Heterocyclics quinolines

A striking demonstration of the reduced activity towards electrophiles for the pyridine ring compared with the benzene ring will be seen later when we consider the fused heterocycles quinoline and isoquinoline (see Section 11.8.1). These contain a benzene ring fused to a pyridine ring electrophilic substitution occurs exclusively in the benzene ring. 

Electron density calculations suggest that electrophilic attack in pyridine (42) is favored at C-3, whereas nucleophilic attack occurs preferentially at C-2 and to a lesser extent at C-4. Cytochrome P-450 mediated ring hydroxylation of pyridine would, therefore, be expected to occur predominantly at C-3, the most electron-rich carbon atom. Although 3-hydroxypyridine is an in vivo metabolite in several species, the major C-oxidation product detected in the urine of most species examined was 4-pyridone (82MI10903). The enzyme system catalyzing the formation of this latter metabolite may involve the molybdenum hydroxylases and not cytochrome P-450 (see next paragraph). In the related heterocycle quinoline (43), positions of high electron density are at C-3, C-6 and C-8, while in isoquinoline (44) they are at C-5, C-7 and C-8. Nucleophilic substitution predictably occurs... 

QUINOLINES AND ISOQUINOLINES. The isomeric heterocycles quinoline (1) and isoquinoline (2) possess structures that occur frequently in alkaloids and pharmaceuticals for example, quinine and morphine. See also Alkaloids. 

A benzene ring can be fused on to the pyridine ring in two ways giving the important heterocycles quinoline, with the nitrogen atom next to the benzene ring, and isoquinoline, with the nitrogen atom in the other possible position. 

Quinolines and isoquinolines can also react with electrophiles at the pyridine side. This can be rationalized by a different reaction mechanism involving the prior introduction of a nucleophile in the heterocyclic quinoline/isoquinoline ring followed by an electrophilic substitution involving attack on the intermediate enamine. Notable is the electrophilic bromination of isoquinoline hydrobromide in a solvent like nitrobenzene that provides 81% yield of 4-bromoisoquinoline, in contrast to the bromination or chlorination of an isoquinoline-aluminum chloride complex that affords 78% of 5-bromoisoquinoline. Exhaustive bromination or chlorination under Lewis acid conditions usually yields mixtures of 5,8-halogenated isoquinolines along with 5,7,8-trisubstituted derivatives. ... 

N-heterocycles (quinolines, isoquinolines and quinoxalines) when a Cp lr catalysts was employed for their reduction in FA/TEA [108]. 

Fisher and Boles (1990) analyzed the dissolved organic matter in two formation water samples from the San Joaquin Basin by GC-MS analysis of combined acid, base, and neutral methylene chloride extracts. They identified various polar aliphatics (fatty acids to C9 with various methyl and ethyl substituents), cyclics (phenols and benzoic acids), and heterocyclics (quinolines). They were able to quantify, at the ppm or sub-ppm level, phenol, methyl-substituted phenols, and benzoic acid. 

A wide class of aiyl-based quaternary surfactants derives from heterocycles such as pyridine and quinoline. The Aralkyl pyridinium halides are easily synthesized from alkyl halides, and the paraquat family, based upon the 4, 4 -bipyridine species, provides many interesting surface active species widely studied in electron donor-acceptor processes. Cationic surfactants are not particularly useful as cleansing agents, but they play a widespread role as charge control (antistatic) agents in detergency and in many coating and thin film related products. 

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

The heterocyclic rings in quinoline (116) and isoquinoline are selectively reduced by Pd on carbon-catalyzed reaction of ammonium formatc[107]. Some benzene rings are also reduced. For example, nitrobenzene is reduced to cyclohexylamine (117) with formic acid. It is important to use a sevenfold excess of formic acid[108]. 

Heterocyclic aromatic compounds can be polycyclic as well A benzene ring and a pyridine ring for example can share a common side m two different ways One way gives a compound called quinoline the other gives isoquinoline... 

Replacing one carbon atom of naphthalene with an a2omethene linkage creates the isomeric heterocycles 1- and 2-a2anaphthalene. Better known by their trivial names quinoline [91-22-5] (1) and isoquinoline [119-65-3] (2), these compounds have been the subject of extensive investigation since their extraction from coal tar in the nineteenth century. The variety of studies cover fields as diverse as molecular orbital theory and corrosion prevention. There is also a vast patent Hterature. The best assurance of continuing interest is the frequency with which quinoline and isoquinoline stmctures occur in alkaloids (qv) and pharmaceuticals (qv), for example, quinine [130-95-0] and morphine [57-27-2] (see Alkaloids). 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

Ubichromenol synthesis, 3, 752 Ugi reaction, 5, 830 Uliginosin B, bromo-molecular dimensions, 3, 621 Ullman and Fetvadjian synthesis quinolines, 2, 477 Ullman synthesis acridines, 2, 470-benzacridines, 2, 470 Ultraviolet light absorbers in polymers, 1, 397-398 Ultraviolet spectroscopy heterocyclic compounds reviews, 1, 78... 

The two alkaloids which have been most completely investigated are quinine and cinchonine. The scission products of both fall into two classes, viz., derivatives of quinoline and derivatives of a second heterocyclic ring system, formerly referred to as the second half of the... 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

The ionization constant of a typical heterocyclic compound (e.g., quinoline) designates the equilibrium involving a proton, a neutral molecule and its cation. With quinazoline, however, two distinct species (hydrated and anhydrous) are involved each of which is in equilibrium with its cation, and can be represented as in the reaction scheme, (7), (8), (3), and (4). 

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. 

Both of these approaches have been attempted, and both are substantially equivalent for heterocyclic (e.g. quinoline and isoquinoline) and homocyclic (naphthalene) systems. Consequently, in the subsequent discussion it is fruitful to include the available work on naphthalene derivatives. In the case of the fused six-membered rings, Eq. (3) is not applied because it does not permit treatment of the 5- and 8-positions, and the available series as a whole are too short to make this treatment useful. 

Spectroscopic evidence indicates that protonation of 2-fluoro-and 2-chloro-quinoline is not appreciable in O.OlJf aqueous hydrochloric acid. Protonation becomes evident in more strongly acidic solution in the case of the chloro compound without any accompanying decomposition, but the fluoro compound hydrolyzes to carbostyril under the latter conditions. The hydrolysis is acid-catalyzed, but it is doubtful whether protonation on the heterocyclic nitrogen is responsible, owing to its low basicity (presumably below that for the chloro compound). An alternative explanation in this case would be hydrogen bond formation with fluorine, Ar—F. .. H-O+H2. 

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