2 CuICl Cl– 2 +2 C2H4 CuIICl2 PdIICl42– Cl– O Pd0 H3C H + HCl Mechanistic Studies on the Wacker Oxidation H2O H O H3C PdIICl3– H+, Cl– PdIICl Pamela Tadross H PdIICl2– HO PdIICl OH H3C PdIICl Cl Cl Pd H2O OH Stoltz Group Literature Presentation December 8, 2008 8 PM, 147 Noyes + H2O Cl– Cl Cl Pd HO – Origins of the Wacker Oxidation F. C. Phillips, 1894: PdCl42– + 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: PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl– Smidt, Wacker Chemie, 1959: Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + 1/2 O2 + 2 HCl 2 CuCl + PdCl42– 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 PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl– Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42– 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 PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl– Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42– 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 PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl– Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42– 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 PdCl42– + C2H4 + H2O Pd(0) + CH3CHO + 2 HCl + 2 Cl– Pd(0) + 2 CuCl2 + 2 Cl– 2 CuCl + PdCl42– 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. ! Prior acetaldehyde production: a) Oxymercuration of acetylene b) Dehydrogenation of ethanol ! First rendered commercial in 1960. ! At one point was responsible for the production of over 2 billion pounds per year of acetaldehyde! ! Wacker process eventually replaced because of more efficient ways of producing acetic acid (i.e. Monsanto 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: [PdII] = 0.005 - 0.04 M – [Cl ] = 0.1 - 1.0 M [H+] = 0.04 -1.0 M ! First order in PdII Rate = –d[C2H4] dt = k [PdCl42–] [C2H4] [Cl–]2 [H+] ! Second order Cl– inhibition ! 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 Conditions: ! First order in PdII [PdII] = 0.005 - 0.04 M – [Cl ] = 0.1 - 1.0 M [H+] = 0.04 -1.0 M Rate = –d[C2H4] dt = k [PdCl42–] [C2H4] [Cl–]2 [H+] ! Second order Cl– inhibition ! First order acid inhibition Source of Chloride Inhibition: 2– Cl Cl Pd Cl Cl – + C2H4 Cl Pd Cl Cl + Cl– – Cl Pd Cl Cl + H2O Cl Pd Cl OH2 + Cl– 1 [Cl–] 1 [Cl–] inhibition 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 Proton Inhibition Conditions: ! First order in PdII [PdII] = 0.005 - 0.04 M – [Cl ] = 0.1 - 1.0 M [H+] = 0.04 -1.0 M Cl Pd Cl OH2 Rate = –d[C2H4] dt = k [PdCl42–] [C2H4] [Cl–]2 [H+] ! Second order Cl– inhibition ! First order acid inhibition –OH – Cl CH2CH2OH Pd Cl OH2 Outer-sphere hydroxide attack: Predicted to be 103 times faster than diffusion controlled process 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 Proton Inhibition Conditions: ! First order in PdII [PdII] = 0.005 - 0.04 M – [Cl ] = 0.1 - 1.0 M [H+] = 0.04 -1.0 M Cl Pd Cl OH2 Cl Pd Cl OH2 Rate = –d[C2H4] dt = k [PdCl42–] [C2H4] [Cl–]2 [H+] ! First order acid inhibition –OH – Cl CH2CH2OH Pd Cl OH2 H2O ! Second order Cl– inhibition – Cl CH2CH2OH Pd Cl OH2 + H+ Outer-sphere hydroxide attack: Predicted to be 103 times faster than diffusion controlled process Outer-sphere water attack: Predicted to occur by an anti hydroxypalladation mechanism 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 Proton Inhibition Conditions: ! First order in PdII [PdII] = 0.005 - 0.04 M – [Cl ] = 0.1 - 1.0 M [H+] = 0.04 -1.0 M Cl Pd Cl OH2 Cl Pd Cl OH2 Rate = –d[C2H4] dt = k [PdCl42–] [C2H4] [Cl–]2 ! First order acid inhibition –OH – Cl CH2CH2OH Pd Cl OH2 H2O ! Second order Cl– inhibition [H+] – Cl CH2CH2OH Pd Cl OH2 + H+ Outer-sphere hydroxide attack: Predicted to be 103 times faster than diffusion controlled process Outer-sphere water attack: Predicted to occur by an anti hydroxypalladation mechanism – – Cl Pd Cl OH2 Cl Pd Cl OH + H+ Cl CH2CH2OH Pd Cl OH2 Inner-sphere hydroxyl attack: Predicted to occur by a syn hydroxypalladation mechanism 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. Kinetic Isotope Effects Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism D D O + PdCl42– + H2O D H D D3C H H D kH kD O + PdCl42– + H2O H + Pd(0) + 2 HCl + 2 Cl– = 1.07 + Pd(0) + 2 HCl + 2 Cl– 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 + PdCl42– + H2O D H D D3C H D kH kD O + PdCl42– + H2O H + Pd(0) + 2 HCl + 2 Cl– H = 1.07 + Pd(0) + 2 HCl + 2 Cl– H3C H KIE for decomposition step determined by competitive isotope effect experiment: O H-shift DH2C D D D + PdCl42– + H2O H H – D HO D kH Pd(OH2)Cl2 H kD H = 1.70 O D-shift HD2C 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 outer-sphere anti hydroxypalladation Cl Cl Pd H2O + H2O KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition. Cl Cl Pd H2O CH2CH2OH – + H+ O +H+ –H+ H3C Cl Cl Pd HO – + H2O Cl Cl Pd H2O CH2CH2OH H – inner-sphere syn hydroxypalladation 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 outer-sphere anti hydroxypalladation Cl Cl Pd H2O KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition. Cl Cl Pd H2O CH2CH2OH + H2O – + H+ fast slow O +H+ –H+ H3C Cl Cl Pd HO – slow + H2O Cl Cl Pd H2O CH2CH2OH inner-sphere syn hydroxypalladation – H fast 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. Kinetic Isotope Effects Early Evidence for an Inner-Sphere Syn Hydroxypalladation Mechanism outer-sphere anti hydroxypalladation Cl Cl Pd H2O KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition. Cl Cl Pd H2O CH2CH2OH + H2O – + H+ O +H+ –H+ H3C Cl Cl Pd HO – slow + H2O Cl Cl Pd H2O CH2CH2OH inner-sphere syn hydroxypalladation – H fast 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 OH Cl Pd Cl H2O Na2CO3 Pd Cl Cl CO O 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 OH Cl Pd Cl H2O Pd Na2CO3 Cl Cl O CO O Key: CO insertion proceeds with retention of stereochemistry at the migrating stereocenter. HO OH Cl Pd Cl CO O Cl Pd Cl CO O O anti hydroxypalladation O syn hydroxypalladation 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 HO Cl Pd Cl H2O Na2CO3 Pd Cl Cl CO O O anti hydroxypalladation 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 HO Cl Pd Cl H2O Na2CO3 Cl Pd Cl CO O 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 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 HO Cl Pd Cl H2O Na2CO3 O CO Cl Pd Cl O anti hydroxypalladation HO H2O D H D D D H CO HO H PdLn D O H O PdLn D O H D H D PdCl2 H H O 2 H2O HO H D PdLn D H CO O HO H D PdLn D H O H D Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239. D H Early Stereochemical Studies Stille's Work Suggests Anti Hydroxypalladation Mechanism HO Cl Pd Cl H2O Na2CO3 O CO Cl Pd Cl O anti hydroxypalladation HO H2O D H D D D H CO HO H PdLn D O H O PdLn D O H D H D PdCl2 H H O 2 H2O HO H D PdLn D H CO O HO H D PdLn D H O H D Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239. D H Early Stereochemical Studies Stille's Work Suggests Anti Hydroxypalladation Mechanism 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 H2O D H D D D H CO HO H PdLn D O H O PdLn D O H D H D PdCl2 H H O 2 H2O HO H D PdLn D H CO O HO H D PdLn D H O H D Stille, J. K. J. Organomet. Chem. 1976, 108, 401. Stille, J. K.; Divakarumi, R. J. J. Organomet. Chem. 1979, 169, 239. D H Bäckvall's Stereochemical Studies Further (More Convincing) Evidence for Outer-Sphere Anti Hydroxypalladation [Cl–] < 1 M [CuCl2] < 1 M O H3C C2H4 + PdCl42– H2O H loss of stereochemical information Cl Cl 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 [CuCl2] < 1 M O H3C C2H4 + PdCl42– H2O H loss of stereochemical information Cl Cl Pd H2O [Cl–] > 3 M [CuCl2] > 2.5 M Cl CH3CHO + OH stereochemical information retained (maybe) 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 [CuCl2] < 1 M O H3C C2H4 + PdCl42– H2O H loss of stereochemical information Cl Cl Pd H2O [Cl–] > 3 M [CuCl2] > 2.5 M Cl CH3CHO + OH stereochemical information retained (maybe) 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]. 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 Cl Pd H2O + H2O Cl Cl Pd H2O CH2CH2OH – + H+ 2 CuCl2 Cl OH + 2 CuCl decomposition CH3CHO ! Chloride displacement of Pd occurs with inversion of stereochemistry at carbon. ! Chlorohydrin formation requires both high [Cl–] and high [CuCl2]. 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 Cl Pd H2O D D + H2O D H Cl Cl Pd H2O OH H D – + H+ 2 CuCl2 H D Cl D H OH anti hydroxypalladation 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 Cl Pd H2O D + H2O D D H Cl Cl Pd H2O OH H D – + H+ 2 CuCl2 H D D H Cl OH anti hydroxypalladation Cl Cl Pd H2O D D + H2O H D Cl Cl Pd H2O OH H D – + H+ 2 CuCl2 H D Cl H D OH syn hydroxypalladation 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 Cl Pd H2O D + H2O D D H Cl Cl Pd H2O OH H D – + H+ 2 CuCl2 H D D H Cl OH anti hydroxypalladation Cl Cl Pd H2O D D + H2O H D Cl Cl Pd H2O OH H D – + H+ 2 CuCl2 H D Cl H D OH 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. 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 An Apparent Contradiction with KIE Studies outer-sphere anti hydroxypalladation Cl Cl Pd H2O KIE 1.07 and competitive KIE of 1.70 indicates that the slow step occurs before decomposition. Cl Cl Pd H2O CH2CH2OH + H2O – + H+ fast slow O +H+ –H+ H3C Cl Cl Pd HO – slow + H2O Cl Cl Pd H2O CH2CH2OH innter-sphere syn hydroxypalladation – H fast 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 Pd H2O + H2O Cl Cl Pd H2O CH2CH2OH – + H+ 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 Pd H2O Cl Cl Pd H2O CH2CH2OH + H2O Cl Cl Pd H2O CH2CH2OH – – + H+ Cl Pd H2O CH2CH2OH + Cl– slow – H Cl Cl Pd H2O OH 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 Pd H2O Cl Cl Pd H2O CH2CH2OH + H2O Cl Cl Pd H2O CH2CH2OH – – + H+ Cl Pd H2O CH2CH2OH + Cl– slow – H Cl Cl Pd H2O OH Since decomposition occurs after the rate-limiting step a primary isotope effect would not be predicted. – Cl Pd H2O CH2CH2OH fast Cl H Pd H2O OH O Cl Pd H OH H2O C CH3 H3C H 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 + PdCl 2– + H O 4 2 H2O + PdCl42– + HO k1 k–1 PdII k–1 HO k1 OH k2 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 + PdCl 2– + H O 4 2 H2O + PdCl42– + HO k1 k–1 PdII k–1 HO k1 OH k2 If hydroxypalladation is anti, isomerization should occur since hydroxypalladation is required to be an equilibrium process. oxidation products If hydroxypalladation is syn, isomerization should not occur since hydroxypalladation is rate limiting. Oxidation of allyl alcohol is directed by the hydroxyl group Rate = –d[C2H4] dt = k [PdCl42–] [olefin] [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 + PdCl 2– + H O 4 2 H H2O + PdCl42– + HO k1 D D k–1 PdII k–1 HO H H D D k1 OH H H D D k2 If hydroxypalladation is anti, isomerization should occur since hydroxypalladation is required to be an equilibrium process. oxidation products If hydroxypalladation is syn, isomerization should not occur since hydroxypalladation is rate limiting. Oxidation of allyl alcohol is directed by the hydroxyl group Rate = –d[C2H4] dt = k [PdCl42–] [olefin] [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 + PdCl 2– + H O 4 2 H H2O + PdCl42– + HO k1 D D k–1 PdII k–1 HO H H D D k1 OH H H D D k2 If hydroxypalladation is anti, isomerization should occur since hydroxypalladation is required to be an equilibrium process. oxidation products If hydroxypalladation is syn, isomerization should not occur since hydroxypalladation is rate limiting. 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 + PdCl 2– + H O 4 2 H H2O + PdCl42– + HO [Cl–] = 3.3 M k1 D D k–1 PdII k–1 H H D D k1 HO OH H H D D k2 If hydroxypalladation is anti, isomerization should occur since hydroxypalladation is required to be an equilibrium process. oxidation products Rate = –d[C2H4] dt = If hydroxypalladation is syn, isomerization should not occur since hydroxypalladation is rate limiting. k [PdCl42–] [olefin] [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 + PdCl 2– + H O 4 2 H H2O + PdCl42– + HO [Cl–] = 3.3 M k1 D D k–1 PdII k–1 HO H H D D k1 OH H Dproceed D Reactions at high and low chlorideHdo not through the same mechanism. k2does not occur through a common Formation of aldehyde and chlorohydrin hydroxypalladation intermediate. 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. Rate = –d[C2H4] dt = k [PdCl42–] [olefin] [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 Pd Cl Cl OH + D D Cl Cl Pd Cl D Cl Cl Pd Cl D + Cl– D 2– – OH – OH + H2O D Cl Cl CD2OH Pd Cl CH + H+ CH2OH outer-sphere anti hydroxypalladation OH 2– Cl Cl CD2OH Pd Cl CH CH2OH + H+ Cl Cl Pd Cl H D H D Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. – + H2O Anti Hydroxypalladation at High [Cl–] Henry's Proposed Pathway 2– Cl Cl Pd Cl Cl OH + D D Cl Cl Pd Cl D Cl Cl Pd Cl D + Cl– D 2– – OH – OH + H2O D Cl Cl CD2OH Pd Cl CH + H+ CH2OH outer-sphere anti hydroxypalladation OH 2– Cl Cl CD2OH Pd Cl CH CH2OH + H+ Cl Cl Pd Cl H D H D Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681. – + H2O Reinterpreting Bäckvall's Results Henry's Proposed Pathway – PdCl4 2– Cl Cl Pd Cl + C2H4 Cl– ligand loss prevented by high concentration of Cl–. + Cl– – Cl Cl Pd Cl + H2O Cl– 2– Cl Cl Pd Cl CH2CH2OH Excess Cl– prevents this intermediate from undergoing decomposition to oxidation products. outer-sphere anti hydroxypalladation 2– Cl Cl Pd Cl CH2CH2OH CuCl2 Cl OH Assumption that oxidation products and chlorohydrin arise from a common 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 F3C H OH + PdCl42– + H2O H2O + PdCl42– + F3C HO H3C H3C F3C CD3 CF3 CD3 Required Properties: ! Substrate cannot undergo oxidation; can only isomerize. oxidation products ! Substrate whose RLS is hydroxypalladation. ! Substrate possesses stereochemistry that can be used to distinguish between syn and anti hydroxypalladation. Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. oxidation products Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe H F3C H OH + PdCl42– + H2O H2O + PdCl42– + F3C HO H3C H3C F3C CD3 k1 CF3 CD3 k–1 k–1 k1 H PdII oxidation products F3C H3C CF3 OH CD3 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. oxidation products Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe H F3C H OH + PdCl42– + H2O H2O + PdCl42– + F3C CF3 HO H3C H3C F3C CD3 k1 CD3 k–1 k–1 k1 H PdII oxidation products F3C H3C For syn hydroxypalladation: Rate = –d[C2H4] dt = oxidation products CF3 OH CD3 OH For anti hydroxypalladation: k [PdCl42–] [olefin] [Cl–]2 [H+] Proton inhibition term must result from an equilibrium that occurs before the rate-limiting hydroxypalladation step. Rate = –d[C2H4] dt = k [PdCl42–] [olefin] [Cl–] Proton inhibition term does not show up in the exchange rate because it results from this exchange equilibrium. Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe H F3C H OH + PdCl42– + H2O H2O + PdCl42– + F3C HO H3C H3C F3C CD3 k1 CF3 CD3 k–1 k–1 k1 H PdII oxidation products F3C H3C For syn hydroxypalladation: Rate = –d[C2H4] dt = CF3 OH oxidation products CD3 OH Observed Kinetics under Wacker Conditions: k [PdCl42–] [olefin] [Cl–]2 [H+] Proton inhibition term must result from an equilibrium that occurs before the rate-limiting hydroxypalladation step. ! Rate expression had a first order proton inhibition term. ! Rate expression was identical to the Wacker rate expression. ! Consistent with syn hydroxypalladation mechanism. Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe H F3C H OH + PdCl42– + H2O H2O + PdCl42– + F3C CF3 HO H3C H3C F3C CD3 k1 CD3 k–1 k–1 k1 H PdII oxidation products F3C H3C Observed Kinetics under High [Cl–] Conditions: ! Rate expression had no first order proton inhibition term. ! Rate expression was identical to what Bäckvall observed at high [Cl–]. ! Consistent with anti hydroxypalladation mechanism. oxidation products CF3 OH CD3 OH For anti hydroxypalladation: Rate = –d[C2H4] dt = k [PdCl42–] [olefin] [Cl–] Proton inhibition term does not show up in the exchange rate because it results from this exchange equilibrium. Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti – H+ F3C HO PdII CD3 CF3 OH CF3 H CH3 + H+ – PdII – H2O D3C OH H CF3 CH3 (R), Z CD3 F3C HO H CH3 PdCl42– CF3 H2O (R), E Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti – H+ F3C HO PdII CD3 CF3 OH CF3 H CH3 + H+ D3C – PdII – H2O OH H CF3 CH3 (R), Z CD3 F3C HO H CH3 PdCl42– CF3 H2O (R), E – H+ syn F3C HO PdII CD3 H CH3 CF3 OH CD3 + H+ – PdII – H2O F3C H (S), E Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. CH3 CF3 OH Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti F3C HO PdII – H+ CD3 CF3 + H+ OH CF3 H CH3 D3C OH – PdII – H2O CF3 CH3 H (R), Z product CD3 F3C CH3 HO H CF3 substrate PdCl42– config % ee [Cl–] [catalyst] % isomerization R 100 0.10 PdCl42– 30 32.5 67.5 R 100 0.05 PdCl42– 48 50.0 50.0 S 100 0.10 PdCl42– 25 72.5 27.5 S 100 0.05 PdCl42– 50 50.0 50.0 H2O (R), E – H+ syn F3C HO PdII CD3 H CH3 CF3 OH %S %R CD3 + H+ – PdII – H2O F3C H (S), E Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. CH3 CF3 OH Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti F3C HO PdII – H+ CD3 CF3 + H+ OH CF3 H CH3 D3C OH – PdII – H2O CF3 CH3 H (R), Z product CD3 F3C CH3 HO H CF3 substrate PdCl42– config % ee [Cl–] [catalyst] % isomerization R 100 0.10 PdCl42– 30 32.5 67.5 R 100 0.05 PdCl42– 48 50.0 50.0 S 100 0.10 PdCl42– 25 72.5 27.5 S 100 0.05 PdCl42– 50 50.0 50.0 H2O (R), E – H+ syn F3C HO PdII CD3 H CH3 CF3 OH %S %R CD3 + H+ – PdII – H2O F3C H (S), E Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. CH3 CF3 OH Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti F3C HO PdII – H+ CD3 CF3 + H+ OH CF3 H CH3 D3C OH – PdII – H2O H CF3 CH3 (R), Z CD3 F3C HO H product substrate CH3 PdCl42– CF3 H2O config % ee [Cl–] R 100 2.0 31 R 100 3.5 S 100 S 100 (R), E – H+ syn F3C HO PdII % isomerization % Z %S %R 30 0.0 100 27 25 0.0 100 2.0 35 32 100 0.0 3.5 45 45 100 0.0 CD3 H CH3 CF3 OH CD3 + H+ – PdII – H2O F3C H (S), E Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832. CH3 CF3 OH Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti F3C HO PdII – H+ CD3 CF3 + H+ OH CF3 H CH3 D3C OH – PdII – H2O H CF3 CH3 (R), Z CD3 F3C HO H product substrate CH3 PdCl42– CF3 H2O config % ee [Cl–] R 100 2.0 31 R 100 3.5 S 100 S 100 (R), E – H+ syn F3C HO PdII % isomerization % Z %S %R 30 0.0 100 27 25 0.0 100 2.0 35 32 100 0.0 3.5 45 45 100 0.0 CD3 H CH3 CF3 OH CD3 + H+ – PdII – H2O F3C H (S), E Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832. CH3 CF3 OH Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti – H+ high [Cl–] F3C HO PdII CD3 CF3 OH CF3 H CH3 + H+ D3C – PdII – H2O OH CF3 CH3 H (R), Z CD3 F3C HO H Conclusions: CH3 PdCl42– CF3 H2O ! At low [Cl–] (Wacker conditions), syn hydroxypalladation is operative. ! At high [Cl–] (Bäckvall's conditions), anti hydroxypalladation is operative. (R), E low [Cl–] – H+ syn F3C HO PdII CD3 H CH3 CF3 OH CD3 + H+ – PdII – H2O F3C H (S), E Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. CH3 CF3 OH Evidence for Syn Hydroxypalladation A New Stereochemical and Kinetic Probe anti – H+ high [Cl–] F3C HO PdII CD3 CF3 OH CF3 H CH3 + H+ D3C – PdII – H2O OH CF3 CH3 H (R), Z Criticism: CD3 F3C ! Trisubstituted alkenes are not standard Wacker substrates. CH3 HO H CF3 PdCl42– ! Substrate cannot undergo oxidation. H2O ! Would be best to study a substrate that can undergo both oxidation and isomerization under both low and high [Cl–] concentrations. (R), E low [Cl–] – H+ syn F3C HO PdII CD3 H CH3 CF3 OH CD3 + H+ – PdII – H2O F3C H (S), E Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498. CH3 CF3 OH 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 [Cl–] > 2 M anti – H+ HO R2 PdII HO R2 H R1 PdCl42– H H2O H – PdII – H2O H H H OH H H (S), Z OH R1 R1 R2 [Cl–] = 0.1 M H R2 O OH – Pd0 – H+ (R), Z reactive conformation Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H (S) R1 Chirality Transfer Studies [Cl–] > 2 M anti – H+ HO R2 PdII H H R1 PdCl42– H H2O R1 H (S), Z R1 H H OH H OH R2 O OH – Pd0 – H+ H R2 H – PdII – H2O [Cl–] = 0.1 M HO R2 R1 H (S) [Cl–] (R), Z reactive conformation H >2M R1 R2 PdII – H+ syn HO R2 PdII H – – H2O H H OH (R), E R1 H H R2 OH [Cl–] = 0.1 M R1 O Pd0 – – H+ Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H OH (R) Chirality Transfer Studies [Cl–] > 2 M anti – H+ HO R2 PdII H H R1 PdCl42– H H2O R1 H (S), Z R1 H H OH H OH R2 O OH – Pd0 – H+ H R2 H – PdII – H2O [Cl–] = 0.1 M HO R2 R1 H (S) [Cl–] (R), Z reactive conformation H >2M R1 R2 PdII – H+ syn HO R2 PdII H – – H2O H H OH (R), E R1 H H R2 OH [Cl–] = 0.1 M R1 O Pd0 – – H+ Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H OH (R) Chirality Transfer Studies Me [Cl–] > 2 M anti HO – H+ Me PdII – PdII – H2O H Me Me H = 0.1 M O Ph – Pd0 – H+ H Me PhPdCl H MeOH Me H (S), Z Me H H Ph H Ph [Cl–] HO H Me H (S) H [Cl–] (R), Z reactive conformation >2M Me Me PdII – H+ syn HO Me PdII H H H – – H2O H H Ph (R), E Me Ph Me [Cl–] = 0.1 M Me O Pd0 – – H+ Ph (R) Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H Chirality Transfer Studies Me [Cl–] > 2 M anti HO – H+ Me PdII – PdII – H2O H Me Me H = 0.1 M O Ph – Pd0 – H+ H Me PhPdCl H MeOH Me H PhPdCl must add syn regardless of the [Cl–] (S) H [Cl–] (R), Z reactive conformation Me H (S), Z Me H H Ph H Ph [Cl–] HO H >2M Me Me PdII – H+ syn HO Me PdII H H H – – H2O H H Ph (R), E Me Ph Me [Cl–] = 0.1 M Me O Pd0 – – H+ Ph (R) Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H Chirality Transfer Studies Me [Cl–] > 2 M anti HO – H+ Me PdII – PdII – H2O H Me Me H Et PdCl42– H H2O = 0.1 M O OH – Pd0 – H+ H Et H (S), Z Et H H OH H OH [Cl–] HO H Et H (S) H [Cl–] (R), Z reactive conformation >2M Et Me PdII – H+ syn HO Me PdII H – – H2O H H OH (R), E Et H H OH Me [Cl–] = 0.1 M Et O Pd0 – – H+ Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H OH (R) Chirality Transfer Studies Me [Cl–] > 2 M anti HO – H+ Me PdII – PdII – H2O H Me Me H Et PdCl42– H H2O = 0.1 M O OH – Pd0 – H+ H Et H (S), Z Et H H OH H OH [Cl–] HO H Et H the stereochemistry of hydroxypalladation (S) must be different at high and low [Cl–] H [Cl–] (R), Z reactive conformation >2M Et Me PdII – H+ syn HO Me PdII H – – H2O H H OH (R), E Et H H OH Me [Cl–] = 0.1 M Et O Pd0 – – H+ Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H OH (R) Chirality Transfer Studies Me [Cl–] > 2 M – PdII – H2O H anti HO – H+ Me PdII Me Et Me H H = 0.1 M O OH – Pd0 ! Excess Cl– prevents syn hydroxypalladation by – H+ prohibiting the ligation of water. H PdCl42– Et H (S), Z Et H H OH H OH [Cl–] HO H Et H (S) Cl– ! Excess prevents "-hydride elimination to oxidation products by prohibiting the necessary dissociation H of a Cl– ligand. – [Cl ] > 2 M Et Me H2O (R), Z reactive conformation PdII – H+ syn HO Me PdII H – – H2O H H OH (R), E Et H H OH Me [Cl–] = 0.1 M Et O Pd0 – – H+ Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745. H OH (R) Mechanism for Oxidation of Olefins under Wacker Conditions 1 [Cl–] Cl Cl Pd Cl Cl O – H3C Cl H Pd H2C CH2 – Cl– 2– 1 inhibition [Cl–] Cl Cl Pd Cl + H2O – Cl– – 1 + CuCl2 + O2 [H+] – Cl OH inhibition – H2O Cl Cl Pd H2O – OH Cl Cl Pd H2O inhibition + H2O – H+ Cl Cl Pd 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 [Cl–] Cl Cl Pd Cl Cl H2C CH2 – Cl– 2– 1 inhibition [Cl–] Cl Cl Pd Cl + H2O – Cl– – O – H3C Cl H Pd 1 + CuCl2 + O2 [H+] – Cl OH inhibition – H2O Cl Cl Pd H2O – OH Cl Cl Pd H2O inhibition + H2O – H+ Cl Cl Pd 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: Cl Pd – Cl Cl Cl Pd H OH !-hydride elimination O – OH OH H dissociation tautomerize 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: Cl Pd – Cl Cl Cl Pd H OH OH OH !-hydride elimination D H H H + Pd(0) + 2 HCl + 2 Cl– D3C D O + PdCl42– + D2O H tautomerize O + PdCl42– + H2O D H dissociation D D O – + Pd(0) + 2 DCl + 2 Cl– H3C H lack of proton incorporation from solvent means that tautomerization mechanism is invalid 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 Henry's Model H H Cl Cl Pd OH H H – H H H Cl Pd O H Cl H O + Pd(0) + HCl H PdII-assisted hydride shift 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 Henry's Model H H Cl Cl Pd OH H H – H H H Cl Pd O O H H + Pd(0) + HCl H Cl PdII-assisted hydride shift Bäckvall's Model Cl Pd – Cl Cl Cl Pd H OH Cl – OH !-hydride elimination reinsertion O + Pd(0) + HCl Pd Cl – OH !-hydride elimination from oxygen H 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 Computational Studies Bäckvall's Model Cl Pd Cl – O H PdIICl OH H3C O + Pd(0) + HCl 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 Pd Cl – O H PdIICl OH H3C O + Pd(0) + HCl H !-hydride elimination from oxygen Goddard's Computations 4-membered TS: 36.3 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. Mechanism for Decomposition to Oxidation Products Computational Studies Bäckvall's Model Cl Pd Cl – O H PdIICl OH H3C O + Pd(0) + HCl 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: 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. O 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 O MeO H O Zearalenone O H H intermediate to Dichroanone O 19-Nortestosterone H O O O O H O Nootkatone Brevicomin OTHP 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 O–Na+ PhH 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 O–Na+ PhH Pd(dba)2 (5 mol%) KHCO3 (1.1 equiv) O air, DMSO, H2O 60 °C O Pd(OAc)2 (2 mol%) Cu(OAc)2•H2O (1 equiv) OH air, DMF, 100 °C O 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 O–Na+ PhH O Pd(dba)2 (5 mol%) KHCO3 (1.1 equiv) O air, DMSO, H2O 60 °C Pd(OAc)2 (2 mol%) Cu(OAc)2•H2O (1 equiv) air, DMF, 100 °C OH O no co-oxidant! O Pd(TFA)2 (10 mol%) ligand (20 mol%) i-Pr OH p-benzoquinone (4 equiv) MeOH, 60 °C O 96% ee Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071. N O N i-Pr From Industrial Process to Synthetic Method Oxidative Cyclizations Give Access to Heterocyclic Compounds H Boc N MeO2C O H O BnO H O O H BnO OBn O O O O O O N H NTs N H N Ts N 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 OH O anti oxypalladation R O PdLn !-hydride elimination R H R O PdLn O syn oxypalladation R O PdLn !-hydride elimination R Stereochemistry of Oxidative Cyclizations Stoltz Group Studies Pd(TFA)2 (5 mol%) pyridine (20 mol%) Na2CO3 (2 equiv) OH MS3Å, O2 (1 atm) PhCH3, 80 °C O 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) MS3Å, O2 (1 atm) PhCH3, 80 °C OH O 95% yield O CO2Et O O NTs 90% yield O 88% yield O 87% yield O NOBn 63% yield O 93% yield 82% yield O O 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 E [PdII] E [PdII] E H OH D O E D OE D anti oxypalladation HO D E H CO2Et CO2Et E H E O [PdII] D E H E H E O [Pd] D syn oxypalladation Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. H OE Stereochemistry of Oxidative Cyclizations Stoltz Group Studies E [PdII] E [PdII] E H OH E H D O E D OE D anti oxypalladation HO O O D + D CO2Et H CO2Et E H E O [PdII] D CO2Et H CO2Et E H CO2Et CO2Et E H E O [Pd] D syn oxypalladation Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. H OE Stereochemistry of Oxidative Cyclizations Stoltz Group Studies E [PdII] E [PdII] E H O HO D OH E H D O O E D D O OE anti oxypalladation O CO2Et CO2Et E H E H O E O [PdII] D E H O E O [Pd] D syn oxypalladation Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. H O OE Stereochemistry of Oxidative Cyclizations Stoltz Group Studies E [PdII] E [PdII] E H O HO D OH E H D O O E D D O anti oxypalladation O OE O O CO2Et CO2Et D CO2Et E H E H O E O [PdII] D CO2Et E H O E O [Pd] D syn oxypalladation Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. H O OE 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) OH benzoquinone (4 equiv) MeOH, 40 °C, 4 h O A D O B A:B:C:D = 16:46:29:9 syn oxypalladation O D C Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036. O D D 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) benzoquinone (4 equiv) MeOH, 40 °C, 4 h OH O A D O B A:B:C:D = 16:46:29:9 syn oxypalladation D O D O C D H D PdCl2(MeCN)2 (10 mol%) Na2CO3 (2 equiv) LiCl (2 equiv) benzoquinone (1 equiv) THF, 65 °C, 24 h OH O A H D O B D A:B:C:D = 6:5:7:82 anti oxypalladation O D C Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036. O D Stereochemistry of Oxidative Cyclizations Stahl Group Studies Ts N H anti aminopalladation LnPd Ts N D DPd Ts N H D Ts N H NHTs Ts N D LnPd D D Ts N HPd Ts N D syn aminopalladation Ts 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 aminopalladation LnPd Ts N D DPd Ts N H D Ts N H No additive: NHTs 2:1 ratio syn:anti aminopalladation products D LnPd D Ts N D Ts N HPd Ts N D syn aminopalladation Ts 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 aminopalladation LnPd Ts N D DPd Ts N H D Ts N H CF3CO2H Additive: NHTs 1:2 ratio syn:anti aminopalladation products D LnPd D Ts N D Ts N HPd Ts N D syn aminopalladation Ts 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 aminopalladation LnPd Ts N D DPd Ts N H D Ts N H NaOAc or Na2CO3 Additive: NHTs exclusively syn aminopalladation products D LnPd D Ts N D Ts N HPd Ts N D syn aminopalladation Ts N D Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. Conclusions Pd Source and Ligands Additive Effects (co-oxidant, acid, base, salts) Solvent Effects (H2O, ROH, DMSO, etc.) syn vs. anti heteropalladation or carbopalladation Olefin Sterics and Electronics Nucleophile Sterics and Electronics The Wacker Oxidation One-Stage Process purge Reactor C2H4, O2 PdCl2, CuCl2, HCl C2H4, CH3CHO Separation Equipment C2H4 ! 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 ethylene. CH3CHO ! Operates at 90-100 °C, 10 atm. C2H4 PdCl2, (CuCl)2, HCl Oxidation Reactor + CH3CHO PdCl2, CuCl2, HCl Separation Equipment ! Yields >95% acetaldehyde. PdCl2, (CuCl)2, HCl N2 Regeneration Reactor air Wiseman, P. Introduction to Industrial Organic Chemistry; 2nd Ed.; Applied Science Publishers: London, 1979; pp. 116-120.