Substituted benzenes halogen substituents

Method of Nys and Rekker The Nys and Rekker method [53,54] has been developed for mono- and di-substituted benzenes. The substituents considered are halogen atoms and hydroxyl, ether, amino, nitro, and carboxyl groups, for which contributions have been calculated by multiple regression analysis (s = 0.106, r = 0.994, F = 1405). Rekker discusses the extension of his approach to other compound classes, such as PAHs, pyridines, quinolines, and isoquinolines. 

A point in case is provided by the bromination of various monosubstituted benzene derivatives it was realized that substituents with atoms carrying free electron pairs bonded directly to the benzene ring (OH, NH2, etc) gave 0- and p-substituted benzene derivatives. Furthermore, in all cases except of the halogen atoms the reaction rates were higher than with unsubstituted benzene. On the other hand, substituents with double bonds in conjugation with the benzene ring (NO2, CHO, etc.) decreased reaction rates and provided m-substituted benzene derivatives. 

In contrast, substituents in 1,2,4-triazoles are usually rather similar in reactivity to those in benzene although nucleophilic substitution of halogen is somewhat easier, forcing conditions are required. 

In the case of mono-olefins halogen substituents again reduce the basicity, as in the case of benzene. Unfortunately no information is available which would permit a comment as to whether the halogen atom causes this effect only if it is directly linked to the C=C double bond or whether an effect is also still exerted by an adjacent saturated halogen-substituted C-atom. With multiple halogen substitution the basicity falls even more as may be seen from the examples of chlorine-substituted ethylenes in Table 17. 

Nucleophilic substitution of halogen atom in aromatic and heteroaromatic halides with a hydroxyamino group proceeds only in substrates that are activated by a strong electron-withdrawing substituent in the benzene ring (e.g. 27, equation 17). Despite this limitation this reaction is useful for synthesis of arylhydroxylamines and usually provides good yields of products. Along with activated aryl halides and sulfonates, activated methyl aryl ethers such as 28 can be used (equation 18). 

A Hammett equation was also established for substituted benzenes. A separate model was established for halogenated benzenes. It has been found that halogen substituents behave differently than substituents such as -CH3 and N02 (Hansch and Leo, 1995). For this reason, an accurate comparison of halogenated substituents and other substituents could not be made. 

Many substituted benzene rings undergo electrophilic aromatic substitution. Common substituents include halogens, OH, NH2, alkyl, and many functional groups that contain a carbonyl. Eiach substituent either increases or decreases the electron density in the benzene ring, and this affects the course of electrophilic aromatic substitution, as we will learn in Section 18.7. 

The effect of fluorine, chlorine, or bromine as a substituent is unique in that the ring is deactivated, but the entering electrophile is directed to the ortho and para positions. This can be explained by an unusual competition between resonance and inductive effects. In the starting material, halogen-substituted benzenes are deactivated more strongly by the inductive effect than they are activated by the resonance effect. However, in the intermediate carbocation, halogens stabilize the positive charge by resonance more than they destabilize it by the inductive effect. 

Returning to Table 12.2, notice that halogen substituents direct an incoming electrophile to the ortho and para positions but deactivate the ring toward substitution. Nitration of chlorobenzene is a typical example of electrophilic aromatic substitution in a haloben-zene its rate is some 30 times slower than the corresponding nitration of benzene. The major products are o-chloronitrobenzene and p-chloronitrobenzene. 

RO- and HO-substituted benzenes are halogenated without the Lewis acid. Benzene rings with meta-directing substituents cannot undergo Friedel-Crafts reactions. Aniline and A-substi-tuted anilines also cannot undergo Friedel-Crafts reactions. 

As for benzene radical cations in solution, substituents containing S and Se deviate from the general trend. Interestingly, also the halogenated benzenes (except CjHsF) follow the same trend as the S- and Se-substituted benzenes, i.e., the ionization potential of the substituent halogen atom rather than the substituent effect as described by the substituent constant governs the ionization potential. 

Substituents exert an influence on the ease of electrophilic attack, just as in benzene chemistry. Strongly electron-withdrawing substituents simply render the pyridine even more inert, however activating groups - amino and oxy, and even alkyl - allow substitution to take place, even though by way of the protonated heterocycle i.e. via a dicationic intermediate. The presence of halogen substituents, which have a... 

Such substitutions follow the same mechanistic route as the displacement of halide from 2- and 4-halo-nitro-benzenes, i.e. the nucleophile first adds and then the halide departs. By analogy with the benzenoid situation, the addition is facilitated by (i) the electron-deficiency at a- and 7-carbons, further increased by the halogen substituent, and (ii) the ability of the heteroatom to accommodate negative charge in the intermediate thus produced. Once again, a comparison of the three possible intermediates makes it immediately plain that this latter is not available for attack at a /3-position, and thus (3 nucleophilic displacements are very much slower - for practical purposes they do not occur. 

Halogens connected to a carbon atom, such as chlorine and fluorine, withdraw electrons from other parts of the molecule and can create a large dipole moment (//) of the C-halogen bond [36] /i = C-Cl, 1.56 C-F, 1.51 C-Br, 1.48 C-I, 1.29 D), and overall reactivity and chemical inertness. The theoretical basis for using the dipole moment as a free energy related parameter in studying drug-receptor interaction and quantitative stmcture-activity relationship (QSAR) has been described for aromatic substituents of mono-substituted benzene derivatives [37]. 

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