SBM 2014-5 Hydrogenation – 2 Lectures John Brown L1 Hydrogenation of Alkenes The main elements involved as catalysts in homogeneous hydrogenation are shown General characteristics of OM catalysis Reactive intermediates are coordinatively unsaturated, with 12, 14 or 16 electron valence shells Coordination numbers are commonly 2 – 6, with square planar (4) and trigonal bipyramid or square-based pyramid (5) common The key metals have variable oxidation states with (I - III) or (0 - II - IV) frequent; most (not all!) reactions involve diamagnetic states 3 The Key Metals in Asymmetric Hydrogenation Rhodium P huge range + + Rh or P2Rh of ligands P need strong donor groups (eg enamide) Ruthenium Iridium P P BINAP and related ligands + Ru close relatives Ir 6-ring chelate P N wide range of reactants with alkenes without varying donor groups secondary donor group alkenes or ketones 4 The basic reactions in OM catalysis are simple Ligand association and dissociation: M + L ML PPh3 PPh3 Pd Ph P Pd + PPh3 Example: PPh3 3 Ph3P PPh3 PPh3 solid state solution cis-Ligand Migration O CH3CH2 O O C C CH2CH3 Example: Ph3P Rh Rh Ph P C PPh3 3 PPh3 O Oxidative addition / reductive elimination H PPh3 H2 PPh3 Example: Cl Ir C O H Ir C O Ph P Ph3P 3 Cl 5 Hydrogenation of alkenes and alkynes is favoured energetically Heat of reaction in KJmol–1 H H H2 Me Me 152.8 Me Me H H H H H2 H H 118.5 Me Me Me Me H Me H Me H2 H H 114.2 Me H Me H H H H H H 155.9 2 H H H H H H O H2 H OH 55.5 Me Me Me Me Metal surfaces (especially of platinum metals) activate hydrogen and are good hydrogenation catalysts Activation of hydrogen without metals is very rare but examples do exist Make the reaction very exothermic through a high energy starting material – a bulky carbene: i-Pr Me i-Pr Me H Me Me 2 N N i-Pr Me i-Pr Me 35 ˚C H H Frustrated Lewis Pairs (acid and base – one accepts H+, the other H–) F C6F5 F C6F5 H F B F B H2 C6F5 C6F5 t-Bu 25 ˚C t-Bu P F P F H t-Bu F t-Bu F Dihydride and dihydrogen complexes of known structure – this show us how dihydrogen can bond to a transition metal. H CO H2, fast H Ph3P Ir PPh3 Ph3P Ir PPh3 Two M-H Cl sigma bonds Cl CO Vaska's compound 16 e Dihydride 18 e H H H H H2, fast iPr P Ir PiPr One H2 acts as iPr3P Ir PiPr3 3 3 H a 2-electron donor Cl Cl H 16 e Dihydrogen complex 18 e The eta-2 dihydride is a probable intermediate in the activation of H2 by a metal complex H2 antibonding orbital acts as acceptor. After coordination the H–H bond is longer and weaker H2 bonding orbital acts as donor. Phosphines and alkenes (also alkynes) are bound to the metal through donor and acceptor orbital interactions In the course of the reaction, aided by phosphorus ligands, the metal must be bound to both hydrogen and the alkene: Donor Acceptor Tertiary phosphines Alkenes Chatt Dewar Duncanson Model Alkene M Alkene M Wilkinsons catalyst (1966)- the first practical homogeneous hydrogenation catalyst reflux in C2H5OH RhCl3 ClRh(PPh3)3 xs. PPh3 NB Change in Rh Usually as a oxidation state trihydrate How does Rh(III) become Rh(I) PPh3 In this procedure; there must be a reducing agent?? How could Cl Rh PPh3 ethanol participate? PPh3 O H H3C idealised square-planar H structure H 16e -coordinatively unsaturated Homogeneous hydrogenation with Wilkinsons catalyst is selective for less substituted double bonds - chemoselectivity O O H2 , cat (PPh3)3RhCl carvone dihydrocarvone H2 , cat H2 , cat (PPh ) RhCl (PPh ) RhCl O 3 3 O 3 3 O Fragment of steroid nucleus What would happen with a heterogeneous catalyst like Pd/C? Examples of simple rhodium homogeneous hydrogenations - control of stereochemistry Alkynes give cis-alkenes: H Me H , Rh cat PPh2Me 2 Me H + HO Me catalyst: Rh X– Me acetone HO Me Me PPh2Me Norbornadiene is removed in the first hydrogenation cycle Alkenes are reduced by cis- addition of dihydrogen O Me O Me Me Me PPh D2, Rh cat D Cl 3 D catalyst: Rh ethanol Ph3P PPh3 part of a steroid D2 adds like H2, to the lower face of the molecule Requirements for successful homogeneous hydrogenation The catalyst must be coordinatively unsaturated, and undergo rapid addition and elimination reactions. The hydrogen affinity must be strong enough to complex H2, but not too strongly that the dihydride is too stabilized. The substrate – alkene, alkyne or carbonyl compound – must be able to bind to the transition metal centre adjacent to bound hydrogen. Intermediates in the catalytic reaction, and especially the alkylhydride, must break down rapidly. Rapid ligand addition and dissociation is helpful. Origins of and requirements for asymmetric hydrogenation of alkenes (Rhodium) Asymmetric Hydrogenation was the first successful example of high enantioselectivity using a purely chemical catalyst: H H H2, cat* H2, cat* X Y X Y X Y H H Product 1 Prostereogenic Product 2 alkene needed Products 1 and 2 are enantiomers Success depends on asymmetry in the product that arises from asymmetry in the ligand of cat*. The atom substituted by H, X and Y is a stereogenic centre; products 1 and 2 are enantiomers. The initial observation (above) and the first successful development (below) in asymmetric hydrogenation Reactions Ligands Me Me CH2 CH3 H , pressure, CO2H 2 P CO2H H 60 ˚C, MeOH Me Cl3RhP3, 0.15% "15% optical purity" "69% optical purity" AcO AcO OMe H2, 1 atm H H H P MeO 20 ˚C, MeOH MeO Me alkene2RhP2Cl MeOCHN CO2H MeOCHN CO H H 2 88% (S)-enantiomer ≥ 95% optical purity Kagans DIOP catalyst for the synthesis of N- acetylphenylalanine - first use of chelating diphosphine 0.2 mol% [ClRh(C8H14)2]2 R,R-DIOP H2, EtOH, C6H6 1 bar, 20˚C HO2C NHCOMe HO2C NHCOMe 72% e.e. (R) H CH PPh H CO H Me O 2 2 HO 2 Me O CH PPh HO CO H C2 axis H 2 2 H 2 DIOP Tartaric acid The Monsanto process for the synthesis of dehydroamino acids (WS Knowles) post 1975 (NB catalyst precursor) OMe OMe OAc OAc H2, MeOH 3 bar, 50˚C HO2C NHCOMe HO2C NHCOMe 96% e.e; 100% e.e. after - recrystallisation / MeOH BF4 Ph OH P MeO OH Rh+ catalyst/ substrate P 1/ >10000 Ph L-DOPA MeO HO2C NH2 Chelating ligand Medical use of L-DOPA? 31 The P NMR species observable in the presence of H2 - only at low temperature H Ph H Ar CO Me Ph Ar 2 H CO2Me MeO P H + Re-face bound MeO P H + Rh NH 2 Rh NH P O MeOH, 223K P O Ph Me Ph O Me Me MeO 10% Enamide complexes irreversible steps Ph CH3 MeO P O + Ar Rh NH (S)-product P H Si-face bound Ph CO2CH3 20 MeO 90% Rhodium asymmetric hydrogenation has been a rich source of reactive intermediates; all cations here: CH CH2 3 H2, catalyst MeO C NHCOMe MeO C NHCOMe 2 2 H SM Product CH2 MeO2C H2 CH2 MeO2C P2H2Rh NH P2Rh O NH Me * O minor H SM Me enamide CH2 Dihydride CO2CH3 Not normally observed RhP2(MeOH)2 HP2Rh NH solvate O SM CH3 O Me SM H major CH2 P Rh H2C NH Monohydride 2 enamide 0 observable at -50 C H CO2CH3 P Rh 2 NH CO2CH3 O Product Reactant manifold Me Transient product complex Computational chemistry indicates a further intermediate between the minor enamide and the dihydride at *. Suggest what this might be. Ligand summary. Types of chelate ligand, all with twofold symmetry axes (C2) H CH PPh Me O 2 2 PPh PPh2 Me O 2 CH2PPh2 H PPh2 Ph2P (R,R)-DIOP (S,S)-PHANEPHOS First chelating chiral (S)-BINAP biphosphine;backbone chirality Example of planar chirality Best known of all chiral ligands; axial chirality OMe Ph Ph OMe Me Me Me But P P P P But P P Me (R,R)-DIPAMP Me Me (R,R)-BisPP* (S,S)-DUPHOS Simple concept; Monsanto ligand for L-DOPA high enantioselectivity synthesis; P-chirality Very effective use of alpha-phospholane 22 substituents Successful asymmetric hydrogenation with rhodium complexes = polar functional group that can also bind to the metal to form a chelate CH2 Ph Et H2 CH3 low e.e. Ph Et H CH2 CH2 Ph NHCOMe Ph CO H 2 H2 H2 CH3 CH3 high e.e. fair e.e. Ph CO H Ph NHCOMe H 2 H + H Rh+ H2Rh 2 CH O CH2 2 O Ph N Ph H Me HO Strong binding Less strong binding Hydrogenation of simple enamides with a rhodium catalyst and DUPHOS-type ligand Synthesis R H R N RCH MgBr 2 NMgBr Ac2O NHAc enamide Hydrogenation Me R H R catalyst P Me H2, 4 atm NHAc NHAc Me iPrOH, -10˚C P E and Z mixture 95- 97% e.e Me as Rh ligand Examples of drug precursors synthesised by asymmetric hydrogenation. Need to vary ligand to optimise results Boc Boc N H , MeOH N 2 PPh2 Rh catalyst N CO2Me N CO2Me Ph P Ac Ac 2 86% e.e. Phanephos CN CN Me H2, MeOH CO H P P CO2H 2 Rh catalyst H H 98% e.e.