The Kumada cross-coupling reaction is a nickel or palladium catalyzed reaction between a Grignard reagent and an organic halide. The reaction proceeds through four steps - oxidative addition, transmetallation, isomerization, and reductive elimination. It is similar to other cross-coupling reactions like Negishi, Stille, Hiyama, and Suzuki reactions. The reaction exhibits cis/trans selectivity and can be made enantioselective using a chiral palladium catalyst. It has applications in synthesizing drugs like Aliskiren and materials for organic solar cells.

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2. KUMADA CROSS-COUPLING REACTION
Dr. Shahid Rasool
Kumada Cross-coupling
reaction
CHEM5128
Advanced Named Reactions
2

3. Key Concepts
• Kumada Cross-Coupling reactions
• Discussion of reacting species, catalysts, solvents
• Mechanism of reaction
• Explanation of mechanism step by step
• Synthetic applications
3

4. Kumada Cross-coupling Reaction:
• Kumada cross-coupling reaction is also known as Kharasch cross-
coupling reaction.
• Ni or Pd catalyzed cross-coupling reaction
• Kumada cross-coupling reaction is between Grignard reagent and
organic halides, triflate etc.
• Overall reaction is given as,
THF, DEE

5. Similar Cross-coupling Reactions:
• This reaction is similar to following reactions which also Ni or Pd,
• Negishi cross-coupling reaction (Organozinc reagents, RZnX)
• Stille cross-coupling reaction (Organostannanes reagents, R4Sn)
• Hiyama cross-coupling reaction (Organosilicons, RSiF3)
• Suzuki cross-coupling reaction (Organoboranes, R3B)

6. Alkyl halides (R-X):
• R = Alkyl, Vinyl, Aryl groups
• High rates have been observed for vinyl or aryl groups
• A limitation for alkyl group is that there are chances of elimination
if there is β-hydrogen.
• X = Cl, Br, I
• Order of rate = I > Br > Cl as bond energy R-I > R-Br > R-Cl
C2H5-
C3H7-
Alkyl group
CH2 CH
Vinyl group Phenyl group Aryl group
R
R CH2 CH2 X


7. Triflates and tosylates:
• R = Alkyl, Vinyl, Aryl groups
• If X = OTf then called Triflates,
• If X = OTs then called Tosylates
• Good leaving groups due to resonance stabilized anions.
• The distribution of charge on large number of atoms provides
stability because it becomes easy for the medium molecules to
solvate it.
OTf = F3C S
O
O
O
OTs = S
O
O
OH3C
F3C S
O
O
O F3C S
O
O
O F3C S
O
O
O

8. Grignard Reagent (R-Mg-X):
• R = Alkyl, Vinyl, Aryl groups
• X = Cl, Br, I, OTf, Ots
• Highly reactive reagent due to C-Mg bond polarity
• C-Mg bond having less bond energy as compared to Mg-X bond,
so it is easily broken.
• Poor functional group tolerance due to high reactivity
• Low temperature synthesis due to high reactivity and low
activation energy
R Mg X
 

9. Catalysts:
• Nickel (Ni) or Palladium (Pd)
• Platinum is also of same group (VIIIB) but too expensive
• Complexes of these metals are used e.g. L2M
• L = bidentate phosphine ligands e.g. dppe, dppp
• dppe = 1,2-Bis(diphenylphosphino)ethane
• dppp = 1,2-Bis(diphenylphosphino)propane
• Pd complexes are air sensitive (Argon/N2 atmosphere)
P
P
Ph
Ph
Ph
Ph
P P
Ph
Ph
Ph
Phdppe dppp

10. Solvent:
• Tetrahydrofuran (THF) or Diethylether (DEE)
• Ethereal solvents are used because
• (1) Dry ether avoid reaction of R-Mg-X with moisture
• (2) Stabilize R-Mg-X through complex formation
• This can be justified by electronic configuration of magnesium,
• 12Mg = 1s22s22p63s23px
03py
03pz
0 (Ground state)
• 12Mg = 1s22s22p63s13px
13py
03pz
0 (Excited state)
Mg
R X
O R
R
O
R
R

11. Overall Pd-catalyzed Mechanism:

12. Steps of mechanism:
• Four steps of mechanism are
• (1) Oxidative addition
• (2) Transmetallation
• (3) Isomerization
• (4) Reductive elimination

13. Step-1, Oxidative addition:
• This step is known to follow concerted mechanism of addition.
• Pd(0) is oxidized to Pd(II)
• R-X is added in concerted way
• Both ‘R’ and ‘X’ are attached to ‘Pd’ through its primary valency.
• Secondary valency ‘4’ is already justified by bidendate ligands.
Pd
L X
L2Pd(0)
R X
L2Pd(0)
R X
R LII

14. Step-2, Transmetallation:
• It is interchanging of metals attached to different groups.
• Irreversible due to thermodynamic (favor based on
electronegativity) or kinetic (favor if empty orbitals in both
metals) reasons
• Redox metallation
• Ligand exchange
• Transmetallation in Kumada cross-coupling reaction
M1 R M2 R' M1 R' M2 R
M1 R M2 M1
M2 R
n+ n+
M1 R M2 X M1 X M2 R
M1
R
X
M2
Pd
L X
R LII
Pd
L X
R LII
MgR1
X
Pd
L R1
R LII
MgX2

15. Step-3, Isomerization:
• Isomerization involves the rearragement of complex in such a way
that R- groups move in adjacent position
• This step is thought to be completed along with the last step of
transmetallation.
Pd
L R1
R LII
Pd
L R1
L RII

16. Step-4, Reductive elimination:
• This step is also known to follow concerted mechanism of
elimination.
• Pd(II) is reduced to Pd(0)
• R-R1 is eliminated from the complex in a concerted way
Pd
L R1
L RII
Pd
L R1
L RII
L2Pd(0)R R1

17. Overall Ni-catalyzed Mechanism:

18. Stereo-selectivity:
• For vinylic alkyl halides, cis-R-X results into cis-product
• For vinylic alkyl halides, trans-R-X results into trans-product
• For R-Mg-X,
• cis or trans-R results into a mixture of cis and trans-products

19. Enantio-selectivity:
• Asymmetric synthesis by Pladium catalyst with chiral ligands
results into one enantiomeric product (>90%)
A: [Methoxyalkyl(ferrocenyl)] monophosphine
B: bis-oxazoline

20. Synthesis of Aliskiren (hypertension drug):
Synthesis of polythiophenes (organic solar cells,
LED):