1.3- Azoles reactivity

The order of azole reactivity will parallel that found for the analogous five-membered heterocycles containing one heteroatom (Chapter 6) [i.e., NH(R) > O > Se > S]. 

Stabilizers UVA 2-(2H-benzotriazol-2-yl)-p-cresol phenol, 2-(5-chloro-2H-benzotriazole-2-yl)-6-(1,1 -dimethylethyl)-4-methyl- 2-(2H-benzotriazol-2-yl)-4,6-bis(1 -methyl-1 -phenylethyl)phenol isopropenyl ethinyl trimethyl piperidol (cellulose diacetate), biphenyl cellulose (UV absorber fro paper), phenylbenzimid-azole (reactive stabilizer for application in cellulosic textiles) Optical brighteners 2,2 -(2,5-thiophenediyl)bis(5-tert-butyl-benzoxazole) Mixtures an ortho-hydroxy tris-aryl-s-triazine compound+hindered hydroxybenzoate compound+hindered amine compound containing a 2,2,6,6-tetraalkylpiperidine or 2,2,6,6-tetraalkylpiperazinone radical ... 

M.o. theory has had limited success in dealing with electrophilic substitution in the azoles. The performances of 7r-electron densities as indices of reactivity depends very markedly on the assumptions made in calculating them. - Localisation energies have been calculated for pyrazole and pyrazolium, and also an attempt has been made to take into account the electrostatic energy involved in bringing the electrophile up to the point of attack the model predicts correctly the orientation of nitration in pyrazolium. ... 

NMR data for 4-methyloxazole have been compared with those of 4-methylthiazole the data clearly show that the ring protons in each are shielded. In a comprehensive study of a range of oxazoles. Brown and Ghosh also reported NMR data but based a discussion of resonance stabilization on pK and UV spectral data (69JCS(B)270). The weak basicity of oxazole (pX a 0.8) relative to 1-methylimidazole (pK 7.44) and thiazole (pK 2.44) demonstrates that delocalization of the oxygen lone pair, which would have a base-strengthening effect on the nitrogen atom, is not extensive. It must be concluded that not only the experimental measurement but also the very definition of aromaticity in the azole series is as yet poorly quantified. Nevertheless, its importance in the interpretation of reactivity is enormous. 

Reactivity of neutral azoles Azolium salts Azole anions... 

In this initial section the reactivities of the major types of azole aromatic rings are briefly considered in comparison with those which would be expected on the basis of electronic theory, and the reactions of these heteroaromatic systems are compared among themselves and with similar reactions of aliphatic and benzenoid compounds. Later in this chapter all the reactions are reconsidered in more detail. It is postulated that the reactions of azoles can only be rationalized and understood with reference to the complex tautomeric and acid-base equilibria shown by these systems. Tautomeric equilibria are discussed in Chapter 4.01. Acid-base equilibria are considered in Section 4.02.1.3 of the present chapter. 

Azole anions are derived from imidazoles, pyrazoles, triazoles or tetrazoles by proto loss from a ring NH group. In contrast to the neutral azoles, azole anions show enhance reactivity toward electrophiles, both at the nitrogen (Section 4.02.1.3.6) and carbon aton (Section 4.02.1.4.1(i)). They are correspondingly unreactive toward nucleophiles. 

The reactivity of these compounds is somewhat similar to that of the azolonium ions, particularly when the cationic species is involved. However, although the typical reaction is with nucleophiles, the intermediate (20) can lose the iV-oxide group to give the simple a-substituted azole (21). Benzimidazole 3-oxides are readily converted into 2-chloroben-... 

Thermal reactions of 1,4,2-dioxa-, 1,4,2-oxathia- and 1,4,2-dithia-azoles are summarized in Scheme 1. The reactive intermediates generated in these thermolyses can often be trapped, e.g. the nitrile sulfide dipole with DMAD. 

Azoles having heteroatoms in the 1,3-orlentatlon are more reactive than those in which the arrangement is 1,2. However, the magnitude of the factor varies. Thus oxazole is 68 times more reactive than Isoxazole, whereas benzoxazole quaternlzes 26 times faster than does 1,2-benzisoxazole (78AHC(22)71). 

Diazo coupling is expected to occur only with highly reactive systems, and experiment bears this out. Diazonium ions couple with the anions of N-unsubstituted imidazoles at the 2-position (e.g. 125 yields 126) and with indazoles (127) in the 3-position. In general, other azoles react only when they contain an amino, hydroxyl, or potential hydroxyl group, e.g. the 4-hydroxypyrazole (128), the triazolinone (129) and the thiazolidinedione (130) (all these reactions occur on the corresponding anions). 

If the reactions of the same substituents on heteroaromatic azoles and on benzene rings are compared, the differences in the reactivities are a measure of the heteroatoms influence. Such influence by the mesomeric effect is smaller when the substituent is /3 to a heteroatom than when it is a or y. The influence by the inductive effect is largest when the substituent is a to a heteroatom. 

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. 

As discussed in Section 4.01.5.2, hydroxyl derivatives of azoles (e.g. 463, 465, 467) are tautomeric with either or both of (i) aromatic carbonyl forms (e.g. 464,468) (as in pyridones), and (ii) alternative non-aromatic carbonyl forms (e.g. 466, 469). In the hydroxy enolic form (e.g. 463, 465, 467) the reactivity of these compounds toward electrophilic reagents is greater than that of the parent heterocycles these are analogs of phenol. 

Pyrazole and indazole anions, in a manner similar to other azole anions, show the expected inversion of reactivity when compared with the cations. They are more reactive towards electrophiles, both at the nitrogen and carbon atoms, and less reactive towards nucleophiles than the corresponding neutral molecules. For practical purposes most of the N -alkylated pyrazoles and indazoles are prepared from the corresponding anions. 

The reactivity of the pyridine-like N-2 atom of pyrazoles and indazoles follows the general trends indicated in Section 4.02.1.3 for azoles. Since this part belongs to the classical chemistry of pyrazoles, earlier results in <66AHC(6)347, 67HC(22)l, B-76MI40402, 79RCR289) will be summarized and occasionally updated. 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

The reactivity of isoxazole toward quaternization is compared with those of pyridine-2-carbonitrile, pyridine and five other azoles in Table 6 (73AJC1949). Isoxazole is least reactive among the six azoles and times less reactive than pyridine. There is also a good correlation between the rate of quaternization and basicity of the azole. 

Table 7 Reactivities of Some Azoles and Other Five-membered Heterocyeles in Acid-catalyzed Deuteriodeprotonation <74jcs(P2)399>...

From the point of view of reactivity, there is little difference between 2-amino-selenazoles and aryl- or alkyl-2-aminoselen azoles, except that the A -arvl derivatives are generally less basic and that their salts are more easily hydrolyzed. 

Minghetti, G., BanditeDi, G. and Bonati, E. (1979) Metal derivatives of azoles. 3. The pyrazolato anion (and homologs) as a mono- or bidentate ligand preparation and reactivity of tri-, hi-, and mononudear... 

The compounds referred to as azolides are heterocyclic amides in which the amide nitrogen is part of an azole ring, such as imidazole, pyrazole, triazole, tetrazole, benzimidazole, benzotriazole, and their substituted derivatives. In contrast to normal amides, most of which show particularly low reactivities in such nucleophilic reactions as hydrolysis, alcoholysis, aminolysis, etc., the azolides are characterized by high reactivities in reactions with nucleophiles within the carbonyl group placing these compounds at about the same reactivity level as the corresponding acid chlorides or anhydrides. 11... 

The reactivity of the various azolides as well as the order of reactivities within this group can be explained on the basis of the quasi-aromatic character of the azole rc-system the lone electron pairs on the acyl-substituted nitrogens N(l) are part of the cyclic tc-system of the azole units, leading to a partial positive charge on N(l) that interferes with the normal carboxamide resonance and exerts an electron-withdrawing effect on the... 

The azolide concept can be extended further to other TV-substituted azoles, such as N-sulfonyl- or TV-phosphorylazoles, for which an analogous gradation of reactivity is observed depending on the choice of the specific azole system. The reactions of these compounds are dealt with in Chapters 10 and 12, respectively. 

Substitution on the carbon atoms of the azole rings has the expected effect electron-withdrawing substituents such as nitro or halogen increase the reactivity of the azolides, whereas alkyl substituents lead to a decrease in transacylation rates. 101... 

---