Efficiency in Synthesis Bioorganic Chemistry Spring 2006 Efficiency in Synthesis short synthetic steps and operations: selectivity minimal raw materials and waste: atom economy Selectivity chemoselectivity: bond types, C=C vs C=O regioselectivity: reaction sites, Markovnikov rule diastereoselectivity: relative stereochemistry, Cram’s rule enantioselectivity: absolute stereochemistry, chiral ligand Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Chemoselectivity regioselectivity & stereoselectivity H2, Pt NaBH4 Metal-catalyzed Reactions 1

Regioselectivity more electropositive metals: Mo, W 1. BH3•THF H3O+ 2. H2O2, NaOH Hg2+, H2O/NaBH4 more electropositive metals: Mo, W Metal-catalyzed Reactions 1

Diastereoselectivity (I) major minor Metal-catalyzed Reactions 1

Diastereoselectivity (II) Metal-catalyzed Reactions 1

Enantioselectivity Metal-catalyzed Reactions 1

Atom Economy Metal-catalyzed Reactions 1

Industrial Processes with Transition Metals (I) Bioorganic Chemistry Spring 2006 Industrial Processes with Transition Metals (I) 1. Oxidation Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Industrial Processes with Transition Metals (II) Bioorganic Chemistry Spring 2006 Industrial Processes with Transition Metals (II) 2. Reduction Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Industrial Processes with Transition Metals (III) Bioorganic Chemistry Spring 2006 Industrial Processes with Transition Metals (III) 3. C-C Bond formation (I): Cross-coupling (Clariant) Ube’s aromatization process for o-tolylbenzonitrile (OTBN) Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Industrial Processes with Transition Metals (IV) Bioorganic Chemistry Spring 2006 Industrial Processes with Transition Metals (IV) 3. C-C Bond formation (II): Olefin metathesis epothiolone A precursor polynorbornene Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Industrial Processes with Transition Metals (V) Bioorganic Chemistry Spring 2006 Industrial Processes with Transition Metals (V) 4. Carbonylation (Fischer-Tropsch process in 1925) (hydrofomylation by Rölen in1938) ibuprofen (Boots, Hoechst) Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Basic Chemistry of Transition Metals (I) Bioorganic Chemistry Spring 2006 Basic Chemistry of Transition Metals (I) organometallics: compounds with M+–C- bonds main group elements: BuLi, MeMgI, Me4Pb (Et2Zn) transition elements:K[(C2H4)PtCl3]•H2O (Zeise, 1827), Ni(CO)4 (Mond, 1890, bp 43 oC), (C5H5)2Fe transition elements: metals with partially filled d (main) or f orbitals (elements or compounds) transition metal complexes: soluble in solvents electron configuration of transition metals: Fe, Co, Pd [noble gas] (n-1)dm ns1(2) np0: Cr [Ar] 3d5 4s1 4p0 Fe [Ar] 3d6 4s2 4p0, Co [Ar] 3d7 4s2 4p0, Pd [Kr] 4d10 5s0 5p0 Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1 Bioorganic Chemistry Spring 2006 Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Basic Chemistry of Transition Metals (II) Bioorganic Chemistry Spring 2006 Basic Chemistry of Transition Metals (II) 18-electron rule: EAN (effective atomic number) a stable complex with an electron configuration of the next higher noble gas: ‘coordinatively saturated’ CO, PPh3, C=C, CC, NR3, RCN: 2 e- donors R, X, H: 1 e- or 2 e- (oxidized state of TM) Ni(CO)4, Pd(PPh3)4, Co2(CO)8, MeMn(CO)5, Cp2Fe violating complexes: early TM or with bulky ligands Me3TaCl2, Me6W, (3-C3H5)2Ni, Ir(CO)(PPh3)2Cl, Cp2Ni Transition Metal Reagents and Catalysts: Innovations in Organic Synthesis by Jiro Tsuji (2000, Wiley) Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Basic Chemistry of Transition Metals (III) Bioorganic Chemistry Spring 2006 Basic Chemistry of Transition Metals (III) structures: coordination number (CN; 4, 5, or 6) Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Basic Chemistry of Transition Metals (IV) Bioorganic Chemistry Spring 2006 Basic Chemistry of Transition Metals (IV) metal-carbon bonding: -bond & -complex -bond (LnM-CH3) C2H4 donation to M M back bonding to C2H4 NH3 (strong -donor, poor -acceptor) R3P (good -donor, good -acceptor) CO (poor -donor, strong -acceptor) Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Basic Reactions of Transition Metals (I) Bioorganic Chemistry Spring 2006 Basic Reactions of Transition Metals (I) oxidative addition (OA): increase in CN oxidation of metals: Grignard reactions substrates: H-X, C-X, H-H, C-H, M’-H, M’-M’, etc. H  DX-Y - DM-X - DM-Y + EVSP + Esteric: exothermic < 0 favored by low DX-Y, high DM-X & DM-Y, nonbonding e- on M, less bulky ligands, and strong -donors (R3P, H-) non-dissociative oxidative addition -allyl (3-allyl) complexes oxidative cyclization: ‘reductive cyclization’ with alkenes ligand: COD, DMF; complex: Ni(cod)2, LmRu(dmf)n coordinative unsaturation: reactive species Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

[A: donor atoms; N, O, S, P] Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

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Basic Reactions of Transition Metals (II) Bioorganic Chemistry Spring 2006 Basic Reactions of Transition Metals (II) reductive elimination (RE): the reverse of ‘OA’ decrease in CN & oxidation state of M a catalytic cycle: reverse of oxidative addition of M cis configuration required between the leaving ligands rate: sp2 carbon > sp3 carbon faster with a large bite angle: bidentate ligands favored: bulky ligands, reduced e- density on M Pd(II): 1,1-RE, retention of configuration (no free-radical) intermolecular (1,2-) elimination Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

Basic Reactions of Transition Metals (III) Bioorganic Chemistry Spring 2006 Basic Reactions of Transition Metals (III) transmetallation: transfer of organic groups (R, H) from more electropositive M’ (main group metals) to less electropositive M (transition metals): from M’ to M alkylation of M: M’ = Mg, Zn, B, Al, Sn, Si, Hg oxidative addition / transmetallation: acyl halides a catalytic cycle of cross-coupling reactions Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

A Catalytic Cycle: Transmetallation Bioorganic Chemistry Spring 2006 A Catalytic Cycle: Transmetallation Oxidative Addition Reductive Elimination Isomerization Transmetallation Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Basic Reactions of Transition Metals (IV) Bioorganic Chemistry Spring 2006 Basic Reactions of Transition Metals (IV) insertion: addition of M-X to an unsat’d substrate coordination/migration: no change in CN & oxidation state carbo(hydro)metallation: X = C (H) ,(1,2)-insertion of unsaturated bonds: syn addition cis coordination: faster with DPPE 1,4-insertion: -allyl complex with butadiene ,(1,1)-insertion: carbonylation sequential insertion: ‘domino reaction’ & polymerization a catalytic cycle of cross-coupling reactions via insertion Heck reactions: Ar-X & alkenes Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

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Metal-catalyzed Reactions 1

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A Catalytic Cycle: Insertion Bioorganic Chemistry Spring 2006 A Catalytic Cycle: Insertion Oxidative Addition Reductive Elimination Elimination Insertion Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Catalytic Cycle (Insertion): Heck Reaction Bioorganic Chemistry Spring 2006 Catalytic Cycle (Insertion): Heck Reaction Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Basic Reactions of Transition Metals (V) Bioorganic Chemistry Spring 2006 Basic Reactions of Transition Metals (V) elimination of ‘H’: dehydrometallation increase in CN & oxidation state of M coordinative unsaturation & cis configuration required -elimination: syn H to M; Ni-H & M-O competitive ‘reductive elimination’ -elimination: for limited No. of metal complexes Mo, W: olefin metathesis [Ru] Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

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Basic Reactions of Transition Metals (VI) Bioorganic Chemistry Spring 2006 Basic Reactions of Transition Metals (VI) effect of coordination: nucleophilic attack on electron-rich ligands becoming electron-poor: alkene, diene, alkyne, CO, arene electrophilic attack on metals or ligands at metals / at ligands change of acidity: nature of ligands; EWG / EDG (CO)4CoH: strong acids (pKaHCl), (PPh3)(CO)3CoH: weak acid (6.96), (PPh3)4CoH: basic asymmetric catalysis: chiral ligands (diphosphines) the Monsanto process for L-dopa by Knowles et al. Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1

Metal-catalyzed Reactions 1

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Ligand Substitution associative mechanism dissociative mechanism Bioorganic Chemistry Spring 2006 Ligand Substitution associative mechanism dissociative mechanism Metal-catalyzed Reactions 1 Metal-catalyzed Reactions 1