Pyrazole relative aromaticity

According to the indices, pyrazole is more aromatic than imidazole. The stability of azoles generally increases with an increasing number of aza-groups, though some exceptions are known. The relative aromaticities of triazoles and tetrazole are questionable. 2H-1,2,3-Triazole (/= 88%) which is the more stable in the gas phase reveals more bond levelling than 1//-1,2,3-triazole (1=13%). 

TT-Electron delocalization in isoxazole seems to be more effective than in oxazole however, isothiazole is less aromatic than thiazole thus it is not a general rule that 1,2-diazoles possess higher aromaticity in comparison with 1,3-diazoles. Oxygen-containing heterocycles are always less aromatic than their sulfur and nitrogen counterparts, e.g. thiazole > imidazole > > oxazole. At the same time, the relative aromaticity of S- and N-containing heterocycles can interchange (pyrazole > isothiazole > isoxazole). 

Magnetic criteria have received wide application mainly as a qualitative test for aromaticity and antiaromaticity. The values of the exaltation of diamagnetic susceptibility (in 10-6A cm-3 mol-1), and therefore aromaticity, decrease in the sequence thiazole (17.0) > pyrazole (15.5) > sydnone (14.1). The relative aromaticity of heterocycles with a similar type of heteroatom can be judged from values of the chemical shifts of ring protons. The latter reveals paramagnetic shifts when Tr-electron delocalization is weakened. For example, in the series of isomeric naphthoimidazoles aromaticity decreases in the sequence naphthof 1,2-djimidazole (8 = 7.7-8.7 ppm) > naphtho[2,3- perimidine (8 = 6.1-7.2 ppm). This sequence agrees with other estimates, in particular with energetic criteria. 

The relative aromaticities of isomers of oxygen and sulfur heterocycles can be predicted in a similar way, e.g., thiatriazoles . Of course, the most stable isomer of a pair, as measured by heat of formation, is not necessarily the most aromatic in fact, imidazole (A7/f = 132.9 kj mol ) is thermodynamically more stable than pyrazole (Hf= 179.4 kj mol-1) <1999JPCA9336>. Nevertheless, the empirical rule that 1,2-nitrogen interactions are more favorable for aromaticity than 1,3-nitrogen interactions is a convenient guide to the relative stabilities of closely related azole isomers in the gas phase <2010T2695>. 

The fact that 3-hydroxypyrazoles are always predominant in the equilibria with their corresponding CH-tautomers is related to their aromaticity. Qualitative interpretations supported the hypothesis that the NH tautomer was less aromatic than the OH tautomer, and the CH tautomer was nonaromatic. Nuclear independent chemical shifts (NICS) values were calculated by using Schleyer s approach in order to determine the relative aromaticity of the pyrazole NH and OH tautomers using pyrrole as a reference. For pyrazole itself, the NICS value was close to pyrrole (—15.1 ppm). The NICS values were found to be —14.55 ppm for the 5-OH tautomer and —14.45 ppm for the 3-OH tautomer, indicating that the OH substituent does not alter the aromaticity of pyrazole and dipolar charges are not relevant. The NH tautomer has a NICS value of —6.75 ppm, intermediate between the OH tautomers and the nonaromatic CH tautomer, the latter with a NICS value of —0.25 ppm. 

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. 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

In an attempt to prepare the lophine (2,4,5-triphenylimidazole) derivative 55, we instead obtained 56 [70], This corresponds to a [l,5]-sigmatropic migration of a methoxy group and proves that the nonaromatic structure 56 is more stable than the aromatic one 55. This prompted us to examine theoretically the problem and study the related case of 57/58 [71]. At the G3B3 level the relative stabilities of 57, 58a, and 58b (in kJ mol1) are 202.3, 41.3, and 0.0, respectively. These studies were extended to other substituents (like fluorine) and to other azoles (like pyrazoles). 

Formylation and bromination of 1,3-disubstituted l//-thieno- and -sele-nolo 3,2-phenyl derivatives, the rates of formylation relative to that of thiophene were 0.61 and 1.77 for the S and Se compounds, respectively (73JOU2216). Although the lone pair on N-l is conjugated with the 5-position, the 5-position is also conjugated with N-2, and as a result there is little overall activation. Moreover, conjugation between N-l and C-5 reduces the aromaticity of the N-containing ring and is therefore unfavorable. 

Amino-1,2-azoles exist as the amino tautomers. Amino-pyrazoles and amino-isothiazoles are relatively well-behaved aromatic amines, for example 3(5)-aminopyrazole undergoes substituent-A-acetylation and easy electrophilic bromination at C-4. Diazotisation and a subsequent Sandmeyer reaction provides routes to halo-isothiazoles and azido-pyrazoles. ... 

A multi-component one-potreaction of ethyl acetoacetate (57), aromatic aldehydes (58), hydrazine (31), and malononitrile (50) in water afforded dihydropyrano[2,3-c] pyrazoles (59) in good yields (79%-95%) under ultrasonic irradiation in relatively short reaction times (15-40 min). In the absence of nltrasound, the products were obtained in comparatively lower yields (70%-86%) and longer reaction times (60-300 min) (Zou et al. 2011). Darandale et al. (2012) reported a simple and practical ultrasound-promoted synthetic protocol for the synthesis of dihydropyrano[2,3-c] pyrazoles (59) nsing sodium bisulfite (NaHSOj) as a green catalyst in solvent-free conditions. The latter method provides the advantage of a shorter reaction time (30 s) and excellent yields (97%-99%) (Scheme 8.19). 

Electrophilic Reactions. Further studies aimed at the correlation of the reactivity of five-membered heteroaromatic rings towards electrophiles have been reported. Acid-catalysed hydrogen exchange rates were measured (n.m.r.) for isoxazole, isothiazole, and their 3- and 5-methyl derivatives. Extrapolated values for the rate constants at 100 °C and pH 0 were obtained and compared with those for other ring systems. Quantitative effects of the methyl groups reflect the relative degree of bond fixation, and indicate that the aromaticity increases in the series isoxazole, pyrazole, and isothiazole. ... 

Hydrogen borrowing and dehydrogenative condensations provide new opportunities for the preparation of both saturated and aromatic heterocycles respectively. The ability to directly access azacycles from stable species such as alcohols and amines allows chemists to circumvent the preparation and use of relatively unstable carbonyls and alkyl halides that conventional methods require. Pyridines, pyrazines, pyrroles, as well as fused bicyclic heteroaromatics, may all be prepared by dehydrogenative condensation this reactivity will likely be extended to pyrimidines, imidazoles, pyrazoles, and triazoles in the near future. Continuous advances in scope and scalability will expand the role of hydrogen transfer in the discovery and production of small molecule therapeutics. 

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