Carbon-Carbon Bond Formation and Synthesis

Heck Reaction The palladium-catalyzed C-C coupling between aryl halides or vinyl halides and activated alkenes in the presence of a base is referred as the "Heck Reaction". Recent developments in the catalysts and reaction conditions have resulted in a much broader range of donors and acceptors being amenable to the Heck Reaction. One of the benefits of the Heck Reaction is its outstanding trans selectivity.

Heck Reaction Overall: A palladium-catalyzed reaction in which the R group of RX, a haloalkene or haloarene, is substituted for a vinylic H of an alkene.

Heck Reaction (consider the alkene) Substitution (H  R) is highly regioselective; most commonly at the less substituted carbon of the double bond. Substitution is highly stereoselective; the E configuration is often formed almost exclusively. E Less substituted, H  Ph substitution occurs here. Neither E nor Z

Heck Reaction Mechanism

Heck Reaction. Conti….. The alkene The base The solvent. The ligand The less the crowding on the alkene, the more reactive it is. The base Triethylamine, Na+/K+ acetate, and sodium hydrogen carbonate are most common. The solvent. Polar aprotic solvents such as DMF, acetonitrile, and DMSO. aqueous methanol may also be used. The ligand Triphenylphosphine, PPh3, is one of the most common.

Suzuki Coupling Suzuki coupling: A palladium-catalyzed reaction of an organoborane (R’-BY2) or organoborate (RB(OMe)2) with an alkenyl, aryl, or alkynyl halide, or triflate (R-X) to yield R-R’. Overall:

Suzuki Coupling These examples illustrate the versatility of the reaction.

Suzuki Coupling Reductive elimination Oxid. Addn Transmetalation R1 and OtBu swap Substitution

Diels-Alder Reaction Diels-Alder reaction: A cycloaddition reaction of a conjugated diene and certain types of double and triple bonds. dienophile: Diene-loving. Diels-Alder adduct: The product of a Diels-Alder reaction.

Diels-Alder Reaction Alkynes also function as dienophiles. Cycloaddition reaction: A reaction in which two reactants add together in a single step to form a cyclic product.

Diels-Alder Reaction We write a Diels-Alder reaction in the following way: The special value of D-A reactions are that they: 1. form six-membered rings. 2. form two new C-C bonds at the same time. 3. are stereospecific and regioselective. Note the reaction of butadiene and ethylene gives only traces of cyclohexene.

Diels-Alder Reaction The conformation of the diene must be s-cis.

Diels-Alder Reaction Steric Restrictions (2Z,4Z)-2,4-Hexadiene is unreactive in Diels-Alder reactions because nonbonded interactions prevent it from assuming the planar s-cis conformation.

Diels-Alder Reaction Reaction is facilitated by a combination of electron-withdrawing substituents on one reactant and electron-releasing substituents on the other.

Diels-Alder Reaction

Diels-Alder Reaction The configuration of the dienophile is retained.

Diels-Alder Reaction Mechanism No evidence for the participation of either radical of ionic intermediates. Chemists propose that the Diels-Alder reaction is a concerted pericyclic reaction. Pericyclic reaction: A reaction that takes place in a single step, without intermediates, and involves a cyclic redistribution of bonding electrons. Concerted reaction: All bond making and bond breaking occurs simultaneously.

Dihalocarbenes in Cyclopropane Synthesis Since dihalocarbenes are electrophiles, they readily react with double bonds to afford cyclopropanes, forming two new carbon–carbon bonds. 19

Carbenes Singlet carbene 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 20

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. 21

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Enamines (and imines, Schiff bases) Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2. Primary amine But secondary amines react to give enamines

Formation of Enamines Enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone. The 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine.

Formation of Enamines Examples:

Enamines – Alkylation at a position. The value of enamines is that the -carbon is nucleophilic. Enamines undergo SN2 reactions with methyl and 1° haloalkanes, -haloketones, and -haloesters. Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide.

Enamines – Acylation at a position Enamines undergo acylation when treated with acid chlorides and acid anhydrides. Could this be made via a crossed Claisen followed by decarboxylation.

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