Benzenoid Substituents

The reactivity of substituents on the fused benzene rings of (benzo)pyridazine derivatives was not discussed in CHEC-I because it is little different from that of the corresponding fused carbocycles, 

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When compared to benzenoid substituents, those attached to carbon atoms of the thiazole ring behave very differently according to their position. As discussed in Section 4.19.1.1, the electron distribution in the thiazole molecule corresponds to position 2 being electron-deficient, position 4 almost neutral and position 5 slightly electron-rich. Thus 2-methyl-thiazole is appredably more reactive than toluene in reactions involving a trace of its... 

Wootton, R., Cranfield, R., Sheppey, G.C. and Goodford, P.J. (1975). Physicochemical-Activity Relationships in Practice. 2. Rational Selection of Benzenoid Substituents. LMetLChem., 18, 607-613. 

General survey Benzenoid substituents Alkyl groups Aryl substituents Carboxy substituents Oxygen substituents Amino and imino groups Thio- and thiol substituents... 

Benzenoid substituents No systematic study of benzenoid substituents has been reported. 

Physicochemical-Aaivity Relationships in Practice. 2. Rational Selection of Benzenoid Substituents. 

The material in the succeeding chapters describes both the synthesis of the indole ring and means of substituent modification which are especially important in indole chemistry. The first seven chapters describe the preparation of indoles from benzenoid precursors. Chapter 8 describes preparation of indoles from pyrroles by annelation reactions. These syntheses can be categorized by using the concept of bond disconnection to specify the bond(s) formed in the synthesis. The categories are indicated by the number and identity of the bond(s) formed. This classification is given in Scheme 1.1. 

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

When activating substituents are present in the benzenoid ring, substitution usually becomes more facile and occurs in accordance with predictions based on simple valence bond theory. When activating substituents are present in the heterocyclic ring the situation varies depending upon reaction conditions thus, nitration of 2(177)-quinoxalinone in acetic acid yields 7-nitro-2(177)-quinoxalinone (21) whereas nitration with mixed acid yields the 6-nitro derivative (22). The difference in products probably reflects a difference in the species being nitrated neutral 2(177)-quinoxalinone in acetic acid and the diprotonated species (23) in mixed acids. 

Conflicting reports on the nitration of phenazine have appeared, but the situation was clarified by Albert and Duewell (47MI21400). The early work suggested that 1,3-dinitroph-enazine could be prepared in 66% yield under standard nitration conditions however, this proved to be a mixture of 1-nitrophenazine and 1,9-dinitrophenazine (24). As with pyrazines and quinoxalines, activating substituents in the benzenoid rings confer reactivity which is in accord with valence bond predictions thus, nitration of 2-methoxy- or 2-hydroxy-phenazine results in substitution at the 1-position. 

In most cases the frequencies of substituent groups attached to these heterocycles differ little from those observed for their benzenoid counterparts. The only notable exception is the spectral behaviour of carbonyl groups attached to position 2. These have attracted much attention as they frequently give rise to doublets, and occasionally multiplets. In the case of (34), (35) (76JCS(P2)l) and (36) (76JCS(P2)597) the doublets arise from the presence of two conformers (cf. Section 3.01.5.2), whereas for the aldehydes (37) the doublets are... 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

In general, substituents removed from the ring by two or more saturated carbon atoms undergo normal aliphatic reactions, and substituents attached directly to fused benzene rings or aryl groups undergo the same reactions as do those on normal benzenoid rings. 

Since two quaternary atoms and four CH atoms appear in the C NMR spectrum, the latter with a benzenoid coupling constant of 7-9 Hz, this is a disubstituted benzene ring, and the C signal with 5c = 162.2 fits a phenoxy C atom. The keto carbonyl (5c = 204.9) and methyl (5c = 26.6) resonances therefore point to an acetyl group as the only meaningful second substituent. Accordingly, it must be either o- or m-hydroxyacetophenone A or B the para isomer would show only four benzenoid C signals because of the molecular symmetry. 

In general, electron-releasing groups (e.g. —NH2, —OH) diminish or prevent covalent hydration by decreasing the electron deficiency in the nucleus. This diminution becomes ineffective if a new kind of stabilizing resonance is facilitated by the substituent, e.g. the urea-type resonance and the 4-aminopyridine-type resonance in 2- and 6-hydroxypteridine, respectively. The reluctance of the anions of these substances to form hydrates is attributed to the stable benzenoid system, e.g. 42, in the anhydrous anion compared with the predominantly lactam form of the neutral species, e.g. 43. 

Alkoxyisoindoles bearing substituents at the carbocyclic ring exist exclusively in the benzenoid structure the o-quinoid form could not be detected spectroscopically (88CB243). 3-(Methylthio)isoindoles are far more reactive than the corresponding alkoxy-isoindoles. These compounds prefer the benzenoid strueture, too (88CB243). 

As a result of most of the early work on the homolytic arylation of monosubstituted benzenoid compounds it was concluded that the attacking radical was directed to the ortho and para positions in the benzene ring regardless of the nature of the substituent. Similarly,... 

In many cases, however, the ortho isomer is the predominant product, and it is the meta para ratio which is close to the statistical value, in reactions both on benzenoid compounds and on pyri-dine. " There has been no satisfactory explanation of this feature of the reaction. One theory, which lacks verification, is that the radical first forms a complex with the aromatic compound at the position of greatest electron density that this is invariably cither the substituent or the position ortho to the substituent, depending on whether the substituent is electron-attracting or -releasing and that when the preliminary complex collapses to the tr-complex, the new bond is most likely to be formed at the ortho position.For heterocyclic compounds such as pyridine it is possible that the phenyl radical complexes with the nitrogen atom and that a simple electronic reorganization forms the tj-complex at the 2-position. 

The greater intensity of the band of the metabolite at 220 mis probably due to the presence of a second, superimposed chromophore which could also account for the shift of the minimum. On the other hand, the band near 300 m/u. has the expected intensity. Its broadness and displacement towards longer wavelength are probably due to the presence of a substituent on the double bond or benzenoid ring. That the assignment to a coumaroyl chromophore is essentially correct is evidenced by the fact that both M and the model compound underwent the same type of reaction on irradiation in the near-ultraviolet (Figure 4). The observed isosbestic points imply that the photoreaction is a simple one, such as A -> B or A = B, and is obviously the well-known light-induced trans- to c/r-isomerization (7) of cinnamic acid derivatives. 

Reactivity of Substituents Attached to Ring Carbon Atoms 5.01.7.1 Reactions of the Benzenoid Ring of Benzotriazole... 

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