Effect of Multiple Substituents

The situation is more complicated if there is more than one substituent on the benzene ring. However, it is usually possible to predict the major products that are formed in an electrophilic aromatic substitution reaction. When the substituents direct to the same position, the prediction is straightforward. For example, consider the case of 2-nitrotoluene. The methyl group directs to the positions ortho and para to itself—that is, to positions 4 and 6. The nitro group directs to positions meta to itself—that is, also to positions 4 and 6. When the reaction is run, the products are found to be almost entirely 2,4-dinitrotoluene and 2,6-dinitrotoluene, as expected  

Note that none of the product where the new nitro group has been added to position 2, between the two groups, is formed. In general, the position between two groups that are meta to each other is not very reactive because of steric hindrance by the groups on either side of this position. 

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The cumulative effects of multiple substituents have been studied at length in search of particularly stable radicals. It is generally found that the repetitive addition of identical substituents leads to a stepwise decrease in RSE values. This is well illustrated by the comparison of the methyl, ethyl, isopropyl, and ferf-butyl radicals with RSE values of 0.0, - 13.8, - 23.3, and - 28.3 kj/mol. Thus, while the stability of the alkyl radicals clearly increases with the number of alkyl substituents attached to the radical center, the substituent ef-... 

Effects of Multiple Substituents on Electrophilic Aromatic Substitution... 

The Houk and Borden groups °° ° have collaborated on a couple of important studies to address the effect of multiple substituents on the Cope rearrangement. They examined the effects of cyano, phenyl, and vinyl substituents at various positions on 1,5 -hexadiene. All three substituents give similar results, but only the cyano and phenyl cases will be discussed here. The cyano case was also examined by Staroverov and Davidson, " coming to the same conclusions as presented here but with a slightly different analysis. 

The effects of multiple substituents in a benzene ring are additive leading to a global a value of Eo, and the reactivity can be expressed as in Equation (5). 

The effect of multiple substituents is usually described in terms of the same resonance (Lewis structure) approaches that are described here for benzene and its monosubstituted derivatives. For a discussion, see Bures, M. G. Roos-Kozel, B. L. Jorgensen, W. L. /. Org. Chem. 1985,107,4490. 180 Perrin, C. /. Am. Chem. Soc. 1977, 99, 5516. Although the conclusions of this paper were questioned (reference 181), there is experimental evidence for the electron transfer pathway in the nitration of naphthalene Johnston, J. F. Ridd, J. H. Sandall, J. P. B. /. Chem. Soc. Chem. Commun. 1989, 244. 

The Effect of Multiple Substituents on Sandwich and T-Shaped n-n Interactions. 

Finally, as shown in Table 13, p for an aromatic ring is also strongly dependent on the other substituents at the double bond it varies from —1.6 to — 5.5 on going from a-methoxystyrenes to stilbenes. This variation, which is related to the well-known non-additivity of multiple substituent effects, and contrasts with what is observed for alkene bromination, is discussed in the next paragraph, devoted to substituent interaction and selectivity relationships in bromination. 

The treatment of non-additivity has also been applied to a large variety of multiple substituent effects on various reactions (Argile et al., 1984) and, in particular, to the bromination of X,Y-disubstituted benzenes where two substituents on the same ring interact strongly (Dubois et al, 1972b) the interaction constant q = — 7.98, associated with a very negative p-value, —12.05, is much higher than those found for the bromination of arylolefins. 

Table 15 Non-additivity of multiple substituent effects p-dependence on X for a substituent Y and interaction constants in arylolefin bromination in methanol at 25°C.

Equations (37)—(39), where the non-additivity of multiple substituent effects is described by a cross-term, express correctly the rate data for bromination and other reactions of polysubstituted substrates. The question arises, therefore has the interaction constant, q, any physicochemical meaning in terms of mechanism and transition state charge To reply to this question, selectivity relationships (42) that relate the p-variation to the reactivity change and not to any substituent constant, have been considered (Ruasse et al., 1984). 

The clustering calculations also provide other kinds of Information about chemical classification of Infrared spectra. These Include the effect of single substituents, carbon skeleton and multiple substitution. These effects were noticeable even under the more difficult circumstance wherein two classes were clustered simultaneously. 

Hammett s equation was also established for substituted phenols from the elementary hydroxyl radical rate constants. The Hammett resonance constant was used to derive a QSAR model for substituted phenols. The simple Hammett equation has been shown to fail in the presence of electron-withdrawing or electron-donating substituents, such as an -OH group (Hansch and Leo, 1995). For this reason, the derived resonance constants such as o°, cr, and o+ were tested in different cases. In the case of multiple substituents, the resonance constants were summed. Figure 5.24 demonstrates a Hammett correlation for substituted phenols. The least-substituted compound, phenol, was used as a reference compound. Figure 5.24 shows the effects of different substituents on the degradation rates of phenols. Nitrophenol reacted the fastest, while methoxyphenol and hydroxyphenol reacted at a slower rate. This Hammett correlation can be used to predict degradation rate constants for compounds similar in structure. 

By similar treatments, the effects of many substituents and combinations of substituents were evaluated, and found to give a reasonably linear correlation with reaction rates when plotted by the Hammett-Taft method. The value of —3.3, determined graphically, is close to the value of — 3.49 reported for solvolysis of substituted cyclohexyl tosylates. Although the general validity of the multiple-path treatment has still to be demonstrated, it may be noted that similar calculations, using an attenuation factor of 0.51, produced a reasonable correlation of substituent effects at C(3> and C(i7) with rates of bromine addition to the 5,6-ethylenic bond [17]. 

While (he TrsubstituenI method has its limitations, particularly when there are signirieant resonance and inductive effects resulting from the presence of multiple substituents, it can work well for a scries of compounds that have similar substitution patterns. 

The analysis of the effect that the different substituents may have on the rate coefficients in this case is particularly hard to perform by using simple inductive effects, as described for instance by the Hammett substituent constants. Note that, despite the fact that most of the 28 carbenium ions exhibit para substitution, the general structure on top of Chart 6, shows a complex substitution pattern at the carbocation centre. In order to asses the effect of multiple substitution at this site, we first considered those compounds that have two fixed hydrogen atoms at the -position of the phenyl group, which according to Hammett classification have crp(H) = 0.0, and the third phenyl group substituted at -position with H (compound 96 in Chart 6) OCH3 (compound 97 in... 

The authors point out that the substituted bromo- and chlorobenzenes fall into two classes based upon the magnitude of the accelerating effect of the substituent upon the reaction rate and the relationship between the rates of the m- and p-substituted halides. Class I comprises the substituents CH3O, HO, Cl and F for which the rate coefficient sequence is o >m>p>u(u = unsubstituted) and Class II comprises the substituents CN and CH3 OOC for which the sequence iso>p>m>u and for which the substituent effects are more powerful. These variations are understood in terms of the negative group effect, it being expected that the extra stabilization of the transition state decreases as the X and Y substituents are further separated from one another. The Class II substituents exhibit a more powerful accelerating effect because of the character of the multiple... 

The reader should note that this additivity is related to, but certainly not the same as, our recently published findings of multiple substituent effects on heats of vapourization, J. S. Chickos, D. G. Hesse and J. F. Liebman, J. Org. Chem., 54, 5250 (1989). 

Rodriquez, C. R, Sirois, S., and Hopkinson, A. C. "Effect of Multiple Halide Substituents on the Acidity of Methanes and Methyl Radicals. Electron Affinities of Chloro and Fluoromethyl Radicals."... 

We will now explore directing effects when multiple substituents are present on a ring. In some cases, the directing effects of all substituents reinforce each other, for example ... 

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