Quinoline ring, reactivity

Quinine has two potentially basic centres, a cyclic tertiary amine at a ring junction, and one in a quinoline ring system. pAfa 8.5 is reasonably basic, and this is most likely from the aliphatic tertiary amine. We need to convince ourselves that the quinoline nitrogen is less basic. This is true. As far as reactivity is concerned, a quinoline ring system behaves as two separate parts, either pyridine or benzene, depending upon the reagent. Thus, quinoline has pATa very similar to that of pyridine, i.e. around 5. 

Different hydrogenolytic reactivity of trifluoromethyl groups with respect to their position on the quinoline ring is observed. All C-F bonds in 2-, 4- and 6-(trifluoromethyl)quinoline are hydrogenolyzed by lithium aluminum hydride (Table 4), but the 3-trifluoromethyl isomer gave 3-(difluoromethyl)-l,2-dihydroquinoline (10) under the same experimental conditions in contrast to these results, sodium borohydride surprisingly reduces 3-(trifluoromethyl)quinoline to the corresponding 3-methylquinoline (Table 4).149... 

The decreasing reactivity of the most familiar aromatic heterocyclic compounds with nucleophilic reagents may be illustrated by the following sequence quinoxaline > acridine > phenanthridine > isoquinoline > quinoline > pyridine. Acridine is alkylated in the 4-position, phenanthridine and quinoxaline in the a-position, isoquinoline in the 1-position, and quinoline and pyridine in the 2- or 4-positions. Weaker nucleophilic reagents seem to enter the 4-position of the pyridine and quinoline rings. If the addition occurs readily and in good yield, the intermediate dihydro derivative may sometimes be isolated otherwise, the product of the subsequent oxidation results. In synthetic work the dihydro derivative is usually directly oxidized. 

The C(8) atom of the quinoline ring is involved in a three-center two-electron bond and the cluster is highly reactive towards Lewis bases such as CO, amines, and phosphines.I ... 

Reactions. Quinoline exhibits the reactivity of benzene and pyridine rings, as weU as its own unique reactions. 

Fused benzene rings are treated as substituents. Thus quinoline, for example, is considered as a substituted pyridine, albeit a very special and important one, and treated alongside other substituted pyridines in the discussion of its structure, reactivity and synthesis. Reactions of quinoline at positions 1-4 are considered as reactions at ring atoms, whilst reactions at positions 5-8 are regarded as reactions of the substituent . 

The benz analogue of 2-trifluoromethylimidazole is inert to aqueous alkali, presumably because formation of the intermediate diazafulvene would disrupt the benzene ring However, two quinoline analogues do undergo hydrolysis with subsequent decarboxylation [4J] (equations 42 and 43) The f4,5-h] isomer is less reactive (equation 42) than the [4,5-f] isomer (equation 43)... 

An interesting use of the Camps quinoline synthesis is in the ring contraction of macrocycles. Treatment of 9 member ring 24 with sodium hydroxide in water furnished quinolin-4-ol 25, while 26 furnishes exclusively quinolin-2-ol 27 under the same reaction conditions (no yield was given for either reaction). The reaction does not work with smaller macrocycles. The authors rationalize the difference in reactivity based upon ground state conformation differences, but do not elaborate. 

The usual order found with halogenonitrobenzenes is F > Cl Br I, the order of Cl and Br being variable, just as in heteroaromatic reactivity. The position of fluorine is of interest the available data indicate that it is usually the same as for nitrobenzene derivatives. Thus, in acid hydrolysis the order F > Cl for 2-halogeno-quinolines can be deduced beyond doubt since the fluoro derivative appears to react in the non-protonated form and the chloro derivative to resist hydrolytic attack even in the protonated form under appropriate conditions (Section II,D, l,d). Furthermore, in the benzo-thiazole ring, fluorine is displaced by the CHgO reagent at a rate 10 times that for chlorine. ... 

The A-oxidation of 3-chloropyridazines increases their reactivity toward methoxide and sulfanilamide anions.The reactivity of 4-chloro- or 4-nitro-quinoline and of chloropyridines toward methoxide ion and piperidine is less than that of the corresponding A-oxides (see Tables II and XI, pp. 270 and 338). The activating effect of the A-oxide moiety in 3-halopyridine A-oxides is greater than that of a nitro group, and in fluoroquinoline A-oxides the activation is transmitted to resonance-activated positions in the adjoining rings. 

As summarized in the following tabulation, the relative rates of piperidino-debromination of the halo-l-nitronaphtholenes (data from Table XII, numbered to show relation to quinolines) provide a good confirmation of the relation of induction (ind.) to resonance activation (res.) and of the extent of transmission of activation to an adjoining ring. Here again, as in the quinoline series, the 8-isomer (346) is more reactive than its resonance-activated 5-bromo isomer (345) and its inductively activated 3- and 6-bromo isomers (351 and... 

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