Pyrazole, aromaticity

The synchronous formation of pyrazole aromaticity in a [3,3]-sigmatropic rearrangement is said to provide a strong thermodynamic driving force for the rearrangement and a low enthalpy barrier (Scheme 21). ... 

The compounds of this article, ie, ftve-membered heterocycles containing two adjacent nitrogen atoms, can best be discussed according to the number of double bonds present. Pyrazoles contain two double bonds within the nucleus, imparting an aromatic character to these molecules. They are stable compounds and can display the isomeric forms, (1) and (2), when properly substituted. Pyrazoles are scarce ia nature when compared to the imidazoles (3), which are widespread and have a central role ia many biological processes. 

The carbon atoms of azole rings can be attacked by nucleophilic (Section 4.02.1.6 electrophilic (Section 4.02.1.4) and free radical reagents (Section 4.02.1.8.2). Some system for example the thiazole, imidazole and pyrazole nuclei, show a high degree of aromati character and usually revert to type if the aromatic sextet is involved in a reaction. Othei such as the isoxazole and oxazole nuclei are less aromatic, and hence more prone to additio reactions. 

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

The 3H- and 4//-pyrazoles and 2H- and 4//-imidazoles (83UP40200) contain two doable bonds in the heterocyclic ring, but in each case the conjugation does not include all the ring atoms hence the compounds are not aromatic. 

Some tetrahydro azoles can be aromatized, but this is more difficult than in the corresponding dihydro series. Thus the conversion of pyrazolidines into pyrazoles is accomplished with chloranil. Imidazolidines are aromatized with great difficulty. 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

The systems discussed here are aromatic systems which undergo a variety of isomerizations on irradiation. Irradiation of imidazoles led to a scrambling of substituents, whereas such scrambling has not been observed in the pyrazoles which undergo photoisomerization to imidazoles. 

The pyrazole ring is particularly difficult to cleave and, amongst the azoles, pyrazoles together with the 1,2,4-triazoles are the most stable and easiest to work with. This qualitative description of pyrazole stability covers the neutral, anionic and cationic aromatic species. On the other hand, the saturated or partially saturated derivatives can be considered as hydrazine derivatives their ring opening reactions usually involve cleavage of the N—C bond and seldom cleavage of the N—N bond. It should be noted, however, that upon irradiation or electron impact the N—N bond of pyrazoles can be broken. 

Three double bonds. The most fully oxidized pyrazoles, the typical non-aromatic representatives of which are the pyrazoline-4,5-diones (1) and the pyrazolidine-3,4,5-triones (2), should be included here. 

Two double bonds. This is the most important class which includes the aromatic compounds pyrazole (3), indazole (4) and isoindazole (5), their non-aromatic isomers, pyrazolenines (or 3iL-pyrazoles 6), isopyrazoles (or 4JT-pyrazoles 7) and 3JT-indazoles (8), and the carbonyl derivatives of pyrazolines with the endocyclic double bond in positions 1, 2 or 3, i.e. (9), (10) and (11), respectively. The indazolones (12) and the pyrazolidinediones (13) and (14) also belong to this group. 

In this section, reactivity studies will be emphasized while in those devoted to synthesis (Section 4.04.3) theoretical calculations on reactions leading to the formation of pyrazoles (mainly 1,3-dipolar cycloadditions) will be discussed. It should be emphasized that the theoretical treatment of reactivity is a very complicated problem and for this reason, most of the calculations have been carried out on aromatic compounds, as they are the easiest to handle. In general, solvents are not taken into account thus, at the best, the situation described theoretically corresponds to reactions taking place in the gas phase. 

The excellent book by the late Professor T. J. Batterham contains all the available information (up to 1973) on pyrazoles and their non-aromatic derivatives (B-73NMR165) and on indazoles (B-73NMR263). The bibliography for pyrazoles and pyrazolones has been updated in (B-76MI40402). It should be emphasized that almost all the principal results about the H NMR spectra of these heterocycles were published at that time, and thus only a summary of the principal conclusions is needed here. 

Neither (71PMH(3)67) nor (B-76MI40402) contains information on non-aromatic derivatives of pyrazole. Table 21 gives some references to these compounds, including aromatic pyrazolones. 

Hi) Pyrazole rings containing carbonyl groups In this subsection compounds with a pyrazole C—O bond will be discussed independently of their aromatic character. In solution the tautomers of pyrazolinones, e.g. (78a), (78b) and (78c), are easily identified by their IR spectra (Figure 18) (76AHC(Sl)l). 

A book (B-71MS) and a review by Nishiwaki (74H(2)473) contain much information about the behaviour of pyrazoles under electron impact. The Nishiwaki review covers mainly the hydrogen scramblings and the skeletal rearrangements which occur. One of the first conclusions reached was that pyrazoles, due to their aromatic character, are extremely stable under electron impact (67ZOR1540). In the dissociative ionization of pyrazole itself, the molecular ion contributes about 45% to the total ion current thus, the molecular ion is the most intense ion in the spectrum. 

Since aromaticity is, at best, a relative value, the problem of the aromaticity of pyrazole, compared to other azoles, is to be found in Section 4.01.1.2, in which the authoritative review by Cook et al. (74AHC(17)255) is summarized. 

After the publication of a book on the prototropic tautomerism of aromatic heterocycles (76AHC(Sl)l) which covered the literature up to 1975, the study of the tautomerism of pyrazoles has not made great strides. In this section the main conclusions of this earlier review will be summarized and comments on a few recent and significant references added. 

Aromatic pyrazoles and indazoles, in the broad sense defined in Sections 4.04.1.1.1 and 4.04.1.1.2, will be discussed here. Tautomerism has already been discussed (Section 4.04.1.5) and acid-base equilibria will be considered in Section 4.04.2.1.3. These two topics are closely related (Scheme 10) as a common anion (156a) or a common cation (156b) is generally involved in the mechanism of proton transfer (e.g. 78T2259). For aromatic pyrazoles with exocyclic conjugation there is also a common anion (157) for the three tautomeric forms... 

Having its pyrazolic 4-position substituted, electrophilic attack on indazoles takes place in the 3-position and in the homocycle (the 5- and 7-positions). The condensation of a benzene ring results in a decrease of the aromaticity of the pyrazole moiety, as in naphthalene compared to benzene, and therefore basic ring cleavage is easier in indazoles than in pyrazoles (Section 4.04.2.1.7(v)). 

The only structures definitely established are those obtained from X-ray measurements. Some of these are shown in Table 30, from which a large number of aromatic pyrazole geometries can be found. 

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). 

As discussed in the theoretical section (4.04.1.2.1), electrophilic attack on pyrazoles takes place at C-4 in accordance with localization energies and tt-electron densities. Attack in other positions is extremely rare. This fact, added to the deactivating effect of the substituent introduced in the 4-position, explains why further electrophilic substitution is generally never observed. Indazole reacts at C-3, and reactions taking place on the fused ring will be discussed in Section 4.04.2.3.2(i). Reaction on the phenyl ring of C- and A-phenyl-pyrazoles will be discussed in Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i), respectively. The behaviour of pyrazolones is quite different owing to the existence of a non-aromatic tautomer. 

Table 31 Kinetic Nitration Studies on Pyrazoles and Aromatic Pyrazolones (Reagent HNO3/H2SO4)...

Many reagents are able to chlorinate aromatic pyrazole derivatives chlorine-water, chlorine in carbon tetrachloride, hypochlorous acid, chlorine in acetic acid (one of the best experimental procedures), hydrochloric acid and hydrogen peroxide in acetic acid, sulfuryl chloride (another useful procedure), etc. iV-Unsubstituted pyrazoles are often used as silver salts. When methyl groups are present they are sometimes chlorinated yielding CCI3 groups. Formation of dimers and trimers (308 R = C1) has also been observed. 

A-Oxidation with peracids (Section 4.04.2.1.3) and the transformation of pyrazoles into 4,4-dihalogeno-2-pyrazolin-5-ones (Section 4.04.2.1.4(v)) have already been discussed. Transformation of non-aromatic 2-pyrazolin-5-ones into the 4-oxo derivatives will be examined in Section 4.04.2.2.l(ii). 

Very little is known about nucleophilic attack on an unsubstituted carbon atom of pyrazoles and their aromatic derivatives (pyrazolones, pyrazolium ions). The SwAr reaction of halogenopyrazoles will be discussed in Section 4.04.2.3.7. Sulfur nucleophiles do not attack the ring carbon atoms of pyrazolium salts but instead the substituent carbon linked to nitrogen with concomitant dequaternization (Section 4.04.2.3.lO(ii)). The ring opening of pyrazolium salts by hydroxide ion occurs only if carbon C-3 is unsubstituted the exact mechanism is unknown and perhaps involves an initial attack of OH on C-3. 

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