Quinoline/isoquinoline nitrogen atom

Reaction of peracids with quinolines and isoquinolines affords the corresponding A-oxides. Typical conditions are treatment of heterocycles with RCO2H in the presence of H2O2 at -100 C or /w-CPBA at 0 C. The quinoline/isoquinoline nitrogen atom reacts less readily with peracids than the tertiary amines. Large substituents and electron-withdrawing groups slow the reaction. 

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)... 

When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

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 chemistry of these polycyclic heterocycles is just what you miglu expect from a knowledge of the simpler heterocycles pyridine and pyrrole Quinoline and isoquinoline both have basic, pyridine-like nitrogen atoms, anc both undergo electrophilic substitutions, although less easily than benzene Reaction occurs on the benzene ring rather than on the pyridine ring, and r mixture of substitution products is obtained. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Phenethyl ketone oximes have been cyclized by a Beckmann rearrangement to isoquinolines 477 (equation 205), but quinoline derivatives 478 can also be obtained as a result of a formal displacement at the nitrogen atom of the oxime (equation 206). 

Isoquinoline, like quinoline, is protonated and alkylated at the nitrogen atom, but electrophilic substitution in the benzene ring is also easily achieved (Scheme 3.14). Sulfonation with oleum gives mainly the 5-sulfonic acid, but fuming nitric acid and concentrated sulfuric acid at 0 C produce a 1 1 mixture of 5- and 8-nitroisoquinolines. Bromination in the presence of aluminium trichloride at 75 °C gives a 78% yield of 5-bromoisoquinoline. 

The parent naphthyridines have basic strengths lower than those of quinoline (4.94) and of isoquinoline (5.40) (c/. Table 6), which has been attributed to the relayed inductive effect of one doubly bound nitrogen atom to the other. The greater basic strengths of the 1,6-and 1,7-isomers as compared to the 1,5- and 1,8-compounds appear to indicate that... 

Quinoline and isoquinoline are basic in nature. Like pyridine, the nitrogen atom of quinoline and isoquinoline is protonated under the usual acidic conditions. The conjugate acids of quinoline and isoquinoline have similar pA a values (4.85 and 5.14, respectively) to that of the conjugate acid of pyridine. 

Alkaloids are basic plant natural products that typically have a nitrogen atom as part of a heterocyclic ring system and indeed are classified on this basis. Thus major classes of alkaloids are based on indole, isoquinoline, pyrrolidine, piperidine, pyrrolizidine, quinoline, tropane, quinolizidine or other heterocyclic ring systems. Other alkaloids are basic monoterpenoid, sesquiterpenoid, diterpenoid, steroid, purine, pyrimidine or peptide entities. Some of these compounds are exceptionally toxic [1,6, 7-12]. 

The o values of rings annelated to pyridine in systems such as quinoline, isoquinoline, benzoquinolines, acridine, and phenanthridine and determined by the basicity of the ring nitrogen atom are predicted186 and found to be small.33,34 This is an important point stressed and elucidated previously,181 and demonstrating the validity of the basic assumptions of the Hammett equation. 

The H(D) atom abstraction rate constants in durene crystals by the impurity molecules quinoline, isoquinoline, quinoxaline, and quinozaline in their excited triplet state were measured by Hoshi et al. [1990] using the phosphorescence method described above. The transfer occurs in the fragment CH N formed by a methyl group of durene and a nitrogen atom of the impurity molecule. In the interval 300-100 K the activation energy drops from 3.5 kcal/mol to 1.6 kcal/mol. Deuteration reduces the... 

From the addition reactions of phthalic anhydride with pyridine, naphthalene was formed in much greater quantity than quinoline isoquinoline was either totally absent or present in only minute amounts. These facts indicated (a) if there were much 1,2-addition of benzyne, it occurred predominantly at the 1,2 and 3,4 atoms in pyridine (b) 1,4-addition took place at carbon atoms in preference to a nitrogen and a carbon atom. Studies with other systems indicate that arynes have a decided preference for 1,4- over 1,2-addition. 

As with pyridine, the nitrogen atoms of quinoline and isoquinoline each bear a lone pair of electrons not involved in aromatic bonding which can be protonated, alkylated, or complexed to Lewis acids. This chapter should be read in conjunction with the chapter on pyridines as several points discussed at length there are also relevant to the chemistry of quinoline and isoquinoline. 

For instance, both quinoline and isoquinoline undergo the Chichibabin reaction (with formal hydride elimination, see Chapter 5) to give 2-aminoquinoline 6.23 and 1-aminoisoquinoline 6.24 respectively. Halogen substituents ortho to the nitrogen atoms are easily displaced, as in the preparations of 6.25 and 6.26. 

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. 

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