Electrophilic substitution relative reactivities

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

If acetoxylation were a conventional electrophilic substitution it is hard to understand why it is not more generally observed in nitration in acetic anhydride. The acetoxylating species is supposed to be very much more selective than the nitrating species, and therefore compared with the situation in (say) toluene in which the ratio of acetoxylation to nitration is small, the introduction of activating substituents into the aromatic nucleus should lead to an increase in the importance of acetoxylation relative to nitration. This is, in fact, observed in the limited range of the alkylbenzenes, although the apparently severe steric requirement of the acetoxylation species is a complicating feature. The failure to observe acetoxylation in the reactions of compounds more reactive than 2-xylene has been attributed to the incursion of another mechan-104... 

The occurrence of a hydrogen isotope effect in an electrophilic substitution will certainly render nugatory any attempt to relate the reactivity of the electrophile with the effects of substituents. Such a situation occurs in mercuration in which the large isotope effect = 6) has been attributed to the weakness of the carbon-mercury bond relative to the carbon-hydrogen bond. The following scheme has been formulated for the reaction, and the occurrence of the isotope effect indicates that the magnitudes of A j and are comparable ... 

Electrophilic Aromatic Substitution. The Tt-excessive character of the pyrrole ring makes the indole ring susceptible to electrophilic attack. The reactivity is greater at the 3-position than at the 2-position. This reactivity pattern is suggested both by electron density distributions calculated by molecular orbital methods and by the relative energies of the intermediates for electrophilic substitution, as represented by the protonated stmctures (7a) and (7b). Stmcture (7b) is more favorable than (7a) because it retains the ben2enoid character of the carbocycHc ring (12). 

MO calculations of the cinnoline ring system show that the relative order of reactivities for electrophilic substitution is 5=8>6 = 7>3 4. This is confirmed experimentally, as nitration of cinnoline with a mixture of nitric and sulfuric acids affords 5-nitrocinnoline (33%) and 8-nitrocinnoline (28%). Similarly, 4-methylcinnoline gives a mixture of 4-methyl-8-nitrocinnoline (28%) and 4-methyl-5-nitrocinnoline (13%). 

The precise numerical values of the calculated electron densities are unimportant, as the most important feature is the relative electron density thus, the electron density at the pyrazine carbon atom is similar to that at an a-position in pyridine and this is manifest in the comparable reactivities of these positions in the two rings. In the case of quinoxaline, electron densities at N-1 and C-2 are proportionately lower, with the highest electron density appearing at position 5(8), which is in line with the observation that electrophilic substitution occurs at this position. 

It is also of significance that in the dilute gas phase, where the intrinsic orientating properties of pyrrole can be examined without the complication of variable phenomena such as solvation, ion-pairing and catalyst attendant on electrophilic substitution reactions in solution, preferential /3-attack on pyrrole occurs. In gas phase t-butylation, the relative order of reactivity at /3-carbon, a-carbon and nitrogen is 10.3 3.0 1.0 (81CC1177). 

The most complete discussion of the electrophilic substitution in pyrazole, which experimentally always takes place at the 4-position in both the neutral pyrazole and the cation (Section 4.04.2.1.1), is to be found in (70JCS(B)1692). The results reported in Table 2 show that for (29), (30) and (31) both tt- and total (tt cr)-electron densities predict electrophilic substitution at the 4-position, with the exception of an older publication that should be considered no further (60AJC49). More elaborate models, within the CNDO approximation, have been used by Burton and Finar (70JCS(B)1692) to study the electrophilic substitution in (29) and (31). Considering the substrate plus the properties of the attacking species (H", Cl" ), they predict the correct orientation only for perpendicular attack on a planar site. For the neutral molecule (the cation is symmetrical) the second most reactive position towards H" and Cl" is the 5-position. The activation energies (kJmoF ) relative to the 4-position are H ", C-3, 28.3 C-5, 7.13 Cr, C-3, 34.4 C-5, 16.9. 

A wide variety of electrophilic species can effect aromatic substitution. Usually, it is a substitution of some other group for hydrogen that is of interest, but this is not always the case. Scheme 10.1 lists some of the specific electrophilic species that are capable of carrying out substitution for hydrogen. Some indication of the relative reactivity of the electrophiles is given as well. Most of these electrophiles will not be treated in detail until Part B. Nevertheless, it is important to recognize the very broad scope of electrophiUc aromatic substitution. 

Other matters that are important include the ability of the electrophile to select among the alternative positions on a substituted aromatic ring. The relative reactivity of different substituted benzenes toward various electrophiles has also been important in developing a firm understanding of electrophilic aromatic substitution. The next section considers some of the structure-reactivity relationships that have proven to be informative. 

The effect of substituents on electrophilic substitution can be placed on a quantitative basis by use ofpartial rate factors. The reactivity of each position in a substituted aromatic compound can be compared with that of benzene by measuring the overall rate, relative to benzene, and dissecting the total rate by dividing it among the ortho, meta, and para... 

The table below gives first-order rate constants for reaction of substituted benzenes with w-nitrobenzenesulfonyl peroxide. From these data, calculate the overall relative reactivity and partial rate factors. Does this reaction fit the pattern of an electrophilic aromatic substitution If so, does the active electrophile exhibit low, moderate, or high substrate and position selectivity ... 

Because it s much easier to measure the acidity of a substituted benzoic acid than it is to determine the relative reactivity of an aromatic ring toward electrophilic substitution, the correlation between the two effects is useful for predicting reactivity. If we want to know the effect of a certain substituent on electrophilic reactivity, we can simply find the acidity of the corresponding benzoic acid. Worked Example 20.1 gives an example. 

Waters61 have measured relative rates of p-toluenesulfonyl radical addition to substituted styrenes, deducing from the value of p + = — 0.50 in the Hammett plot that the sulfonyl radical has an electrophilic character (equation 21). Further indications that sulfonyl radicals are strongly electrophilic have been obtained by Takahara and coworkers62, who measured relative reactivities for the addition reactions of benzenesulfonyl radicals to various vinyl monomers and plotted rate constants versus Hammett s Alfrey-Price s e values these relative rates are spread over a wide range, for example, acrylonitrile (0.006), methyl methacrylate (0.08), styrene (1.00) and a-methylstyrene (3.21). The relative rates for the addition reaction of p-methylstyrene to styrene towards methane- and p-substituted benzenesulfonyl radicals are almost the same in accord with their type structure discussed earlier in this chapter. 

The thiophene ring can be elaborated using standard electrophilic, nucleophilic, and organometallic chemistry. A variety of methods have been developed to exploit the tendency for the thiophene ring (analogous to that of furan and pyrrole) to favor electrophilic substitution and metallation at its a-carbons. Substitution at the p-carbons is more challenging, but this problem can also be solved by utilizing relative reactivity differences. 

Electrophilic substitution in furan, thiophene, selenophene and pyrrole has, up to 1970, been comprehensively reviewed by Marino.66 Italian workers have determined the relative reactivities of selenophene and thiophene as well67 relative rates are given in Table I. Including furan, the order of reactivity is furan > selenophene > thiophene. 

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