Benzylic position

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

The reaction of 2.4-dimethylthiazole with butyllithium shows that, in contrast to 2-methylthiazole, the benzyl position (the 2-position) is the most reactive. The effect of the substituent in the 4-position may well be steric 4-r-butyl-2-methylthiazole in the same reaction gives no 5-substituted product (223). 

Halogenation (Section 11 12) Free radical halo genation of alkylbenzenes is highly selective for substitution at the benzylic position In the exam pie shown elemental bromine was used Alterna Lively N bromosuccinimide is a convenient re agent for benzylic bromination... 

Oxidation (Section 11 13) Oxidation of alkylben zenes occurs at the benzylic position of the alkyl group and gives a benzoic acid derivative Oxidiz mg agents include sodium or potassium dichro mate in aqueous sulfuric acid Potassium perman ganate (KMn04) is also an effective oxidant... 

The benzylic position in tetralin can be selectively oxidized to the hydroperoxide... 

The efficiency of reduction of benzophenone derivatives is greatly diminished when an ortho alkyl substituent is present because a new photoreaction, intramolecular hydrogen-atom abstraction, then becomes the dominant process. The abstraction takes place from the benzylic position on the adjacent alkyl chain, giving an unstable enol that can revert to the original benzophenone without photoreduction. This process is known as photoenolization Photoenolization can be detected, even though no net transformation of the reactant occurs, by photolysis in deuterated hydroxylic solvents. The proton of the enolic hydroxyl is rapidly exchanged with solvent, so deuterium is introduced at the benzylic position. Deuterium is also introduced if the enol is protonated at the benzylic carbon by solvent ... 

The benzylic position in alkylbenzenes is analogous to the allylic position in alkenes. Thus a benzylic C—H bond, like an allylic one, is weaker than a C—H bond of an alkane, as the bond dissociation energies of toluene, propene, and 2-rnethylpropane attest ... 

From cumene Almost all the phenol produced in the United States is prepared by this method. Oxidation of cumene takes place at the benzylic position to give a hydroperoxide. On treatment with dilute sulfuric acid, this hydroperoxide is converted to phenol and acetone. 

When the benzylic position was protected, an indole could be prepared without side products. 

Side-chain bromination at the benzylic position occurs when an alkylbenzene is treated with /V-bromosuccinimide (NBS). For example, propylbenzene gives (l-bromopropyl)benzene in 97% yield on reaction tvith NBS in the presence of benzoyl peroxide, (PhC02)2f as a radical initiator. Bromination occurs exclusively in the benzylic position and does not give a mixture of products. 

Reaction occurs exclusively at the benzylic position because the benzylic radical intermediate is stabilized by resonance. Figure 16.20 shows how the benzyl radical is stabilized by overlap of its p orbital with the ring 77 electron system. 

The benzylic position of an alkylbcnzene can be brominated by reaction with jV-bromosuccinimide, and the entire side chain can be degraded to a carboxyl group by oxidation with aqueous KMnCfy Although aromatic rings are less reactive than isolated alkene double bonds, they can be reduced to cyclohexanes by hydrogenation over a platinum or rhodium catalyst. In addition, aryl alkyl ketones are reduced to alkylbenzenes by hydrogenation over a platinum catalyst. 

Aziridinium ion-based click chemistry provides convenient access to pyrazolo[l,2-ajpyrazoles, active inhibitors of penicillin-binding proteins [58, 59]. Ring-opening of aziridinium ions 32 at the benzylic position with hydrazine, followed by intramolecular cyclization, gave pyrazolidin-3-ones 37 in excellent yields (Scheme 12.27). Heating of the hydrazides 37 with aromatic aldehydes at reflux in absolute... 

An open-chain transition state model, based on the improved Cram model (Section A.2.), was proposed for the prediction of the stereochemical outcome1 2. Under kinetic control, if the substituent R1 in the benzylic position is of medium size, the syn-isomer is formed as the major product2. 

When the nucleophile is a stabilized carbanion such as the enolate of acetylacetone, 1-benzoylacetophenone, diethylmalonate, or ethyl acetatoacetone, the reaction proceeds similarly. The monosubstituted complex is isolated as long as it contains an acidic hydrogen in the benzylic position. In addition, for the case of diketones CH2(COR)2 (R = Me, Ph, OEt), a deacetylation is observed in an acidic medium [92,93]. These features are the same as described above in the case of the substitution of Cl by stabilized carbanions in monochloroaromatics (the second chlorine being an inert arene substituent [99] Scheme XVII, Eq. (31) and Tables 10 and 11. 

However, many anomalous results have been reported for these substrates. The benzylic position is not always the most favored. One thing certain is that aromatic hydrogens are seldom abstracted if there are aliphatic ones to compete (note from Table 5.3, that D for Ph—H is higher than that for any alkyl H bond). Several a- scales (similar to the a, ct, and scales discussed in Chapter 9) have been developed for benzylic radicals. ... 

The bromine atom is much more selective than the chlorine atom. As indicated on page 906, it is often possible to brominate tertiary and benzylic positions selectively. High regioselectivity can also be obtained where the neighboring-group mechanism (p. 899) can operate. 

Al-Bromosuccinimide is also a highly regioselective brominating agent at other positions, including positions a to a carbonyl group, to a C=C triple bond, and to an aromatic ring (benzylic position). When both a double and a triple bond are in the same molecule, the preferred position is a to the triple bond. ... 

Radicals have also been generated at benzylic positions and shown to couple with epoxides, forming an alcohol. ... 

For a method that gives good yields at benzylic positions, see Santamaria, J. Jroundi, R. Rigaudy, J. Tetrahedron Lett., 1989, 30, 4677. 

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