Transcript Ch 26 C-C bond formation

C-C Bond formation
Chapter 26
1
Carbon–Carbon Bond Forming Reactions
• To form the carbon skeletons of complex molecules, organic
chemists need an extensive repertoire of carbon–carbon bond
forming reactions.
• We have earlier looked at reactions of organometallic reagents
such as Grignard, organolithium and organocuprate reagents
with carbonyl and other substrates to form larger molecules.
• The focus of this chapter will be on additional carbon–carbon
bond forming reactions which utilize a variety of starting
materials and conceptually different reactions.
• Three such reactions involve coupling of an organic halide
with an organometallic reagent or alkene: (1) Organocuprate
coupling reactions, (2) Suzuki reaction, and (3) Heck reaction.
2
3
4
5
Also enolates
O
R
R X
O
O
LDA, -78 °C
O
CH2O
THF
HO
RN
O
O
RN
O
Br
O
O
O
O
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Also enamines
NMe2
O
RX
Me2NH
R
aq. acidic
work-up
pH4
O
O
NH
pH4
N
O
RX
R
aq. acidic
work-up
7
Preparing organolithium reagents: Metal halogen exchange
1) 2eq. t-BuLi, THF, -78 °C
Br
R
2) RX
Use two equivalents of t-butyl lithium
Br
Li
Li
-78 °C
(dry ice-acetone)
Hexane
H
Br
H
Li
H
Br
8
Troublesome side reactions:
Alkylation with alkylbromides from organolithium preparation
Br
Br
Li
Li
-78 °C
(dry ice-acetone)
Hexane
H
H
H
Br
Li
Elimination reactions with alkylbromides from organolithium
preparation or intended alkyl halide
Br
RT
H
Li
9
H
Br
Br
H
Li
Li
-78 °C
(dry ice-acetone)
Hexane
H
H
-78 °C
THF
Br
Li
10
Organolithium pKa’s
pKa 70
H
tert-butyl lithium
Li
pKa 65
H
Li
sec-butyl lithium
Li
n-butyl lithium
pKa 62
H
pKa 60
methyl lithium
H3C Li
H3C H
pKa 43
vinyl lithium
Li
H
pKa 42
H
Li
phenyl lithium
11
More reactive
Less reactive
RLi > RNa > RK > RMgX > R2Zn > R2CuLi > R3Al > R3B > R4Si
MgBr
Li
MgBr2
+
LiBr
12
Coupling Reactions of Organocuprates
• Organocuprate reagents react with a variety of functional
groups 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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General Features of Organocuprate
Coupling Reactions
• 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.
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Making vinyl halides for cuprate reactions
R
R
1) 9-BBN
R
2) X2, Heat
H
X
1) 9-BBN
R
2) X2, NaOR'
H
X
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Coupling to Form Hydrocarbons
• 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.
• This means that using this methodology, a given
hydrocarbon can often be made by two different routes.
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Retro Synthetic analysis (Cuprates)
“….the grand thing is to be able to reason backwards. That is a very
useful accomplishment, and a very easy one, but people do not
practice it much.”
Sherlock Holmes in “A Study in Scarlet”
Br
CuI
R
Break into equal size fragments at branch points or
appropriately adjacent to functionality
?
Br
Retro Synthetic analysis (Cuprates)
or
?
Br
=
I
Cu
Br
2
ICu
=
Br
Organopalladium Mediated Reactions
Suzuki Reaction
R
BY2
+
Pd(PPh3)4
R'
X
R
R'
Base
R'-I > R'-OTf > R'-Br >> R'-Cl
R & R' = alkyl, aryl, alkenyl, alkynyl
Heck Reaction
R
X
R'
H
R
Pd(0)
R'
Base
-HX
R = aryl, alkenyl or benzyl
X = Cl, Br, I,
O
O S CF3
O
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Organopalladium Compounds
• 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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Organopalladium Compounds
• 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.
• “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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Oxidative Addition and Reductive Elimination
22
Details of the Suzuki Reaction
• 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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Examples of the Suzuki Reaction
24
Organoboranes in Suzuki Reaction
• Two types of organoboranes can be used in the Suzuki
reaction: vinylboranes and arylboranes.
• 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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Preparation of Arylboranes
• 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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27
Synthesis Using the Suzuki Reaction
• The Suzuki reaction was a key step in the synthesis of
bombykol, the sex pheromone of the female silkworm moth.
• The synthesis of humulene illustrates that an intramolecular
Suzuki reaction can form a ring.
Figure 26.2
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Retrosynthetic Analysis of Suzuki Reaction
R"
R"
Aryl-Aryl links
R"
(R"O)2B
Br
or
Br
R
B(OR")2
R
R
Aryl-Alkenyl links
R"
(R"O)2B
R"
Br
R
B(OR")2
or
R
R
Alkenyl-Alkenyl links
(R"O)2B
R"
R
R"
Br
Br
R
R"
Br
or
R"
B(OR")2
R
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Synthesis using Suzuki Coupling
reaction in Loy Lab
B(OH)2
2
S
S
Pd(PPh3)4
1
Na2CO3
Br
(HO)2B
dioxane/H2O
S
1,4-di(thiophen-3-yl)benzene
New monomers for making flame resistant polymers
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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.
• One H atom of the alkene starting material is replaced by the
R’ group of the vinyl or aryl halide.
• 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.
31
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.
32
Examples of the Heck Reaction
33
Using the Heck Reaction in Synthesis
• 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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35
Retrosynthetic Analysis of Heck Reaction
Br
R"
R
R"
R
Advantage over Suzuki Coupling: fewer steps (No boranic ester
is needed)
36
Heck Reaction in Loy Lab
Si(OEt)3
Br
1 eq.
Pd(OAc)2
Br
Et3N
2 eq.
(EtO)3Si
(EtO)3Si
Dye for making fluorescent nanoparticles
37
Carbenes
• 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.
Singlet
carbene
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Dihalocarbenes
• Dihalocarbenes, :CX2, are especially useful reactive
intermediates since they are readily prepared from
trihalomethanes (CHX3) by reaction with strong base.
• For example, 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.
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40
Dihalocarbenes in 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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Carbene Addition to Alkenes
• Cyclopropanation is a concerted reaction, so both bonds are
formed in a single step.
• 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.
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Methylene, The Simplest Carbene
• Methylene, :CH2, is readily prepared by heating
diazomethane, which decomposes and loses nitrogen.
• The reaction of methylene produced in this manner with
an alkene often leads to a complex mixture of products.
• Thus the reaction cannot be reliably used for
cylcopropane synthesis.
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Polymerization of carbenes:
Thermal of Lewis acid catalyzed
H2C
N
N
H H
BF3
-N2
n
Noble metal catalyzed
O
OEt
L2PdCl2
CO2Et CO2Et CO2Et CO2Et
N
N
-N2
EtO2C EtO2C EtO2C
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Polymerization of carbenes: Mechanism
Cl
Initiation
O
O H3N
EtO
Pd
EtO
N
-N2
N
N
O
Cl
OEt
H3N
Pd
Cl
N
Propagation
O
H3N
EtO
OEt
O
EtO
Cl
Pd
Pd
Cl
O
N
O
H3N
H3N
N
O
Cl
Pd
n
OEt
O
OEt
Carbene insertions
OEt
Termination
EtO
H3N
O
Cl
Pd
n
O
OEt
EtO
H3N
O
Cl
n
O
Pd(0)
OEt
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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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47
Alkene Metathesis
• Alkene (olefin) metathesis is a reaction between two alkene
molecules that results in the interchange of the carbons of
their double bonds.
• Two  and two  bonds are broken and two new  and two
new  bonds are formed.
48
Catalysts for 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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Usefulness of Metathesis Reactions
• 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 2,2disubstituted alkenes (R2C=CH2) are excellent metathesis
substrates because high yields of a single alkene product are
obtained.
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Examples of Alkene Metathesis
51
Drawing the Products of Alkene Metathesis
Figure 26.2
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53
Retrosynthetic Analysis of Metathesis Reaction
R
R
R'
R'
Are precursors available?
Will cross reaction ( R ≠ R’) be dominant
54
Br
Br
Br
?
?
55
Metathesis in Loy Lab
2 eq.
Grubb's 2nd Gen Cat.
CH2Cl2
2 eq. CH2=CH2
Grubbs 2nd Generation Catalyst
CH3
H 3C
N
CH3
N
H 3C
H 3C
CH3
Cl
Cl
Ru
Ph
P
56
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 intramolecular rather than intermolecular
metathesis.
57
Ring Closing Metathesis (RCM) in Synthesis
• Epothilone A is a promising anticancer agent that was first
isolated from soil bacteria from the banks of the Zambezi
River in South Africa.
• Sch38516 is an antiviral agent active against influenza A.
58
Ring Opening Metathesis Polymerization
n
Grubbs Cat.
DCM
n +
n H2C CH2
Poly(norbornene)
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Ring Opening Metathesis Polymerization
Of benzvalene
Benzvalene is a less
stable isomer of
benzene
ΔH = -282 kJ/mole
Metathesis catalyst
heat
n
n
60
General synthesis strategies
1) Build carbon framework with enolate
reactions and other C-C bond building
reactions (Suzuki, Heck, Metathesis,
Cuprates, Diels-Alder, & more.)
1) Use functionalities to activate C-C bond
building chemistry
2) Functional group conversions to provide
desired organic substituents
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Directions in Synthesis
1) Regio- and stereochemical specificity
1) More atom efficiency (less waste).
1) Reactions using aqueous or non-toxic
solvents (H2O, alcohols)
2) Reactions using less hazardous starting
materials
62
Some practice: How would you make
1,7-diphenylheptane
Br
63
Some practice: How would you make
(Z)-cyclooctene
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