2Carbon-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 ,-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.
3Carbon-Carbon Bond-Forming Reactions 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.
4Carbon-Carbon Bond-Forming Reactions 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.
5Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction: GeneralThe 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.
6Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction: Uses a Pd CatalystOrganopalladium 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:
7Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction: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.
8Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction: A Reaction with a Pd Catalyst
9Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction:
10Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction: The boranesThe 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.
11Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction: The boranesArylboranes, which have a boron atom bonded to a benzene ring, are prepared from organolithium reagents by reaction with trimethyl borate [B(OCH3)3]
12Carbon-Carbon Bond-Forming Reactions The Suzuki Reaction: Mechanistic Details
13Carbon-Carbon Bond-Forming Reactions 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.
14Carbon-Carbon Bond-Forming Reactions The Heck Reaction: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.
15Carbon-Carbon Bond-Forming Reactions The Heck Reaction:
16Carbon-Carbon Bond-Forming Reactions The Heck Reaction: RetrosynthesisTo 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.
17Carbon-Carbon Bond-Forming Reactions The Heck Reaction:
18Carbon-Carbon Bond-Forming Reactions 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.
19Carbon-Carbon Bond-Forming Reactions 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 elimination.
20Carbon-Carbon Bond-Forming Reactions Carbenes and Cyclopropane Synthesis:
21Carbon-Carbon Bond-Forming Reactions Carbenes and Cyclopropane Synthesis:Since dihalocarbenes are electrophiles, they readily react with double bonds to afford cyclopropanes, forming two new carbon—carbon bonds.
22Carbon-Carbon Bond-Forming Reactions 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.
23Carbon-Carbon Bond-Forming Reactions 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.
24Carbon-Carbon Bond-Forming Reactions The Simmons-Smith Reaction: