C-C Bond formation
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C-C Bond formation. Chapter 26. 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.

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C c bond formation

C-C Bond formation

Chapter 26


C c bond formation

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.


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Also enolates


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Also enamines


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Preparing organolithium reagents: Metal halogen exchange


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Troublesome side reactions:

Alkylation with alkylbromides from organolithium preparation

Elimination reactions with alkylbromides from organolithium preparation or intended alkyl halide


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Organolithium pKa’s


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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


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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”

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


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Retro Synthetic analysis (Cuprates)


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Organopalladium Mediated Reactions

Suzuki Reaction

Heck Reaction


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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:


C c bond formation

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


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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


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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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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

Aryl-Aryl links

Aryl-Alkenyl links

Alkenyl-Alkenyl links


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Synthesis using Suzuki Coupling reaction in Loy Lab

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.


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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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Examples of the Heck Reaction


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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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Retrosynthetic Analysis of Heck Reaction

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


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Heck Reaction in Loy Lab

Dye for making fluorescent nanoparticles


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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


C c bond formation

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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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.

43


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Polymerization of carbenes:

Thermal of Lewis acid catalyzed

Noble metal catalyzed


C c bond formation

Polymerization of carbenes: Mechanism

Carbene insertions


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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.


C c bond formation

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.


C c bond formation

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 2,2-disubstituted 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


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Drawing the Products of Alkene Metathesis

Figure 26.2


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Retrosynthetic Analysis of Metathesis Reaction

Are precursors available?

Will cross reaction ( R ≠ R’) be dominant


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?

?


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Metathesis in Loy Lab


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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 intramolecular rather than intermolecular metathesis.


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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

Poly(norbornene)


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Ring Opening Metathesis Polymerization

Of benzvalene

Benzvalene is a less stable isomer of benzene

ΔH = -282 kJ/mole


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General synthesis strategies

  • Build carbon framework with enolate reactions and other C-C bond building reactions (Suzuki, Heck, Metathesis, Cuprates, Diels-Alder, & more.)

  • Use functionalities to activate C-C bond building chemistry

  • Functional group conversions to provide desired organic substituents


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Directions in Synthesis

  • Regio- and stereochemical specificity

  • More atom efficiency (less waste).

  • Reactions using aqueous or non-toxic solvents (H2O, alcohols)

  • Reactions using less hazardous starting materials


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Some practice: How would you make

1,7-diphenylheptane


C c bond formation

Some practice: How would you make

(Z)-cyclooctene


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