Electrophilic reactions quinoline/isoquinoline

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 lone-pair electron on the nitrogen is responsible for electrophilic reactions on its side. Thus, heterocyclic nitrogen atom of quinoline and isoquinolines react with electrophiles, as alkyl halides, alkyl sulfates, alkyl-toluene-p-sulfonates, etc., providing quinolinium and isoquinolinium salts. 

Quinolines and isoquinolines can also react with electrophiles at the pyridine side. This can be rationalized by a different reaction mechanism involving the prior introduction of a nucleophile in the heterocyclic quinoline/isoquinoline ring followed by an electrophilic substitution involving attack on the intermediate enamine. Notable is the electrophilic bromination of isoquinoline hydrobromide in a solvent like nitrobenzene that provides 81% yield of 4-bromoisoquinoline, in contrast to the bromination or chlorination of an isoquinoline-aluminum chloride complex that affords 78% of 5-bromoisoquinoline. Exhaustive bromination or chlorination under Lewis acid conditions usually yields mixtures of 5,8-halogenated isoquinolines along with 5,7,8-trisubstituted derivatives. ... 

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). 

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. 

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. 

A systematic and intensive theoretical study of reactivity has been reported by Brown and his colleagues,8,115,139-142 who discussed the reactivity of pyridine, quinoline, and isoquinoline in terms of localization energies. They investigated the values of these indices, first of all for electrophilic substitution, with regard to the value of the Coulomb integral of the heteroatom orbital and the orbitals adjacent to it (auxiliary inductive parameters). They demonstrated that the course of electrophilic substitution can be estimated from theoretical reactivity indices if 77-electron densities are used for reactions that occur readily and localization energies for those occurring only reluctantly. 

Alkynylbenzaldimines can produce isoquinolines (Scheme 7). The use of electrophiles and base yielded 3,4-disubstituted quinolines <2002JOC3437, 20010L2973>, whereas the palladium-catalyzed carbonylation gave 4-aroylquinolines <20020L193, 2002JOC7042>. Cyclization followed by Heck reaction gave rise to 4-alkenyl-substituted quinolines <2002TL3557>. 

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.)... 

Quinoline forms part of quinine (structure at the head of this chapter) and isoquinoline forms the central skeleton of the isoquinoline alkaloids, which we will discuss at some length in Chapter 51. In this chapter we need not say much about quinoline because it behaves rather as you would expect—its chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution favours the benzene ring and nucleophilic substitution favours the pyridine ring. So nitration of quinoline gives two products—the 5-nitroquinolines and the 8-nitroquinolines—in about equal quantities (though you will realize that the reaction really occurs on protonated quinoline. 

OCH3 and NH3, give exclusive attack at the hard electrophilic centres, i.e. C—F, whereas soft nucleophiles displace bromine. This is further evidence for the importance of ion-dipole interactions, regarding attack at C—F bonds. Reactions of perfluoro-quinoline and -isoquinoline with hard and soft nucleophiles have also revealed a sensitivity towards a change in orientation of attack with the nature of the nucleophile [114] (Figure 9.42). 

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