Aromatic substitutions

In aromatic substitution of the electrophilic type, a cation or potential cation attacks the benzene ring. The transition state or intermediate, whichever it may be, has largely covalent bonds holding 

In sulfonation on the other hand, a tritium isotope effect is observed.287 Sulfonation is a reversible reaction and the fact that it is less exothermic is compatible with a slow, rate-determining dissociation of the intermediate. The transition state for the slow second step has a less covalent carbon-hydrogen bond than the ground state and hence the reaction is faster for deprotonation than for detritonation. 

Although an electrophilic reagent should and probably does form -complexes with the aromatic substrate, it is not useful to consider such complexes as intermediates. They represent points on a possible path, but only one of several possible paths, to the a-bonded transition state. If there is a complete equilibrium between the ground state, the 7r-complex, and the transition state, then the particular path taken by the 

An indication of the nature of the transition state in aromatic substitution is provided by the existence of some extrathermodynamic relationships among rate and acid-base equilibrium constants. Thus a simple linear relationship exists between the logarithms of the relative rates of halogenation of the methylbenzenes and the logarithms of the relative basicities of the hydrocarbons toward HF-BFS (or-complex equilibrium).288 270 A similar relationship with the basicities toward HC1 ( -complex equilibrium) is much less precise. The jr-complex is therefore a poorer model for the substitution transition state than is the x-complex. 

Where they do not hold, it breaks down. For example, recent work has provided new data on isomer distribution that fails to fit the previous correlations with the dipole moment of the reagent aromatic compound.290 

Intramolecular substitution by arylnitrenes has been known for a long time and the cyclization of o-azidobiphenyls to carbazoles is representative of an important series of nitrene reactions that yield heterocycles. Only fairly recently has an intermolecular counterpart of these reactions been observed. Originally when phenyl azide was thermolyzed in benzene only azobenzene (11%), aniline (18%), and tars were obtained, and no diphenylamine was found. Abramovitch considered that phenylnitrene is not sufficiently electrophilic to attack benzene, so he decomposed a series of aryl azides (bearing strongly electron-withdrawing substituents, NO2, CN, CF3) in solvents activated 

The question arose as to whether the formation of diarylamines involved a direct substitution or occurred via the prior formation and subsequent ring opening of an aziridine intermediate. The very electrophilic pen-tafluorophenylnitrene was generated by the deoxygenation of nitrosopen-tafluorobenzene in anisole at low temperature in an attempt to resolve this question  

Further support for the notion that arylnitrenes need to be much more electrophilic than phenylnitrene to accomplish aromatic substitution comes from the work of Huisgen. 4,5-Dimethyl-2-pyrimidinylnitrene (P3T-N) readily gives substitution with activated aromatics (e.g., naphthalene, anthracene, anisole, and others)  

Even benzene undergoes substitution with very electrophilic arylnitrenes, and in one case the intermediate azepine has been trapped using TCNE  

Tetrafluoropyridinylnitrene, perhaps the most electrophilic arylnitrene yet generated, gives the highest yield and its other reactions, too, are more reminiscent of carbethoxy and sulphonylnitrenes.  

The chemistry of aromatic systems is dominated by the enhanced stability associated with the presence of a cyclic conjugated system containing 4n 

The enhanced stability arising from the property of aromaticity is known as the resonance energy and for benzene this is 150.6 kJ mok.  

In considering the aromatic ring as a functional group, we have to examine the influence of substituents on the overall electron density of the aromatic ring, and their effect at specific sites (see 4.1 and 4.2). Secondly, we have to consider the influence of these substituents on the Wheland intermediate. 

There are other reactions of aromatic compounds, such as metalla-tion reactions, which involve the C-H o-system. 

Substituents fall into a number of groups. There are those which activate the ring by electron donation and can also stabilize the Wheland intermediate. Secondly, there are those which deactivate the ring by electron withdrawal, but their lone pairs can stabilize a Wheland intermediate. Finally, there are substituents which both deactivate the ring and destabilize the Wheland intermediate. 

Aromatic electrophilic substitution is used commercially to produce styrene polymers with ion-exchange properties by the incorporation of sulfonic acid or quaternary ammonium groups [Brydson, 1999 Lucas et al., 1980 Miller et al., 1963]. Crosslinked styrene-divinyl-benzene copolymers are used as the starting polymer to obtain insoluble final products, usually in the form of beads and also membranes. The use of polystyrene itself would yield soluble ion-exchange products. An anion-exchange product is obtained by chloromethylation followed by reaction with a tertiary amine (Eq. 9-38) while sulfonation yields a cation-exchange product (Eq. 9-39)  

Natural rubber and other 1,4-poly-1,3-dienes are cyclized by treatment with strong protonic acids or Lewis acids [Golub, 1969 Subramaniam, 1988]. The reaction involves protonation of the double bond (Eq. 9-40) followed by cyclization via attack of the carhocation on the double bond of an adjacent monomer unit (Eq. 9-41). Some bicyclic and polycyclic 

Cyclization is a key reaction in the production of carbon fibers from polyacrylonitrile (PAN) (acrylic fiber see Sec. 3-14d-2). The acrylic fiber used for this purpose usually contains no more than 0.5-5% comonomer (usually methyl acrylate or methacrylate or methacrylic acid). Highly drawn (oriented) fibers are subjected to successive thermal treatments—initially 200-300°C in air followed by 1200-2000°C in nitrogen [Riggs, 1985]. PAN undergoes cyclization via polymerization through the nitrile groups to form a ladder structure (XXVII). Further reaction results in aromatization to the polyquinizarine structure (XXVIII) 

Other polymers undergo cyclization, but there are no commercial applications. Poly (methacrylic acid) cyclizes by anhydride formation and poly(methyl vinyl ketone) by condensation (with dehydration) between methyl and carbonyl groups. 

Hydrogenation of double bonds is practiced with some elastomers such as SBR and NBR to increase high temperature and oxidative resistance [Hsieh, 1998 Hsieh and Quirk, 1996, Wrana et al., 2001], Only partial hydrogenation is performed since some double bonds are required to achieve the subsequent crosslinking required to achieve elastic behavior. 

The introduction or replacement of substituents on aromatic rings by substitution reactions is one of the most fundamental transformations in organic chemistry. On the basis of the reaction mechanism, these substitution reactions can be divided into (a) electrophilic, (b) nucleophilic, (c) radical, and (d) transition metal catalyzed. In this chapter we consider the electrophilic and nucleophilic substitution mechanisms. Radical substitutions are dealt with in Chapter 11 and transition metal-catalyzed reactions are discussed in Chapter 9 of Part B. 

In Chapter 1 it was stated that the principal reaction of benzene and its derivatives is substitution rather than addition. Indeed, electrophilic substitution in aromatic systems is one of the most important reactions in chemistry and has many commercial applications. 

The 7i-electron cloud above and below the plane of the benzene ring is a source of electron density and confers nucleophilic properties on the system. Thus, reagents that are deficient in electron density, electrophiles, are likely to attack, whilst electron-rich nucleophiles should be repelled and therefore be unlikely to react. Furthermore, in electrophilic substitution the leaving group is a proton, but in nucleophilic substitution it is a hydride ion, H the former process is energetically more favourable. In fact, nucleophilic aromatic substitution is not common, but it does occur in certain circumstances. 

The carbocation generated by the addition of an electrophile to an alkene is destroyed in the second step by the addition of a nucleophilic species  

Both carbon atoms become sp hybridized and the double bond is lost. A similar second step in aromatic molecules would result In destruction of the resonance-stabilized system and therefore does not occur. 

The hybridization state of the carbon atom that is attacked changes from sp to sp and the planar aromatic system is destroyed. An unstable carbocation is simultaneously produced and so it is clear that this step is energetically unfavourable. It is therefore the slower step of the sequence. 

In the second step, a proton is abstracted by a basic species present in the reaction mixture. The attacked carbon atom reverts to sp2 hybridization and planarity and aromaticity are restored. This fast step is energetically favourable and is regarded as the driving force for the overall process. The product is a substituted benzene derivative. 

Most examples of electrophilic aromatic substitution proceed by this sequence of events  

These reactions give the retrosynthetically useful transform  

In many ways, the principles of substitution, elimination, and addition converge in aromatic systems in what is genetically called aromatic substitution.256 Addition to electrophilic centers, substitution of carbocations, nucleophilic displacement, and elimination of leaving groups are all mechanistic features of various aromatic substitution reactions. 

Chapter 2. Acids, Bases, Functional Group Exchanges 

When an unactivated aryl halide (333) is treated with a very strong base, an elimination reaction is possible that generates an intermediate called a benzyne (336). Benzyne is electron deficient and will be attacked by nucleophiles in a reaction that opens the Jt bond not part of the aromatic cloud, and produces a new carbanion (337). Protonation completes the sequence to give the aromatic substitution product 338. 

Section 2.1 l.B will deal with the most fundamental aromatic substitution reactions. This subject is usually presented in detail in undergraduate textbooks. The treatment varies greatly with the text, however, and leading references are usually absent. This discussion is intended only as a brief review. 

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The nitration, sulphonation and Friedel-Crafts acylation of aromatic compounds (e.g. benzene) are typical examples of electrophilic aromatic substitution. 

This led to the introduction of the concepts of inductive and resonance effects and to the establishment of the mechanism of electrophilic aromatic substitution. 

A more detailed classification of chemical reactions will give specifications on the mechanism of a reaction electrophilic aromatic substitution, nucleophilic aliphatic substitution, etc. Details on this mechanism can be included to various degrees thus, nucleophilic aliphatic substitutions can further be classified into Sf l and reactions. However, as reaction conditions such as a change in solvent can shift a mechanism from one type to another, such details are of interest in the discussion of reaction mechanism but less so in reaction classification. 

The student when preparing disubstituted benzenes should bear in mind VorlSnder s Rules of aromatic substitution, which form the most convenient modification of Crum Brown s earlier rules. Vorl5nder stated that if a substance... 

The course of aromatic substitution has been placed on a more scientific basis by the following rules of Hammick and Illingworth (jfour. Chem. Soc., 930. 2358), If a monosubstituted benzene derivative has the formula CgHsXY, where X is the atom joined to the benzene ring and Y is an atom or group of atoms attached to X, then —... 

The mechanism of the aromatic substitution may involve the attack of the dectrophilic NOj" " ion upon the nucleophilic aromatic nucleus to produce the carboniiim ion (I) the latter transfers a proton to the bisulphate ion, the most basic substance in the reaction mixture... 

A brief account of aromatic substitution may be usefully given here as it will assist the student in predicting the orientation of disubstituted benzene derivatives produced in the different substitution reactions. For the nitration of nitrobenzene the substance must be heated with a mixture of fuming nitric acid and concentrated sulphuric acid the product is largely ni-dinitrobenzene (about 90 per cent.), accompanied by a little o-dinitrobenzene (about 5 per cent.) which is eliminated in the recrystallisation process. On the other hand phenol can be easily nitrated with dilute nitric acid to yield a mixture of ortho and para nitrophenols. It may be said, therefore, that orientation is meta with the... 

The following rules, relating to the course of aromatic substitution (Hammick and Illingworth, 1930), will be found useful ... 

Aromatic Substitution (Carey Sundberg, Chapter 11) Intramolecular Wittig Reaction Sigmatropic Rearrangements... 

These studies at the same time aroused my interest in the mechanistic aspects of the reaetions, including the complexes of RCOF and RF with BF3 (and eventually with other Lewis acid fluorides) as well as the complexes they formed with aromatics. 1 isolated for the first time at low temperatures arenium tetrafluoroborates (the elusive (T-complexes of aromatic substitutions), although I had no means to pursue their structural study. Thus my long fascination with the chemistry of car-bocationic complexes began. 

It looks as though we can get B from A (which is used in frame 247) and so the nitro group is the obvious source of the amino group. It will also allow us to hydrolyse one ether specifically by nucleophilic aromatic substitution. 

The development of theoretical organic chemistry was intimately entwined with the development of that particular aspect of it concerned with aromatic substitution the history of this twin growth has been authoritatively traced. Only the main developments, particularly as they affect nitration, will be noted here. 

For the electronic theory of organic chemistry 1926 was the annus mirabilis, and, particularly, as they applied to aromatic substitution, the... 

These parameters, q. and are two of a number of such parameters whose values are used as indices of reactivity in electrophilic aromatic substitution. " However, they are not completely independent quantities as the following discussion shows. 

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. ... 

Brown noticed that the reactivities of toluene relative to benzene in aromatic substitutions were proportional to the ratios in which toluene underwent p- and -substitutions. This point is illustrated in table 7.3. 

The selectivity relationship merely expresses the proportionality between intermolecular and intramolecular selectivities in electrophilic substitution, and it is not surprising that these quantities should be related. There are examples of related reactions in which connections between selectivity and reactivity have been demonstrated. For example, the ratio of the rates of reaction with the azide anion and water of the triphenylmethyl, diphenylmethyl and tert-butyl carbonium ions were 2-8x10 , 2-4x10 and 3-9 respectively the selectivities of the ions decrease as the reactivities increase. The existence, under very restricted and closely related conditions, of a relationship between reactivity and selectivity in the reactions mentioned above, does not permit the assumption that a similar relationship holds over the wide range of different electrophilic aromatic substitutions. In these substitution reactions a difficulty arises in defining the concept of reactivity it is not sufficient to assume that the reactivity of an electrophile is related... 

Nitration in sulphuric acid is a reaction for which the nature and concentrations of the electrophile, the nitronium ion, are well established. In these solutions compounds reacting one or two orders of magnitude faster than benzene do so at the rate of encounter of the aromatic molecules and the nitronium ion ( 2.5). If there were a connection between selectivity and reactivity in electrophilic aromatic substitutions, then electrophiles such as those operating in mercuration and Friedel-Crafts alkylation should be subject to control by encounter at a lower threshold of substrate reactivity than in nitration this does not appear to occur. 

The development of linear free energy correlations of the rate of aromatic substitutions has been discussed ( 7.3). We record here the results of such correlations for nitration. 

The first three of a series of papers by Ridd and co-workers on Inductive and Field effects in Aromatic Substitution have appeared. Results of studies of the nitration of 4-phenylp5nidine and of 4-benzylpyridine in aqueous sulphuric acid were reported and use of the usual criteria (para 8.2) showed that in each case the conjugate acid was the species undergoing nitration. The values of where fm refers to the corresponding homocyclic compound (biphenyl or diphenylmethane) when plotted against r, the distance between the... 

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

Reduction of arenes by catalytic hydrogenation was described m Section 114 A dif ferent method using Group I metals as reducing agents which gives 1 4 cyclohexadiene derivatives will be presented m Section 1111 Electrophilic aromatic substitution is the most important reaction type exhibited by benzene and its derivatives and constitutes the entire subject matter of Chapter 12... 

We call this reaction electrophihc aromatic substitution, it is one of the fundamental processes of organic chemistry... 

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