Carbon-Carbon Bond Formation | Organic Chemistry 3

Carbon-carbon bond formation is studied in this chapter: coupling reactions with organocuprate reagents, Suzuki reaction, Heck reaction, Sonogashira reaction, properties and preparation of carbenes, carbene reactivities, Simmons-Smith reaction, metathesis reaction.

Coupling Reactions with Organocuprate Reagents

Review of organocuprate preparation:
 

 

Review of organocuprate coupling reactions:

  • Reaction with acid chlorides:

 

  • Reaction with epoxides:

 

  • Reaction with α,β-unsaturated carbonyl compounds:

 

Reaction with organic halides:
 


Conversion of an organic halide into a hydrocarbon containing a new C-C bond by nucleophilic attack of an R group of the organocuprate.

  • The coupling works best with methyl and 1o alkyl halides, as well as vinyl and aryl halides.
  • The halogen of the organic halide can be Cl, Br, or I.

Suzuki Reaction

Organopalladium compounds:

A palladium catalyst is used in the Suzuki reaction, which proceeds via an organopalladium intermediate. This intermediate is usually prepared in situ from a palladium source such as Pd(PPh3)4 or Pd(OAc)2.

During a reaction, palladium is coordinated to a variety of groups called ligands, which typically donate electron density to the metal. The use of phosphine, such as triphenylphosphine, as a ligand is particularly common because it is a good electron-donating ligand.

 

Oxidative addition and reductive elimination:

Reactions with metal catalyst involve 2 critical steps:

  • Oxidative addition: insertion of a metal atom into a covalent bond of a reagent, usually resulting in the formation of a new metal-carbon bond.

  • Reductive elimination: cleavage of a metal-carbon bond, typically yielding a new covalent bond between two carbon atoms and releasing the metal species.


These processes are crucial for the activation of small molecules and for catalytic cycles in various chemical reactions, such as the Suzuki reaction.

 

Suzuki reaction:
 

 

Coupling of an organoborane with an organic halide in the presence of a palladium catalyst and a base.
[R = aryl or vinyl; X = Br or I; R' = aryl or vinyl; Y = OH or OR].


Mechanism:

  1. Oxidative addition: coordination of the palladium catalyst with the aryl or vinyl halide to form an organopalladium compound.
  2. Transmetallation: transfer of an alkyl group from boron center of a nucleophilic boron intermediate to palladium. The nucleophilic boron intermediate is obtained from the reaction between the organoborane and hydroxide ions (HO-).
  3. Reductive elimination: formation of a carbon-carbon bond resulting in the release of the desired product and regeneration of the palladium catalyst.

 

 

The Suzuki reaction is stereospecific, proceeding with retention of stereochemistry at the carbon-carbon bond forming site.

Heck Reaction

Heck reaction:
 


Coupling of an alkene with an organic halide in the presence of a palladium catalyst and an amine base.
[R = aryl or vinyl; X = Br or I; Z = H, Ph, COOR, or CN].


Mechanism:

  1. Oxidative addition: coordination of the palladium catalyst with the aryl or vinyl halide to form an organopalladium compound.
  2. Alkene insertion: addition of the aryl or vinyl group and palladium to the double bond of the alkene.
  3. β-hydride elimination: transfer of a β-proton to the palladium center, resulting in the formation of a new double bond and release of the alkene.
  4. Reductive elimination: elimination of HX resulting in regeneration of the palladium catalyst.

 

 

The Heck reaction is a substitution reaction in which a H atom of the starting alkene is replaced by the vinyl or aryl group of the halide. The new C-C bond is formed on the less substituted carbon to give a trans alkene.

The Heck reaction is stereospecific, proceeding with retention of stereochemistry at the carbon-carbon bond forming site.

Sonogashira Reaction

Sonogashira reaction:
 

 

Coupling of a terminal alkyne with an organic halide in the presence of a palladium catalyst, a copper cocatalyst, and an amine base.
[R = aryl or vinyl; X = Cl, Br, I, or OTf]


Mechanism:

  1. Oxidative addition: coordination of the palladium catalyst with the aryl or vinyl halide to form an organopalladium compound.

  2. Alkyne activation: coordination of the terminal alkyne to the copper via deprotonation with the amine base.

  3. Transmetallation: transfer of the alkynyl group from the copper to the palladium, displacing the halide ligand.

  4. Reductive elimination: formation of a carbon-carbon bond between the alkynyl group and the aryl or vinyl group. This step results in the release of the desired product and regeneration of the palladium catalyst.

 

Properties and Preparation of Carbenes

Properties of carbenes:

A carbene is a highly reactive molecule containing a neutral divalent carbon atom with only 6 valence electrons. Singlet carbenes in particular are sp2 hybridized with a lone pair of electrons and a vacant p orbital, making them ambiphilic (nucleophilic and electrophilic). A carbene is highly reactive because carbon does not have an octet of electrons.

 

Carbenes are important intermediates in organic chemistry and have applications in various chemical reactions, including cyclopropanation, olefin metathesis, and insertion reactions.

 

Preparation of carbenes:

Carbenes are often generated in situ and used as reactive intermediates rather than isolated. 

  • Dihalocarbenes:

Mechanism:

  1. Deprotonation of a trihalomethane with a strong base to form a carbanion.
  2. Loss of a good leaving group, a chloride anion, to form the carbene.

 

  • Stable cyclic carbenes:

Stable cyclic carbenes, exemplified by N-heterocyclic carbenes (NHCs) and cyclic (alkyl)(amino)carbenes (CAACs), are molecules featuring a ring structure and nitrogen neighbors. These carbenes are noteworthy for their stability due to several factors: the stabilizing effects of the neighboring atoms on the lone pair and the vacant p orbital of the carbene, and the steric hindrance provided by the ring structure, which prevents unwanted reactions.


They are commonly prepared by deprotonation of iminium or azolium salts using strong anionic bases:
 

Reactivity of Carbenes

Addition to an alkene:


Conversion of an alkene into a dihalocyclopropane.

Concerted reaction due to the ambiphilic nature of the carbene ⇒ both C-C bonds are formed in a single step.

The addition of a carbene to an alkene is syn. Therefore, the reaction is stereospecific: the relative position of the substituents in the alkene reactant is retained.

Simmons-Smith Reaction

Simmons-Smith reaction:


Conversion of an alkene into a cyclopropane.

Mechanism:

  1. Reaction of CH2I2 with Zn(Cu) to form (iodomethyl)zinc iodide, called the Simmons-Smith reagent.
  2. Transfer of the CH2 group from the Simmons-Smith reagent to the alkene to form a cyclopropane.

 

  • The Simmons-Smith reaction does not involve a free carbene. Rather, the CH2 group is bonded to the metal and is therefore called a carbenoid.
  • The Simmons-Smith reaction is stereospecific: the relative position of the substituents in the alkene reactant is retained.

Metathesis

Metathesis catalysts:

Olefin metathesis relies on complex transition metal catalysts featuring carbon-metal double bonds. These catalysts, which typically contain ruthenium (Ru), tungsten (W), or molybdenum (Mo), facilitate the rearrangement of carbon-carbon double bonds. In particular, one of the most common types of catalysts was developed by Grubbs and uses Ru as the central metal atom.

 

Olefin metathesis:


Reaction between 2 alkenes that results in the interchange of the carbons of their double bonds.

Mechanism:

  1. Reaction of the activated metal-carbene with the alkene to form a metallocyclobutane.
  2. Elimination of an alkene, usually ethylene gas, to form a new metal-carbene complex.
  3. Addition of the metal-carbene complex to the starting alkene to form another metallocyclobutane.
  4. Elimination of the desired alkene, resulting in regeneration of the ruthenium catalyst.

 

 

  • Olefin metathesis is an equilibrium process that results in a mixture of alkenes as products. However, when terminal alkenes are involved, ethylene gas (CH2=CH2) is produced as one of the metathesis products. As ethylene escapes from the reaction mixture, it drives the reaction towards completion ⇒ Terminal alkenes are excellent metathesis substrates, resulting in the formation of a single alkene product.
  • When a diene is used as the starting material, ring closure occurs via intramolecular metathesis. This process is called ring-closing olefin metathesis.

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Organocuprate reagents can react with a wide range of electrophiles, including alkyl halides, acid chlorides, acid anhydrides, and epoxides. Nucleophilic addition of the organocuprate to the electrophilic carbon atom of these compounds results in the formation of new carbon-carbon bonds, allowing the synthesis of complex organic molecules.

Examples include the formation of ketones from acid chlorides or anhydrides, the synthesis of alcohols from epoxides, and the coupling of organocuprates with alkyl halides to form alkylated products. 

The Suzuki reaction is a palladium-catalyzed cross-coupling reaction used to form carbon-carbon bonds between aryl or vinyl boronic acids and aryl or vinyl halides. The reaction typically involves the use of a palladium catalyst, a base such as sodium hydroxide, and a solvent such as an ether or alcohol.

The mechanism of the Suzuki reaction involves oxidative addition of the aryl or vinyl halide to the palladium catalyst, followed by transmetallation with the aryl or vinyl boronic acid to form an organopalladium intermediate. Reductive elimination then occurs, resulting in the formation of the desired coupled product and regeneration of the palladium catalyst.

The Heck reaction is a palladium-catalyzed coupling reaction used to form carbon-carbon bonds between aryl or vinyl halides and alkenes. The reaction typically involves the use of a palladium catalyst, a base such as triethylamine or potassium carbonate, and a solvent such as DMF or toluene.

The mechanism of the Heck reaction involves oxidative addition of the aryl or vinyl halide to the palladium catalyst, followed by insertion of the alkene or alkyne into the palladium-carbon bond. β-hydride elimination then occurs, resulting in the formation of the desired coupled product and regeneration of the palladium catalyst.

In the Heck reaction, common catalysts include palladium(II) salts such as palladium acetate [Pd(OAc)2] and palladium(II) chloride [PdCl2], often in conjunction with phosphine ligands that stabilize the palladium catalyst and improve its reactivity. These catalysts function by coordinating to the alkene and the aryl or vinyl halide, facilitating the formation of carbon-carbon bonds. The palladium catalyst undergoes a series of oxidative addition, transmetallation, and reductive elimination steps, thereby transferring the aryl or vinyl group to the alkene.

The Sonogashira reaction is a palladium-catalyzed coupling reaction used to form carbon-carbon bonds between terminal alkynes and aryl or vinyl halides. The reaction typically involves the use of a palladium catalyst, a copper(I) co-catalyst, a base such as triethylamine or potassium carbonate, and a solvent such as DMF or toluene.

The mechanism of the Sonogashira reaction involves oxidative addition of the aryl or vinyl halide to the palladium catalyst, followed by transmetallation with the terminal alkyne to form an organopalladium intermediate. Alkyne insertion then occurs, followed by reductive elimination, resulting in the formation of the desired coupled product and regeneration of the palladium catalyst.

Certainly, C-C bond formation can exhibit both stereo- and regioselectivity. An example is the Suzuki reaction, which involves the coupling of an organoboron compound with a halide using a palladium catalyst. This reaction is known for its ability to couple aryl, vinyl, or alkyl groups with high degree of selectivity under mild conditions. Stereochemistry is typically preserved in the reaction, making the Suzuki coupling a powerful tool for constructing complex molecules with defined configurations.

A carbene is a highly reactive neutral species that consists of a carbon atom with two nonbonded electrons and only six electrons in its valence shell, giving it a divalent state and a linear or bent geometry. Singlet carbenes have a pair of electrons in the same orbital (sp2 hybridization) and are ambiphilic, while triplet carbenes have their two electrons in separate orbitals (p orbitals, sp hybridization), making them more reactive towards electron-deficient alkenes.

Carbenes can be formed in chemical reactions by several methods, including the decomposition of diazo compounds in the presence of heat or light, which releases nitrogen gas and creates a carbene, or by alpha-elimination reactions, in which a compound loses a proton and a leaving group to form the carbene.

The Simmons-Smith reaction is a chemical reaction used to convert alkenes into cyclopropane rings. It involves the reaction of an alkene with a carbenoid species generated from diiodomethane (CH2I2) and a zinc-copper couple (Zn-Cu), which forms a highly reactive intermediate that adds to the double bond of the alkene to produce a cyclopropane.

This reaction is specifically useful for synthesizing cyclopropane rings, thus creating new carbon-carbon (C-C) single bonds between the carbon atoms of the original double bond and the methylene (—CH2—) group of the carbenoid. The Simmons-Smith reaction is considered a stereospecific process, typically retaining the stereochemistry of the reactant alkene in the product cyclopropane.

Metathesis is a reaction where two alkene groups exchange places, typically facilitated by transition metal catalysts like ruthenium or molybdenum. The reaction involves the breaking and forming of carbon-carbon double bonds.

The mechanism of metathesis involves the coordination of alkene substrates to the metal catalyst, followed by the formation of a metallacyclobutane intermediate through a cyclic transition state. This intermediate undergoes ring-opening and reformation to yield the exchanged alkene products.