Substitution, electrophilic isomer distributions

Electrophilic Substitution.—The isomer distributions and the rates relative to those of the parent heterocyclic compounds for acetylation, benzoylation, chlorination, and bromination of benzo[Z>]thiophen and benzo[6]furan have been determined. It was found that although the orientation of substitution in the two bicyclic systems is different, the effect caused by annelation on the reactivity of the a- and jS-positions is substantially the same in the two rings the reactivity of the a-position is always decreased by a similar factor, and the reactivity of the j8-position is increased (with some exceptions) in both systems. The different orientation observed in the... 

Study of isomer distribution in substitution of benzene rings already carrying one substituent presents some potential pitfalls. Inspection of product ratios for ortho, meta, and para substitution, as in investigation of electrophilic substitution (Section 7.4, p. 392), might be expected to give misleading results because of the side reactions that occur in radical substitution. The isomeric substituted cyclo-hexadienyl radicals first formed by radical attack partition between the simple substitution route and other pathways (Equation 9.102). In order for the... 

The reaction of N-alkylated pyrroles with carbenoids leads exclusively to substitution products. Due to the pharmaceutical importance of certain pyrrolylacetates, the reaction with alkyl diazoacetates (Scheme 45) has been systematically studied using about 50 different catalysts.13 Both the 2- and 3-alkylated products (216) and (217) could be formed and the ratio was dependent on the size of the JV-alkyl group and ester and also on the type of catalyst used. This has been interpreted as evidence that transient cyclopropane intermediates were not involved because if this were the case, the catalyst should not have influenced the isomer distribution. Instead, the reaction was believed to proceed by dipolar intermediates, whereby product control is determined by the position of electrophilic attack by the carbenoid. Similar alkylations with dimethyl diazomalonate gave greater selectivity and yields.164... 

Isomer distributions and a /3 ratios depend strongly on the electrophilic reagent. Data referring to fourteen substitutions of thiophene are summarized in Table VIII. In acetylation, the isomer distribution... 

Isomer Distributions and a j8 Reactivity Ratios in Electrophilic Substitutions of Thiophene ... 

For displacement reactions the partial rate factors af and /3f are calculated directly from the ratios of the rate constants of the heterocyclic and the benzene derivatives. For the electrophilic substitutions in which the proton is replaced, they may be easily calculated from the overall relative rates and the isomer distributions ... 

Recently, more accurate determinations of isomer distributions and a /3 reactivity ratios in electrophilic substitutions of benzofuran and benzothiophene have been determined using the gas chromatographic technique.77 The data are summarized in Table XVI which also includes a /3 reactivity ratios referring to electrophilic displacement reactions such as protodesilylation and to side-chain reactions related to electrophilic substitution, such as the solvolysis of 1-arylethyl-acetates239 and 1-arylethyl- -nitrobenzoates.240... 

The reactivity ratios vary over a wide range, depending on the nature of the electrophile and the conditions used. Temperature appears to be an important factor in determining the isomer distribution, at least in acetylation. The amounts of a-substituted isomer in benzothiophene and /3-substituted isomer in benzofuran increases, as the temperature increases (Table XVII). Plots of loga// against 1 /T are linear for the acetylation of both systems over the range of temperature examined. It is possible that at higher temperatures ( > 250°) an inversion of the orientation pattern could be observed ... 

If the alkyl substituent is in position 3, the 2-position is the most favored from the electronic point of view, being ortho to the alkyl group and alpha to the heteroatom. The other a position (5) is, however, free from steric effects. Consequently, reactions of 3-alkyl thiophenes, -furans, and -pyrroles yield a mixture of 2- and 5-substituted isomers, the composition of which depends on the nature of the heteroatom, the electrophile, and the size of the alkyl group. Table XXI reports the isomer distribution in the acylation of 3-methyl-, 3-isopropyl-, and 3-i-butylthiophenes and shows the importance of the steric factor in determining the orientation. 

The same workers590,591 also showed that, in the Pd(II)-catalyzed acetoxylation of substituted arenes, a complete reversal of the usual pattern of isomer distribution for electrophilic aromatic substitution or anodic oxidation of aromatics is observed. To explain these results it was suggested that acetoxylation by Pd(OAc)2 takes place via the following addition-elimination sequence ... 

The fluorination of aromatic compounds with xenon difluoride has been extensively investigated. The fluorination of benzene with xenon difluoride in the presence of hydrogen fluoride as a catalyst results in the formation of fluorobenzene in 68% yield. Monosub-stituted aromatic systems are reported to give high yields of monofluorinated compounds, the isomer distributions of which arc similar to those observed in electrophilic substitution (Table... 

The isomer distribution for anodic acetoxylation of a number of monosubstituted benzenes has been determined [122]. The reaction closely resembles ordinary electrophilic aromatic substitution processes, perhaps on the side of low-selectivity reactions. The isotope effect, A h//cd, for nuclear acetoxylation in anisole was found to be 1.0, whereas for a-substitution in ethylbenzene a value of 2.6 was observed. The interpretation of these values is not straightforward [126]. 

The partial rate factors and the isomer distribution in the amination by di-methylamino radical cation of toluene, isopropylbenzene, -butylbenzene, biphenyl and naphtalene are reported in Table 7. These partial rate factors are far the highest ever observed in homolytic substitutions so that the general character of the homolytic amination allows a more relevant analogy to be drawn with the electrophilic substitutions than with the homol5rtic arylation, the only homol5rtic substitution for which numerous and accurate quantitative data exist in homo-cyclic aromatic series. 

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