Electrophilic substitution imidazole

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). 

Electrophilic substitution occurs readily in Af-phenyl groups, e.g. 1-phenyI-pyrazoIes, -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. 

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Most electrophilic substitutions in benzimidazole (31 R = H) occur primarily in the 5-position. In multiple bromination the order followed, 5 > 7 > 6,4 > 2, parallels molecular orbital calculations. In benzimidazole itself the 4(7)- and 5(6)-positions are tautomerically equivalent. Fusion of a benzene ring deactivates C-2 to electrophilic attack to such an extent that it is around 5000 times less reactive than the 2-position of imidazole. Strong electron donors at C-5 direct halogenation to the 4-position, whereas electron-withdrawing groups favor C-4 or C-6 substitution (84MI21). 

From silylated iV-sulfamoyl-protected imidazoles or pyrazoles, imidazolyl or pyr-azolyl anions can be generated with the strong base CsF (carbodesilylation) and subsequently treated with electrophiles. In this way 5-substituted imidazoles or pyrazoles can be prepared after the deprotection of N(l) [181... 

Imidazole is a n-electron-excessive heterocycle. Electrophilic substitution normally occurs at C(4) or C(5), whereas nucleophilic substitution takes place at C(2). The order of reactivity for electrophilic substitution for azoles is ... 

The apparently first kinetic study of a metal-assisted electrophilic substitution in a Co(III) complex is recent. The bromination of Co(NH3)5imidH is complicated by the presence of different bromine species in solution (Brj, HOBr and Brj"). In addition, successive brominations of the coordinated imidazole occur. Rate data can be interpreted in terms of reaction of the conjugate base of the Co(III) complex with Brj, and a suggested mechanism for the first steps is (Rq = Co(NH3)5 ")... 

The dimethylaminomethyl group (entry 9) is easily introduced by a Mannich reaction, and lithiation occurs readily at -78°C (88JOC5685). After reaction with a variety of electrophiles, hydrolysis can be performed directly with aqueous acid to give 2-substituted imidazoles in good yield. However, the 2-lithio anion 47 was found to be quite basic, despite the base-weakening effect of coordination with the amino substituent, and thus it was capable of deprotonating the 2-butyl derivative 48 as it was formed by reaction with 1-bromobutane (Scheme 42). No such side-reac-... 

Electrophilic substitution in imidazole occurs preferentially in the 4(5)-positions (4- and 5-positions in N-unsubstituted imidazoles are tautomer-ically equivalent) with the 2-position being much less reactive [70AHC(12)103 80AHC(27)241 84MI7 90AHC(47)165], It is usually dif-... 

Oxazoles resemble 1-substituted imidazoles in their positional reactivity order for electrophilic substitution, 5 > 4 > 2 [59LA(626)83, 59LA(626)92 74AHC(17)99 84MI29]. The compounds can be regarded as hybrids of... 

Although thiazoles structurally resemble imidazoles and oxazoles, they are less reactive with electrophiles. Calculated 7r-densities (48BSF1021) and localization energies (61CCC156) largely agree with experimental observations that positional specificities for electrophilic substitution are 5... 

Electrophilic substitutions Although oxazole, imidazole and thiazoles are not very reactive towards aromatic electrophilic substitution reactions, the presence of any electron-donating group on the ring can facilitate electrophilic substitution. For example, 2-methoxythiazole is more reactive... 

A number of 2-substituted imidazoles were found to be 4(5)-alkylated by soft electrophiles. Thus, 2-phenylimidazole (112) reacts with 3-thienylmethyl bromide to give mainly 4- and 4,5-di-substituted products A-alkylation occurs only to a minor extent (Equation 2). Similarly, 2-methoxybenzyl chloride gives rise mainly to C-substituted products. Benzyl bromide, a harder electrophile, gives largely A-benzyl derivatives of (112). 

The Hammett cr+ constant for the 4(5)-position of imidazole is around -1 for C-2 it is of the order -0.8 (86CHE587). The electrophilic substitutions which do occur at the 2-position invariably involve preformation of an anion at that position. The 2-proton, which should be the least active in a conventional SEAr sense, turns out to be the most labile over a wide pH range, and there is a marked rate acceleration on going from imidazole to imidazolium cation. Any negative charge generated at C-2 is stabilized by the adjacent pyrrole-type nitrogen (see Section 3.4.1.8.2). 

The reactivity of the five-membered heterocycles pyrrole, furan, thiophen and imidazole (Fig. 8-10) is characterised by interactions with electrophilic reagents. The precise nature of these reactions depends upon the particular ring system. Thiophens undergo facile electrophilic substitution, whereas the other compounds exhibit a range of polymerisation and other Lewis acid-initiated reactions upon treatment with electrophiles. We saw a number of examples of Lewis acid-promoted reactions of furans and pyrroles in Chapter 6. Although reactions of complexes of five-membered heterocyclic ligands have not been widely investigated, a few examples will illustrate the synthetic potential. 

Substituted imidazole 1-oxides 228 are predicted to be activated toward electrophilic aromatic substitution, nucleophilic aromatic substitution, and metallation as described in Section 1. Nevertheless little information about the reactivity of imidazole 1-oxides in these processes exists. The reason for this lack may be the high polarity of the imidazole 1-oxides, which makes it difficult to find suitable reaction solvents. Another obstacle is that no method for complete drying of imidazole 1-oxides exists and dry starting material is instrumental for successful metallation. Well documented and useful is the reaction of imidazole 1-oxide 228 with alkylation and acylation reagents, their function as 1,3-dipoles in cycloadditions, and their palladium-catalyzed direct arylation. 

Grimmett, M. R., Advances in Imidazole Chemistry, 12, 103 27, 241 Electrophilic Substitution in the Azines, 47, 325 Halogenation of Heterocycles I. Five-member ed Rings, 57, 291 II. Six and Seven-numbered Rings, 58, 271 III. Heterocycles Fused to Other Aromatic and Heteroaromatic Rings, 59, 245. 

The azametallocenes, such as 206 and 208, are less stable than their cyclopentadienyl analogs.158 The pKa for azaferrocene (206) is similar to that of quinoline, whereas the manganese compound was a much weaker base.158 Azaferrocene yields a picrate and a methiodide, but, as might be expected, it does not undergo electrophilic substitution.158 The mass spectra of azametallocenes have been discussed.1636 The preparation of cyclopentadienyliodobis(imidazole)cobalt(III)iodide has been reported.1630... 

Imidazole is reported159 to be coupled at position 2, in contrast with the other electrophilic substitutions which occur preferentially at position 4. This peculiar orientation, together with the observation that 1-methylimidazole does not couple with diazonium compounds,160 supports the view that ionization of the N-H bond is a prerequisite for coupling. 

Electrophilic substitution reactions of oxazoles, imidazoles, and thiazoles... 

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