Pyrazole nitration

An important development of the synthesis described above is derived from the observations of Scott, O Donovan and Reilly [159], which were taken up by others [109]. l-Guanyl-3,5-dimethylpyrazole nitrate reacts with alkyl- and aryl-amines in hot water, ethanol, or without solvent to give good yields of guanidines. Use of this pyrazole nitrate or other salt for obtaining guanidines now competes with older methods if yield and ease of isolation of the product are the main considerations [95, 138, 140, 143, 160-164]. 

Guany 1-3,5-dimethy l-pyrazole nitrate Fungi (Mold), Yeast Amino acid oxidase, Aspergillus oryzae enzyme, Chymotrypsin,... 

Guanyl-3,5-dimethy l-pyrazole nitrate Alkaloids Enzymes... 

Guanyl-3,5-dimethyl-pyrazole nitrate Fungi (Mold), Yeast... 

Thekinetics of nitration in sulphuric acid of both pyrazole and imidazole have been studied. Data have already been quoted (tables 8.1, 8.3) to support the view that the nitration of both of these compounds at C(4)... 

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. ... 

Oxidation of N -substituted pyrazoles to 2-substituted pyrazole-l-oxides using various peracids (30) facilitates the introduction of halogen at C, followed by selective nitration at C. The halogen atom at or is easily removed by sodium sulfite and acts as a protecting group. Formaldehyde was... 

Azoles can form stable compounds in which metallic and metalloid atoms are linked to nitrogen. For example, pyrazoles and imidazoles Af-substituted by B, Si, P and Hg groups are made in this way. Imidazoles with a free NH group can be Af-trimethylsilylated and Af-cyanated (with cyanogen bromide). Imidazoles of low basicity can be Af-nitrated. 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

Pyrazoles can undergo nitration at several positions 4-bromo-l-methylpyrazole yields the 3,5-dinitro product. 1-Methylpyrazole 2-oxide yields the 5-nitro derivative. 

The basicity of pyrazole and its relation with imidazole basicity (due both to enthalpy and entropy changes (77MI40403)) have been discussed on theoretical grounds (Section 4.04.1.2.1). The pK values of 90 pyrazoles have been determined by Gonzalez et al. (68BSF707,68BSF5009) and it is essentially his work that will be discussed below. A selection of pK values are shown in Table 28. The pK values for some other pyrazoles have been measured in connection with nitration studies (Section 4.04.2.1.4(ii)) (71JCS(B)2365). 

With iodine in carbon tetrachloride, 4-methylpyrazole affords a deep-red oil for which the structure (266) has been proposed. Nitric acid, silver nitrate and iodine together convert pyrazole into 1,3,4-triiodopyrazole (267 = R" = I, = H). The fV-iodopyrazoles are... 

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. 

Pyrazole is very stable in acid media and even under more vigorous nitration conditions neither ring opening nor ring oxidation was observed (for oxidation to pyrazolones with a mixture of bromine and nitric acid see Section 4.04.2.1.4(v)). 

The principal results on the nitration of pyrazoles are shown in Scheme 23. If the substituent is a phenyl group, it can compete with the pyrazole ring and para-nitration is often observed (Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i)). 

The mechanism of the reaction is now well known due to a series of kinetic studies by Katritzky et al. (Table 31). The nature, free base or conjugate acid, of the substrate depends on the substituents in the pyrazole ring and on the acidity of the nitrating mixture. 

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

The difference in the susceptibility of the 3- and 4-positions in the free-base form of pyrazole towards nitration is a relatively small factor in favour of the 4-position ca. 1 log unit). Doubtless for the more usual nitration via the conjugate acid the difference is considerably greater. 

Nitration of 4-(2-thienyl)- (301) and 4-(3-thienyl)-pyrazoles (302) mainly occurs on the thiophene ring, but when acetyl nitrate is used as the nitration agent small quantities of products nitrated on the pyrazole ring are isolated (position of the nitro group uncertain) (80CS( 15)102). Pyrazol-l -ylpyridines (303) undergo electrophilic reactions (bromination, chlorination and nitration) preferentially in the pyrazole ring. Thus, the nitration of (303 R = R = = H) either with a mixture of nitric acid and sulfuric acid at 10-15 °C or with... 

A -Pyrazolines such as (410) are oxidized by iodine, mercury(II) acetate and trityl chloride to pyrazolium salts (411), and compound (410) even reduces silver nitrate to Ag° (69JOU1480). Electrochemical oxidation of l,3,5-triaryl-2-pyrazolines has been studied in detail (74BSF768, 79CHE115). They Undergo oxidative dimerization and subsequent transformation into the pyrazole derivative (412). 

We have already noted (Section 4.04.2.1.4(xi)) that alkyl groups on pyrazoles are oxidized with permanganate to carboxylic acids. Silver nitrate and ammonium persulfate transform 4-ethyl-1-methylpyrazole (436) into the ketone (437) (72JHC1373). The best yield was obtained starting with the alcohol (438) and using an acid dichromate solution as oxidizing agent. 

Withasomnine Pyrazole, 1-phosphoryl-reactions, 5, 271 Pyrazole, 1-silyl-synthesis, 5, 236 Pyrazole, 1-stannyl-synthesis, 5, 236 Pyrazole, 1-styryl-synthesis, 5, 233 Pyrazole, 1-thienyl-reactions, 5, 268 Pyrazole, 4-(2 -thienyl)-nitration, 5, 238 Pyrazole, 4-(3 -thienyl)-nitration, 5, 238 Pyrazole, trifluoromethyl-synthesis, 5, 284... 

Aqueous solutions of dimetiiylgold(III) nitrate easily react with pyrazole and 3,5-dimethylpyrazole to form the pyrazolate complexes 271 (R = H, Me) [85 JOM (295)401]. However, 3,5-diphenylpyrazole gives the complex [Me2Au(3,5-Ph2pzH)2], where the ligand is not deprotonated. To obtain the 3,5-diphenylpyra-zolate complex, dimethylgold(III) iodide must be reacted with silver diphenylpyra-zolate. 

Similar peculiarities had been noted previously on nitration of phenylpyridines - and pyrazoles as well as on sulfonating phenylpyrazoles. ... 

Cyclooctane-l,5-diyl-bis(pyrazol-l-yl)borate (L) with cobalt(II), nickel(II), and zinc(II) nitrates gives [(j -L)M] (M = Co, Ni, Zn) strongly stabilized by the C—H M agostic interactions, which justifies their inclusion in the class of organometallic complexes [89AGE205, 91ICA(183)203, 92IC974]. 

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