Heteroaromatic bases

It is a simple matter to determine an ionization constant and also to predict its magnitude. When these values do not agree, and if ringopening has been carefully excluded, the likelihood of covalent hydration must be considered. Equilibria encountered during the determination of the ionization constant of a hydrating heteroaromatic base are shown in the following diagram. Similar equilibria exist for... 

Our next step was to assess whether the methodology used to calculate hydration free energy differences for simple carbonyl-containing compounds9 was suitable for heteroaromatic bases. Since our drug design strategy entailed analysis of purine riboside hydration, a series of azanaphthalenes was initially selected for analysis in part because of their structural similarity to purines and in part because of the extensive... 

E. Buncel, in The Chemistry of Functional Groups, Supplement F (Ed. S. Patai), Chap. 27, Wiley, Chichester 1982 E. Buncel, M. R. Crampton, M. J. Strauss and F. Terrier, Electron-Deficient Aromatic- and Heteroaromatic-Base Interactions, Elsevier, Amsterdam, 1984. 

Electron Deficient Aromatic- and Heteroaromatic-Base Interactions. 

F. Terrier, Eiectron Deficient Aromatic and Heteroaromatic Base Interactions. The Chemistry of Anionic Sigma Complexes, pp. 78-85. Elsevier, Amsterdam, 1984. 

Homolytic alkylation of homocyclic aromatic substrates is of much less interest than homolytic arylation because, in addition to the low selectivity, which also characterizes arylation, yields are usually poor, due to side reactions which compete seriously with the simple substitution reaction. The behavior of nonprotonated heteroaromatic substrates is similar. The case is quite different with protonated heteroaromatic bases because side reactions are eliminated or minimized, yields are generally good, and, above all, the selectivity is very high. Moreover, very versatile and easily available sources of alkyl radicals can be used under simple experimental condition it follows that homolytic alkylation of protonated heteroaromatic bases can be considered one of the main reactions of this class of compounds. 

O3yhydroperoxides. Peroxides of the oxyhydro type are obtained by the addition of hydrogen peroxide to ketones. High yields of alkyl radicals are then often obtained by reaction with ferrous salts. 1-Meth-oxycyclohexyl hydroperoxide is easily obtained from cyclohexanone and hydrogen peroxide in methanol. It gives rise to the 5-(methoxy-carbonyl)-pentyl radical, which has been used to alkylate protonated heteroaromatic bases in high yield [Eq. (6)]. 

The oxidative decarboxylation of carboxylic acids is the most convenient source for the alkylation of protonated heteroaromatic bases owing to their easy availability and the high versatility of the reaction, which permits methyl, primary, secondary, and tertiary alkyl radicals to be obtained under very simple experimental conditions. The following methods have been utilized. 

This method can be used with heteroaromatic bases, such as thiazoles or pyrazines, which complex with the silver salt and reduce its catalytic activity. A disadvantage of the method is that the heteroaromatic base can be only partially protonated under these conditions. 

Oxidation of tertiary alcohols by lead tetraacetate gives alkyl radicals by /3-scission of the initially formed alkoxy radicals. The reaction has been used to alkylate protonated heteroaromatic bases using 1-methyl-cyclohexanol. (Scheme 4). 

The acyl radicals obtained by hydrogen abstraction from aldehydes easily attack protonated heteroaromatic bases. With secondary and tertiary acyl radicals decarbonylation competes with the aromatic acylation [Eq. (12)]. 

Some oxaziranes can be prepared very simply from ketones and N-chloroamines. Thus 2-methyl-3,3-pentamethyleneoxazirane is easily obtained from cyclohexanone and iV-methylchloramine its reduction by ferrous salts gives an alkyl radical, which has been used to alkylate, in high yield, protonated heteroaromatic bases in aqueous solution (Scheme 5). 

It is influenced by both the nature of the heteroaromatic base and the radical source. 

A quite different reaction course was observed with benzoyl peroxide. The increase in the decomposition rate on going from nonprotonated to protonated quinoline is relatively small. The high decomposition rate of decanoyl peroxide in the presence of protonated heteroaromatic bases was mainly ascribed to the nucleophilic character of the alkyl radicals, which allows the complete capture of the nonyl radicals escaping from the solvent cage and the consequently rapid induced decomposition. The... 

There is spectroscopic evidence that the initial step of the photochemical process is hydrogen abstraction by the excited state of the heteroaromatic base [Eq. (23)]. 

The alkylation with alcohols and amines can lead to alkyl derivatives or a-hydroxy and a-aminoalkyl derivatives according to the nature of the heteroaromatic base and the reaction conditions. The intermediate products in both cases are, however, the a-hydroxy and a-aminoalkyl dihydro derivatives, which can be aromatized by disproportionation or oxidation, while the loss of water or ammonia leads to the alkyl derivatives (Scheme 7). 

The ease of abstraction of hydrogen in the a-position of alcohols and amines is due to the electrophilic character of the abstracting species (the excited heteroaromatic base, particularly if it is protonated). 

The homolytic alkylation of protonated heteroaromatic bases is characterized by a very high selectivity (Table II). 

This high sensitivity to polar effects of the homolytic alkylation of protonated heteroaromatic bases has been interpreted in terms of the transition state.This would be similar to a w-complex in which an enhanced contribution of polar forms (5) would explain the high sensitivity to polar influence. 

Two sources of acyl radicals have proved to be useful for the homolytic acylation of protonated heteroaromatic bases the oxidation of aldehydes and the oxidative decarboxylation of a-keto acids. The oxidation... 

Also in this case the acyl radical can be oxidized by the ferric salt, but in the presence of protonated heteroaromatic bases the aromatic attack successfully competes with the oxidation. The process has great versatility and can be carried out with a large variety of aldehydes (aliphatic, a,jS-unsaturated, aromatic, and heteroaromatic). 

The acyl radicals attack the protonated heteroaromatic bases with good results, although the oxidizing medium can lead to the competitive processes of Eqs. (31) and (32). 

The high reactivity of protonated heteroaromatic bases towards acyl radicals is shown by the success of the reaction with the pivaloyl radical, which usually undergoes rapid decarbonylation [Eq. (33)]. 

Protonated heteroaromatic bases are therefore more reactive than simple olefins toward acyl radicals. The radical addition of pivalaldehyde to olefins is, in fact, characterized by a radical chain, whose propagation is determined by decarbonylation of the pivaloyl radical and addition of <-butyl radical to the olefin. The synthetic interest is great in the case of substrates with only one reactive position, such as benzothiazole, ... 

It is possible to obtain selective monoacylation even if the heteroaromatic base has more free reactive positions, by taking advantage of the protonation equilibria of the starting base and the reaction products. Thus with 4-cyanopyridine, which has two free reactive positions, the introduction of an acyl group in position 2 decreases the basic character and therefore allows selective monoacylation by the precipitation of the unprotonated reaction product. 

The homolytic acylation of protonated heteroaromatic bases is, as with alkylation, characterized by high selectivity. Only the positions a and y to the heterocyclic nitrogen are attacked. Attack in the position or in the benzene ring of polynuclear heteroaromatics has never been observed, even after careful GLC analysis of the reaction products. Quinoline is attacked only in positions 2 and 4 the ratio 4-acyl- to 2-acylquinoline was 1.3 with the acetyl radical from acetaldehyde, 1.7 with the acetyl radical from pyruvic acid, and 2.8 with the benzoyl radical from benzaldehyde. 

The high selectivity of homolytic acylation of protonated heteroaromatic bases and the fact that under the same experimental conditions homocyclic substrates (benzene, anisole, nitrobenzene, protonated aniline, and A,A-dimethylaniline) are not attacked, indicate that polar effects play a dominant role. Only aromatic substrates with very strong electron-deficient character give rise to significant homolytic acylation. 

Also, the results of the substituent effects in homolytic acylation of protonated heteroaromatic bases must be connected, as for homolytic alkylation, with the polar characteristics of the acyl radicals and the aromatic substrates, but not with the stabilization of the intermediate a-complexes. 

The a-oxyalkyl radicals used for alkylating heteroaromatic bases are formed by the oxidation of alcohols and ethers with a variety of electrophilic radicals or photochemically. 

Oxidation of alcohols with a variety of oxidizing agents leads to a-hydroxyalkyl radicals. These attack protonated heteroaromatic bases only when obtained from methanol or primary alcohols, with secondary alcohols no attack takes place, probably owing to the ease with which such a-hydroxyalkyl radicals are oxidized. (This limitation does not apply to radiation-induced oxyalkylation, see later.)... 

If the mechanism in acid and without acid are the same, one might have expected 4-alkylation under both conditions, and the failure to observe any 4-alkylation when acid is not present is as yet unexplained. Possibly with nonprotonated bases the hydroxyalkylation occurs according to Scheme 11, in which dimerization of two radicals within the solvent cage would lead to attack only at position 2, while in acid the attack could take place, at least in part, according to Scheme 12 but with protonated base, leading to both the isomers (2 and 4), as in the hydroxyalkylation by oxidation of alcohols. The much higher affinity of alkyl radicals toward protonated heteroaromatic bases in comparison with nonprotonated bases would support this interpretation. 

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