Benzylic carbon, nucleophilic substitution intermediate

Nucleophilic Substitution at Benzyl Derivatives. The sharp break from a stepwise to a concerted mechanism that is observed for nucleophilic substitution of azide ion at X-l-Y (Figs. 2.2 and 2.5) is blurred for nucleophilic substitution at the primary 4-methoxybenzyl derivatives (4-MeO,H)-3-Y. For example, the secondary substrate (4-MeO)-l-Cl reacts exclusively by a stepwise mechanism through the liberated carbocation intermediate (4-MeO)-T, which shows a moderately large selectivity toward azide ion ( az/ s = 100 in 50 50 (v/v) water/ trifluoroethanol). The removal of an a-Me group from (4-MeO)-l-Cl to give (4-MeO,H)-3-Cl increases the barrier to ionization of the substrate in the stepwise reaction relative to that for the concerted bimolecular substitution of azide ion. The result is that both of these mechanisms are observed concurrently for nucleophilic substitution of azide ion at (4-MeO,H)-3-Cl in water/acetone solvents. These concurrent stepwise and concerted nucleophilic substitution reactions of azide ion with (4-MeO,H)-3-Cl show that there is no sharp borderline between mechanisms for substitution at primary benzylic carbon, but instead a region of overlap where both mechanisms are observed. 

Nucleophile addition to styrene derivatives (e.g. 75) coordinated with Cr(CO)3 is another example of addition-electrophile trapping.23,128 Addition of reactive anions is selective at the 3-position of the styrene ligand, leading to the stabilized benzylic anion (76). The intermediate reacts with protons and a variety of carbon electrophiles to give substituted alkylbenzene ligands (in 77) (equation 52). 

An SN1 reaction on the carbon atom next to the ring has a large negative p value. In this example, a tertiary benzylic cation is the intermediate and the rate-determining step is, of course, the formation of the cation. The cation is next to the ring but delocalized round it and the p value is -4.5, about the same value, though negative, as that for the nucleophilic substitution on nitrobenzenes by the addition-elimination mechanism that we saw in the last section. 

With this acetal, instead of hydrolyzing the intermediate benzyllithium, one can let it warm to room temperature, and an internal nucleophilic substitution takes place, whereby the acetal moiety behaves as a leaving group, and a trans-disubstituted cyclopropane is formed in 60-70% yield [39,41]. The first-formed stereogenic center remains unaffected in this second step, whereas the benzylic lithiated carbon is able to epimerize [38,39], leading to the more stable trans-cyclopropane [42-44] (Scheme 20). 

The same differential behavior can be observed with amine nucleophiles. For example, calcium triflate promotes the aminolysis of propene oxide 84 with benzylamine to give 1-(A -benzyl)amino-2-propanol 85, the result of attack at the less substituted site <03T2435>, and which is also seen in the solventless reaction of epoxides with heterocyclic amines under the catalysis of ytterbium(III) triflate <03SC2989>. Conversely, zinc chloride directs the attack of aniline on styrene oxide 34 at the more substituted carbon center <03TL6026>. A ruthenium catalyst in the presence of tin chloride also results in an SNl-type substitution behavior with aniline derivatives (e.g., 88), but further provides for subsequent cyclization of the intermediate amino alcohol, thus representing an interesting synthesis of 2-substituted indoles (e.g., 89) <03TL2975>. 

S)-l is obtained from the bis(methyl carbonate) of (Z)-2-butene-l,4-diol and l,2-bis(tosyl-amino)ethane through a tandem pa]ladium(0)-catalyzed allylic substitution in the presence of (R)-BINAP (I) as chiral ligand79. Equilibration of the 7t-allylpalladium intermediates formed before the intramolecular nucleophilic attack is necessary for high enantioselectivity. Thus, only a racemic piperazine is produced in the reaction of the more nucleophilic l,2-bis(benzyl-amino)ethane with the diacetate of (Z)- or ( )-2-butene-l,4-diol. 

Ionization of substrates 1 and 2 leading to the symmetrically 1,1-disubstituted diastereomeric Ti-allyl complexes 3 and 4 also allows complete conversion to one product enantiomer, provided that nucleophilic attack occurs at the carbon bearing substituent R2. High enantiomeric excess may be achieved if a rapid equilibration between the two intermediate re-allyl species is established and the soft carbanion preferentially attacks one of them. Interconversion of the reactive complexes is possible via epimerization by nucleophilic attack of free palladium(O) anti to the jr-allyl complex or by n-a-n rearrangement involving the formation of a Pd-C c-bond at the symmetrically substituted allyl terminus. This process is only fast for R1 = H, due to a low degree of steric congestion or for R1 = aryl because of rc-benzyl participation. 

The reluctance of the carbyne carbon to react with nucleophiles is revealed by the reaction with LiEt3BH (see Scheme 6). Here the most electrophilic site is not the carbyne carbon but the ipara position of the aryl ring in the carbyne substituent Both ruthenium and osmium five coordinate, cationic, carbyne complexes undergo this reaction. The structure of a representative example, the osmium compound derived from the p-tolyl carbyne complex, has been determined by X-ray crystallography [16]. The unusual vinylidene complex reacts with HCl to produce a substituted benzyl derivative. The reaction may proceed through the intermediate a-vinyl complex depicted in Scheme 6 although there is also the possibility that the vinylidene compound is in equilibrium with the carbene tautomer as shown below. 

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