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Chapter 26 Topics:

• Organocuprate Coupling.• R-X + (R')2CuLi

• Suzuki Coupling.• R-X + Organoborane

• Heck Reaction.• R-X + Alkene

• Dihalocarbene addition.• :CX2 + Alkene

• Simmons-Smith Reaction.• ICH2ZnI + Alkene

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Coupling Reactions of Organocuprates:

• Recall that organocuprate reagents react a variety of functional compounds including acid chlorides, epoxides and ,-unsaturated carbonyl compounds.

• Organocuprate reagents also react with organic halides R'—X to form coupling products R—R' that contain a new C—C bond.

• Only one R group of the organocuprate is transferred to form the product, while the other becomes part of the RCu, a reaction product.

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• Methyl, 1°, cyclic 2°, vinyl and aryl halides can be used. Reactions with vinyl halides are stereospecific.

• The halogen (X) may be Cl, Br or I.• Tertiary (3°) halides are too sterically hindered to react.

Carbon-Carbon Bond-Forming Reactions

Coupling Reactions of Organocuprates:

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• Since organocuprate reagents are prepared in two steps from alkyl halides (RX), this method ultimately converts two organic halides (RX and R'X) into a hydrocarbon R—R' with a new carbon—carbon bond.

• Note that this means that using this methodology, a given hydrocarbon can often be made by two different routes.

Coupling Reactions of Organocuprates:

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The Suzuki Reaction: General

• The Suzuki reaction is a palladium-catalyzed coupling of a vinyl or aryl halide (R'X) with an organoborane (RBY2) to form a product (R—R') with a new C—C bond.

• Pd(PPh3)4 is the typical palladium catalyst.

• The reaction is carried out in the presence of a base such as NaOH or NaOCH2CH3.

• The halogen is usually Br or I.• The Suzuki reaction is completely stereospecific.

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The Suzuki Reaction: Uses a Pd Catalyst• Organopalladium compounds are compounds that

contain a carbon—palladium bond.• During a reaction, Pd is coordinated to a variety of

groups called ligands, which donate electron density to (or sometimes withdraw electron density from) the metal.

• A common electron donating ligand is phosphine, some derivatives of which are shown:

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• A general ligand bonded to a metal is often designated as “L.” Pd bonded to four ligands is denoted as PdL4.

• Organopalladium intermediates are generally prepared in situ during the course of a reaction, from another palladium reagent such as Pd(OAc)2 or Pd(PPh3)4. Note that “Ac” is the abbreviation for the acetyl group, CH3C=O, so OAc is the abbreviation for CH3CO2¯.

• Usually only a catalytic amount of Pd reagent is used.• Two common processes, called oxidative addition and

reductive elimination, dominate many reactions of palladium compounds.

The Suzuki Reaction:

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The Suzuki Reaction: A Reaction with a Pd Catalyst

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The Suzuki Reaction:

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• Vinylboranes, which have a boron atom bonded to a carbon—carbon double bond, are prepared by hydroboration using catecholborane, a commercially available reagent.

• Hydroboration adds H and B in a syn fashion to form a trans vinylborane. With terminal alkynes, hydroboration always places the boron atom on the less substituted terminal carbon.

The organoboranes used in the Suzuki reaction are acquired from two sources.

The Suzuki Reaction: The boranes

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• Arylboranes, which have a boron atom bonded to a benzene ring, are prepared from organolithium reagents by reaction with trimethyl borate [B(OCH3)3]

Carbon-Carbon Bond-Forming Reactions

The Suzuki Reaction: The boranes

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The Suzuki Reaction: Mechanistic Details

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• The Heck reaction is a Pd-catalyzed coupling of a vinyl or aryl halide with an alkene to form a more highly substituted alkene with a new C—C bond.

• Palladium(II) acetate [Pd(OAc)2] in the presence of a triarylphosphine [P(o-tolyl)3] is the typical catalyst.

• The reaction is carried out in the presence of a base such as triethylamine.

• The Heck reaction is a substitution in which one H atom of the alkene starting material is replaced by the R' group of the vinyl or aryl halide.

The Heck Reaction:

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• The alkene component is typically ethylene or a monosubstituted alkene (CH2=CHZ).

• When Z = Ph, COOR or CN in a monosubstituted alkene, the new C—C bond is formed on the less substituted carbon to afford a trans alkene.

• The halogen is typically Br or I.• When a vinyl halide is used as the organic halide,

the reaction is stereospecific.

The Heck Reaction:

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The Heck Reaction:

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• To use the Heck reaction in synthesis, you must determine what alkene and what organic halide are needed to prepare a given compound.

• To work backwards, locate the double bond with the aryl, COOR, or CN substituent, and break the molecule into two components at the end of the C=C not bonded to one of these substituents.

The Heck Reaction: Retrosynthesis

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The Heck Reaction:

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• A carbene, R2C:, is a neutral reactive intermediate that contains a divalent carbon surrounded by six electrons: the lone pair, and two each from the two R groups.

• These three groups make the carbene carbon sp2 hybridized, with a vacant p orbital extending above and below the plane containing the C and the two R groups.

• The lone pair occupies an sp2 hybrid orbital.

Carbenes and Cyclopropane Synthesis:

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• Dihalocarbenes, :CX2, are especially useful reactive intermediates since they are readily prepared from trihalomethanes (CHX3) by reaction with strong base, e.g., treatment of chloroform (CHCl3) with KOC(CH3)3 forms dichlorocarbene, :CCl2.

• Dichlorocarbene is formed by a two-step process that results in the elimination of the elements of H and Cl from the same carbon.

• Loss of the two elements from the same carbon is called elimination.

Carbenes and Cyclopropane Synthesis:

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Carbenes and Cyclopropane Synthesis:

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• Since dihalocarbenes are electrophiles, they readily react with double bonds to afford cyclopropanes, forming two new carbon—carbon bonds.

Carbenes and Cyclopropane Synthesis:

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• Carbene addition occurs in a syn fashion from either side of the planer double bond.

• Carbene addition is a stereospecific reaction, since cis and trans alkenes yield different stereoisomers as products.

• Cyclopropanation is a concerted reaction, so both bonds are formed in a single step.

Carbenes and Cyclopropane Synthesis:

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The Simmons-Smith Reaction:

• Nonhalogenated cyclopropanes can be prepared by the reaction of an alkene with diiodomethane, CH2I2, in the presence of a copper-activated zinc reagent called zinc-copper couple [Zn(Cu)]. This is known as the Simmons-Smith reaction.

• The reaction is stereospecific.

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The Simmons-Smith Reaction:

Carbon-Carbon Bond-Forming Reactions