Nitrogen atom isoquinoline

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... 

Substituents in the 4-position of these compounds are also a to a multiply-bonded nitrogen atom, but because of bond fixation they are relatively little influenced by this nitrogen atom even when it is quaternized (333). This is similar to the situation for 3-substituents in isoquinolines, cf. Chapter 2.02. In general, substituents in the 4- and 5-positions of imidazoles, thiazoles and oxazoles show much the same reactivity of the same substituents on benzeneoid compounds (but see Section 4.02.3.9.1). 

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. 

The first successful axially chiral phosphinamine ligand in asymmetric catalysis was QUINAP 60 (Figure 8) reported by Brown in 1993 and the original synthesis has since been modified.94 The donor nitrogen atom is incorporated in an isoquinoline unit to form a six-membered chelate ring. 

The synthesis of compound 135 (Scheme 12) includes the production of isoquinoline 132 via a Bischler-Napieralski reaction, its reduction and alkylation on the nitrogen atom followed by cyclization of N-alkyl derivatives 134 in the presence of acids (83JHC1477 Scheme 36). 

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. 

Attempts to prepare the isomeric indoloisoquinoline system in the coupling of 3-isoquinolyl triflate and o-anilineboronic acid led to an unexpected result. In the course of the follow-up reactions the nitrogen atom in the isoquinoline ring had to be protected as the A -oxidc to divert the cyclization of the nitrene into the 4-position. The intermediate diazonium salt, however under certain conditions underwent a spontaneous ring closure to the benzofuro[3,2-c]isoquinoline system, which on heating rearranges to the benzisoxazolo[2,3-o]isoquinoline (3.6.),7... 

The report made in connection with a reaction between 1-dimethylaminoisoquinoline and Mel at 20° invites speculation. Quater-nization of the annular nitrogen atom results.94 This contrasts with reaction at the side chain of both 2-dimethylaminopyridine97 102 and 2-dimethylaminoquinoline94 under similar conditions. Perhaps the neighboring peri-hydrogen causes the dimethylamino group to adopt a conformation that minimizes its steric effect and thereby allows the isoquinoline to react at the annular position. 

Quinazoline. As with cinnoline, quinazoline (56) preferentially undergoes quaternization at the isoquinoline nitrogen atom. The N-... 

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 fourth "letter" in this chemical alphabet is the substituent at the 2-position, the nitrogen atom, of the isoquinoline ring. The primary substituents found here are the hydrogen and methyl groups, and they are arranged by increasing number ... 

To all rules, there are always exceptions. These have been made to allow unexpected natural isoquinolines that just happen to present unexpected substituents that nature for some reason chose to contribute to this collection. Mention has been made of an occasional carbonyl group disrupting the aromaticity of the benzene ring (this is the basis of the quinonic isoquinolines). The nitrogen atom (position 2) occasionally displays an amide group (these have been entered at the fourth letter of the structural alphabet). Several natural compounds demand a hydroxyl or methoxyl function at the isoquinoline 3- or 4-positions. When this occurs, the compound is listed as a footnote under the parent structure. 

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