1. 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/.http://creativecommons.org/about/license/ 5 Slides about Palladium- Catalyzed 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).

2. 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/.http://creativecommons.org/about/license/ 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 Metal-Catalyzed Cross-Coupling Reactions

3. 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/.http://creativecommons.org/about/license/ Rate-determining step: oxidative addition of alkyl halide to palladium Accelerated by electron- withdrawing groups on the alkyl ligands Can be extended to cross- coupling of alkynylmetals and benzylic electrophiles; known as Sonagashira alkynylation 2 PhC≡CZnBr + BrCH 2 Ph → PhC ≡ CCH 2 Ph + PhCH 2 CH 2 Ph Heating and increased solvent polarity increase the yield of the reaction 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: PhCH 2 Br + Me 4 Sn → PhCH 2 CH 3 + Me 3 SnBr Stille Reaction

4. 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/.http://creativecommons.org/about/license/ Buchwald-Hartwig Cross Coupling Reaction Oxidative addition of aryl halide Substitution of halide with base Substitution of base with amine Reductive elimination to yield aryl amine and reform catalyst Reacts aryl halides and amines to form aryl amines primary aryl alcohols to form diaryl ethers 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) 2 PN=P(i-BuNCH 2 CH 2 ) 3 N allows to for highly functionalized aryl amines Mild reaction conditions Lower catalyst loading Mechanism:

5. 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/.http://creativecommons.org/about/license/ Tsuji-Trost Reaction 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 Example Allylation can be enantioselective with chiral bisphosphine ligands Reaction could lead to cyclization intramolecular nucleophilic attack instead Mechanism:

6. 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/.http://creativecommons.org/about/license/ Palladium-catalyzed C-C coupling between aryl or vinyl halides and activated alkenes in the presence of a base. 1 The Heck Reaction 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.

7. 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/.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, anti- spasmotic drugs –UV absorbers