12.3 Organocopper reagents
9 min read•august 21, 2024
Organocopper reagents are powerful tools in organic synthesis, offering unique reactivity and selectivity. These compounds excel at forming , particularly in conjugate additions and . Their ability to control stereochemistry makes them valuable in complex molecule synthesis.
Understanding the different types of organocopper reagents, such as Gilman and , is crucial for synthetic planning. These compounds' structure, bonding, and preparation methods influence their reactivity. Mastering organocopper chemistry opens up new possibilities in organic synthesis and catalysis.
Types of organocopper reagents
- Organocopper reagents play a crucial role in organic synthesis due to their unique reactivity and selectivity
- These reagents allow for precise control in carbon-carbon bond formation and functional group transformations
- Understanding different types of organocopper compounds enhances synthetic planning and execution in complex molecule synthesis
Gilman reagents
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Organocopper cross-coupling reaction for C–C bond formation on highly sterically hindered ... View original
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Organocopper cross-coupling reaction for C–C bond formation on highly sterically hindered ... View original
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Re-orienting coupling of organocuprates with propargyl electrophiles from S N 2′ to S N 2 with ... View original
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Organocopper cross-coupling reaction for C–C bond formation on highly sterically hindered ... View original
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Organocopper cross-coupling reaction for C–C bond formation on highly sterically hindered ... View original
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Organocopper cross-coupling reaction for C–C bond formation on highly sterically hindered ... View original
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Re-orienting coupling of organocuprates with propargyl electrophiles from S N 2′ to S N 2 with ... View original
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- Consist of dialkylcuprates with the general formula R2CuLi
- Prepared by reacting organolithium compounds with copper(I) salts in a 2:1 ratio
- Exhibit enhanced reactivity and selectivity compared to simple organolithium reagents
- Commonly used in and cross-coupling processes
- Examples include dimethylcuprate (Me2CuLi) and diphenylcuprate (Ph2CuLi)
Normant cuprates
- Higher-order cuprates with the general formula R2Cu(CN)Li2
- Formed by reacting organolithium compounds with copper(I) cyanide
- Demonstrate increased thermal stability and reactivity compared to
- Particularly effective in SN2' reactions and conjugate additions to α,β-unsaturated carbonyl compounds
- Examples include lithium dimethylcyanocuprate and lithium dibutylcyanocuprate
Heterocuprates
- Contain two different organic groups attached to copper
- Prepared by sequential addition of different organolithium reagents to copper salts
- Allow for selective transfer of one organic group while the other acts as a non-transferable ligand
- Useful in chemoselective transformations and asymmetric synthesis
- Examples include RCu(2-thienyl)CNLi2 and PhCu(Me)Li
Structure and bonding
- Organocopper compounds exhibit unique structural features due to copper's electronic configuration
- Understanding these structural aspects is crucial for predicting reactivity and designing effective synthetic strategies
- The bonding in organocopper reagents influences their stability, reactivity, and selectivity in organic transformations
Copper oxidation states
- Copper primarily exists in +1 oxidation state in organocopper reagents
- Cu(I) forms linear or trigonal planar complexes due to its d10 electronic configuration
- Copper's ability to access multiple oxidation states (+1, +2, +3) enables various reaction mechanisms
- Cu(I) compounds are typically colorless or pale yellow, while Cu(II) compounds are often blue or green
- Redox processes involving Cu(I)/Cu(III) are important in many organocopper-mediated reactions
Ligand effects
- Nature of ligands significantly influences the reactivity and selectivity of organocopper reagents
- Electron-donating ligands increase electron density on copper, enhancing nucleophilicity
- π-acceptor ligands (phosphines) can stabilize reactive intermediates and modulate reactivity
- Chiral ligands enable asymmetric transformations by creating a chiral environment around copper
- Examples of common ligands include alkyl groups, cyanide, phosphines, and N-heterocyclic carbenes
Aggregation in solution
- Organocopper compounds often form aggregates in solution, affecting their reactivity
- Aggregation state depends on factors like solvent polarity, temperature, and concentration
- Lower-order aggregates (dimers, trimers) are generally more reactive than higher-order structures
- Polar solvents (THF, ether) tend to break up aggregates, increasing reactivity
- Additives like TMEDA or HMPA can be used to control aggregation and enhance reactivity
Preparation methods
- Synthesis of organocopper reagents requires careful control of reaction conditions
- Various methods allow for the preparation of different types of organocopper compounds
- Choice of preparation method depends on desired reactivity, stability, and functional group tolerance
From organolithium compounds
- Most common method for preparing Gilman reagents and other organocopper compounds
- Involves reacting organolithium reagents with copper(I) salts (CuI, CuBr, CuCN)
- Typically performed at low temperatures (-78°C to 0°C) to control reactivity
- Stoichiometry crucial for determining the type of organocopper reagent formed
- Example:
From Grignard reagents
- Alternative method using less reactive organometallic precursors
- Grignard reagents (RMgX) react with copper(I) salts to form organocopper compounds
- Generally requires higher temperatures compared to organolithium method
- Useful when organolithium reagents are too reactive or unavailable
- Example:
Direct copper insertion
- Involves direct insertion of copper metal into organic halides
- Useful for preparing functionalized organocopper reagents
- Often requires activation of copper (copper powder, Rieke copper)
- Tolerates many functional groups incompatible with organolithium or Grignard reagents
- Example:
- X = Br, I
- Often performed in polar aprotic solvents (DMF, DMSO)
Reactivity and mechanisms
- Organocopper reagents exhibit unique reactivity patterns distinct from other organometallics
- Understanding reaction mechanisms is crucial for predicting outcomes and optimizing conditions
- Reactivity can be fine-tuned by modifying the structure of the organocopper reagent
SN2' reactions
- Organocopper reagents excel at SN2' (conjugate displacement) reactions
- Involve nucleophilic attack at the γ-position of allylic substrates
- Proceed with inversion of configuration at the γ-carbon
- Mechanism involves initial π-complexation followed by oxidative addition and reductive elimination
- Example: reaction of allyl acetate with dimethylcuprate to form 1-butene
Conjugate addition reactions
- Hallmark reaction of organocopper reagents, especially with α,β-unsaturated carbonyl compounds
- Proceed via initial coordination to the π-system followed by 1,4-addition
- Highly chemoselective for 1,4-addition over 1,2-addition
- Can be rendered enantioselective using chiral ligands or auxiliaries
- Example: addition of methylcuprate to cyclohexenone to form 3-methylcyclohexanone
Cross-coupling reactions
- Organocopper reagents participate in various cross-coupling reactions
- Include Ullmann coupling, Castro-Stephens coupling, and copper-catalyzed azide-alkyne cycloaddition
- Often involve Cu(I)/Cu(III) redox cycles
- Mechanism typically includes oxidative addition, transmetalation, and reductive elimination steps
- Example: Ullmann coupling of aryl halides to form biaryls
Synthetic applications
- Organocopper reagents find widespread use in organic synthesis due to their unique reactivity
- These compounds enable transformations that are difficult or impossible with other organometallics
- Applications range from simple functional group interconversions to complex natural product synthesis
Carbon-carbon bond formation
- Organocopper reagents excel at forming new carbon-carbon bonds
- Particularly useful for adding alkyl, aryl, and vinyl groups to various substrates
- Allow for selective functionalization of complex molecules
- Enable construction of quaternary carbon centers
- Examples include:
- Conjugate addition to enones
- Carbocupration of alkynes
- Cross-coupling reactions to form biaryls
Stereochemistry control
- Organocopper reagents often exhibit high levels of stereoselectivity
- Enable stereospecific SN2' reactions with allylic substrates
- Allow for diastereoselective conjugate additions to chiral enones
- Can be used in combination with chiral ligands for enantioselective transformations
- Examples include:
- Asymmetric conjugate addition to form chiral β-substituted ketones
- Stereospecific coupling of chiral alkylcopper reagents
Functional group transformations
- Organocopper compounds facilitate various functional group interconversions
- Allow for selective manipulations in the presence of sensitive functionalities
- Enable chemoselective transformations difficult with other organometallics
- Useful for late-stage functionalization of complex molecules
- Examples include:
- Conversion of to alkenes via β-elimination
- Selective reduction of α,β-unsaturated carbonyl compounds
- Copper-catalyzed azide-alkyne cycloadditions (click chemistry)
Comparison with other organometallics
- Organocopper reagents possess unique properties that distinguish them from other organometallic compounds
- Understanding these differences is crucial for selecting the appropriate reagent for a given transformation
- Comparison with other organometallics helps in predicting reactivity and designing synthetic strategies
Organocopper vs organolithium
- Organocopper reagents are generally less basic and nucleophilic than organolithium compounds
- Exhibit higher functional group tolerance compared to highly reactive organolithiums
- Show greater selectivity for conjugate addition (1,4-addition) over direct addition (1,2-addition)
- Form weaker carbon-metal bonds, leading to different reactivity patterns
- Examples of differences:
- Methylcuprate adds 1,4 to enones, while methyllithium adds 1,2
- Organocopper tolerates esters, while organolithium typically reacts with esters
Organocopper vs organomagnesium
- Organocopper compounds are less basic than Grignard reagents
- Show higher selectivity in additions to carbonyl compounds and related substrates
- Exhibit greater tolerance for functional groups sensitive to Grignard reagents
- Often used in tandem with Grignard reagents for transmetalation reactions
- Examples of differences:
- Organocopper reagents selectively add 1,4 to enones, while Grignards often give mixtures
- Organocopper compounds tolerate nitriles, while Grignards typically add to nitriles
Organocopper vs organozinc
- Organocopper reagents are generally more reactive than organozinc compounds
- Show higher nucleophilicity in addition reactions
- Exhibit different selectivity patterns in cross-coupling reactions
- Organozinc compounds often require copper catalysis to enhance reactivity
- Examples of differences:
- Organocopper reagents directly add to enones, while organozinc often requires catalysis
- Organozinc compounds show higher functional group tolerance in some cases
Catalytic organocopper chemistry
- Catalytic use of copper has revolutionized many organic transformations
- Allows for more atom-economical and environmentally friendly processes
- Enables new reactivity patterns not accessible with stoichiometric organocopper reagents
- Catalytic systems often show improved functional group tolerance and selectivity
Copper-catalyzed coupling reactions
- Copper catalysts facilitate various carbon-carbon and carbon-heteroatom bond-forming reactions
- Include Ullmann coupling, Goldberg reaction, and Chan-Lam coupling
- Often proceed via Cu(I)/Cu(III) catalytic cycles
- Allow for coupling of aryl halides, phenols, amines, and other nucleophiles
- Examples include:
- Copper-catalyzed N-arylation of amines (Ullmann-type reaction)
- Copper-catalyzed oxidative coupling of terminal alkynes (Glaser coupling)
Asymmetric catalysis
- Chiral copper complexes enable enantioselective transformations
- Allow for the synthesis of enantioenriched products from achiral starting materials
- Commonly used in asymmetric conjugate additions and cycloadditions
- Chiral ligands create a chiral environment around the copper center
- Examples include:
- Enantioselective conjugate addition of organozinc reagents to enones
- Asymmetric copper-catalyzed azide-alkyne cycloadditions
Green chemistry applications
- Copper catalysis aligns with many principles of green chemistry
- Enables more efficient and environmentally friendly synthetic processes
- Allows for the use of less toxic and more abundant metal compared to precious metal catalysts
- Facilitates reactions in aqueous media or under solvent-free conditions
- Examples include:
- Copper-catalyzed click chemistry for bioconjugation
- Aqueous-phase Ullmann coupling reactions
Handling and safety considerations
- Proper handling of organocopper reagents is crucial for safety and successful reactions
- Understanding the properties and reactivity of these compounds is essential for safe laboratory practices
- Implementing appropriate safety measures protects researchers and ensures reliable experimental results
Air and moisture sensitivity
- Most organocopper reagents are highly sensitive to air and moisture
- Exposure leads to rapid decomposition, often accompanied by color changes
- Requires use of inert atmosphere techniques (Schlenk line, glove box)
- Anhydrous solvents and rigorously dried glassware are essential
- Proper quenching procedures needed to safely dispose of unused reagents
Storage and disposal
- Store organocopper reagents under inert atmosphere, preferably at low temperatures
- Use sealed containers or ampoules for long-term storage
- Dispose of unused reagents by careful quenching with isopropanol or other proton sources
- Never dispose of organocopper compounds directly into waste containers
- Keep detailed records of storage conditions and expiration dates
Toxicity and precautions
- Many organocopper compounds are toxic and should be handled with caution
- Avoid skin contact or inhalation of vapors or dust
- Work in well-ventilated areas or fume hoods to minimize exposure
- Use appropriate personal protective equipment (gloves, lab coat, goggles)
- Be aware of potential fire hazards associated with pyrophoric organocopper species
- Have proper fire extinguishing equipment readily available
Recent advances
- Organocopper chemistry continues to evolve with new reagents and methodologies
- Recent developments expand the scope and utility of organocopper reactions
- Advances in this field impact various areas of organic synthesis and materials science
New organocopper reagents
- Development of novel organocopper species with unique reactivity profiles
- Introduction of stabilized organocopper reagents for improved handling and storage
- Design of chiral organocopper complexes for asymmetric transformations
- Exploration of heterobimetallic copper complexes for enhanced reactivity
- Examples include:
- Copper(III) complexes as reactive intermediates in C-H functionalization
- Fluoroalkylcopper reagents for selective fluoroalkylation reactions
Improved synthetic methods
- Optimization of existing protocols for preparing organocopper reagents
- Development of milder and more selective copper-catalyzed transformations
- Integration of flow chemistry techniques for safer handling of organocopper species
- Exploration of photoredox/copper dual catalysis for novel transformations
- Examples include:
- Copper-catalyzed asymmetric propargylation reactions
- Electrochemical generation of organocopper reagents
Applications in total synthesis
- Increasing use of organocopper chemistry in the synthesis of complex natural products
- Exploitation of copper's unique reactivity for key bond-forming steps
- Application of copper-catalyzed reactions for late-stage functionalization
- Integration of organocopper methods in diversity-oriented synthesis
- Examples include:
- Use of copper-catalyzed azide-alkyne cycloaddition in the synthesis of bioactive peptides
- Application of asymmetric copper-catalyzed conjugate addition in steroid synthesis
Key Terms to Review (20)
Aldehydes: Aldehydes are organic compounds containing a carbonyl group (C=O) where the carbon is bonded to at least one hydrogen atom, making them distinct from ketones. This unique structure allows aldehydes to participate in various chemical reactions, particularly those involving nucleophiles, making them important intermediates in organic synthesis and a key feature in many biochemical processes.
Alkyl halides: Alkyl halides are organic compounds containing a carbon chain bonded to a halogen atom (such as fluorine, chlorine, bromine, or iodine). These compounds are significant in organic synthesis as they can undergo various reactions, including substitution and elimination, making them versatile intermediates in the formation of more complex molecules.
Carbanion mechanism: A carbanion mechanism refers to a reaction pathway in which a carbanion, a negatively charged carbon species, acts as a nucleophile to initiate a reaction. In these mechanisms, the carbanion can attack electrophiles, leading to the formation of new carbon-carbon or carbon-heteroatom bonds. This type of mechanism is particularly relevant in the context of organocopper reagents, where the unique properties of carbanions facilitate various nucleophilic substitutions and additions.
Carbon-carbon bonds: Carbon-carbon bonds are the connections formed between carbon atoms, which are fundamental to organic molecules and play a crucial role in determining the structure and reactivity of organic compounds. These bonds can be single, double, or triple, affecting the geometry and physical properties of the molecules they comprise. Understanding these bonds is key for working with organocopper reagents, as they often participate in forming new carbon-carbon bonds during synthesis reactions.
Conjugate addition reactions: Conjugate addition reactions involve the addition of a nucleophile to the β-carbon of an α,β-unsaturated carbonyl compound. This type of reaction allows for the formation of new carbon-carbon bonds and is significant in organic synthesis, particularly when using organometallic reagents like organocopper reagents. The outcome of these reactions often leads to more complex molecules, enhancing synthetic pathways.
Electrophilicity: Electrophilicity refers to the ability of a chemical species to act as an electrophile, meaning it is attracted to electrons and can accept an electron pair from a nucleophile during a chemical reaction. This characteristic is crucial in organic reactions, as electrophiles are often key players in mechanisms such as nucleophilic acyl substitution, functional group transformations, and organocopper reactions. Understanding electrophilicity helps in predicting reaction pathways and the reactivity of various organic compounds.
Formation of carbon-carbon bonds: The formation of carbon-carbon bonds is a fundamental process in organic chemistry that involves the creation of connections between carbon atoms, which is essential for building complex organic molecules. This process allows for the construction of various structures, including alkanes, alkenes, alkynes, and aromatic compounds, facilitating the synthesis of a wide range of chemical entities. Efficient methods for creating these bonds are critical in both synthetic organic chemistry and the development of pharmaceuticals and materials.
Gilman Reagents: Gilman reagents, also known as organocuprates, are organometallic compounds that contain lithium or copper atoms bonded to carbon atoms. They are highly versatile in organic synthesis and are particularly useful for nucleophilic substitutions and additions to carbonyl compounds, allowing for the formation of carbon-carbon bonds.
Henry Gilman: Henry Gilman was a prominent chemist known for his contributions to organic chemistry, particularly in the development of methods for synthesizing carbon-carbon bonds and studying organocopper reagents. His work laid the foundation for key techniques in organic synthesis, influencing how enolates can be alkylated and enhancing our understanding of reaction mechanisms in forming complex molecules.
Heterocuprates: Heterocuprates are a class of organocopper reagents that feature two different types of metal centers, typically copper and another metal, which can facilitate unique reactivity patterns in organic synthesis. These reagents are particularly known for their ability to act as nucleophiles, allowing for the formation of carbon-carbon bonds through cross-coupling reactions with various electrophiles. The presence of the additional metal component can enhance the selectivity and efficiency of these reactions.
Metalation mechanism: The metalation mechanism is a process in which a metal reagent, often a transition metal or organometallic compound, interacts with an organic molecule to form a new metal-carbon bond. This mechanism is crucial for facilitating various transformations in organic synthesis, particularly when using organocopper reagents that can effectively insert into carbon-hydrogen bonds, creating a new reactive site for further reactions.
Normant cuprates: Normant cuprates are a class of organocopper reagents characterized by their stable, non-aggregated forms that are useful in various organic transformations. They are named after the chemist who first described their unique properties and reactivity. These reagents are particularly significant for their ability to undergo nucleophilic reactions, enabling the formation of carbon-carbon bonds in synthetic organic chemistry.
Organometallic character: Organometallic character refers to the unique properties and behaviors exhibited by compounds that contain a bond between a carbon atom and a metal atom. This characteristic plays a significant role in reactivity, where the carbon-metal bond can exhibit ionic, covalent, or polar-covalent properties depending on the metal's electronegativity and oxidation state, impacting the compound's ability to participate in various chemical reactions.
Pyrophoric Nature: Pyrophoric nature refers to the ability of a substance to spontaneously ignite upon exposure to air, typically due to its high reactivity with oxygen. This characteristic is crucial for certain organometallic compounds, including organocopper reagents, as it dictates how these compounds must be handled and stored to prevent accidents during their use in synthetic organic chemistry.
Richard R. Schrock: Richard R. Schrock is an American chemist known for his significant contributions to the field of organic chemistry, particularly in the development of metal-catalyzed reactions such as olefin metathesis. His work has greatly advanced the understanding and application of organocopper reagents, which are important tools in organic synthesis for forming carbon-carbon bonds.
Selectivity in nucleophilic attack: Selectivity in nucleophilic attack refers to the preference of a nucleophile to react with a specific electrophile or a specific site within a molecule over others. This concept is crucial in organic synthesis, where the outcomes of reactions depend heavily on the chosen nucleophile and the electrophilic centers present in substrates. Selectivity influences product formation, yielding desired compounds while minimizing side reactions and byproducts.
Sn2' reactions: sn2' reactions are a specific type of nucleophilic substitution reaction where a nucleophile attacks a carbon atom that is also undergoing a simultaneous rearrangement. This reaction often involves the migration of a neighboring group and typically occurs at tertiary or secondary carbons, where steric hindrance is a consideration. The dual process of substitution and rearrangement leads to unique reaction pathways, making it an important concept in understanding complex organic transformations.
Stability of Carbanions: The stability of carbanions refers to the relative tendency of these negatively charged carbon species to remain in their anionic form without undergoing protonation or other reactions. Factors such as electronegativity, hybridization, and resonance significantly affect carbanion stability, making it an essential concept in understanding reaction mechanisms involving nucleophiles and their behavior in various organic transformations.
Synthesis of alcohols: The synthesis of alcohols involves the creation of alcohol compounds, typically through various chemical reactions that introduce hydroxyl groups (-OH) into organic molecules. This process is essential in organic chemistry as alcohols serve as vital intermediates in the production of a wide range of chemicals, including pharmaceuticals, solvents, and fuels. Two notable methods to synthesize alcohols include using Grignard reagents and organocopper reagents, both of which play significant roles in forming new carbon-carbon bonds and facilitating alcohol formation.
Toxicity: Toxicity refers to the degree to which a substance can cause harm to living organisms. It encompasses various factors, including the type of chemical, the dose, the route of exposure, and the duration of exposure. Understanding toxicity is essential for assessing the safety of compounds used in chemical reactions, especially when dealing with organocopper reagents that can have harmful effects on human health and the environment.