Relative reactivities of heterocycles

4 Electrophilic Attack on Carbon General Considerations 3.3.1.4.1 Relative reactivities of heterocycles 

Electrophilic substitution is much easier than in benzene. Thiophene reacts about as readily as mesitylene pyrrole and furan react as readily as phenol or even resorcinol. Electrophilic substitution of heterocycles has been reviewed (86HC(44/2)l), (90AHC(47)87), and the following conclusions were reached  

The electrophilic substitution of thiophene is much easier than that of benzene thus, thiophene is protonated in aqueous sulfuric acid about 103 times more rapidly than benzene, and it is brominated by molecular bromine in acetic acid about 109 times more rapidly than benzene. Benzene in turn is between 103 and 107 times more reactive than an uncharged pyridine ring to electrophilic substitution. 

Partial rate factors and cr+ values for detritiation have been calculated from rates of deuteriation for indole, 1-methylindole, 2-methylindole, 1,2-dimethylindole, and A-methylisoindole and confirm the known reactivity patterns. Isoindole is the most reactive, being approximately 104 times more reactive than indole (87JCS(P2)59l). 

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Another static approach that can give us the relative reactivity of heterocycles as dienes for Diels-Alder reactions is evaluation of their aromatic stability through the ring bond order uniformity. If, for a moment, we examine reactivity of the heterocycle on the basis of FMO energy gap with cyclopropene as a dienophile, it is obvious that the most reactive heterocycle is 1,3-thiazole. It had a FMO energy gap of only 9.609 eV (Table 26). That finding is almost... 

The relative reactivity of heterocyclic and carbocyclic olefins toward 9-BBN are depicted in Chart 6.22 [3]. 

The relative reactivity of azine rings and their ring-positions is determined by a number of factors that are considered in this section. Data and examples are taken up in Sections III and IV on the comparative reactivity of mono- and bi-cyclic azines. It is of interest to note that nucleophilic substitution comprises a sizeable section in the heterocyclic chemistry textbooks by Albert and by Katritzky and Lagowski. ... 

There are conflicting generalizations in the heterocyclic literature as to the relative reactivity of a- and y-positions in azines toward nucleophiles. Variations in the relative reactivity are attributed in this and subsequent sections to specific factors operating in addition to activation by azine-nitrogen. Another possible source of variation may be a decrease in selectivity with increasing reactivity of one or both reagents, an effect established in electrophilic aromatic... 

On the basis of the reaction of alkyl radicals with a number of polycyclic aromatics, Szwarc and Binks calculated the relative selectivities of several radicals methyl, 1 (by definition) ethyl, 1.0 n-propyl, 1.0 trichloromethyl, 1.8. The relative reactivities of the three alkyl radicals toward aromatics therefore appears to be the same. On the other hand, quinoline (the only heterocyclic compound so far examined in reactions with alkyl radicals other than methyl) shows a steady increase in its reactivity toward methyl, ethyl, and n-propyl radicals. This would suggest that the nucleophilic character of the alkyl radicals increases in the order Me < Et < n-Pr, and that the selectivity of the radical as defined by Szwarc is not necessarily a measure of its polar character. 

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

Table 3 Relative reactivity of 2,5-dinitro derivatives of five-membered heterocycles and 1,4-dinitrobenzene towards some nucleophiles ...

The relative reactivities of many five-membered heterocycles in acylation reactions130, 141-143 have been determined by the competitive method, which has the advantage over the kinetic one of not requiring a complete knowledge of the reaction kinetics. 

The reaction between 2-(thien-2-yl)pyrroles and tetracyanoethene nicely illustrates the relative reactivities of the two heterocycles 1,2,2-tricyanoethenylation takes place only in the pyrrole ring <2005T11991>. 

While quantitative measurements of pseudobase formation in aqueous alcoholic solutions may be used as indications of the relative susceptibilities to nucleophilic attack for closely related cations,9,53,75,218 such data are not directly comparable with equilibrium and rate data for pseudobase formation in either water or the pure alcohol (or even with data in aqueous alcoholic solutions of other compositions). Several workers218,257,261,262 have reported rate constants for hydroxide ion attack on heterocyclic cations in aqueous alcoholic solutions without any apparent attempt to consider the complications that arise in such media as a result of the competition between hydroxide and alkoxide ions as nucleophiles. The only attempt to measure the relative reactivities of hydroxide and alkoxide ions toward a heterocyclic cation appears to be the work of Gravitz and Jencks306 for the IV,0-trimethylenephthalimidium cation (158). In this study, product analysis indicated the relative proportions of hydroxide and alkoxide adduct... 

At least semiquantitative data on the isomer distribution for the halogenation of a given unsaturated heterocycle have been reported, although no quantitative comparisons of the relative reactivities of different heterocycles are available. As a prelude to examining possible theoretical correlations between the observed site of halogenation and a heterocycle s electronic structure, it is useful to discern... 

Table 7 contains data on the relative reactivity of tellurophene and related heterocycles in typical electrophilic substitution reactions <1973J(P2)2097>. 

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