1. 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

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

3. 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

4. Diastereoselectivity (I)
major
minor
Metal-catalyzed Reactions 1

5. Diastereoselectivity (II)
Metal-catalyzed Reactions 1

6. Enantioselectivity
Metal-catalyzed Reactions 1

7. Atom Economy
Metal-catalyzed Reactions 1

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

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

15. 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

16. 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

17. 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

18. 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

19. Metal-catalyzed Reactions 1

20. Metal-catalyzed Reactions 1

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

22. Metal-catalyzed Reactions 1

23. Metal-catalyzed Reactions 1

24. Metal-catalyzed Reactions 1

25. Metal-catalyzed Reactions 1

26. 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

27. Metal-catalyzed Reactions 1

28. Metal-catalyzed Reactions 1

29. 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

30. Metal-catalyzed Reactions 1

31. 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

32. 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

33. Metal-catalyzed Reactions 1

34. Metal-catalyzed Reactions 1

35. Metal-catalyzed Reactions 1

36. Metal-catalyzed Reactions 1

37. 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

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

39. 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

40. Metal-catalyzed Reactions 1

41. Metal-catalyzed Reactions 1

42. 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

43. Metal-catalyzed Reactions 1

44. Metal-catalyzed Reactions 1

45. Metal-catalyzed Reactions 1

46. Metal-catalyzed Reactions 1

47. Metal-catalyzed Reactions 1

48. Metal-catalyzed Reactions 1

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