Reactions at the Benzylic Position

Any carbon atom attached directly to a benzene ring is called a benzylic position  

In the following sections, we will explore reactions that can occur at the benzylic position. 

Recall from Section 13.10 that chromic acid (H2Cr04) is astrong oxidizing agent used to oxidize primary or secondary alcohols. Chromic acid does not readily react with benzene or with alkanes  

Interestingly, however, alkylbenzenes are readily oxidized by chromic acid. The oxidation takes place selectively at the benzylic position  

Although the aromatic moiety itself is stable in the presence of chromic acid, the benzylic position is particularly susceptible to oxidation. Notice that the alkyl group is entirely excised, leaving only the benzylic carbon atom behind. The product is benzoic acid, irrespective of the identity of the alkyl group. The only condition is that the benzylic position must have at least one proton. If the benzylic position lacks a proton, then oxidation does not occur. 

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Normal alkenes—which are particularly not electron-rich—are oxidized at the allylic position by PCC, resulting in the formation of enones.264 Aromatic compounds suffer a similar reaction at the benzylic positions, yielding aromatic ketones265 or aromatic aldehydes.266 These oxidations normally demand quite harsh conditions with excess of PCC, long reaction times and high temperature. Therefore, they hardly compete with the oxidation of alcohols, which is normally made under quite mild conditions. 

Scheme 3. H—D exchange reaction at the benzylic position with D20 and premixed catalyst (10% Pd/C and H2).

Arene(tricarbonyl)chromium complexes undergo a number of synthetically important transformations not usually observed for uncomplexed arenes. The chromium tricarbonyl moiety facilitates nucleophilic, electrophilic, and radical reactions at the benzylic position. Upon complexation, one side of the aromatic ring and adjacent functionalities is blocked by the metal carbonyl moiety and highly stereoselective reactions are usually observed even at relatively remote positions. In addition, the protons of the complexed aromatic ring have a substantially higher acidity and are readily removed and further substituted by electrophiles. Finally, the aromatic ring is activated toward addition reactions using a variety of nucleophiles. 

The stereodirecting power of the chromium ligand does not only apply to reactions at the benzylic position or using rigid ring systems, but also to more remote sites. Reaction of mesylate complex (50) with sodium acetate affords (51) with... 

Like allyl- and propargylmagnesium compounds, benzylmagnesium halides when reacted with a substrate give rise in part to products substituted at the allylic, i.e., here at the ortho position THF favors reaction at the benzylic position . 

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. 

Reaction selectivity of the parent ortho-QM has also been explored with a variety of amino acid and related species.30 In these examples, the rates of alkylation and adduct yields were quantified over a range of temperatures and pH values. The initial QM3 was generated by exposing a quaternary benzyl amine (QMP3) to heat or ultraviolet radiation (Scheme 9.10). Reversible generation of QM3 was implied by subsequent exchange of nucleophiles at the benzylic position under alternative photochemical or thermal activation.30 Report of this work also included the first suggestion that the reversible nature of QM alkylation could be used for controlled delivery of a potent electrophile. 

In the absence of reversible reaction, for example when water acts as the lone nucleophile, QMP11 is consumed with a half-life of approximately 0.5 h as measured by its diminished ability to cross-link DNA (Scheme 9.18).69 Elimination of acetate to form the first of two possible QM intermediates (QM12) is likely rate-determining in this process since subsequent addition by water is estimated to occur with a half-life in the millisecond range.56 The resulting hydroxy substituent at the benzylic position does not eliminate and regenerate QM12 under ambient conditions. Thus, water... 

The reaction mechanisms have been clarified in some detail7In method (a) a complex sequence starts with the acetoxy cyclopropenium ion 126 and the cyclo-propenyl acetate 127 and finally leads to adducts 128 containing two moles of arylmalononitrile, which were isolated and shown to be the preferential precursors of quinocyclopropenes. In method (b) the ambivalent arylmalononitrile anion102) is reversibly attacked at the benzylic position at low temperatures, whilst at higher temperature (after dissociation of 114) attack at the o- and p-positions of the... 

For a few select cases, the cyclic aUcene 62a-c with simple primary alkyls as substituents were readily hydrogenated with SimplePHOX ligand 7a and 7c. Importantly, no epimerization at the benzylic position was observed, and hydrogenation gave entirely cis product with most substrates. Aromatization of the dihydronapthe-lene substrates 63a-b was a frequent side reaction, even at high pressures. 

Two precedent examples had been reported of the enantioselective [2+2+2] cycloaddition of alkynes. In one case, an enantioposition-selective intermolecular reaction of a triyne with acetylene generated an asymmetric carbon at the benzylic position of a formed benzene ring [19]. In the other case, an intramolecular reaction of a triyne induced helical chirality [20]. Both reactions were developed by chiral Ni catalysts. 

A possible mechanism of oxidation of methylene groups to carbonyl groups involves autoxidation (oxidation by molecular oxygen) at the benzylic position. Autoxidation of arylalkanes is a facile reaction with low activation energies for example, 6.0 kcal/mole for 1,1-diphenylethane and 13.3 kcal/mole for toluene. ... 

Benzenechromium tricarbonyl 371 is deprotonated by BuLi in EtiO-THF at —40 °C in a reaction that needs carefnl control for good yields . The prodnct 372 can be sily-lated to give 373 in 60% yield (Scheme 158). Toluenechrominm tricarbonyl lithiates non-regioselectively on the ring (bnt at the benzylic position with Na or K bases). Excess base can lead to polylithiation . 

A special case of functionalized aryllithium reagents appears when the corresponding aryl group bears a ketal moiety at the benzylic position due to the lability of the benzyUc carbon-oxygen bonds. However, working under Barbier-type conditions and using naphthalene (10%) as the electron carrier catalyst, the reaction of chlorinated materials 242 afforded, after hydrolysis with water, the corresponding polyfunctionalized products 243 (Scheme 81). ... 

Treatment of Af-phenylazetidine 315 with lithium and a catalytic amount of DTBB (5%) in THF at — 15°C led to a solution of the corresponding y-functionalized organohthium intermediate 316, which by reaction with different electrophiles at temperatures ranging between —78 and 20 °C, and final hydrolysis, afforded the expected functionalized amines 317. The same reaction using azetidine 318 yielded products 320, functionalized at the benzylic position, intermediates 319 being involved in the process (Scheme 93) . ... 

In systems where steric interference is not a factor, C-H insertion at a methylene site is strongly preferred over that at methyl sites. A striking example of this effect is the reaction with 4-ethyltoluene (Eq. 24) [137]. The only C-H activation product formed is 202, derived from C-H insertion at the methylene site. A Hammett study on the benzylic C-H activation indicated that the transition-state build-up of positive charge at the benzylic position is stabilized by resonance. 

Substituted 1,2,4-triazoles have received less attention than their isomeric counterparts, but those results that are available indicate that their lithio derivatives are less stable than their 1-substituted isomers. Thus, in addition to undergoing the expected a-lithiation and reaction at the 5-position, 3-phenyl-4-benzyl-1.2.4-triazole also gave products resulting from ring-opening, even at -78°C (Scheme 65) (86JHC1257). 

Meldrum s acid, like other 1,3-dicarboxyl compounds, was amenable to radical reactions at C-5. The radical reaction between Meldrum s acid benzyl alkyl ethers mediated by InCl3/Cu(OTf)2 has been reported to proceed regioselectively at the benzylic position of the ether moiety (Scheme 35) <2006AGE1949>. Radical reaction of Meldrum s acid and alkenes was carried out with 2equiv of ceric ammonium nitrate (CAN) to give the a-carboxy-lactones which were subsequently subjected to decarboxylative methylenation affording the a-methylene lactones in 35-50% yield (Scheme 35) <2006SL1523>. 

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