Quinoline, aromaticity electrophilic substitution reaction

Pyridine is converted into perfluoropiperidine (82) in low yield by reaction with fluorine in the presence of cobalt trifluoride (50JCS1966) quinoline affords (83) under similar conditions (56JCS783). Perfluoropiperidine can be obtained electrochemically. This is useful, as it may be readily aromatized to perfluoropyridine by passing it over iron or nickel at ca. 600 °C (74HC(14-S2)407). Recently, pyridine has been treated with xenon difluoride to yield 2-fluoropyridine (35%), 3-fluoropyridine (20%) and 2,6-difluoropyridine (11%), but it is not likely that this is simply an electrophilic substitution reaction (76MI20500). 

Udenfriend et al. observed that aromatic compounds are hydroxyl-ated by a system consisting of ferrous ion, EDTA, ascorbic acid, and oxygend Aromatic and heteroaroinatic compounds are hydroxylated at the positions which are normally most reactive in electrophilic substitutions. For example, acetanilide gives rise exclusively to the o-and p-hydroxy isomers whereas quinoline gives the 3-hydroxy prod-uct. - The products of the reaction of this system w ith heterocyclic compounds are shown in Table XIII. 

These systems nitrate aromatic compounds by a process of electrophilic substitution, the character of which is now understood in some detail ( 6.1). It should be noted, however, that some of them can cause nitration and various other reactions by less well understood processes. Among such nitrations that of nitration via nitrosation is especially important when the aromatic substrate is a reactive one ( 4.3). In reaction with lithium nitrate in acetic anhydride, or with fuming nitric acid, quinoline gives a small yield of 3-nitroquinoline this untypical orientation (cf. 10.4.246) may be a consequence of nitration following nucleophilic addition.5... 

Predict the product of electrophilic aromatic substitution reactions of pyridine and quinoline. 

The reaction of quinoline (78) with bromine and sulfuric acid gives a bromi-nated quinoline derivative via reaction with Br+, but where Note that quinoline is a base, and it will react with sulfuric acid to form an ammonium salt. Remember that pyridine is much less reactive than benzene in electrophilic aromatic substitution reactions. Therefore, assume that the ring containing nitrogen is much less reactive. This leaves C5-C8 as potential sites for electrophilic substitution. Indeed, 78 reacts with bromine and srdfuric acid to give a mixture of 5-bromoquinoline and 8-bromoquinoline, with 5-bromoquinoline being the major product. ... 

Quinoline and isoquinoline show that electrophilic aromatic substitution reactions are the more reactive benzene ring because the pyridine ring is less reactive. Indole undergoes electrophilic aromatic substitution primarily in the pyrrole ring because it is much more reactive than the benzene ring 24, 25, 26, 27, 28, 29, 30, 51, 53. 

The azanaphthalenes (benzopyridines) quinoline and isoquinoline contain an electron-poor pyridine ring, susceptible to nucleophilic attack, and an electron-rich benzene ring that enters into electrophilic aromatic substitution reactions, usually at the positions closest to the heterocyclic unit. 

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. 

Electrophilic aromatic substitutions Quinoline and isoquinoline undergo electrophilic aromatic substitution on the benzene ring, because a benzene ring is more reactive than a pyridine ring towards such reaction. Substitution generally occurs at C-5 and C-8, e.g. bromination of quinoline and isoquinoline. 

Recently37, the importance of CT complexes in the chemistry of heteroaromatic N-oxides has been investigated in nucleophilic aromatic substitutions. Electron acceptors (tetracyanoethylene and p-benzoquinones) enhance the electrophilic ability of pyridine-N-oxide (and of quinoline-N-oxide) derivatives by forming donor-acceptor complexes which facilitate the reactions of nucleophiles on heteroaromatic substrates. 

This pattern of reactivity is reflected in most reactions of electrophiles with complexes containing aromatic ligands the rates of reaction are modified but the position of substitution is unchanged with respect to the free ligand. The reactivity of a range of quinoline complexes with electrophiles has been studied in some detail and the products have been shown to be substituted in exactly the same sites as the free ligands. For example, di(8-oxyquinolinato)copper(n) reacts with molecular bromine to yield di(5,7-dibromo-8-oxyquinolinato)copper(n) (Fig. 8-3). 

In a manifestation of the reaction shown above, quinoline rings have also been formed by the cycloaddition of /V-arylketenimines 543 with 3,4-dihydro-2//-pyran 455 under high-pressure conditions (Scheme 100) <2001H(55)1971>. The reaction is proposed to proceed via the initial formation of 544 by attack of the enol ether on the protonated ketenimine subsequent electrophilic aromatic substitution gives 545. Protonation of the enamine to give 546 is followed by elimination to produce 547. Protection of the alcohol with 455 gives 548. 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

The first step in the Combes reaction is the acid-catalyzed condensation of the diketone with the aromatic amine to form a Schiff base (imine), which then isomerizes to the corresponding enamine. In the second step, the carbonyl oxygen atom of the enamine is protonated to give a carbocation that undergoes an electrophilic aromatic substitution. Subsequent proton transfer, elimination of water and deprotonation of the ring nitrogen atom gives rise to the neutral substituted quinoline system. 

The same concept was applied in the synthesis of aryl-substituted piperidines by the TfOH-catalyzed reaction of piperi-dones with benzene (eq 35). In the TfOH-catalyzed reactions, acetyl-substituted heteroaromatic compounds, such as pyridines, thiazoles, quinolines, and pyrazines can condense with benzene in good yields via the dicationic intermediates (eq 36). Amino alcohols have also been found to ionize cleanly to the dicationic intermediates, which were directly observed by low-temperature NMR. Amino alcohols can react with benzene in triflic acid by electrophilic aromatic substitution with 70 99% yields (eq 37). Similarly, amino acetals can react with benzene in triflic acid medium to give l-(3,3-diphenylpropyl)amines or l-(2,2-diphenylethyl)amines in 50 99% yield (eq 38). ... 

Oxidative cyclizations are generally facilitated by the use of Pd(OAc)2 in acetic acid under reflux. The initial step in these oxidative cyclization reactions is believed to be the electrophilic palladation of the aromatic ring. An example is presented in the preparation of anti-malarial agent quindoline, isolated from a West African plant Cryptolepis sanguinolenta, which was synthesized through an oxidative cyclization of the appropriately 3-substituted quinoline in the presence of two equivalents of Pd(OAc)2 in trifluoroacetic acid. ... 

Quinolinyl moiety has been applied in the Negishi reaction either as an electrophile or as nucleophile. 2- or 4-substituted quinolinyl triflates or bromides have been used extensively for introduction of aromatic rings at the C2 or C4 positions of the heterocycle. In a representative example, Murata et al. employed a Negishi reaction in his effort toward the formal synthesis of antitumor compound camptothecin. In accordance to that, 2-chloropyridine was allowed to react with lithium naphthalenide, followed by zinc chloride, to afford the corresponding zinc pyridine salt. Reaction of the resulting organozinc intermediate with 2-chloro-3-quinoline carboxylate provided the hetero biaryl core of camptothecin. ... 

An aryne multicomponent reaction involving isoquinoline and 5-bromo-1-methylisatin resulted in spirooxazino isoquinolines (Scheme 66).The reaction occurs with a number of iV-substituted isatins. Quinoline can replace the isoquinoline as well. Carbonyls other than the isatins can trap the anion as well. A variety of aromatic, aliphatic, and heteroaromatic aldehydes can function as the electrophile. When pyridine replaces isoquinoUne as the nucleophilic trap, the reaction forms an oxindole but not an oxazino pyridine derivative (14SL608). 

Since heteroaromatic compounds sometimes exhibit interesting physical properties and biological activities, construction of substituted heteroaromatics has drawn some attention. Heteroaromatics can be divided into two major categories. One is the tt-electron-sufhcient heteroaromatics, such as pyrrole, indole, furan, and thiophene those easily react with electrophiles. The other is the 7r-electron-deficient heteroaromatics, such as pyridine, quinoline, and isoquinoline those have the tendency to accept the nucleophilic attack on the aromatic ring. Reflecting the electronic nature of heteroaromatics, the TT-electron-deflcient ones are usually used as the electrophiles.t The rr-electron-sufficient heteroaromatics having simple structures, such as 2-iodofuran and 2-iodothio-phene, have also been utilized as the electrophiles. Not only the electronic nature of the heteroaromatics but also coordination of the heteroatom to the palladium complexes influence catalytic activity. This is another reason why the couphng reaction did not proceed efficiently in some cases. 

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