Multiple Substituents

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  

In this case, the methyl group directs to the ort o positions (the para position is already occupied), and the nitro group directs to the positions that are meta to the nitro group. In this case, both the methyl group and the nitro group direct to the same two locations. Since the two locations are identical (by symmetry), only one product is obtained. 

In other cases, the directing effects of the various substituents may compete with each other. In such cases, the more powerful activating group dominates the directing effects. 

Select the most powerful activator and identify the positions that are ortho or para to that group. 

Begin by identifying the effect of each group on the aromatic ring. 

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Substitution of chloropolymer is possible using a variety of nucleophiles. The most common are sodium salts of alcohols and phenols. Thermoplastics are obtained using a single substituent, whereas multiple substituents of sufficiently different size lead to elastomers (2). Liquid crystal behavior similar to polysHoxanes has been noted in most homopolymers. The homopolymer formed using trifluoroethanol as a substituent has received a fair amount of academic scmtiny (7). 

Halogens are named as substituents in the following way fluoro, chloro, bromo, and iodo. Essentially, we add the letter 0 at the end to say that they are substituents. If there are multiple substituents of the same kind (for example, if there are five chlorine atoms in fhe compound), we use fhe same prefixes fhaf we used earlier when classifying fhe number of double and friple bonds ... 

If there are multiple substituents, then every substituent must be numbered ... 

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). 

Trost et alJ2 also explored the compatibility of di-, tri-, and tetrasubstituted allenes with their intermolecular Alder-ene protocol. Multiple substituents present the opportunity for a mixture of products to arise from differing regio- and chemoselectivity. 1,1-Disubstituted allenes were coupled to methyl vinyl ketone with excellent chemo-selectivity only when one set of /3-hydrogens was activated by an cy-ester or amide (Equation (69)). If the /3-hydrogens were of similar acidity, a mixture of products was obtained, as in the coupling of allenol 103 with methyl vinyl ketone dienes 104 and 105 are produced in a 1.3 1 mixture (Equation (70)). 

In an extensive investigation of the stereochemical memory effect, a series of six diastereomeric pairs of substrates was prepared to probe the effect of single, then multiple substituents on the 5-exo cyclization of amines onto alkene radical cations [144,145]. Overall, these cyclizations were highly dia-stereoselective and were accounted for by a transition-state model employing a chairlike transition state with attack of the nucleophilic amine on the opposite face of the alkene radical to the one shielded by the phosphate anion in the initial contact ion pair (Scheme 34), as exemplified in Schemes 35 and 36. 

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-... 

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. 

As part of their review, Blunt and Stothers developed from their data a table of substituent chemical shifts for a variety of substituents at a wide range of positions. When applied to the appropriate steroid framework it becomes possible to make reasonably good predictions of steroid, 3C chemical shifts. The appropriate warnings about multiple substituent interactions are given. Considerable data on the interactions of multiple hydroxyl groups have been generated, (46, 47) and these provide useful guides for other substituents as well. 

Fuchs, R. Carlton, D. M. Multiple substituent effects in the solvolysis and thiosulfate reactions of 4-substituted a-chloro-3-nitrotoluenes. /. Org. Chem. 1962, 27,1520-1523. 

For rings with multiple substituents, begin numbering at one substituent and proceed in the direction that gives the lowest numbers to the remaining substituents. 

Phenol is an important industrial chemical. More than 3 billion pounds are produced each year. The major uses of phenol are as a disinfectant and in the production of polymers. Complex phenols, with multiple substituents and functional groups, are common in nature, although the simple phenols are seldom encountered. 

Effects of Multiple Substituents on Electrophilic Aromatic Substitution... 

To predict products of compounds with multiple substituents, look for the most strongly activating substituent(s). 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

Vecera, 1973) none of these systems involves a sufficient number of substituents for our purpose. The necessary additional data have now been supplied (Fujio et al, unpublished). Schade and Mayr (1988) later demonstrated that various sets of solvolysis rates, determined under different conditions, especially in different solvents, are linearly correlated with each other, and by using these linear correlations, the solvolytic data obtained under different conditions were converted into a standard set in ethanol at 25°C this data set does not appear to be more extensive than ours as regards variety of substituents, but it provides evidence for the linearity between multiple substituent effects in ethanolysis and those in any other solvolyses, especially in the standard set in 85% aqueous acetone at 0°C. 

A number of computational studies have looked at the benzene dimer with multiple substituents, such as 78 and 79 and 80. All of them show an additivity effect (i.e., increased binding) with each new substituent, regardless of whether the substituent is an EWG or an EDG, and regardless of whether the substitution is on one ring or on both rings. This additivity is not seen in the T-shape configuration. ... 

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