Fusing rings to pyridines quinolines and isoquinolines

Similarly, the large a-CH couplings of pyridine, quinoline, and isoquinoline can be used to locate substituents or fused rings in these heterocycles [73 d, i], N-Oxidation and protonation further enhance Jcu of the a-CH bond in pyridine (Table 4.68) due to the positive charge at nitrogen. To conclude, the sites of oxidation and protonation can be derived from the magnitudes of JC I in pyridines, azines, and their fused derivatives [467]. 

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. 

Oxidation of quinoline and isoquinoline under vigorous conditions with potassium permanganate results in oxidative degradation of the benzo-fused ring and formation of pyridine-2,3- and -3,4-dicarboxylic acid respectively. As expected, the presence of electron-donating substituents facilitates the reaction while electron-withdrawing substituents make oxidation much more difficult. Apart from A-oxide formation, little study has been devoted to the oxidation of other benzo-fused 7r-deficient systems. 

Uncharged pyridines are resistant to hydroxide ion at usual temperatures. Pyridine itself reacts with hydroxide ions under extreme conditions (KOH-air, 300°C) to give 2-pyridone, the stable tautomer of 2-hydroxypyridine, which is formed by oxidation of the initial adduct. As is expected, this reaction is facilitated by electron-withdrawing groups and fused benzene rings quinoline and isoquinoline form... 

Polycyclic aromatic heterocycles that contain pyridine rings fused with benzene rings include quinoline and isoquinoline. Quinine, used to treat malaria, is an example of a naturally occurring quinoline. 

An indication of the deactivating effect of replacing a CH=CH by an imine (CH=N-) is that the electrophilic substitution of quinoline and isoquinoline, in which a benzenoid ring is fused to a pyridine ring, takes place in the benzenoid ring at C-5 and to a lesser extent at C-8 (Scheme 4.25). 

Quinolines and isoquinolines are susceptible to addition of nucleophiles only at the heterocyclic ring. In quinoline, there is only one a- and one y-position prone for attack, whereas in isoquinoline, two a-type positions in which 1-position is much more favored due to the inability of nitrogen atom to delocalize a negative charge. In general, the nucleophilic attack is easier in these bicyclic systems in comparison to pyridine compounds because of the associated resonance stabilization offered by the fused-benzene ring. 

Quinoline and isoquinoline, the two possible structures in which a benzene ring is annelated to a pyridine ring, represent an opportunity to examine the effect of fusing one aromatic ring to another. Clearly, both the effect the benzene ring has on the reactivity of the pyridine ring, and vice versa, and comparisons with the chemistry of naphthalene must be made. Thus the regiose-lectivity of electrophilic substitution, which in naphthalene is faster at an a-position, is mirrored in quinoline/isoquinoline chemistry by substitution at 5-... 

The pyridine ring can be fused with benzene rings to produce polycyclic aromatic heterocycles. The most important examples are quinoline and isoquinoline, analogs of naphthalene (Sec. 4.13) but with N in place of CH at C-1 or C-2. 

There exist many types of azoloquinolines, and therefore it is necessary to define the objects of interest to be described in this review. The tricyclic azoloquinolines reviewed in this article have an azole ring fused to the benzene ring of quinoline (not isoquinoline derivatives) in positions / g, and h. This means that the benzene ring is between azole and pyridine rings, and all of them are ortho-peri condensed. The azole and benzene rings do not have a common heteroatom, and also a carbon... 

Halogenations of quinoline, isoquinoline, acridine, and phenanthridine will be discussed here. Reaction usually occurs in a homocyclic fused ring rather than in the 7r-deficient pyridine moiety, especially in acidic media. Relatively mild conditions suffice, but under more vigorous regimes radical involvement can result in heteroring halogenation. Substituents are able to modify reactivity and regiochemistry. 

Quinoline, 1-azanaphthalene and isoquinoline are aromatic nitrogen compounds characterized by a double-ring structure (as shown in Fig. 1) that contains a benzene ring fused to pyridine at two adjacent carbon atoms [1]. These compounds are stable. Quinoline is a high-boihng hquid and isoquinoline is a low-melting solid, each with sweetish odor [2]. 

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. 

Space restrictions mean that the reactivity of multiheteroatom systems or fused systems where both rings are heterocyclic cannot be covered in this section - the reader is referred to the relevant CHEC volumes. Space again dictates that the chemistries of oxygen- and sulfur-containing six-membered heterocycles, and the chemistry of monocyclic six-membered heterocycles with more than one heteroatom, are only briefly indicated alongside the description of pyridine/quinoline/isoquinoline chemistry, but especially where these are not shown by the pyridine prototypes, but again the reader should study the CHEC volumes for a full discussion. The inclusion of an extra heteroatom in a six-membered system exaggerates the effect of the first and so often it is possible to predict properties by extrapolation however, the same is not true for the five-membered systems, so these heterocycles with more than one heteroatom are considered in detail and separately. 

It is generally recognized that the fused-ring derivatives of pyridine sustain a ring current, but no attempts have apparently been made to evaluate it. Diamagnetic susceptibility exaltation measurements84 give values for naphthalene of 30.5 X 10-6, quinoline 29.9 X 10-6, and isoquinoline 27.8 X 10-6 cm8 mole-1. 

Factors (a) and (b) together explain the fact that the [cl-fused systems are stronger bases than those that are 161-fused. A further point to note is that isoquinoline is less basic than the isosteric thienopyridines, but the reverse is true for quinoline. The introduction of methyl groups into the pyridine ring has the expected effect of increasing base strength Dressier and Joullie48 list pKt values for a number of methyl derivatives in the [3,2-c]- and [2,3-c]-fused series. 

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