Handout-2010

SINTESIS KIMIA ORGANIK

Carbon—Carbon Bond-Forming Reactions in
Organic Synthesis
Coupling Reactions of Organocuprates

• Recall that organocuprate reagents react a variety of functional

compounds including acid chlorides, epoxides and α,β
β-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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 Coupling Reactions of Organocuprates

• 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.

Coupling Reactions of Organocuprates

• 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.

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The Suzuki Reaction—A Reaction with 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:

The Suzuki Reaction—A Reaction with a Pd Catalyst

• A general ligand bonded to a metal is often designated as

“L.” Pd bonded to four ligands is denoted as PdL4.
• Organopalladium compounds 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¯ .
• In most useful reactions, only a catalytic amount of Pd
reagent is used.
• Two common processes, called oxidative addition and
reductive elimination, dominate many reactions of palladium
compounds.
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 The Suzuki Reaction—A Reaction with a Pd Catalyst

The Suzuki Reaction—Mechanistic Details

• The Suzuki reaction is a palladium-catalyzed coupling of an

organic 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.
• Vinyl or aryl halides are most often used, and the halogen is
usually Br or I.
• The Suzuki reaction is completely stereospecific.

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The Suzuki Reaction—Mechanistic Details

The Suzuki Reaction—Mechanistic Details

The organoboranes used in the Suzuki reaction are

acquired from two sources.

• 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.

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The Suzuki Reaction—Mechanistic Details

• Arylboranes, which have a boron atom bonded to a benzene

ring, are prepared from organolithium reagents by reaction
with trimethyl borate [B(OCH3)3]

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The Suzuki Reaction—Mechanistic Details

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The Heck Reaction

• 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.

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The Heck Reaction

• The alkene component is typically ethylene or a

monosubstituted alkene (CH2=CHZ).
• The halogen is typically Br or I.
• 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.
• When a vinyl halide is used as the organic halide, the
reaction is stereospecific.

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The Heck Reaction

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The Heck Reaction

• 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.

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The Heck Reaction

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Carbenes and Cyclopropane Synthesis

• 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.

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 Carbenes and Cyclopropane Synthesis

• 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 α
elimination. 19

Carbenes and Cyclopropane Synthesis

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Carbenes and Cyclopropane Synthesis

• Since dihalocarbenes are electrophiles, they readily react

with double bonds to afford cyclopropanes, forming two new
carbon—carbon bonds.

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Carbenes and Cyclopropane Synthesis

• 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.

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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

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 Alkene Metathesis

• Alkene or olefin metathesis is a reaction between two

alkene molecules that results in the interchange of the
carbons of their double bonds.
• Two σ and two π bonds are broken and two new σ and
two new π bonds are formed.

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Alkene Metathesis
• Olefin metathesis occurs in the presence of a complex
transition metal catalyst that contains a carbon-metal
double bond. The metal is typically ruthenium (Ru),
tungsten (W), or molybdenum (Mo).
• In a widely used catalyst called Grubbs catalyst, the
metal is Ru.
• Metathesis catalysts are compatible with the presence
of many functional groups (such as OH, OR, and C=O).

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 Alkene Metathesis

• Because olefin metathesis is an equilibrium process

and with many alkene substrates yields a mixture of
starting material and two or more alkene products, it is
useless for preparative processes.

• However, with terminal alkenes, one metathesis product

is ethylene gas (CH2=CH2), which escapes from the
reaction mixture and drives the equilibrium to the right.
Thus, monosubstituted alkenes (RCH=CH2) and 2,2-
disubstituted alkenes (R2C=CH2) are excellent
metathesis substrates because high yields of a single
alkene product are obtained.

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Alkene Metathesis—Examples

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 Alkene Metathesis—Drawing the Products

Drawing the products of

olefin metathesis using
styrene (PhCH = CH2) as
starting material

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Alkene Metathesis—The Mechanism

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Ring Closing Metathesis (RCM)
When a diene is used as a starting material, ring closure occurs.
These reactions are typically run in very dilute solution so that the
reactive ends of the same molecule have a higher probability of
finding each other. High dilution favors intermolecular rather than
intramolecular metathesis. Virtually any ring size can be prepared.

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