Protonated heterocycles

The nitration of phenylpyridines and related compounds has attracted attention for a long time, and measurements of isomer proportions have been made for several compounds of this type. Nitration occurs in the phenyl ring. For 2-phenylpyridine and 2-phenylpyridine i-oxide measurements of the dependence of rate of nitration upon acidity in 75-81 % sulphuric acid at 25 °C show that both compounds are nitrated as their cations (table 8.1). The isomer distribution did not depend significantly upon the acidity, and by comparison with the kinetic data for quinolinium ( 10.4.2) the partial rate factors illustrated below were obtained.They should be compared with those for the nitration of 2-nitrobiphenyl ( 10.1). The protonated heterocyclic groups are much... 

In this section three main aspects will be considered. Firstly, the basic strengths of the principal heterocyclic systems under review and the effects of structural modification on this parameter will be discussed. For reference some pK values are collected in Table 3. Secondly, the position of protonation in these carbon-protonating systems will be considered. Thirdly, the reactivity aspects of protonation are mentioned. Protonation yields in most cases highly reactive electrophilic species. Under conditions in which both protonated and non-protonated base co-exist, polymerization frequently occurs. Further ipso protonation of substituted derivatives may induce rearrangement, and also the protonated heterocycles are found to be subject to ring-opening attack by nucleophilic reagents. 

A Hammett correlation was not observed, due to enhanced conjugation (4) between the electron-releasing groups and the protonated heterocyclic nitrogen. ... 

Acyl radicals obtained by the oxidation of aldehydes or the oxidative decarboxylation of a-keto acids react selectively at the a- or y-position of the protonated heterocyclic nitrogen. Pyridines, quinolines, pyrazines and quinoxalines all react as expected yields are typically 40 to 70%. Similarly, pyridines can be carbamoylated in acid media at C-2 (Scheme 38). 

The acid-catalyzed dimerization of pyrroles and indoles also involves electrophilic attack by the 2H- or 3//-protonated species upon the non-protonated heterocycles (Schemes 6, 7 and 8, Section 3.05.1.2.2), and 3,3-dimethyl-3//-indole has been reported to react with 7r-electron-rich aromatic compounds to yield the 2-ary.l-3,3-dimethyl-2,3-dihydroindoles (77S343). In the absence of a nucleophile strong acids promote the interchange of substituents at the 2- and 3-positions of 2,3,3-trisubstituted 3//-indoles, e.g. (510) (511) (62JOC1553). 

Table 4.70. Carbon-Fluorine Coupling Constants of Isomeric Fluoropyridines and of 2-Fluoropurine (in Hz) [469]. If available, Couplings of the Protonated Heterocycles are Printed in Parentheses.

These results seem to indicate that there are two pathways leading to the nitro products for the 2- and 4-phenylpyrimidines. Nitration of the free base, or of the protonated heterocycle, leads to meta nitration. However, if an N-nitro intermediate is formed, which can undergo intramolecular nitration in a solvent cage, then ortho attack results (Fig. 12). 

The Friedel-Crafts alkylation and acylation are of very little, if any, synthetic interest when applied to heterocyclic aromatic bases the substitution of protonated heterocycles by nucleophilic carbon-centered radicals is instead successful. This reaction, because of the dominant polar effect which is mainly related to the charge-transfer character of the transition state (Scheme 1), reproduces most of the aspects of the Friedel-Crafts aromatic substitution, but reactivity and selectivity are the opposite. 

The general reaction mechanism is shown in Scheme 2. The high rate constants (from 10s to 108 m 1 s 1) for addition of nucleophilic radicals to protonated heterocycles [3] reduce other possible competitive side reactions of the radicals involved, strongly contributing to the synthetic interest. 

The presence of a strong acid such as trifluoroacetic acid is beneficial, because the protonated heterocycles possess increased reactivity. Satisfactory yields were also obtained using BTI in the absence of added acid, which was, however, produced from BTI. An idea about the applicability of this methodology can be formed from Table 4.8. 

The use of tandem mass spectrometry <88MI 711-08) to study the collision-induced dissociation of protonated heterocycles has invited further attention in the 1990s. Thus following collisional acti-... 

F. Minisci and co-workers generated alkyl radicals from alkyl iodides under simple conditions (thermal decomposition of dibenzoyl peroxide) and used it for selective C-C bond formation on protonated heterocycles. The method was successfully applied to complex substrates, such as 6-iodo-1,2,3,4-diisopropylidene-a-galactose, which was reacted with protonated 2-methylquinoline to give the corresponding C-nucleoside in excellent yield. 

The Introduction of substituent groups into protonated heterocyclic bases by fre r gicals, pioneered by Miniscl and well reviewed over the past few years,continues tjgbe actively explored f gther studies on alkylations, acylations, and carboethoxylatlons have been reported. 

There are too few diffraction data for the NH+.. X- system of protonated heterocycles. We thus had to look for correlations between the Fh. . o force constants and the R(0.. 0) distances (Fig. 10). The compounds chosen cover a rather wide range of R(0.. O) distances, between... 

An instructive and useful process is the two-component coupling of an alkene with an electrophilic radical the latter will of course not react with the protonated heterocycle, but after addition to the alkene, a nucleophilic radical is generated, which will react. ... 

Nucleophilic displacement of halogen with ammonia and amines can be accelerated by carrying out the displacements in acid solution, when the protonated heterocycle is more reactive than the neutral heterocycle. Halogen can also be easily removed hydrogenolytically, for example treatment of 2,4-dichloropyrimidine, readily available from uracil, with hydrogen, in the presence of palladium, or with hydrogen iodide, gives pyrimidine itself. ... 

Iron catalyzed free radical amination of aromatics or free radical carbamylation, alkylation of protonated heterocycles (see 1st edition). 

The homoljdic amination is of less use with heterocyclic than with homocyclic aromatic compounds because either the heteroccylic compounds are too deactivated (protonated heteroaromatic bases) or they are unstable in the strongly acidic medium usually required by the reaction. Thus, quinoline cannot be aminated because the protonated heterocyclic nitrogen deactivates both rings. In the... 

Particularly suitable models were provided by the homolytic substitutions of 4-substituted pyridines and 2- and 4-substituted quinolines, which are selectively attacked respectively in the positions 2, 4 and 2 by nucleophilic carbon free radicals. The positional selectivity is in fact always determined by the protonated heterocyclic nitrogen, wliich has a much more activating effect than the common substituents. 

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