Effects of Substituents in Electrophilic Substitution

Unfortunately only in a few cases have attempts been made to achieve quantitative analysis of isomer mixtures, and it is possible that in many cases when it is stated that only one isomer is formed, 

Correct structure proofs were earlier difficult to obtain, usually involving several reaction steps, and the structures were, therefore, assigned by analogy in many cases. However, through Raney nickel desulfurization (cf. Section VII,C), through NMR spectroscopy,and through polarographic analysis such problems are now easily solved. 

With weakly directing — I + M-substituents such as the halogens, the a-directing power of the ring sulfur dominates and substitution appears to occur exclusively in the 5-position. 2-Chloro-, 2-bromo-, and 2-iodo-thiophene are sulfonated both with chlorosulfonic aeid and in the 5-position. In the chlorination of chloro- 

If the activating effect of a I + M-substituent (such as CH3, NHCOCH3, SCH3, or OCH3) were equal in the 3- and 5-positions, one would, of course, expect that substitution should occur in the 5-position because of the directing power of the sulfur. The experimental results show, however, that such substituents activate the 3-position much more than the 5-position. Thus the nitration of 

3- nitro-2-methylthiophene. Similarly, from the nitration of 2-meth-oxythiophene a 24% yield of the 3-nitro and a 36% yield of the 5-nitro isomers were isolated. In the acylation of 2-methoxythio-phene both isomers were also isolated, but in low total yield.  

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The electronic effects of substituents in arenium ions deserves quantitative estimation on a wider scale because a comparison of the data with the accumulated data on the effect of substituents in electrophilic substitutions will help to judge how close the transition states of these reactions are to the structure of arenium ions. 

There were two schools of thought concerning attempts to extend Hammett s treatment of substituent effects to electrophilic substitutions. It was felt by some that the effects of substituents in electrophilic aromatic substitutions were particularly susceptible to the specific demands of the reagent, and that the variability of the polarizibility effects, or direct resonance interactions, would render impossible any attempted correlation using a two-parameter equation. - o This view was not universally accepted, for Pearson, Baxter and Martin suggested that, by choosing a different model reaction, in which the direct resonance effects of substituents participated, an equation, formally similar to Hammett s equation, might be devised to correlate the rates of electrophilic aromatic and electrophilic side chain reactions. We shall now consider attempts which have been made to do this. 

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... 

A Summary of Substituent Effects in Aromatic Substitution A summary of the activating and directing effects of substituents in electrophilic aromatic substitution is shown in Table 16.2. 

The effects of substituents in electrophilic aromatic substitution processes,... 

In studies concerning the effects of substituents in electrophilic aromatic substitution, particularly in orientational control of the entering group, in reaction rates, and most recently in details of the substitution process itself, steric and polar effects of the substituent and the reagent appear to be factors simultaneously affecting the reaction. 

Table 16-1 Effects of Substituents in Electrophilic Aromatic Substitution...

The model adopted by Ri and Eyring is not now acceptable, but some of the more recent treatments of electrostatic effects are quite close to their method in principle. In dealing with polar substituents some authors have concentrated on the interaction of the substituent with the electrophile whilst others have considered the interaction of the substituent with the charge on the ring in the transition state. An example of the latter method was mentioned above ( 7.2.1), and both will be encountered later ( 9.1.2). They are really attempts to explain the nature of the inductive effect, and an important question which they raise is that of the relative importance of localisation and electrostatic phenomena in determining orientation and state of activation in electrophilic substitutions. 

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

These results do not, as noted above, give any direct indication of the difference in transmission ability of =N versus =CH—. For this, one must compare the effects of substituents in 9.113 with 9.114, though even here the results are blurred because of the dual transmission pathway. It is difficult to make the comparison using a conventional electrophilic substitution (except by prelabeling, e.g., as in detritiation) because substitution at the desired point is likely to be a minor component and difficult to measure accurately. The side-chain carbocation method has therefore been used. 

Side-chain reactions in which a deiocalizable positive charge is developed in the transition state are frequently considered together with electrophilic aromatic substitutions 60 the analogy between these two classes of reactions has been confirmed also in heteroaromatic chemistry.61 However, a comparison of the solvolysis data with those referring to electrophilic substitutions (Tables XVII-XIX) indicates that tellurophene behaves in a different way in the two types of reactions. As concerns the reactivity, tellurophene is less reactive than furan in electrophilic substitution but more reactive than furan in the solvolysis of 1 (2-aryl)ethyl acetates as concerns the k,tJkH reactivity ratios, tellurophene appears to be more sensitive to substituent effects than selenophene in electrophilic substitutions and less sensitive in side-chain reactions. 

Contrary to earlier views, the effect of substituents in the aromatic nucleus on the point of entry of the mercury is the same as in other electrophilic substitutions. For instance, mercuration of toluene gives mainly the ortho-and the / ara-compound, and that of nitrobenzene gives mainly the meta-derivative. However, at elevated temperatures mercuric acetate is not very selective and mixtures of the possible isomers are obtained. Mercuric perchlorate is much more specific e.g., in 60% perchloric acid at 23° nitrobenzene is mercurated to the extent of 89% in the meta-position.190... 

The modem electronic theory of organic chemistry was first systematically applied by the present author for discussing the directing effects of substituents in thiophene. Although the directii effects of substituents and the isomeric distribution in electrophilic substitution are best discussed and understood in terms of the influence of the substituents on the energies of the transition states, the often simpler approach of considering their effect on the electron densities of the ground state was used (cf. Section II,A,2). ... 

The relative basicities of aromatic hydrocarbons, as represented by the equilibrium constants for their protonation in mixtures of hydrogen fluoride and boron trifluoride, have been measured. The effects of substituents upon these basicities resemble their effects upon the rates of electrophilic substitutions a linear relationship exists between the logarithms of the relative basicities and the logarithms of the relative rate constants for various substitutions, such as chlorination and... 

The more extensive problem of correlating substituent effects in electrophilic substitution by a two-parameter equation has been examined by Brown and his co-workers. In order to define a new set of substituent constants. Brown chose as a model reaction the solvolysis of substituted dimethylphenylcarbinyl chlorides in 90% aq. acetone. In the case ofp-substituted compounds, the transition state, represented by the following resonance structures, is stabilized by direct resonance interaction between the substituent and the site of reaction. 

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