Substitution, electrophilic monosubstituted benzenes

The most familiar set of organic reactions is perhaps the electrophilic aromatic substitutions. For monosubstituted benzenes the major products from the process are either o- or p-disubstituted benzenes or m-disubstituted analogs. 

Table 58. Observed and Calculated (in parentheses) Isomer Distribution in Electrophilic Substitution of Monosubstituted Benzenes (Data used for determining the parameters A, B and D are given by italics)...

If, on the other hand, the encounter pair were an oriented structure, positional selectivity could be retained for a different reason and in a different quantitative sense. Thus, a monosubstituted benzene derivative in which the substituent was sufficiently powerfully activating would react with the electrophile to give three different encounter pairs two of these would more readily proceed to the substitution products than to the starting materials, whilst the third might more readily break up than go to products. In the limit the first two would be giving substitution at the encounter rate and, in the absence of steric effects, products in the statistical ratio whilst the third would not. If we consider particular cases, there is nothing in the rather inadequate data available to discourage the view that, for example, in the cases of toluene or phenol, which in sulphuric acid are nitrated at or near the encounter rate, the... 

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

We will restrict our consideration to reactions of substituted benzenes and to nitrogen heteroaromatic systems in which the reaction takes place first with the n system. The simplest example of reaction of a monosubstituted benzene with an electrophile (Lewis acid) is shown in Scheme 11.1. The electrophile may attach itself to the n system (step A) in four distinct modes, ipso, ortho, meta, and para. The reactivity of the aromatic ring and the mode of attachment of the electrophile will be influenced by the specific nature of the substituent group, which may be X , Z, or C type. Detachment of the electro-... 

A quantitative description of the reactivity of monosubstituted benzenes to electrophilic substitution based on considerations of inductive effect parameters and con-jugative effect parameters from the 13 C chemical shifts of the aromatic compounds has been proposed.3 MO calculations on the proton migration in the ipso adducts formed in the reaction of CH3+ and SiH3+ with benzene have been described.4 With SiH3+ the ipso adduct is the most stable of possible isomers, whereas for CH3+ the >ara-protonated isomer is the most stable. 

A review of experimental work prompted the suggestion of the importance of dipolar interactions (Hammond and Hawthorne, 1956). de la Mare and Kidd (1959), observing a parallelism in the parajmeta and ortho/meta ratios, predicted the ortho effect to be primarily electronic in origin. Norman and Radda (1961) explored the general significance of this idea. They studied the orthojpara ratios for the substitution of a series of monosubstituted benzenes by two reagents with the same electrophilic properties but different steric requirements. The reactions, nitration by N02+ and chlorination by CI+, fulfill the requirements. The results are summarized in Table 3. 

Summary of Electrophilic Substitution Reactions of Deactivated Monosubstituted Benzenes... 

Deactivated monosubstituted benzenes Traditionally, qualitative discussions of electrophilic substitution emphasize the deactivating influence of positive or partial positive charges on substituent atoms (Ingold, 1953). Only in recent years, however, have valid quantitative measurements been performed to allow the elucidation of the extent of the deactivation of the aromatic nucleus by such groups. The available information, still very limited in scope, is summarized in Table 18. 

The observations for the electrophilic substitution reactions of the monosubstituted benzenes have been examined for adherence to a linear free-energy relationship. As shown, the Selectivity Relationship,... 

Regioselectivity in the formation of regioisomers is also observed in electrophilic aromatic substitution reactions. In the case of monosubstituted benzene derivatives, there are three possible regiosomeric products that form at different rates, based on the mechanism of the reaction (see Figure 13). see also Berzelius, Jons Jakob Chirality Dalton, John Davy, Humphry Molecular Structure Scheele, Carl Wohler, Friedrich. 

With monosubstituted benzenes a mixture of isomeric biphenyls is obtained. The substitution pattern corresponds to that observed in electrophilic aromatic substitution, consistent with a mechanism involving electrophilic attack by PdCl2 shown in Eq. (388). 

Aromatic bromides (3, 286). The definitive paper on electrophilic aromatic bromination with bromine and thallium(lll) acetate has been published. The two most oul.standingfeaturc.s are I) monobromination is observed in almost all cases, and 2) exclusive para substitution is observed with almost all monosubstituted benzenes. Electron-withdrawing groups inhibit bromination of monosubstituted benzenes. It... 

The distribution rates for iodination of monosubstituted benzene derivatives have been reported. Under conditions of thermodynamic control (elevated temperature), meta substitution is observed. Under conditions of kinetic control (room temperature), a significant preference for para substitution is observed for compounds containing oriha- puru-directing substituent groups. Ortho substitution results when chelation of TTFA with the directing substituent permits intramolecular delivery of the electrophile. For example, methyl benzoate gives almost exclusively or/ho-lhallation (95%). 

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 substitution of pure benzene by an electrophile will result in the formation of a monosubstituted product, which is capable of undergoing further substitution reactions. When designing the strategy for the synthesis of an aromatic compound, there are two principal points that must be borne in mind, namely first, the reactivity of the monosubstituted product compared with that of the original benzene and second, the position on the aromatic ring where the second substitution reaction will take place. These two issues will now be examined, and it will be seen that they are, at least to some extent, dependent upon each other. 

The relative ease of attack (by an electrophile) at the ortho-lmeta-lpara-positions can be determined experimentally from partial rate factors. These compare the rate of attack at one position in the monosubstituted benzene with the rate of attack at one position in benzene. The higher the partial rate factor at a given position, the faster the rate of electrophilic substitution. 

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