5 Slides about PalladiumCatalyzed Coupling Reactions
Useful properties of Palladium:
•Relatively inert
•Usually has high yield and selectivity
•Less expensive than Platinum, which has similar properties
Palladium can be used in a wide variety of reactions:
•Stille- between organohalides & organotin compounds
•Buchwald-Hartwig- between aryl halide & amine or aryl alcohol
•Tsuji-Trost- between alkene & a nucleophile
•Heck- between alkenes & alkyl halides
This presentation was created as part of the requirements for Chemistry 165 "Organometallics" at Harvey Mudd College during the
fall semester 2009. The authors of this presentation are Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan (Harvey
Mudd College).
Created by Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan and posted on VIPEr June 2010. Copyright Brette Chapin 2010. This work is licensed under the Creative Commons Attribution Non-commercial Share Alike License.
To view a copy of this license visit http://creativecommons.org/about/license/.
Metal-Catalyzed Cross-Coupling
Reactions
• Metal undergoes oxidative addition
o One alkyl substituent and a nucleophile bind to the
metal catalyst
• Second substituent also binds/ coordinates to the metal
complex
o Occurs through transmetallation or nucleophilic
attack
• Metal complex undergoes reductive elimination
o Forms a new compound that combines the two
substituents
• Reforms the catalyst
Created by Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan and posted on VIPEr June 2010. Copyright Brette Chapin 2010. This work is licensed under the Creative Commons Attribution Non-commercial Share Alike License.
To view a copy of this license visit http://creativecommons.org/about/license/.
Stille Reaction
• Rate-determining step: oxidative
addition of alkyl halide to
palladium
• Accelerated by electronwithdrawing groups on the alkyl
ligands
The Stille Reaction is a cross-coupling
reaction that is an effective way to form
a carbon-carbon bond.1
R groups are any type of alkyl halides.
For example:
PhCH2Br + Me4Sn → PhCH2CH3 + Me3SnBr
• Can be extended to crosscoupling of alkynylmetals and
benzylic electrophiles; known as
Sonagashira alkynylation2
PhC≡CZnBr + BrCH2Ph → PhC≡CCH2Ph + PhCH2CH2Ph
• Heating and increased solvent
polarity increase the yield of the
reaction
Created by Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan and posted on VIPEr June 2010. Copyright Brette Chapin 2010. This work is licensed under the Creative Commons Attribution Non-commercial Share Alike License.
To view a copy of this license visit http://creativecommons.org/about/license/.
Buchwald-Hartwig Cross Coupling Reaction
•Reacts aryl halides and
•amines to form aryl amines
•primary aryl alcohols to form
diaryl ethers
Mechanism:
R
R
PdLn
X
NH
R'
R
L
n
R
Pd
L
NHR'
n
Pd
X
-Base
R
HBase
L
H2NR'
n
Pd
-X
Base
•Oxidative addition of aryl halide
•Substitution of halide with base
•Substitution of base with amine
•Reductive elimination to yield aryl
amine and reform catalyst
•A significant improvement to diaryl
ether synthesis
•Can be done at room temp
•Catalyst is air-stable
•High yields
•Broader scope (highly
functionalized aryl groups)
•Changing ligand tunes reactivity
•(t-Bu)2PN=P(i-BuNCH2CH2)3N
allows to for highly functionalized
aryl amines
•Mild reaction conditions
•Lower catalyst loading
Created by Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan and posted on VIPEr June 2010. Copyright Brette Chapin 2010. This work is licensed under the Creative Commons Attribution Non-commercial Share Alike License.
To view a copy of this license visit http://creativecommons.org/about/license/.
Tsuji-Trost Reaction
Mechanism:
• Example
OAc
CO2Me 2.5% (pi-allylPdCl)2
7.5% (R,R)-standard TBSO
OAc
TBSO
OAc
Ph
CO2Me
CO2Me
THF, rt
CO2Me
Ph
•Allylation can be enantioselective
• with chiral bisphosphine ligands
• Oxidative addition of allyl acetate, bromate or
carbonate
• Nucleophilic addition of enolates, amine, active
methylenes or phenols via η3 π-allyl complex
• Reductive elimination to yield alkylated alkene
and reform catalyst
• Reaction could lead to cyclization
• intramolecular nucleophilic attack instead
OH
MeO2C
OH
Pd2(dba)3
dppb
OH
O
THF
Created by Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan and posted on VIPEr June 2010. Copyright Brette Chapin 2010. This work is licensed under the Creative Commons Attribution Non-commercial Share Alike License.
To view a copy of this license visit http://creativecommons.org/about/license/.
The Heck Reaction
Palladium-catalyzed C-C coupling between aryl or vinyl halides and activated alkenes in
the presence of a base.1
Description of Mechanism
•Oxidative Addition of the alkyl halide to the palladium
catalyst.
•Coordination of the alkene to the palladium catalyst.
•Migratory insertion of alkene
•Internal rotation, palladium partially attaches to
Hydrogen
•Beta hydride elimination
•Newly formed alkene released
•Reductive Elimination to reform the palladium
catalyst.
Optimizing the Heck Reaction
•Utilize homogeneous biphasic catalysis to yield high
activity and selectivity and recycle the catalyst.
•Use polar solvent to prevent metal precipitation.
•Use Supercritical carbon dioxide solvent to reduce
toxicity.
•Use glass bead technology to further eliminate the
palladium leaching.
Created by Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan and posted on VIPEr June 2010. Copyright Brette Chapin 2010. This work is licensed under the Creative Commons Attribution Non-commercial Share Alike License.
To view a copy of this license visit http://creativecommons.org/about/license/.
Applications
• Pathway to compounds that cannot
otherwise be easily synthesized
• Synthesizing industrial compounds
– Making pharmaceuticals
• Anti-cancer, anti-oxidant, anti-fungal, antispasmotic drugs
– UV absorbers
Created by Athena Anderson, Brette Chapin, Michelle Hansen and Kanny Wan and posted on VIPEr June 2010. Copyright Brette Chapin 2010. This work is licensed under the Creative Commons Attribution Non-commercial Share Alike License.
To view a copy of this license visit http://creativecommons.org/about/license/.