Carbocations, benzylic alkyl halides

Primary and secondary alkyl halides undergo only E2 reactions they do not undergo El reactions because, to do so, they would have to form relatively unstable carbocations. Tertiary alkyl halides and all allylic and benzylic halides (as long as they have a hydrogen bonded to an sp j8-carbon) undergo both E2 and El reactions (Table 10.3). 

Rearrangement is especially prevalent with primary alkyl halides of the type RCH2CH2X and R2CHCH2X Aluminum chloride induces ionization with rearrangement to give a more stable carbocation Benzylic halides and acyl halides do not rearrange... 

Because of resonance stabilization, a primary allylic or benzylic carbocation is about as stable as a secondary alkyl carbocation and a secondary allylic or benzylic carbocation is about as stable as a tertiary alkyl carbocation. This stability order of carbocations is the same as the order of S l reactivity for alkyl halides and tosylates. 

Alkylation of Alkynes. Organic halides can alkylate acetylenes in the presence of Lewis acids. In most cases, however, the products are more reactive than the starting acetylenes. This and the ready polymerization of acetylenes under the reaction conditions result in the formation of substantial amounts of byproducts. Allyl, benzyl, and tert-alkyl halides giving stable carbocations under mild conditions are the best reagents to add to acetylenes.44 56... 

Non-deprotonated amides are weak nucleophiles and are only alkylated by trialkyl -oxonium salts or dimethyl sulfate at oxygen or by some carbocations at nitrogen [16, 83]. Alkylation with primary or secondary alkyl halides under basic reaction conditions is usually rather difficult, because of the low nucleophilicity and high basicity of deprotonated amides. Non-cyclic amides are extremely difficult to N-alkylate, and few examples of such reactions (mainly methylations, benzylations, or allyla-tions) have been reported (Scheme 6.21). 4-Halobutyramides, on the other hand, can often be cyclized to pyrrolidinones in high yield by treatment with bases (see Scheme 1.8) [84—86]. 

Because they form relatively stable carbocations, benzyl halides undergo SnI reactions more easily than do most alkyl halides. 

The Br is more electronegative than C and hence the bond is polarized as shown. The 7i-electron cloud is electron rich, so the aromatic 71-system can stabilize an adjacent carbocation and hence the benzylic halide is more reactive than a simple alkyl halide. 

Benzylic and allylic halides readily undergo SnI reactions because they form relatively stable carbocations. While primary alkyl halides (such as CH3CH2Br and CH3CH2CH2Br) cannot undergo SnI reactions because their carbocations are too... 

We have seen that methyl halides and primary alkyl halides undergo only Sn2 reactions because methyl cations and primary carbocations, which would be formed in an Sisjl reaction, are too unstable to be formed in an Sn2 reaction. Tertiary alkyl halides undergo only S jl reactions because steric hindrance makes them unreactive in an Sn2 reaction. Secondary alkyl halides as well as benzylic and allylic halides (unless they are tertiary) can undergo both S jl and Sn2 reactions because they form relatively stable carbocations and the steric hindrance associated with these alkyl halides is generally not very great. Vinylic and aryl halides do not undergo either S jl or Sn2 reactions. These results are summarized in Table 10.6. 

Because the first step is the rate-determining step, the rate of an El reaction depends on both the ease with which the carbocation is formed and how readily the leaving group leaves. The more stable the carbocation, the easier it is formed because more stable carbocations have more stable transition states leading to their formation. Therefore, the relative reactivities of a series of alkyl halides with the same leaving group parallel the relative stabilities of the carbocations. A tertiary benzylic halide is the most reactive alkyl halide because a tertiary benzylic cation—the most stable carbocation—is the easiest to form (Sections 7.7 and 10.8). 

Due to the ambident reactivity of pyrroles and indoles, alkylations of such jt-excessive heterocycles can provide a mixture of N- and C-alkylated products. It is therefore of note that Bogdal has been able to achieve the regioselective N-alkylation of a number of azaheterocycles (i.e., pyrrole, imidazole, pyrazole, indole and carbazole) in "dry" media under microwave irradiation <97H(45)715>. The reactions were carried out by simply adsorbing a mixture of the heterocyclic compound, an alkyl halide and a catalytic amount of tetrabutylammonium bromide on a solid support (e.g., KOH, K2CO3), followed by irradiation in an open vessel for 1-10 min. Alternatively, the direct benzylation of pyrrole by the thermal decomposition of N-benzyl-N-nitrosobenzamide, which is believed to proceed by an essentially free carbocation, afforded only the C-2 and C-3 substituted pyrroles <97JOC8091>. 

Of the simple alkyl halides that we have studied so far, this means (for all practical purposes) that only tertiary halides react by an S l mechanism. (Later we shall see that certain organic halides, called allylic halides and benzylic halides, can also react by an S l mechanism because they can form relatively stable carbocations see Sections 13.4 and 15.15.)... 

Primary and secondary allylic and benzylic halides can react either by an Sn2 mechanism or by an Sn 1 mechanism in ordinary nonacidic solvents. We would expect these halides to react by an 5 2 mechanism because they are structurally similar to primary and secondary alkyl halides. (Having only one or two groups attached to the carbon bearing the halo n does not prevent 5 2 attack.) But primary and secondary allylic and benzylic halides can also react by an S l mechanism because they can form relatively stable allylic catbocadoiis and ben-zylic carbocations, and in this regard they differ from primary and secondary alkyl halides. ... 

The fast reaction of benzylic and allylic halides is a result of the resonance stabilization that is available to the intermediate carbocations formed. Tertiary halides are more reactive than secondary halides, which are in turn more reactive than primary or methyl halides because alkyl substituents are able to stabilize the intermediate carbocations by an electron-releasing effect. The methyl carbocations have no alkyl groups and are the least stable of all carbocations mentioned thus far. Vinyl and aryl carbocations are extremely unstable because the charge is localized on an sp -hybridized carbon (double-bond carbon) rather than one that is sp -hybridized. 

Before leaving the topic of oxidation of alkyl halides, it is worthwhile noting that benzylic (C6H5CH2X X = Cl, Br, I) and allylic (RCH=CH-CH2X X = Cl, Br, I) halides and related compounds that form stabilized carbocations, have long been known to undergo oxidation by heating them with hexamethylenetetramine (l,2,5,8-tetraazatricyclo[3.3.1.1 ]decane) in water. ... 

Under the appropriate conditions, tertiary alkyl halides, benzylic halides, and allylic halides, that is, species capable of generating stable carbocations (Table 7.2), are found to undergo reactions that are generally classified as SnI. 

The relative stability of benzylic carbocations, radicals, and carbanions makes it possible to manipulate the side chains of aromatic rings. Functionalization at the benzylic position, for example, is readily accomplished by free-radical halogenation and provides access to the usual reactions (substitution, elimination) that we associate with alkyl halides. 

Under radical initiation conditions, typically peroxides, hypervalent iodine reagents can be homolytically cleaved to iodine-centered radicals. These iodine centered radicals abstract a hydrogen atom from a labile benzylic C—H bond to yield a resonance-stabilized benzylic radical. At this point in the mechanism, researchers seem divided on the next step. Some propose a second single electron transfer (SET) to form a benzylic carbocation, ° which undergoes ionic reactions to form product. Others suggest radical combination to form an alkyl halide or organic peroxide which reacts further under the reaction conditions to form product. 

Second, the mechanism shows that a carbocation is formed in the rate-determining step. This explains why tertiary alkyl halides undergo SnI reactions, but primary and secondary alkyl halides do not. Tertiary carbocations are more stable than primary and secondary carbocations and, therefore, are the most easily formed. (In Section 9.5 we will see that allylic and benzylic halides undergo S l reactions, because they too form relatively stable carbocations.)... 

Table 9.4 summarizes the reactivity of alkyl halides in Sn2 and SnI reactions. Primary alkyl halides, secondary alkyl halides, and methyl halides undergo only Sn2 reactions because of their relatively unstable carbocations. All tertiary halides (alkyl, allylic, and benzylic) undergo only SnI reactions, because steric hindrance makes them unreactive in Sn2 reactions. Primary and secondary allylic and benzylic halides undergo both SnI and Sn2 reactions. Vinylic and aryl halides cannot undergo either SnI or Sn2 reactions. 

The rate of an SnI reaction depends on the ease of carbocation formation. Tertiary alkyl halides and all allylic and benzylic halides are the only ones that form relatively stable carbocations, so they are the only ones that undergo SnI reactions. 

Alkyl iodides afford mixtures of radical- and ion-derived photoproducts in solution, with the latter usually predominating. Indeed, this is a powerful method for generating carbocations, including many that cannot be readily prepared by other methods. Alkyl bromides display similar photobehavior, but with a lower proportion of ionic products. Analogous behavior has also been observed for phenyl thioethers and selenoethers, as well as some organosilicon iodides. In a process related to the formation of ionic intermediates, irradiation of dihalomethanes in the presence of alkenes results in cyclopropanation, a synthetically useful procedure that complements traditional methods. This chapter, which is concerned with alkyl halides, is a major expansion of an earlier review. The solution-phase photobehavior of aryl, benzylic, and homobenzylic hahdes has been reviewed, along with that of alkyl systems." The photobehavior of alkyl halides in the gas phase has also been reviewed. ... 

Activation of the Benzylic Position. Both chromium com-plexed carbanions and carbocations are stabilized at the benzylic position. Dialkylation of alkyl halides at the benzylic position occurs via stabilized carbanions under mild conditions (eq 16). Regio- and stereoselective products are obtained via the benzylic carbanions, depending on the conformation of the tricarbonyl group to the arene (eq 17). (Styrene)chromium complexes stabilize negative charges at the benzylic position by addition of... 

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