Zinc Chloride aromatic substitution

The rate-determining step is the electrophilic aromatic substitution as in the closely related Friedel-Crafts reaction. Both reactions have in common that a Lewis acid catalyst is used. For the Blanc reaction zinc chloride is generally employed, and the formation of the electrophilic species can be formulated as follows ... 

The electrophile 4 adds to the aromatic ring to give a cationic intermediate 5. Loss of a proton from 5 and concomitant rearomatization completes the substitution step. Subsequent hydrolysis of the iminium species 2 yields the formylated aromatic product 3. Instead of the highly toxic hydrogen cyanide, zinc cyanide can be used. The hydrogen cyanide is then generated in situ upon reaction with the hydrogen chloride. The zinc chloride, which is thereby formed, then acts as Lewis acid catalyst. 

The zinc chloride-catalysed iodination of aromatics by iodine monochloride in acetic acid at 25.2 °C is first-order in each reagent329. The relative rates are given in Table 76 and the reactivities of the higher substituted aromatics are less... 

Furthermore, the reaction of aromatic ethers with a stoichiometric amount of BTMA Br3 in dichloromethane-methanol or acetic acid-zinc chloride under mild conditions gave, selectively, mono-, di-, or tribromo-substituted aromatic ethers in quantitative yields (Fig. 10) (ref. 15). 

Electron-rich aromatic compounds, such as phenol, anisole and A,./V-dimethylaniline, add to bis(2-trichloroethyl) azodicarboxylate under the influence of lithium perchlorate, boron trifluoride etherate or zinc chloride to yield para-substituted products 74, which are transformed into the anilines 75 by means of zinc and acetic acid86. Triflic acid (trifluoromethanesulphonic acid) catalyses the reactions of phenyl azide with benzene, toluene, chlorobenzene and naphthalene, to give TV-arylanilines (equation 34)87. 

Chloromethylation is a useful method for substitution of —CFI2C1 for an aromatic hydrogen, provided one starts with a reasonably reactive arene. The reagents are methanol and hydrogen chloride in the presence of zinc chloride ... 

Various dehydrating agents—concentrated sulphuric acid, zinc chloride, phosphorus pentoxide—can be used. Sulphuric acid, although perhaps the most convenient, has the disadvantage that it tends to sulphonate the aromatic substances employed. At a low temperature, however, diphenylmethane can be obtained from benzyl alcohol and benzene. At 140° phosphorus pentoxide condenses benzene and diphenylcarbinol to triphenylmethane (see B., 7,1204). Not only substituted benzyl alcohols, but even mandelic acid can be brought within the scope of the reaction, while in place of benzefte its nitro, amino or phenolic derivatives may be used. 

BTF is known to react with strong Lewis-Acids such as AICI3. [42] However, milder Lewis-Acids do not readily react with BTF. Zinc chloride catalyzed Friedel-Crafts acylation (8.1) leads to better yields in refluxing BTF compared to sym-tetrachloroethane. [43] The deactivating trifluoromethyl group is presumably responsible for the inertness of BTF towards aromatic substitution under these conditions. Titanium tetrachloride has successfully been used for Sakurai [44]... 

Quinolinyl moiety has been applied in the Negishi reaction either as an electrophile or as nucleophile. 2- or 4-substituted quinolinyl triflates or bromides have been used extensively for introduction of aromatic rings at the C2 or C4 positions of the heterocycle. In a representative example, Murata et al. employed a Negishi reaction in his effort toward the formal synthesis of antitumor compound camptothecin. In accordance to that, 2-chloropyridine was allowed to react with lithium naphthalenide, followed by zinc chloride, to afford the corresponding zinc pyridine salt. Reaction of the resulting organozinc intermediate with 2-chloro-3-quinoline carboxylate provided the hetero biaryl core of camptothecin. ... 

It is believed that the formation of complex between formaldehyde and zinc chloride polarizes formaldehyde so that the electrophilic aromatic substitution can occur, as displayed here. 

The correspondingly substituted benzophenones are obtained in a yield not exceeding 35%, using substituted benzonitriles [20]. E. N. Zil -berman and N. A. Rybakova [21-23] modified the procedure for conducting the Hoesch reaction and S3mthesized a number of aromatic hy-droxyketones in 60-89% yield. According to the procedure they developed, hydrogen chloride is passed into an ether solution of the nitrile and zinc chloride for 2-3 hr at a temperature of 2-5°C, and then resorcinol is added. 

Addition of an T -allyl-Fp complex to this compound affords an T -aIlyl-Fp-substituted cycloheptatriene system. Two double bonds are involved in an (T -diene)iron complex. The remaining free double bond of the silyl enol ether attacks as a nucleophile at the cationic r -alkene-Fp moiety to form an (Tj -diene)iron complexed cyclopentane annulated cycloheptadienone. Treatment with CAN in methanol under carbon monoxide atmosphere releases the methoxycarbonyl-substituted free ligand (Scheme 4-25). Reaction of the Ti -dienyliumiron intermediate of Scheme 4-25 with an ( , Z)-isomeric mixture of ri -crotyl-Fp proceeds with high diastereoselectivity. Four new stereogenic centers are formed in the course of this formal [3+2] cycloaddition. A hetero [3+2] cycloaddition is also feasible between T -ailyl-Fp complexes and aromatic aldehydes in the presence of zinc chloride or titanium(IV) chloride to provide tetrahydrofuran derivatives (Scheme 4-26). A 1,2-shift of the iron complex fragment occurs in the course of this reaction. Employment of imines affords the corresponding pyrrolidines. ... 

Friedel-Crafts and Other Alkylation Reactions. A variety of r-butyl-substituted aromatics have been prepared with isobutene in the presence of acids (eqs 19-21). Due to steric factors, the regiochemistry is enhanced. Isobutene can be alkylated by benzylic and allylic halides in the presence of Zinc Chloride (eqs 22-24). ... 

After a Michael addition, the expected conjugated addition product 14a is formed in 92% yield. The corresponding benzylic chloride (12b) requires a reaction time of 48 h leading to the benzylic zinc chloride (13b). Allylation of 13b provides the aromatic benzoate 14b in 87% yield (Scheme 7.6). The use of DMSO/ THF mixture has a favorable effect allowing the synthesis of substituted benzylic reagents such as 3 [9]. Similarly, the preparation of alkylzinc iodides is facilitated... 

Selective reduction to hydroxylamine can be achieved in a variety of ways the most widely applicable systems utilize zinc and ammonium chloride in an aqueous or alcoholic medium. The overreduction to amines can be prevented by using a two-phase solvent system. Hydroxylamines have also been obtained from nitro compounds using molecular hydrogen and iridium catalysts. A rapid metal-catalyzed transfer reduction of aromatic nitroarenes to N-substituted hydroxylamines has also been developed the method employs palladium and rhodium on charcoal as catalyst and a variety of hydrogen donors such as cyclohexene, hydrazine, formic acid and phosphinic acid. The reduction of nitroarenes to arylhydroxyl-amines can also be achieved using hydrazine in the presence of Raney nickel or iron(III) oxide. ... 

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