Organic Chemistry Laboratory

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Teresa Scott
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1 344 Organic hemistry Laboratory Introduction to organometallic chemistry Portraits:

2 Periodic Table Alkali metals s electrons Electronegativity Transition metals d electrons Main group p electrons

3 What is organometallic chemistry? Organic hemistry Organometallic hemistry Inorganic hemistry arbon -M bonds Metals Organometallic chemistry = Study of compounds containing a arbon-metal bond Organometallic chemistry = Organic synthesis using metals

4 Organometallics s-block compounds Organomagnesium halides (Grignard reagents) Organolithiums Lithium diorganocuprates (Gilman reagents) Loudon p

5 Formation of Grignard reagents radical anion Why use diethyl ether as the solvent? Loudon p

harge distribution hlorobenzene A typical organic compound = positively charged -0.22-0.

6 harge distribution hlorobenzene A typical organic compound = positively charged = negatively charged d + d l X H = 2.20 X = 2.55 X l = X = Pauling electronegativity NPA charges, B3LYP/6-31G(d)

harge distribution Phenyl lithium An organometallic compound = positively charged -0.25-0.27 d - d + = negatively charged -0.

7 harge distribution Phenyl lithium An organometallic compound = positively charged d - d + = negatively charged Li X H = 2.20 X = 2.55 X Li = 0.98 X Mg = X = Pauling electronegativity NPA charges, B3LYP/6-31G(d)

arbon-metal bond polarity drives reactivity R E A T I V I T Y -M bond Δ Electronegativity # % ionic character* -K 2.55 0.82 = 1.73 68 -Na 2.55 0.93 = 1.62 63 -Li 2.55 0.98 = 1.57 61 -Mg 2.55 1.31 = 1.

8 arbon-metal bond polarity drives reactivity R E A T I V I T Y -M bond Δ Electronegativity # % ionic character* -K = Na = Li = Mg = Ti = Al = u = O = l = Br = H = Ionic Polar covalent ovalent # Pauling electronegativity, Χ * % ionic character = [(Χ Χ M ) Χ ]

9 Reactivity of Grignard reagents d - d + ~50 % ionic character carbanion conjugate acid pka = 43 d - d + protonolysis pka 15.7 d - d + protonolysis Loudon p

10 Reactivity of Grignard reagents -atom bonded to metal in RMgX has carbanion character, reacts as a nucleophile The -atom in a typical organic compound is electrophilic (=O, -O, -N, -l) d - d - d + d + new - bond 3 o alcohol Loudon p

Reactivity of Grignard reagents -0.60 +1.25 Mg -0.62 X O -0.51 +1.

11 Reactivity of Grignard reagents Mg X O O -atom of PhMgBr is nucleophilic -atom of O 2 is electrophilic LUMO of O 2 NPA/NBO calculation, B3LYP/6-31G(d) Loudon p. 1018

12 Metal exchange and coupling reactions Metal exchange (transmetallation) between RLi and ux to form lithium diorganocuprate Lithium diorganocuprates are useful for - bond forming reactions Good: Not so good: Ideal:

13 Palladium: One metal, many reactions Suzuki-Miyaura Pd-catalyzed - bond formation Mizoroki-Heck Negishi 2010 Nobel Prize in hemistry

14 Energy atalysis Many reactions are favorable thermodynamically but proceed slowly at room temp/pressure A + B A + B DG (rxn) Reaction progress Loudon p. 170

15 Understanding the catalytic cycle A + B Precatalyst Product atalyst Substrate A Intermediate 2 Intermediate 1 Byproduct Z Substrate B

16 Understanding the catalytic cycle A + B Pd(PPh 3 ) 4-2 PPh 3 Pd(PPh 3 ) 2 intermediate 2 intermediate 1 3 key steps a) Oxidative addition b) Transmetallation byproduct Z c) Reductive elimination

17 Kumada coupling the catalytic cycle Pd(PPh 3 ) 4 Pd(PPh 3 ) 4-2 PPh 3 Pd(PPh 3 ) 2 intermediate 2 intermediate 1 3 key steps a) Oxidative addition b) Transmetallation byproduct Z c) Reductive elimination

18 Ligands Ligands are molecules bonded to a transition metal via donor atoms such as P, N,, etc. Ligands act as Lewis bases (i.e. electron donors) toward the transition metal 2,2 -Bipyridine (bpy) Triphenyl phosphine (PPh 3 ) N-heterocyclic carbene (NH) Loudon p

19 Metal-ligand compounds are called coordination complexes - serve as precatalysts Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium Loudon p

20 Kumada coupling the catalytic cycle Pd(PPh 3 ) 4 Pd(PPh 3 ) 4-2 PPh 3 Pd(PPh 3 ) 2 reductive elimination oxidative addition intermediate 2 intermediate 1 3 key steps a) Oxidative addition transmetallation b) Transmetallation byproduct Z c) Reductive elimination

21 Key steps of the cycle oxidative addition First step of typical - coupling catalytic cycle Pd(PPh 3 ) 4 Addition of organic substrate (Ph-Br) to Pd(PPh 3 ) 2 species Substrate can be aryl, alkenyl, or alkynyl halide Pd(0) Number of bonds to Pd increases by 2 oxidative addition Pd oxidation state increases by 2 (Pd 0 to Pd II ) Loudon p ,

22 Kumada coupling the catalytic cycle Pd(PPh 3 ) 4 Pd(PPh 3 ) 4-2 PPh 3 Pd(PPh 3 ) 2 reductive elimination oxidative addition intermediate 2 intermediate 1 3 key steps a) Oxidative addition transmetallation b) Transmetallation byproduct Z c) Reductive elimination

23 Key steps of the cycle transmetallation Middle step of typical - coupling catalytic cycle Pd(PPh 3 ) 4 Exchange reaction between Ar-MgBr and oxidative addition product R = aryl, alkenyl, alkynyl group M = B (Suzuki), Sn (Stille), Zn (Negishi), etc. Pd(II) transmetallation Organic group Ar replaces Br on Pd atom Pd oxidation state and coordination number unchanged Drive toward less polar -M bond in transmetallation product

24 Kumada coupling the catalytic cycle Pd(PPh 3 ) 4 Pd(PPh 3 ) 4-2 PPh 3 Pd(PPh 3 ) 2 reductive elimination oxidative addition intermediate 2 intermediate 1 3 key steps a) Oxidative addition transmetallation b) Transmetallation byproduct Z c) Reductive elimination

25 Key steps of the cycle reductive elimination Final step of typical - coupling catalytic cycle Pd(PPh 3 ) 4 Elimination of product (Ph-Ar) from transmetallation product Pd(II) reductive elimination oupling product Ph-Ar released, active catalyst Pd(PPh 3 ) 2 reformed Pd oxidation state and coordination number decrease by 2 Loudon p ,

26 Summary Organometallic chemistry - the chemistry of compounds containing a -M bond Grignard and organolithium reagents - polar -M bond, carbanion character, strong bases, carbon nucleophiles, - bond forming - used in stoichiometric (1:1 or greater) amounts Pd-catalyzed coupling reactions - a catalyst provides alternate, lower DG route to a product - a catalyst is not consumed but can participate in many turnovers - ligands coordinate to transition metal to form pre-catalyst complex - metal-ligand complexes serve as catalysts for organic reactions - bond forming/breaking takes place on metal atom - catalytic coupling cycle: oxidative addition, transmetallation, reductive elimination - Pd-catalyzed - bond forming reactions are hugely important in pharma and industry - Practice problem set!

Writing a Correct Mechanism

Chapter 2 1) Balancing Equations Writing a Correct Mechanism 2) Using Arrows to show Electron Movement 3) Mechanisms in Acidic and Basic Media 4) Electron rich Species: Nucleophile or Base? 5) Trimolecular