Pyrazole electrophilic substitution

In spite of their reluctance to undergo electrophilic substitution, pyrazole hydrochlorides react under comparatively mild conditions (80-100°) with sulfur dichloride, sulfur monochloride, and even thionyl chloride to give sulfides (59).544 Earlier it was erroneously... 

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. ... 

Results for the neutral pyrazole molecule show a considerable spread. The tt-electron and total (Tr-l-cr) densities predict electrophilic substitution at the 4-position as found. Results for thiazole also agree with experimentally determined electrophilic and nucleophilic reactivity. 

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). 

The most complete discussion of the electrophilic substitution in pyrazole, which experimentally always takes place at the 4-position in both the neutral pyrazole and the cation (Section 4.04.2.1.1), is to be found in (70JCS(B)1692). The results reported in Table 2 show that for (29), (30) and (31) both tt- and total (tt cr)-electron densities predict electrophilic substitution at the 4-position, with the exception of an older publication that should be considered no further (60AJC49). More elaborate models, within the CNDO approximation, have been used by Burton and Finar (70JCS(B)1692) to study the electrophilic substitution in (29) and (31). Considering the substrate plus the properties of the attacking species (H", Cl" ), they predict the correct orientation only for perpendicular attack on a planar site. For the neutral molecule (the cation is symmetrical) the second most reactive position towards H" and Cl" is the 5-position. The activation energies (kJmoF ) relative to the 4-position are H ", C-3, 28.3 C-5, 7.13 Cr, C-3, 34.4 C-5, 16.9. 

A-Halogenated pyrazoles are unstable compounds (Cl>Br>I) that are seldom isolated. 1-Bromopyrazoles resemble NBS and may be important in the process of C-bromination, not because of an A to C rearrangement but by acting as a source of the powerfully electrophilic brominium ion (Section 4.04.2.1.4(v)). 4-Substituted pyrazoles can form... 

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. 

Halogenation is one of the most studied electrophilic substitutions in the pyrazole series (67HC(22)1, B-76MI40402). The results concern chlorination, bromination and iodination since there is no report on direct fiuorination of pyrazoles (fiuoropyrazoles are prepared by other... 

Pyrazolo[3,4-c]pyrazole, tetrahydro-rearrangement, 5, 250 Pyrazolo[4,3-c]pyrazole, tetraaryl-electrophilic substitution, 6, 1035 oxidation, 6, 1034-1035 reduction, 6, 1035 vacuum pyrolysis, 6, 1035 Pyrazolo[ 1,2-n]pyrazole-1,5-diones synthesis, 6, 991 Pyrazolo[ 1,2-n]pyrazoles reactions, 6, 1038 ring opening, 6, 983... 

Thieno[3,4-d]oxazole-3a(4H)-carboxylic acid, dihydro-2-methyl-synthesis, 6, 1020 Thieno[2,3-d Joxazoles synthesis, 6, 990 Thieno[3,2-g]pteridine structure, 3, 284 lH-Thieno[3,4-c]pyran-2-ones synthesis, 4, 1032 Thienopyrazines synthesis, 4, 1022-1024 Thieno[2,3-6]pyrazines, 4, 1023 electrophilic substitution, 4, 1024 Thieno[3,4-6]pyrazines, 4, 1024 Thieno[3,4-c]pyrazole, 4,6-dihydro-3-hydroxy-carbamates... 

In the reactions of electrophilic substitution, isoxazole is far less active than the five-membered heterocycles with one hetero atom and pyrazole. It is closer to pyridine, but more reactive. 

Heating isoxazole derivatives with aqueous-alkaline permanganate leads to a complete degradation of the heterocycle. With arylisoxa-zoles this results in readily identifiable aromatic acids, from which can be deduced the orientation of electrophilic substitution reac-tions. ° Also, the stability of various heterocycles can be compared. Thus, under these reaction conditions, the pyrazole ring is more stable than that of isoxazole (cf. 197198). ... 

In a manner analogous to that seen with N-substituted pyrazoles (Section II,D), isothiazole undergoes lithiation at the 5-position, adjacent to the 5p -heteroatom, and reaction with electrophiles then leads to a variety of 5-substituted derivatives (Scheme 74) [64JCS446 72AHC(14)1 84JMC1245]. 

Electrophilic substitution occurs readily in iV-phenyl groups, e.g., 1-phenyl-pyrazoles, -imidazoles and -pyrazolinones are all nitrated and halogenated at the para position. The aryl group is attacked preferentially when the reactions are carried out in strongly acidic media where the azole ring is protonated. 

Oxidation of N, -substituted pyrazoles to 2-substituted pyrazole-] -oxides using various peracids facilitates the introduction of halogen at C i, followed by selective nitration at C4. The halogen aiom at C3 or C5 is easily removed by sodium sulfite and acts as a protecting group. Formaldehyde was used to direct the selective introduction of electrophiles at C in a simple one-pot procedure. 

The results of Katritzky, Schofield, and their co-workers show a remarkable deactivation of the pyrazole and phenyl rings toward electrophilic substitution combined with a high selectivity for para substitution. 

In the case of 1,3-diphenylfuro[3,2-c]pyrazole (58) most electrophilic substitutions, e.g., Vilsmeier formylation, Friedel-Crafts acylation, and monobromination, take place in the furan ring. Excess bromine gives the second bromination in the 4-position of the 1-phenyl group, but nitration gives the l-(4-nitrophenyl) derivative and a second, uncharacterized, product (78YZ204). 

The regioselectivity by electrophilic aromatic substitution is conserved when switching to acidic reaction conditions. Thus 2-substituted pyrazole 1-oxide 123 was nitrated regio and monoselectively at C3 by HN03-H2S04 to give 124 in quantitative yield (1992ACSA972). Further nitration takes place first at the benzyl 4-position, and then at the pyrazole 5-position (Scheme 39). 

Broraination in the 4-position is the most facile reaction of all pyrazole electrophilic substitutions. Aqueous bromine is usually employed,208,286,555,556 or bromine in neutral solvents,208,557-574 or else hypobromous acid562 or such agents as N-bromosuccinimide.565 During bromination in aqueous solution543, 566 it is usual to neutralize the hydrobromic acid formed by the addition of an equimolar quantity of sodium acetate, but this is by no means necessary. Bromination in the presence of a catalyst such as iron may result in the introduction of two or even three bromine atoms,557 although Buchner and Fritsche94 earlier considered the introduction of more than one impossible. See also Michaelis.541 The action of bromine on 1,3-... 

In a strongly acidic medium the pyrazole nucleus exists as a cation from which the hydrogen atom at position 4 cannot be displaced by electrophilic substitution such as nitrosation. In a less acidic medium the weakly basic 2-nitrogen atom of a 1-phenylpyrazole is not pro-tonated, and the pyrazole activated by the electron-donating amino group is readily nitrosated in position 4. See also Grandberg and Klyuchko.600 Nitrosation in the 4-position of l-phenyl-3-methyl-5-sulfanilamidopyrazole occurred successfully.601... 

Phosphorus oxychloride at 230-250° phosphorylates 1-substituted pyrazoles in the 4-position. By the action of alcohols, the phosphonodi-chlorides (58) are converted into esters.919 Phosphorylation here is presumably an electrophilic substitution. 

A further example of electrophilic substitution is the synthesis of pyrazole aldehydes by formylation with dimethylformamide.620,628... 

Nucleophilic substitutions in the pyrazole series have been much less studied than electrophilic substitutions. 

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