Electrophilic aromatic substitution quinoline

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. 

The initial product is a dihydroquinoline it is formed via Michael-like addition, then an electrophilic aromatic substitution that is facilitated by the electron-donating amine function. A mild oxidizing agent is required to form the aromatic quinoline. The Skraup synthesis can be used with substituted anilines, provided these substituents are not strongly electron withdrawing and are not acid sensitive. 

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

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. 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

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). ... 

The initially formed imine will tautomerize to a conjugated enamine and cyclization now occurs by electrophilic aromatic substitution. The enamine will normally prefer to adopt the first configuration shown in which cyclization is not possible, and (perhaps for this reason or perhaps because it is difficult to predict which quinoline will be formed from an unsymmetri-cal 1,3-dicarbonyl compound) this has not proved a very important quinoline synthesis. However, the synthetic plan is sound, and we shall describe two important variants on this theme, one for quinolines and one for quinolones. 

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 present Brpnsted or Lewis acid (A) activates the Schiff base III for an electrophilic addition of an electron-rich alkene, generahng a carbenium ion IV, which is stabilized by an electron-donating group. A final intramolecular electrophilic aromatic substitution gives the 1,2,3,4-tetrahydro-quinolines V (Scheme 13.109). 

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. 

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. 

In less acidic media, quinoline is substituted by electrophilic reagents predominantly at the 3-position, although the reason for this is not clear see P. B. D. de la Mare and J. H. Ridd, Aromatic Substitution, p. 198. Butter-worths, London, 1959. 

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. ... 

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. 

Among dichloro bis-electrophiles, malonyl chloride with enamine 183b affords pyridone 189, probably resulting from C-alkylation and cyclocondensation followed by aromatization (02T2821). Finally, o-chloro-benzoylchloride leads to C-benzoylation and subsequent intramolecular substitution of the isolable intermediate to yield quinoline 190 (03ARK (is.2)146). 

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). 

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). 

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