Specific Electrophilic Substitution Reactions

At this point, we focus on specific eiectrophiiic substitution reactions. The kinds of data that have been especiaiiy pertinent in eiucidating mechanistic detaii inciude iinear free-energy reiationships, kinetic studies, isotope effects, and seiectivity patterns. In generai, the basic questions to be asked about each mechanism are (1) What is the active eiectrophiie (2) Which step in the generai mechanism for EAS is rate determining (3) What are the orientation and seiectivity patterns  

A substantiai body of data inciuding reaction kinetics, isotope effects, and structure-reactivity reiationships is avaiiabie for aromatic nitration. As anticipated from the generai mechanism for eiectrophiiic substitution, there are three distinct steps. Conditions under which each of the first two steps is rate determining have been recognized. The third step is usuaiiy very fast. 

Attack on the aromatic ring forming the cationic intermediate 

The existence of the nitronium ion in sulfiiric-nitric acid mixtures can be demonstrated by both cryoscopic measurements and spectroscopy. An increase in the strong acid concentration increases the rate of reaction by shifting the equilibrium of Step 1 to the right. Addition of a nitrate salt has the opposite effect by suppressing the preequilibrium dissociation of nitric acid. It is possible to prepare crystalline salts of nitronium ions such as nitronium tetrafluoroborate. Solutions of these salts in organic solvents nitrate aromatic compounds rapidly.  

There are three general types of kinetic situations that have been observed for aromatic nitration. Aromatics of modest reactivity exhibit second-order kinetics in mixtures of nitric acid with the stronger sulfuric or perchloric acid. Under these 

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In our research, three chemical modification approaches were investigated bromination, sulfonylation, and acylation on the aromatic ring. The specific objective of this paper is to present the chemical modification on the PPO backbone by a variety of electrophilic substitution reactions and to examine the features that distinguish modified PPO from unmodified PPO with respect to gas permeation properties, polymer solubility and thermal behavior. 

Tyrosine may be targeted specifically for modification through its phenolate anion by acylation, through electrophilic reactions such as the addition of iodine or diazonium ions, and by Mannich condensation reactions. The electrophilic substitution reactions on tyrosine s ring all occur at the ortho position to the —OH group (Figure 1.11). Most of these reactions proceed effectively only when tyrosine s ring is ionized to the phenolate anion form. 

Substitution reactions allow the aromatic sextet of tt electrons to be regenerated after attack by the electrophile has occurred. Electrophiles attack the tt system of benzene to form a delocalized nonaromatic carboca-tion (arenium ion or ct complex). Some specific examples of electrophilic substitution reactions of benzene are summarized below (see Chapter 5). 

The protonation studies are of interest in another connection. If protonation of metallocenes can be considered to be a simple form of electrophilic attack, it is possible that other types of electrophilic substitution reactions may proceed through initial coordination of the electrophile with the central metal atom (14, 93). The mechanism of acylation of metallocenes may therefore be more complex than might be expected by analogy to similar reactions of benzenoid compounds. Clearly more studies are needed along these lines, better to define specific metal effects on the properties and reactions of these remarkable compounds. 

In general, free ligand pyridines show a great reluctance to take part in electrophilic substitution reactions. Forcing conditions are frequently required, and low yields and specificity are normally observed. In principle, co-ordination to a metal ion capable of back-donation should increase the tendency for electrophilic attack, since back-donation results in an increase in n electron density. 

Open-chain SE2 reactions are special cases of electrophilic attack on a C=C double bond in the sense 5.132, with attack specifically at C-3, and followed by the loss of an electrofugal group from the stereogenic centre. The most studied of these are the electrophilic substitution reactions of stereodefined allylsilanes,... 

Mills and Nixon found that an annelated small ring had directional capability in the electrophilic substitution reactions talcing place at the benzene fragment [1]. More specifically, they established that the free /9-position in /1-hydroxyindan is more susceptible to electrophilic substitution than the a-site (Fig. 1) as revealed by bromine or diazo group substitutions. The opposite should be the case in /9-hydroxytetralin. 

Phenols are highly activated towards electrophilic attack, which occurs readily at the 2- and 4-positions. For example, phenol reacts with bromine at room temperature in ethanol and in the absence of a catalyst to give 2,4,6-tribromophenol. Other electrophilic substitution reactions such as nitration, sulfonation, Friedel-Crafts, chlorination and nitrosation also proceed readily and hence care is needed to ensure multisubstitution does not occur. Protection of specific ring positions can also prevent unwanted substitution. Relatively mild conditions are usually employed. 

The reason for the failure of the above methods to furnish the desired specific methoxy substituted derivatives lies in the mechanism of the above reactions. These, being typical acid catalysed aromatic electrophilic substitution reactions, are well known to opara position than at the ortho. In the cyclisation reaction, the preference to cyclisation at the para position is even greater, quite often almost exclusive. 

Electrophilic substitution is the classical reaction which is always cited as characterizing aromatic compounds as distinguished from olefinic compounds. Among the many electrophilic substitution reactions, the Friedel-Crafts synthesis has played a central role in both practical and theoretical organic chemistry. The substitution of one hydrogen isotope by another, e.g., the substitution of D+ for H+, is a specific case of conventional aromatic substitution. 

The tricyclic system has also been constructed from an indole via electrophilic substitution reactions at positions 3 and/or 4. Synthesis of tricyclic ergoline synthons from 5-methoxy-lH-indole-4-carboxaldehyde has been described [45]. Sodium cyanoborohydride mediated reductive amination provided easy access to l,3,4,5-tetrahydrobenz[cd]indole-4-amines, compounds which show specificity for serotonin and dopamine receptors. 

The reaction between SO3 and the aromatic substrate is an electrophilic substitution reaction of the second order, and in the specific case of LAB, this reaction proceeds in accordance with the mechanism shown in Figure 5.5 [3]. 

Because of the limitations of specific electrophilic functionalization reactions, there has been a need to develop general functionalization reactions which proceed efficiently to introduce a variety of different functional groups. One of the most useful general functionalization reactions which has been developed is the use of ring-substituted 1,1-diphenylethylenes as described in the following section. 

Chapter 15 described the use of this transformation in the preparation of monosubstituted benzenes. In this chapter we analyze the effect of such a first substituent on the reactivity and regioselectivity (orientation) of a subsequent electrophilic substitution reaction. Specifically, we shall see that substituents on benzene can be grouped into (1) activators (electron donors), which generally direct a second electrophilic attack to the ortho and para positions, and (2) deactivators (electron acceptors), which generally direct electrophiles to the meta positions. We will then devise strategies toward the synthesis of polysubstituted arenes, such as the analgesics depicted on the previous page. 

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 applicability of the two-parameter equation and the constants devised by Brown to electrophilic aromatic substitutions was tested by plotting values of the partial rate factors for a reaction against the appropriate substituent constants. It was maintained that such comparisons yielded satisfactory linear correlations for the results of many electrophilic substitutions, the slopes of the correlations giving the values of the reaction constants. If the existence of linear free energy relationships in electrophilic aromatic substitutions were not in dispute, the above procedure would suffice, and the precision of the correlation would measure the usefulness of the p+cr+ equation. However, a point at issue was whether the effect of a substituent could be represented by a constant, or whether its nature depended on the specific reaction. To investigate the effect of a particular substituent in different reactions, the values for the various reactions of the logarithms of the partial rate factors for the substituent were plotted against the p+ values of the reactions. This procedure should show more readily whether the effect of a substituent depends on the reaction, in which case deviations from a hnear relationship would occur. It was concluded that any variation in substituent effects was random, and not a function of electron demand by the electrophile. ... 

Introduction of substituents on the carbocyclic ring relies primarily on electrophilic substitution and on organometallic reactions. The former reactions are not under strong regiochcmical control. The nitrogen atom can stabilize any of the C-nng o-complexes and both pyrrole and benzo ring substituents can influence the substitution pattern, so that the position of substitution tends to be dependent on the specific substitution pattern (Scheme 14.1). 

Now that we ve outlined the general mechanism for electrophilic aromatic substitution we need only identify the specific electrophile m the nitration of benzene to have a fairly clear idea of how the reaction occurs... 

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