Electrophilic substitution, definition

In the first instance, acidity influences the acid-base equilibria of the reactants. The amine is a Bronsted base. Aniline, a typical substrate, has pKa = 4.6, which means that the protonation shown in Scheme 3-11 is almost complete under normal conditions of diazotization (pH < 1). The base is definitely a much better reagent than the anilinium ion for nitrosation because the latter is an electrophilic substitution. One expects — simply on the basis of the equilibrium shown in Scheme 3-11 — that the rate of diazotization should decrease linearly with increasing acid concentration or, at higher acidities, with the Hammett acidity function h0 (for acidity functions see Rochester, 1970 Cox and Yates, 1983). 

The results of these studies allow the behavior of the aromatic portion of a ligand to be predicted with some degree of confidence, if that of the free ligand is known or can be surmised. Coordination appears to have a small but definite effect on the nature of the transition state for electrophilic substitution (or its ease... 

Thiophene is far more reactive than benzene in electrophilic substitution reactions. Reaction with bromine in acetic acid has been calculated to be 1.76 x 109 times faster than with benzene (72IJS(C)(7)6l). This comparison should, of course, be treated with circumspection in view of the fact that the experimental conditions are not really comparable. Benzene in the absence of catalysts is scarcely attacked by bromine in acetic acid. More pertinent is the reactivity sequence for this bromination among five-membered aromatic heterocycles, the relative rates being in the order 1 (thiophene) and 120 (furan) or, for trifluoroacetylation, 1 (thiophene), 140 (furan), 5.3 xlO7 (pyrrole) (B-72MI31300, 72IJS(C)(7)6l). Among the five-membered heteroaromatics, thiophene is definitely the least reactive. 

The intermediate 1,5-dicarbonyl compounds of type 24 (Scheme 1) can be constructed not only on the basis of meta-alkoxy-substituted benzyl ketones (C4 + Ci synthesis, Section II,C), but also under definite conditions starting from aryl ketones (C2 + C3 synthesis). Thus, in a molecule of acylveratrole derivatives of type 79, the excess of 7r-electron density due to the presence of two ortho-methoxy groups allows such compounds to be involved in electrophilic substitutions with benzoin (73URP2 74KGS1575). 

An attempt has been made to analyse whether the electrophilicity index is a reliable descriptor of the kinetic behaviour. Relative experimental rates of Friedel-Crafts benzylation, acetylation, and benzoylation reactions were found to correlate well with the corresponding calculated electrophilicity values. In the case of chlorination of various substituted ethylenes and nitration of toluene and chlorobenzene, the correlation was generally poor but somewhat better in the case of the experimental and the calculated activation energies for selected Markovnikov and anti-Markovnikov addition reactions. Reaction electrophilicity, local electrophilicity, and activation hardness were used together to provide a transparent picture of reaction rates and also the orientation of aromatic electrophilic substitution reactions. Ambiguity in the definition of the electrophilicity was highlighted.15... 

Trifluoroacetylation of tetraamine 118 is the only definite example of electrophilic substitution on a double proton sponges203. The products of this reaction were di- 191 and tetraketones 192 isolated with 5 and 8% yields, respectively (equation 15). 

Numerous cases of C-H bond activation are known, for which the reaction mechanism cannot be definitely attributed to either typical oxidative addition to a nucleophilic metal center or to an electrophilic substitution at an electron-deficient metal ion. In some cases the mechanism is not at all clear. 

Electrophilic substitution of 3-substituted indoles could proceed in three ways (i) initial attack at a 3-position followed by 1,2-migration to the 2-position (ii) initial attack at the 3-position followed by reversal (when possible), then (iii) or (iii) direct attack at the 2-position. It has been definitely demonstrated, in the case of some irreversible substitutions, that the migration route operates, but equally it has been demonstrated that direct attack at an a position can occur. 

Electrophilic substitution This is not meant to be a definitive account of aromaticity. It will suffice if we consider only one tj of chemical reaction and two of the physical properties of benzene to demonstrate the point. 

Further and more definitive examples of electrophilic substitution reactions in the thiathiophthen series have been described. " In the parent compound, in which both 2- and 3-positions are available for attack, formylation has been proved to occur at the 3-position, as would be anticipated from earlier experimental and theoretical work. 2-t-Butyl-6a-thiathiophthen formylates in the 4-position. The thiathiophthen aldehydes show characteristic absorption bands in the i.r. at ca. 1670 cm analogous to that shown by thiophen-2-aldehyde (1673 cm ), implying electronreleasing properties at the 3- (or 4-) position. 

Probably the most important development of the past decade was the introduction by Brown and co-workers of a set of substituent constants,ct+, derived from the solvolysis of cumyl chlorides and presumably applicable to reaction series in which a delocalization of a positive charge from the reaction site into the aromatic nucleus is important in the transition state or, in other words, where the importance of resonance structures placing a positive charge on the substituent - -M effect) changes substantially between the initial and transition (or final) states. These ct+-values have found wide application, not only in the particular side-chain reactions for which they were designed, but equally in electrophilic nuclear substitution reactions. Although such a scale was first proposed by Pearson et al. under the label of and by Deno et Brown s systematic work made the scale definitive. 

An HSAB analysis of singlet carbene reactivity based on B3LYP/6-31G computations has calculated the extent of charge transfer for substituted alkenes,122 and the results are summarized in Figure 10.3 The trends are as anticipated for changes in structure of both the carbene and alkene. The charge transfer interactions are consistent with HOMO-LUMO interactions between the carbene and alkene. Similarly, a correlation was found for the global electrophilicity parameter, co, and the ANmax parameters (see Topic 1.5, Part A for definition of these DFT-based parameters).123... 

In order to gain an insight into the mechanism on the basis of the slope of a Type A correlation requires a more complicated procedure. Consider the Hammett equation. The usual statement that electrophilic reactions exhibit negative slopes and nucleophilic ones positive slopes may not be true, especially when the values of the slopes are low. The correct interpretation has to take the reference process into account, for example, the dissociation equilibrium of substituted benzoic acids at 25°C in water for which the slope was taken, by definition, as unity (p = 1). The precise characterization of the process under study is therefore that it is more or less nucleophilic than the reference process. However, one also must consider the possible influence of temperature on the value of the slope when the catalytic reaction has been studied under elevated temperatures there is disagreement in the literature over the extent of this influence (cf. 20,39). The sign and value of the slope also depend on the solvent. The situation is similar or a little more complex with the Taft equation, in which the separation of the molecule into the substituent, link, and reaction center may be arbitrary and may strongly influence the values of the slopes obtained. This problem has been discussed by Criado (33) with respect to catalytic reactions. 

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