Aromatic substitution, general mechanism

The scope of electrophilic aromatic substitution is quite large both the aromatic com pound and the electrophilic reagent are capable of wide variation Indeed it is this breadth of scope that makes electrophilic aromatic substitution so important Elec trophilic aromatic substitution is the method by which substituted derivatives of benzene are prepared We can gam a feeling for these reactions by examining a few typical exam pies m which benzene is the substrate These examples are listed m Table 12 1 and each will be discussed m more detail m Sections 12 3 through 12 7 First however let us look at the general mechanism of electrophilic aromatic substitution... 

If the Lewis base ( Y ) had acted as a nucleophile and bonded to carbon the prod uct would have been a nonaromatic cyclohexadiene derivative Addition and substitution products arise by alternative reaction paths of a cyclohexadienyl cation Substitution occurs preferentially because there is a substantial driving force favoring rearomatization Figure 12 1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution For electrophilic aromatic substitution reactions to... 

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... 

Figure 12 3 adapts the general mechanism of electrophilic aromatic substitution to the nitration of benzene The first step is rate determining m it benzene reacts with nitro mum ion to give the cyclohexadienyl cation intermediate In the second step the aro maticity of the ring is restored by loss of a proton from the cyclohexadienyl cation... 

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

Cycloalkene (Section 5 1) A cyclic hydrocarbon characterized by a double bond between two of the nng carbons Cycloalkyne (Section 9 4) A cyclic hydrocarbon characterized by a tnple bond between two of the nng carbons Cyclohexadienyl anion (Section 23 6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism It is represented by the general structure shown where Y is the nucleophile and X is the leaving group... 

Scheme 10.2. Generalized Mechanism for Electrophilic Aromatic Substitution...

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

A substantial body of data, including reaction kinetics, isotope effects, and structure-reactivity relationships, has permitted a thorough understanding of the steps in aromatic nitration. As anticipated from the general mechanism for electrophilic substitution, there are three distinct steps ... 

In general, the reaction between a phenol and an aldehyde is classified as an electrophilic aromatic substitution, though some researchers have classed it as a nucleophilic substitution (Sn2) on aldehyde [84]. These mechanisms are probably indistinguishable on the basis of kinetics, though the charge-dispersed sp carbon structure of phenate does not fit our normal concept of a good nucleophile. In phenol-formaldehyde resins, the observed hydroxymethylation kinetics are second-order, first-order in phenol and first-order in formaldehyde. 

Figure 12.1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution. For electrophilic aromatic substitution reactions to... 

Cyclohexadienyl anion (Section 23.6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism. It is represented by the general structure shown, where Y is the nucleophile and X is the leaving group. 

There are many other kinds of electrophilic aromatic substitutions besides bromination, and all are thought to occur by the same general mechanism. Let s look at some of these other reactions briefly. 

It is regrettable that the evidence afforded by reaction kinetics is rarely, if ever, uniquely consistent with a single mechanism or a single explanation. The results for nucleophilic aromatic substitution reactions are no exception. Legitimate questions can be raised with respect to the extent to which observations made on a particular system permit generalization to other systems. Even for the specific systems studied points of detail arise, and choices have to be made where alternatives are possible. Every such choice introduces an element of uncertainty and imposes a limitation on the extent to which the reaction mechanism is, in fact, known. 

It has also been argued10,40 that the second mechanism (rapid, reversible interconversion of II and IV) cannot be general. The basis for this contention is the fact that electrophilic catalysis is rare in nucleophilic aromatic substitution of non-heterocyclic substrates, an exception being the 2000-fold acceleration by thorium ion of the rate of reaction of 2,4-dinitrofluorobenzene with thiocyanate... 

Resole syntheses entail substitution of formaldehyde (or formaldehyde derivatives) on phenolic ortho and para positions followed by methylol condensation reactions which form dimers and oligomers. Under basic conditions, pheno-late rings are the reactive species for electrophilic aromatic substitution reactions. A simplified mechanism is generally used to depict the formaldehyde substitution on the phenol rings (Fig. 7.21). It should be noted that this mechanism does not account for pH effects, the type of catalyst, or the formation of hemiformals. Mixtures of mono-, di-, and trihydroxymethyl-substituted phenols are produced. 

The difference in reactivity is not as much as is generally observed in nucleophilic aromatic substitution in solution by an addition-elimination mechanism (ref. 25). Substituents with electron withdrawing capabilities enhance the rate of the reaction therefore decabromobiphenyl ether reacts nearly 2 times faster than 1,2,3,4-tetrabromodibenzodioxin. 

The textbook definition of a reactive intermediate is a short-lived, high-energy, highly reactive molecule that determines the outcome of a chemical reaction. Well-known examples are radicals and carbenes such species cannot be isolated in general, but are usually postulated as part of a reaction mechanism, and evidence for their existence is usually indirect. In thermal reactivity, for example, the Wheland intermediate (Scheme 9.1) is a key intermediate in aromatic substitution. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

That cytochrome P450-catalyzed aromatic hydroxylation proceeded by a mechanistic pathway that was generally consistent with the rules of electrophilic aromatic substitution was never in doubt because of the abundance of experimental evidence supporting this conclusion. Despite the certainty of product formation, establishing the exact mechanism that defines the pathway has proved to be difficult. 

The title system in AN forms a homogeneous solution. The generation of NO cation takes place. As known, NO is a remarkable, diverse reagent not only for nitrosation and nitration but also for oxidation. Kochi et al. (1973) christened a new general mechanism oxidative aromatic substitution to describe aromatic snbstitntion reactions (Kochi 1990, Bosch and Kochi 1994). This mechanism incorporates ground-state electron transfer before the substitution step (see also Skokov and Wheeler 1999). 

It should be emphasized that the wide scope of nucleophilic aromatic photosubstitution does not imply that it will work indiscriminately with any combination of aromatic compound and nucleophile. On the contrary, there are pronounced selectivities. The general picture now arising shows a field with certainly as much variability and diversification as chemists, in the course of growing experience, have learned to appreciate in the area of classical (thermal) aromatic substitution. It is one of the aims of this article to contribute to a description and understanding of the various reaction paths and mechanisms of nucleophilic aromatic photosubstitution, hopefully to the extent that valuable predictions on the outcome of the reaction in novel systems will become feasible. 

Two steps must be considered in the mechanism of homolytic acylation, in addition to the formation of the acyl radical. The first fits in with the generally accepted mechanism of homolytic aromatic substitution, that is, the addition of the acyl radical to the aromatic nucleus to give an adduct in which the unpaired electron is delocalized over the residual heteroaromatic system (u-complex 6). 

Bromination of benzene follows the same general mechanism of the electrophilic aromatic substitution. The bromine molecule reacts with FeBr3 by donating a pair of its electrons to it, which creates a more polar Br—Br bond. 

Since 1985, a major effort has been devoted to incorporating heterocyclic units within the backbone of poly(arylene etherjs (PAE). Heterocyclic units within PAE generally improve certain properties such as strength, modulus and the glass transition temperature. Nucleophilic and electrophilic aromatic substitution have been successfully used to prepare a variety of PAE containing heteorcyclic units. Many different heterocyclic families have been incorporated within PAE The synthetic approaches and the chemistry, mechanical and physical properties of PAE containing different families of heterocyclic units are discussed. Emphasis is placed on the effect variations in chemical structure (composition) have upon polymer properties. 

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