H+ –H+

H3C H

fast – slow – Cl Cl Cl Cl Pd + H O Pd HO 2 H2O CH2CH2OH

inner-sphere syn hydroxypalladation anti pathway has decomposition as the slow step

syn pathway has hydroxypalladation as the slow step

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. Early Stereochemical Studies Stille's Work Suggests Anti Hydroxypalladation Mechanism

Cl H2O Cl CO O Pd Pd Cl Na2CO3 Cl O

Key: CO insertion proceeds with retention of stereochemistry at the migrating stereocenter.

Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239. Early Stereochemical Studies Stille's Work Suggests Anti Hydroxypalladation Mechanism

Cl H2O Cl CO O Pd Pd Cl Na2CO3 Cl O

Key: CO insertion proceeds with retention of stereochemistry at the migrating stereocenter.

HO OH

Cl CO O Cl CO O Pd Pd Cl Cl O O

anti hydroxypalladation syn hydroxypalladation

Cl H2O Cl CO O Pd Pd Cl Na2CO3 Cl O

anti hydroxypalladation

Cl H2O Cl CO O Pd Pd Cl Na2CO3 Cl O

anti hydroxypalladation

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

Cl H2O Cl CO O Pd Pd Cl Na2CO3 Cl O

anti hydroxypalladation

HO D HO D O CO H H O H H H2O PdL PdL D n D n H D D D O D H PdCl2 O H H 2 O HO PdL HO PdL H2O n CO n O

H H H H H H D D D D D D

Cl H2O Cl CO O Pd Pd Cl Na2CO3 Cl O

anti hydroxypalladation

HO D HO D O CO H H O H H H2O PdL PdL D n D n H D D D O D H PdCl2 O H H 2 O HO PdL HO PdL H2O n CO n O

H H H H H H D D D D D D

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.

anti hydroxypalladation

HO D HO D O CO H H O H H H2O PdL PdL D n D n H D D D O D H PdCl2 O H H 2 O HO PdL HO PdL H2O n CO n O

H H H H H H D D D D D D

Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239. Bäckvall's Stereochemical Studies Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation

[Cl–] < 1 M O [CuCl2] < 1 M loss of stereochemical information H3C H

H O 2– 2 Cl Cl C2H4 + PdCl4 Pd H2O

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. Bäckvall's Stereochemical Studies Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation

[Cl–] < 1 M O [CuCl2] < 1 M loss of stereochemical information H3C H

H O 2– 2 Cl Cl C2H4 + PdCl4 Pd H2O

[Cl–] > 3 M CH3CHO [CuCl2] > 2.5 M stereochemical + information OH retained (maybe) Cl

[Cl–] < 1 M O [CuCl2] < 1 M loss of stereochemical information H3C H

H O 2– 2 Cl Cl C2H4 + PdCl4 Pd H2O

[Cl–] > 3 M CH3CHO [CuCl2] > 2.5 M stereochemical + information OH retained (maybe) Cl

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].

– Cl Cl Cl Cl 2 CuCl2 Pd Pd + Cl + H2O + H H2O H2O CH2CH2OH OH + 2 CuCl decomposition

! Chloride displacement of Pd occurs with inversion of CH3CHO stereochemistry at carbon.

! Chlorohydrin formation requires – both high [Cl ] and high [CuCl2].

D – Cl Cl D H H D Pd Cl Cl 2 CuCl2 H O + D H 2 + H2O Pd + H H2O OH Cl OH D H D

anti hydroxypalladation

D – Cl Cl D H H D Pd Cl Cl 2 CuCl2 H O + D H 2 + H2O Pd + H H2O OH Cl OH D H D

anti hydroxypalladation

D – Cl Cl H D H H Pd Cl Cl 2 CuCl2 H O + D D 2 + H2O Pd + H H2O OH Cl OH D H D

syn hydroxypalladation

D – Cl Cl D H H D Pd Cl Cl 2 CuCl2 H O + D H 2 + H2O Pd + H H2O OH Cl OH D H D

anti hydroxypalladation

D – Cl Cl H D H H Pd Cl Cl 2 CuCl2 H O + D D 2 + H2O Pd + H H2O OH Cl OH D H D

syn hydroxypalladation

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.

KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs outer-sphere anti hydroxypalladation before decomposition.

– Cl Cl Cl Cl Pd Pd + + H2O + H H2O H2O CH2CH2OH fast slow

O +H+ –H+

H3C H

fast – slow – Cl Cl Cl Cl Pd + H O Pd HO 2 H2O CH2CH2OH

innter-sphere syn hydroxypalladation anti pathway has decomposition as the slow step

syn pathway has hydroxypalladation as the slow step

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. Bäckvall's Stereochemical Studies Reconciling Stereochemical Results with Kinetic Data

– Cl Cl Cl Cl Pd Pd + + H2O + H H2O H2O CH2CH2OH

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. Bäckvall's Stereochemical Studies Reconciling Stereochemical Results with Kinetic Data

– Cl Cl Cl Cl Pd Pd + + H2O + H H2O H2O CH2CH2OH

– Cl Cl Cl Pd Pd + Cl– H2O CH2CH2OH H2O CH2CH2OH slow

– H Cl Cl Pd OH H2O

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. Bäckvall's Stereochemical Studies Reconciling Stereochemical Results with Kinetic Data

– Cl Cl Cl Cl Pd Pd + + H2O + H H2O H2O CH2CH2OH

– Cl Cl Cl Pd Pd + Cl– H2O CH2CH2OH H2O CH2CH2OH slow

– H Cl Cl Since decomposition occurs after the rate-limiting step Pd OH a primary isotope effect would not be predicted. H2O

– Cl O Cl Pd H OH Pd Cl H H2O C H2O CH2CH2OH Pd OH H2O H3C H fast CH3

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. Evidence for Syn Hydroxypalladation The Isomerization of Allyl Alcohol Under Wacker Conditions

OH 2– 2– HO + PdCl4 + H2O H2O + PdCl4 +

k1 k–1 PdII k–1 k1 HO OH

oxidation products

Oxidation of allyl alcohol is directed by the hydroxyl group

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Evidence for Syn Hydroxypalladation The Isomerization of Allyl Alcohol Under Wacker Conditions

OH 2– 2– HO + PdCl4 + H2O H2O + PdCl4 +

k1 k–1 PdII k–1 k1 HO OH

k2 If hydroxypalladation is anti, If hydroxypalladation is syn, isomerization should occur since isomerization should not occur hydroxypalladation is required to since hydroxypalladation is rate be an equilibrium process. oxidation products limiting.

Oxidation of allyl alcohol is directed by the hydroxyl group

2– –d[C2H4] k [PdCl ] [olefin] Rate = = 4 dt [Cl–]2 [H+]

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Evidence for Syn Hydroxypalladation The Isomerization of Allyl Alcohol Under Wacker Conditions

H H

H OH 2– 2– HO D + PdCl4 + H2O H2O + PdCl4 + H D D k1 k–1 H H D PdII k–1 k1 HO OH

H H D D

Oxidation of allyl alcohol is directed by the hydroxyl group

2– –d[C2H4] k [PdCl ] [olefin] Rate = = 4 dt [Cl–]2 [H+]

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Evidence for Syn Hydroxypalladation The Isomerization of Allyl Alcohol Under Wacker Conditions

H H

H OH 2– 2– HO D + PdCl4 + H2O H2O + PdCl4 + H D D k1 k–1 H H D PdII k–1 k1 HO OH

H H D D

Isomerization product was < 3% of the total deuterated allyl alcohol when the reaction was stopped after one half-life.

Hydroxypalladation is NOT an equilibrium process!

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Evidence for Syn Hydroxypalladation The Isomerization of Allyl Alcohol Under Isomerization Conditions

H H

H OH 2– [Cl–] = 3.3 M 2– HO D + PdCl4 + H2O H2O + PdCl4 + H D D k1 k–1 H H D PdII k–1 k1 HO OH

H H D D

2– –d[C2H4] k [PdCl ] [olefin] Rate = = 4 dt [Cl–]

Only isomerization observed.

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Evidence for Syn Hydroxypalladation The Isomerization of Allyl Alcohol Under Isomerization Conditions

H H

H OH 2– [Cl–] = 3.3 M 2– HO D + PdCl4 + H2O H2O + PdCl4 + H D D k1 k–1 H H D PdII k–1 k1 HO OH

Reactions at high and low chlorideH do nHotD proDceed through the same mechanism.

Formation of aldehyde and chlorohydrink2 does not occur through a common If hydroxypalladation is anti, hydroxypalladation intermediate. If hydroxypalladation is syn, isomerization should occur since isomerization should not occur hydroxypalladation is required to since hydroxypalladation is rate be an equilibrium process. oxidation products limiting.

2– –d[C2H4] k [PdCl ] [olefin] Rate = = 4 dt [Cl–]

Only isomerization observed.

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Anti Hydroxypalladation at High [Cl–] Henry's Proposed Pathway

2– – Cl Cl OH Pd + OH Cl Cl – Cl Cl Pd + Cl Cl D D D D

– 2– OH Cl Cl CD OH Cl Cl Pd 2 + Pd + H2O Cl CH + H Cl D D CH2OH

outer-sphere anti hydroxypalladation

– 2– OH Cl Cl Cl Cl CD OH Pd Pd 2 + Cl CH + H Cl H + H2O D H CH2OH D

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Anti Hydroxypalladation at High [Cl–] Henry's Proposed Pathway

2– – Cl Cl OH Pd + OH Cl Cl – Cl Cl Pd + Cl Cl D D D D

– 2– OH Cl Cl CD OH Cl Cl Pd 2 + Pd + H2O Cl CH + H Cl D D CH2OH

outer-sphere anti hydroxypalladation

– 2– OH Cl Cl Cl Cl CD OH Pd Pd 2 + Cl CH + H Cl H + H2O D H CH2OH D

Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. Reinterpreting Bäckvall's Results Henry's Proposed Pathway

– Cl Cl Cl– ligand loss prevented by high PdCl 2– + C H Pd + Cl– 4 2 4 Cl concentration of Cl–.

– 2– H O Excess Cl– prevents this intermediate Cl Cl – 2 Cl Cl Pd + Cl Pd from undergoing decomposition to Cl Cl CH CH OH 2 2 oxidation products.

outer-sphere anti hydroxypalladation

2– Assumption that oxidation products Cl Cl CuCl2 OH Pd Cl and chlorohydrin arise from a common Cl CH2CH2OH intermediate is NOT valid.

Gregor, N.; Zaw, K.; Henry, P. M. Organometallics 1984, 3, 1251. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

H H

F3C OH 2– 2– F3C CF3 + PdCl4 + H2O H2O + PdCl4 + HO F C CD H3C 3 3 H3C CD3

Required Properties: ! Substrate cannot undergo oxidation; can only isomerize.

! Substrate whose RLS is hydroxypalladation. oxidation products oxidation products ! Substrate possesses stereochemistry that can be used to distinguish between syn and anti hydroxypalladation.

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

H H

F3C OH 2– 2– F3C CF3 + PdCl4 + H2O H2O + PdCl4 + HO F C CD H3C 3 3 H3C CD3

k1 k–1

k–1 k1 H PdII oxidation products oxidation products F3C CF3

H3C CD3 OH OH

Exchange is completely symmetric, thus the rate of isomerization depends only on the rate of formation of the hydroxypalladate and not on its equilibrium concentration.

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

H H

F3C OH 2– 2– F3C CF3 + PdCl4 + H2O H2O + PdCl4 + HO F C CD H3C 3 3 H3C CD3

k1 k–1

k–1 k1 H PdII oxidation products oxidation products F3C CF3

H3C CD3 OH OH

For syn hydroxypalladation: For anti hydroxypalladation:

2– 2– –d[C2H4] k [PdCl ] [olefin] –d[C2H4] k [PdCl ] [olefin] Rate = = 4 Rate = = 4 dt [Cl–]2 [H+] dt [Cl–]

Proton inhibition term must result from an Proton inhibition term does not show up in the equilibrium that occurs before the rate-limiting exchange rate because it results from this hydroxypalladation step. exchange equilibrium.

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

H H

F3C OH 2– 2– F3C CF3 + PdCl4 + H2O H2O + PdCl4 + HO F C CD H3C 3 3 H3C CD3

k1 k–1

k–1 k1 H PdII oxidation products oxidation products F3C CF3

H3C CD3 OH OH

For syn hydroxypalladation: Observed Kinetics under Wacker Conditions: Rate expression had a first order proton 2– ! –d[C2H4] k [PdCl4 ] [olefin] inhibition term. Rate = = dt [Cl–]2 [H+] ! Rate expression was identical to the Wacker rate expression. Proton inhibition term must result from an equilibrium that occurs before the rate-limiting ! Consistent with syn hydroxypalladation hydroxypalladation step. mechanism.

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

H H

F3C OH 2– 2– F3C CF3 + PdCl4 + H2O H2O + PdCl4 + HO F C CD H3C 3 3 H3C CD3

k1 k–1

k–1 k1 H PdII oxidation products oxidation products F3C CF3

H3C CD3 OH OH

For anti hydroxypalladation: Observed Kinetics under High [Cl–] Conditions:

! Rate expression had no first order proton 2– –d[C2H4] k [PdCl ] [olefin] inhibition term. Rate = = 4 dt [Cl–] ! Rate expression was identical to what – Bäckvall observed at high [Cl ]. Proton inhibition term does not show up in the exchange rate because it results from this ! Consistent with anti hydroxypalladation exchange equilibrium. mechanism.

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 + – PdII – H PdII CF CF 3 – H O H 3 H CH3 2 CH3 (R), Z

CD3 F3C 2– CH3 PdCl HO 4

H CF3 H2O (R), E

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 + – PdII – H PdII CF CF 3 – H O H 3 H CH3 2 CH3 (R), Z

CD3 F3C 2– CH3 PdCl HO 4

H CF3 H2O (R), E

CD CD F C 3 3 + 3 CH3 + CH3 – H + H F3C HO CF3 CF3 II II – Pd syn Pd H OH – H2O H OH (S), E

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 + – PdII – H PdII CF CF 3 – H O H 3 H CH3 2 CH3 (R), Z

product CD3 F3C substrate % 2– CH3 PdCl isomeriz- HO 4 – config % ee [Cl ] [catalyst] ation % S % R R 100 0.10 PdCl 2– 30 32.5 67.5 H CF3 H2O 4 2– R 100 0.05 PdCl4 48 50.0 50.0 (R), E 2– S 100 0.10 PdCl4 25 72.5 27.5 2– S 100 0.05 PdCl4 50 50.0 50.0

CD CD F C 3 3 + 3 CH3 + CH3 – H + H F3C HO CF3 CF3 II II – Pd syn Pd H OH – H2O H OH (S), E

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 + – PdII – H PdII CF CF 3 – H O H 3 H CH3 2 CH3 (R), Z

CD CD F C 3 3 + 3 CH3 + CH3 – H + H F3C HO CF3 CF3 II II – Pd syn Pd H OH – H2O H OH (S), E

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 + – PdII – H PdII CF CF 3 – H O H 3 H CH3 2 CH3 (R), Z

CD3 substrate product F3C 2– CH3 PdCl [Cl–] HO 4 config % ee % isomerization % Z % S % R R 100 2.0 31 30 0.0 100 H O H CF3 2 R 100 3.5 27 25 0.0 100 (R), E S 100 2.0 35 32 100 0.0 S 100 3.5 45 45 100 0.0

CD CD F C 3 3 + 3 CH3 + CH3 – H + H F3C HO CF3 CF3 II II – Pd syn Pd H OH – H2O H OH (S), E

Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 + – PdII – H PdII CF CF 3 – H O H 3 H CH3 2 CH3 (R), Z

CD CD F C 3 3 + 3 CH3 + CH3 – H + H F3C HO CF3 CF3 II II – Pd syn Pd H OH – H2O H OH (S), E

Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 II – H+ II – Pd Pd CF3 CF3 – – H O H high [Cl ] H CH3 2 CH3 (R), Z

CD3 Conclusions: F3C CH3 PdCl 2– ! At low [Cl–] (Wacker conditions), syn hydroxypalladation is HO 4 operative.

H CF3 H2O ! At high [Cl–] (Bäckvall's conditions), anti hydroxypalladation is (R), E operative.

– low [Cl ] CD CD F C 3 3 + 3 CH3 + CH3 – H + H F3C HO CF3 CF3 II II – Pd syn Pd H OH – H2O H OH (S), E

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe

CD3 CF3 anti F3C OH + H+ D C OH HO 3 II – H+ II – Pd Pd CF3 CF3 – – H O H high [Cl ] H CH3 2 CH3 (R), Z

Criticism: CD3 ! Trisubstituted alkenes are not standard Wacker substrates. F3C CH3 PdCl 2– HO 4 ! Substrate cannot undergo oxidation. H CF H O 3 2 ! Would be best to study a substrate that can undergo both – (R), E oxidation and isomerization under both low and high [Cl ] concentrations.

– low [Cl ] CD CD F C 3 3 + 3 CH3 + CH3 – H + H F3C HO CF3 CF3 II II – Pd syn Pd H OH – H2O H OH (S), E

Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Chirality Transfer Studies

H HO R1 R2

H H (R), Z reactive conformation

Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. Chirality Transfer Studies R2 [Cl–] > 2 M H OH II – Pd 1 H R anti HO – H2O H H OH R2 (S), Z + – H PdII R1 H H R2 – [Cl ] = 0.1 M O OH – Pd0 H 1 HO – H+ R R1 PdCl 2– H R2 4 (S) H H H2O H – 1 (R), Z [Cl ] > 2 M R2 R reactive H II conformation – Pd H HO – H2O H OH – H+ H R2 R1 (R), E II syn Pd H OH R2 1 [Cl–] = 0.1 M O R H – Pd0 – H+ OH

Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. (R) Chirality Transfer Studies R2 [Cl–] > 2 M H OH II – Pd 1 H R anti HO – H2O H H OH R2 (S), Z + – H PdII R1 H H R2 – [Cl ] = 0.1 M O OH – Pd0 H 1 HO – H+ R R1 PdCl 2– H R2 4 (S) H H H2O H – 1 (R), Z [Cl ] > 2 M R2 R reactive H II conformation – Pd H HO – H2O H OH – H+ H R2 R1 (R), E II syn Pd H OH R2 1 [Cl–] = 0.1 M O R H – Pd0 – H+ OH

Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. (R) Chirality Transfer Studies Me [Cl–] > 2 M H Ph – PdII H Me anti HO – H2O H H Ph Me (S), Z + – H PdII Me H H Me – [Cl ] = 0.1 M O Ph – Pd0 H HO – H+ Me Me H Me PhPdCl (S)

H H MeOH H – (R), Z [Cl ] > 2 M Me Me reactive H II conformation – Pd H HO – H2O H Ph – H+ H Me Me (R), E II syn Pd H Ph Me [Cl–] = 0.1 M O Me H – Pd0 – H+ Ph (R) Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. Chirality Transfer Studies Me [Cl–] > 2 M H Ph – PdII H Me anti HO – H2O H H Ph Me (S), Z + – H PdII Me H H Me – [Cl ] = 0.1 M O Ph – Pd0 H HO – H+ Me Me H Me PhPdCl PhPdCl must add (S) syn regardless of H H MeOH the [Cl–] H – (R), Z [Cl ] > 2 M Me Me reactive H II conformation – Pd H HO – H2O H Ph – H+ H Me Me (R), E II syn Pd H Ph Me [Cl–] = 0.1 M O Me H – Pd0 – H+ Ph (R) Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. Chirality Transfer Studies Me [Cl–] > 2 M H OH – PdII H Et anti HO – H2O H H OH Me (S), Z + – H PdII Et H H Me – [Cl ] = 0.1 M O OH – Pd0 H HO – H+ Et Et PdCl 2– H Me 4 (S) H H H2O H – (R), Z [Cl ] > 2 M Me Et reactive H II conformation – Pd H HO – H2O H OH – H+ H Me Et (R), E II syn Pd H OH Me [Cl–] = 0.1 M O Et H – Pd0 – H+ OH

Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. (R) Chirality Transfer Studies Me [Cl–] > 2 M H OH – PdII H Et anti HO – H2O H H OH Me (S), Z + – H PdII Et H H Me – [Cl ] = 0.1 M O OH – Pd0 H HO – H+ Et Et PdCl 2– H Me 4 the stereochemistry of hydroxypalladation (S) must be different at high and low [Cl–] H H H2O H – (R), Z [Cl ] > 2 M Me Et reactive H II conformation – Pd H HO – H2O H OH – H+ H Me Et (R), E II syn Pd H OH Me [Cl–] = 0.1 M O Et H – Pd0 – H+ OH

Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. (R) Chirality Transfer Studies Me [Cl–] > 2 M H OH – PdII H Et anti HO – H2O H H OH Me (S), Z + – H PdII Et H H Me – [Cl ] = 0.1 M O OH – Pd0 H ! Excess Cl– prevents syn hydroxypalladation by HO – H+ Et Et PdCl 2– prohibiting the ligation of water. H Me 4 (S) ! Excess Cl– prevents "-hydride elimination to oxidation H H H2O products by prohibiting the necessary dissociation – H of a Cl ligand. – (R), Z [Cl ] > 2 M Me Et reactive H II conformation – Pd H HO – H2O H OH – H+ H Me Et (R), E II syn Pd H OH Me [Cl–] = 0.1 M O Et H – Pd0 – H+ OH

Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. (R) Mechanism for Oxidation of Olefins under Wacker Conditions

1 1 inhibition inhibition [Cl–] [Cl–]

H2C CH2 + H2O 2– – – – Cl Cl – Cl Cl Cl – Cl Cl Cl Pd Pd Pd Cl Cl Cl H2O

O 1 + – + CuCl2 inhibition – H [H+] + O2 H3C H

– – – Cl Cl – H2O Cl Cl + H2O Cl Cl Pd Pd Pd OH H2O OH HO

syn hydroxypalladation

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. Mechanism for Oxidation of Olefins under Wacker Conditions

1 1 inhibition inhibition [Cl–] [Cl–]

H2C CH2 + H2O 2– – – – Cl Cl – Cl Cl Cl – Cl Cl Cl Pd Pd Pd Cl Cl Cl H2O

O 1 + – + CuCl2 inhibition – H [H+] + O2 H3C H

– – – Cl Cl – H2O Cl Cl + H2O Cl Cl Pd Pd Pd OH H2O OH HO

syn hydroxypalladation

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. Mechanism for Decomposition to Oxidation Products

Moiseev's Mechanism:

– – O Cl Cl Cl Cl Pd Pd OH OH H OH -hydride H ! dissociation tautomerize elimination

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. Mechanism for Decomposition to Oxidation Products

Moiseev's Mechanism:

– – O Cl Cl Cl Cl Pd Pd OH OH H OH -hydride H ! dissociation tautomerize elimination

D D O 2– – + PdCl4 + H2O + Pd(0) + 2 HCl + 2 Cl D D D3C D

H H O 2– – + PdCl4 + D2O + Pd(0) + 2 DCl + 2 Cl H H H3C H

lack of proton incorporation from solvent means that tautomerization mechanism is invalid

Henry's Model

– H H H H H O Cl Cl H O Pd + Pd(0) + HCl OH Cl Pd H H H H Cl

PdII-assisted hydride shift

Henry's Model

– H H H H H O Cl Cl H O Pd + Pd(0) + HCl OH Cl Pd H H H H Cl

PdII-assisted hydride shift

Bäckvall's Model

– – – Cl Cl Cl Cl Cl Cl Pd Pd Pd OH H OH OH !-hydride reinsertion elimination

O + Pd(0) + HCl !-hydride elimination from oxygen H

– Cl Cl O H Pd O PdIICl + Pd(0) + HCl OH H3C H !-hydride elimination from oxygen 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. Mechanism for Decomposition to Oxidation Products Computational Studies Bäckvall's Model

– Cl Cl O H Pd O PdIICl + Pd(0) + HCl OH H3C H !-hydride elimination from oxygen Goddard's Computations

4-membered TS: 36.3 kcal/mol

– Cl Cl O H Pd O PdIICl + Pd(0) + HCl OH H3C H β-hydride elimination from oxygen Goddard's Computations

4-membered TS: 36.3 kcal/mol Cl-mediated reductive elimination TS: 18.7 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. From Industrial Process to Synthetic Method Preparations of Methyl Ketones from Terminal Olefins

Clement, 1964: O PdCl2 (10 mol%) oxidant

H2O (12-17%), O2 DMF

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 Method Preparations of Methyl Ketones from Terminal Olefins

Clement, 1964: O PdCl2 (10 mol%) oxidant

H2O (12-17%), O2 DMF

oxidant = CuCl2•2H2O (10 mol%) or p-benzoquinone

OH MeO O H H O O H H MeO O O intermediate to Zearalenone Dichroanone 19-Nortestosterone H O O O O O H OTHP

Nootkatone Brevicomin intermediate to Coriolin Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241. Tsuji, J. Synthesis 1984, 369. From Industrial Process to Synthetic Method Oxidative Cyclizations Give Access to Heterocyclic Compounds

Moritani, 1973:

PdCl2(PhCN)2 (1 equiv) R R PhH O–Na+ O

Hosokawa, T.; Maeda, K.; Koga, K.; Moritani, I. Tetrahedron Lett. 1973, 10, 739. From Industrial Process to Synthetic Method Oxidative Cyclizations Give Access to Heterocyclic Compounds

Moritani, 1973:

PdCl2(PhCN)2 (1 equiv) R R PhH O–Na+ O

Pd(dba)2 (5 mol%) Pd(OAc)2 (2 mol%) KHCO3 (1.1 equiv) Cu(OAc)2•H2O (1 equiv)

O air, DMSO, H2O OH air, DMF, 100 °C O 60 °C no co-oxidant!

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. From Industrial Process to Synthetic Method Oxidative Cyclizations Give Access to Heterocyclic Compounds

Moritani, 1973:

PdCl2(PhCN)2 (1 equiv) R R PhH O–Na+ O

Pd(dba)2 (5 mol%) Pd(OAc)2 (2 mol%) KHCO3 (1.1 equiv) Cu(OAc)2•H2O (1 equiv)

O air, DMSO, H2O OH air, DMF, 100 °C O 60 °C no co-oxidant!

O Pd(TFA)2 (10 mol%) ligand (20 mol%) i-Pr N N i-Pr p-benzoquinone O OH (4 equiv) MeOH, 60 °C 96% ee O

Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071. From Industrial Process to Synthetic Method Oxidative Cyclizations Give Access to Heterocyclic Compounds

H H Boc O N BnO O O MeO2C H H O BnO OBn

O O O O N H O

NTs N N N H Ts O

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. Stereochemistry of Oxidative Cyclizations

PdLn

H R O O OH R R anti PdL !-hydride oxypalladation n elimination

H R O O O PdLn R R syn PdL !-hydride oxypalladation n elimination Stereochemistry of Oxidative Cyclizations Stoltz Group Studies

Pd(TFA)2 (5 mol%) pyridine (20 mol%) Na2CO3 (2 equiv)

OH MS3Å, O2 (1 atm) O PhCH3, 80 °C 95% yield

Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892. Stereochemistry of Oxidative Cyclizations Stoltz Group Studies

Pd(TFA)2 (5 mol%) pyridine (20 mol%) Na2CO3 (2 equiv)

OH MS3Å, O2 (1 atm) O PhCH3, 80 °C 95% yield

O O CO2Et O

O NTs O NOBn

90% yield 88% yield 63% yield 82% yield

O O O O

87% yield 93% yield 62% yield

Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892. Stereochemistry of Oxidative Cyclizations Stoltz Group Studies

II E [PdII] E [Pd ] E H H D E E E OH D O D O anti oxypalladation HO

CO2Et D CO2Et

E E H E H H E H E E O [PdII] D O [Pd] D O

syn oxypalladation

Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. Stereochemistry of Oxidative Cyclizations Stoltz Group Studies

II E [PdII] E [Pd ] E H H D E E E OH D O D O anti oxypalladation HO O O D + CO2Et CO2Et CO2Et D H H CO2Et CO2Et CO2Et

E E H E H H E H E E O [PdII] D O [Pd] D O

syn oxypalladation

Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. Stereochemistry of Oxidative Cyclizations Stoltz Group Studies

II E [PdII] E [Pd ] E H H D E E E O OH D O D O O O anti oxypalladation HO O

CO2Et D CO2Et

E E H E H H E H E E O O [PdII] D O [Pd] D O O O syn oxypalladation

Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. Stereochemistry of Oxidative Cyclizations Stoltz Group Studies

II E [PdII] E [Pd ] E H H D E E E O OH D O D O O O anti oxypalladation O HO O O

CO2Et CO2Et D D CO2Et CO2Et

E E H E H H E H E E O O [PdII] D O [Pd] D O O O syn oxypalladation

Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. Stereochemistry of Oxidative Cyclizations Hayashi Group Studies H H D

Pd(MeCN)4(BF4)2 (5 mol%) (S,S)-ip-boxax (Pd/L* = 1/2) O O D A B benzoquinone (4 equiv) MeOH, 40 °C, 4 h OH A:B:C:D = 16:46:29:9 syn O D O D oxypalladation C D

Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036. Stereochemistry of Oxidative Cyclizations Hayashi Group Studies H H D

Pd(MeCN)4(BF4)2 (5 mol%) (S,S)-ip-boxax (Pd/L* = 1/2) O O D A B benzoquinone (4 equiv) MeOH, 40 °C, 4 h OH A:B:C:D = 16:46:29:9 syn O D O D oxypalladation C D

H H D PdCl2(MeCN)2 (10 mol%) Na2CO3 (2 equiv) LiCl (2 equiv) O O D A B benzoquinone (1 equiv) THF, 65 °C, 24 h OH D A:B:C:D = 6:5:7:82

anti D oxypalladation O O C D

Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036. Stereochemistry of Oxidative Cyclizations Stahl Group Studies

Ts N H anti LnPd aminopalladation Ts DPd Ts N N D H D Ts N H NHTs

D Ts N D LnPd Ts HPd Ts N N D D syn Ts aminopalladation N D

Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. Stereochemistry of Oxidative Cyclizations Stahl Group Studies

Ts N H anti LnPd aminopalladation Ts DPd Ts N N D H D Ts N H NHTs No additive: 2:1 ratio syn:anti aminopalladation products D Ts N D LnPd Ts HPd Ts N N D D syn Ts aminopalladation N D

Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. Stereochemistry of Oxidative Cyclizations Stahl Group Studies

Ts N H anti LnPd aminopalladation Ts DPd Ts N N D H D Ts N H

NHTs CF3CO2H Additive: 1:2 ratio syn:anti D aminopalladation products Ts N D LnPd Ts HPd Ts N N D D syn Ts aminopalladation N D

Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. Stereochemistry of Oxidative Cyclizations Stahl Group Studies

Ts N H anti LnPd aminopalladation Ts DPd Ts N N D H D Ts N H

NHTs NaOAc or Na2CO3 Additive: exclusively syn D aminopalladation products Ts N D LnPd Ts HPd Ts N N D D syn Ts aminopalladation N D

Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. Conclusions

Pd Source and Ligands

Additive Effects Solvent (co-oxidant, acid, base, Effects salts) (H2O, ROH, DMSO, etc.) syn vs. anti heteropalladation or carbopalladation

Olefin Nucleophile Sterics and Electronics Sterics and Electronics The Wacker Oxidation One-Stage Process

purge

C2H4 t n n o i e

Reactor t a m r p i a u C2H4, O2 PdCl2, CuCl2, HCl C2H4, CH3CHO p q e S E

! 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. CH3CHO

Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120. The Wacker Oxidation Two-Stage Process

! Required brick and rubber-lined reactors and titanium pipes.

! Uses ambient air as O2 source and impure mixtures of CH CHO ethylene. 3

! Operates at 90-100 °C, 10 atm.

! Yields >95% acetaldehyde.

C H t

2 4 n

PdCl2, (CuCl)2, HCl n o i e Oxidation t a m r

Reactor p i a u + CH CHO p

3 e q E PdCl2, CuCl2, S HCl

PdCl2, (CuCl)2, HCl N 2 Regeneration Reactor air

Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120.