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C-C Bond formation

Chapter 26

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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.

3

4

5

6

Also enolates

O LDA, -78 °C

THF

OR X

CH2O

OR

O

HO

RN O

RNOBr

O

O

O

O O

7

Also enamines

OMe2NH

pH4

NMe2RX

aq. acidic work-up

OR

O

pH4

NRX

aq. acidic work-up

ONH

R

8

Br Li

-78 °C(dry ice-acetone)Hexane

Li

H

Use two equivalents of t-butyl lithium

Br

Br

LiH

H

Br1) 2eq. t-BuLi, THF, -78 °C

2) RX R

Preparing organolithium reagents: Metal halogen exchange

9

Br

H

Li

-78 °C(dry ice-acetone)Hexane

Li

H

Br

H

LiBr

Br

H Li

RT

Troublesome side reactions:

Alkylation with alkylbromides from organolithium preparation

Elimination reactions with alkylbromides from organolithium preparation or intended alkyl halide

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Br

H

Li

-78 °C(dry ice-acetone)Hexane

Li

H

Br

-78 °CTHF

H

H

Br

Li

11

H

pKa 70

tert-butyl lithium

H Li

pKa 65

sec-butyl lithium

H Li

pKa 62

n-butyl lithium

pKa 43

Li

H

pKa 42

H3C H

pKa 60

H3C Li

H

Li

methyl lithium

vinyl lithium

phenyl lithium

Li

Organolithium pKa’s

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LiMgBr2

MgBr+ LiBr

RLi > RNa > RK > RMgX > R2Zn > R2CuLi > R3Al > R3B > R4Si

More reactive Less reactive

13

• 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.

Coupling Reactions of Organocuprates

14

• 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.

General Features of Organocuprate Coupling Reactions

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R1) 9-BBN

2) X2, Heat

R

XH

R1) 9-BBN

2) X2, NaOR'

R X

H

Making vinyl halides for cuprate reactions

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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.

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

Coupling to Form Hydrocarbons

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

CuIR

Break into equal size fragments at branch points or appropriately adjacent to functionality

Br?

Retro Synthetic analysis (Cuprates)

?

or

=Br

CuI

Br

=Br

ICu 2

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Organopalladium Mediated Reactions

Suzuki Reaction

Heck Reaction

R X R' HPd(0)

Base-HX

R'R

X = Cl, Br, I, O SO

OCF3

R = aryl, alkenyl or benzyl

R BY2+ R' X

Pd(PPh3)4

BaseR R'

R'-I > R'-OTf > R'-Br >> R'-Cl

R & R' = alkyl, aryl, alkenyl, alkynyl

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• 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:

Organopalladium Compounds

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• 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.

Organopalladium Compounds

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Oxidative Addition and Reductive Elimination

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• 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.

Details of the Suzuki Reaction

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Examples of the Suzuki Reaction

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• 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.

Organoboranes in Suzuki Reaction

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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].

Preparation of Arylboranes

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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"

R

R"

Br

(R"O)2Bor

R

R"

B(OR")2

Br

Aryl-Aryl links

R

R"

R

R"(R"O)2B

Br or

R

R"Br

B(OR")2

Aryl-Alkenyl links

R"

R

R"(R"O)2B

or

R

R"Br

R

Br B(OR")2

Alkenyl-Alkenyl links

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Synthesis using Suzuki Coupling reaction in Loy Lab

S

Br

B(OH)2

(HO)2BNa2CO3

dioxane/H2O

Pd(PPh3)42 1S

S

1,4-di(thiophen-3-yl)benzene

New monomers for making flame resistant polymers

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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.

• 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.

The Heck Reaction

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• 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.

The Heck Reaction

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Examples of 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.

Using the Heck Reaction in Synthesis

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Retrosynthetic Analysis of Heck Reaction

R

R"

R

R"Br

Advantage over Suzuki Coupling: fewer steps (No boranic ester is needed)

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Heck Reaction in Loy Lab

(EtO)3Si

2 eq.

Pd(OAc)2

Et3N

Br

Br

1 eq.

(EtO)3Si

Si(OEt)3

Dye for making fluorescent nanoparticles

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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

Singlet carbene

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• 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.

Dihalocarbenes

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

Dihalocarbenes in Cyclopropane Synthesis

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• 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.

Carbene Addition to Alkenes

4343

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:

N

O

OEt

N -N2

CO2Et

EtO2C

CO2Et

EtO2C

CO2Et

EtO2C

CO2EtL2PdCl2

H2CN

N BF3 H H

n-N2

Thermal of Lewis acid catalyzed

Noble metal catalyzed

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N

O

EtO

N

N

O

EtO

N

H3N Pd

Cl

Cl O OEt

H3N Pd Cl-N2

Initiation

Propagation

O OEt

H3N Pd Cl

NO

OEtN

O OEt

PdClOEtO

H3N

O OEt

PdClOEtO

H3N n

Termination

O OEt

PdClOEtO

H3N nO OEt

Cl

OEtO

H3N nPd(0)

Polymerization of carbenes: Mechanism

Carbene insertions

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• 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.

The Simmons–Smith Reaction

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• 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.

Alkene Metathesis

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• 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).

Catalysts for Metathesis

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• 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.

Usefulness of Metathesis Reactions

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Examples of Alkene Metathesis

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Figure 26.2

Drawing the Products of Alkene Metathesis

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54

Retrosynthetic Analysis of Metathesis Reaction

R'R R

R'

Are precursors available?

Will cross reaction ( R ≠ R’) be dominant

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BrBr ?

Br ?

56

Metathesis in Loy Lab

CH2=CH2

Grubb's 2nd Gen Cat.CH2Cl22 eq.

2 eq.

RuPh

P

Cl

Cl

NN

H3C

CH3

CH3 CH3

H3C

H3C

Grubbs 2nd Generation Catalyst

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• 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.

Ring Closing Metathesis (RCM)

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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.

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Ring Opening Metathesis Polymerization

Grubbs Cat.

DCM n

n

Poly(norbornene)

+ H2C CH2n

60

Ring Opening Metathesis PolymerizationOf benzvalene

Benzvalene is a less stable isomer of benzene

Metathesis catalyst

n

heat

n

ΔH = -282 kJ/mole

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General synthesis strategies1) 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 Synthesis1) 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

63

Br

Some practice: How would you make 1,7-diphenylheptane

64

Some practice: How would you make (Z)-cyclooctene