Carbon Bond-Formation Involving Carbocations

Carbon-Carbon Bond Formation Involving Carbocations 

The formation of carbon-carbon bonds by electrophilic attack on the n system is an important reaction in aromatic chemistry, with both Friedel-Crafts alkylation and acylation following this pattern (see Chapter 11). There also are valuable synthetic procedures in which carbon-carbon bond formation results from electrophilic attack by a carbocation on an alkene. The reaction of a carbocation with an alkene to form a new carbon-carbon bond is both kinetically accessible and thermodynamically favorable because a n bond is replaced by a stronger x bond. 

There are, however, important problems that must be overcome in the application of this reaction to synthesis. The product is a new carbocation which can react further. Repetitive addition to alkene molecules leads to polymerization. Indeed, this is the mechanism of acid-catalyzed polymerization of alkenes. There is also the possibility of rearrangement. A key requirement for adapting the reaction of carbocations with alkenes to the synthesis of small molecules is control of the reactivity of the newly formed carbocation intermediate. Synthetically valuable carbocation-alkene reactions require a suitable termination step. We have already encountered one successful strategy in the reaction of alkenyl and allylic silanes and stannanes with electrophilic carbon (see Chapter 8). In those reactions, the silyl or stannyl substituent is eliminated and a stable alkene is formed. 

The increased reactivity of the silyl- and stannyl-substituted alkenes enhances the synthetic utility of carbocation-alkene reactions. 

Silyl enol ethers offer both enhanced reactivity and an effective termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation which cannot be achieved by base-catalyzed alkylation because 

Secondary benzylic bromides, allylic bromides, and a-chloro ethers can undergo analogous reactions using ZnBr2 as the catalyst.1 2 Primary iodides react with silyl 

There are, however, important problems that must be overcome in the application of this reaction to synthesis. One is that the product is a new carbocation, which 

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Carbon-Carbon Bond Formation Involving Carbocations... 

Carbon-carbon bond formation is one of the oldest and most important topics of organic chemistry, and for a long time has been dominated by Friedel-Crafts and Grignard reactions. The former are based on stabilized carbocations as reagents and are exemplified by benzene alkylation (Equation 1), while the latter involve stabilized carbanions and are exemplified by acetone alkylation (Equation 2). 

The cation pool method opens a new aspect of the chemistry based on carbocations, which have been considered to be difficult to manipulate in normal reaction media. These methods involve the generation of carbocations in the absence of nucleophiles, spectroscopic characterization, and reactions with a variety of carbon nucleophiles to achieve direct carbon-carbon bond formation. 

A significant modification in the stereochemistry is observed when the double bond is conjugated with a group that can stabilize a carbocation intermediate. Most of the specific cases involve an aryl substituent. Examples of alkenes that give primarily syn addition are Z- and -l-phenylpropene, Z- and - -<-butylstyrene, l-phenyl-4-/-butylcyclohex-ene, and indene. The mechanism proposed for these additions features an ion pair as the key intermediate. Because of the greater stability of the carbocations in these molecules, concerted attack by halide ion is not required for complete carbon-hydrogen bond formation. If the ion pair formed by alkene protonation collapses to product faster than reorientation takes place, the result will be syn addition, since the proton and halide ion are initially on the same side of the molecule. 

Many radical cations derived from cyclopropane (or cyclobutane) systems undergo bond formation with nucleophiles, typically neutralizing the positive charge and generating addition products via free-radical intermediates [140, 147). In one sense, these reactions are akin to the well known nucleophilic capture of carbocations, which is the second step of nucleophilic substitution via an Sn 1 mechanism. The capture of cyclopropane radical cations has the special feature that an sp -hybridized carbon center serves as an (intramolecular) leaving group, which changes the reaction, in essence, to a second-order substitution. Whereas the SnI reaction involves two electrons and an empty p-orbital and the Sn2 reaction occurs with redistribution of four electrons, the related radical cation reaction involves three electrons. 

Heterolytic retrosynthetic disconnection of a carbon-carbon bond in a molecule breaks the TM into an acceptor synthon, a carbocation, and a donor synthon, a carbanion. In a formal sense, the reverse reaction — the formation of a C-C bond — then involves the union of an electrophilic acceptor synthon and a nucleophilic donor synthon. Tables 1.1 and 1.2 show some important acceptor and donor synthons and their synthetic equivalents. "... 

The major method for cation photogeneration involves photoheterolysis of carbon-heteroatom bonds leading to formation of carbocations and the heteroatom anionic leaving group [Eq. (6)] [5,6,51]. Leaving groups have included halide, acetate, hydroxide, tosylate, 4-cyanophenoxide, cyanide, and phosphonium chloride. 

This type of reaction begins when a ir bond of an alkene donates an electron pair to an acid (H+)—an acid-base reaction where the alkene is a weak base. The Jt bond is broken as the new Br—H bond is formed, and the remaining carbon of the former double bond becomes a carbocation. The reaction of cyclohexene with acid to form secondary cation 294 illustrates this process. The cationic center then reacts with the nucleophilic gegenion (Br" from HBr) to produce bromocyclohexane. The latter portion of this sequence is analogous to the second step (coupling) of an Sjsfl reaction. The initial reaction usually involves formation of a solvent separated carbocation intermediate, but this depends on the solvent. A tight ion pair intermediate can react in the substitution step to give the same product. The net result of this cationic reaction is addition of H and Br across the jt bond. 

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