Benzene derivatives substitution reactions

Quite early on (p. 361) in this discussion of linear free energy relationships consideration was restricted to the side-chain reactions of m- and p-substituted benzene derivatives. The reactions of o-substituted benzene derivatives, and indeed of aliphatic compounds, were excluded because of the operation of steric and other effects, which led to non-linear, or even to apparently random, plots. 

In contrast with the behavior of the benzene derivatives, the reaction of a-cyanoalkyl (principally cyanomethyl) ions with other aromatic substrates, leads mainly to the expected substitution products, ArCH(R)CN (equation 39). This difference in behavior (not as pronounced in the thiophene system)132 has been rationalized by molecular orbital considerations.18,41,133 Examples of these successful syntheses are collected in Table 3. 

Phosphinine and its derivatives are clearly aromatic however, they are considerably more reactive than benzene. The most significant influence on the reactivity of these molecules is the presence of the lone pair on phosphorus, and two significant reactions are its complexation with a variety of metals, and nucleophilic attack to form (ultimately) A5-phosphorins. The 71-system can undergo [4+2] cycloadditions, under milder conditions than benzene. Electrophilic substitution reactions on carbon are considered to be impossible <2001CRV1229>. 

During their work on the arylation of aromatic compounds by substitution, Fujiwara, et al. observed biaryl formation when aromatic compounds were placed in the presence of olefin-palladium complexes and silver nitrate.80 Developing this reaction as a method for biphenyl synthesis, these authors showed that the more stable the olefin-palladium complex was, the lower the yield. Ethylene dichloropalladium proved to be the best choice, when used with silver nitrate. However, the reaction required stoichiometric amounts of both catalysts (Scheme 10.47). Benzene derivatives substituted by electron-donating or -withdrawing groups reacted as well, but a mixture of regioisomers was produced, except for nitrobenzene, which only gave m,m -dinitrobiphenyl. 

We finish Chapter 18 by learning some additional reactions of substituted benzenes that greatly expand the ability to synthesize benzene derivatives. These reactions do not involve the benzene ring itself, so they are not further examples of electrophilic aromatic substitution. In Seaion 18.13 we return to radical halogenation, and in Section 18.14 we examine useful oxidation and reduction reactions. 

The variety of synthetic possibilities which may be envisaged should result in the rapid development of these reactions. Note that using a different principle related to the aromatic trimerization of alkynes by cobalt (Heck, 1969), benzene derivatives substituted in well defined positions (CXXIII) may be obtained in moderate yields (13-59%) by reaction of cobaltocy-clopentadienyls (CXXII) (Wakatsuki et al, 1974) with alkynes according to Scheme 12. 

A point in case is provided by the bromination of various monosubstituted benzene derivatives it was realized that substituents with atoms carrying free electron pairs bonded directly to the benzene ring (OH, NH2, etc) gave 0- and p-substituted benzene derivatives. Furthermore, in all cases except of the halogen atoms the reaction rates were higher than with unsubstituted benzene. On the other hand, substituents with double bonds in conjugation with the benzene ring (NO2, CHO, etc.) decreased reaction rates and provided m-substituted benzene derivatives. 

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... 

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]. 

Piperazinothiazoies (2) were obtained by such a replacement reaction, Cu powder being used as catalyst (25. 26). 2-Piperidinothiazoles are obtained in a similar way (Scheme 2) (27). This catalytic reaction has been postulated in the case of benzene derivatives as a nucleophilic substitution on the copper-complexed halide in which the halogen possesses a positive character by coordination (29). For heterocyclic compounds the coordination probably occurs on the ring nitrogen. 

Electrophilic substitution of thiophene occurs largely at the 2-position and the reactivity of the ring is greater than that of benzene. 3-Substituted derivatives are generally prepared by indirect means or through ring cyclization reactions. 

Nucleophilic Substitutions of Benzene Derivatives. Benzene itself does not normally react with nucleophiles such as haUde ions, cyanide, hydroxide, or alkoxides (7). However, aromatic rings containing one or more electron-withdrawing groups, usually halogen, react with nucleophiles to give substitution products. An example of this type of reaction is the industrial conversion of chlorobenzene to phenol with sodium hydroxide at 400°C (8). 

Reactions of acetylene and iron carbonyls can yield benzene derivatives, quinones, cyclopentadienes, and a variety of heterocycHc compounds. The cyclization reaction is useful for preparing substituted benzenes. The reaction of / fZ-butylacetylene in the presence of Co2(CO)g as the catalyst yields l,2,4-tri-/ f2 butylbenzene (142). The reaction of Fe(CO) and diphenylacetylene yields no less than seven different species. A cyclobutadiene derivative [31811 -56-0] is the most important (143—145). 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the... 

Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

In the early work, benzene formed the basis of a variety of multi-armed structures. Analogs bearing from 2—6 arms were prepared and compared for cation binding ability. The only indication of mode of synthesis for the hexa-substituted benzene derivative is that it was obtained on reaction of benzene-hexakis(methanethiol) and l-bromo-3,6,9-trioxatridecane . The reaction is illustrated in Eq. (7.6), below, devoid of reaction conditions and yields which were not specified. 

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. 

It should be pointed out that the existence of stable structures of the intermediate-complex type (also known as a-complexes or Wheland complexes) is not of itself evidence for their being obligate intermediates in aromatic nucleophilic substitution. The lack of an element effect is suggested, but not established as in benzene derivatives (see Sections I,D,2 and II, D). The activated order of halogen reactivity F > Cl Br I has been observed in quantita-tivei36a,i37 Tables II, VII-XIII) and in many qualitative studies (see Section II, D). The reverse sequence applies to some less-activated compounds such as 3-halopyridines, but not in general.Bimolecular kinetics has been established by Chapman and others (Sections III, A and IV, A) for various reactions. 

Only a-substituted quinoxalines are discussed because the reactions of 5- and 6-substituted quinoxalines are similar to those of the corresponding benzene derivatives. 

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