Reduction of C–C π-Bonds Alkene Hydrogenation H R H H2 Cat R' H H H R H R' Heterogenous catalyst Cat = Pd/C Pd(OH)2/C Pearlman's cat Raney Ni Pt/C PtO2 Adam's cat Rh/Al2O3 etc weak aggressive Heterogeneous Reductions Rates H Sterics > > > > e- Rich > e- Poor H2 pressure 1 ATM 100 ATM > Stereochemistry Me Pt/ H2 Me Suprafacial Addition Me H H Me Stereoselectivity Often Controlled by Steric Accessibility Me H2 Cat Me Me Pt/ H2 H H Me Me Me H Me 70:30 Wilkinson’s Catalyst (Homogeneous) Synthesis: Ph3P EtOH RhCl3·xH2O + PPh3 Cl + Ph3P=O + HCl Rh Ph3P PPh3 Most effective for simple Ar3P. Cl Rh 2 nL LnRh Cl L = PPh3, PAr3, PR3, etc Suprafacial Addition of Hydrogen Across Alkene R' R' R H2 (1 to 100 atm) cat. (PPh3)3RhCl rt to >100 °C R R' H R R H R' Example: R Me AcO R D2 cat. (PPh3)3RhCl Me AcO Note: No H/D scrambling. D D H Rate Difference With Alkene Substitution • Approximately 50-fold rate difference depending on alkene substitution. • In general, better ligand = faster rate. • Some alkenes (e.g. ethylene, butadiene) bind so tightly they are slow to reduce. Ph3P Cl Rh Ph3P ~ PPh3 k25°C (x 102 M–1s–1) 32 R ≥ R 30 > R1 R1 > R 27 R R1 10 2 Example in synthesis: MeMe Me Me Me O MeMe H2 cat. (PPh3)3RhCl OBz Me O OBz R > 0.6 Good Chemoselectivity vs. NO2 H2 cat. (PPh3)3RhCl NH2 NO2 w/ Pd/C or Ri-Ni H2 cat. (PPh3)3RhCl + CO2Me CO2Me 96% vs. CO2Me 4% >49% 26% w/ PtO2 or Pd/BaSO4 Mechanism: Hydrogen First L L Rh L Cl –L/+solv L H H +L/-solv Rh Cl L Cl solv L H Rh solv solv L L H Cl L Cl H Rh H L Note: Neutral complexes less Lewis acidic and electron-rich. H2 H Rh solv H L Oxidative addition to hydrogen fast. Cationic Rhodium Complexes • Alkene or diene complexes are pre-catalysts: 2 H2 Ph2P Rh PPh2 solv. Ph2 P solv + Rh P solv Ph2 • Most common type of catalyst for asymmetric alkene hydrogenation (with chiral ligands). • Highly efficient. Often can use <<0.1% catalyst in reaction. • Prepared with non-coordinating counter-ion (BF4- , PF6- , B[3,5-C6H3(CF3)]4-. • Less alkene scrambling than with neutral complexes. • Because of Lewis-acidity of the complex, can be substrate directed… see more later. Cationic Rhodium Complexes • More active complexes from more electron-rich ligands. complex [substrate] (mM) kint x 104 (s-­‐1) [Rh(NBD)(PPh3)2]+ 5.3 0.1 [Rh(NBD)(PPh2Me)2]+ 3.7 3.0 [Rh(NBD)(PPhMe2)2]+ 3.5 6.0 • Complexes with bidentate ligand more active than those with monodentate ligands. • Sensitive to acidity (basicity) of reaction… deprotonation can lead to neutral complex. Mechanism: Olefin First L • Cationic complexes are: Rh L H2 –C8H16/+solv H :D H L R Rh L • More electrophlic, therefore more likely to bind alkene or directing group. • Less likely to undergo oxidative addition. R solv solv :D solv L L H R H R L Rh solv D L rds solv Rh L H Rh L D D H2 H R • D = Directing Group, typically imine, alcohol, ether, carbonyl, etc. • Note: L2Rh(solv)2 can react with H2 but is not kinetically relevant. Cationic Iridium Catalysts • Prototypical (and first) example is Crabtree’s catalyst: + Ir PF6– N PCy3 Crabtree, Acc. Chem. Res. 1979, 12, 331. • Precatalyst. Diene reduced to give LnIr(III)H2+. O Br Br H2 cat. [Ir(COD)(Cy3P)(py)]PF6 O Br Br Cationic Iridium Catalysts Are Very Reactive complex T (°C) Solvent Turnover Frequency (h-­‐1) 1-­‐hexene cyclohexene Me2C=CMe2 [Ir(COD)(PCy3)(py)]+ 0 CH2Cl2 6,400 4,500 4,000 [Ir(COD)(PPh2Me)2]+ 0 CH2Cl2 5,100 3,800 50 [Ir(COD)(PPh3)2]+ 0 acetone 10 0 0 [Rh(COD)(PPh3)2+ 25 CH2Cl2 4,000 10 0 [Ru(H)Cl(PPh3)3] 25 C6H6 9,000 7 0 [RhCl(PPh3)3] 25 C6H6/EtOH 650 700 0 [RhCl(PPh3)3] 0 C6H6/EtOH 50 70 0 • Note: the fact that it reacts at all was surprising (3rd row). Directed Hydrogenation Binding Directs Metal to the Proximal Face of the Alkene Lewis Basic "Directing Group" DG: LnM + H2 Ln H DG M H Reduction Occurs on Proximal Face of the Alkene Ln H DG M H DG H H - LnM • Works best with highly Lewis Acidic Catalysts (ie cationic ones). • Requires conformationally defined substrate. Directed Hydrogenation Examples R OH H2 (1 atm) 20% [Ir(COD)(Cy3P)(py)]PF6 R OH R = H, >99:1 R = Me, 33:1 rt, CH2Cl2 Me Me Me O H2 (1 atm) 5% [Ir(COD)(Cy3P)(py)]PF6 N N H Me O N rt, CH2Cl2 O N H O >99:1 Me Me H2 (800 psi) 10% [Rh(nbd)(diphos)]BF4 OH Me Me Me H Me 70:1 OH Note: reaction happens towards large isopropyl group! Directed Hydrogenation Acyclic Stereocontrol OH Me R Ph OH H2 Me (1) R H OH R H Et favored P (1) = Me Ph Rh P Ph Ph H Et R OH BF4- Asymmetric Hydrogenation Chiral Biaryls OMe R' R' O PR2 PR2 R' O R' O R' R' O BINAP 3,3'-(OR)2-BINAP 3,3'-diAlkyl-BINAP 3,3'-diAr-BINAP X PR2 PR2 X X PR2 PR2 X SEGPHOS, R' = H Difluorphos, R' = F SunPhos, R' = Me H8-BINAP, X = CH2 SYNPHOS, X = O O n( ) O PR2 PR2 Me PR2 PR2 MeO MeO N R' TUNEPHOS (n = 1-6) Me Me PR2 PR2 Me OMe MeO-BIPHEP, R' = H Cl-MeO-BIPHEP, R' = Cl Garphos Me N PR2 PR2 OMe OMe R' MeO MeO PR2 PR2 MeO MeO P-Phos Me HexaPHEMP • BINAP first example in class, reported by Noyori. • Biaryl axis in tetra-sub. biaryls stable to racemization (to >100 °C). Lots of Phosphine Substituents! R' R' PR2 PR2 tBu Me R= Me Me oTol Ph pTol Xyl Me DMTB tBu CF3 iPr O NMe2 Me Me Me Me Me CF3 iPr DIPDMA OMe bisCF3 Furyl iPr Cy tBu Ferrocene Backbones NMe2 Me Fe PR'2 PR2 Fe Ph Ph Fe PR2 Ph Me2N Josiphos PR2 Me PR2 Mandyphos Me PR2 Mandyphos Ph PR'2 PR2 Fe Me Walphos Chiral Backbones Me Me Me O PAr2 PAr2 O Me Me O PAr2 PAr2 O Me DIOP NorPhos Phanephos Me PAr2 H H PPh2 PPh2 MeDIOP PAr2 PPh2 PPh2 R PAr2 PAr2 N O N PAr2 PAr2 R Me BDPMI BDPP SPIROPhos Aliphatic Bisphosphines Me P Me Me P Me Me-DuPHOS Ph Ph P P Ph P P Ph Ph-BPE BINAPHANE P-Chiral Phosphines P MeO P Me tBu OMe P Me tBu P Me tBu P Tri-chicken-foot Phos tBu-MiniPhos DIPAMP H P tBu H P tBu TangPhos H P tBu P tBu tBu H P tBu DuanPhos Chiral P,N Ligands Me Me O O Ar2P Ar2PO N O N O N R R PHOX N Ar2P SimplePhox Fe R PryPHOX N PR2 R Phosphites, Phosphates,Phosphoramidites O Phosphite P tBu O Ph O Phosphate O P OiPr P O O Ph O Me P O O O Ph Me P N Me O O Phosphoramidite Me O P N P N Me O Ph MonoPhos Ph Me O Me Me O Me P N O Me O Ph SIPhos Monsanto L-Dopa Process: Entry Into Asymmetric Reductions CO2H MeO AcO HN CO2H [Rh(I)+]/DIPAMP MeO Me HN AcO H2 O CO2H HO Me HN HO O Me O 95 %ee L-DOPA Parkinson's Treatment Ph H3C P Ph PAMP ee <100 °C P OMe P OMe O PPh2 PPh2 PPh2 O PPh2 PPh2 PPh2 Chiraphos Prophos DIOP Ph DIPAMP • Over 57 different ligands have been shown to be effective in this reaction. William Knowles, Nobel Prize 2001 Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998. Tang, W.; Zhang, X. Chem Rev 2003, 103, 3029. Alkene Geometry Often Does Not Matter With Some Catalysts CO2Me Me HN Me [Rh(I)+]/(R,R)-Pr-DuPhos CO2Me Me H2 O HN Me O 99.6% ee Me CO2Me HN Me O CO2Me [Rh(I)+]/(R,R)-Pr-DuPhos Me H2 HN Me O Other Examples CO2Me NHCbz CO2Me NHCbz [Rh(I)+]/DIPAMP H2 PrO2C N OMe N PrO2C OMe 95% ee Boc N N Boc R-Phanephos-Rh OMe O Boc N N CBz H2, 1.5 atm –40 °C R-BINAP-Rh OMe O H2, 70 atm Boc N OMe N Boc O 86% ee Boc N N CBz OMe O 99% ee Process Has Been Very Carefully Studied CO2Me Ph Ph2 P S Rh P S Ph2 k1 k–1 k1 = 1.4 x 104 M–1·s–1 k–1 = 5.2 x 10–1 s–1 ΔH‡ = 18.3 kcal/mol ΔS‡ = +2 eu S = MeOH s–1 k4 = 23 = 17 kcal/mol ΔS‡ = +6 eu slow step at –40 °C ΔH‡ k4 Ph2 H P Rh P Ph2 S S, – Ph CH2Ph CO2Me NH O observable at low temp NHAc CO2Me Ph2 Ph P Rh P O Ph2 k3 S NH X-ray k2 NHAc H CO2Me H2 k2 = 1.0 x 102 M–1·s–1 ΔH‡ = 6.3 kcal/mol ΔS‡ = –28 eu slow step at 25 °C Ph H Ph2 H P Rh CO Me P H NH 2 Ph2 O k3 > 1 s–1 only invisible species Halpern and Landis Enantioselectivity with DIPAMP: A Surprise CO2Et HN Ph O Rh P P * H2 CO2Et H H Ph H S expected AcHN NHAc H H Ph H R observed EtO2C Halpern, J. Science 1982, 217, 401 minor major Rate-determining step k"2 ≈ 600 k'2 Not observed! Observed! Actual Mechanism • Dependence on T and P Landis and Halpern JACS 1987 109 1746 ee p H2 (atm) 84% R 1 21% S 20 8% S 100 Curtin-Hammett Kinetics ΔΔG MeO2C P * P Rh O NH Ph CO2Me CO2Me H HN P Ph H Rh * P O HN Ph O Rh P P * reactive observed MeO2C H NH P Rh Ph * H P O Other Enamines NHAc NHAc [Rh(I)+]/(R,S,R,S)-Me-PennPhos R H 98% ee P H NHAc tBu H2 R Me [Rh(I)+]/(R,R)-Me-DuPhos tBu R H H2 P H R PennPhos NHAc 99% ee • Other enamines can also be reduced with these catalyst systems. • In general, substrates need to have a stabilized N-carbonyl enamine tautomer. Me [Rh(I)+]/DuanPhos NHAc H2 Et NHAc 97% ee • In some cases, both alkene isomers can be reduced to the same enantiomer. Examples of Other Substrate Classes CO2Et iPr [Rh(I)+]/(R,R)-Et-DuPhos OAc CO2Et iPr H2 OAc 96.1 %ee [Rh(I)+]/(S,S,R,R)-TangPhos H2 Me OAc OAc 97 %ee Me [Rh(I)+]/R,S-Josphos MeO2C CO2Me H2 MeO2C CO2Me 99 %ee • Note: In all cases, alkene is substituted with a donor group to coordinate and orient catalyst. Industrially Important Example CF3 N F N NH2 O F F N N CF3 N F Rh/Josiphos N 7 atm H2 F F N N NH2 O 94% ee Januvia • Januvia is a Merck drug for the treatment of diabetes. • First process-scale synthesis: Hansen, K. B.,et al. Org. Proc. Res. Dev. 2005, 9 (5), 634 (won 2006 Presidential Green Chemistry Award) • Second process-scale synthesis: Directed evolution to develop a transaminase enzyme capable of setting the stereocenter. Science 2010, 329, 305 (won 2010 Presidential Green Chemistry Award) Enantioselective Alkene Hydrogenation Using Ruthenium • L2Ru(II)(OAc)2 are very effective at hydrogenating functionalized alkene. Unsaturated Carboxylic Acids: CO2H Me cat. [Ru-(S)-BINAP(OAc)2] MeOH, 13 atm H2 CO2H MeO MeO 97% ee (S)-Naproxen Me Me CO2H Me cat. [Ru-(R)-BIPHEMP(OAc)2] MeOH, 180 atm H2 F CO2H F Me Me CO2H cat. [Ru-(S)-H8BINAP(OAc)2] MeOH, 1.5 atm H2 Me 94% ee Me Me CO2H 97% ee Mechanism for Ruthenium Cat. Hydrogenation of Alkenes O Me R HO O O H R R HO P * R O Ru O O P P O Me P * R O Ru * R O Ru P O O O R O P Me R H2 O R H 2 HOR H HO2CR P * P R R H O R Ru R O O P P * R O H * H HOR P H O R Ru O O P HOR R O H H O Ru O O Me R R HO2CR R Halpern Allylic Alcohols Also Effective Substrates Me Me Me cat. [Ru(S-BINAP)(CF3CO2)2] OH 30 atm H2, rt Me Me Me OH 96% ee Me Me cat. [Ru(S-TolBINAP)(OAc)2] Me 30 atm H2, rt OH Me Me Me OH 98 % ee • Homoallylic alcohols are also reasonable substrates, but not longer homologues. Me cat. [Ru(S-BINAP)(OAc)2] Me OH Me 100 atm H2, rt Me Me OH Me 92 % ee Me Me Me cat. [Ru(S-BINAP)(OAc)2] OH no reaction 100 atm H2, rt Noyori JACS 1987,109,1596. Enantioselective Alkene Hydrogenation with Iridium Me cat. [Ir]BArf Me 50 atm H2 97% ee MeO Me Me cat. [Ir]BArf MeO [Ir]BArf = 50 atm H2 Me Me Me CF3 O Me otol2P N Ir B tBu CF3 81% ee cat. [Ir]BArf CO2Et Me 50 atm H2 CO2Et Me 84% ee Pfaltz ACIE 1998, 37, 2897 • Tri-substituted alkenes work best. • First example of asymmetric tetra-substituted alkene hydrogenation. 4 Enantioselective Alkene Hydrogenation with Iridium Me Me Me cat. [Ir]BArf Me 50 atm H2 MeO MeO AcO Me Me Me Me 93% ee Me [Ir]BArf = Me Me cat. [Ir]BArf 50 atm H2 AcO Me Me Me Me O otol2P Me CF3 N B Ir Ph CF3 4 Me Me >98% de Pfaltz Science 2006, 311, 642.