Nitrations quinoline

The first three reactions are all electrophilic substitution a bromination of a pyrrole, the nitration quinoline, and a Friedel-Crafts acylation of thiophene. Bromination occurs on the pyrrole at only remaining site. Nitration of quinoline occurs on the benzene rather than the quinoline r-fi (actually giving a mixture of 5- and 8-nitroquinolines, but don t worry if you didn t see t- Mi p. 1174), and the acylation would occur next to sulfur. 

The positional selectivity for proton exchange is partly mirrored in nitrations, quinoline gives approximately equal amounts of 5- and 8-nitro-quinolines, whereas isoquinoline produces almost exclusively the... 

Nitration of quinoline with HNO3 in acetic anhydride furnishes only small amounts of identifiable products such as 4 and 5 (< 1 %) and 3-nitroquinoline 6 (6%), probably resulting from an initial 1,2-addition (cf the bromination, p 319). Transition metals can exert special directional effects. For instance, Zr(N03)4 nitrates quinoline to give the 7-nitro derivative 7 ... 

On acetylation it gives acetanilide. Nitrated with some decomposition to a mixture of 2-and 4-nitroanilines. It is basic and gives water-soluble salts with mineral acids. Heating aniline sulphate at 190 C gives sulphanilic add. When heated with alkyl chlorides or aliphatic alcohols mono- and di-alkyl derivatives are obtained, e.g. dimethylaniline. Treatment with trichloroethylene gives phenylglycine. With glycerol and sulphuric acid (Skraup s reaction) quinoline is obtained, while quinaldine can be prepared by the reaction between aniline, paraldehyde and hydrochloric acid. 

These systems nitrate aromatie eompounds by a proeess of electro-philie substitution, the eharacter of whieh is now understood in some detail ( 6.1). It should be noted, however, that some of them ean eause nitration and various other reactions by less well understood processes. Among sueh nitrations that of nitration via nitrosation is especially important when the aromatic substrate is a reactive one ( 4.3). In reaetion with lithium nitrate in aeetie anhydride, or with fuming nitrie aeid, quinoline gives a small yield of 3-nitroquinoline this untypieal orientation (ef. 10.4.2 ) may be a eonsequenee of nitration following nucleophilic addition. ... 

This method is exemplified by its application to quinoline, isoquinoline, cinnoline, and isoquinoline 2-oxide, which are nitrated as their conjugate acids. The rate profiles for these compounds and their N- or O-methyl perchlorates show closely parallel dependences upon acidity (fig. 2.4). Quaternisation had in each case only a small effect upon the rate, making the criterion a very reliable one. It has the additional advantage of being applicable at any temperature for which kinetic measurements can be made (table 8.1, sections B and D). 

These arguments were originally applied to the 4-nitration of 2,6-lutidine i-oxide and quinoline i-oxide, and use of the data available... 

Because of these difficulties, special mechanisms were proposed for the 4-nitrations of 2,6-lutidine i-oxide and quinoline i-oxide, and for the nitration of the weakly basic anilines.However, recent remeasurements of the temperature coefficient of Hq, and use of the new values in the above calculations reconciles experimental and calculated activation parameters and so removes difficulties in the way of accepting the mechanisms of nitration as involving the very small equilibrium concentrations of the free bases. Despite this resolution of the difficulty some problems about these reactions do remain, especially when the very short life times of the molecules of unprotonated amines in nitration solutions are considered... 

The preparative nitration of quinoline in mixed acid has been described several times, and has usually been carried out under unnecessarily severe conditions good yields of 5- and 8-nitroquinoline in roughly... 

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)... 

Little is known quantitatively about substituent effects in the nitration of derivatives of azanaphthalenes. In preparative experiments 4-hydroxy-quinoline, -cinnoline, and -quinazoline give the 6- and 8-nitro compounds, but with nitric acid alone 4-hydroxyquinoline and 2,4-di-hydroxyquinoline react at With nitric acid, 4-hydroxycinnoline... 

Recently kinetic data have become available for the nitration in sulphuric acid of some of these hydroxy compounds (table 10.3). For 4-hydroxyquinoline and 4-methoxyquinoline the results verify the early conclusions regarding the nature of the substrate being nitrated in sulphuric acid. Plots of log Q against — (Lf + logioflHao) fo " these compounds and for i-methyl-4-quinolone have slopes of i-o, i-o and 0-97 at 25 C respectively, in accord with nitration via the majority species ( 8.2) which is in each case the corresponding cation of the type (iv). At a given acidity the similarity of the observed second-order rate constants for the nitrations of the quinolones and 4-methoxy-quinoline at 25 °C supports the view that similarly constructed cations are involved. Application of the encounter criterion eliminates the possibilities of a... 

Ochiai and Okamoto showed that nitration of quinoline i-oxide in sulphuric acid at o °C gave 5- and 8-nitroquinoline i-oxides with a trace of the 4-isomer, but that at 60-100 °C 4-nitration became overwhelmingly dominant. The orientation depends not only upon temperature but also upon acidity, and kinetic studies (table 8.4 table 10.3) show that two processes are occurring the nitration of the free base (vil, R = O at C(4), favoured by low acidities and high temperatures, and the nitration of the cation (vil, R = OH), favoured by high acidities and low temperatures. ... 

Alkylation a.ndAryla.tion, The direct introduction of carbon—carbon bonds in quinoline rings takes place in low yield and with Htde selectivity. The most promising report involves carboxyHc acids with ammonium persulfate and silver nitrate (31). 

Electrophilic substitution reactions of unsubstituted quinoxaline or phenazine are unusual however, in view of the increased resonance possibilities in the transition states leading to the products one would predict that electrophilic substitution should be more facile than with pyrazine itself (c/. the relationship between pyridine and quinoline). In the case of quinoxaline, electron localization calculations (57JCS2521) indicate the highest electron density at positions 5 and 8 and substitution would be expected to occur at these positions. Nitration is only effected under forcing conditions, e.g. with concentrated nitric acid and oleum at 90 °C for 24 hours a 1.5% yield of 5-nitroquinoxaline (19) is obtained. The major product is 5,6-dinitroquinoxaline (20), formed in 24% yield. 

Doebner-von Miller synthesis, 2, 466 hydrazination, 2, 238 NMR, 2, 120 Quinoline, 5-methyl-nitration, 2, 50, 318 Quinoline, 6-methyl-mercuration, 2, 321 N-oxide... 

Quinoline, 5-nitro-oxidation, 2, 210 synthesis, 2, 318 Quinoline, 6-nitro-nitration, 2, 318 Quinoline, 7-nitro-nitration, 2, 318 synthesis, 2, 318 Quinoline, 8-nitro-... 

Ewins has synthesised both substances from m-methoxybenzoic acid, which on nitration gave 2-nitro-3-methoxybenzoic acid, and this, on reduction and treatment with methyl iodide, yielded damasceninic acid, which, by esterification with methyl alcohol, furnished damascenine. Kaufmann and Rothlen found that the additive product of 8-methoxy-quinoline and methyl sulphate, on oxidation with permanganate, yields formyldamasceninic acid, MeO. CgH3(NMe. CHO). COOH, which can be transformed into damasceninic acid by warming with dilute hydrochloric acid. ... 

Trimethyloxazolo[4,5-/]quinoline prepared from 2,7-dimethyl-6-methoxyquinoline using nitration, demethylation (or reversed), reduction, and cy-clization with acetic anhydride confirms unambigously the structure of the aromatic part of the antibiotic X-537A after nitration and alkaline degradation (71JOC3621). 

Subs tituted-1,2,3-oxadiazolo[4,5-/]quinoline 47 originated after nitration, reduction, and diazotization of alkaloid quinine during the study of its stmcture and reactions (53RZC495, 54RZC61). 

The nitration of l,2,5-selenadiazolo[3,4-/] quinoline 77 with benzoyl nitrate affords the 8-nitro derivative 78, whereas methylation with methyl iodide or methyl sulfate afforded the corresponding 6-pyridinium methiodide 79 or methosulfate 80, respectively (Scheme 29). The pyridinium salt 80 was submitted to oxidation with potassium hexacyanoferrate and provided 7-oxo-6,7-dihydro derivative 81 or, by reaction of pyridinium salt 79 with phenylmagnesium bromide, the 7-phenyl-6,7-dihydro derivative 82. Nucleophilic substitution of the methiodide 79 with potassium cyanide resulted in the formation of 9-cyano-6,9-dihydroderivative 83, which can be oxidized by iodine to 9-cyano-l,2,5-selenadiazolo [3,4-/]quinoline methiodide 84. All the reactions proceeded in moderate yields (81IJC648). 

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

Oxidation of 5-arylazo-6-aminoquinoline 146 with copper sulfate in pyridine gave the corresponding 2-aryltriazolo[4,5-/]quinolines 147. Condensation of halo-genated nitrobenzenes with triazolo[4,5-/]quinoline 145 yielded the appropriate 2H- and 3//-aryl derivatives. The nitration of 3-phenyl-3//-triazolo[4,5-/]quino-line 147 occurred at position 4 of the phenyl ring (Scheme 46) (73T221). 

Den Hertog and Overhoff - observed that when pyridine in sulfuric acid is added to molten potassium sodium nitrate the 3-nitro derivative is formed at 300°C, whereas at 450°C 2-nitropyridme is the main product. The latter is probably a free-radical process. Schorigin and Toptschiew obtained 7-nitroquinoline by the action of nitrogen peroxide on quinoline at 100°C, possibly through the homolytic addition of NOa. Laville and Waters reported that during the decomposition of pernitrous acid in aqueous acetic acid, quinoline is nitrated in the 6- and 7-positions. They considered that the reaction proceeds as shown in Scheme 3. 

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