5-Substituted pyrazoles, tautomerism

Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NFI groups in the conjugate acid, e.g. in (138 EWS = electron-withdrawing substituent) the 2-NFI is more acidic than 1-NFI and hence for the neutral form the 3-substituted pyrazole is the more stable. 

In a neutral azole, the apparent rate of formation of an A-substituted derivative depends on the rate of reaction of a given tautomer and on the tautomeric equilibrium constant. For example, with a 3(5)-substituted pyrazole such as (199), which exists as a mixture of two tautomers (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)] is a function of the rate constants Ha and fcs, as well as of the composition of the tautomeric mixture (Scheme 16) <76AHC(Si)l). 

The transformation used above to enumerate tautomers would lead to identical products when applied to symmetrically substituted pyrazoles. The set of structures generated in the enumeration process is converted to a sorted list of canonical SMILES [23] from which duplicates are easily eliminated. Structures registered in alternative tautomeric forms are converted to identical lists of SMILES that can each be represented by their common first member. This effectively extends the definition of canonical SMILES to cover an ensemble of tautomeric forms and makes it possible to check for duplicate structures without having to register multiple forms [16, 26]. 

There are several reports in the literature dealing with the bimolecular [3 + 2] cycloaddition reactions of alkynyl-substituted diazo compounds. Propargyl diazoacetate 212, when stored for 2 weeks at 0 °C, was transformed into an oligomer to which the constitution 213 was assigned (273) (Scheme 8.50). The alkynyl-diazoketone 214 requires a much higher temperature and is transformed into pyrazole 215, which probably arises from intermolecular cycloaddition, pyrazole tautomerization, and carbenic N/H insertion (274). The inter-intramolecular... 

After a paper devoted to GIAO/B3LYP calculations of 13 monosubstituted benzenes and 21 1-substituted pyrazoles [148] that allowed discussion of some structural problems (such as conformation, tautomerism, and structure of salts) we have continued to use this combination of experimental (in solution and in the solid state, CPMAS NMR) and calculated values as a very useful exploratory technique. For instance, we have used II, 13C, and 15NNMR spectroscopy to study compounds 149-154. In para-disubstituted derivatives 149,151,152,153, in the solid state (no free rotation) the signals of the ortho carbons are split (one is close to N2) and, thanks to the calculated values, they can be assigned [149],... 

N. K. Kochetkov and A. N. Nesmeyanov showed that / -chlorovinyl ketones react with hydrazine in ethanolic solution to give high yields of 3-substituted pyrazoles.297 Unlike hydroxymethylene ketones, which by tautomerism give mixtures of isomeric pyrazoles, /3-chloro-vinyl ketones react with phenylhydrazine to give only one isomer, a point which was verified experimentally.340 This can only be explained... 

Structure and reactivity of neutral pyrazole, its anion and its cation. 2.2 Structure and reactivity of substituted pyrazoles. 2.3 Structure and reactivity of indazoles. 2.4 Dipole moments Structural Methods. 3.1 X-Ray diffraction. 3.2 Microwave spectroscopy. 3.3 H NMR spectroscopy. 3.4 C NMR spectroscopy. 3.5 Nitrogen NMR spectroscopy 3.6 UV spectroscopy. 3.7 JR spectroscopy. 3.8 Mass spectrometry. 3.9 Photoelectron spectroscopy. 3.10 Electron spin resonance spectroscopy Thermodynamic Aspects. 4.1 Intermolecular forces. 4.2 Stability and stabilization. 4.3 Conformation and configuration Tautomerism... 

Molecular structures of4-tert-butylpyrazoles. Trofimenko and co-workers reported an interesting study of the buttressing effects observed for three tert-huiy substituted pyrazoles in both the solution and solid state that employed X-ray crystallography and measurements. The authors found that the major tautomers in solution were consistent with the X-ray single crystal tautomeric preferences for the three analogues. The shifts shown... 

Rapid tautomerism, involving switching of hydrogen from one nitrogen to the other, as in imidazoles (see 24.1.1.1), means that substituted pyrazoles are inevitably mixtures, and a nomenclature analogous to that used for imidazoles is employed to signify this 3(5)-methylpyrazole, for example. In some cases, one tautomer is predominant. ... 

Less vigorous conditions than those described above converted diethyl (ethoxymethylene)malonate 205 and (3,4-dimethylphenyl)hydra-zine monohydrochloride 206 into pyrazol-3-one 208 (01JMC3730, 04H2537) (Scheme 46). The reaction took place in ethanol or methanol containing aqueous potassium carbonate via conjugate substitution of ethoxide ion, intramolecular acyl substitution and tautomerization of intermediate pyrazol-3-one 207. 

Khalil et al. (05PS479) reacted hydrazine hydrate with ethyl acetoacetate, ethyl benzoylacetate or ethyl nicotinoylacetate in boiling ethanol and obtained 5-substituted pyrazol-3-ols la-c (Scheme 75). The existence of pyrazoles 325a-c predominantly in their enol tautomeric form was confirmed by spectroscopic data as well as by phase-transfer catalysis (PTC) alkylations, affording O-monoalkylated or O- and... 

The ramification of the tautomerization is that alkylation of unsymmetrically substituted pyrazoles often gives rise to a mixture of two isomers, one is the iV-1 alkylation and the other is the N-2 alkylation. The ratio depends on the nature of the substrate and the electrophile as well as on the solvent and base (vide infra). 

The high m.p. and b.p. of p3rrazole compared with 1-alkyl or aryl substituted pyrazoles are due to intermolecular hydrogen bonding which results in the dimmer. It is a tautomeric substance. Pyrazole is a weak basic and forms salts with inorganic adds the imino hydrogen... 

An early example is the cyclic trimer of AfAf-bis(pentadeuterophenyl)-l-amino-3-iminopropene 15, the dianil of malonaldehyde (Figure 14.8) dissolved in CS2. This trimer dominates at low temperature whereas at room temperature a monomer is observed [40,41]. In the trimer a triple proton transfer is observed. With respect to a single molecule, the two other molecules constitute catalysts that accept a proton at one nitrogen site and transfer another proton to the other nitrogen site. Thus, the tautomerism is Unked to an intermolecular proton transfer. The double proton transfers in solid cyclic carboxylic acids dimers 16 [42], bis-arylformamidine dimers 17 [43], substituted pyrazole dimers 18 [44], and the triple proton transfer in cyclic substituted solid pyrazole trimers 19 [44] constitute similar processes. 

Figure 14.9 Solid state tautomerization of a substituted pyrazole tetramer 20 [44] (a) and of pyrazole-4-carboxylic acid 21 (b) [45, 46].

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

Complex tautomerism for azoles with heteroatoms in the 1,2-positions occurs for pyrazoles which are not substituted on nitrogen. Scheme 10 shows the four important tautomeric structures (148)-(151) for 3-methylpyrazolin-5-one, and (152) and (153) as examples of other possible structures. A detailed investigation of this system disclosed that in aqueous solution (polar medium) the importance of the tautomers is (149) > (151) (150) or (148), whereas in cyclohexane solution (non-polar medium) (151) > (148) (149) or (150). 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

For )V-unsubstituted pyrazoles the tautomeric proton was generally located without ambiguity. 3-Substituted tautomers were favoured in the solid state (45), (46) and (48) (Table 5). For the pyrazolyltriazole (47) the authors (77JHC65) concluded that the X-ray analysis indicates that the proton on the pyrazole ring populates either nitrogen atom to... 

Accounting for this effect, it was possible to apply dynamic NMR spectroscopy to measure energy barriers to the prototropic rearrangements of pyrazoles. Temperature-variable spectra of a series of 4-substituted pyra-zoles 5 and 6 have been studied in methanol-d4 solutions and the free energy barriers of the degenerate type 2a 2b tautomerization reported (93CJC1443). 

The conclusions about the influence of azole ring substituents on the tautomeric equilibria are summarized in Table VIII. Although sufficient data are available for pyrazoles and imidazoles, it is difficult to correlate them within any well-defined scheme. The energy differences between pairs of tautomers are generally quite small and attempts to analyze these using, for example, the Taft-Topson model failed [95JCR(S)172]. In the case of mono-substituted compounds, Hammet-type equations... 

X-Ray crystal structure determinations of l-(aminocarbonyl)-3-methyl-4-methoxy-l//-pyrazol-5(2H)-one 107 (R = H) and l-(phenylaminocar-bonyl)-3-methyl-4-methoxy-l//-pyrazol-5(2H)-one 107 (R = Ph) demonstrated that both molecules exist in the crystal exclusively as NH-CO tautomers (97T5617). The tautomeric form similar to 104b is realized in the crystal of 4,4-dichloro-substituted pyrazolone 108 (93BSB735). 

All triazoles, tetrazoles, and unsymmetrically substituted imidazoles and pyrazoles can exist in two tautomeric forms, e.g., 1 2 and 3 4. However, attempts to isolate the individual tautomers have been unsuccessful, always leading to one isomer (for summaries of this aspect of the tautomerism of imidazoles, see references 1 and 2). Although the isolation of both tautomers of a number of com-... 

The cydoaddition of different 1,3-dipoles such as azides [331, 341] and diazoalkanes [342-344] to acceptor-substituted allenes was thoroughly investigated early and has been summarized in a comprehensive review by Broggini and Zecchi [345], The primary products of the 1,3-dipolar cycloadditions often undergo subsequent fast rearrangements, for example tautomerism to yield aromatic compounds. For instance, the five-membered heterocycles 359, generated regioselectively from allenes 357 and diazoalkanes 358, isomerize to the pyrazoles 360 (Scheme 7.50) [331]. 

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