Pyridine like nitrogen

The pyridine-like nitrogen of the 2H-pyrrol-2-yiidene unit tends to withdraw electrons from the conjugated system and deactivates it in reactions with electrophiles. The add-catalyzed condensations described above for pyrroles and dipyrromethanes therefore do not occur with dipyrromethenes. Vilsmeier formylation, for example, is only successful with pyrroles and dipyrromethanes but not with dipyrromethenes. 

For the NH azoles (Table 3), the two tautomeric forms are usually rapidly equilibrating on the NMR timescale (except for triazole in HMPT). The iV-methyl azoles (Table 4) are fixed chemical shifts are shifted downfield by adjacent nitrogen atoms, but more by a pyridine-like nitrogen than by a pyrrole-like iV-methyl group. 

In general, the solubility of heterocyclic compounds in water (Table 33) is enhanced by the possibility of hydrogen bonding. Pyridine-like nitrogen atoms facilitate this (compare benzene and pyridine). In the same way, oxazole is miscible with water, and isoxazole is very soluble, more so than furan. 

Substituents cannot directly conjugate with /3-pyridine-like nitrogen atoms. Azole substituents which are not a or y to a pyridine-like nitrogen react as they would on a benzene ring. Conjugation with an a-pyridine-like nitrogen is much more effective across a formal double bond thus the 5-methyl group in 3,5-dimethyl-l,2,4-oxadiazole (323) is by far the more reactive. 

A different type of rearrangement occurs when suitable side chains are a to a pyridine-like nitrogen atom. In the monocyclic series this can be generalized by Scheme 43. For a given side chain the rate of rearrangement is l,2,4-oxadiazoles>isoxazoles> 1,2,5-oxadiazoles. Typical side chains include hydrazone, oxime and amidine. Some examples are shown in Table 9 (79AHC(25)147). Similar rearrangements for benzazoles are discussed in Section 4.02.3.2.4. 

Such groups a to a pyridine-like nitrogen atom are expected to undergo Michael additions. Examples are known in the imidazole series. 

Amino and sulfur analogues of pyrazolones also yield the aromatic quaternary salt (231 X = NH or S). If the pyrazole bears a substituent with a second pyridine-like nitrogen atom, an intramolecular bridge can be formed by reaction with a dihalogenoalkane. Thus pyrazol-I -ylpyridines react with 1,2-dibromoethane to form (233) (81JHC9). 

Note that nitrogen atoms have different roles depending on the structure of the molecule. The nitrogen atoms in pyridine and pyrimidine are both in double bonds and contribute only one tt electron to the aromatic sextet, just as a carbon atom in benzene does. The nitrogen atom in pyrrole, however, is not in a double bond and contributes two tt electrons (its lone pair) to the aromatic sextet. In imidazole, both kinds of nitrogen are present in the same molecule— a double-bonded "pyridine-like" nitrogen that contributes one v electron and a pyrrole-like" nitrogen that contributes two. 

Just as there are heterocyclic analogs of benzene, there are also many heterocyclic analogs of naphthalene. Among the most common are quinoline, iso-quinoline, indole, and purine. Quinoline, isoquinoline, and purine all contain pyridine-like nitrogens that are part of a double bond and contribute one electron to the aromatic it system. Indole and purine both contain pyrrole-like nitrogens that contribute two - r electrons. 

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. 

Purine has three basic, pyridine-like nitrogens with lone-pair electrons in sp2 orbitals in the plane of the ring. The remaining purine nitrogen is nonbasic and pyrrole-like, with its lone-pair electrons as part of the aromatic i- electron system. 

Alkylation of the pyridine-like nitrogen in 1 with the Meerwein s salt allowed the preparation of a derivative 2 of this ring system suitable for the evaluation of intercalating properties (Scheme 1) <2000BML1767, 1996BML2831>. 

It also follows that a compound like imidazole has one pyridine-like nitrogen, and one pyrrolelike nitrogen. We may thus expect to see imidazole having properties resembling a combination of either pyridine- or pyrrole-like reactivity. The availability and location of lone pair electrons is crucial to our imderstanding of imidazole chemistry, and it often helps to include these in the stmcture. 

The formation of jp -carbanions adjacent to pyridine-like nitrogen in 6-membered heteroaromatic rings is complicated by the fact that with alkyl and aryllithiums, 1,2-nucleophilic addition to the azomethine double bond (Scheme 103) normally occurs in preference to metalation [88H2659, 88MI2 88T1 90H(31)1155 91AHC(52)187]. 

The C(5) position of 1-substituted 1,2,3-triazoles is activated towards nucleophilic attack by a pyridine-like nitrogen, and the equivalent C(4) and C(5) positions of 2-substituted 1,2,3-triazoles are weakly activated. However, a suitable leaving group, such as a halogen, is generally required for nucleophilic substitution <88BSB573>. 

As polyazaheterocycles with pyridine-like nitrogen atoms, pteridines are not noted for ready electrophilic substitution <1996CHEC-II(7)679>. No significant new examples appear to have been reported during the period covered by this chapter. 

The substitution of pteridines at positions adjacent to the pyridine-like nitrogen atoms in either the pyrimidine or the pyrazine is a well-established synthetic procedure and remains an important contributor to the synthesis of complex substituted pteridines. Significant extensions of these methods have been described at both the pyrimidine and pyrazine rings. 

The presence of the pyridine-like nitrogen deactivates the 1,3-azoles toward electrophilic attack, and increases their affinity towards nucleophilic attack. 

Like 1,3-azoles, due to the presence of a pyridine-like nitrogen atom in the ring, 1,2-azoles are also much less reactive towards electrophilic substitutions than furan, pyrrole or thiophene. However, 1,2-azoles undergo electrophilic substitutions under appropriate reaction conditions, and the main substitution takes place at the C-4 position, for example bromination of 1,2-azoles. Nitration and sulphonation of 1,2-azoles can also be carried out, but only under vigorous reaction conditions. 

The introduction of a pyridine-like nitrogen into a benzene ring tends to make a derivative more crystalline and less volatile this effect is greater for the diazines, especially pyridazine and pyrazine. Wien a hydrogen-bond donor substituent is also carried, the difference from the benzenoid compound becomes even more marked. 

Finally one can conclude that despite still remaining uncertainties there exist some firmly established aromaticity regularities in series of six-membered heterocycles. They are (1) Increase in the electronegativity of the heteroatom leads to decrease of aromaticity (2) Aromaticity falls with increasing the number of pyridine-like nitrogens in the ring (3) Transition from simple azines to their benzoderivatives is also accompanied by a decrease of aromaticity. 

The reliability of semi-empirical methods (AMI, PM3, and MNDO) for the treatment of tautomeric equilibria has been tested for a series of five-membered nitrogen heterocycles, including 1,2,3-triazole and benzotriazole. The known tendency of MNDO to overestimate the stability of heterocycles with two or more adjacent pyridine-like lone pairs is also present in AMI and to a somewhat lesser extent in PM3. Tautomers with a different number of adjacent pyridine-like nitrogens cannot be adequately treated by these semi-empirical methods. Both AMI and PM3 represent major improvements over MNDO in the case of lactam-lactim tautomerism. The stability of N-oxides as compared to N-hydroxy tautomers is overestimated by PM3 method. All three methods give reliable ionization potentials and dipole moments (90ZN(A)1328). 

Chemical shifts for aromatic azoles are recorded in Tables 17-20. Fast tautomerism renders two of the C-13 chemical shifts equivalent for the NH derivatives just as in the proton spectra (Table 17). However, data for the A-methyl derivatives (Table 18) clearly indicate that the carbon adjacent to a pyridine-like nitrogen shows a chemical shift at lower field than that adjacent to a pyrrole-like N-methyl group (in contrast to the H chemical shift behavior). In azoles containing oxygen (Table 19) and sulfur (Table 20), the chemical shifts are generally at lower field than those for the wholly nitrogenous analogues, but the precise positions vary. 

The analogous reactions of pyridines with these electrophilic reagents at the lone pair on the nitrogen atom are well known. All neutral azoles contain a pyridine-like nitrogen atom and therefore similar reactions with electrophiles at this nitrogen would be expected. However, the tendency for such reactions varies considerably in particular, successive heteroatom substitutions markedly decrease the ease of reaction. One convenient quantitative measure of the tendency for such reactions to occur is found in the basicity of these compounds this is treated in Section 3.4.1.3.5 and 3.4.1.3.7. 

N-Oxidation may be formally considered as quatemization of pyridine-like nitrogen atom by the HO+ cation, formed by heterolysis of 0-0 bond in the peracid molecule. Indeed, common features exist between N-alkylation and N-oxidation both reactions are second order (first order at each reagent). The reaction constant, p, for oxidation of 3- and 4-substituted pyridines by PhC03H in aqueous dioxane is -2.35, Close to the p value for N-alkylation (Chem. of the Heterocyclic N-oxides, N-Y, Acad. Press, 197l). 

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