Substituents in benzene derivatives

In view of the extremely wide variety of groups which occur as substituents in benzene derivatives and for which substituent constants have been calculated, it is surprising that almost none of them... 

The isolated-molecule method stems from the pioneering work of Wheland and Pauling (1935) on the orientation effects of substituents in benzene derivatives. It assumes that electrophilic and nucleophilic reagents attack preferentially at positions of high and low charge (qf) respectively, thus providing a more precise formulation of earlier... 

Charton has recently examined substituent effects in the ortho position in benzene derivatives and in the a-position in pyridines, quinolines, and isoquinolines. He concludes that, in benzene derivatives, the effects in the ortho position are proportional to the effects in the para position op). However, he finds that effects of a-sub-stituents on reactions involving the sp lone pair of the nitrogen atoms in pyridine, quinoline, and isoquinoline are approximately proportional to CT -values, or possibly to inductive effects (Taft s a ). He also notes that the effects of substituents on proton-deuterium exchange in the ortho position of substituted benzenes are comparable to the effects of the same substituents in the a-position of the heterocycles. 

The problems encountered in any attempt to treat the transmission of the effects of one substituent in a disubstituted heterocycle through the heterocyclic nucleus to a reaction site in the other substituent (i.e. the side-chain) are enormous, and it is consequently not surprising that relatively little work has been done in this area. First, while in benzene derivatives there are three positions, i.e. three relations between substituent and reacting side-chain to be considered, the number of complexities is much greater in heterocycles. Thus, e.g., in pyridine alone, after elimination of the orientations involving a vicinal relationship between substituent R and the side-chain Y to which no Hammett-type relation is likely to be applicable, the following cases should be considered ... 

From Table 3, it can be seen that the reactivity of acyl acetanilide, such as BAA or AAA, is higher than that of the other reductant reported from our laboratory, i.e., acetanilide (AA), N-acetyl-p-methylaniline (p-APT), acetylacetone (AcAc), and ethyl acetoacetate (EAcAc). Moreover, the promoting activities of derivatives of acetoacetanilide were affected by the ortho substituent in benzene ring, and the relative rate of polymerization Rr) decreased with the increase of the bulky ortho substituent to the redox reaction between Ce(IV) ion and substituted acetoacetanilide. 

Aromatic molecules with no polar substituent include benzene derivatives or other, more polyaromatic molecules, such as naphthalene, phenanthrene, and anthracene. These are polarizable. Paraffins are not polarizable by comparison. In gas-liquid systems, aromatic molecules will show stronger interactions with polar stationary phases that paraffins of comparable boiling point and, thus, polar stationary phases can aid in improving separation of substituted aromatics. 

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],... 

Orientation effects in benzene derivatives operate in two ways. If the substituent is inductive there are large first order charge displacements at the ortho and para positions, and these can be estimated approximately using the atom polarizabilities (which is very small at the meta position). The changes of bond order, however, and consequently of free valence, vanish in first order and hence depend on Sa. The charge g g at position s therefore increases or decreases from the value unity in the... 

The difference between bromine and chlorine as the substituents is slight. I.R. measurements (Tamres, 1952) of the displacement of the OD-valency vibration of CH3OD dissolved in benzene derivatives also show only a slight difference between bromobenzene and chlorobenzene. 

More important and more widely applicable criteria of protonation sites are available in the effects of more distant substituents, in particular meta and para in benzene derivatives, which are as a rule purely electronic in origin. Exceptionally, they may be complicated by steric effects (e.g., in polysubstituted derivatives). The most widely useful approach is that of Hammett (1940), who suggested that the effects of substituents on the ionization constants of benzoic acid may be taken as a measure of their effectiveness in other systems involving other reaction centres and in reactions other than acid-base equilibria. He thus defined substituent constants, a, by the equation... 

Table 5.6 gives characteristic chemical shifts for the aromatic protons in benzene derivatives. To a first approximation, the shifts induced by substituents are additive. So, for example, an aromatic proton which has a -NO2 group in the para position and a -Br group in the ortho position will appear at approximately 7.82 ppm [(7.26 + 0.38(p-NO2) + 0.18(o-Br)]. 

In 1Q37 Hammett recognised-3 iImI I he electronic influence of a substituent, X jnight be assessed by studying reactions ina.side. chain at Y in benzene derivatives ( T and 10). 

In benzene derivatives, electron-donating substituents direct into the ortho-and para-positions, while in the case of the electron-withdrawing substituents considerable meta-addition is observed (Table 3.1) otherwise a more equal distribution is established [reactions (6)-(9) and Table 3.1]. In agreement with the pronounced regioselectivity, ipso-addition at a bulky substituent such as the chlorine substituent in chlorobenzene is disfavored. Evidence for this is the low HC1 yield in the case of chlorobenzene, the low yield of para adduct in 4-methyl-phenol (Table 3.1), or the decarboxylation in the case of benzoic acid [reactions (6) and (10)]. 

A number of authors have studied substitution with the nitro group in benzene derivatives containing ortho-para directing substituents, when nitric acid with acetic anhydride was used. The experiments led to the conclusion that replacement of water in the nitrating mixtures by acetic anhydride produces an increase of the ratio of ortho- to para- isomers. 

A. Domenicano, Structural Substituent Effects in Benzene Derivatives. In Accurate Molecular Structures, A. Domenicano and I. Hargittai, eds., Oxford University Press, Oxford, 1992, pp. 437-468 See, also, A. R. Campanelli, A. Domenicano, F. Ramondo, I. Hargittai, Group Electronegativities from Benzene Ring Deformations A Quantum Chemical Study. J. Phys. Chem. A, 2004, 108, 4940-1948. 

Clearly, therefore, there is a very wide spread in reactivity, as in electrophilic substitution in benzene derivatives, but here we have the contrasting feature that the orientation pattern is relatively insensitive to the substituent. Consequently, it is important to establish the nature of this unusual orientating influence arising from the five fluorine... 

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