M.C. White Chem 153 Hydrogenation -140 Week of october 15. 2002 Wilkinson,'s original report Wilkinson's Catalyst Ph3p H,(I atm), benzene,rt Functionality tolerated Ph groups indicates that the metal hydride intermediate is primarily H2:D2(1:1) covalent in character (lacks hydridic properties characteristic Minimal H/D scrambling in the product is of strongly ionic M-H). See dicative of formation of a dihydrometal ON Structure& Bonding pg 28 intermediate that transfers both of its hydrido 6.1% Ethylene is not hydrogenated under these conditions butstoichiometric hydrogen transfer from preformed dihydride complex occurs. Data indicates that formation of an ethylene/ Rh(CI(PPh3b complex inhibits hydrogen PhaP P Ph3P,, aPE activation by the complex This implies that dihydride H(I atm), benzene, rt formation precedes olefin PPh cycle The stereochemical outcome of this experiment indicates that the mechanism involves stereospecific cis hydrometallation of the unsaturated substrate followed by stereospecific reductive elimination from the resulting alkenyl (or alkyl) hydrido species Phap PPh3 C3h7- CH3 H,(50 atm), benzene CH, CH3 hexane HO, C COH D2(I atm), benzene H 2C COH 20°C cis- hexene trans-hexene meso compound major product observed (>20:1) Wilkinson Chem Soc(A)1966, 1711
M.C. White, Chem 153 Hydrogenation -140- Week of October 15, 2002 Wilkinson's original report: Wilkinson’s Catalyst Ph3P Rh(I) Ph3P PPh3 Cl cat. H2 (1 atm), benzene, rt quantitative Investigations into the reactivity of (PPh3)RhCl uncovered its high activity as a homogeneous hydrogenation catalyst. This was the first homogeneous catalyst that compared in rates with heterogeneous counterparts. Wilkinson J. Chem. Soc. (A) 1966, 1711. O C N NO2 O R O OR O OH Functionality tolerated Ph3P Rh(I) Ph3P PPh3 Cl Cl Rh(III) Ph3P H PPh3 H PPh3 Ph3P Rh(I) Ph3P PPh3 Cl Data indicates that formation of an ethylene/ Rh(Cl)(PPh3)3 complex inhibits hydrogen activation by the complex. This implies that dihydride formation precedes olefin complexation in the catalytic cycle. cat. H2 (1 atm), benzene, rt Ethylene is not hydrogenated under these conditions but...stoichiometric hydrogen transfer from preformed dihydride complex occurs. + rt + Ph3P Rh(I) Ph3P PPh3 Cl C3H7 CH3 C3H7 CH3 H H Compatibility with carbonyl groups indicates that the metal hydride intermediate is primarily covalent in character (lacks hydridic properties characteristic of strongly ionic M-H). See Structure & Bonding pg. 28. H2 (50 atm), benzene 20oC cis- hexene: trans-hexene (>20:1) + hexane HO2C CO2H Ph3P Rh(I) Ph3P PPh3 Cl D2 (1 atm), benzene 20oC H H D D HO2C H H CO2H The stereochemical outcome of this experiment indicates that the mechanism involves stereospecific cis hydrometallation of the unsaturated substrate followed by stereospecific reductive elimination from the resulting alkenyl (or alkyl) hydrido species. meso compound major product observed Ph3P Rh(I) Ph3P PPh3 Cl cat. H2: D2 (1:1) H H 50% D D 43.9% H D 6.1% Minimal H/D scrambling in the product is indicative of formation of a dihydrometal intermediate that transfers both of its hydrido ligands to the unsaturated substrate
M.C. White Chem 153 Hydrogenation-141- Week of october 15, 2002 Wilkinson: substrate selectivity .N PPh3 rate of hydrogenation of PhaP competition unsaturated substrate I mol% unsaturated rate of hydrogenation of substrate H2(1 atms ), benzene,rt aturated 1-octene substrate saturated substrate competition figure 14.7 HO→ Unsaturated substrates containing functionality are hydrogenated more rapidly than their unfunctionalized counterparts. The effect is suggested to result from polar functional group assisted olefin coordination to the catalyst. Terminal alkynes are hydrogenated more rapidly than terminal alkenes. This selectivity may be enhanced by use of acidic alcohol co-solvents (e.g. in benzene also 1-heptyne, 1-octyne Terminal alkenes between C6-C12 are hydrogenated at the same rate. The same is observed for terminal alkynes. An C+H9 ncrease in carbon chain length does not appear to affect also. l-decene. 1-dodecene olefin/catalyst interaction Conjugated dienes are reduced slower than isolated alkenes 0.75 Internal and branched alkenes(alkynes) are hydrogenated slower than terminal alkenes(alkynes). These differences are C3h rationalized in terms of steric effects on olefin interaction 0.54 with the catalyst and have been used to effect selective C3h alkene hydrogenations in polyene compounds 0.17 C3h Candlin Faraday Discuss. Chem. Soc. 1968(46)60
M.C. White, Chem 153 Hydrogenation -141- Week of October 15, 2002 Ph3P Rh(I) Ph3P PPh3 Cl 1 mol% H2 (1 atms.), benzene, rt + unsaturated substrate + saturated substrate competition figure = rate of hydrogenation of unsaturated substrate rate of hydrogenation of 1-octene Wilkinson: substrate selectivity Candlin Faraday Discuss. Chem. Soc. 1968 (46) 60. HO HO EtO C3H7 , C4H9 C2H5 C2H5 C2H5 also 1-heptyne, 1-octyne also, 1-decene, 1-dodecene C3H7 C3H7 C3H7 C3H7 NC unsaturated substrate competition figure 14.7 9.1 3.4 1.8 1.7 2.6 0.92 0.75 0.71 0.69 0.54 0.17 1.0 cyclohexene 1,3-cyclooctadiene Terminal alkenes between C6-C12 are hydrogenated at the same rate. The same is observed for terminal alkynes. An increase in carbon chain length does not appear to affect olefin/catalyst interaction. Internal and branched alkenes (alkynes) are hydrogenated slower than terminal alkenes (alkynes). These differences are rationalized in terms of steric effects on olefin interaction with the catalyst and have been used to effect selective alkene hydrogenations in polyene compounds. Unsaturated substrates containing functionality are hydrogenated more rapidly than their unfunctionalized counterparts. The effect is suggested to result from polar functional group assisted olefin coordination to the catalyst. Terminal alkynes are hydrogenated more rapidly than terminal alkenes. This selectivity may be enhanced by use of acidic alcohol co-solvents (e.g. in benzene/ 2,2,2-trifluoroethanol, 1-hexyne: 1-octene (12:1). Conjugated dienes are reduced slower than isolated alkenes
M.C. White, Chem 153 Hydrogenation-142- Week of october 15. 2002 Wilkinson hydrogenation: classic dihydride mechanism aPPh3 a PPh PPh solution structure determined by NMr strong T-acids(e.g. ethylene)bind PPh electron rich rh center and inhibit hydrogenation +PPh3l-PPh +PPh3|-PPh: alytic cycle PPh H Ph m M Cl PPh wPPh3 H PhaP CI PPh coordinatively unsaturated complex reacts w/H2 10Tx reductive migratory PhaEn MlCL elimination PPh3 Insertion RDS Phal mediates observed by NMR or as isolated Halpern Chem. Comm. 1973 629 solids in the reaction system. Formation of Halpern J. Mol. Catal. 1976(2)65 e-products"results in a reduction in Halpern Inorg. Chim. Acta. 1981(50)11 te of hy
M.C. White, Chem 153 Hydrogenation -142- Week of October 15, 2002 Wilkinson hydrogenation: classic dihydride mechanism Ph3P Rh(I) Ph3P PPh3 Cl H2 Ph3P Rh(III) H PPh3 Cl H PPh3 oxidative addition -PPh3 Ph3P Rh(I) S PPh3 Cl solution structure determined by NMR. Ph3P Rh(III) H PPh3 Cl H R +PPh3 Ph3P Rh(III) PPh3 Cl H S R migratory insertion RDS Ph3P Rh(III) H PPh3 Cl H S -PPh3 +PPh3 H2 reductive elimination oxidative addition catalytic cycle coordinatively unsaturated complex reacts w/ H2 104 x faster than Rh(Cl)PPh3 Ph3P Rh(I) PPh3 Cl strong π-acids (e.g. ethylene) bind tightly to the electron rich Rh center and inhibit hydrogenation Ph3P Rh(I) Ph3P Cl Cl Rh(I) PPh3 PPh3 Ph3P Rh(I) Ph3P Cl Cl Rh(III) H H PPh3 PPh3 H2 Intermediates observed by NMR or as isolated solids in the reaction system. Formation of these "side-products" results in a reduction in the rate of hydrogenation. Halpern Chem. Comm. 1973 629. Halpern J. Mol. Catal. 1976 (2) 65. Halpern Inorg. Chim. Acta. 1981 (50) 11
M.C. White Chem 153 Hydrogenation-143- Week of october 15, 2002 Wilkinson site selectivii Site selective hydrogenation: sterics ketone activated -disubstituted atm), rt aPPh3 high levels of selective MPPh Chlorotris(triphenylphosphine)rhodium I tetrasubstituted Strem catalog 2001-2003 I mol% 1g=$42 =0 H,(I atm), benzene/EtoH, rt Pedro!C19913815 Site selective hydrogenation: sterics and electronics HcO CH(CH3 CH CH(CH3)C2Hs HO TOH trisubstituted HO Mel cis-disubstituted only site of 92% m198023114e cis vs. trans-disubstituted olefins Ph3p COMe COrMe H,(I atm), benzene/acetone, rt rans-disubstituted OAc PGE PGEI Schneider JOC 1973(38)951
M.C. White, Chem 153 Hydrogenation -143- Week of October 15, 2002 Wilkinson: site selectivity Ph3P Rh(I) Ph3P PPh3 Cl Ph3P Rh(I) Ph3P PPh3 Cl Strem catalog 2001-2003 1g = $42 O Chlorotris(triphenylphosphine)rhodium I O O O O O H O O 1 mol% O H2 (1 atm), benzene/EtOH, rt 95% Pd/C acetone, H2 (1 atm), rt 75% ketone activated cis-disubstituted tetrasubstituted O CH(CH3)C2H5 O O H OMe O O O H H3CO O O H MeO HO OH H conjugated diene trisubstituted trisubstituted cis-disubstituted O CH(CH3)C2H5 O O H OMe O O O H H3CO O O H MeO HO OH H Ph3P Rh(I) Ph3P PPh3 Cl ~30 mol% H2 (1 atm), tol, rt 92% only site of hydrogenation O HO CO2Me OAc cis-disubstituted trans-disubstituted Ph3P Rh(I) Ph3P PPh3 Cl H2 (1 atm), benzene/acetone, rt 80% cat. O HO OAc CO2Me cis vs. trans-disubstituted olefins: PGE Schneider JOC 1973 (38) 951. 2 PGE1 Site selective hydrogenation: sterics highly active heterogeneous catalysts often cannot achieve high levels of selectivity. Site selective hydrogenation: sterics and electronics Pedro JOC 1996 (61) 3815. Fisher J. Med. Chem. 1980 (23) 1134. Ivermectin
M.C. White Chem 153 Hydrogenation -144- Week of october 15. 2002 Wilkinson: diastereoselectivity Ph3 Ba,, PPh3 PhaP Cl I mol% H2 (1 atm. ) benzene/EtoH, rt R=H: 73%endo R=Me 92%endo R Rationale for observed diastereoselectivity Olefin binds the catalyst from the least sterically hindered exo face. Subsequent cis hydrometallation of the exo face followed by stereospecific reductive elimination of Ph3 Pu, the alkyl metal hydrido intermediate results in overall cis addition of H, to the leas sterically hindered exo face of the olefin. Rousseau J. Mol. Cat. 1979(5)163 Jardine Prog. Inorg. Chem. 1981(28)63 olefin complexation and hydrogenation from sterically less hindered face Ph3p a PPha Bno OMOM OMOM 30mo% H2(I atm ) tol, rt OBn Lowary OL 2000(2)167
M.C. White, Chem 153 Hydrogenation -144- Week of October 15, 2002 Wilkinson: diastereoselectivity Ph3P Rh(I) Ph3P PPh3 Cl 1 mol% H2 (1 atm.), benzene/EtOH, rt Me H endo exo Me R R R R = H : 73% endo R = Me : 92% endo Rationale for observed diastereoselectivity: Olefin binds the catalyst from the least sterically hindered exo face. Subsequent cis hydrometallation of the exo face followed by stereospecific reductive elimination of the alkyl metal hydrido intermediate results in overall cis addition of H2 to the least sterically hindered exo face of the olefin. Cl Rh(III) Ph3P H PPh3 H R vs. Cl Rh(III) Ph3P H PPh3 H R Rousseau J. Mol. Cat. 1979 (5) 163. Jardine Prog. Inorg. Chem. 1981 (28) 63. BnO OMOM BnO OBn olefin complexation and hydrogenation from sterically less hindered face Ph3P Rh(I) Ph3P PPh3 Cl 30 mol% H2 (1 atm.), tol, rt 83% BnO OMOM BnO Lowary OBn OL 2000 (2) 167
M.C. White, Chem 153 Hydrogenation-145- Week of october 15. 2002 wilkinson: directing group effects Phb, 0.04mol% note: when pd/c was used a mixture of cis and trans K+B. 0.04 mol% Meo H2(6.8 atm, 100psi ) benzene, 50C CIs Isomer( exclusIv reaction without the alkoxide is OK attibuted to the steric hinderance of the PPh tri-substituted double bond, which renders it less able to coordinate to the Rh. The protonated alcohol is not a strong enough nucleophile to associatively displace the anionic chloride ligand Base-assisted formation of the alkoxide results in effective displacement of the chloride ligand and trisubstituted thus directs olef leo Thompson JACS 1974(96)6232 Jardine Prog. Inorg. Chem. 1981(28)63
M.C. White, Chem 153 Hydrogenation -145- Week of October 15, 2002 Wilkinson: directing group effects MeO OH trisubstituted Ph3P Rh(I) Ph3P PPh3 Cl 0.04 mol% H2 (6.8 atm, 100psi), benzene, 50oC no reaction Ph3P Rh(I) Ph3P PPh3 Cl 0.04 mol% H2 (6.8 atm, 100psi), benzene, 50oC 68% K+ BMeO OH H MeO O-K+ trisubstituted H O Rh H PPh3 H PPh3 cis isomer (exclusive) note: when Pd/C was used a mixture of cis and trans isomers resulted Thompson JACS 1974 (96) 6232. Jardine Prog. Inorg. Chem. 1981 (28) 63. The slow reaction without the alkoxide is attibuted to the steric hinderance of the tri-substituted double bond, which renders it less able to coordinate to the Rh. The protonated alcohol is not a strong enough nucleophile to associatively displace the anionic chloride ligand. Base-assisted formation of the alkoxide results in effective displacement of the chloride ligand and thus directs olefin complexation from the same face
M C. White, Chem 153 Hydrogenation -146 Week of october 15. 2002 Schrock-Osborn /Crabtree: Cationic catalysts y3 (PF6) H cis-oxidative ClS-migratory (PF6) PC (PF6) solvated active catalyst Crabtree Acc Chem Res 1979(12)331 Turnover Frequency(ToF) Wilkinsons catalyst ordinatively"unsat benzene/EtOH 25C atonic hydrogenation catalysts Schrock-Osborn catalyst (PF6) weakly coordinating solvents PPh provides the olefin substrate with relatively free access to the metal,s reactive site. These cationic catalysts are also P Crabtree's catalyst (PF6) TOF =mol reduced substrate/mol catalyst/h
M.C. White, Chem 153 Hydrogenation -146- Week of October 15, 2002 Schrock- Osborn /Crabtree: Cationic catalysts Diene ligated cationic catalysts mode of activation: Ir(I) PCy3 N (PF6-) Ir(III) PCy3 H (PF6-) H N Ir(III) PCy3 H (PF6-) N + + + S Ir(I) PCy3 N (PF6-) + repeat S Ir(I) S PCy3 N (PF6-) + diene ligated catalyst precursor solvated active catalyst H2 cis-oxidative addition cis-migratory insertion cis-reductive elimination Crabtree Acc Chem Res 1979 (12) 331. Ph3P Rh(I) Ph3P PPh3 Cl Ir(I) N PCy3 (PF6-) Rh(I) PPh3 PPh3 (PF6-) + + Turnover Frequency (TOF) TOF = mol reduced substrate/mol catalyst/h CH2Cl2, 25oC CH2Cl2, 25oC benzene/EtOH, 25oC Schrock-Osborn catalyst Crabtree's catalyst Wilkinson's catalyst 650 4000 6400 700 10 4500 13 ---- 3800 ---- ---- 4000 "Coordinatively" unsaturated cationic hydrogenation catalysts are the most active homogeneous hydrogenation catalysts developed thus far. Use of weakly coordinating solvents provides the olefin substrate with relatively free access to the metal's reactive site. These cationic catalysts are also remarkably selective
M.C. White, Chem 153 Hydrogenation -147- Week of october 15. 2002 Cationic catalysts: substrate-directed hydrogenations -J3 2.5mo% CH,Ch, H,(I atm),rt The availability of a second"open"coordination 98% site on the catalyst now makes it possible to bind a Pd/C(EtOH), 1: 5 (sterics) ligating group on the substrate in addition to the lefin. This "two-point"binding has important Py mplications on the selectivity of product formation (PF6) The ability of a late metal complex to effectively bind hard functionality(hydroxyls, ketones, etc.) is attributed to the lewis acidic properties impa on the complex by the overall positive charge Crabtree JOC 1986(51)2655 Other functionalities with lewis basic sites also direct Esters: above abore above d/C1.35:1 (±) PdC1.26:1 Pd/C 1:4 For a comprehensive review of cyclic and acyclic ubstrate- directed hydrogenations see: Hoveyda 0 Evans, and Fu Chem. Rev. 1993(93)1307 and >99:1 D.A. Evans. Chem 206 notes Pd/C 1: 9(steric approach control)
M.C. White, Chem 153 Hydrogenation -147- Week of October 15, 2002 Cationic catalysts: substrate-directed hydrogenations CH2Cl2, H2 (1 atm), rt Me OH Ir(I) PCy3 N (PF6-) + 2.5 mol% Me OH H i-Pr OH Me H Ir(III) Cy3P Py (PF6-) H + Me OH H 98% 64:1 Pd/C (EtOH), 1:5 (sterics) Crabtree JOC 1986 (51) 2655. The availability of a second "open" coordination site on the catalyst now makes it possible to bind a ligating group on the substrate in addition to the olefin. This "two-point" binding has important implications on the selectivity of product formation. The ability of a late metal complex to effectively bind hard functionality (hydroxyls, ketones, etc...) is attributed to the lewis acidic properties imparted on the complex by the overall positive charge. Other functionalities with lewis basic sites also direct: CO2Me Me H CO2Me Me Me O Me O Me Me H O Me Me O Me Me H Esters: 56:1 Pd/C 1.35:1 above 124:1 Pd/C 1.26:1 above Ketones: 97% >99% 999:1 Pd/C 1:4 above >99% Ethers N H N O O N H N O O Me above >99:1 Pd/C 1:9 (steric approach control) H Amides: 5 mol% (±) (±) (±) For a comprehensive review of cyclic and acyclic substrate-directed hydrogenations see: Hoveyda, Evans, and Fu Chem. Rev. 1993 (93) 1307 and D.A. Evans; Chem 206 notes
M.C. White/Q. Chen Chem 153 Hydrogenation -148- Week of october 15. 2002 High catalyst loadings diminished yields and selectivities CH] Ch, H2(1 atm),rt decrease in selectivity is observed at higher catalyst selectivity loadings. It is possible that higher catalyst loadings yield (ratio A: B) promote the formation of dimeric( Crabtree suggested LH-M) species that no longer have the"oper 2.5mo/% coordination site necessary for providing effect directing effects in olefin hydrogenation. NO 48% experimental data exists thus far to support this Stork JACS 1983(105)1072 Crabtree JOC 1986(51)2655 Dimished yields are observed with higher catalyst loadings. This can be rationalized on the basis that higher catalyst loadings promote the irreversible trimerization of the coordinatively unsaturated catalysts to yield inactive triiridium hydride bridged complexes. Such complexes have been isolated by Crabtree from reaction mixtures of more sterically hindered olefins that did not proceed to 2.775 Crabtree Acc. Chem. Res. 1979(12)331
M.C. White/Q. Chen Chem 153 Hydrogenation -148- Week of October 15, 2002 High catalyst loadings: diminished yields and selectivities Dimished yields are observed with higher catalyst loadings. This can be rationalized on the basis that higher catalyst loadings promote the irreversible trimerization of the coordinatively unsaturated catalysts to yield inactive triiridium hydride bridged complexes. Such complexes have been isolated by Crabtree from reaction mixtures of more sterically hindered olefins that did not proceed to completion. Crabtree Acc. Chem. Res. 1979 (12) 331. CH2Cl2, H2 (1 atm), rt Me OH Ir(I) PCy3 N (PF6-) + 2.5 mol% Me OH H Me OH H 99% 139:1 yield selectivity (ratio A:B) 20 mol% 48% A B 74:1 Stork JACS 1983 (105) 1072. Crabtree JOC 1986 (51) 2655. A decrease in selectivity is observed at higher catalyst loadings. It is possible that higher catalyst loadings promote the formation of dimeric (Crabtree suggested M-H-M) species that no longer have the "open" coordination site necessary for providing effective directing effects in olefin hydrogenation. No experimental data exists thus far to support this hypothesis
M C. White, Chem 153 Hydrogenation -149 Week of october 15. 2002 Synthetic applications of directed hydrogenations MOMO Rh(NBD)DIPHOS-4)] BF4 NaH. THF MOMO Me osem H2(800ps), MOMO Me osem Paquette OL 2002 (4)937 aPC (PF6) H Ir( CODXpy)PCy3)'PF6 Me OH HO 99% Yield dr. 11: 1 at cl arriault OL 2001 (3)1925
M.C. White, Chem 153 Hydrogenation -149- Week of October 15, 2002 Synthetic applications of directed hydrogenations O O O OH H H OSEM MOMO Me O O O OH H OSEM MOMO MOMO Me MOMO [Rh(NBD)(DIPHOS-4)]+BF4- NaH, THF H2 (800 psi), rt Paquette OL 2002 (4) 937. HO H OH O Me H2, CH2Cl2 HO H OH O Me Me Barriault OL 2001 (3) 1925. HO HO O Me H HO HO O Me H Me H Rh(I) Ph2 P P Ph2 (BF4-) + ()n= 3 68% [Ir(COD)(py)(PCy3)]+PF6- 99% Yield, d.r. 11:1 at C10 10 Ir(I) PCy3 N (PF6-) +