Benzene derivatives reactions

A number of kinetic studies on hydrogen exchange of derivatives of furan,53 thiophene,53-58 pyrrole,53 selenophene,59 imidazole,60 oxazole,60 thiazole,80 and indole61 have been reported. The kinetic picture is the same as for benzene derivatives reactions follow pseudo first-order kinetics and the k1 values increase markedly as the acidity of the medium increases. 

Properties Colorless liquid. Decomposed by hot water stable to cold water. D 1.23 (15C), bp 71.4C, vapor d 3.9 (air = 1), flash p54F (12.2C). Soluble in methanol alcohol, ether, and benzene. Derivation Reaction between methanol and carbonyl chloride. 

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. 

Let us illustrate this with the example of the bromination of monosubstituted benzene derivatives. Observations on the product distributions and relative reaction rates compared with unsubstituted benzene led chemists to conceive the notion of inductive and resonance effects that made it possible to explain" the experimental observations. On an even more quantitative basis, linear free energy relationships of the form of the Hammett equation allowed the estimation of relative rates. It has to be emphasized that inductive and resonance effects were conceived, not from theoretical calculations, but as constructs to order observations. The explanation" is built on analogy, not on any theoretical method. 

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... 

CHjO), + 3CH,OH + 3HC1 —> 3CH3OCH2CI + 3H,0 Monoalkyl benzene derivatives yield para chloromethjd compounds, frequently accompanied by small amounts of the ortho isomeride. The reaction is similar in some respects to that of Friedel and Crafts. Chloromethylation is of great value in synthetic work as the —CH,C1 group can be converted into other groups such as —CH,OH, —CHO, —CH,OR, —CH,CN, —CH,CH(COOC.,Hs)2 and —CH,. 

Simple cyclobutanes do not readily undergo such reactions, but cyclobutenes do. Ben-zocyclobutene derivatives tend to open to give extremely reactive dienes, namely ortho-c]uin(xlimethanes (examples of syntheses see on p. 280, 281, and 297). Benzocyclobutenes and related compounds are obtained by high-temperature elimination reactions of bicyclic benzene derivatives such as 3-isochromanone (C.W. Spangler, 1973, 1976, 1977), or more conveniently in the laboratory, by Diels-Alder reactions (R.P. Thummel, 1974) or by cycliza-tions of silylated acetylenes with 1,5-hexadiynes in the presence of (cyclopentadienyl)dicarbo-nylcobalt (W.G, Aalbersberg, 1975 R.P. Thummel, 1980). 

This reaction sequence is much less prone to difficulties with isomerizations since the pyridine-like carbons of dipyrromethenes do not add protons. Yields are often low, however, since the intermediates do not survive the high temperatures. The more reactive, faster but less reliable system is certainly provided by the dipyrromethanes, in which the reactivity of the pyrrole units is comparable to activated benzene derivatives such as phenol or aniline. The situation is comparable with that found in peptide synthesis where the slow azide method gives cleaner products than the fast DCC-promoted condensations (see p. 234). 

Reaction that can be carried out by the oxidative coupling of radicals may also be initiated by irradiation with UV light. This procedure is especially useful if the educt contains oleflnic double bonds since they are vulnerable to the oxidants used in the usual phenol coupling reactions. Photochemically excited benzene derivatives may even attack ester carbon atoms which is generally not observed with phenol radicals (I. Ninoraiya, 1973 N.C. Yang, 1966). 

Benzoic acid and naphthoic acid are formed by the oxidative carbonylation by use of Pd(OAc)2 in AcOH. t-Bu02H and allyl chloride are used as reoxidants. Addition of phenanthroline gives a favorable effect[360], Furan and thiophene are also carbonylated selectively at the 2-position[361,362]. fndole-3-carboxylic acid is prepared by the carboxylation of 1-acetylindole using Pd(OAc)2 and peroxodisulfate (Na2S208)[362aj. Benzoic acid derivatives are obtained by the reaction of benzene derivatives with sodium palladium mal-onate in refluxing AcOH[363]. 

The benzene derivative 401 by the intermolecular insertion of acrylate[278], A formal [2 + 2+2] cycloaddition takes place by the reaction of 2-iodonitroben-zene with the 1,6-enyne 402. The neopentylpalladium intermediate 403 undergoes 6-endo-lrig cyclization on to the aromatic ring to give 404[279],... 

The benzene derivative 409 is synthesized by the Pd-catalyzed reaction of the haloenyne 407 with alkynes. The intramolecular insertion of the internal alkyne, followed by the intermolecular coupling of the terminal alkyne using Pd(OAc)2, Ph3P, and Cul, affords the dienyne system 408, which cyclizes to the aromatic ring 409[281]. A similar cyclization of 410 with the terminal alkyne 411 to form benzene derivatives 412 and 413 without using Cul is explained by the successive intermolecular and intramolecuar insertions of the two triple bonds and the double bond[282]. The angularly bisannulated benzene derivative 415 is formed in one step by a totally intramolecular version of polycycli-zation of bromoenediyne 414[283,284],... 

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. 

Partial rate factors may be used to estimate product distributions in disubstituted benzene derivatives The reactivity of a particular position in o bromotoluene for example is given by the product of the partial rate factors for the corresponding position in toluene and bromobenzene On the basis of the partial rate factor data given here for Fnedel-Crafts acylation predict the major product of the reaction of o bromotoluene with acetyl chlonde and aluminum chloride... 

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). 

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. 

The work of Hyatt on cyclotriveratrylene—derived octopus molecules contrasts with this. Of course, these species have the advantage of ligand directionality absent in the benzene-derived octopus molecules. Except for the shortest-armed of the species (i.e., n = 1), all of the complexing agents (i.e., n = 2—4) were capable of complexing alkali metal cations. Synthesis of these species was accomplished as indicated below in Eq. (7.7). These variations of the original octopus molecules were also shown to catalyze the reaction between benzyl chloride and potassium acetate in acetonitrile solution and to effect the Wittig reaction between benzaldehyde and benzyltriphenylphos-phonium chloride. 

A particularly interesting case is the reaction of the enamino ketone (47), which under similar conditions gives the intermediate product (80), which then undergoes cyclization to the benzene derivative dimethyl 3-pyrrolidino-5-methyl phthalate (81). 

Although the application of the Hammett equation to side-chain reactions of disubstituted benzene derivatives (1) is relatively straightforward, the introduction of a heteroatom somewhere in the aromatic... 

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. 

The problems encountered in any attempt to treat the transmission of the effects of one substituent in a disubstituted heterocycle through the heterocyclic nucleus to a reaction site in the other substituent (i.e. the side-chain) are enormous, and it is consequently not surprising that relatively little work has been done in this area. First, while in benzene derivatives there are three positions, i.e. three relations between substituent and reacting side-chain to be considered, the number of complexities is much greater in heterocycles. Thus, e.g., in pyridine alone, after elimination of the orientations involving a vicinal relationship between substituent R and the side-chain Y to which no Hammett-type relation is likely to be applicable, the following cases should be considered ... 

Whereas only one dehydrobenzene, benzyne, has been detected, two pyridynes are possible. Thus, the scheme we can write ab initio for the action of a nucleophile on the isomeric monosubstituted derivatives of pyridine involving 2,3- (26) and/or 3,4-pyridyne (31) is more complicated than that for the analogous reaction of the corresponding benzene derivative. The validity of this scheme can be checked using data available in the hterature on reactions of halogenopyridines with potassium amide and hthium piperidide involving pyridynes. 

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. 

Recently, Kochetkov and Khomutova have reported on the mercuration of isoxazoles with mercuric acetate. The reaction occurs quite smoothly, more readily than for benzene derivatives and results in a 90-100% yield of 4-acetoxymercury derivatives (74) whose structure was proved by converting them to known 4-bromoisoxazoles (75). Under these reaction conditions isoxazole itself is oxidized by mercuric acetate, mercurous salts being thereby produced. 

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