10.7 Organometallic Coupling Reactions
3 min read•may 7, 2024
are game-changers in organic chemistry. They use metal-containing compounds to form new , expanding our ability to build complex molecules. These reactions have revolutionized how we make drugs, materials, and more.
The magic happens through a dance of , , and . Palladium-based catalysts are the stars of the show, enabling a wide range of couplings. The Suzuki reaction, which links boronic acids with halides, is a standout for making biaryls.
Organometallic Coupling Reactions
Mechanism of organometallic coupling reactions
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- Involve formation of new carbon-carbon bonds using organometallic compounds (contain metal-carbon bond like or reagents) as reactants
- General mechanism:
- Oxidative addition: Metal inserts into carbon-halogen bond of organic halide, increasing metal oxidation state by two
- Transmetalation: Organic group from another organometallic compound transfers to metal center, replacing halogen
- Reductive elimination: Two organic groups on metal center combine forming new carbon-carbon bond, regenerating original metal catalyst
- Forms new carbon-carbon single bond between two sp2-hybridized carbons (aryl, alkenyl, or alkynyl groups)
- Metal acts as catalyst, facilitating new carbon-carbon bond formation without being consumed
- involves repeated oxidative addition, transmetalation, and reductive elimination steps
Diorganocopper vs organopalladium compounds
- ():
- Prepared by treating organolithium or Grignard reagent with copper(I) salt
- React with organic halides or tosylates forming new carbon-carbon bonds
- Limited to sp3-sp3 and sp3-sp2 carbon-carbon bond formation
- Used in reaction to form symmetric biaryls ()
- Organopalladium compounds:
- Prepared in situ from palladium(0) catalyst and organic halide or
- Higher reactivity and broader substrate scope vs diorganocopper reagents
- Facilitate sp2-sp2, sp2-sp, and sp-sp carbon-carbon bond formation
- Tolerate wide range of functional groups, enabling complex molecule synthesis
- Used in reactions (Suzuki, Negishi, Heck, Stille, Sonogashira)
- Organopalladium compounds largely replaced diorganocopper reagents in modern synthetic chemistry due to versatility and efficiency
Suzuki-Miyaura reaction for biaryl synthesis
- Palladium-catalyzed reaction between aryl or alkenyl (or ester) and aryl or alkenyl halide (or pseudohalide)
- Boronic acids: stable, non-toxic, tolerant to various functional groups
- Aryl halides: iodides, bromides, or chlorides (reactivity decreases in that order)
- Mechanism:
- Oxidative addition of to palladium(0) catalyst
- Transmetalation of aryl group from boronic acid to palladium center, aided by base
- Reductive elimination forming biaryl product and regenerating palladium(0) catalyst
- Widely used to synthesize biaryl compounds (important structural motifs in pharmaceuticals, natural products, functional materials)
- Enables efficient synthesis of unsymmetrical biaryls with controlled substitution pattern
- Allows late-stage functionalization and diversification of lead compounds in drug discovery
- Advantages in pharmaceutical development:
- Mild reaction conditions, high functional group tolerance, low toxicity of reagents
- Readily available and diverse boronic acids and aryl halides
- Scalable and cost-effective for industrial-scale synthesis
Transition Metals in Organometallic Coupling Reactions
- (e.g., palladium, nickel, copper) play a crucial role as catalysts in coupling reactions
- coordinate to the metal center, influencing reactivity and selectivity
- Cross-coupling reactions involve two different organic groups, expanding synthetic possibilities
- of the product can be controlled through careful selection of catalysts and reaction conditions
Key Terms to Review (31)
Anti stereochemistry: Anti stereochemistry describes the spatial arrangement in a chemical reaction where two substituents are positioned on opposite sides of a double bond or ring structure after the reaction. It is particularly relevant in the halogenation of alkenes, resulting in products where the added atoms are located across from each other.
Aryl Halide: An aryl halide is an organic compound that consists of a halogen atom (such as chlorine, bromine, or iodine) bonded directly to an aromatic ring. These compounds are widely used in organic synthesis and play a crucial role in various chemical reactions, including organometallic coupling reactions and the Grignard reaction.
Biaryl Synthesis: Biaryl synthesis refers to the formation of a carbon-carbon bond between two aromatic rings, resulting in the creation of a biaryl compound. This type of reaction is a crucial tool in organic chemistry, particularly in the synthesis of complex molecules and the development of pharmaceuticals and functional materials.
Boronic Acid: Boronic acids are organoboron compounds containing the functional group R-B(OH)2, where R is an organic substituent. They are versatile intermediates in organic synthesis, particularly in coupling reactions, and have diverse applications in various fields.
Carbon-Carbon Bonds: Carbon-carbon bonds are covalent chemical bonds formed between two carbon atoms, which are the fundamental building blocks of organic chemistry. These bonds are crucial in the context of drawing chemical structures and organometallic coupling reactions, as they allow for the formation of complex organic molecules.
Catalytic Cycle: A catalytic cycle is a series of elementary steps in which a catalyst participates in the transformation of reactants into products, and is then regenerated to continue the cycle. It is a fundamental concept in understanding the mechanism of catalyzed chemical reactions, including those involved in organometallic coupling reactions.
Cross-Coupling: Cross-coupling is a type of organic reaction in which two different organic fragments are coupled together in the presence of a transition metal catalyst to form a new carbon-carbon bond. This reaction is a powerful tool in organic synthesis, allowing for the construction of complex molecules from simpler building blocks.
Diorganocopper Reagents: Diorganocopper reagents are a class of organometallic compounds containing two organic groups bonded to a copper atom. These reagents are widely used in organic synthesis for carbon-carbon bond formation reactions, particularly in the context of organometallic coupling reactions.
Gilman Reagent: The Gilman reagent, also known as the cuprate reagent, is an organometallic compound used in organic chemistry for the formation of carbon-carbon bonds through coupling reactions. It is a powerful tool in the synthesis of complex organic molecules.
Gilman reagent (LiR2Cu): A Gilman reagent is an organometallic compound used in organic chemistry that consists of lithium, copper, and two organic groups attached to the copper. It is employed in nucleophilic substitution reactions for creating carbon-carbon bonds between organic halides and alkenes or alkynes.
Gilman reagents (LiR2Cu): Gilman reagents are organometallic compounds composed of lithium, copper, and an organic group (R2), used in organic chemistry for coupling reactions. They facilitate the formation of carbon-carbon bonds by reacting with organic halides.
Heck Reaction: The Heck reaction is a palladium-catalyzed organic coupling reaction that forms carbon-carbon bonds between an aryl or vinyl halide and an alkene. It is a powerful tool in organic synthesis for the construction of complex molecules.
Ligands: Ligands are atoms, ions, or molecules that bind to a central metal atom or ion, forming a coordination complex. They are an essential component in organometallic coupling reactions, acting as the functional groups that facilitate the formation of new carbon-carbon bonds.
Negishi Coupling: Negishi coupling is a palladium-catalyzed cross-coupling reaction that allows for the formation of carbon-carbon bonds between an organohalide and an organozinc compound. It is a powerful tool in organic synthesis for the construction of complex organic molecules.
Organocopper: Organocopper compounds are a class of organometallic compounds containing carbon-copper bonds. They are widely used in organic synthesis, particularly in coupling reactions, due to their versatility and reactivity.
Organometallic Coupling Reactions: Organometallic coupling reactions are a class of organic reactions that involve the formation of carbon-carbon bonds through the coupling of an organometallic compound with an organic halide or pseudohalide. These reactions are widely used in organic synthesis for the construction of complex organic molecules.
Organopalladium: Organopalladium compounds are a class of organometallic compounds that contain a carbon-palladium bond. These compounds are widely used in organic synthesis, particularly in cross-coupling reactions, due to their unique reactivity and versatility.
Oxidative Addition: Oxidative addition is a fundamental organometallic reaction in which a metal complex adds an atom or molecule across a covalent bond, resulting in the metal center increasing its oxidation state and coordination number. This process is crucial in understanding the reactivity of alkyl halides, organometallic coupling reactions, and the reactions of arylamines.
Palladium-catalyzed Cross-Coupling: Palladium-catalyzed cross-coupling is a powerful organic reaction that allows the formation of carbon-carbon bonds between two different organic fragments. It is a widely used tool in organic synthesis, particularly in the construction of complex molecules.
Pseudohalide: A pseudohalide is a monovalent anion that behaves similarly to a halide ion (such as fluoride, chloride, bromide, or iodide) in chemical reactions, despite not being a true halogen. These anions have a central atom bonded to multiple atoms, giving them a pseudohalide-like structure and reactivity.
R2CuLi: R2CuLi is an organometallic compound consisting of an alkyl group (R) and a lithium copper (I) species. This type of compound is commonly used in organic synthesis, particularly in coupling reactions to form carbon-carbon bonds.
Reductive Elimination: Reductive elimination is a fundamental organometallic reaction in which two ligands attached to a metal center are removed as a new covalent bond is formed between them. This process is crucial in various organic transformations, including cross-coupling reactions and the synthesis of arylamines.
Sonogashira Coupling: Sonogashira coupling is a powerful carbon-carbon bond forming reaction that combines an alkyne and an aryl or vinyl halide in the presence of a copper(I) catalyst and a palladium(0) catalyst to produce a substituted alkyne product. This reaction is widely used in organic synthesis for the construction of complex molecules.
Stereochemistry: Stereochemistry is the study of the three-dimensional arrangement of atoms in molecules and how this arrangement affects the chemical and physical properties of the substance. It examines the spatial orientation of atoms and their relationship to one another, which is crucial in understanding many organic chemistry concepts.
Stille Coupling: Stille coupling is a palladium-catalyzed cross-coupling reaction that forms carbon-carbon bonds between an organotin compound and an organic halide or pseudohalide. It is a powerful tool in organic synthesis for the construction of complex molecules.
Suzuki Coupling: Suzuki coupling is a type of palladium-catalyzed cross-coupling reaction used to form carbon-carbon bonds between an organoboron compound and an organohalide. It is a powerful tool in organic synthesis for the construction of biaryl and other substituted aromatic compounds.
Suzuki-Miyaura Reaction: The Suzuki-Miyaura reaction is a powerful carbon-carbon bond forming reaction that utilizes an organoboron compound and an organohalide in the presence of a palladium catalyst to generate a new carbon-carbon bond. This reaction is a key tool in organic synthesis and has found widespread applications in the pharmaceutical, agrochemical, and materials science industries.
Suzuki–Miyaura reaction: The Suzuki-Miyaura reaction is a type of organometallic coupling reaction where a carbon-carbon bond is formed between a boron compound and an organohalide, in the presence of a palladium catalyst. It is widely used in the synthesis of complex organic compounds, including pharmaceuticals and polymers.
Transition Metals: Transition metals are a group of metallic elements in the periodic table that have partially filled d-orbitals. They exhibit unique chemical properties, such as the ability to form complex compounds and participate in a variety of oxidation-reduction reactions, making them particularly useful in organic chemistry reactions like organometallic coupling.
Transmetalation: Transmetalation is a type of ligand exchange reaction in organometallic chemistry where a metal center is substituted with a different metal. This process is particularly important in the context of Grignard reagents and organometallic coupling reactions, as it allows for the transfer of organic groups between different metal species.
Ullmann Coupling: Ullmann coupling is a type of organic reaction that involves the formation of carbon-carbon bonds through the use of copper catalysts. It is an important tool in organic synthesis, particularly in the construction of biaryl compounds.